{"sentence": "Electronic properties of DNA are believed to play a crucial role in many phenomena in living organisms , for example the location of DNA lesions by base excision repair ( BER ) glycosylases and the regulation of tumor-suppressor genes such as p53 by detection of oxidative damage . However , the reproducible measurement and modelling of charge migration through DNA molecules at the nanometer scale remains a challenging and controversial subject even after more than a decade of intense efforts . Here we show , by analysing 162 disease-related genes from a variety of medical databases with a total of almost 20,000 observed pathogenic mutations , a significant difference in the electronic properties of the population of observed mutations compared to the set of all possible mutations . Our results have implications for the role of the electronic properties of DNA in cellular processes , and hint at the possibility of prediction , early diagnosis and detection of mutation hotspots .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22355784"}
{"sentence": "In this study , we compared the effects of SKI-606 with Iressa , Src/Abl and EGF-R kinase inhibitors , respectively , on selected parameters in HeLa and SiHa cervical cancer cell lines , which express E6/E7 oncoproteins of high-risk HPV types 18 and 16 , respectively . Our results show that SKI-606 and Iressa inhibit cell proliferation and provoke G(0)-G(1) cell cycle arrest and reduction of S and G(2)-M phase using 2 and 5\u2009\u03bcM concentrations of these inhibitors . In contrast , SKI-606 induces differentiation to an epithelial phenotype \" mesenchymal-epithelial transition \" ; thus SKI-606 causes a dramatic decrease in cell motility and invasion abilities of HeLa and SiHa cancer cells , in comparison to untreated cells and Iressa-treated cells in which these parameters are only slightly affected . These changes are accompanied by a regulation of the expression patterns of E-cadherin and catenins . The molecular pathway analysis of Src/Abl inhibitor revealed that SKI-606 blocks the phosphorylation of \u03b2-catenin and consequently converts its role from a transcriptional regulator to a cell-cell adhesion molecule . Our findings indicate that SKI-606 inhibits signaling pathways involved in regulating tumor cell migration and invasion genes via \u03b2-catenin alteration , suggesting that Src inhibitor , in comparison to EGF-R , is a promising therapeutic agent for human cervical cancer .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20862378"}
{"sentence": "Epirubicin was developed as a semi-synthetic anthracycline derivative to circumvent the cardiotoxic limitations associated with the use of doxorubicin in the clinic . Anthracycline compounds have been demonstrated to form covalent drug-DNA adducts utilising endogenous and exogenous sources of formaldehyde ; however , previous investigations of the formation of epirubicin-DNA adducts provide conflicting evidence for adduct formation . This work provides evidence that epirubicin acts to form drug-DNA adducts at physiologically relevant concentrations and demonstrates that the rate of formation of epirubicin-DNA adducts is slower than that observed for other anthracycline compounds , explaining why they are only detectable under defined experimental conditions . Formation of covalent epirubicin-DNA adducts improves the apoptotic profile of epirubicin and provides opportunities to overcome drug resistance and cardiotoxic limitations .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23263186"}
{"sentence": "BACKGROUND & AIMS GUCY2C is the intestinal receptor for the paracrine hormones guanylin and uroguanylin that converts guanosine-5'-triphosphate to cyclic guanosine monophosphate ( cGMP ) . It functions as a tumor suppressor ; its loss disrupts intestinal homeostasis and promotes tumorigenesis . We investigated the effects of GUCY2C loss on intestinal cell proliferation , metabolism , signaling , and tumorigenesis in mice . METHODS Intestinal cell proliferation and metabolism were examined in Gucy2c(-/-) and colon cancer cells by microscopy , immunoblot , and functional analyses . Microarray analyses compared gene expression profiles of intestine cell from Gucy2c(-/-) and wild-type mice. v akt murine thymoma viral oncogene homolog ( AKT ) regulation and signaling were examined , and the role of AKT in GUCY2C-dependent tumorigenesis was defined in Gucy2c(-/-)Akt1(-/-) mice . RESULTS The size and number of intestinal crypts increased in Gucy2c(-/-) mice ; the associated epithelial cells showed accelerated proliferation , increased glycolysis , and reduced oxidative phosphorylation , which was reversed by oral administration of cGMP . Conversely , activating guanylyl cyclase C in human colon cancer cells delayed cell-cycle progression , decreased DNA synthesis and colony formation , reduced glycolysis , and increased mitochondrial adenosine triphosphate production . AKT signaling pathways were activated in intestines of Gucy2c(-/-) mice , associated with increased AKT phosphorylation . Disruption of AKT activity , pharmacologically or genetically , reduced DNA synthesis , proliferation , and glycolysis , and increased mitochondrial biogenesis . Intestinal tumorigenesis increased after administration of azoxymethane to Gucy2c(-/-) mice , compared with wild-type mice , but was eliminated in Gucy2c(-/-)Akt1(-/-) mice . CONCLUSIONS GUCY2C is a tumor suppressor that controls proliferation and metabolism of intestinal epithelial cells by inactivating AKT signaling . This receptor and its ligands , which are paracrine hormones , might be novel candidates for anticolorectal cancer therapy .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19737566"}
{"sentence": "The effects of dose per fraction on the ability of amifostine exposure to elevate angiostatin levels in the serum of mice and to inhibit spontaneous metastases formation using the well-characterized murine Sa-NH sarcoma were investigated . Amifostine was administered intraperitoneally at doses of 50 , 100 , or 200 mg/kg every other day for 6 days to C3Hf/Kam mice until tumors reached an average size of 8 mm in diameter . Amifostine was again administered immediately following surgical removal of the tumor-bearing limbs by amputation , and then once more 2 days later . Nontumor-bearing control animals were treated using the same dosing and surgery schedules . The average number of pulmonary metastases per animal was determined for each experimental group . A significant reduction ( P <.05 ) in the average number of pulmonary metastases was observed only in the group of animals exposed to a dose per fraction of 50 mg/kg . A dose of 100 mg/kg was less effective while 200 mg/kg had no effect on metastases formation in this study . The effects of amifostine exposure on serum levels of the angiogenesis inhibitor angiostatin were also determined using Western analysis . Correlating with the antimetastatic effect measured , exposure of animals to 50 mg/kg of amifostine resulted in a four-fold enhanced serum level of angiostatin above control levels . This phenomenon occurred in both tumor-bearing as well as nontumor-bearing animals . In contrast , a dose of 200-mg/kg amifostine administered intraperitoneally under these conditions had no measurable effect on angiostatin serum levels in this animal system . The enhanced ability of relatively low doses of amifostine to inhibit spontaneous metastases formation suggests that effective antimetastatic therapies with amifostine can be designed with minimal toxic side effects . While the dose responses for angiostatin production and metastases inhibition by amifostine are well correlated , the precise mechanism of action underlying these phenomena is unclear but is suggestive of a redox driven process(es) .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12577239"}
{"sentence": "Many different cellular pathways have evolved to protect the genome from the deleterious effects of DNA damage that result from exposure to chemical and physical agents . Among these is a process called transcription-coupled repair ( TCR ) that catalyzes the removal of DNA lesions from the transcribed strand of expressed genes , often resulting in a preferential bias of damage clearance from this strand relative to its non-transcribed counterpart . Lesions subject to this type of repair include cyclobutane pyrimidine dimers that are normally repaired by nucleotide excision repair ( NER ) and thymine glycols ( TGs ) that are removed primarily by base excision repair ( BER ) . While the mechanism underlying TCR is not completely clear , it is known that its facilitation requires proteins used by other repair pathways like NER . It is also believed that the signal for TCR is the stalled RNA polymerase that results when DNA damage prevents its translocation during transcription elongation . While there is a clear role for some NER proteins in TCR , the involvement of BER proteins is less clear . To explore this further , we studied the removal of 7-methylguanine ( 7MeG ) and 3-methyladenine ( 3MeA ) from the dihydrofolate reductase ( dhfr ) gene of murine cell lines that vary in their repair phenotypes. 7MeG and 3MeA constitute the two principal N-methylpurines formed in DNA following exposure to methylating agents . In mammalian cells , alkyladenine DNA alkyladenine glycosylase ( Aag ) is the major enzyme required for the repair of these lesions via BER , and their removal from the total genome is quite rapid . There is no observable TCR of these lesions in specific genes in DNA repair proficient cells ; however , it is possible that the rapid repair of these adducts by BER masks any TCR . The repair of 3MeA and 7MeG was examined in cells lacking Aag , NER , or both Aag and NER to determine if rapid overall repair masks TCR . The results show that both 3MeA and 7MeG are removed without strand bias from the dhfr gene of BER deficient ( Aag deficient ) and NER deficient murine cell lines . Furthermore , repair of 3MeA in this region is highly dependent on Aag , but repair of 7MeG is equally efficient in the repair proficient , BER deficient , and NER deficient cell lines . Strikingly , in the absence of both BER and NER , neither 7MeG nor 3MeA is repaired . These results demonstrate that NER , but not TCR , contributes to the repair of 7MeG , and to a lesser extent 3MeA .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12509290"}
{"sentence": "Breast cancer metastasis is the most common cause of cancer-related death in women . Thus , seeking targets of breast tumor cells is an attractive goal towards improving clinical treatment . The present study showed that CCL18 from tumor-associated macrophages could promote breast cancer metastasis via PITPNM3 . In addition , we found that pachymic acid ( PA ) could dose-dependently inhibit migration and invasion of MDA-MB-231 cells , with or without rCCL18 stimulation . Furthermore , evidence was obtained that PA could suppress the phosphorylation of PITPNM3 and the combination of CCL18 and PITPNM3 . Therefore , we speculate that PA could inhibit breast cancer metastasis via PITPNM3 .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22901140"}
{"sentence": "It is now largely accepted that ribosomal proteins may be implicated in a variety of biological functions besides that of components of the translation machinery . Many evidences show that a subset of ribosomal proteins are involved in the regulation of the cell cycle and apoptosis through modulation of p53 activity . In addition , p53-independent mechanisms of cell cycle arrest in response to alterations of ribosomal proteins availability have been described . Here , we identify human rpL3 as a new regulator of cell cycle and apoptosis through positive regulation of p21 expression in a p53-independent system . We demonstrate that the rpL3-mediated p21 upregulation requires the specific interaction between rpL3 and Sp1 . Furthermore , in our experimental system , p21 overexpression leads to a dual outcome , activating the G\\u2081/S arrest of the cell cycle or the apoptotic pathway through mitochondria , depending on its intracellular levels . It is noteworthy that depletion of p21 abrogates both effects . Taken together , our findings unravel a novel extraribosomal function of rpL3 and reinforce the proapoptotic role of p21 in addition to its widely reported ability as an inhibitor of cell proliferation .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "23255119"}
{"sentence": "Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase ( SOD1 ) have been linked to familial amyotrophic lateral sclerosis ( FALS ) . However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear . Here we examined DNA damage , p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly(93)-->Ala ( G93A ) SOD1 , typical of FALS . DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine ( 8-oxodGuo ) and DNA strand breaks . Significantly higher levels of DNA damage , increased p53 activity , and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells . Western blot , FACS , and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA . Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1 . These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53 . This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "20097285"}
{"sentence": "Diarylquinoline compounds are newly synthesized derivatives of the new anti-tuberculosis drug , TMC207 . In this study , nine diarylquinoline compounds were screened for cytotoxic activity against human tumor cells , and their mechanisms of action were investigated . Among the nine compounds , STM-57 [ N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methl)-N-(3,4-dichlorophenyl)-3-(4 -methylpiperazin-1-yl)propanamide ] showed potent cytotoxic activity . STM-57 induced caspase-independent cell death in the human nasopharyngeal carcinoma cell line , CNE-2 . Further investigation showed that STM-57 induced autophagy , as determined with the increased expression of green fluorescent protein-light chain3 ( GFP-LC3 ) and increased LC3-II levels . STM-57 inhibited the phosphorylation of Akt and the mammalian target of rapamycin ( mTOR ) in CNE-2 cells . The intracellular calcium concentration and reactive oxygen species levels were increased in CNE-2 cells following treatment with STM-57 , whereas the mitochondrial transmembrane potential ( \u0394\u03a8m ) and ATP concentrations were decreased .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23291974"}
{"sentence": "P53 has an important role in the processing of starvation signals . P53-dependent molecular mediators of the Warburg effect reduce glucose consumption and promote mitochondrial function . We therefore hypothesized that the retention of wild-type p53 characteristic of primary glioblastomas limits metabolic demands induced by deregulated signal transduction in the presence of hypoxia and nutrient depletion . Here we report that short hairpin RNA-mediated gene suppression of wild-type p53 or ectopic expression of mutant temperature-sensitive dominant-negative p53(V135A) increased glucose consumption and lactate production , decreased oxygen consumption and enhanced hypoxia-induced cell death in p53 wild-type human glioblastoma cells . Similarly , genetic knockout of p53 in HCT116 colon carcinoma cells resulted in reduced respiration and hypersensitivity towards hypoxia-induced cell death . Further , wild-type p53 gene silencing reduced the expression of synthesis of cytochrome c oxidase 2 ( SCO2 ) , an effector necessary for respiratory chain function . An SCO2 transgene reverted the metabolic phenotype and restored resistance towards hypoxia in p53-depleted and p53 mutant glioma cells in a rotenone-sensitive manner , demonstrating that this effect was dependent on intact oxidative phosphorylation . Supplementation with methyl-pyruvate , a mitochondrial substrate , rescued p53 wild-type but not p53 mutant cells from hypoxic cell death , demonstrating a p53-mediated selective aptitude to metabolize mitochondrial substrates . Further , SCO2 gene silencing in p53 wild-type glioma cells sensitized these cells towards hypoxia . Finally , lentiviral gene suppression of SCO2 significantly enhanced tumor necrosis in a subcutaneous HCT116 xenograft tumor model , compatible with impaired energy metabolism in these cells . These findings demonstrate that glioma and colon cancer cells with p53 wild-type status can skew the Warburg effect and thereby reduce their vulnerability towards tumor hypoxia in an SCO2-dependent manner . Targeting SCO2 may therefore represent a valuable strategy to enhance sensitivity towards hypoxia and may complement strategies targeting glucose metabolism .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22120717"}
{"sentence": "Von Hippel-Lindau ( VHL ) is a tumor suppressor that negatively regulates the production of angiogenic factors . Mutations in the VHL gene cause VHL syndrome , which is characterized by highly vascularized tumors . Here we report a c.464T>A mutation of the VHL gene in three patients with hemangioblastoma from a Chinese family . This mutation was not reported previously and was absent in the unaffected family members . The mutation is predicted to cause Val to Glu substitution at VHL protein residue 155 in a conserved region . Previous biochemical studies demonstrated that residue Val-155 was critical for VHL protein binding to chaperonin TRiC/CCT , an essential step for proper VHL protein folding . Our finding of naturally occurring VHL V155E mutation in patients with VHL syndrome supports the functional importance of Val-155 residue in VHL protein and illustrates the diversity of VHL gene defects underlying VHL syndrome .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23203444"}
{"sentence": "Inhibition of cell proliferation by fenoterol and fenoterol derivatives in 1321N1 astrocytoma cells is consistent with \u03b2(2)-adrenergic receptor ( \u03b2(2)-AR ) stimulation . However , the events that result in fenoterol-mediated control of cell proliferation in other cell types are not clear . Here , we compare the effect of the \u03b2(2)-AR agonists ( R,R')-fenoterol ( Fen ) and ( R,R')-4-methoxy-1-naphthylfenoterol ( MNF ) on signaling and cell proliferation in HepG2 hepatocarcinoma cells by using Western blotting and [ (3)H]thymidine incorporation assays . Despite the expression of \u03b2(2)-AR , no cAMP accumulation was observed when cells were stimulated with isoproterenol or Fen , although the treatment elicited both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt activation . Unexpectedly , isoproterenol and Fen promoted HepG2 cell growth , but MNF reduced proliferation together with increased apoptosis . The mitogenic responses of Fen were attenuated by 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol ( ICI 118,551 ) , a \u03b2(2)-AR antagonist , whereas those of MNF were unaffected . Because of the coexpression of \u03b2(2)-AR and cannabinoid receptors ( CBRs ) and their impact on HepG2 cell proliferation , these G\u03b1(i)/G\u03b1(o)-linked receptors may be implicated in MNF signaling . Cell treatment with ( R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone ( WIN 55,212-2 ) , a synthetic agonist of CB(1)R and CB(2)R , led to growth inhibition , whereas inverse agonists of these receptors blocked MNF mitogenic responses without affecting Fen signaling . MNF responses were sensitive to pertussis toxin . The \u03b2(2)-AR-deficient U87MG cells were refractory to Fen , but responsive to the antiproliferative actions of MNF and WIN 55,212-2 . The data indicate that the presence of the naphthyl moiety in MNF results in functional coupling to the CBR pathway , providing one of the first examples of a dually acting \u03b2(2)-AR-CBR ligand .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22776956"}
{"sentence": "Vascular endothelial growth factor ( VEGF ) is one of the most important mediators of angiogenesis . Single-chain ( sc)-VEGF protein containing an N-terminal Cys-tag has been designed for site-specific modification with a variety of imaging and therapeutic moieties . Site-specific labeling of scVEGF with thiol-reactive prosthetic group , N-[2-(4-(18)F-fluorobenzamido) ethyl ] maleimide ( [ (18)F]FBEM ) for positron emission tomography ( PET ) imaging of VEFGR may provide a new tracer which has great potential for clinical translation.Methods : [ (18)F]FBEM-scVEGF was synthesized by site-specific conjugation of ( 18)F-FBEM to a thiol group in Cys-tag of scVEGF at room temperature . The functional activity after labeling was tested by immunofluorescence staining , cellular uptake and efflux . The tumor targeting and in vivo properties were evaluated by biodistribution and microPET studies in tumor-bearing mice.Results : The radiolabeling yield and specific activity of [ (18)F]FBEM-scVEGF were 20.6 \ufffd 15.1% ( based on starting [ (18)F]FBEM , uncorrected , n = 5 ) and 58.8 \ufffd 12.4 GBq/\ufffdmol , respectively . Noninvasive microPET and direct tissue sampling experiments demonstrated that [ (18)F]FBEM-scVEGF had VEGFR specific tumor uptake in MDA-MB-435 , U87MG and 4T1 xenograft models . The optimal tumor uptake was achieved at 2 h p.i. , which can be partially , but significantly blocked by co-injection of non-labeled scVEGF protein . Overall , [ (18)F]FBEM-scVEGF showed VEGFR specific tumor uptake.Conclusion : The scVEGF was site-specifically labeled with ( 18)F via [ (18)F]FBEM prosthetic group and the tracer [ (18)F]FBEM-scVEGF exhibited high receptor binding affinity and tumor targeting efficacy . Further study of [ (18)F ] FBEM-scVEGF to evaluate angiogenesis in cancer and other disease types is warranted .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22768028"}
{"sentence": "Cellular senescence can be a functional barrier to carcinogenesis . We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response ( DDR ) . We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease ( IBD ) . In vitro experiments tested the ability of macrophages to induce senescence in primary cells . Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "22970173"}
{"sentence": "ABSTRACT : Cell size homeostasis is a conserved attribute in many eukaryotic species involving a tight regulation between the processes of growth and proliferation . In budding yeast S. cerevisiae , growth to a \" critical cell size \" must be achieved before a cell can progress past START and commit to cell division . Numerous studies have shown that progression past START is actively regulated by cell size control genes , many of which have implications in cell cycle control and cancer . Two initial screens identified genes that strongly modulate cell size in yeast . Since a second generation yeast gene knockout collection has been generated , we screened an additional 779 yeast knockouts containing 435 new ORFs ( of the yeast genome ) to supplement previous cell size screens . Upon completion , 10 new strong size mutants were identified : nine in log-phase cells and one in saturation-phase cells , and 97% of the yeast genome has now been screened for cell size mutations . The majority of the logarithmic phase size mutants have functions associated with translation further implicating the central role of growth control in the cell division process . Genetic analyses suggest ECM9 is directly associated with the START transition . Further , the small ( whi ) mutants mrpl49\u0394 and cbs1\u0394 are dependent on CLN3 for cell size effects . In depth analyses of new size mutants may facilitate a better understanding of the processes that govern cell size homeostasis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23234503"}
{"sentence": "More effective treatments for metastatic lung cancer remain a pressing clinical need . In this study , we identified migration inducting gene-7 ( MIG-7 ) protein as critical for COX-2/prostaglandin E2 ( PGE2)- and Akt/GSK-3\u03b2-dependent tumor invasion/metastasis . COX-2/PGE2 activated EP4 to enhance Akt and GSK-3\u03b2 phosphorylation and \u03b2-catenin/T-cell factor/lymphoid enhancer factor signaling leading to MIG-7 upregulation . RNAi-mediated attenuation of MIG-7 blocked COX-2/PGE2- and Akt/GSK-3\u03b2-mediated migration/invasion effects . Furthermore , MIG-7 protein inhibited protein phosphatase 2A to sustain Akt/GSK-3\u03b2 phosphorylation and cancer-cell migration/invasion . Cancer cells overexpressing MIG-7 exhibited increased expression of ZEB-1 and Twist in parallel with epithelial-mesenchymal transition , metastasis and cancer lethality . MIG-7 protein level positively correlated with advanced stages of human lung cancers . MIG-7 thus offers a theranostic target for cancer metastases arising from aberrant activation of the cellular COX-2/PGE2 and Akt/GSK-3\u03b2 signaling pathways .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23149922"}
{"sentence": "BACKGROUND The uneven distribution of recombination across the length of chromosomes results in inaccurate estimates of genetic to physical distances . In wheat ( Triticum aestivum L. ) chromosome 3B , it has been estimated that 90% of the cross over events occur in distal sub-telomeric regions representing 40% of the chromosome . Radiation hybrid ( RH ) mapping which does not rely on recombination is a strategy to map genomes and has been widely employed in animal species and more recently in some plants . RH maps have been proposed to provide i ) higher and ii ) more uniform resolution than genetic maps , and iii ) to be independent of the distribution patterns observed for meiotic recombination . An in vivo RH panel was generated for mapping chromosome 3B of wheat in an attempt to provide a complete scaffold for this Gb segment of the genome and compare the resolution to previous genetic maps . RESULTS A high density RH map with 541 marker loci anchored to chromosome 3B spanning a total distance of 1871.9 cR was generated . Detailed comparisons with a genetic map of similar quality confirmed that i ) the overall resolution of the RH map was 10.5 fold higher and ii ) six fold more uniform . A significant interaction ( r = 0.879 at p = 0.01 ) was observed between the DNA repair mechanism and the distribution of crossing-over events . This observation could be explained by accepting the possibility that the DNA repair mechanism in somatic cells is affected by the chromatin state in a way similar to the effect that chromatin state has on recombination frequencies in gametic cells . CONCLUSIONS The RH data presented here support for the first time in vivo the hypothesis of non-casual interaction between recombination hot-spots and DNA repair . Further , two major hypotheses are presented on how chromatin compactness could affect the DNA repair mechanism . Since the initial RH application 37 years ago , we were able to show for the first time that the iii ) third hypothesis of RH mapping might not be entirely correct .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22827734"}
{"sentence": "BACKGROUND Angiogenesis is an essential process in cancer growth maintenance , and metastasis . Angiopoietin-2 promotes tumor angiogenesis by priming the vasculature and potentiating the effects of cytokines at the front of active neovascularization . Enhanced expression of angiopoietin-2 has been reported in lung cancer tissue . Survivin is one of the inhibitors of apoptosis protein that has been shown to play a key role in cancer progression , and in tumor angiogenesis . Also plays a key role in tumor cell resistance to anticancer agents and ionizing radiation . AIM To measure the serum levels of angiopoietin-2 and survivin as possible angiogenic factors in lung cancer patients with the assessment of their interrelationships and clinical significance . PATIENTS AND METHODS Patients with lung cancer as NSCLC ( n=70 ) and healthy volunteers ( n=10 ) were enrolled . Serum angiopoietin-2 and survivin concentrations were measured using enzyme-linked immunosorbent assay ( ELIZA ) . RESULTS Median serum angiopoietin-2 levels with lung cancer ( 2730pg/mL ) ranged from 1171 to 6541pg/mL was higher than the median of the control group ( 1795pg/mL ) ranged from 1076 to 2730/mL , p<0.001 . Median serum survivin levels were also higher in patients with lung cancer ( 53.0pg/mL ) ranged from 39.3 to 96.3pg/mL than the median of the control group ( 48.8pg/mL ) ranged from 38.0 to 74.6pg/mL , but did not reach statistical significance p=0.206 . In all patients with lung cancer , serum angiopoietin-2 was not significantly correlated with survivin ( r=0.073 , p=0.657 ) . Neither serum angiopoietin-2 nor survivin showed significant relation with the serum angiopoietin-2 or survivin levels depending on the cell types , stage progression , and metastasis among the patients with NSCLC . CONCLUSIONS Our study suggests that serum angiopoietin-2 is a useful marker for the diagnosis of NSCLC by ELIZA technique .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23587231"}
{"sentence": "Mesotheliomas are malignant tumors of the pleural and peritoneal membranes which are often associated with asbestos exposure and with Simian virus 40 ( SV40 ) infection . Telomerase activity is repressed in somatic cells and tissues but is activated in immortal and malignant cells . We evaluated telomerase activity in seven primary malignant mesothelioma biopsies and matched lung specimens and 20 mesothelioma cell lines and eight corresponding primary tumor cultures . All the tumor biopsies , and nearly all primary cell mesothelioma cultures and cell lines were telomerase positive . The findings in cell lines paralleled those observed in primary cultures in cases where paired samples were available . Next , we found that SV40 , a DNA tumor virus present in approximately 50% of mesothelioma biopsies in the USA , induced telomerase activity in primary human mesothelial cells , but not in primary fibroblasts . Telomerase activity became detectable as early as 72 h following wild-type ( strain 776 ) SV40 infection , and a clear DNA ladder was detectable 1 week after infection . The amount of telomerase activity increased during passage in cell culture and appeared to parallel increases in the cellular amounts of the SV40 large T-antigen . Thus , SV40 infection leads to telomerase activity before the infected mesothelial cells become transformed and immortalized . SV40 infection of human fibroblasts did not cause detectable telomerase activity . We also determined that the SV40 small t-antigen ( tag ) plays an important role in inducing telomerase activity because this activity was undetectable or minimal in mesothelial cells infected and/or transformed by SV40 tag mutants . Asbestos alone did not induce telomerase activity , and asbestos did not influence telomerase activity in mesothelial cells infected with SV40 . Induction of telomerase activity by SV40 may be related to the very high rate of mesothelial cell immortalization that is characteristically associated with SV40 infection of mesothelial cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "11857086"}
{"sentence": "OBJECTIVE To elucidate the direct effects of gonadotropin-releasing hormone agonist ( GnRHa ) on the growth of human uterine leiomyoma cells , cell proliferation and apoptosis in cultured leiomyoma cells treated with GnRHa were investigated . METHODS Isolated leiomyoma cells were subcultured in DMEM supplemented with 10% FBS for 5 days and stepped down to serum-free conditions for an additional 6 days in the presence or absence of graded concentrations of GnRHa ( 10(-9) mol/l to 10(-12) mol/l ) . The effects of GnRHa on the number of viable cells , expression of proliferating cell nuclear antigen ( PCNA ) , Fas and Fas ligand , and apoptosis in cultured leiomyoma cells were examined by MTT ( 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide ) assay , immunocytochemical analysis , Western blot analysis and TUNEL assay respectively . RT-PCR was performed to detect the expression of GnRH receptor mRNA in cultured leiomyoma cells . RESULTS Treatment with GnRHa resulted in a decrease in the number of cultured viable leiomyoma cells assessed by MTT assay in a dose-dependent manner compared with that in control cultures ( P<0.01 ) . The growth inhibition of cultured leiomyoma cells treated with GnRHa in concentrations higher than 10(-10) mol/l was associated with the suppression of the proliferative potential characterized by a decrease in PCNA-positive rate of the cultured cells ( P<0.01 ) and an increase in the apoptosis-positive rate assessed by TUNEL assay ( P<0.05 and P<0.01 ) . GnRHa markedly increased the expression of Fas and induced the expression of Fas ligand in the cultured leiomyoma cells on the basis of Western blot analysis . These direct effects of GnRHa on the number of viable cultured leiomyoma cells , PCNA-positive rate , apoptosis-positive rate and Fas/Fas ligand expression in the cultured leiomyoma cells were only attained after the 4-day treatment . RT-PCR analysis revealed that GnRH receptor mRNA was expressed in cultured leiomyoma cells . CONCLUSIONS The present results demonstrate that GnRHa directly inhibits the growth of human uterine leiomyoma cells by suppressing cell proliferation and inducing apoptosis , which might be associated with the increase in Fas expression and the induction of Fas ligand expression in the cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "11888853"}
{"sentence": "Recent studies indicate that cyclooxygenase-2 ( COX-2 ) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer . A human pancreatic adenocarcinoma cell line , Mia PaCa-2 , was incubated for 18 hours with 5 micromol/L of rofecoxib ( Vioxx ) , a selective COX-2 inhibitor . Total RNA was isolated and gene expression analyzed by DNA microarray chips . In a separate experiment , athymic mice were orthotopically injected with 7.5 x 10(5) Mia PaCa-2 cells through a minilaparotomy . After 1 month , laparotomy was repeated to measure tumor size , and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days . Tumor growth was assessed by comparing volume before and after treatment . In vitro , rofecoxib decreased gene expression of cyclin D1/PRAD1 , a key component of cell cycle progression , while increasing expression of several cell cycle arrest genes , including p21/WAF1 , p33/ING , GADD34 , and GADD45 ( P < 0.05 ) . In vivo , tumor growth was significantly reduced in treated vs. control mice ( P < 0.05 ) . No systemic toxicity was observed in mice receiving rofecoxib . These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12504222"}
{"sentence": "The BLM helicase is a member of the RecQ DNA helicase family and is mutated in the cancer-prone disorder Bloom syndrome . BLM plays a role in a number of cellular processes including DNA double-strand break repair , Holliday junction dissolution , and chromosome segregation . In Drosophila melanogaster , the BLM ortholog ( DmBlm ) is encoded by the mus309 gene . To study the role of DmBlm in double-strand break repair , we utilized a genetic assay in which a targeted DNA double-strand gap is created through excision of a P transposable element . By recovering and molecularly analyzing individual repair products from wild-type and mus309 male pre-meiotic germline cells , we demonstrated that the DmBlm helicase is involved in homologous recombination downstream of strand invasion . This assay can be adapted to test the roles of numerous DNA metabolic factors in DNA double-strand gap repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20225150"}
{"sentence": "There is a complex interplay between the immune system and a developing tumor that is manifest in the way that the balance of Tcell subsets in the local tumor environment reflects clinical outcome . Tumor infiltration by CD8(+) Tcells and regulatory Tcells ( Treg ) is associated with improved and reduced survival , respectively , in many cancer types . However , little is known of the prognostic value of immunological parameters measured in peripheral blood . In this study , peripheral CD8(+) T cells and Treg from 43 patients with malignant mesothelioma or advanced non-small-cell lung cancer scheduled to commence palliative chemotherapy were assessed by flow cytometry and evaluated for association with patient survival . Patients had a higher proportion of peripheral Treg , proliferating CD8(+) Tcells and CD8(+) Tcells with an activated effector phenotype compared with age-matched healthy controls . Higher proportions of Treg and proliferating CD8(+) Tcells were both associated with poor survival in univariate analyses ( hazard ratio [ HR ] 3.81 , 95% CI 1.69-8.57 ; p<0.01 and HR 2.86 , 95% CI 1.26-6.50 ; p<0.05 , respectively ) . CD8(+) Tcell proliferation was independently predictive of reduced survival in multivariate analysis ( HR 2.58 , 95% CI 1.01-6.61 ; p<0.05 ) . These findings suggest that peripheral CD8(+) T cell proliferation can be a useful prognostic marker in patients with thoracic malignancies planned for palliative chemotherapy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23069871"}
{"sentence": "Epstein-Barr virus ( EBV ) induces an uncoordinated S-phase-like cellular environment coupled with multiple prophase-like events in cells replicating the virus . The EBV encoded Ser/Thr kinase BGLF4 has been shown to induce premature chromosome condensation through activation of condensin and topoisomerase II and reorganization of the nuclear lamina to facilitate the nuclear egress of nucleocapsids in a pathway mimicking Cdk1 . However , the observation that RB is hyperphosphorylated in the presence of BGLF4 raised the possibility that BGLF4 may have a Cdk2-like activity to promote S-phase progression . Here , we investigated the regulatory effects of BGLF4 on cell cycle progression and found that S-phase progression and DNA synthesis were interrupted by BGLF4 in mammalian cells . Expression of BGLF4 did not compensate Cdk1 defects for DNA replication in S. cerevisiae . Using time-lapse microscopy , we found the fate of individual HeLa cells was determined by the expression level of BGLF4 . In addition to slight cell growth retardation , BGLF4 elicits abnormal chromosomal structure and micronucleus formation in 293 and NCP-TW01 cells . In Saos-2 cells , BGLF4 induced the hyperphosphorylation of co-transfected RB , while E2F1 was not released from RB-E2F1 complexes . The E2F1 regulated activities of the cyclin D1 and ZBRK1 promoters were suppressed by BGLF4 in a dose dependent manner . Detection with phosphoamino acid specific antibodies revealed that , in addition to Ser780 , phosphorylation of the DNA damage-responsive Ser612 on RB was enhanced by BGLF4 . Taken together , our study indicates that BGLF4 may directly or indirectly induce a DNA damage signal that eventually interferes with host DNA synthesis and delays S-phase progression .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22768064"}
{"sentence": "Peroxisome proliferator-activated receptor-\u03b3 ( PPAR\u03b3 ) is an anti-inflammatory molecule . To study its biologic function in myeloid cells , dominant-negative PPAR\u03b3 ( dnPPAR\u03b3 ) was overexpressed in a myeloid-specific bitransgenic mouse model . In this bitransgenic system , overexpression of the dnPPAR\u03b3-Flag fusion protein in myeloid-lineage cells abnormally elevated frequencies and total numbers of IL-7R\u03b1(-)Lin(-)c-Kit(+)Sca-1(-) , Lin(-)/Scal(+)/c-Kit(+) , common myeloid , and granulocyte-monocyte progenitor populations in the BM. dnPPAR\u03b3 overexpression led to up-regulation of IL-1\u03b2 , IL-6 , and TNF\u03b1 in the blood plasma . As a result , CD11b(+)Ly6G(+) cells were systemically increased in association with activation of Stat3 , NF-\u03baB , Erk1/2 , and p38 molecules . Myeloid-derived suppressor cells ( MDSCs ) inhibited the proliferation and lymphokine production of wild-type CD4+ T cells in vitro . CD4+ T cells from doxycycline-treated bitransgenic mice displayed reduced proliferation and lymphokine release . Both CD4+ and CD8+ T-cell populations were decreased in doxycycline-treated bitransgenic mice . Multiple forms of carcinoma and sarcoma in the lung , liver , spleen , and lymph nodes were observed in doxycycline-treated bitransgenic mice . BM transplantation revealed that a myeloid-autonomous defect was responsible for MDSC expansion , immunosuppression , and tumorigenesis in these mice . These studies suggest that anti-inflammatory PPAR\u03b3 in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis , MDSC expansion , immunosuppression , and the development of cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "22053106"}
{"sentence": "The endothelial cell-specific microRNA ( miRNA ) , miR-126 , is considered a master regulator of physiological angiogenesis . Transplanted mesenchymal stem cells ( MSCs ) release soluble factors contributing to neoangiogenesis and cardiac repair . Therefore , we hypothesized that the over-expression of miR-126 may prolong MSC survival and enhance the cell secretome , thereby improving post-infarction angiogenesis and cardiac function . In this study , MSCs harvested from male C57BL/6 mouse bone marrow were infected in vitro with miR-126 ( MSC(miR-126) ) by using recombinant lentiviral vectors ; the control cells were either non-transfected or transduced with mock vectors ( MSC(null) ) . The results showed an increased secretion of angiogenic factors and a higher resistance against hypoxia in MSC(miR-126) compared with the control cells . The expression of the Notch ligand Delta-like ( Dll)-4 in the MSC(miR-126) group was also increased . For in vivo experiments , MSC(miR-126) cultures were intramyocardially injected into the infarct region of the hearts of female C57BL/6 mice ( an acute myocardial infarction model ) who had undergone ligation of the left anterior descending coronary artery . The survival of MSC(miR-126) cultures , determined by Sry expression , was increased at 7 days after transplantation . MSC(miR-126)-treated animals showed significantly improved cardiac function as assessed by echocardiography 2 weeks later . The expression levels of angiogenic factors and Dll-4 in the infarcted myocardium were further increased by MSC(miR-126) compared with MSCs or MSC(null) cultures . Furthermore , fluorescent microsphere and histological studies revealed that myocardial blood flow and microvessel density were significantly increased in the MSC(miR-126)-transplanted animals . In addition , we found increased immature vessel proliferation following the transplantation of MSC(miR-126) cultures in which the expression of Dll-4 had been knocked down . However , blood vessels with lumen were barely detected , which indicated that Dll-4 plays a key role in tubulogenesis . We conclude that the transplantation of MSCs overexpressing miR-126 can further enhance functional angiogenesis in the ischemic myocardium possibly by the secretion of angiogenic factors and the activation of Dll-4 , thus increasing MSC survival . Therefore , MSCs modified with miR-126 may represent a novel and efficient therapeutic approach for ischemic angiogenesis and the improvement of cardiac function .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23229021"}
{"sentence": "ABSTRACT : BACKGROUND : The ubiquitin-proteasome system and macroautophagy ( hereafter referred to autophagy ) are two complementary pathways for protein degradation . Emerging evidence suggests that proteasome inhibition might be a promising approach for tumor therapy . Accumulating data suggest that autophagy is activated as a compensatory mechanism upon proteasome activity is impaired . METHOD : Autophagy activation was measured using acridine orange staining and LC3 transition . Cell viability and apoptosis were measured using MTT assay and flow cytometry , respectively . Beclin 1 expression vectors or shRNA against Beclin 1 ( shBeclin 1 ) were transfected to investigate the role of Beclin 1 in autophagy activation and cytotoxicity of ovarian cancer cells induced by proteasome inhibitors . RESULTS : Proteasome inhibitors suppressed proliferation and induced autophagy in ovarian cancer cells . Neither phosphoinositide 3-kinase ( PI3K ) inhibitors nor shRNA against Beclin 1 could abolish the formation of acidic vacuoles and the processing of LC3 induced by proteasome inhibitors . Moreover , Beclin 1 overexpression enhanced anti-proliferative effects of proteasome inhibitors in ovarian cancer cells . CONCLUSIONS : For the first time , the current study demonstrated that proteasome inhibitors induced PI3K and Beclin 1-independent autophagy in ovarian cancer cells . In addition , this study revealed autophagy-independent tumor suppressive effects of Beclin 1 in ovarian cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23270461"}
{"sentence": "Despite an increasing incidence of human breast cancer , its etiology remains unknown . Since some environmental chemicals are stored in human breast fat and are rodent mammary carcinogens , determining the genotoxic potential of environmental agents in this key target tissue is important . An assay was developed for detecting genotoxic activity , as unscheduled DNA synthesis ( UDS ) , induced by chemicals and UV radiation in early passage cultures of normal human mammary epithelial cells ( HMEC ) derived from 5 different women . In order to measure UDS in culture , reduction in the percentage of cells in S-phase was accomplished either by depriving the cells of epidermal growth factor and bovine pituitary extract or by contact inhibition of growth . Cultures were incubated with test chemicals for 24 h in the presence of [ 3H]-thymidine . UDS was quantitated autoradiographically as net grains per nucleus ( nuclear grains minus cytoplasmic background , population average ) with > or = 6 net nuclear grains considered in repair for any individual cell . A positive response was observed with UV radiation , benzo(a)-pyrene , aflatoxin B1 , ethylmethanesulfonate , 1,6-dinitropyrene , 2-acetylaminofluorene , and tobacco smoke condensate but not 7,12-dimethylbenz(a)anthracene or 2,3,7,8-tetrachlorodibenzo-p-dioxin . These results demonstrate that HMEC from all 5 women examined have the ability to metabolize a variety of environmental chemicals to DNA-reactive forms . Furthermore , some chemicals known either to cause mammary cancer in rodents or to be contaminants in human breast tissue are genotoxic in HMEC . A positive response in passage 9 cultures was observed only with direct acting agents , suggesting that HMEC may lose their metabolic capabilities in longer-term cultures . The HMEC UDS assay may be used to address the role of environmental agents in human breast cancer by determining whether chemicals are DNA reactive or metabolized to DNA reactive species in this critical target tissue .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1394185"}
{"sentence": "The aim of the present study was to investigate whether CBSCs [ (umbilical) cord blood stem cells ] can be a new source of DCs ( dendritic cells ) , which can generate more potent antigen-specific immune responses and anti-tumour effects . CBSCs and PBMCs ( peripheral blood mononuclear cells ) were collected , cultured and differentiated into DCs . Surface markers , secreting cytokines , antigen-presentation activity , antigen-specific cell-mediated immunity and cytotoxic killing effects induced by these two DC origins were evaluated and compared . CBSCs were expanded by ex vivo culture . The expression of surface markers in CBSC-derived DCs were higher than those in PBMC-derived DCs treated with LPS ( lipopolysaccharide ) . The CBSC-derived DCs mainly secreted IL ( interleukin)-6 , IL-10 and TNF ( tumour necrosis factor)-\u03b1 , whereas PBMC-derived DCs mainly secreted IL-5 and IFN ( interferon)-\u03b3 . The CBSC-derived DCs had better antigen-presentation abilities when stimulated with LPS or TNF-\u03b1 , induced higher numbers of IFN-\u03b3-secreting antigen-specific CD8+ T-cells , as assessed using an ELISpot ( enzyme-linked immunosorbent spot ) assay , and stimulated more potent antigen-specific CTL ( cytotoxic T-cell ) activities ( P<0.01 , one-way ANOVA ) . CBSC-derived DCs had quicker and greater ERK ( extracellular-signal-regulated kinase ) and Akt phosphorylation , and weaker p38 phosphorylation , than PBMC-derived DCs when stimulated with LPS . In conclusion , CBSC-derived DCs have the ability to induce stronger antigen-specific immunity and more potent anti-tumour effects and therefore could be a good source of DCs for use in DC-based cancer vaccines and immunotherapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22264240"}
{"sentence": "Vascular endothelial growth factor A ( VEGF-A ) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis . SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase . We have developed a reproducible murine model for neuroblastoma , a childhood cancer , based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells . We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels , that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml , and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals . Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity . SU5416 treatment also suppressed tumor angiogenesis , despite an increase in plasma VEGF-A levels per ml tumor volume during therapy . Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12906318"}
{"sentence": "PURPOSE The difference in radiosensitivity between two isogenic tumour cell lines was evaluated to determine whether factors such as sublethal and potentially damage repair , DNA double-strand break repair and fidelity of repair can be related to differences in radiosensitivity . MATERIALS AND METHODS The cell lines used were the ovarian carcinoma A2780s and a radiation-resistant derivative A2780cp . Radiation response was measured in terms of cell survival , recovery of sublethal ( SLD ) and potentially lethal damage ( PLD ) , induction of and recovery of DNA strand breaks , and fidelity of DNA repair using a cell-free plasmid assay . RESULTS While A2780cp was more resistant to radiation than A2780s , it showed less ability for recovery of SLD and PLD . DNA strand-break induction was the same for both cell lines , while only at very high doses did A2780cp show greater DNA strand-break recovery than A2780s . Fidelity of rejoining DNA was significantly higher in the A2780cp cell line . CONCLUSION The difference in radiosensitivity between these two cell lines was not related to recovery of PLD or SLD or to the induction of DNA damage . It appears that fidelity of DNA rejoining , which was significantly higher in the resistant cell line , may be related to the difference in radiosensitivity .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12556337"}
{"sentence": "It is thought that high linear energy transfer ( LET ) radiation induces more complex DNA damage than low-LET particles , specifically clustered DNA damage that causes cells to repair DNA double strand breaks ( DSB ) more slowly and leads to severe biological consequences . The present study aimed to investigate the role of exogenously added glutathione ( GSH ) on ( 12)C-beam ( 287keV/mum ) and ( 7)Li-beam ( 60keV/mum ) induced chromosome aberration ( CA ) formation , particularly on exchange aberration formation . In order to characterize the role of GSH in the joining of DNA DSBs , we induced DNA lesions with bleomycin ( Blem ) in conjunction with either high- or low-LET radiation ( X-rays ) since the chemistry of the free DNA ends created by Blem and X-rays is similar . CHO cells were exposed to reduced GSH at a concentration of 2mM for 3h before radiation . Treatment with Blem ( 20mug/ml ) was carried out for 2h before the cells were exposed to radiation . Our results show that the frequency of chromosomal aberration increases with increased LET . Heavy ion exposed cells show a higher frequency of CA over time than do X-irradiated cells . An analysis of the first post-irradiation mitosis of exposed CHO cells shows that high-LET radiation induces more breaks than exchange-type aberrations and exogenous GSH has no influence on high-LET radiation-induced DNA damage . The DNA lesions induced by low-LET radiation interact relatively strongly with Blem-induced lesions whereas interaction between Blem and high-LET radiations was poor . This could be attributed to differences in repair kinetics and qualitative differences in the DNA lesions induced by Blem and high-LET radiation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20100593"}
{"sentence": "Considerable debate centers on the optimal treatment for vulvar melanoma , as well as those clinicopathological factors influencing prognosis . We reviewed 80 patients with vulvar melanoma seen between 1949 and 1990 . Primary tumors were assessed according to Chung ( 47 patients ) and Breslow ( 65 patients ) microstaging systems . Fifty-nine patients ( 76% ) underwent radical vulvectomy , ten patients ( 13% ) had a partial vulvectomy , and nine patients ( 12% ) had a wide local excision . Fifty-six also underwent inguinal node dissection . Median follow-up was 193 months . Median survival was 63 months . Ten-year survival by Chung level was as follows : I 100% ; II , 81% ; III , 87% ; IV , 11% ; V , 33% . Ten-year survival by tumor thickness was as follows : 0.75 mm , 48% ; 0.75-1.5 mm , 68% ; 1.51-3.0 mm , 44% ; greater than 3.0 mm , 22% . Increased depth of invasion was associated with increased incidence of inguinal node metastasis . Cox regression analysis demonstrated prognostic significance for tumor thickness ( P less than 0.001 ) , inguinal node metastasis ( P less than 0.001 ) , and older age at diagnosis ( P less than 0.001 ) . Radical vulvectomy did not seem to improve survival over less radical procedures . Based on this experience , we recommend radical local excision for patients with malignant melanoma of the vulva . Patients who have more than a superficially invasive melanoma should also have inguinal lymph node dissection .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1612500"}
{"sentence": "The ultraviolet radiation present in sunlight is immune suppressive . Recently we showed that solar-simulated ultraviolet radiation ( ultraviolet A + B ; 295-400 nm ) , applied after immunization , suppressed immunologic memory and the elicitation of delayed-type hypersensitivity to the common opportunistic pathogen , Candida albicans . Further , we found that wavelengths in the ultraviolet A region of the solar spectrum ( 320-400 nm ) , devoid of ultraviolet B , were equally effective in activating immune suppression as ultraviolet A + B radiation . Here we report on the mechanisms involved . Maximal immune suppression was found when mice were exposed to solar-simulated ultraviolet radiation 7-9 d post immunization . No immune suppression was found in ultraviolet-irradiated mice injected with monoclonal anti-interleukin-10 antibody , or mice exposed to solar-simulated ultraviolet radiation and injected with recombinant interleukin-12 . Suppressor lymphocytes were found in the spleens of mice exposed to ultraviolet A + B radiation . In addition , antigen-specific suppressor T cells ( CD3+ , CD4+ , DX5+ ) were found in the spleens of mice exposed to ultraviolet A radiation . Applying liposomes containing bacteriophage T4N5 to the skin of mice exposed to solar-simulated ultraviolet A + B radiation , or mice exposed to ultraviolet A radiation , blocked immune suppression , demonstrating an essential role for ultraviolet-induced DNA damage in the suppression of established immune reactions . These findings indicate that overlapping immune suppressive mechanisms are activated by ultraviolet A and ultraviolet A + B radiation . Moreover , our findings demonstrate that ultraviolet radiation activates similar immunologic pathways to suppress the induction of , or the elicitation of , the immune response .", "label": [0, 1, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12230501"}
{"sentence": "ATM(Tel1) and ATR(Rad3) checkpoint kinases phosphorylate the C-terminus of histone H2AX ( H2A in yeasts ) in chromatin flanking DNA damage , establishing a recruitment platform for checkpoint and repair proteins . Phospho-H2A/X ( gammaH2A/X)-binding proteins at double-strand breaks ( DSBs ) have been characterized , but those required for replication stress responses are unknown . Here , we present genetic , biochemical , small angle X-ray scattering ( SAXS ) , and X-ray structural studies of the Schizosaccharomyces pombe Brc1 , a 6-BRCT-domain protein that is structurally related to Saccharomyces cerevisiae Rtt107 and mammalian PTIP . Brc1 binds gammaH2A to form spontaneous and DNA damage-induced nuclear foci . Spontaneous Brc1 foci colocalize with ribosomal DNA repeats , a region prone to fork pausing and genomic instability , whereas DNA damage-induced Brc1 foci colocalize with DSB response factors. gammaH2A binding is critical for Brc1 function . The 1.45 A resolution crystal structure of Brc1-gammaH2A complex shows how variable BRCT insertion loops sculpt tandem-BRCT phosphoprotein-binding pockets to facilitate unique phosphoprotein-interaction specificities , and unveils an acidic DNA-mimicking Brc1 surface . From these results , Brc1 docking to gammaH2A emerges as a critical chromatin-specific response to replication-associated DNA damage .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20094029"}
{"sentence": "Angiogenesis is the process of new blood vessel formation from pre-existing ones . Angiogenic factors contribute to neovascularization that takes place in angiogenesis-dependent diseases , including cancer . Inhibiting the activity of the angiogenic factors to block the angiogenesis pathways is the current strategy of cancer therapy . Basic fibroblast growth factor ( bFGF ) is regarded as one of the most important angiogenic factors . Herein , we selected polyoxometalates ( POMs ) with different structures to study the interactions between bFGF and POMs . The results show that POMs could bind to the protein with high affinity , causing detectable changes in conformation and biophysical properties of protein . In addition , POMs could effectively inhibit the cell proliferation induced by bFGF . Significantly , we found that the structure , size and composition of POMs play a key role in the interactions between bFGF and POMs . This study will be meaningful for future screening and design of polyoxometalate-based anticancer drugs .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23123725"}
{"sentence": "INTRODUCTION HER2 and estrogen receptor ( ER ) are important in breast cancer and are therapeutic targets of trastuzumab ( Herceptin ) and tamoxifen , respectively . Retinoids inhibit breast cancer growth , and modulate signaling by HER2 and ER . We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects . METHODS The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture , BT474 and SKBR3 . Assays of proliferation , apoptosis , differentiation , cell cycle distribution , and receptor signaling were performed . RESULTS In HER2-overexpressing/ER-positive BT474 cells , combining all-trans retinoic acid ( atRA ) with tamoxifen or trastuzumab synergistically inhibited cell growth , and altered cell differentiation and cell cycle . Only atRA/trastuzumab-containing combinations induced apoptosis . BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids ( atRA , 9-cis-retinoic acid , 13-cis-retinoic acid , or N-(4-hydroxyphenyl) retinamide ( fenretinide ) ( 4-HPR) ) combined with trastuzumab . In BT474 cells , none of the single agents except 4-HPR induced apoptosis , but again combinations of each retinoid with trastuzumab did induce apoptosis . In contrast , the single retinoid agents did cause apoptosis in SKBR3 cells ; this was only modestly enhanced by addition of trastuzumab . The retinoid drug combinations altered signaling by HER2 and ER . Retinoids were inactive in trastuzumab-resistant BT474 cells . CONCLUSIONS Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells . Treatment with such combinations may have benefit for breast cancer patients .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20696059"}
{"sentence": "Colorectal tumors are continuously exposed to an inflammatory environment , which together with mitogenic signals sustain several cancer hallmarks . Nuclear factor-kappa B ( NF\\u03baB ) is a major regulator of inflammation and variation in NF\\u03baB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer ( CRC ) development , and/or a rapidly progressing disease . In this study , 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NF\\u03baB pathway-associated genes . Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival , whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility . Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC . Heterozygous and polymorphic TNFAIP3 ( rs6920220 ) , heterozygous NLRP3 ( Q705K ) and polymorphic NF\\u03baB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC ( aHR = 5.2 , 95% CI : 2.5-10.9 , P < 0.001 ) . TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa ( P < 0.0001 ) and loss of heterozygosity of 6q23.3 ( TNFAIP3 ) was detected in 17% of cases , whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations . We propose that TNFAIP3 ( rs6920220 ) , NLRP3 ( Q705K ) and NF\\u03baB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers . Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22843550"}
{"sentence": "1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine ( ECyd ) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers . The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells . Here , we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer ( NPC ) . In a panel of 6 NPC cell lines , ECyd effectively inhibited cellular proliferation at nM concentrations ( IC(50) : approximately 13-44nM ) . Moreover , cisplatin-resistant NPC cells were highly sensitive to ECyd ( at nM concentration ) . The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest , PARP cleavage ( a hallmark of apoptosis ) and Bcl-2 downregulation , indicating induction of apoptosis by ECyd in NPC cells . Unexpectedly , ECyd-induced significant downregulation of TIGAR , a newly described dual regulator of apoptosis and glycolysis . More importantly , this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH , the major reducing power critically required for cell proliferation and survival . We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd . Indeed , overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition , demonstrating a novel mechanistic action of ECyd on TIGAR . We demonstrated for the first time that an RNA-directed nucleoside analog , ECyd , exerts its antitumor activity via downregulation of a novel regulator of apoptosis , TIGAR . Moreover , ECyd may represent a novel therapy for NPC .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "20219441"}
{"sentence": "Angiotensin II type 1 receptor ( AT1R ) promotes tumor invasion , migration , metastasis and angiogenesis . We explored the potential antitumor effects of AT1R antagonists in breast cancer . We found that angiotensin II promoted cell proliferation and upregulated the expression of vascular endothelial growth factor A ( VEGF-A ) in MCF-7 cells . Losartan downregulated the expression of VEGF-A in MCF-7 cells treated with angiotensin II . Candesartan downregulated the expression of VEGF-A in mice bearing MCF-7 xenografts and inhibited tumor growth and angiogenesis . AT1R and VEGF-A expression correlated with increased microvascular density in 102 breast cancer patients . Our data suggest that AT1R antagonists might be useful to suppress breast cancer by inhibiting the angiotensin II .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23092556"}
{"sentence": "Chemoresistance represents a major obstacle to successful treatment for malignant glioma with temozolomide . N ( 7)-methyl-G and N ( 3)-methyl-A adducts comprise more than 80% of DNA lesions induced by temozolomide and are processed by the base excision repair , suggesting that the cellular resistance could be caused , in part , by this efficient repair pathway , although few studies have focused on this subject . The aim of this study was to evaluate the cellular responses to temozolomide treatment associated with methoxyamine ( blocker of base excision repair ) in glioblastoma cell lines , in order to test the hypothesis that the blockage of base excision repair pathway might sensitize glioblastoma cells to temozolomide . For all the tested cell lines , only T98G showed significant differences between temozolomide and temozolomide plus methoxyamine treatment , observed by reduced survival rates , enhanced the levels of DNA damage , and induced an arrest at G2-phase . In addition , of apoptotic cells ( sub-G1 fraction ) were observed at 48h . Western blot analysis demonstrated that APE1 and FEN1 presented a slightly reduced expression levels under the combined treatment , probably due to AP sites blockade by methoxyamine , thus causing a minor requirement of base excision repair pathway downstream to the AP removal by APE1 . On the other hand , PCNA expression in temozolomide plus methoxyamine-treated cells does not rule out the possibility that such alteration might be related to the blockage of cell cycle ( G2-phase ) , as observed at 24h of recovery time . The results obtained in the present study demonstrated the efficiency of methoxyamine to overcome glioblastoma resistance to temozolomide treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22828727"}
{"sentence": "Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis . Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy . Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches . Here , we identified harmine ( \u03b2-carboline alkaloid ) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth . Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction . Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells . Moreover , harmine not only induced endothelial cell cycle arrest and apoptosis , but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay . Finally , harmine inhibited tumor growth by reducing tumor angiogenesis , as demonstrated by a xenograft tumor model . Our results suggested a novel mechanism and bioactivity of harmine , which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells .", "label": [0, 0, 0, 0, 1, 0, 1, 1, 1, 0], "id": "23300602"}
{"sentence": "It has been demonstrated that growth factors produced by breast cancer cells stimulate aromatase expression in both breast cancer and adjacent adipose fibroblasts and stromal cells . However , whether these growth factors affect aromatase activity by other mechanisms still remain unclear . In the current study , MCF-7aro and T47Daro aromatase transfected breast carcinoma cells were used to explore the mechanisms of post-transcriptional regulation of aromatase activity by growth factor pathways . Our study reveals that PI3K/Akt and MAPK inhibitors suppressed aromatase activity in MCF-7aro cells . However , PI3K/Akt pathway inhibitors stimulated aromatase activity in T47Daro cells . This is due to enhanced MAPK phosphorylation as compensation after the PI3K/Akt pathway has been blocked . IGF-1 treatment increased aromatase activity in both breast cancer cell lines . In addition , LTEDaro cells ( long-term estrogen deprived MCF-7aro cells ) which have enhanced MAPK activity , show higher aromatase activity compared to parental MCF-7aro cells , but the aromatase protein level remains the same . These results suggest that aromatase activity could be enhanced by growth factor signaling pathways via post-transcriptional mechanisms .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21112394"}
{"sentence": "Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer ( NSCLC ) despite poor response rates and limited response duration . It has been reported that tumor expression of ERCC1 , a key component in nucleotide excision repair , may correlate with clinical response to platinum agents . We found that most primary lung tumor specimens demonstrated a stronger protein expression of poly ( ADP ribose ) polymerases 1 ( PARP1 ) than their normal counterparts . We therefore hypothesized that combining PARP inhibition with platinum compounds may be an approach to improve platinum-based therapy for NSCLC . Drug combination experiments revealed that two distinct PARP inhibitors , olaparib and veliparib not only potentiated the cell killing by cisplatin but also conferred cytotoxicity as a single agent specifically in ERCC1-low HCC827 and PC9 but not in ERCC1-high A549 and H157 lung cancer cells . Moreover , siRNA knockdown of ERCC1 in A549 and H157 cells increased their sensitivities to both cisplatin and olaparib in a synergistic manner in our model . Furthermore , mechanistic studies indicated that combined PARP inhibitor and cisplatin could lead to sustained DNA double strand breaks , prolonged G2/M cell cycle arrest with distinct activation of checkpoint kinase 1 signaling , and more pronounced apoptosis preferentially in lung cancer cells with low ERCC1 expression . Collectively , these data suggest that there is a synergistic relationship between PARP inhibition and low ERCC1 expression in NSCLC that could be exploited for novel therapeutic approaches in lung cancer therapy based on tumor ERCC1 expression .", "label": [0, 0, 0, 0, 1, 1, 0, 1, 0, 0], "id": "23275151"}
{"sentence": "Loss of heterozygosity ( LOH ) in 16q appears in cases of Wilms ' tumor . Within this region , known as common fragile site FRA16D , the WWOX tumor suppressor gene is located . Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis . The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms ' tumor samples . We evaluated the correlation between expression of WWOX and genes involved in proliferation ( Ki67 ) , apoptosis ( BCL2 , BAX ) , signal transduction ( ERBB4 , ERBB2 , EGFR ) , cell cycle ( CCNE1 , CCND1 ) , cell adhesion ( CDH1 ) and transcription ( TP73 ) using real-time RT-PCR in 23 tumor samples . We also analyzed the potential causes of WWOX gene expression reduction i.e. , promoter methylation status ( MethylScreen method ) and loss of heterozygosity ( LOH ) status . We revealed a positive correlation between WWOX expression and BCL2 , BCL2/BAX ratio , EGFR , ERBB4 isoform JM-a , TP73 and negative correlation with both cyclins . Loss of heterozygosity of the WWOX gene was observed only at intron 8 , however , it had no influence on the reduction of its expression levels . Contrary to LOH , methylation of the region covering the 3 ' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels . In the present study we reveal that in Wilms ' tumors the WWOX expression levels are positively associated with the process of apoptosis , signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle ( by cyclin E1 and D1 ) . Moreover , our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22842668"}
{"sentence": "To investigate whether altered energy metabolism induces the Warburg effect and results in tumor malignancy , the respiratory enzyme citrate synthase ( CS ) was examined , silenced , and the effects analyzed . In human cervical carcinoma cells , RNAi-mediated CS knockdown induced morphological changes characteristic of the epithelial-mesenchymal transition ( EMT ) . This switch accelerated cancer cell metastasis and proliferation in in vitro assays and in vivo tumor xenograft models . Notably , CS knockdown cells exhibited severe defects in respiratory activity and marked decreases in ATP production , but great increases in glycolytic metabolism . This malignant progression was due to activation of EMT-related regulators ; altered energy metabolism resulted from deregulation of the p53/TIGAR and SCO2 pathways . This phenotypic change was completely reversed by p53 reactivation via treatment with proteasome inhibitor MG132 or co-knockdown of E3 ligase HDM2 and partially suppressed by ATP treatment . This study directly links the Warburg effect to tumor malignancy via induction of the EMT phenotype .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23139858"}
{"sentence": "Ovarian cancer , one of inflammation-associated cancers , is the fifth leading cause of cancer deaths among women . Inflammation in the tumor microenvironment is associated with peritoneal tumor dissemination and massive ascites , which contribute to high mortality in ovarian cancer . Tumor suppressor p53 is frequently deleted or mutated in aggressive and high-grade ovarian cancer , probably aggravating cancer progression and increasing mortality . We therefore investigated the influence of p53 on proinflammatory chemokines in ovarian cancer cells . A PCR array of the chemokine network revealed that ovarian cancer cells with low or mutated p53 expression expressed high levels of proinflammatory chemokines such as CXCL1 , 2 , 3 and 8 . Transient transfection of p53 into p53-null ovarian cancer cells downregulated proinflammatory chemokines induced by tumor necrosis factor-\u03b1 ( TNF ) , a proinflammatory cytokine abundantly expressed in ovarian cancer . Furthermore , p53 restoration or stabilization blocked TNF-induced NF-\u03baB promoter activity and reduced TNF-activated I\u03baB . Restoration of p53 increased ubiquitination of I\u03baB , resulting from concurrently reduced proteasome activity followed by stability of I\u03baB . A ubiquitination PCR array on restoration of p53 did not reveal any significant change in expression except for Mdm2 , indicating that the balance between p53 and Mdm2 is more important in regulating NF-\u03baB signaling rather than the direct effect of p53 on ubiquitin-related genes or I\u03baB kinases . In addition , nutlin-3 , a specific inducer of p53 stabilization , inhibited proinflammatory chemokines by reducing TNF-activated I\u03baB through p53 stabilization . Taken together , these results suggest that p53 inhibits proinflammatory chemokines in ovarian cancer cells by reducing proteasomal degradation of I\u03baB . Thus , frequent loss or mutation of p53 may promote tumor progression by enhancing inflammation in the tumor microenvironment .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23300534"}
{"sentence": "There are many growth factors influencing the expansion of multiple myeloma ( MM ) . Angiogenesis is a process that may enhance MM growth , in various manners . Among them , insulin-like growth factor-1 ( IGF-1 ) is a major factor , acting in many levels . The aim of the study was to measure serum levels of IGF-1 in newly diagnosed MM patients and to correlate them with clinical stage of the disease and with markers of angiogenesis , such as vascular endothelial growth factor ( VEGF ) , hepatocyte growth factor ( HGF ) , and interleukin-6 and 15 ( IL-6 and IL-15 ) . Serum levels of the above factors were measured , by ELISA , in 57 newly diagnosed MM patients and in 20 healthy controls . There was no difference in serum levels of IGF-1 in MM patients and in controls , contrary to angiogenic factors , which were higher in MM patients ( p < 0.001 ) . Similarly , IGF-1 did not correlate with clinical stage of the disease nor the other angiogenic factors , which also correlated with each other ( p < 0.001 ) . Serum IGF-1 concentrations are not influenced in MM patients . Therefore , although it is a proliferation cytokine , it cannot be used as marker of disease activity .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23266941"}
{"sentence": "BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas . By binding specific DNA sequences , BCL6 controls the transcription of a variety of genes involved in B-cell development , differentiation and activation . BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma ( DLBCL ) , the most common lymphoma in adulthood , and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease . In many DLBCL patients , BCL6 overexpression is achieved through translocation ( or hypermutation of its promoter ( However , many other DLBCLs overexpress BCL6 through an unknown mechanism . Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1\u2013CUL1\u2013F-box protein ( SCF ) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 ( refs 5 , 6 ) . The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines , and this inactivation of FBXO11 correlated with increased levels and stability of BCL6 . Similarly , FBXO11 was either deleted or mutated in primary DLBCLs . Notably , tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation . Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation , inhibited cell proliferation , and induced cell death . FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice , and the tumorigenicity was suppressed by FBXO11 reconstitution . We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization . The deletions/mutations found in DLBCLs are largely monoallelic , indicating that FBXO11 is a haplo-insufficient tumour suppressor gene .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22113614"}
{"sentence": "BACKGROUND Agricultural products and by products provide the primary materials for a variety of technological applications in diverse industrial sectors . Agro-industrial wastes , such as cotton and curaua fibers , are used to prepare nanofibers for use in thermoplastic films , where they are combined with polymeric matrices , and in biomedical applications such as tissue engineering , amongst other applications . The development of products containing nanofibers offers a promising alternative for the use of agricultural products , adding value to the chains of production . However , the emergence of new nanotechnological products demands that their risks to human health and the environment be evaluated . This has resulted in the creation of the new area of nanotoxicology , which addresses the toxicological aspects of these materials . PURPOSE AND METHODS Contributing to these developments , the present work involved a genotoxicological study of different nanofibers , employing chromosomal aberration and comet assays , as well as cytogenetic and molecular analyses , to obtain preliminary information concerning nanofiber safety . The methodology consisted of exposure of Allium cepa roots , and animal cell cultures ( lymphocytes and fibroblasts ) , to different types of nanofibers . Negative controls , without nanofibers present in the medium , were used for comparison . RESULTS The nanofibers induced different responses according to the cell type used . In plant cells , the most genotoxic nanofibers were those derived from green , white , and brown cotton , and curaua , while genotoxicity in animal cells was observed using nanofibers from brown cotton and curaua . An important finding was that ruby cotton nanofibers did not cause any significant DNA breaks in the cell types employed . CONCLUSION This work demonstrates the feasibility of determining the genotoxic potential of nanofibers derived from plant cellulose to obtain information vital both for the future usage of these materials in agribusiness and for an understanding of their environmental impacts .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22848179"}
{"sentence": "A key issue in the development of the central nervous system ( CNS ) is understanding the molecular mechanisms regulating cell number . The present study examines the role of CD81 ( previously known as TAPA , the target of the antiproliferative antibody ) in the control of brain size and glial cell number . CD81 is a member of the tetraspanin family of proteins . This group of small membrane proteins is associated with the regulation of cell migration and mitotic activity . Glial cells express CD81 , and antibodies directed against this protein suppress the mitotic activity of cultured cells . In this study , we examine the effects of the CD81 -/- mutation on the CNS of mature mice . These mice have extremely large brains , as much as 30% larger than the brains of wild-type ( +/+ ) littermates . The increase in brain weight is accompanied by an increase in the number astrocytes and microglia , whereas the number of neurons and oligodendrocytes in the CD81 -/- animals appears to be normal . When the CD81 -/- mutation is placed on different genetic backgrounds , there is a remarkable range in the penetrance of the null allele phenotype , demonstrating that the mutation can be affected by modifier loci . This work provides support for the role of CD81 in the regulation of astrocyte and microglial number , perhaps by regulating cell proliferation by a contact inhibition-dependent mechanism .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "12357429"}
{"sentence": "The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals , and sporadically in non-Jews . Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora years ago . The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers , and to estimate the age at which the mutation arose . Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5\\u2009MB , encompassing the BRCA1 gene locus . Estimation of mutation age was based on a subset of 11 markers spanning a region of using a previously developed algorithm applying the maximum likelihood method . Overall , 188 participants ( 154 carriers and 34 noncarriers ) from 115 families were included : Ashkenazi , Iraq , Kuchin-Indians , Syria , Turkey , Iran , Tunisia , Bulgaria , non-Jewish English , non-Jewish Malaysian , and Hispanics . Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago . In Ashkenazim , it is a founder mutation that arose 61 generations ago , and with a small group of founder mutations was introduced into the Hispanic population ( conversos ) years ago , and into the Iraqi-Jewish community years ago . The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently . We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews , and arose about 61 generations ago and arose independently at least twice in non-Jews .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22763381"}
{"sentence": "Class switch recombination ( CSR ) in B lymphocytes is initiated by introduction of multiple DNA double-strand breaks ( DSBs ) into switch ( S ) regions that flank immunoglobulin heavy chain ( IgH ) constant region exons . CSR is completed by joining a DSB in the donor S mu to a DSB in a downstream acceptor S region ( e.g. , S gamma1 ) by end-joining . In normal cells , many CSR junctions are mediated by classical nonhomologous end-joining ( C-NHEJ ) , which employs the Ku70/80 complex for DSB recognition and XRCC4/DNA ligase 4 for ligation . Alternative end-joining ( A-EJ ) mediates CSR , at reduced levels , in the absence of C-NHEJ , even in combined absence of Ku70 and ligase 4 , demonstrating an A-EJ pathway totally distinct from C-NHEJ . Multiple DSBs are introduced into S mu during CSR , with some being rejoined or joined to each other to generate internal switch deletions ( ISDs ) . In addition , S-region DSBs can be joined to other chromosomes to generate translocations , the level of which is increased by absence of a single C-NHEJ component ( e.g. , XRCC4 ) . We asked whether ISD and S-region translocations occur in the complete absence of C-NHEJ ( e.g. , in Ku70/ligase 4 double-deficient B cells ) . We found , unexpectedly , that B-cell activation for CSR generates substantial ISD in both S mu and S gamma1 and that ISD in both is greatly increased by the absence of C-NHEJ . IgH chromosomal translocations to the c-myc oncogene also are augmented in the combined absence of Ku70 and ligase 4 . We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20133803"}
{"sentence": "Osteogenesis imperfecta ( OI ) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma . OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2 . The most remarkable and pathognomonic feature , observed in of affected individuals , is a predisposition to develop hyperplastic callus after fractures or surgical interventions . To identify the molecular cause of OI type V , we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations . We found a heterozygous de novo mutation in the 5'-untranslated region of IFITM5 ( the gene encoding Interferon induced transmembrane protein 5 ) , 14 bp upstream of the annotated translation initiation codon ( c.-14C>T ) . Subsequently , we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing , thereby confirming that this is the causal mutation for the phenotype . IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation . The mutation c.-14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon . In vitro , eukaryotic cells were able to recognize this start codon , and they used it instead of the reference translation initiation signal . This suggests that five amino acids ( Met-Ala-Leu-Glu-Pro ) are added to the N terminus and alter IFITM5 function in individuals with the mutation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22863195"}
{"sentence": "OBJECTIVES Recently , it was revealed that carnosine inhibits growth of cells isolated from human malignant glioma . In order to understand how this effect is mediated , experiments were performed that addressed a possible influence of carnosine on energy metabolism . METHODS Cells from the glioma line T98G and primary cultured cells from human malignant glioma were cultivated in the presence of carnosine and inhibitors of cellular energy metabolism . As a specific inhibitor for anaerobic glycolysis , oxamate , and as an inhibitor for mitochondrial oxidative phosphorylation , potassium cyanide , were used , and the influence on ATP production was determined using cell-based assays . RESULTS The experiments identified glycolysis as crucial for ATP production in gliomas . In addition , ATP production by mitochondrial activity did not significantly contribute to ATP production and carnosine was identified to be an inhibitor of the vital anaerobic glycolysis . DISCUSSION Carnosine might be considered as a potential drug for the treatment of malignant glioma or other tumors since it inhibits the glycolytic energy metabolism that is crucial for cancer cells and malignant gliomas as shown in the current study . This is especially interesting since the dipeptide is a naturally occurring substance that should be well tolerated .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19909581"}
{"sentence": "Mutations in adenomatous polyposis coli ( APC ) gene are found in more than 80% of colorectal cancer ( CRC ) patients . The nuclear transcription factor Nrf2 plays a central role in the regulation of oxidative stress and inflammation . Previously , we have shown that chronic inflammation in Nrf2(-/-) ( Nrf2 knockout ; KO ) mice resulted in higher expression of inflammatory markers and cytokines , coupled with higher inflammatory damage to the colonic crypt cells , as compared to the Nrf2(+/+) ( wild type ; WT ) mice . Induction of mutation in the colon by administration of carcinogen , AOM prior to DSS-induced inflammation resulted in higher tumor incidence and numbers in Nrf2KO mice . These results indicate that Nrf2-dependent inhibition of inflammation appears to be critical in inhibiting mutation-initiated colorectal carcinogenesis . In this study , we aim to investigate if loss of Nrf2 would dose-dependently promote intestinal tumorigenesis in Apc(min/+) mice . To demonstrate the in vivo mechanisms , we constructed both Apc mutated and Nrf2 deficient strain Apc(min/+) mice with C57BL/6 Nrf2KO mice to obtain F1 , Apc(min/+) ;Nrf2(+/-) and F2 , Apc(min/+) ;Nrf2(-/-) mice . Nrf2KO decreased the protein expression of antioxidant enzyme NQO1 in Apc(min/+) . In contrast , Nrf2KO enhanced the expression of inflammatory markers such as COX-2 , cPLA , LTB(4) in Apc(min/+) . Finally , Nrf2KO resulted in higher level of PCNA and c-Myc expression in intestinal tissue , indicating the deficiency of Nrf2 promotes proliferation of intestinal crypt cells in Apc(min/+) . Taken together , our results suggest that Nrf2KO attenuates anti-oxidative stress pathway , induces inflammation , and increases proliferative potential in the intestinal crypts leading to enhanced intestinal carcinogenesis and adenomas in Apc(min/+) . \u00a9 2012 Wiley Periodicals , Inc .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "22911891"}
{"sentence": "Peptide growth factors have been implicated in progression of prostate cancer ( PCa ) to the androgen-independent state ; however , much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial . Heparin-binding epidermal growth factor-like growth factor ( HB-EGF ) , a prostate stroma-derived factor , promotes survival , proliferation , and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro . To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype , we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF ( LNCaP/sHB ) . LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice , in comparison to control cells . LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker , neuron-specific enolase , compared with control tumors . In castrates , increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor ( AR ) levels . In vitro , AR protein levels were reduced in LNCaP/sHB cells , and in transient transfection assays using an androgen-responsive promoter ( mouse mammary tumor virus-long terminal repeat ) , LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls . This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo . These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12446587"}
{"sentence": "Most hepatocellular carcinomas ( HCC ) develop in the context of severe liver fibrosis and cirrhosis caused by chronic liver inflammation , which also results in accumulation of reactive oxygen species ( ROS ) . In this study , we examined whether the stress-activated protein kinase p38\u03b1 ( Mapk14 ) controls ROS metabolism and development of fibrosis and cancer in mice given thioacetamide to induce chronic liver injury . Liver-specific p38\u03b1 ablation was found to enhance ROS accumulation , which appears to be exerted through the reduced expression of antioxidant protein HSP25 ( Hspb1 ) , a mouse homolog of HSP27 . Its reexpression in p38\u03b1-deficient liver prevents ROS accumulation and thioacetamide-induced fibrosis. p38\u03b1 deficiency increased expression of SOX2 , a marker for cancer stem cells and the liver oncoproteins c-Jun ( Jun ) and Gankyrin ( Psmd10 ) and led to enhanced thioacetamide-induced hepatocarcinogenesis . The upregulation of SOX2 and c-Jun was prevented by administration of the antioxidant butylated hydroxyanisole . Intriguingly , the risk of human HCC recurrence is positively correlated with ROS accumulation in liver . Thus , p38\u03b1 and its target HSP25/HSP27 appear to play a conserved and critical hepatoprotective function by curtailing ROS accumulation in liver parenchymal cells engaged in oxidative metabolism of exogenous chemicals . Augmented oxidative stress of liver parenchymal cells may explain the close relationship between liver fibrosis and hepatocarcinogenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23271722"}
{"sentence": "Biallelic mutations in MCPH1 cause primary microcephaly ( MCPH ) with the cellular phenotype of defective chromosome condensation . MCPH1 encodes a multifunctional protein that notably is involved in brain development , regulation of chromosome condensation , and DNA damage response . In the present studies , we detected that MCPH1 encodes several distinct transcripts , including two major forms : full-length MCPH1 ( MCPH1-FL ) and a second transcript lacking the six 3 ' exons ( MCPH1\\u0394e9-14 ) . Both variants show comparable tissue-specific expression patterns , demonstrate nuclear localization that is mediated independently via separate NLS motifs , and are more abundant in certain fetal than adult organs . In addition , the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells , demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation . Strikingly however , both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response ; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation , while MCPH1\\u0394e9-14 was evenly distributed in the nucleus . In summary , our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22952573"}
{"sentence": "Pyruvate constitutes a critical branch point in cellular carbon metabolism . We have identified two proteins , Mpc1 and Mpc2 , as essential for mitochondrial pyruvate transport in yeast , Drosophila , and humans . Mpc1 and Mpc2 associate to form an complex in the inner mitochondrial membrane . Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metabolism , with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates . Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake , and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidation . A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier . Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1 , changing single amino acids that are conserved throughout eukaryotes . These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22628558"}
{"sentence": "OBJECTIVES Oxidative stress and pro-inflammatory mediators have been implicated in breast carcinogenesis . We attempted to evaluate the markers of oxidative stress , antioxidant mechanism and the inflammatory pathway in patients with breast cancer . METHODS This study was carried out in departments of Biochemistry and Surgery , Maulana Azad Medical College and associated Hospitals , New Delhi , India . A total of 60 cases of carcinoma of the breast and 60 healthy controls were included in the study . The parameters that were assayed include markers of oxidative stress-conjugated dienes , thiobarbitone reactive substances ( TBARS ) , antioxidants-superoxide dismutase ( SOD ) , catalase ( CAT ) , glutathione peroxidase ( GPx ) , glutathione ( GSH ) and markers of inflammation-interleukin-6(IL-6) and ferritin . RESULTS There was a significant decline in the antioxidant levels and a significant rise in oxidant levels in patients with carcinoma of the breast , compared to controls . The inflammatory markers-IL-6 and ferritin-were also significantly higher in patients with breast cancer . A significantly positive correlation was observed between the IL-6 levels and conjugated dienes with the stage of breast carcinoma ; whilst a significantly negative correlation was observed between the levels of conjugated dienes and superoxide dismutase and superoxide dismutase levels with the disease staging . CONCLUSIONS This study underlines the interplay between inflammatory pathways and oxidative stress in the pathogenesis of breast cancer . MINI ABSTRACT : An intense research is underway to identify the possible risk factors and the molecular mechanisms involved in pathogenesis of breast cancer . Inflammation and oxidative stress are two such etiologies investigated in our study .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20571235"}
{"sentence": "PURPOSE Metabolic dependence on glucose utilisation has been described for different tumours characterised by activation of Akt , upregulation of GLUT1 , M2PK and TKTL1 . To date , however , little is known about glucose metabolism in breast cancer tissue . METHODS We analysed 55 breast cancer specimens , 26 adjacent ductal carcinomas in situ ( DCIS ) and 23 adjacent normal breast tissues for expression of glycolytic markers by immunohistochemistry . RESULTS We found expression of pAkt in 49% , GLUT1 in 25% , M2PK in 68% and TKTL1 in 31% of the tumours investigated . Expression of pAkt and Her2neu are positively correlated with borderline significance ( P = 0.055 ) . Expression of pAkt , GLUT1 and TKTL1 were higher in breast cancer and DCIS than in normal tissue . Surprisingly , M2PK expression was highest in normal breast tissue . CONCLUSIONS We found a glycolytic phenotype in a high percentage of breast cancer samples . Inhibition of glycolysis might evolve as a future option for breast cancer therapy .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19655166"}
{"sentence": "Past studies have shown that amplified insulin-like growth factor 1 ( IGF1)/IGF1 receptor ( IGF1-R ) signalling has an important role in colorectal cancer ( CRC ) development , progression and resistance to treatment . In this report , we demonstrate that downregulation of microRNA-497 ( miR-497 ) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells . MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3 ' untranslated region ( 3'UTR ) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa . However , only overexpression of miR-497 led to suppression of the IGF1-R 3'UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells . This was associated with inhibition of cell survival , proliferation and invasion , and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5-fluorouracil , and the death ligand tumour necrosis factor-related apoptosis-inducing ligand . The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling , as overexpression of an active form of Akt reversed its impact on cell survival and proliferation , recapitulating the effect of overexpression of IGF1-R . Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1 , where these miRs are located at proximity . Similarly to miR-195 , the members of the same miR family , miR-424 that was upregulated , and miR-15a , miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa , did not appear to have a role in regulating the expression of IGF1-R . Taken together , these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.Oncogene advance online publication , 18 June 2012 ; doi:10.1038/onc.2012.214 .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22710713"}
{"sentence": "Candida albicans infections are very frequent in cancer patients , whose immune system is often compromised , but whether this fungal pathogen affects cancer progression is unknown . C. albicans infection involves endogenous production of inflammatory cytokines such as tumour necrosis factor alpha ( TNF-alpha ) and interleukin-18 ( IL-18 ) . Increased levels of these cytokines have already been correlated with metastasis of most common cancer types . In this study , a well-established model of IL-18-dependent hepatic melanoma metastasis was used to study whether C. albicans can alter the ability of murine B16 melanoma ( B16M ) cells to colonize the liver . First , we determined the ability of intrasplenically ( IS ) injected B16M cells to metastasize into the liver of mice challenged with 5 x 10(4) C. albicans cells by three different routes ( intravenous , IV ; intrasplenic , IS ; or intraperitoneal , IP ) 12 h prior to injection of B16M cells . We demonstrated that C. albicans significantly increased metastasis of B16M cells with all three fungal injection routes . Pro-metastatic effects occurred when hepatic colonization with B16M cells place after the peak of TNF-alpha and IL-18 levels had been reached in the hepatic blood of fungal challenged mice . In a second set of experiments , mice were fungal challenged 4 days after injection of B16M cells . In these mice , C. albicans also potentiated the growth of established micro-metastases . Significantly , the fungal challenge had pro-metastatic effects without the C. albicans being able to reach the liver , suggesting that soluble factors can promote metastasis in remote sites . Mouse treatment with antifungal ketoconazol abrogated hepatic TNF-alpha stimulation by C. albicans and prevented the enhancement of hepatic metastasis in fungal challenged-mice . Therefore , the pro-inflammatory microenvironment generated by the host's systemic response to C. albicans stimulates circulating cancer cells to metastasize in the liver .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20035374"}
{"sentence": "Protein tyrosine kinase 6 ( PTK6 ) is a non-receptor tyrosine kinase expressed in epithelial cancers . Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice by preventing signal transducer and activator of transcription 3 activation . Relocalization of PTK6 in prostate cancers contributes to increased growth . Although not expressed in normal breast or ovary , PTK6 promotes anchorage-independent survival of breast and ovarian tumor cells . We identified several potential PTK6 substrates in the human SW620 colon cancer cell line using mass spectrometry , including FAK ( focal adhesion kinase ) . We show that FAK is a direct substrate of PTK6 in vitro and in vivo . Expression of membrane-targeted active PTK6 ( Palm-PTK6-YF ) induces constitutive activation of FAK and cell morphology changes , which are independent of SRC family kinases in Src-/- , Yes-/- , Fyn-/- ( SYF ) mouse embryonic fibroblasts ( MEFs ) . Palm-PTK6-YF expressing SYF cells are transformed and overcome contact inhibition , form colonies in transformation assays , proliferate in suspension and form tumors in a xenograft model . Expression of FAK and Palm-PTK6-YF in Fak-/- MEFs synergistically activates AKT and protects cells against anoikis . However , expression of Palm-PTK6-YF in Akt1/2-/- MEFs fails to protect cells from anoikis , indicating AKT is critical in PTK6 and FAK-mediated survival signaling . In a conditional Pten knockout murine prostate cancer model , we identify prostate epithelial cells with enhanced activation of endogenous PTK6 and FAK at the plasma membrane . Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis , which can be rescued by exogenous expression of FAK . Our data reveal important roles for a PTK6-FAK-AKT signaling axis in promoting anchorage-independent cell survival .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23027128"}
{"sentence": "BACKGROUND Although chemotherapy offers promise of increased survival for children with medulloblastoma and glioblastoma multiforme , drug resistance occurs frequently , resulting in tumor progression and death . Resistance to nitrosoureas and methylating agents , which damage DNA , can be mediated by a DNA repair protein , O6-alkylguanine-DNA alkyltransferase ( AGAT ) . Depletion of this protein with alkylguanines or methylating agents , however , restores tumor cell sensitivity to the cytotoxicity of chloroethylnitrosoureas ( e.g. , carmustine [ BCNU] ) . PURPOSE This study was designed to determine whether resistance to the activity of nitrosourea ( the drug BCNU ) in BCNU-resistant human medulloblastoma ( D341 Med ) and human glioblastoma multiforme ( D-456 MG ) can be reversed by the methylating agent streptozocin and the O6-substituted guanines O6-methylguanine and O6-benzylguanine . METHODS Xenografts were grown subcutaneously in athymic BALB/c mice . BCNU was administered as a single intraperitoneal injection at doses of 100 mg/m2 , 75 mg/m2 , or 38 mg/m2--i.e. , 1.0 , 0.75 , or 0.38 , respectively , of the dose lethal to 10% of treated animals ( LD10 ) . Mice were treated intraperitoneally with a single dose of O6-benzylguanine or O6-methylguanine ( 240 mg/m2 ) or with streptozocin ( 600 mg/m2 ) daily for 4 days . Response was assessed by tumor growth delay and tumor regression . AGAT activity in the xenografts was measured at 1 and 6 hours after pretreatment , at the time tumors were excised . RESULTS Pretreatment with O6-benzylguanine , O6-methylguanine , or streptozocin reduced AGAT activity to 4% , 25% , and 95% of control values , respectively , in D341 Med and 0% , 0% , and 25% of control values , respectively , in D-456 MG 1 hour after injection . After 6 hours , levels changed to 7% , 61% , and 116% of control values in D341 Med and 0% , 79% , and 21% of control values in D-456 MG , respectively . Both D341 Med and D-456 MG xenografts were completely resistant to BCNU at its LD10 . Pretreatment with O6-benzylguanine increased BCNU sensitivity in both types of xenograft . In contrast , treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone , reflecting the more efficient depletion of AGAT by O6-benzylguanine . Following therapy with BCNU plus O6-benzylguanine at 0.38 LD10 , tumor regressions were seen in eight of 10 D341 Med and in all 10 D-456 MG xenografts . CONCLUSION We recommend comprehensive clinical toxicologic evaluation of combination therapy with O6-benzylguanine plus BCNU , which would allow subsequent design of phase I clinical trials .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1334154"}
{"sentence": "Glycolysis is known to be the primary energy source in most cancer cells . We investigated here the effect of clotrimazole ( 1-(alpha-2-chlorotrityl)imidazole ) , the antifungal azole derivative , which was recently recognized as calmodulin antagonist , on the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate , the two stimulatory signal molecules of glycolysis , and on ATP content and cell viability in LL/2 Lewis lung carcinoma cells and CT-26 colon adenocarcinoma cells . We found that clotrimazole induced a significant , dose- and time-dependent reduction in the levels of glucose 1,6-bisphosphate , fructose 1,6-bisphosphate , ATP , and cell viability . These findings suggest that clotrimazole causes a reduction in glycolysis and ATP levels , which eventually leads to cell destruction after 3 h of treatment . Since cell proliferation was also reported to be inhibited by calmodulin antagonists , this substance is most promising agent in treatment of cancer by inhibiting both cell proliferation and the glycolytic supply of ATP required for cancer cell growth .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "12242083"}
{"sentence": "RKIP-1 is a metastasis suppressor that is frequently downregulated in aggressive cancers . However , the consequences of RKIP loss in primary or immortalized cells have not yet been explored . Using HEK-293 RKIP depleted ( termed HEK-499 ) and Flp-In T-Rex-293 RKIP inducible cell lines combined with whole transcriptome analysis , we show that RKIP-1 silencing accelerates DNA synthesis and G1/S transition entry by inducing the expression of cdc6 , MCM 2 , 4 , 6 , 7 , cdc45L , cyclin D2 , cyclin E2 , cyclin D1 , SKP2 and the downregulation of p21(cip1) . Moreover , RKIP depletion accelerates the time from nuclear envelop breakdown ( NEB ) to anaphase markedly , while the upregulation of RKIP shortened the NEB to anaphase time . We show that RKIP depletion induces the expression of NEK6 , a molecule known to enhance G2/M transition , and down-regulates G2/M checkpoint molecules like Aurora B , cyclin G1 and sertuin that slow the G2/M transition time . These subtle changes in the kinetics of the cell cycle culminate in a higher proliferation rate of HEK-499 compared to control cells . Finally , we show that RKIP depletion enhances cellular motility by inducing the expression/stabilization of \u03b2-catenin , vimentin , MET and PAK1 . Overall , our data suggest that modulation of the cell cycle checkpoints and motility by RKIP may be fundamental to its metastasis suppressive function in cancer and that RKIP role in a cell is more intricate and diverse than previously thought .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21180766"}
{"sentence": "Missense substitutions of uncertain clinical significance in the BRCA1 gene are a vexing problem in genetic counseling for women who have a family history of breast cancer . In this study , we evaluated the functions of 29 missense substitutions of BRCA1 in two DNA repair pathways . Repair of double-strand breaks by homology-directed recombination ( HDR ) had been previously analyzed for 16 of these BRCA1 variants , and 13 more variants were analyzed in this study . All 29 variants were also analyzed for function in double-strand break repair by the single-strand annealing ( SSA ) pathway . We found that among the pathogenic mutations in BRCA1 , all were defective for DNA repair by either pathway . The HDR assay was accurate because all pathogenic mutants were defective for HDR , and all nonpathogenic variants were fully functional for HDR . Repair by SSA accurately identified pathogenic mutants , but several nonpathogenic variants were scored as defective or partially defective . These results indicated that specific amino acid residues of the BRCA1 protein have different effects in the two related DNA repair pathways , and these results validate the HDR assay as highly correlative with BRCA1-associated breast cancer .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23161852"}
{"sentence": "Objective To investigate the effect of bufalin on nucleus-mitochondria localization of human telomerase reverse transcriptase(hTERT) by exploring its effect on proliferation and apoptosis in human esophageal squamous carcinoma EC9706 cells . Methods EC9706 cells were treated with bufalin at various concentrations , and then the cell growth inhibition of EC9706 cells was examined by CCK-8 assay and the 50% inhibitory concentration ( IC(50) ) was calculated.Cell cycle analysis was performed by flow cytometry with PI staining , and nucleus morphology of apoptosis were observed by fluorescence microscopy with Hoechst 33342 staining . The apoptotic index was measured by flow cytometry with Annexin V-FITC/PI double staining. hTERT subcellular localization and protein expression were determined by Western blotting and multiple immunofluorescence labling combined with laser confocal scanning microscopy . Results The proliferation of EC 9706 cells was significantly inhibited by bufalin along with the increase of processing time and concentrations ( p<0.01 ) . After the EC9706 cells were exposed to 100 nmol/L bufalin,the number of cells gradually decreased in G(1) phase and increased in S and G(2)/M phases(p<0.05) . The typical nucleus morphological changes of apoptosis were observed and the apoptotic index was increased(p<0.01) . The expression of hTERT decreased in nucleus but increased in mitochondria(p<0.05) . Conclusions Bufalin can inhibit the proliferation of human esophageal squamous carcinoma EC9706 cells in a time- and dose-dependent manner . It can arrest cell cycle in S and G(2)/M phases and induce the apoptosis of EC 9706 cells. hTERT is localized in both nucleus and mitochondria,and can be partially translocated from nucleus to mitochondria during the bufalin-induced apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23286398"}
{"sentence": "Diphenyl ditelluride ( DPDT ) is a potential prototype for the development of novel biologically active molecules . Thus , it is important to evaluate the toxic effects of this compound . In the present study , we evaluated the cytotoxic , genotoxic and mutagenic properties of DPDT in Chinese hamster fibroblast ( V79 ) cells , in strains of the yeast Saccharomyces cerevisiae both proficient and deficient in several DNA repair pathways and in Salmonella typhimurium . DPDT induced frameshift mutations in both S.typhimurium and a haploid wild-type strain of S.cerevisiae . Mutants of S.cerevisiae defective in base excision repair and recombinational repair were more sensitive to DPDT . The results of a lactate dehydrogenase leakage assay suggest that DPDT is cytotoxic to V79 cells . At cytotoxic concentrations , this compound increased thiobarbituric reactive species levels and decreased the glutathione:GSSH ratio in yeast and V79 cells . DPDT generated single- and double-strand DNA breaks in V79 cells , both with and without metabolic activation , as revealed by alkaline and neutral comet assays . Moreover , an induction of oxidative DNA base damage was indicated by a modified comet assay using formamidopyrimidine DNA glycosylase and endonuclease III . Treatment with DPDT also induced micronucleus formation in V79 cells . Pre-incubation with N-acetylcysteine reduced DPDT's oxidative , genotoxic and mutagenic effects in yeast and V79 cells . Our results suggest that the toxic and mutagenic properties of DPDT may stem from its ability to disturb the redox balance of the cell , which leads to oxidative stress and the induction of DNA damage .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20123696"}
{"sentence": "We examined the influence of the level of dietary protein or vitamin E ( VE ) on oxidative damage to DNA , lipids , and protein in the liver after total body irradiation ( TBI ) with X-rays at 1 or 4 Gy . Levels of 8-hydroxydeoxyguanosine , thiobarbituric acid-reactive substances , and protein carbonyls in the liver did not differ among the groups that did not receive TBI . However , oxidative damage to lipids and protein was increased by TBI only in the 1% protein group . DNA damage , lipid peroxidation , or protein oxidation in the liver was increased by TBI in a dose-dependent manner , and the damage was consistently higher in the 1% than in the 20% protein group . In the 1% protein group , a greater decrease in relative spleen weight by TBI was also observed . Concentrations of antioxidants ( vitamins C and E and glutathione ) in the liver were lower and the concentration of nonheme iron in the liver was higher in the 1% than in the 20% protein group . Mice fed a 1% protein diet became susceptible to TBI-induced oxidative damage , and decreases in antioxidant levels and an increase in iron level were involved in the mechanism of this susceptibility . These results suggest that dietary VE and protein can prevent oxidative damage to DNA , lipid , and protein in mice subjected to TBI . Consumption of a VE-free diet significantly increased 8-hydroxydeoxyguanosine levels in DNA from mice fed the 1% protein diet with TBI , but such changes were not detected in DNA from mice fed the 20% protein diet .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12734064"}
{"sentence": "IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy . Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality . This study tested the ability of IL-15 to block apoptosis , prevent immunosuppression , and improve survival in sepsis . Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia . The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle . In addition to survival studies , splenic cellularity , canonical markers of activation and proliferation , intracellular pro- and antiapoptotic Bcl-2 family protein expression , and markers of immune cell apoptosis were evaluated by flow cytometry . Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo . IL-15 blocked sepsis-induced apoptosis of NK cells , dendritic cells , and CD8 T cells . IL-15 also decreased sepsis-induced gut epithelial apoptosis . IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA . IL-15 increased both circulating IFN-gamma , as well as the percentage of NK cells that produced IFN-gamma . Finally , IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia . In conclusion , IL-15 prevents two immunopathologic hallmarks of sepsis , namely , apoptosis and immunosuppression , and improves survival in two different models of sepsis . IL-15 represents a potentially novel therapy of this highly lethal disorder .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20026737"}
{"sentence": "BACKGROUND/PURPOSE Although angiogenic factors may play an important role in the biology of neuroblastoma , which frequently spreads hematogenously , the mechanism remains unclear . The authors studied tumor progression and invasion from the perspective of angiogenesis and sought to understand the features of this type of tumor . METHODS Thirty-one specimens were resected from patients with neuroblastoma and the expression of vascular endothelial growth factor ( VEGF ) , and its receptor ( Flk-1 ) was examined using immunohistochemistry . The authors looked for correlations among the expressions of VEGF and its receptor with various clinicopathologic factors . In addition , they examined the expression and location of VEGF and Flk-1 mRNA in 10 primary neuroblastoma using in situ hybridization . RESULTS Both in situ hybridization and immunohistochemistry showed the presence of VEGF expression within the neuroblastoma cells . We found VEGF mRNA in neuroblastoma cells but not vascular endothelial cells according to in situ hybridization . Further , Flk-1 mRNA was present both in neuroblastoma cells and vascular endothelial cells . The level of VEGF expression was higher in unfavorable histology , using the criteria of Shimada , than in favorable histology . CONCLUSION The authors suggest that paracrine and autocrine systems are involved in the angiogenesis of neuroblastoma , and the expression of VEGF correlates with the prognosis in neuroblastoma .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12483647"}
{"sentence": "Contact inhibition is the process by which cells switch from a motile growing state to a passive and stabilized state upon touching their neighbors . When two cells touch , an adhesion link is created between them by means of transmembrane E-cadherin proteins . Simultaneously , their actin filaments stop polymerizing in the direction perpendicular to the membrane and reorganize to create an apical belt that colocalizes with the adhesion links . Here , we propose a detailed quantitative model of the role of cytoplasmic beta-catenin and alpha-catenin proteins in this process , treated as a reaction-diffusion system . Upon cell-cell contact the concentration in alpha-catenin dimers increases , inhibiting actin branching and thereby reducing cellular motility and expansion pressure . This model provides a mechanism for contact inhibition that could explain previously unrelated experimental findings on the role played by E-cadherin , beta-catenin , and alpha-catenin in the cellular phenotype and in tumorigenesis . In particular , we address the effect of a knockout of the adenomatous polyposis coli tumor suppressor gene . Potential direct tests of our model are discussed .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20550888"}
{"sentence": "The hypoxic tumor microenvironment is associated with malignant progression and poor treatment response . The glucose transporter Glut-1 is a prognostic factor and putative hypoxia marker . So far , studies of Glut-1 in cancer have utilized conventional immunohistochemical analysis in a series of individual biopsy or surgical specimens . Tissue microarrays , however , provide a rapid , inexpensive means of profiling biomarker expression . To evaluate hypoxia markers , tissue cores must show the architectural features of hypoxia ; i.e. viable tissue surrounding necrotic regions . Glut-1 may be a useful biomarker to validate tissue microarrays for use in studies of hypoxia-regulated genes in cancer . In this study , we carried out immunohistochemical detection of Glut-1 protein in many tumor and normal tissue types in a range of tissue microarrays . Glut-1 was frequently found in peri-necrotic regions , occurring in 9/34 lymphomas , 6/12 melanomas , and 5/16 glioblastomas ; and in 43/54 lung , 22/84 colon , and 23/60 ovarian tumors . Expression was rare in breast ( 6/40 ) and prostate ( 1/57 ) tumors , and in normal tissue , was restricted to spleen , tongue , and CNS endothelium . In conclusion , tissue microarrays enable the observation of Glut-1 expression in peri-necrotic regions , which may be linked to hypoxia , and reflect previous studies showing differential Glut-1 expression across tumor types and non-malignant tissue .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20395120"}
{"sentence": "AIMS AND BACKGROUND To investigate a six-drug combination in patients with nonmetastatic Ewing sarcoma , focusing on chemotherapy-induced necrosis and chemotherapy toxicity in adult and pediatric patients . METHODS AND STUDY DESIGN Alternating cycles of vincristine ( 1.5 mg/m2 ) , doxorubicin ( 80 mg/m2 ) and cyclophosfamide ( 1200 mg/m2 ) ( weeks 0 , 6 , 13 , 22 and 31 ) , ifosfamide ( 9 g/m2 ) , vincristine ( 1.5 mg/m2 ) , and actinomycin D ( 1.5 mg/m2 ) ( weeks 3 , 16 , 25 and 34 ) , and ifosfamide ( 9 g/m2 ) and etoposide ( 450 mg/m2 ) ( weeks 9 , 19 , 28 and 37 ) were administered . Primary chemotherapy-induced necrosis was graded : G3 ( complete necrosis ) , G2 ( microfoci of tumor cells ) and G1 ( macrofoci of tumor cells ) . RESULTS From 1996 to 1999 , 50 patients with Ewing sarcoma were enrolled . The median age was 23.5 years ( range , 4-56 ) . Chemotherapy-induced necrosis ( in 28 patients ) was G3 in 36% , G2 in 21% and G1 in 43% . At a median follow-up of 110 months ( range , 36-129 ) , 5-year overall survival and event-free survival were 72% and 66% , respectively . According to histologic response , 5-year event-free survival was 90% in G3 , 83% in G2 , and 42% in G1 ( P = 0.02 ) . In adult and pediatric ( <18 years ) patients , the incidence of G4 leukopenia was 62% and 74% , respectively , with febrile neutropenia in 13% and 21% , respectively . G4 thrombocytopenia occurred in 3% of cycles in adults and in 7% in pediatric patients . Platelet and red blood cell transfusions were required respectively in 1% and 11% of cycles in adults and in 6% and 24% of cycles in pediatric patients . CONCLUSIONS The six-drug combination can be administered safely in adult and pediatric populations . About 40% of patients have a poor chemotherapy-induced tumor necrosis , leading to poor probability of survival . New strategies are recommended to improve survival of poor responders to the six-drug combination .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20572576"}
{"sentence": "Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma . Cancer and anticancer therapy are associated with oxidative stress , and disorders of antioxidant balance may be involved in the toxicity associated with anticancer treatment . The aim of the present study was to investigate the changes of serum retinol , alpha-tocopherol and C-reactive protein during the first month of treatment with cetuximab and chemotherapy . Twenty-five consecutive patients with metastatic colorectal carcinoma treated with a combination of chemotherapy and cetuximab were included in the present study . Serum retinol and alpha-tocopherol were determined by high-performance liquid chromatography and serum C-reactive protein was determined using commercial kits . Significant correlation was observed between baseline concentrations of retinol and C-reactive protein ( r(s)=-0.54 , p<0.01 ) . Median survival of patients who had baseline serum retinol below 1.25 \u00b5mol/L was 10 mo compared to 18 mo for patients who had serum retinol equal or above 1.25 \u00b5mol/L ( p<0.05 ) ; median survival of patients who had serum C-reactive protein below 24 mg/L was significantly longer compared to patients with C-reactive protein levels equal or above 24 mg/L ( 18 vs. 7 mo , p<0.05 ) , but no difference in survival was observed based on alpha-tocopherol levels . Twenty-two patients had evaluation of retinol , alpha-tocopherol and C-reactive protein at least once during the follow up . Serum concentration of alpha-tocopherol decreased significantly during the therapy , but retinol and C-reactive protein concentrations remained unchanged . In conclusion , a significant correlation was observed between serum retinol and C-reactive protein . Serum alpha-tocopherol decreased significantly during the first month of combination therapy with cetuximab . Low retinol and high C-reactive protein concentrations were predictive of poor prognosis in this patient population .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20924143"}
{"sentence": "Using monolayer cultures of clonally isolated C3 and T5 rat prostate cancer cells , we determined that acidic ( aFGF ) and basic ( bFGF ) fibroblast growth factors profoundly enhanced T5 cell thymidine incorporation with half-maximum stimulation at 0.53 and 0.35 ng/ml , respectively . In contrast , aFGF or bFGF enhancement of C3 cell thymidine incorporation was about 5% of that of T5 cells , and effects were principally mitogen concentration independent . Saturation analyses and cross-linking studies established that both C3 and T5 cells contained high-affinity FGF receptors of 120 and 145 kilodaltons and that receptor content and Kd of C3 and T5 cells were comparable. aFGF or bFGF stimulation of T5 cell thymidine incorporation profoundly decreased as cell plating density was reduced from 1.5 x 10(5) to 1.0 x 10(4) cells/well . The modest response of C3 cells to either aFGF or bFGF also decreased as cell plating density was reduced . Because heparin preserves FGF biological activity and enhances bFGF binding to high-affinity FGF receptors , we examined the effect of heparin on FGF stimulation of C3 cell thymidine incorporation . We found that changes in cell plating density and/or medium heparin concentration had variable , inconsistent effects . These were C3 cell plating density associated and included inhibition or modest enhancement of FGF effects . Binding analyses established that high-affinity bFGF binding of C3 and T5 cells immediately prior to assessing FGF-stimulated thymidine incorporation was comparable and independent of cell plating density , implying that C3 cell FGF insensitivity was not attributable to differences in C3 and T5 cell FGF receptor content at the time of mitogen stimulation.(ABSTRACT TRUNCATED AT 250 WORDS )", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1445801"}
{"sentence": "Intra-arterial infusion with cisplatin ( CDDP ) and bleomycin ( BLM ) was carried out in 21 patients with locally recurrent uterine cervical cancer who were previously treated with irradiation alone . Patients were treated with a bolus infusion into both internal iliac arteries of 50 mg/m2 of CDDP and 30 mg/m2 of BLM . Two to four courses of the infusion therapy were given to each patient , and the response rate , the tumor and serum drug concentrations , and the cell kinetics in tumor tissue were evaluated . The response rate ( CR+PR ) was 71.4% according to the WHO criteria . There was no difference , in the tumor tissue concentrations of CDDP and BLM between responders and nonresponders . Although the DNA ploidy of tumor cells was not significantly different between the two groups before treatment , both the labeling index with BrdU and the proliferation index with flow cytometry significantly increased 24 hours after treatment in responding tumors but not in nonresponding tumors . These results show that intra-arterial infusion with CDDP and BLM improves the prognosis of recurrent cervical cancer and that labeling and proliferation indices may be useful for determining the response of cervical cancer to intra-arterial chemotherapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1280402"}
{"sentence": "cAMP-signaling plays an essential role in modulating the proliferation of different cell types , including cancer cells . Until now , the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases . In the present study , a significant overexpression of soluble adenylyl cyclase ( sAC ) , an alternative source of cAMP , was found in human prostate carcinoma and , therefore , the contribution of this cyclase was investigated in the prostate carcinoma cell lines LNCaP and PC3 . Suppression of sAC activity by treatment with the sAC-specific inhibitor KH7 or by sAC-specific knockdown mediated by siRNA or shRNA transfection prevented the proliferation of prostate carcinoma cells , led to lactate dehydrogenase release , and induced apoptosis . Cell cycle analysis revealed a significant rise in the G2-phase population 12 hours after sAC inhibition , which was accompanied by the down-regulation of cyclin B1 and CDK1. sAC-dependent regulation of proliferation involves the EPAC/Rap-1/B-Raf signaling pathway . In contrast , protein kinase A does not play a role . In conclusion , the present study suggests a novel sAC-dependent signaling pathway that controls the proliferation of prostate carcinoma cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23255611"}
{"sentence": "Curcumin ( diferuloylmethane ) is a polyphenol derived from the plant turmeric ( Curcuma longa ) , which is commonly used as a spice . Although anti-carcinogenic , anti-oxidant , anti-inflammation , and anti-angiogenic properties have been reported , the effect of curcumin on breast cancer metastasis is unknown . Matrix metalloproteinase-9 ( MMP-9 ) is a major component in cancer cell invasion . In this study , we investigated the inhibitory effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate ( TPA)-induced MMP-9 expression and cell invasion and the molecular mechanisms involved in MCF-7 cells . Our results showed that curcumin inhibits TPA-induced MMP-9 expression and cell invasion through suppressing NF-\u03baB and AP-1 activation . Also , curcumin strongly repressed the TPA-induced phosphorylation of p38 and JNK and inhibited TPA-induced translocation of PKC\u03b1 from the cytosol to the membrane , but did not affect the translocation of PKC\u03b4 . These results indicate that curcumin-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the PKC\u03b1 , MAPK and NF-\u03baB/AP-1 pathway in MCF-7 cells . Curcumin may have potential value in restricting breast cancer metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22921746"}
{"sentence": "Hypoxia-inducible factor-1 ( HIF-1 ) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis ( i.e. , the Warburg effect ) , which is critical to supplying cancer cells with the biomass needed for proliferation . Previous studies have shown that cetuximab , an EGF receptor-blocking monoclonal antibody , downregulates the alpha subunit of HIF-1 ( HIF-1\\u03b1 ) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1\\u03b1 is required for cetuximab-induced antiproliferative effects . However , the mechanism underlying these actions has yet to be identified . In this study , we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration , the two major energy-producing pathways , in live cells . We found that cetuximab downregulated lactate dehydrogenase A ( LDH-A ) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma ( HNSCC ) cells in an HIF-1\\u03b1 downregulation-dependent manner . HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1\\u03b1 and were highly glycolytic . Overexpression of a HIF-1\\u03b1 mutant ( HIF-1\\u03b1/\\u0394ODD ) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest , which could be overcome by knockdown of LDH-A expression . Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab . Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells . These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 1, 0], "id": "23920275"}
{"sentence": "Application of adenovirus vectors ( Adv ) in metastatic cancer treatment is limited . We previously demonstrated that covalent conjugation of polyethleneglycol ( PEG ) to Adv enhances therapeutic effects and decreases toxic side-effects after systemic administration , but the level of immune response to PEGylated Adv ( PEG-Ad ) was not examined . Here , we examined the effect of PEGylation of Adv on the production of anti-Adv antibodies and antitumor response . We constructed a set of PEG-Ad using 5-kDa PEG , with modification rates of 30% , 45% and 90% . After systemic administration of Advs to rats , we examined the level of anti-Adv immunoglobulin ( Ig)G and IgM in serum . The levels of anti-Adv IgG and anti-Adv IgM in rats treated with unmodified Adv were higher than those in control group . Rats treated with PEG-Ad that had a 90% modification rate showed lower level of anti-Adv IgG and anti-Adv IgM than those treated with unmodified Adv , whereas rats treated with PEG-Ad that had a 30% or 45% modification rate showed a similar level of anti-Adv IgG and IgM to those treated with unmodified Adv. Systemic administration of PEG-Ad that had a 90% modification rate , and expressed tumor necrosis factor-alpha , significantly reduced the number of metastatic colonies in the lung compared to unmodified Adv , with negligible side effects . These results suggest that systemic administration of PEG-Ad with an appropriate PEG modification rate has the potential to reduce the production of antibodies against Adv and increase the therapeutic response against metastatic cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20823571"}
{"sentence": "BACKGROUND The c-Met receptor tyrosine kinase is aberrantly activated in many solid tumors . In a prior study we showed that prostate cancer PC-3 cells exhibit constitutively activated c-Met without exogenous hepatocyte growth factor ( HGF ) ; however whether this characteristic is due to an endogenous HGF/c-Met autocrine loop remains controversial . In the current study we examined the response of PC-3 cells to an anti-HGF neutralizing antibody or a small molecule Met kinase inhibitor ( BMS-777607 ) . METHODS Cell scattering was tested by monitoring cell morphology after HGF stimulation . Cell migration was examined by both \" wound-healing \" and transwell assasy and invasion was detected by Matrigel-coated transwell assay . Proliferation , survival and anoikis were determined by MTT , colony formation and trypan blue exclusion assay , respectively . Gene and protein expression were assessed by real-time PCR and Western blot , respectively . RESULTS Although HGF mRNA could be detected in PC-3 cells , the molecular weight of secreted \" HGF \" protein was inconsistent with the functional recombinant HGF . Furthermore , conditioned medium from PC-3 cell cultures was ineffective at triggering either motogenic behavior or c-Met signaling in DU145 , another prostate cancer cell line expressing c-Met but lacking basal c-Met activation . PC-3 cells also were not responsive to the anti-HGF neutralizing antibody in experiments assessing proliferation , migration , or c-Met signaling . BMS-777607 treatment with micromolar doses nonetheless led to significant inhibition of multiple PC-3 cell functions including proliferation , clonogenicity , migration and invasion . At the molecular level , BMS-777607 suppressed autophosphorylated c-Met and downstream c-Src and Akt pathways . CONCLUSIONS These results suggest that the constitutive c-Met activation in PC-3 is independent of autocrine stimulation . Because PC-3 cells were responsive to BMS-777607 but not the anti-HGF antibody , the findings also indicate that under circumstances where c-Met is constitutively hyperactive in the absence of functional HGF , targeting the c-Met receptor remains a viable therapeutic option to impede cancer progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22639908"}
{"sentence": "High concentrations of lactic acid ( LA ) are found under various pathophysiological conditions and are accompanied by an acidification of the environment . To study the impact of LA on TNF secretion , human LPS-stimulated monocytes were cultured with or without LA or the corresponding pH control . TNF secretion was significantly suppressed by low concentrations of LA ( < or = 10 mM ) , whereas only strong acidification had a similar effect . This result was confirmed in a coculture model of human monocytes with multicellular tumor spheroids . Blocking synthesis of tumor-derived lactate by oxamic acid , an inhibitor of lactate dehydrogenase , reversed the suppression of TNF secretion in this coculture model . We then investigated possible mechanisms underlying the suppression . Uptake of [ 3-(13)C]lactate by monocytes was shown by hyphenated mass spectrometry . As lactate might interfere with glycolysis , the glycolytic flux of monocytes was determined . We added [ 1,2-(13)C(2)]glucose to the culture medium and measured glucose uptake and conversion into [ 2,3-(13)C(2)]lactate . Activation of monocytes increased the glycolytic flux and the secretion of lactate , whereas oxygen consumption was decreased . Addition of unlabeled LA resulted in a highly significant decrease in [ 2,3-(13)C(2)]lactate secretion , whereas a mere corresponding decrease in pH exerted a less pronounced effect . Both treatments increased intracellular [ 2,3-(13)C(2)]lactate levels . Blocking of glycolysis by 2-deoxyglucose strongly inhibited TNF secretion , whereas suppression of oxidative phosphorylation by rotenone had little effect . These results support the hypothesis that TNF secretion by human monocytes depends on glycolysis and suggest that LA and acidification may be involved in the suppression of TNF secretion in the tumor environment .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20026743"}
{"sentence": "We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy . Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment . Platinum-DNA adduct levels were measured by atomic absorbance spectrometry . DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA . In a \" blinded \" study of 21 patients receiving combination cisplatin/carboplatin drug therapy , there was a direct relationship between DNA damage in leukocytes and disease response ( summary two-sided p = 0.00011 ) . The cohort of patients had 15 different tumor types , suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor . In leukocytes in vivo , persistence and accumulation were prominent features of the cisplatin-DNA adduct profile . Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro ( three , T-cells ; three , B-cells ; one , monocytic ; one , promyelocytic ) , using a host cell reactivation assay with cisplatin-damaged pRSVcat . In the three T cell lines studied , host cell reactivation efficiency was directly related to the cells ' abilities to repair cisplatin-damaged cellular DNA ( correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS )", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1486863"}
{"sentence": "Background . An important goal of personalized cancer therapy is to tailor specific therapies to the mutational profile of individual patients . However , whole genome sequencing studies have shown that the mutational profiles of cancers evolve over time and often differ between primary and metastatic sites . Activating point mutations in the PIK3CA gene are common in primary breast cancer tumors , but their presence in breast cancer bone metastases has not been assessed previously . Results . Fourteen patients with breast cancer bone metastases were biopsied by three methods : CT-guided bone biopsies ; bone marrow trephine biopsies ; and bone marrow aspiration . Samples that were positive for cancer cells were obtained from six patients . Three of these patients had detectable PIK3CA mutations in bone marrow cancer cells . Primary tumor samples were available for four of the six patients assessed for PIK3CA status in their bone metastases . For each of these , the PIK3CA mutation status was the same in the primary and metastatic sites . Conclusions . PIK3CA mutations occur frequently in breast cancer bone metastases . The PIK3CA mutation status in bone metastases samples appears to reflect the PIK3CA mutation status in the primary tumour . Breast cancer patients with bone metastases may be candidates for treatment with selective PIK3CA inhibitors .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22970388"}
{"sentence": "The relevance of many BRCA2 variants of uncertain significance ( VUS ) to breast cancer has not been determined due to limited genetic information from families carrying these alterations . Here , we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain ( DBD ) missense mutations using a multifactorial likelihood model of cancer causality . Next , we evaluated the use of a homology-directed DNA break repair ( HDR ) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD . Compared with the known status of these variants based on the multifactorial likelihood model , the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [ 95% confidence interval ( CI ) : 75.3%-100% ] and specificity was estimated at 100% ( 95% CI : 81.5%-100% ) . A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results . When applied to 33 additional VUS , the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity . Thus , in the absence of genetic evidence , a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD , suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23108138"}
{"sentence": "OBJECTIVE To construct the eukaryotic expression vector for Max interacting protein 1 ( Mxi1 ) . METHODS The full length cDNA of Mxi1 gene obtained from fetal lymphocyte and KG1 cells were inserted into plasmid pDs-red2-N1 respectively to generate pDs-red2-N1/Mri1 ( wild/mutation type ) . Then the recombinant vector was transfected into Cos-7 cells via liposome. 48 hours post transfection , mRNA of Mri1 gene was detected by RT-PCR and Mxi1 protein expression was detected by flow cytometry and fluorescence microscope in the Cos-7 cells . RESULTS The eukaryotic expression vector of Mxi1 was constructed and transfected into eukaryotic cells successfully . The expression of red fluorescence protein in the transfected Cos-7 cells was observed under fluorescence microscope which implied the expression of Mxi1 . The transfect efficiency of both wild and mutation type were in a high level in 3 days after transfected , which lasted to 6 d . RT-PCR amplified the total RNA extracted from the transfected Cos-7 cells could find increased mRNA level of Mxi1 gene . CONCLUSION We successfully constructed the eukaryote expression vector for Mri1 gene ; Cos-7 cells transfected with the vector via liposome could express Mxi1 protein . These could be useful for the further study of the Myc gene modulation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22997883"}
{"sentence": "Mitochondrial uncoupling protein 2 ( UCP2 ) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix , thus reducing electron leakage from respiratory chain and mitochondrial superoxide production . Here , we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species ( ROS ) production inhibiting pancreatic adenocarcinoma cell growth . We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase ( GAPDH ) , formation of autophagosomes , and the expression of the autophagy marker LC3-II . Consistently , UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2 . Furthermore , we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death , as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine ( CQ ) or 3-methyladenine ( 3-MA ) , or the radical scavenger NAC . Intriguingly , the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine , the standard chemotherapeutic drug for pancreatic adenocarcinoma , supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy . Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23124112"}
{"sentence": "Bone marrow transplantation ( BMT ) , used to treat severe hematological malignancies , often leads to potentially fatal acute graft-versus-host disease ( GVHD ) , despite attempts for better matching and/or use of immune suppressive agents . We reported that embryo-derived PreImplantation-Factor plays a determining role in developing maternal/host tolerance towards the semi/allogenic embryo and regulating systemic immune response . Synthetic PIF ( PIF ) treatment is effective preventing immune attack in non-pregnant models of autoimmunity . Herein , we test PIF ability to prevent acute GVHD development in semi or totally allogenic murine models . We examine PIF's regulatory effect in vivo and in vitro , to control deleterious GVHD while maintaining its ability to preserve beneficial graft vs. leukemia ( GVL effect ) . Bone marrow and spleen cells from C57BL/6 donors were transplanted to semi-allogenic ( C57BL/6\ufffdBALB/c ) F1 or allogenic ( BALB/c ) recipients , and then treated with PIF1mg/kg/day/2weeks . Short-term PIF administration reduced acute GVHD in both models and increased survival for up to four months after semi-(or totally ) allogenic BMT . The obtained effect was coupled with lessened skin ( semi-allogenic ) and decreased liver inflammation ( both models ) as well as reduced colon ulceration ( allogenic ) . Both GVHD associated cytokines and chemokines gene expression were decreased in the liver . PIF further lowered circulating interleukin-17 , but not interferon-\u03b3 levels . PIF treatment was demonstrated in vivo and in vitro to lead to decreased iNOS expression and in LPS-activated macrophages to lower nitric oxide secretion . Significantly , PIF did not impair the beneficial GVL effect in the B-cell leukemia model . PIF primarily acts by inducing regulatory phenotype on monocytes/APC , which controls T-cell proliferation . Overall our data demonstrates that PIF protects against semi/allogenic GVHD long-term by reducing both target organ and systemic inflammation and by lowering oxidative stress , all while preserving the beneficial GVL effect .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23266739"}
{"sentence": "Hesperetin , a flavonoid from citrus fruits , has several bioactivities such as anti-inflammatory , antihypertensive , antiatherogenic effects . However , studies elucidating the role and the mechanism(s) of action of hesperetin in cervical cancer are sparse . In this study , we investigated the mechanism of the antiproliferative and apoptotic actions exerted by hesperetin on human cervical cancer SiHa cells . The viability of SiHa cells was evaluated using the MTT assay , apoptosis by acridine orange/ethidium bromide , propidium iodide , TUNEL assay , and Annexin V-Cy3 , cell cycle distribution and mitochondrial transmembrane potential using flow cytometry , and apoptotic marker genes using quantitative real-time PCR . The treatment of SiHa cells with hesperetin ( IC(50,) 650\u03bcm ) showed a marked concentration- and time-dependent inhibition of proliferation and induced the G2/M phase in a dose-dependent manner after 24h . There was an attenuation of mitochondrial membrane potential with increased expression of caspase-3 , caspase-8 , caspase-9 , p53 , Bax , and Fas death receptor and its adaptor protein Fas-associated death domain-containing protein ( FADD ) , indicating the participation of both death receptor- and mitochondria-related mechanisms . Furthermore , hesperetin-induced apoptosis was confirmed by TUNEL and Annexin V-Cy3 . This study shows that hesperetin exhibits a potential anticancer activity against human cervical cancer cell lines in vitro through the reduction in cell viability and the induction of apoptosis . Altogether , these data sustain our contention that hesperetin has anticancer properties and merits further investigation as a potential therapeutic agent .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22913657"}
{"sentence": "Hormone-dependent estrogen receptor positive ( ER+ ) breast cancers generally respond well to anti-estrogen therapy . Unfortunately , hormone-independent estrogen receptor negative ( ER- ) breast cancers are aggressive , respond poorly to current treatments and have a poor prognosis . New approaches and targets are needed for the prevention and treatment of ER- breast cancer . The NF-\u03baB signaling pathway is strongly implicated in ER- tumor genesis , constituting a possible target for treatment . Hydrogen sulfide-releasing aspirin ( HS-ASA ) , a novel and safer derivative of aspirin , has shown promise as an anti-cancer agent . We examined the growth inhibitory effect of HS-ASA via alterations in cell proliferation , cell cycle phase transitions , and apoptosis , using MDA-MB-231 cells as a model of triple negative breast cancer . Tumor xenografts in mice , representing human ER- breast cancer , were evaluated for reduction in tumor size , followed by immunohistochemical analysis for proliferation , apoptosis and expression of NF-\u03baB . HS-ASA suppressed the growth of MDA-MB-231 cells by induction of G(0)/G(1) arrest and apoptosis , down-regulation of NF-\u03baB , reduction of thioredoxin reductase activity , and increased levels reactive oxygen species . Tumor xenografts in mice , were significantly reduced in volume and mass by HS-ASA treatment . The decrease in tumor mass was associated with inhibition of cell proliferation , induction of apoptosis and decrease in NF-\u03baB levels in vivo . HS-ASA has anti-cancer potential against ER- breast cancer and merits further study .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 1], "id": "22209867"}
{"sentence": "Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability . Here we describe a novel , oral DNA vaccine that targets stable , proliferating endothelial cells in the tumor vasculature rather than tumor cells . Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 ( FLK-1 ) of proliferating endothelial cells in the tumor vasculature . This vaccine effectively protected mice from lethal challenges with melanoma , colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting . CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen , resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases . Angiogenesis in the tumor vasculature was suppressed without impairment of fertility , neuromuscular performance or hematopoiesis , albeit with a slight delay in wound healing . Our strategy circumvents problems in targeting of genetically unstable tumor cells . This approach may provide a new strategy for the rational design of cancer therapies .", "label": [1, 1, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12415261"}
{"sentence": "G-quadruplex structures are an attractive target for the development of anticancer drugs , as their formation in human telomere induces a DNA damage response followed by apoptosis in cancer cells . However , the development of new anticancer drugs by means of structural-based drug design is hampered by a lack of accurate information on the exact G-quadruplex conformation adopted by the human telomeric DNA under physiological conditions . Several groups reported that , in a molecular crowded , cell-like environment , simulated by polyethylene glycol ( PEG ) , the human telomeric DNA adopts the parallel G-quadruplex conformation . These studies have suggested that 40% ( w/v ) PEG concentration induces complete structural conversion from the other known human telomeric G-quadruplex conformations to the parallel G-quadruplex , thus simplifying the high structural polymorphism existing in the absence of PEG . In this study , we demonstrate that the structural conversion to the parallel G-quadruplex is not a complete reaction at physiological temperature . We report a complete kinetic and thermodynamic characterization of the conformational transitions involving the ( TTAGGG)(4)TT and ( TTAGGG)(8)TT human telomeric DNA sequences in K(+) solution containing PEG . Our data show that the hybrid-type and parallel conformations coexist at equilibrium in the presence of PEG at physiological temperature and the degree of the quadruplex interconversion depends on the PEG molecular weight . Further , we find that telomeric DNA folds in the parallel quadruplex in the seconds time scale , a much larger time scale than the one reported for the hybrid quadruplex folding ( The whole of our data allow us to predict the relative amount of each G-quadruplex conformation as a function of temperature and time . The effect of other crowding agents like Ficoll 400 and glycerol on the quadruplex interconversion has been also explored .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22268560"}
{"sentence": "We evaluated the clinical significance of indoleamine 2 , 3-dioxygenase ( IDO ) expression in breast cancer patients with bone metastasis . IDO activity can be measured by the tryptophan(Trp)/kynurenine(Kyn) ratio . Trp and Kyn levels were measured by high-performance liquid chromatography ( HPLC ) . The serum IDO levels of postoperative breast cancer patients with a high number of bone metastases were lower than those of patients with a single metastasis lesion . In addition , IDO activity increased in the cases in which the number of metastatic lesions to the bone increased . These results suggest that the expression of IDO in breast cancer patients with bone metastasis may play a critical role in immunosuppression in these patients .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23267883"}
{"sentence": "INTRODUCTION Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks ( DSBs ) . DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis . Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact . Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer . METHODS Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide ( EC ) treatment . Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy . RESULTS EC treatment induced nuclear foci of gammaH2AX , conjugated ubiquitin , and Rad51 in a substantial amount of cases . In contrast , BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases . The presence of BRCA1- , gammaH2AX- , or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy . DNA damage response ( DDR ) competence was further evaluated by considering all four repair indicators together . A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not . CONCLUSIONS High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy . Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity , and merits further studying into its usefulness in exclusion of non-responder patients .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20205718"}
{"sentence": "Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer , and to date no therapies exist targeting this oncogene . K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways , and much effort has been focused on developing drugs targeting components of these pathways . To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance , we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors . Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested , demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors . We further examined signaling downstream of K-RAS , and detected a robust reduction of pERK levels upon K-RAS knock down . In contrast , no effect on pAKT levels could be observed due to almost undetectable basal expression levels . To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance , three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition . Tumors of all three models regressed upon MEK inhibition , but showed less pronounced response to PI3K inhibition . The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor . These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22952903"}
{"sentence": "Cell migration plays important roles in natural processes involving embryonic development , inflammation , wound healing , cancer metastasis and angiogenesis . Cell migration on various biomaterials is also believed to improve the rate of wound healing and implant therapies in the tissue-engineering field . This study measured the distance traversed , or mileage , of mouse fibroblasts on a silk fibroin surface . Fibroblasts on the fibroin surface moved with better progress during 24 h than cells on collagen or fibronectin surfaces . Results obtained by quantitative real-time reverse transcription-polymerase chain reaction ( qRT-PCR ) revealed that fibroblasts on the fibroin surface expressed transforming growth factor \\u03b2-induced protein ( TGFBI ) , which is an extracellular matrix ( ECM ) protein , stronger than on other surfaces in the early cell-culture stages . These results demonstrate that the fibroin surface shows higher potential to enhance cell migration and the production of ECM than a collagen or fibronectin surface .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23565596"}
{"sentence": "Mouse models of Alzheimer disease ( AD ) have been generated based on Amyloid-\\u03b2 Precursor Protein ( A\\u03b2PP ) and the Presenilin ( PSEN ) gene mutations associated with familial AD ( FAD ) . Such models have provided valuable insights into AD pathogenesis and represent an important research tool for the discovery of potential treatments . To model amyloid deposition in AD , we generated a new mouse line based on the presence of two copies of the genomic region encoding human wild-type A\\u03b2PP as well as a mutation ( L166P ) in the murine Psen1 . By months of age , these mice have begun to develop cerebral A\\u03b2 pathology with a significant increase in the levels of A\\u03b2PP C-terminal fragments and A\\u03b242 , as well as increase A\\u03b242/A\\u03b240 ratio . Since in the brain and other tissues of these mice , wild-type human A\\u03b2PP mRNA and protein levels are comparable to those of endogenous A\\u03b2PP , this model may allow studies about the role of A\\u03b2PP isoforms in the pathogenesis of AD . This animal model may be suitable to test drugs aimed at inhibiting expression or altering splicing and processing of A\\u03b2PP , without artifacts associated with the presence of mutations in A\\u03b2PP or overexpression due to the use of exogenous promoters . These features of the new model are of critical importance in assessing the success of therapeutic interventions .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22874668"}
{"sentence": "Group VIB Phospholipase A(2) ( iPLA(2)\u03b3 ) is distributed in membranous organelles in which \u03b2-oxidation occurs , that is , mitochondria and peroxisomes , and is expressed by insulin-secreting pancreatic islet \u03b2-cells and INS-1 insulinoma cells , which can be injured by inflammatory cytokines , for example , IL-1\u03b2 and IFN-\u03b3 , and by oxidants , for example , streptozotocin ( STZ ) or t-butyl-hydroperoxide ( TBHP ) , via processes pertinent to mechanisms of \u03b2-cell loss in types 1 and 2 diabetes mellitus . We find that incubating INS-1 cells with IL-1\u03b2 and IFN-\u03b3 , with STZ , or with TBHP causes increased expression of iPLA(2)\u03b3 mRNA and protein . We prepared INS-1 knockdown ( KD ) cell lines with reduced iPLA(2)\u03b3 expression , and they proliferate more slowly than control INS-1 cells and undergo increased membrane peroxidation in response to cytokines or oxidants . Accumulation of oxidized phospholipid molecular species in STZ-treated INS-1 cells was demonstrated by LC/MS/MS scanning , and the levels in iPLA(2)\u03b3-KD cells exceeded those in control cells. iPLA(2)\u03b3-KD INS-1 cells also exhibited higher levels of apoptosis than control cells when incubated with STZ or with IL-1\u03b2 and IFN-\u03b3 . These findings suggest that iPLA(2)\u03b3 promotes \u03b2-cell proliferation and that its expression is increased during inflammation or oxidative stress as a mechanism to mitigate membrane injury that may enhance \u03b2-cell survival .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23213352"}
{"sentence": "Odontogenic tumors originate from the remains of migrating enamel epithelium after the completion of normal tooth genesis . These enamel epithelium remnants exhibit the ability to recapitulate the events that occur during tooth formation . Several lines of evidence suggest that aberrance in the signaling pathways similar to the ones that are used during tooth development , including the WNT pathway , might be the cause of odontogenic tumorigenesis and maintenance . In this study we demonstrated that WNT5A expression was intense in both the epithelial component of ameloblastomas , the most common epithelial odontogenic tumor , and in this tumor's likely precursor cell , the enamel epithelium located at the cervical loop of normal developing human tooth buds . Additionally , when WNT5A was overexpressed in enamel epithelium cells ( LS-8 ) , the clones expressing high levels of WNT5A ( S ) exhibited characteristics of tumorigenic cells , including growth factor independence , loss of anchorage dependence , loss of contact inhibition , and tumor formation in immunocompromised mice . Moreover , overexpression of WNT5A drastically increased LS-8 cell migration and actin reorganization when compared with controls . Suppression of endogenous WNT5A in LS-8 cells ( AS ) greatly impaired their migration and AS cells failed to form significant actin reorganization and membrane protrusion was rarely seen . Taken together , our data indicate that WNT5A signaling is important in modulating tumorigenic behaviors of enamel epithelium cells in ameloblastomas .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20008136"}
{"sentence": "Circulating tumour cells ( CTCs ) shed into blood from primary cancers include putative precursors that initiate distal metastases . Although these cells are extraordinarily rare , they may identify cellular pathways contributing to the blood-borne dissemination of cancer . Here , we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing , identifying Wnt2 as a candidate gene enriched in CTCs . Expression of WNT2 in pancreatic cancer cells suppresses anoikis , enhances anchorage-independent sphere formation , and increases metastatic propensity in vivo . This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 ( also known as TAK1 ) kinase . In humans , formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes , and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases . Thus , molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22763454"}
{"sentence": "To assess the importance of changes in DNA methylation in an X-ray-induced cellular transformation process , methylation patterns of five nuclear protooncogenes in fifteen transformant clones were studied and compared to that of the parental non-transformed cell line m5S/1M . All transformants examined revealed an alteration in DNA methylation in some of the genes , although these changes were variable among them . A comparison of cellular characteristics with corresponding DNA methylation changes in different clones suggested that the loss of contact inhibition and the gain of anchorage independency were associated with increases of methylation in many genes , whereas the acquisition of tumorigenicity was often accompanied by a decrease of methylation in the N-myc and c-myc genes . Resultant data indicate that the alteration of DNA methylation is closely related to transformation process , yet how this involvement occurs is complex and remains unclear .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "1483264"}
{"sentence": "OBJECTIVE To explore the association between DNA damage induced by vinyl chloride monomer ( VCM ) and polymorphisms of DNA repair genes and xenobiotic metabolism genes of VCM . METHODS Comet assay was employed to detect DNA damage . Based on the status of DNA damage , the VCM exposure workers were divided into two groups : DNA damage group ( 75 ) and control group ( 75 ) . Case-control design was used to investigate the association between the genetic polymorphisms and DNA damage induced by VCM . Genotypes of XRCC1 ( Arg194Trp , Arg280His and Arg399Gln ) , XPD ( Ile199Met , Asp312Asn and Lys751Gln ) and CYP2E1 were identified by the PCR-RFLP . PCR assay was used to detect positive and null genotype of GSTT1 and GSTM1 . RESULTS Univariate analysis showed that the CYP2E1 c1c2/c2c2 and XPD751 Lys/Gln and Gln/Gln genotypes were significantly associated with the increased levels of DNA damage , XRCCI 339 Arg/Gln and Gln/Gln genotypes were significantly associated with the decreased levels of DNA damage ( P < 0.01 , P < 0.05 , respectively ) . Logistic regression analysis showed that there was significant association between the genotypes of XRCC1 194 , XRCC1 399 , XPD 751 , CYP2E1 and DNA damages . A prominent risk decreasing of DNA damage was observed for those individuals possessing XRCC1 399Arg/Gln + Gln/Gln genotypes ( OR : 0.35 , 95%CI : 0.12 approximately 1.01 , respectively ) ; The results also showed that there were significant associations between CYP2E1 c1c2/c2c2 and DNA damage both in high and low VCM-exposed groups ( OR : 2.57 , 95%CI : 1.01 approximately 6.59 and OR : 2.57 , 95%CI : 0.99 approximately 6.87 ) . CONCLUSION Cumulative exposure dose and genotypes of XRCC1 194 , XRCC1 399 , XPD 751 and CYP2E1 may modulate the DNA damage induced by VCM exposure .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20426969"}
{"sentence": "Studies were performed to test the hypothesis that urethane-induced murine lung tumors exhibit xenobiotic resistance and alterations in pulmonary cytochrome P-450 enzymes. 1,1-Dichloroethylene , naphthalene , and paraquat were administered to tumor-bearing and control mice to elicit acute lung cytotoxicity , and responses were evaluated in tumors ( papillary and solid ) , uninvolved surrounding tissue , and untreated control lung. 1,1-Dichloroethylene ( 125 mg/kg , i.p. ) and naphthalene ( 225 mg/kg , i.p. ) caused preferential necrosis of Clara cells in control lungs and uninvolved tissue of tumor-bearing lungs . In contrast , papillary and solid tumors were both resistant to 1,1-dichloroethylene-induced cytotoxicity . Paraquat ( 10 , 20 mg/kg , i.v. ) elicited Clara cell damage in control lungs and uninvolved lung tissue of tumor-bearing mice , with minor disruption of the alveolar epithelium . Neither papillary nor solid tumors sustained any apparent cell damage from paraquat . Immunoblots of P-450 enzymes confirmed constitutive expression of CYP2B1 in control lung and uninvolved lung tissue of tumor-bearing mice , but this P-450 enzyme was not detected in either adenomas or carcinomas . Lung CYP1A1 was inducible by beta-naphthoflavone in non-tumor-bearing mice and uninvolved tissue of tumor-bearing mice ; however , inducibility was decreased in adenomas and abolished in carcinomas . These results demonstrate resistance of lung tumor cells to chemically induced cytotoxicity and diminished expression of cytochrome P-450 enzymes in tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1458468"}
{"sentence": "Context:The ubiquitin-proteasome system and macroautophagy are two major pathways for intracellular protein degradation . Emerging lines of evidence have shown that blockade of ubiquitin-proteasome system by proteasome inhibitors activates macroautophagy.Objective:The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors.Design:Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy , as well as LC3-II transition using Western blot . To ascertain the effect of Beclin 1 , cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1 . Cell viability and apoptotic cells were measured using MTT assay and flow cytometry , respectively.Results:Proteasome inhibitors decreased Beclin 1 expression . In addition , treatment with PI3K inhibitors 3-MA or wortmannin , as well as knockdown of Beclin 1 expression , was unable to affect autophagic responses mediated by proteasome inhibitors . Overexpression of Beclin 1 enhanced proteasome inhibitor-mediated cytotoxicity of thyroid cancer cells via suppression of survivin.Conclusions:Proteasome inhibitors cause Beclin 1-independent macroautophagic responses of thyroid cancer cells in a Beclin 1-independent manner . Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23264393"}
{"sentence": "Energy deregulation and abnormalities of tumor cell metabolism are critical issues in understanding cancer . Hereditary leiomyomatosis renal cell carcinoma ( HLRCC ) is an aggressive form of RCC characterized by germline mutation of the Krebs cycle enzyme fumarate hydratase ( FH ) , and one known to be highly metastatic and unusually lethal . There is considerable utility in establishing preclinical cell and xenograft models for study of disorders of energy metabolism , as well as in development of new therapeutic approaches targeting of tricarboxylic acid ( TCA ) cycle enzyme-deficient human cancers . Here we describe a new immortalized cell line , UOK 262 , derived from a patient having aggressive HLRCC-associated recurring kidney cancer . We investigated gene expression , chromosome profiles , efflux bioenergetic analysis , mitochondrial ultrastructure , FH catabolic activity , invasiveness , and optimal glucose requirements for in vitro growth . UOK 262 cells have an isochromosome 1q recurring chromosome abnormality , i(1)(q10) , and exhibit compromised oxidative phosphorylation and in vitro dependence on anaerobic glycolysis consistent with the clinical manifestation of HLRCC . The cells also display glucose-dependent growth , an elevated rate of lactate efflux , and overexpression of the glucose transporter GLUT1 and of lactate dehydrogenase A ( LDHA ) . Mutant FH protein was present primarily in edematous mitochondria , but with catalytic activity nearly undetectable . UOK 262 xenografts retain the characteristics of HLRCC histopathology . Our findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this TCA cycle enzyme-deficient form of kidney cancer . This tumor model is the embodiment of the Warburg effect . UOK 262 provides a unique in vitro and in vivo preclinical model for studying the bioenergetics of the Warburg effect in human cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19963135"}
{"sentence": "We investigated the effects of valproic acid ( VPA ) , a histone deacetylase inhibitor , in combination with hydralazine , a DNA methylation inhibitor , on the expression of cell-surface Fas and MHC-class I-related chain molecules A and B ( MICA and B ) , the ligands of NKG2D which is an activating receptor of NK cells , and on production of their soluble forms in HOS , U-2 OS and SaOS-2 human osteosarcoma cell lines . We also examined the susceptibility of these cells to Fas- and NK cell-mediated cell death . VPA did not increase the expression of Fas on the surface of osteosarcoma cells , while hydralazine did , and the combination of VPA with hydralazine increased the expression of cell-surface Fas . In contrast , the combination of VPA with hydralazine did not increase the production of soluble Fas by osteosarcoma cells . Both VPA and hydralazine increased the expression of cell-surface MICA and B in osteosarcoma cells , and their combination induced a greater increase in their expression . VPA inhibited the production of both soluble MICA and MICB by osteosarcoma cells while hydralazine produced no effect . Both VPA and hydralazine enhanced the susceptibility of osteosarcoma cells to Fas- and NK cell-mediated cell death and the combination of VPA with hydralazine further enhanced the effects . The present results suggest that combined administration of VPA and hydrazine is valuable for enhancing the therapeutic effects of immunotherapy for osteosarcomas .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22576685"}
{"sentence": "In order to prevent photodestruction by high light , photosynthetic organisms have evolved a number of mechanisms , known as non-photochemical quenching ( NPQ ) , that deactivate the excited states of light harvesting pigments . Here we investigate the NPQ mechanism in the cyanobacterium Synechocystis sp . PCC 6803 mutant deficient in both photosystems . Using non-linear laser fluorimetry , we have determined molecular photophysical characteristics of phycocyanin and spectrally distinct forms of allophycocyanin for the cells in non-quenched and quenched states . Our analysis of non-linear fluorescence characteristics revealed that NPQ activation leads to an decrease in the relaxation times of both allophycocyanin fluorescence components , F660 and F680 , and a 5-fold decrease in the effective excitation cross-section of F680 , suggesting an emergence of a pathway of energy dissipation for both types of allophycocyanin . In contrast , NPQ does not affect the rates of singlet-singlet exciton annihilation . This indicates that , upon NPQ activation , the excess excitation energy is transferred from allophycocyanins to quencher molecules ( presumably 3'hydroxyechinenone in the orange carotenoid protein ) , rather than being dissipated due to conformational changes of chromophores within the phycobilisome core . Kinetic measurements of fluorescence quenching in the Synechocystis mutant revealed the presence of several stages in NPQ development , as previously observed in the wild type . However , the lack of photosystems in the mutant enhanced the magnitude of NPQ as compared to the wild type , and allowed us to better characterize this process . Our results suggest a more complex kinetics of the NPQ process , thus clarifying a multistep model for the formation of the quenching center .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22484220"}
{"sentence": "INTRODUCTION Cell-cell interaction is an essential component of atherosclerotic plaque development . Activated monocytes appear to play a central role in the development of atherosclerosis , not only through foam cell formation but also via the production of various growth factors that induce proliferation of different cell types that are involved in the plaque development . Using serum free co-culture method , we determined the effect of monocytes on endothelial cell proliferation . METHODS Endothelial cell proliferation is determined by the amount of [ 3H]thymidine incorporated in to the DNA . Basic fibroblast growth factor ( b-FGF ) , vascular endothelial growth factor ( VEGF ) and interleukin-8 ( IL-8 ) levels in the conditioned medium were determined by ELISA . RESULTS Conditioned medium from unactivated monocytes partially inhibited endothelial cell proliferation , whereas conditioned medium from activated monocytes promoted endothelial cell proliferation . The mitogenic effect of conditioned medium derived from activated monocytes is due to the presence of b-FGF , VEGF and IL-8 . Neutralizing antibodies against b-FGF , VEGF and IL-8 partially reversed the mitogenic effect of conditioned medium derived from activated monocytes . When b-FGF , VEGF and IL-8 were immunoprecipitated from conditioned medium derived from activated monocytes , it is less mitogenic to endothelial cells . CONCLUSION Activated monocytes may play an important role in the development of atherosclerotic plaque by producing endothelial cell growth factors .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12699839"}
{"sentence": "BACKGROUND/AIMS Analysis of cystic fluid may be useful in distinguishing between benign and malignant cysts which has significant impact on their management . The aim of our study was to assess the diagnostic utility of carcinoembryonic antigen ( CEA ) and K-ras gene mutation in pancreatic cysts fluid . METHODS The study included 56 patients with pancreatic cystic fluid collected for analysis . The cysts were classified as benign ( simple cysts , pseudocysts , serous cystadenoma ) - 39 patients or premalignant/malignant ( mucinous cystadenoma , IPMN , cystadenocarcinoma ) - 17 patients . The patients history , CEA fluid concentrations and presence of K-ras mutation were analyzed . RESULTS CEA were higher in patients with malignant cysts ( mean levels 238\u00b112.5ng/ml ; range 32.8-4985ng/ml ) compared to benign lesions ( mean levels 34.5\u00b13.7ng/ml ; range 3.9-693ng/ml ; p<0.001 ) . K-ras mutation correctly classified 11 of 17 patients with premalignant/malignant lesions . It was also detected in 1 patient with final diagnosis of benign cyst ( the sensitivity 64.7% and the specificity 97.4% ; p<0.01 ) . If CEA and molecular analysis were combined in that cysts with either CEA level>45ng/ml or presence of K-ras mutation , than 16 of 17 premalignant/malignant cysts were correctly identified ( 94.1% ) . CONCLUSION Molecular analysis of pancreatic cyst fluid adds diagnostic value to the preoperative diagnosis and should be considered when cyst cytologic examination is negative for malignancy .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23127529"}
{"sentence": "BACKGROUND : The issue remains unresolved as to whether low frequency magnetic fields can affect cell behaviour , with the possibility that they may be in part responsible for the increased incidence of leukaemia in parts of the population exposed to them . METHODS : Combined treatment of HeLa cells with gamma-irradiation ( 1 , 3 and 5 Grays ) and extra low frequency magnetic fields of Hz was carried out under rigorously controlled conditions . RESULTS : Synchronised cells progressing from S-phase arrived at mitosis on average marginally ahead of irradiation controls not exposed to ELF . In no instance out of a total of twenty separate experiments did this \" double-insult \" further delay entry of cells into mitosis , as had been anticipated . CONCLUSION : This apparently \" non-genotoxic \" agent ( ELF ) appears to be capable of affecting cells that would normally arrest for longer in G2 , suggesting a weakening of the stringency of the late cycle ( G2 ) checkpoint .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12069691"}
{"sentence": "The topoisomerase II ( topo II ) DNA incision-and-ligation cycle can be poisoned ( for example following treatment with cancer chemotherapeutics ) to generate cytotoxic DNA double-strand breaks ( DSBs ) with topo II covalently conjugated to DNA . Tyrosyl-DNA phosphodiesterase 2 ( Tdp2 ) protects genomic integrity by reversing 5'-phosphotyrosyl-linked topo II-DNA adducts . Here , X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 \\u03b2-2-helix-\\u03b2 DNA damage-binding ' grasp ' , helical ' cap ' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove . The Tdp2 DNA-binding surface is highly tailored for engagement of 5'-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing . Structural , mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase ( EEP ) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2-mediated resistance to anticancer topoisomerase drugs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23104055"}
{"sentence": "ABSTRACT : INTRODUCTION : Tumor cell migration and invasion are critical initiation steps in the process of breast cancer metastasis , the primary cause of breast cancer morbidity and death . Here we investigated the role of p21Cip1 ( p21 ) , a member of the core cell cycle machinery , in transforming growth factor-beta ( TGF\u03b2)-mediated breast cancer cell migration and invasion . METHODS : A mammary fat pad xenograft mouse model was used to assess the mammary tumor growth and local invasion . The triple negative human breast cancer cell lines MDA-MB231 and its sub-progenies SCP2 and SCP25 , SUM159PT , SUM149PT , SUM229PE and SUM1315MO2 were treated with 5 ng/ml TGF\u03b2 and the protein expression levels were measured by Western blot . Cell migration and invasion were examined using the scratch/wound healing and Transwell assay . TGF\u03b2 transcriptional activity was measured by a TGF\u03b2/Smad reporter construct ( CAGA12-luc ) using luciferase assay. q-PCR was used for assessing TGF\u03b2 downstream target genes . The interactions among p21 , p/CAF and Smad3 were performed by co-immunoprecipitation . In addition , Smad3 on DNA binding ability was measured by DNA immunoprecipitation using biotinylated Smad binding element DNA probes . Finally , the association among active TGF\u03b2/Smad signaling , p21 and p/CAF with lymph node metastasis was examined by immunohistochemistry in tissue microarray containing 50 invasive ductal breast tumors , 25 of which are lymph node positive . RESULTS : We found p21 expression to correlate with poor overall and distant metastasis free survival in breast cancer patients . Furthermore , using xenograft animal models and in vitro studies , we found p21 to be essential for tumor cell invasion . The invasive effects of p21 were found to correlate with Smad3 , and p/CAF interaction downstream of TGF\u03b2. p21 and p/CAF regulates TGF\u03b2-mediated transcription of pro-metastatic genes by controlling Smad3 acetylation , DNA binding and transcriptional activity . In addition , we found that active TGF\u03b2/Smad signaling correlates with high p21 and p/CAF expression levels and lymph node involvement using tissue microarrays from breast cancer patients . CONCLUSIONS : Together these results highlight an important role for p21 and p/CAF in promoting breast cancer cell migration and invasion at the transcriptional level and may open new avenues for breast cancer therapy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22995475"}
{"sentence": "A new triphenylphosphine adduct of cyclopalladated ferrocenylpyridazine containing a chloride anion , 2a , has been synthesized from the reaction of the chloride-bridged palladacyclic dimer 1a with triphenylphosphine . The corresponding adducts 3a,b containing iodide anion have been readily prepared through anion exchange reactions of 2a,b with NaI in acetone . These complexes were characterized by elemental analysis , IR and 1H-NMR . Additionally , their crystal structures have been determined by X-ray diffraction and intermolecular C-H\u00b7\u00b7\u00b7X ( Cl , Br , I ) bonds were found in the crystals . The use of these palladacycles as catalysts for the Suzuki and Sonogashira reactions was examined . The complexes 2a,b exhibited higher catalytic activity than the corresponding 3a,b in the Suzuki reaction . However , the order of activity of adducts with varying halogen anions is 3a > 2a in the Sonogashira reaction .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22572935"}
{"sentence": "BACKGROUND Recent data indicate the Signal Transducer and Activator of Transcription 3 ( STAT3 ) pathway is required for VEGF production and angiogenesis in various types of cancers . STAT3 inhibitors have been shown to reduce tumor microvessel density in tumors but a direct anti-angiogenic activity has not been described . METHODOLOGY/PRINCIPAL FINDINGS We investigated the direct action of a small molecule inhibitor of STAT3 ( LLL12 ) in human umbilical cord vascular endothelial cells ( HUVECs ) in vitro , in a Matrigel model for angiogenesis in vivo , and its antitumor activity in a xenograft model of osteosarcoma . LLL12 ( 100 nM ) significantly inhibited VEGF-stimulated STAT3 phosphorylation in HUVECs , reduced their proliferation/migration and inhibited VEGF-induced tube formation . Morphologic analysis of LLL12 treated HUVECs demonstrated marked changes in actin/tubulin distribution and bundling . In scid mice , LLL12 reduced microvessel invasion into VEGF-infused Matrigel plugs by \u223c90% at a dose of 5 mg/kg daily . Following a period of tumor progression ( 2 weeks ) , LLL12 completely suppressed further growth of established OS-1 osteosarcoma xenografts . Pharmacodynamic studies showed robust phosphorylated STAT3 in control tumors , whereas phospho-STAT3 was not detected in LLL12-treated OS-1 tumors . Treated tumors demonstrated decreased proliferation ( Ki67 staining ) , and decreased microvessel density ( CD34 staining ) , but no significant increase in apoptosis ( TUNEL staining ) , relative to controls . Assay of angiogenic factors , using an antibody array , showed VEGF , MMP-9 , Angiopoietin1/2 , Tissue Factor and FGF-1 expression were dramatically reduced in LLL12-treated tumors compared to control tumors . CONCLUSIONS These findings provide the first evidence that LLL12 effectively inhibits tumor angiogenesis both in vitro and in vivo .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "22530037"}
{"sentence": "We have recently identified ICBP90 as being a protein able to bind in vitro a CCAAT box of the topoisomerase II alpha gene promoter . The aim of the present work was to check whether ICBP90 is able to regulate in vivo topoisomerase II alpha expression in human lung fibroblasts under various proliferating conditions . Transient transfection experiments performed on moderately growing human lung fibroblasts ( 50% of confluence ) showed that overexpression of ICBP90 is associated with an elevation of topoisomerase II alpha expression and an increase of the cell proliferation rate . In highly proliferating human lung fibroblasts ( 20% confluence ) overexpression of ICBP90 had no effect . In contrast , in non-proliferating fibroblasts ( 100% confluence ) overexpression of ICBP90 allowed recovery of topoisomerase II alpha expression levels with a concomitant overgrowth of confluent cell cultures . Our results show that ICBP90 regulates topoisomerase II alpha expression and is able to overcome cell contact inhibition signaling , suggesting that increased ICBP90 expression may be involved in carcinogenesis .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "12530060"}
{"sentence": "The insulin-like growth factor ( IGF ) pathway represents one of the most studied molecular regulatory networks in oncology . Clinical trials investigating the therapeutic value of anti-IGF1 receptor ( IGF1R ) therapies in cancer , including prostate cancer , are ongoing . However , the multiple functions of the IGF network in the prostate are not entirely known . To elucidate the effects of IGF and insulin ( INS ) on prostate cells , we stimulated prostate cancer ( PC3 , DU145 , LNCaP , DUCaP ) and noncancerous prostate cells ( EP156T , RWPE-1 ) and observed differing responses : whereas cancer cells responded to IGF and INS exposure by way of enhanced cell proliferation and glucose consumption , basal to luminal differentiation was induced in noncancerous cells . The same diverse responses were observed when the growth factor receptors IGF1R or INSR were overexpressed . Down-regulation of IGF1R or INSR isoform A ( INSRA ) also inhibited only proliferation of cancer cells . The proliferative response induced by the INSR in cancer cells was mediated solely by the INSRA . Moreover we observed that the receptors of the IGF network mutually influence their expression and exert redundant functions , thus underscoring the functional molecular network formed by IGF , INS , IGF1R , and INSR . Collectively we found that both IGF1R and INSRA have oncogenic effects in prostate cancer , but the IGF network also has important physiological functions in the noncancerous prostate . These data provide new insights into the biology of the IGF network in the prostate , thereby facilitating the design and interpretation of clinical studies investigating IGF1R targeting agents .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22903612"}
{"sentence": "Dietary exposure to aflatoxins is one of the major risk factors for hepatocellular carcinoma . Individual susceptibility to aflatoxin-induced hepatocarcinogenesis may be modulated by both genetic and environmental factors affecting metabolism . A cross-sectional study was performed to evaluate determinants of the formation of aflatoxin covalently bound to albumin ( AFB1-albumin adducts ) . A total of 474 subjects who were free of liver cancer and cirrhosis and were initially selected as controls for previous case-control studies of aflatoxin-induced hepatocarcinogenesis in Taiwan , were employed in this study . Aflatoxin-albumin adducts were determined by competitive enzyme-linked immunosorbent assay , hepatitis B surface antigen and antibodies to hepatitis C virus by enzyme immunoassay , as well as genotypes of glutathione S-transferase M1-1 and T1-1 by polymerase chain reaction . The detection rate of AFB1-albumin adducts was significantly higher in males ( 42.5% ) than in females ( 21.6% ) ( multivariate-adjusted odds ratio=2.6 , 95% confidence interval=1.4-5.0 ) . The formation of detectable albumin adducts was moderately higher in hepatitis B surface antigen carriers ( 42.8% ) than in non-carriers ( 36.6% ) ( multivariate-adjusted odds ratio=1.4 , 95% confidence interval=1.0-2.1 ) . In addition , the detection rate of AFB1-albumin adducts tended to increase with the increasing number of null genotypes of glutathione S-transferase M1-1 and glutathione S-transferase T1-1 . In conclusion , this cross-sectional study has assessed the relative contributions of environmental exposure and host susceptibility factors in the formation of AFB1-albumin adducts in a well characterised Chinese adult population . This study further emphasises the necessity to reduce aflatoxin exposure in people living in an area endemic for chronic hepatitis B virus infection .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12434285"}
{"sentence": "Many cells in mammals exist in the state of quiescence , which is characterized by reversible exit from the cell cycle . Quiescent cells are widely reported to exhibit reduced size , nucleotide synthesis , and metabolic activity . Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes . In contrast , we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition . By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data , we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells , with greater overflow flux from the pentose phosphate pathway back to glycolysis . Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts . By feeding the cells labeled glutamine , we also detected a \" backwards \" flux in the tricarboxylic acid cycle from \u03b1-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts ; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis . The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid , and in part toward excretion of extracellular matrix proteins . Thus , reduced metabolic activity is not a hallmark of the quiescent state . Quiescent fibroblasts , relieved of the biosynthetic requirements associated with generating progeny , direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole .", "label": [0, 0, 1, 0, 1, 0, 0, 0, 0, 0], "id": "21049082"}
{"sentence": "Hypoxia-inducible factor ( HIF ) 1\u03b1 and 2\u03b1 are transcription factors responsible for the cellular response to hypoxia . The functional roles of HIF1\u03b1 and HIF2\u03b1 in cancer are distinct and vary among different tumor types . The aim of this study was to evaluate the compartment-specific role(s) of HIF1\u03b1 and HIF2\u03b1 in breast cancer . To this end , immortalized human fibroblasts and MDA-MB-231 breast cancer cells carrying constitutively active HIF1\u03b1 or HIF2\u03b1 mutants were analyzed with respect to their metabolic function(s) and ability to promote tumor growth in an in vivo setting . We observed that activation of HIF1\u03b1 , but not HIF2\u03b1 , in stromal cells promotes a shift toward aerobic glycolysis , with increased L-lactate production and a loss of mitochondrial activity . In a xenograft model , HIF1\u03b1-activated fibroblasts promoted the tumor growth of co-injected MDA-MB-231 cells without an increase in angiogenesis . Conversely , HIF2\u03b1-activated stromal cells did not favor tumor growth and behaved as the empty vector controls . Similarly , activation of HIF1\u03b1 , but not HIF2\u03b1 , in MDA-MB-231 cells promoted a shift toward aerobic glycolysis , with increased glucose uptake and L-lactate production . In contrast , HIF2\u03b1 activation in cancer cells increased the expression of EGFR , Ras and cyclin D1 , which are known markers of tumor growth and cell cycle progression . In a xenograft model , HIF1\u03b1 activation in MDA-MB-231 cells acted as a tumor suppressor , resulting in an almost 2-fold reduction in tumor mass and volume . Interestingly , HIF2\u03b1 activation in MDA-MB-231 cells induced a significant in tumor mass and volume . Analysis of mitochondrial activity in these tumor xenografts using COX ( cytochrome C oxidase ) staining demonstrated elevated mitochondrial oxidative metabolism ( OXPHOS ) in HIF2\u03b1-tumors . We conclude that the role(s) of HIF1\u03b1 and HIF2\u03b1 in tumorigenesis are compartment-specific . HIF1\u03b1 acts as a tumor promoter in stromal cells but as a tumor suppressor in cancer cells . Conversely , HIF2\u03b1 is a tumor promoter in cancer cells . Mechanistically , HIF1\u03b1-driven aerobic glycolysis in stromal cells supports cancer cell growth via the paracrine production of nutrients ( such as L-lactate ) that can \" feed \" cancer cells . However , HIF1\u03b1-driven aerobic glycolysis in cancer cells inhibits tumor growth . Finally , HIF2\u03b1 activation in cancer cells induces the expression of known pro-oncogenic molecules and promotes the mitochondrial activity of cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22894905"}
{"sentence": "HGF signaling induces epithelial cells to disassemble cadherin-based adhesion and increase cell motility and invasion , a process termed epithelial-mesenchymal transition ( EMT ) . EMT plays a major role in cancer metastasis , allowing individual cells to detach from the primary tumor , invade local tissue , and colonize distant tissues with new tumors . While invasion of vascular and lymphatic networks is the predominant route of metastasis , nerves also can act as networks for dissemination of cancer cell to distant sites in a process termed perineual invasion ( PNI ) . Signaling between nerves and invasive cancer cells remains poorly understood , as does cellular decision making that selects the specific route of invasion . Here we examine how HGF signaling contributes to PNI using reductionist culture model systems . We find that TGF\u03b2 , produced by PC12 cells , enhances scattering in response to HGF stimulation , increasing both cell-cell junction disassembly and cell migration . Further , gradients of TGF\u03b2 induce migratory mesenchymal cells to undergo chemotaxis towards the source of TGF\u03b2 . Interestingly , VEGF suppresses TGF\u03b2-induced enhancement of scattering . These results have broad implications for how combinatorial growth factor signaling contributes to cancer metastasis , suggesting that VEGF and TGF\u03b2 might modulate HGF signaling to influence route selection during cancer progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21075102"}
{"sentence": "Glioblastoma multiforme is the most aggressive primary brain tumor in adults . Overexpression of the EGF receptor ( EGFR ) is recognized as a widespread oncogenic signature in glioblastoma multiforme , but the complexity of its contributions is not fully understood , nor the most effective ways to leverage anti-EGFR therapy in this setting . Hypoxia is known to drive the aggressive character of glioblastoma multiforme by promoting aerobic glycolysis rather than pyruvate oxidation carried out in mitochondria ( OXPHOS ) , a phenomenon termed the Warburg effect , which is a general feature of oncogenesis . In this study , we report that hypoxia drives expression of the pyruvate dehydrogenase kinase ( PDK1 ) and EGFR along with the hypoxia-inducing factor ( HIF)-1\\u03b1 in human glioblastoma multiforme cells . PDK1 is a HIF-1-regulated gene and our findings indicated that hypoxia-induced PDK1 expression may promote EGFR activation , initiating a feed-forward loop that can sustain malignant progression . RNAi-mediated attenuation of PDK1 and EGFR lowered PDK1-EGFR activation and decreased HIF-1\\u03b1 expression , shifting the Warburg phenotype to OXPHOS and inhibiting glioblastoma multiforme growth and proliferation . In clinical specimens of glioblastoma multiforme , we found that immunohistochemical expression of PDK1 , EGFR , and HIF-1\\u03b1 were elevated in glioblastoma multiforme specimens when compared with normal brain tissues . Collectively , our studies establish PDK1 as a key driver and candidate therapeutic target in glioblastoma multiforme .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 1, 0], "id": "24148623"}
{"sentence": "Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development , and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer . Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival , dependent on biological context . In this study , status of DNA damage response ( DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features ; 479 breast cancers were examined for expression of DDR proteins \u03b3H2AX , BRCA1 , pChk2 , and p53 , DNA damage-sensitive tumor suppressors Fhit and Wwox , and Wwox-interacting proteins Ap2\u03b1 , Ap2\u03b3 , ErbB4 , and correlations among proteins , tumor subtypes , and clinical features were assessed . In a multivariable model , triple negative cancers showed significantly reduced Fhit and Wwox , increased p53 and Ap2\u03b3 protein expression , and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins . Disease-free survival was associated with subtype , Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins . These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets . Expression of Wwox and its interactor , ErbB4 , was highly significantly reduced in metastatic tissues vs. matched primary tissues , suggesting that Wwox signal pathway loss contributes to lymph node metastasis , perhaps by allowing survival of tumor cells that have detached from basement membranes , as proposed for the role of Wwox in ovarian cancer spread .", "label": [1, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "21069451"}
{"sentence": "OBJECTIVE Ovarian carcinomas mostly appear as large cystic masses . However , the exact prevalence of cysts in epithelial ovarian cancer ( EOC ) has never been documented as well as the tumor factors that are related to the presence of cysts . Demonstrating the prevalence of cysts in EOC is essential for research focused on predictive and prognostic biomarkers in ovarian cyst fluid . STUDY DESIGN From 233 patients with primary EOC who underwent surgery , pathological data were collected from pathology reports . Univariate and multivariate logistic regression were used to analyze the relationship between the presence of cysts and other tumor characteristics . RESULTS Cysts in EOC were present in 83.7% of the patients and were mostly ( 61% ) multilocular . The most common histological subtypes ( serous , mucinous , endometrioid , clear cell ) contained cysts in more than 85% of the cases . In univariate regression analysis , early FIGO stage , low tumor grade and a large tumor size were significantly associated with the presence of cysts ( OR ( 95% CI)=5.312 ( 1.81-15.57 ) , 6.906 ( 2.31-20.66 ) and 1.169 ( 1.08-1.27 ) , respectively ) . In multivariate regression analysis , apart from tumor size , only tumor grade was independently associated with the presence of cysts ( adjusted OR ( 95% CI)=4.234 ( 1.36-13.22) ) . CONCLUSIONS The large majority of all EOCs contained cysts . Histological subtype , FIGO stage , tumor necrosis and age were not associated with the presence of cystic EOC . In contrast , tumor grade and tumor size were independently related to the presence of cystic EOC . This means that cystic EOCs represent a subgroup of larger and more well-differentiated tumors . The evident relationship between the presence of cysts and differentiation grade is interesting from a clinical point of view as grading is especially important for the prognosis and treatment of patients with stage I EOC .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20303211"}
{"sentence": "A common metabolic change in cancer is the acquisition of glycolytic phenotypes . Increased expression of glycolytic enzymes is considered as one contributing factor . The role of mitochondrial defects in acquisition of glycolytic phenotypes has been postulated but remains controversial . Here we show that functional defects in mitochondrial respiration could be induced by oncogenic H-Ras(Q61L) transformation , even though the mitochondrial contents or mass was not reduced in the transformed cells . First , mitochondrial respiration , as measured by mitochondrial oxygen consumption , was suppressed in NIH-3T3 cells transformed with H-Ras(Q61L) . Second , oligomycin or rotenone did not reduce the cellular ATP levels in the H-Ras(Q61L) transformed cells , suggesting a diminished role of mitochondrial respiration in the cellular energy metabolism . Third , inhibition of glycolysis with iodoacetic acid reduced ATP levels at a much faster rate in H-Ras(Q61L) transformed cells than in the vector control cells . The reduction of cellular ATP levels was reversed by exogenously added pyruvate in the vector control cells but not in H-Ras(Q61L) transformed cells . Finally when compared to the HRas(Q61L) transformed cells , the vector control cells had increased resistance toward glucose deprivation . The increased resistance was dependent on mitochondrial oxidative phosphorylation since rotenone or oligomycin abolished the increased survival of the vector control cells under glucose deprivation . The results also suggest an inability of the H-Ras(Q61L) transformed cells to reactivate mitochondrial respiration under glucose deprivation . Taken together , the data suggest that mitochondrial respiration can be impaired during transformation of NIH-3T3 cells by oncogeneic H-Ras(Q61L) .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19923925"}
{"sentence": "Polycyclic aromatic hydrocarbons ( PAHs ) likely play a role in many cancers even in never-smokers . We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures , multiple genetic polymorphisms in genes related to metabolic and repair pathways , and nucleotide excision repair ( NER ) capacity . In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran , we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes . NER capacity was evaluated by a modified comet assay , and aromatic DNA adduct levels were measured in blood by32P-postlabeling . Multivariable regression models were compared by Akaike's information criterion ( AIC ) . Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides ( mean : 5.8 \u00b1 3.1 ) . DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype , and was higher in the MPO homozygote risk-allele genotype . The sum of risk alleles in these genes significantly correlated with the log-adduct level ( r = 0.4 , p < 0.001 ) . Compared with the environmental model , adding Phase I SNPs and NER capacity provided the best fit , and could explain 17% more of the variation in adduct levels . NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes . Female non-smokers in this population had PAH-related DNA adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies , with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23175176"}
{"sentence": "Recent studies have shown that the transcription factor , nuclear factor kappaB ( NF-kappaB ) , regulates critical survival pathways in a variety of different cell types , including human pancreatic cancer cells . The activation of NF-kappaB is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor , inhibitor of nuclear factor kappaBalpha . We investigated the effects of PS-341 , a peptide boronate inhibitor of the proteasome in human pancreatic cancer cells in vitro and in vivo . Comparison of PS-341's effects on the growth of eight different human pancreatic cancer cell lines revealed marked heterogeneity in drug responsiveness , ranging from highly resistant ( IC50 > 10 microM ; Panc-48 , HS766T , and Mia-PaCa-2 ) to extremely sensitive ( IC50 < 40 nM ; L3.6pl , Hpaf2 , and BxPC3 ) . However , these effects did not correlate with differential inhibition of NF-kappaB activation . Direct quantification of apoptosis revealed that PS-341's effects on cell growth largely correlated with sensitivity to programmed cell death . Evaluation of PS-341's effects on established orthotopic tumor xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug ( 1 mg/kg ) led to significant reductions in the volumes of L3.6pl tumors but not Mia-PaCa-2 tumors . Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that PS-341 induced DNA fragmentation and activation of caspase-3 in L3.6pl tumors but not in Mia-PaCa-2 tumors . However , histological examination of drug-treated tumors revealed extensive central necrosis and reductions in microvessel density and VEGF expression in both tumor types . Taken together , our results demonstrate that PS-341 inhibits the growth of human pancreatic tumors via direct effects on tumor cells and indirect effects on the tumor vasculature .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "12516957"}
{"sentence": "Epidemiological studies suggest that dietary polyunsaturated fatty acids ( PUFA ) may influence breast cancer progression and prognosis . In order to study potential mechanisms of action of fatty acid modulation of tumor growth , we studied , in vitro , the influence of n-3 and n-6 fatty acids on proliferation , cell cycle , differentiation and apoptosis of MCF-7 human breast cancer cells . Both eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) inhibited the MCF-7 cell growth by 30% and 54% , respectively , while linoleic acid ( LA ) had no effect and arachidonic acid ( AA ) inhibited the cell growth by 30% ( p < 0.05 ) . The addition of vitamin E ( 10uM ) to cancer cells slightly restored cell growth . The incubation of MCF-7 cells with PUFAs did not alter the cell cycle parameters or induce cell apoptosis . However , the growth inhibitory effects of EPA , DHA and AA were associated with cell differentiation as indicated by positive Oil-Red-O staining of the cells . Lipid droplet accumulation was increased by 65% , 30% and 15% in the presence of DHA , EPA and AA , respectively ; ( p < 0.05 ) . These observations suggest that fatty acids may influence cellular processes at a molecular level , capable of modulating breast cancer cell growth .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12550055"}
{"sentence": "Overexpression and amplification of cyclin D1 were investigated by immunohistochemistry and differential polymerase chain reaction ( dPCR ) in 440 formalin-fixed primary breast carcinoma tissues . Overexpression of cyclin D1 was detected in 60% ( 263/440 ) and amplification of cyclin D1 was noted in 27% ( 119/440 ) of the primary breast carcinomas . Molecular analysis demonstrated that cyclin D1 was amplified in 30% ( 7/23 ) of the comedo DCIS , 22% ( 9/41 ) of the comedo DCIS and 32% ( 13/41 ) of the adjacent invasive ductal carcinomas , 30% ( 82/270 ) of the invasive ductal carcinomas , 27% ( 9/33 ) of the invasive lobular carcinomas , 19% ( 4/21 ) of the colloid carcinomas and 13% ( 2/15 ) of the medullary carcinomas . Cyclin D1 was amplified in 11% ( 2/19 ) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions . Our observation showed that cyclin D1 was strongly positive in 61% ( 14/23 ) of the comedo subtype , 61% ( 11/18 ) of the non-comedo subtype , 59% ( 24/41 ) of the comedo DCIS and 63% ( 26/41 ) of the adjacent invasive ductal carcinomas , 53% ( 10/19 ) of the non-comedo DCIS and 58% ( 11/19 ) of the adjacent invasive lesions , 58% ( 157/270 ) of the invasive ductal carcinomas , 73% ( 24/33 ) of the invasive lobular carcinomas , 52% ( 11/21 ) of the colloid carcinomas and 27% ( 4/15 ) of the medullary carcinomas . A significant association was observed between in situ components and adjacent invasive lesions for cyclin D1 expression ( p<0.05 ) and amplification ( p<0.05 ) . A significant relationship was noted between amplification of cyclin D1 and lymph node metastases ( p<0.05 ) but not with histological grade ( p>0.05 ) , estrogen receptor status ( p>0.05 ) and proliferation index ( Ki-67 and PCNA ) ( p>0.05 ) . However , overexpression of cyclin D1 was statistically associated with well differentiated tumors ( p<0.05 ) and estrogen receptor positivity ( p<0.05 ) . No relationship was seen with nodal status ( p>0.05 ) and proliferation index ( Ki-67 and PCNA ) ( p>0.05 ) . These observations suggest that tumors positive for cyclin D1 protein may have features of good prognosis but amplification of cyclin D1 gene could be an indicator of tumors with poor prognostic features . Although majority of the Malaysian patients belong to younger age group ( <50 years old ) , amplification and expression of cyclin D1 was not statistically associated with patient age ( p>0.05 ) . These observations indicate that amplification and up-regulation of cyclin D1 may be independent of patient age . Moreover , overexpression and amplification of cyclin D1 in preinvasive , preinvasive and adjacent invasive lesions , and invasive carcinomas suggest that the gene may play an important role in early and late stages of breast carcinogenesis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "11836618"}
{"sentence": "Although there have been numerous studies of site-specific mutagenesis by dGuo adducts of benzo[a]pyrene diol epoxides ( B[a]P DEs ) , the present study represents the first example of site-specific mutagenesis by dGuo adducts of the highly carcinogenic benzo[c]phenanthrene 3,4-diol 1,2-epoxides ( B[c]Ph DEs ) . The eight adducts that would result from cis- and trans-opening at C-1 of four optically active isomers of B[c]Ph DEs by the N(2)-amino group of dGuo were incorporated into 5'-TTCGAATCCTTCCCCC ( context III ) and 5'-GGGGTTCCCGAGCGGC ( context IV ) at the underlined site . These modified oligonucleotides along with unmodified controls were ligated into single-stranded M13mp7L2 , which were then used to transfect SOS-induced Escherichia coli . Upon replication of the lesions in each of the two sequence contexts , mutational analysis of the progeny was performed by differential hybridization . For the 16 adducts , the mutation frequencies varied over 2 orders of magnitude with a reasonably even distribution ( 0.4-1% for three adducts , 1-2% for six adducts , 3-7.4% for five adducts , and one adduct each at 11 and 39% ) . For all but this last adduct , the mutation frequency for a given B[c]Ph DE adduct was less than for its B[a]P analogue with the same stereochemistry in the same sequence . For the vectors containing adducts with S configuration at the site of attachment of the hydrocarbon to the dGuo base , the main base substitution was G --> T followed by G --> A. In contrast , for the vectors containing adducts with R configuration , the main base substitution was G --> A. The most notable observation in the present study is the low frequency of mutations induced by the B[c]Ph DE-dGuo adducts relative to their B[a]P counterparts . A possible structural basis for this difference is proposed .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12482245"}
{"sentence": "To search for potential biomarkers used to monitor the process of immortalization , we investigated the relative level of telomerase activity and other immortal phenotypes in the SHEE esophageal epithelial cell line . This human fetal esophageal epithelial cell line , induced by human papilloma virus ( HPV ) 18 E6E7 , was continually propagated over 100 passages . Fourteenth passage cells ( SHEE14 ) were cultured in a flask with a serum-free medium and continually cultured to the 30th passage ( SHEE30 ) . Cells of SHEE14 , SHEE20 and SHEE30 were examined according to cell morphology , cell cycle , apoptosis , contact-inhibition growth , anchorage- dependency , dose-dependency to epithelial growth factors ( EGF ) , telomerase activity and tumorigenicity . The SHEE14 cells exhibited good differentiation with contact-inhibition and anchorage-dependent growth . The SHEE20 cells exhibited increase of senescent and apoptotic cells , and difficulty in propagation . The SHEE30 cells exhibited a higher proliferative index and some undifferentiated cells , with weakened contact-inhibition and anchorage-dependent growth . The telomerase was activated in cells of SHEE30 , but not in SHEE14 and SHEE20 cells . The different response to dose-dependency to EGF was not statistically different in SHEE14 and SHEE30 . Three groups of cells displayed lack of tumor formation in nude mice . Compared with SHEE14 and SHEE20 , SHEE30 cells were of immortalized status with immortal phenotype , which consisted of telomerase activity , increase of cell proliferation , weakened contact-inhibition and anchorage-dependent growth , dose dependency to EGF and lack of tumor formation . From passage 14 to 30th passage , SHEE cells went through cellular senescence , apoptosis and immortalization . With a view toward diagnostic and biological aspects , telomerase activity is a crucial step and a cardinal requirement for immortalization . The telomerase activity and other immortal phenotypes are potential markers for monitoring the process of immortalization .", "label": [0, 0, 0, 1, 1, 0, 0, 1, 0, 0], "id": "12373308"}
{"sentence": "In cancer cells , glucose is often converted into lactic acid , which is known as the ' Warburg effect ' . The reason that cancer cells have a higher rate of aerobic glycolysis , but not oxidative phosphorylation , remains largely unclear . Herein , we proposed an epigenetic mechanism of the Warburg effect . Fructose-1,6-bisphosphatase-1 ( FBP1 ) , which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells . Restoration of FBP1 expression suppressed anchorage-independent growth , indicating the relevance of FBP1 downregulation in carcinogenesis . Indeed , FBP1 was downregulated in gastric carcinomas ( P<0.01 , n=22 ) and gastric cancer cell lines ( 57% , 4/7 ) . Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells . Moreover , FBP1 downregulation was reversed by pharmacological demethylation . Its promoter was hypermethylated in gastric cancer cell lines ( 57% , 4/7 ) and gastric carcinomas ( 33% , 33/101 ) . Inhibition of NF-kappaB restored FBP1 expression , partially through demethylation of FBP1 promoter . Notably , Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer ( hazard ratio : 3.60 , P=0.010 ) . In summary , we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1 . Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer . Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19881551"}
{"sentence": "A new cell line of human ovarian clear cell adenocarcinoma ( CCC ) , TU-OC-1 , was established and characterized . The cells showed a polygonal-shaped morphology and grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle . The chromosome numbers ranged from 64 to 90 . A low rate of proliferation was observed , similar to other CCC cell lines tested ( OVTOKO , RMG-I , and OVAS ) , and the doubling time was 38.4h . The respective IC50 values of cisplatin and paclitaxel were 12.2\u03bcM and 58.3nM . Mutational analysis revealed that TU-OC-1 cells harbored a PIK3CA mutation at codon 542 ( E542K ) in exon 9 , which is a mutation hot spot on this gene . We observed that phosphorylated Akt protein was overexpressed in TU-OC-1 cells by western blot analysis . Heterotransplantation to nude mice produced tumors that reflected the original . This cell line may be useful to study the chemoresistant mechanisms of CCC and contribute to novel treatment strategies .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23430509"}
{"sentence": "Epithelial-to-mesenchymal transition ( EMT ) in cancer cells is considered to be a prerequisite for acquiring invasive/migratory phenotype and subsequent metastasis . This study provides molecular evidence associated with the antimetastatic effect of black tea polyphenol extracts ( BTE ) , which contain polyphenols including gallic acid , gallocatechin , catechin , epigallocatechin-3-gallate , epicatechin-3-gallate , and theaflavin 3,3'-digallate , in an an oral squamous cell culture system by showing a nearly complete inhibition on the invasion ( p < 0.001 ) of SCC-4 cells via reduced activities of MMP-2 ( p < 0.001 ) and u-PA ( p < 0.001 ) . Immunoblot was performed to find that BTE could induce up-regulation of epithelial markers such as E-cadherin and inhibit mesenchymal markers such as snail-1 and vimentin . BTE inhibited p-FAK and p-paxillin , indicating the anti-EMT effect of BTE in oral squamous cell carcinoma . BTE was evidenced by its inhibition of the tumor growth of SCC-4 cells via cancer cell xenografted nude mice mode . These results suggested that BTE could reduce invasion by reversing EMT in human oral cancer cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22827697"}
{"sentence": "OBJECTIVE Angiogenesis represents a key element in the pathogenesis of malignancy . There are no robust data on prognostic factors for overall survival ( OS ) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor ( VEGF)-targeted therapy . The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer . METHODS Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naive metastatic colorectal cancer were collected from three Turkey cancer centers . Cox proportional hazards regression was used to identify independent prognostic factors for OS . RESULTS The median OS for the whole cohort was 19 months ( 95% CI , 14.3 to 23.6 months ) . Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology ( ASMO ) were independent predictors of short survival : serum lactate dehydrogenase ( LDH ) greater than the upper limit of normal ( ULN ; p<0.001 ) ; neutrophils greater than the ULN ( p<0.0014 ) ; and progression free survival ( PFS ) less than 6 months ( p =0.001 ) . CONCLUSION Serum LDH and neutrophil levels were the main prognostic factors in predicting survival , followed by PFS . This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22631638"}
{"sentence": "ABSTRACT Partial DNA fragments of Botrytis cinerea field isolates encoding the putative osmosensor histidine kinase gene ( BcOS1 ) were cloned by polymerase chain reaction amplification and the predicted amino acid sequences were compared between dicarboximide-sensitive and resistant field isolates . The predicted BcOS1p is highly homologous to osmosensor histidine kinase OS1p from Neurospora crassa including the N-terminal six tandem repeats of approximately 90 amino acids . Four dicarboximide-resistant isolates of B. cinerea ( Bc-19 , Bc-45 , Bc-682 , and Bc-RKR ) contained a single base pair mutation in their BcOS1 gene that resulted in an amino acid substitution in the predicted protein . In these resistant isolates , codon 86 of the second repeat , which encodes an isoleucine residue in sensitive strains , was converted to a codon for serine . The mutation of Botrytis field resistant isolates was located on the second unit of tandem amino acid repeats of BcOS1p , whereas the point mutations of the fifth repeat of OS1p confer resistance to both dicarboximides and phenylpyrroles and also osmotic sensitivity in Neurospora crassa . These results suggest that an amino acid substitution within the second repeat of BcOS1p is responsible for phenotypes of field resistant isolates ( resistant to dicarboximides but sensitive to phenylpyrroles , and normal osmotic sensitivity ) in B. cinerea .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "18944142"}
{"sentence": "Uncontrolled estrogen exposure can induce an imbalance in BCL2/BAX expression in endometrial cells , leading to precancerous lesions and type I endometrial adenocarcinoma . This study aimed to explore the mechanism underlying this phenomenon . We show that the activated estrogen receptor can suppress the expression of BAX by upregulating a group of microRNAs including hsa-let-7 family members and hsa-miR-27a , thereby promoting an increased BCL2/BAX ratio as well as enhanced survival and proliferation in the affected cells . These ER-regulated hsa-let-7 microRNAs can be detected in most hyperplastic endometria , suggesting their potential utility as indicators of estrogen over-exposure .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22014978"}
{"sentence": "BACKGROUND Thymidine phosphorylase ( TYMP ) is an angiogenic factor that has potent chemotactic activity for endothelial cells and is involved in 5-fluorouracil ( 5-FU ) metabolism . In colorectal cancer ( CRC ) , previous studies evaluating the relationship between TYMP expression and clinicopathological features have yielded inconsistent results . The aim of this study was to investigate the prognostic value of TYMP , its association with other angiogenic factors , proliferation markers and , to our knowledge , for the first time its relationship with extracellular matrix components . MATERIALS AND METHODS Formalin-fixed , paraffin-embedded specimens from 97 patients with CRC were immunostained for TYMP , vascular endothelial growth factor ( VEGF ) , microvascular density ( CD34 ) , proliferation marker ( Ki-67 ) , proliferating cell nuclear antigen ( PCNA ) , p53 oncoprotein and extracellular matrix components ( collagen type IV , fibronectin , tenascin and laminin ) . Survival curves were calculated with the Kaplan-Meier method . RESULTS Immunoreactivity was observed in the cytoplasm ( cyt ) and nucleus ( n ) of the tumor cells , as well in the stroma ( st ) , endothelium and tumor-associated macrophages . High TYMPcyt expression was observed in 7.2% of the cases , moderate in 22.7% and weak in 59.9% , while 10.3% were negative . High TYMPst expression was observed in 58.8% of the cases . TYMPcyt expression was correlated with the VEGF expression of tumor cells and VEGF expression of vessels ( p=0.014 and p=0.022 , respectively ) . TYMPst expression was correlated with VEGF expression and tenascin ( p=0.014 and p=0.011 , respectively ) . Patients with higher TYMPcyt expression had a more favorable overall survival ( p=0.041 ) in univariate analysis compared to patients without TYMP expression . CONCLUSION These findings suggest that TYMP plays an important role in angiogenesis , extracellular matrix remodeling and in the prognosis of patients with CRC , but further studies are needed to clearly define its role in CRC .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23160694"}
{"sentence": "Hepatocellular carcinoma ( HCC ) , one of the most frequent and deadliest cancers , has been increasing considerably in the United States . In the absence of a proven effective therapy for HCC , novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC . Recently , we have reported that resveratrol , a compound present in grapes and red wine , significantly prevents diethylnitrosamine ( DENA)-induced liver tumorigenesis in rats , although the mechanism of action is not completely understood . In the present study , we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis . There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study ( 20 weeks ) . Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals . Dietary resveratrol ( 50-300 mg/kg ) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA . Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2-related factor 2 ( Nrf2 ) . Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated , at least in part , in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats . The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20501860"}
{"sentence": "Hepatocellular carcinoma ( HCC ) is the fifth most common cancer worldwide . Major risk factors of HCC include infection with hepatitis B or C viruses , alcohol and non-alcoholic fatty liver disease . HCC is difficult to diagnose at early stage , and has a very poor survival rate when diagnosed at a late stage . The majority of HCC-related deaths result from local invasion ( to cause liver failure ) or distant metastases . There is an urgent need to identify effective molecular targets for the treatment of the disease . As the target of an established class of therapeutic agent thiazolidinediones ( TZDs ) , peroxisome-proliferator-activated receptor \u03b3 ( PPAR\u03b3 ) has been widely studied for its role in the development of HCC . A substantial body of evidence based on in vitro and in vivo models indicates that the activation of PPAR\u03b3 is able to inhibit HCC cell proliferation and tumor growth through inducing cell cycle arrest and apoptosis via the regulation of a panel of downstream effector molecules . PPAR\u03b3 activation also induces an inhibitory effect on HCC metastasis . Meanwhile , there is new evidence suggesting that PPAR\u03b3 inhibition could also be anti-tumorigenic . In the present review , we summarize the available information on the role of PPAR\u03b3 in HCC development and spread , and discuss whether PPAR\u03b3 activation by TZDs could play a role in the treatment of HCC , summarizing both in vitro and in vivo . Considering the available data , PPAR\u03b3 seems to exert beneficial effects against HCC and may therefore represent as a therapeutic target .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22742931"}
{"sentence": "A growing number of studies have demonstrated an association between serum levels of insulin-like growth factors ( IGFs ) and IGF binding protein-3 ( IGFBP-3 ) and increased risk for various cancers . The aim of this study was to evaluate the relationship between levels of IGF-II or IGFBP-3 in cervical scrapes with cervical cancer and precancerous lesions : low-grade squamous intraepithelial lesion ( LSIL ) and high-grade squamous intraepithelial lesion ( HSIL). 4 groups of cases were examined : LSIL ( n=20 ) , HSIL ( n=28 ) , cervical cancer ( n=45 ) , and controls ( n=51 ) . Control subjects were women with normal , HPV DNA-negative Papanicolau ( Pap ) test . IGF-II and IGFBP-3 levels in cervical scrapes were measured by ELISA . Results show that median protein levels of IGF-II were significantly lower in cervical cancer cases vs. controls ( 446.5 ng/mg vs. 1,168.6 ng/mg , p<0.001 ) . Significantly higher values of IGFBP-3 were found in HSIL vs. controls ( median : 549.5 ng/mg vs. 216 ng/mg ; p=0.018 ) , and were not affected by HR HPV infection , meanwhile no significant differences were observed in IGFBP-3 levels between LSIL or cervical cancer as compared to controls . These data suggests that the progression to cervical cancer is associated with alterations in the IGF system and not affected by HR HPV infection . More studies are needed to understand the possible role of IGFBP-3 in cervical carcinogenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20945273"}
{"sentence": "The high affinity fibronectin receptor ( FNR ) is expressed by hematopoietic cells , fibroblasts , and proliferating epidermal cells . Expression of this integrin is altered by chemical and viral transformation , suggesting that FNR dysfunction may play a role in growth control . This study demonstrates that exposing FA-K562 cells to glycine-arginine-glycine-aspartate-serine ( GRGDS ) , a peptide ligand of the FNR , specifically stimulates p34/cdc2- and cyclin A-associated kinase activities . This occurs within 2 h of peptide addition . The 110-kDa form of the retinoblastoma protein appears within 3 h of GRGDS addition , consistent with activation of a G1/S kinase . DNA staining profiles demonstrate that GRGDS induces cell cycle progression within 24 h . Increased anchorage-independent growth is subsequently observed in GRGDS-treated FA-K562 cells . The control peptide , GRGES , which cannot bind the FNR , has none of these effects . This demonstrates that an extracellular integrin ligand can regulate cell proliferation . Furthermore , these results suggest that integrins link the extracellular environment and intracellular growth regulators .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1464591"}
{"sentence": "Exposure to ultraviolet B ( UVB ) radiation ( 280-320 nm ) is the primary etiologic factor associated with the development of basal cell carcinoma ( BCC ) . The outgrowth of these keratinocyte-derived skin lesions is enhanced by the ability of UVB to impair an immune response that would otherwise eliminate them . Studies in a range of inbred mouse strains as well as mast cell-depleted mice reconstituted with mast cell precursors support a functional link between histamine-staining dermal mast cells and the extent of susceptibility to UVB-induced systemic immunomodulation . Humans , like mouse strains , display variations in dermal mast cell prevalence . In a study of Danish and South Australian BCC patients and control subjects , one 4-mm punch biopsy of non-sun-exposed buttock skin was sampled from each participant . This skin site was investigated to avoid any changes in mast cell prevalence caused by sun exposure . Two sections ( 4 microm ) per biopsy were immunohistochemically stained for detection of histamine-containing dermal mast cells . Computer-generated image analysis evaluated dermal mast cell prevalence in both sections by quantifying the total number of mast cells according to the total dermal area ( expressed as mast cells per square millimeter ) . This technique enabled us to detect heterogeneity of dermal mast cell prevalence in buttock skin between individuals and provided evidence of an association between high dermal mast cell prevalence and BCC development in two diverse populations . We hypothesize that mast cells function in humans , as in mouse strains , by initiating immunosuppression following UV irradiation and , thereby , allowing a permissive environment for the development of BCC . Thus , a high dermal mast cell prevalence as demonstrable in buttock skin is a significant predisposing factor for development of BCC in humans .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12231192"}
{"sentence": "Radiation-induced carcinogenesis is a major concern both for astronauts on long-term space missions and for cancer patients being treated with therapeutic radiation . Exposure to radiation induces oxidative stress and chronic inflammation , which are critical initiators and promoters of carcinogenesis . Many studies have demonstrated that non-steroidal anti-inflammatory drugs and antioxidants can reduce the risk of radiation-induced cancer . In this study , we found that a synthetic triterpenoid , CDDO-Me ( bardoxolone methyl ) , was able to protect human colon epithelial cells ( HCECs ) against radiation-induced transformation . HCECs that were immortalized by ectopic expression of hTERT and cdk4 and exhibit trisomy for chromosome 7 ( a non-random chromosome change that occurs in 37% of premalignant colon adenomas ) can be transformed experimentally with one combined exposure to 2 Gy of protons at 1 GeV/nucleon followed 24 h later by 50 cGy of ( 56)Fe ions at 1 GeV/nucleon . Transformed cells showed an increase in proliferation rate and in both anchorage-dependent and independent colony formation ability . A spectrum of chromosome aberrations was observed in transformed cells , with 40% showing loss of 17p ( e.g. loss of one copy of p53 ) . Pretreatment of cells with pharmacological doses of CDDO-Me , which has been shown to induce antioxidative as well as anti-inflammatory responses , prevented the heavy-ion-induced increase in proliferation rate and anchorage-dependent and independent colony formation efficiencies . Taken together , these results demonstrate that experimentally immortalized human colon epithelial cells with a non-random chromosome 7 trisomy are valuable premalignant cellular reagents that can be used to study radiation-induced colorectal carcinogenesis . The utility of premalignant HCECs to test novel compounds such as CDDO-Me that can be used to protect against radiation-induced neoplastic transformation is also demonstrated .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20681796"}
{"sentence": "MYC deregulation is common in human cancer . IG-MYC translocations that are modeled in E\u03bc-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders . Deregulated expression of MYC results in increased mTOR complex 1 ( mTORC1 ) signaling . As tumors with mTORC1 activation are sensitive to mTORC1 inhibition , we used everolimus , a potent and specific mTORC1 inhibitor , to test the requirement for mTORC1 in the initiation and maintenance of E\u03bc-Myc lymphoma . Everolimus selectively cleared premalignant B cells from the bone marrow and spleen , restored a normal pattern of B-cell differentiation , and strongly protected against lymphoma development . Established E\u03bc-Myc lymphoma also regressed after everolimus therapy . Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity . Therefore , mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23242809"}
{"sentence": "The role of energy deregulation and altered/adapted metabolism in tumor cells is an increasingly important issue in understanding cancer . Hereditary leiomyomatosis and renal cell carcinoma ( HLRCC ) is an aggressive form of RCC characterized by germline mutation of fumarate hydratase ( FH ) , followed by somatic loss of the remaining wild-type allele and known to be a highly metastatic and lethal malignancy compared to other RCCs . The intrinsic loss of normal tricarboxylic acid ( TCA ) cycle presumably aids tumorigenesis due to the necessary metabolic alterations required and the enforced dependence on glycolysis derived energy , mimicking the Warburg effect . Thus , there is considerable utility in establishing a preclinical cell model from these tumors to study energy metabolism deregulation , as well as developing new targeted therapeutic approaches for TCA cycle enzyme-deficient cancers . Here , we describe a new immortalized cell line , UOK268 , derived from a patient's primary HLRCC-associated kidney cancer . This represents the first primary renal cell line to model TCA cycle gene loss and provides a perfect partner cell line to our previously described metastasis-derived HLRCC-associated cell line , UOK262 . We identified a novel germline FH missense mutation , p.His192Asp , and the subsequent loss of heterozygosity in UOK268 . The UOK268 cell line expressed mutant FH protein , which localized to the mitochondria , but with loss of almost all catalytic activity . The UOK268 cells had severely compromised oxidative phosphorylation and increased glycolytic flux . Ingenuity pathways analysis of human mitochondria-focused cDNA microarray ( hMitChip3 ) gene chip data confirmed the altered mRNA expression patterns of genes involved in several important pathways , such as lipid metabolism , apoptosis , and energy production/glycolysis . UOK268 provides a unique model of a primary cell line demonstrating an enforced , irreversible Warburg effect and , combined with UOK262 , provides a unique invitro preclinical model for studying the bioenergetics of the Warburg effect in human cancer .", "label": [0, 0, 1, 0, 0, 1, 0, 1, 0, 0], "id": "22867999"}
{"sentence": "Numerous small potentially bioactive peptides are derived from the selective processing of the amino acid secretogranin II ( SgII ) precursor , but only the 31-42 amino acid segment termed secretoneurin ( SN ) is well-conserved from sharks to mammals . Both SNa and SNb paralogs have been identified in some teleosts , likely arising as a result of the specific genome duplication event in this lineage . Only one copy of the putative lamprey SgII ( 188 amino acids ) could be identified which gives rise to a divergent agnathan SN that contains the signature YTPQ-X-LA-X(7)-EL sequence typical of the central core of all known SN peptides . In rodent models , SN has regulatory effects on neuroinflammation and neurotransmitter release , and possesses therapeutic potential for the induction of angiogenesis . The wide distribution of SN in neuroendocrine neurons and pituitary cells suggests important endocrine roles . The clearest example of the endocrine action of SN is the stimulatory effects on pituitary luteinizing hormone release from goldfish pituitary and mouse L\u03b2T2 gonadotroph cells , indicative of an important role in reproduction . Several lines of evidence suggest that the SN receptor is most likely a G-protein coupled protein . Microarray analysis of SN effects on dispersed goldfish pituitary cells in vitro reveals novel SN actions that include effects on genes involved in notch signaling and the guanylate cyclase pathway . Intracerebroventricular injection of SN increases feeding and locomotory behaviors in goldfish . Given that SgII appeared early in vertebrate evolution , SN is an old peptide with emerging implications as a new multifunctional hormone .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22036841"}
{"sentence": "p38 kinases activated by growth factors , hormones , and environmental stresses exert diverse functions in regulating normal and malignant cell pathophysiology . Enhanced levels of activated p38 isoforms have been linked with poor prognosis in breast cancer , although the mechanistic basis for this association is poorly understood . In this study , we report that p38 activation in cervical cancer cells is driven by osteopontin ( OPN ) , an extracellular matrix-associated cytokine that drives invasive progression . OPN regulates CD44-mediated p38 phosphorylation that induces NF-\u03baB activation and NF-\u03baB-dependent expression of furin , an extracellular protease implicated in human papilloma virus ( HPV ) processing that enhances cervical cancer cell motility . OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells . OPN-induced furin expression and cell motility was impeded by blockades to MKK3/6 , p38\u03b1/\u03b2 or NF-\u03baB signaling . In a mouse xenograft model of human cervical cancer , tumor growth was enhanced by OPN overexpression and blocked by short hairpin RNA ( shRNA)-mediated OPN silencing . Furin overexpression similarly augmented tumor growth in the model , whereas blocking MKK3/6 , p38 , or furin reduced OPN-induced cervical tumor growth . Analysis of clinical specimens revealed that enhanced expression of OPN , phosphorylated NF-\u03baB , p65 , and furin correlated with cervical cancer progression , further strengthening the in vitro and in vivo results . In summary , our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20980434"}
{"sentence": "The contribution of a type II restriction-modification system ( R-M system ) to genome integrity and cell viability was investigated . We established experimental conditions which enabled the achievement of hemimethylated and unmethylated states for the specific bases of the recognition sequences of the host's DNA . To achieve this , we constructed the MboII R-M system containing only one ( i.e . M2.MboII ) out of two functional MboII methyltransferases found in Moraxella bovis . Using the incomplete R-M system we were able to perturb the balance between methylation and restriction in an inducible manner . We demonstrate that upon the SOS-induced DNA repair in the mitomycin C treated cells , restriction significantly reduces cell viability . Similar results for the well-studied wild type EcoRI R-M system , expressed constitutively in Escherichia coli , were obtained . Our data provide further insights into the benefits and disadvantages of maintaining of a type II R-M system , highlighting its impact on host cell fitness .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20134230"}
{"sentence": "Our previous studies have shown that genistein inhibits the growth of PC3 prostate cancer cells and induces apoptosis by inhibiting nuclear factor kappaB ( NF-kappaB ) and Akt signaling pathways . To better understand the precise molecular mechanism(s) by which genistein exerts its effects on PC3 cells , we utilized cDNA microarray to interrogate 12,558 known genes to determine the gene expression profiles altered by genistein treatment . We found a total of 832 genes that showed a greater than twofold change after genistein treatment from two independent experiments with a high degree of concordance . Among these genes , 774 genes were down-regulated and 58 genes were up-regulated with genistein treatment . Cluster analysis showed nine different types of expression alternations . These genes were also subjected to cluster analysis according to their biological functions . We found that genistein regulated the expression of genes that are critically involved in the regulation of cell growth , cell cycle , apoptosis , cell signaling transduction , angiogenesis , tumor cell invasion and metastasis . Reverse transcription-polymerase chain reaction ( RT-PCR ) analysis was used to confirm the results of cDNA microarray , and the results of RT-PCR were consistent with the microarray data . We conclude that genistein affected the expression of a large number of genes that are related to the control of cell survival and physiologic behaviors . The gene expression profiles provide comprehensive molecular mechanism(s) by which genistein exerts its pleiotropic effects on cancer cells . Genistein-induced regulation of these genes may be further exploited for devising chemopreventive and/or therapeutic strategies for prostate cancer .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "12468598"}
{"sentence": "The effects of glucocorticoid ( GC ) on the proliferation of Dunn Osteosarcoma ( OS ) cells were examined under in vitro culture conditions . Dexamethasone ( Dex ) inhibited the proliferation of Dunn OS cells in a dose-dependent manner , while the addition of anti-GC , RU486 , to the culture medium in part recovered Dex-induced growth inhibition . The number of maximum binding sites ( Bmax ) and the dissociation constant ( Kd ) value of glucocorticoid receptor ( GR ) in Dunn OS cells were 19,560 sites/cell and 5.2 +/- 0.8 nM , respectively . RU486 competed with labeled Dex against GR at a concentration of 10(-6) M. Western blot analysis of [ 3H]Dex-mesylate-labeled cell homogenate and immunohistochemical staining against GR further confirmed the presence of GR . Dex treatment of Dunn OS cells resulted in apoptosis with the characteristic internucleosomal DNA cleavage shown by the DNA ladder pattern in agarose gel electrophoresis . These data demonstrate that GC inhibits the proliferation of Dunn OS cells via GR , for which one possible mechanism in vitro is induction of apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12553047"}
{"sentence": "BACKGROUND NF\u03baB signaling is of paramount importance in the regulation of apoptosis , proliferation , and inflammatory responses during human development and homeostasis , as well as in many human cancers . Receptor Tyrosine Kinases ( RTKs ) , including the Fibroblast Growth Factor Receptors ( FGFRs ) are also important in development and disease . However , a direct relationship between growth factor signaling pathways and NF\u03baB activation has not been previously described , although FGFs have been known to antagonize TNF\u03b1-induced apoptosis . METHODOLOGY/PRINCIPAL FINDINGS Here , we demonstrate an interaction between FGFR4 and IKK\u03b2 ( Inhibitor of NF\u03baB Kinase \u03b2 subunit ) , an essential component in the NF\u03baB pathway . This novel interaction was identified utilizing a yeast two-hybrid screen [ 1 ] and confirmed by coimmunoprecipitation and mass spectrometry analysis . We demonstrate tyrosine phosphorylation of IKK\u03b2 in the presence of activated FGFR4 , but not kinase-dead FGFR4 . Following stimulation by TNF\u03b1 ( Tumor Necrosis Factor \u03b1 ) to activate NF\u03baB pathways , FGFR4 activation results in significant inhibition of NF\u03baB signaling as measured by decreased nuclear NF\u03baB localization , by reduced NF\u03baB transcriptional activation in electophoretic mobility shift assays , and by inhibition of IKK\u03b2 kinase activity towards the substrate GST-I\u03baB\u03b1 in in vitro assays . FGF19 stimulation of endogenous FGFR4 in TNF\u03b1-treated DU145 prostate cancer cells also leads to a decrease in IKK\u03b2 activity , concomitant reduction in NF\u03baB nuclear localization , and reduced apoptosis . Microarray analysis demonstrates that FGF19 + TNF\u03b1 treatment of DU145 cells , in comparison with TNF\u03b1 alone , favors proliferative genes while downregulating genes involved in apoptotic responses and NF\u03baB signaling . CONCLUSIONS/SIGNIFICANCE These results identify a compelling link between FGFR4 signaling and the NF\u03baB pathway , and reveal that FGFR4 activation leads to a negative effect on NF\u03baB signaling including an inhibitory effect on proapoptotic signaling . We anticipate that this interaction between an RTK and a component of NF\u03baB signaling will not be limited to FGFR4 alone .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21203561"}
{"sentence": "ABSTRACT : BACKGROUND : Survivin , a member of the family of inhibitor of apoptosis proteins , functions as a key regulator of mitosis and programmed cell death . YM155 , a novel molecular targeted agent , suppresses survivin , which is overexpressed in many tumor types . The aim of this study was to determine the antitumor activity of YM155 in SK-NEP-1 cells . METHODS : SK-NEP-1 cell growth in vitro and in vivo was assessed by MTT and nude mice experiments . Annexin V/propidium iodide staining followed by flow cytometric analysis was used to detect apoptosis in cell culture . Then gene expression profile of tumor cells treated with YM155 was analyzed with real-time PCR arrays . We then analyzed the expression data with MEV ( Multi Experiment View ) cluster software . Datasets representing genes with altered expression profile derived from cluster analyses were imported into the Ingenuity Pathway Analysis tool . RESULTS : YM155 treatment resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner . Annexin V assay , cell cycle , and activation of caspase-3 demonstrates that YM155 induced apoptosis in SK-NEP-1 cells . YM155 significantly inhibited growth of SK-NEP-1 xenografts ( YM155 5 mg/kg : 1.45 +/- 0.77 cm3 ; YM155 10 mg/kg : 0.95 +/- 0.55 cm3 ) compared to DMSO group ( DMSO : 3.70 +/- 2.4 cm3 ) or PBS group cells ( PBS : 3.78 +/- 2.20 cm3 , ANOVA P < 0.01 ) . YM155 treatment decreased weight of tumors ( YM155 5 mg/kg : 1.05 +/- 0.24 g ; YM155 10 mg/kg : 0.72 +/- 0.17 g ) compared to DMSO group ( DMSO : 2.06 +/- 0.38 g ) or PBS group cells ( PBS : 2.36 +/- 0.43 g , ANOVA P < 0.01 ) . Real-time PCR array analysis showed between Test group and control group there are 32 genes significantly up-regulated and 54 genes were significantly down-regulated after YM155 treatment . Ingenuity pathway analysis ( IPA ) showed cell death was the highest rated network with 65 focus molecules and the significance score of 44 . The IPA analysis also groups the differentially expressed genes into biological mechanisms that are related to cell death , cellular function maintenance , cell morphology , carbohydrate metabolism and cellular growth and proliferation . Death receptor signaling ( 3.87E-19 ) , TNFR1 signaling , induction of apoptosis by HIV1 , apoptosis signaling and molecular mechanisms of cancer came out to be the top four most significant pathways . IPA analysis also showed top molecules up-regulated were BBC3 , BIRC3 , BIRC8 , BNIP1 , CASP7 , CASP9 , CD5 , CDKN1A , CEBPG and COL4A3 , top molecules down-regulated were ZNF443 , UTP11L , TP73 , TNFSF10 , TNFRSF1B , TNFRSF25 , TIAF1 , STK17A , SST and SPP1 , upstream regulator were NR3C1 , TP53 , dexamethasone , TNF and Akt . CONCLUSIONS : The present study demonstrates that YM155 treatment resulted in apoptosis and inhibition of cell proliferation of SK-NEP-1cells . YM155 had significant role and little side effect in the treatment of SK-NEP-1 xenograft tumors . Real-time PCR array analysis firstly showed expression profile of genes dyes-regulated after YM155 treatment . IPA analysis also represents new molecule mechanism of YM155 treatment , such as NR3C1 and dexamethasone may be new target of YM155 . And our results may provide new clues of molecular mechanism of apoptosis induced by YM155 .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23267699"}
{"sentence": "Although contact inhibition is a fundamental process for multicellular organisms , how proliferation is inhibited at high cellular densities remains poorly characterized . Here we show that 4E-BP1 , one major repressor of cap-dependent translation , plays a critical role in density-mediated cell cycle arrest. 4E-BP1 promoter is activated and 4E-BP1 protein amount increases as cells reach confluence . Conversely , a much less marked density-dependent inhibition of cell proliferation is observed upon 4E-BP1 silencing . We further show that at high density , progression through the G\u2081 phase of the cell cycle is faster and Cyclin D1 protein is induced in different cell types where 4E-BP1 has been either downregulated ( stable shRNA expression or transient siRNA transfection ) or removed ( knock-out ) . Thus 4E-BP1 appears as an important mediator of contact inhibition .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20372058"}
{"sentence": "Whole body hyperthermia ( WBH ) has been used as an adjunct to radio-/chemotherapy in patients with various malignant diseases . Although clear evidence is still missing , it has been hypothesized that an activation of the immune system might contribute to the therapeutic effect of WBH . To examine whether a treatment with 60-minute 41.8 degrees C WBH as an adjunct to chemotherapy ( WBH-CT ) induces an activation of T cells , blood samples were collected at numerous time points before and up to 48 h post-treatment . The aim of this study was to examine the effect of WBH-CT on the expression of a broad range of activation markers on peripheral blood lymphocytes ( PBL ) , on serum cytokines and intracellular cytokine levels in T cells , and the capacity of these cells to proliferate . Immediately after 41.8 degrees C WBH-CT treatment , a drastic increase in peripheral natural killer ( NK ) cells ( P<0.05 ) and CD56+ cytotoxic T lymphocytes ( CTL ; P<0.01 ) in the patients ' peripheral blood was observed . At 5 h post-treatment , the percentages of both effector cell types had returned to baseline levels . This transient phenomenon was accompanied by a short period of reduced T cell activity , indicated by diminished serum levels of soluble interleukin-2 receptors ( sIL-2R ) at 3 h post-WBH-CT ( P<0.05 ) and decreased lymphocytic proliferation at the same point in time . This first phase was followed by a marked but short-lived increase in the patients ' serum levels of interleukin-6 ( IL-6 ; P<0.01 ) during the first 5 h following treatment , with a subsequent decrease to baseline levels at 24 h and significantly increased serum levels of tumor necrosis factor-alpha ( TNF-alpha ) at 0 h ( P<0.01 ) , 3 h ( P<0.05 ) , 5 h ( P<0.05 ) and 24 h ( P<0.01 ) post-WBH-CT . The third phase of the immunological consequences of WBH-CT consisted of an increase in the percentage of peripheral cytotoxic T lymphocytes ( CTL ) expressing CD56 , reaching a maximum at 48 h post-WBH ( P<0.01 ) . Furthermore , the percentage of CD4+ T cells expressing the T cell activation marker CD69 increased nearly two-fold over time , reaching its maximum at 48 h ( P<0.05 ) . As an additional marker for T cell activation , serum levels of sIL-2R increased markedly ( P<0.01 ) , reaching maximum levels at the same point in time . Elevated intracellular concentrations of interferon-gamma ( IFN-gamma ) and/or TNF-alpha in CD8+ T cells were found in 4 out of 5 patients at 24 h post-WBH-CT . Since similar changes were not observed in patients receiving chemotherapy alone , this is the first study to provide evidence for prolonged WBH-CT-induced activation of human T cells .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12439605"}
{"sentence": "Elevated aerobic glycolysis in cancer cells ( the Warburg effect ) may be attributed to respiration injury or mitochondrial dysfunction , but the underlying mechanisms and therapeutic significance remain elusive . Here we report that induction of mitochondrial respiratory defect by tetracycline-controlled expression of a dominant negative form of DNA polymerase \\u03b3 causes a metabolic shift from oxidative phosphorylation to glycolysis and increases ROS generation . We show that upregulation of NOX is critical to support the elevated glycolysis by providing additional NAD+ . The upregulation of NOX is also consistently observed in cancer cells with compromised mitochondria due to the activation of oncogenic Ras or loss of p53 , and in primary pancreatic cancer tissues . Suppression of NOX by chemical inhibition or genetic knockdown of gene expression selectively impacts cancer cells with mitochondrial dysfunction , leading to a decrease in cellular glycolysis , a loss of cell viability , and inhibition of cancer growth in vivo . Our study reveals a previously unrecognized function of NOX in cancer metabolism and suggests that NOX is a potential novel target for cancer treatment .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "22589701"}
{"sentence": "BACKGROUND Anti-angiogenic treatment of glioblastoma characteristically results in therapy resistance and tumor progression via diffuse infiltration . Monitoring tumor progression in these patients is thwarted because therapy results in tumor invisibility in contrast-enhanced ( CE ) MRI . To address this problem , we examined whether tumor progression could be monitored by metabolic mapping using ( 1)H MR spectroscopic imaging ( MRSI ) . METHODS We treated groups of BALB/c nu/nu mice carrying different orthotopic diffuse-infiltrative glioblastoma xenografts with bevacizumab ( anti-vascular endothelial growth factor [ VEGF ] antibody , n = 13 ) , cabozantinib ( combined VEGF receptor 2/c-Met tyrosine kinase inhibitor , n = 11 ) , or placebo ( n = 15 ) and compared CE-MRI with MRS-derived metabolic maps before , during , and after treatment . Metabolic maps and CE-MRIs were subsequently correlated to histology and immunohistochemistry . RESULTS In vivo imaging of choline/n-acetyl aspartate ratios via multivoxel MRS is better able to evaluate response to therapy than CE-MRI . Lactate imaging revealed that diffuse infiltrative areas in glioblastoma xenografts did not present with excessive glycolysis . In contrast , glycolysis was observed in hypoxic areas in angiogenesis-dependent compact regions of glioma only , especially after anti-angiogenic treatment . CONCLUSION Our data present MRSI as a powerful and feasible approach that is superior to CE-MRI and may provide handles for optimizing treatment of glioma . Furthermore , we show that glycolysis is more prominent in hypoxic areas than in areas of diffuse infiltrative growth . The Warburg hypothesis of persisting glycolysis in tumors under normoxic conditions may thus not be valid for diffuse glioma .", "label": [0, 0, 1, 0, 0, 0, 1, 0, 0, 0], "id": "24158109"}
{"sentence": "It is well established that hyperplasia and decreased apoptosis of airway smooth muscle cells ( ASMCs ) play an important role in the asthmatic airway remodeling . Tumor suppressor PTEN gene with phosphatase activity plays an important regulatory role in embryonic development , cell proliferation , and apoptosis , cell cycle regulation , migration ( invasion ) of the cytoskeleton . We hypotheses that PTEN gene could affect the growth and viability of ASMCs through the regulation of PI3K/Akt , MAPK , and cell cycle-related gene expression . We constructed a recombinant adenovirus to transfect ASMCs . Cells were divided into the overexpression of PTEN gene group ( Ad-PTEN-GFP ) , negative control group ( Ad-GFP ) , and blank control group ( DMEM ) . The cell apoptosis of ASMCs were evaluated by Hoechst-33342 staining and PE-7AAD double-labeled flow cytometry . The cell cycle distribution was observed by flow cytometry with PI staining . The expression of PTEN , p-Akt , total-Akt , p-ERK1/2 , total-ERK1/2 , cleaved-Caspases-3 , Caspases-9 , p21 , and Cyclin D1 were tested by the Western blotting . Our study revealed that overexpression of PTEN gene did not induce apoptosis of human ASMCs cultured in vitro . However , overexpression of PTEN inhibited proliferation of human ASMCs cultured in vitro and was associated with downregulation of Akt phosphorylation levels , while did not affect ERK1/2 phosphorylation levels . Moreover , overexpression of PTEN could induce ASMCs arrested in the G0/G1 phase through the downregulation of Cyclin D1 and upregulation of p21 expressions .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23275086"}
{"sentence": "Angiogenesis , the formation of new blood vessels from pre-existing vascular beds , is essential for tumor growth , invasion , and metastasis . Luteolin is a common dietary flavonoid found in fruits and vegetables . We studied the antiangiogenic activity of luteolin using in vitro , ex vivo , and in vivo models . In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation , migration , invasion and tube formation of endothelial cells , which are key events in the process of angiogenesis . Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay ( CAM ) and matrigel plug assay . Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9 . Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT , ERK , mTOR , P70S6K , MMP-2 , and MMP-9 in HUVECs . Proinflammatory cytokines such as IL-1\u03b2 , IL-6 , IL-8 , and TNF-\u03b1 level were significantly reduced by the treatment of luteolin in PC-3 cells . Luteolin ( 10 mg/kg/d ) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model , indicating that luteolin inhibited tumorigenesis by targeting angiogenesis . CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin . Moreover , luteolin reduced cell viability and induced apoptosis in prostate cancer cells , which were correlated with the downregulation of AKT , ERK , mTOR , P70S6K , MMP-2 , and MMP-9 expressions . Taken together , our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "23300633"}
{"sentence": "The contribution that mitochondrial bioenergetics could have in cancer development is debated . Here , we have generated HCT116-derived colocarcinoma cell lines expressing different levels of the beta catalytic subunit of the mitochondrial H+-adenosine triphosphate synthase to assess the contribution of mitochondrial bioenergetics in colon cancer progression . The generated cells exhibit large ultrastructural , transcriptomic , proteomic and functional differences in their mitochondria and in their in vivo tumor forming capacity . We show that the activity of oxidative phosphorylation defines the rate of glucose utilization by aerobic glycolysis . The aggressive cellular phenotype , which is highly glycolytic , is bound to the deregulated expression of genes involved in metabolic processes , the regulation of the cell cycle , apoptosis , angiogenesis and cell adhesion . Remarkably , the molecular and ultrastructural analysis of the tumors derived from the three HCT116 cell lines under study highlight that tumor promotion inevitably requires the selection of cancer cells with a repressed biogenesis and functional activity of mitochondria , i.e. the highly glycolytic phenotype is selected for tumor development . The tumor forming potential of the cells is a non-genetically acquired condition that provides the cancer cell with a cell-death resistant phenotype . An abrogated mitochondrial respiration contributes to a diminished potential for reactive oxygen species signaling in response to 5-fluorouracil treatment . Treatment of cancer cells with dichloroacetate partially restores the functional differentiation of mitochondria and promotes tumor regression , emphasizing the reversible nature of the metabolic trait of cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20080835"}
{"sentence": "D-type cyclins play a pivotal role in G(1)-S progression of the cell cycle , and their expression is frequently deregulated in cancer . Cyclin D1 has a half-life of only min as a result of its ubiquitylation and proteasomal degradation , with various F-box proteins , including Fbxo4 , Fbxw8 , Skp2 , and Fbxo31 , having been found to contribute to its ubiquitylation . We have now generated Fbxo4-deficient mice and found no abnormalities in these animals . Cyclin D1 accumulation was thus not observed in Fbxo4(-/-) mouse tissues . The half-life of cyclin D1 in mouse embryonic fibroblasts ( MEFs ) prepared from Fbxo4(-/-) , Fbxw8(-/-) , and Fbxo4(-/-) ; Fbxw8(-/-) mice also did not differ from that in wild-type MEFs . Additional depletion of Skp2 and Fbxo31 in Fbxo4(-/-) ; Fbxw8(-/-) MEFs by RNA interference did not affect cyclin D1 stability . Although Fbxo31 depletion in MEFs increased cyclin D1 abundance , this effect appeared attributable to upregulation of cyclin D1 mRNA . Furthermore , abrogation of the function of the Skp1-Cul1-F-box protein ( SCF ) complex or the anaphase-promoting complex/cyclosome ( APC/C ) complexes did not alter the half-life of cyclin D1 , whereas cyclin D1 degradation was dependent largely on proteasome activity . Our genetic analyses thus do not support a role for any of the four F-box proteins examined in cyclin D1 degradation during normal cell cycle progression . They suggest the existence of other ubiquitin ligases that target cyclin D1 for proteolysis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22124152"}
{"sentence": "BACKGROUND Peritoneal transport status is important not only for prescription , but also as a prognostic index . Flt-1 and Flk-1 , the major vascular endothelial growth factor receptors involved in angiogenesis and hyperpermeability , may play a potent role in determining peritoneal transport characteristics . However , the relationship between them has not been studied to date . We hypothesized that Flt-1 and Flk-1 expression in the peritoneal vasculature of uremic patients could be closely related to baseline peritoneal transport status . METHODS Thirty-six new patients without a previous history of peritonitis were enrolled . Clinical parameters such as age , sex , height , weight , causes of renal failure , and residual renal function were assessed . Parietal peritoneal biopsies were obtained during implantation of peritoneal dialytic catheters . Flt-1 and Flk-1 were semi-quantitatively evaluated by immunohistochemical staining . Peritoneal microvascular density ( MVD ) was counted . Within 6 weeks after commencing peritoneal dialysis , a standard peritoneal equilibration test was performed , and the dialysate-to-plasma concentration ratio for creatinine at 4 h ( D4/P Cr ) was determined . The patients were divided into two groups based on the D4/P Cr : more than 0.65 ( Group H , n = 22 ) and less than or equal to 0.65 ( Group L , n = 14 ) . The 24-h peritoneal protein excretion ( PPE ) was assayed . Flt-1 and Flk-1 were correlated with peritoneal MVD , D4/P Cr , and PPE . RESULTS Flt-1 and Flk-1 were detected in the peritoneal vasculature of uremic patients . Flt-1 expression was similar between the two groups , but Flk-1 expression in Group H was significantly higher than that in Group L ( p = 0.001 ) . Flt-1 expression did not show significant correlations with peritoneal MVD , D4/P Cr , and PPE . However , Flk-1 expression showed significant correlations with the above three parameters ( p < 0.001 for all ) . CONCLUSIONS For the first time , the expressions of Flt-1 and Flk-1 in peritoneal vasculature of uremic patients were detected . Flk-1 expression in peritoneal vasculature of uremic patients is closely correlated with the number of peritoneal microvessels , peritoneal small solute transport rate , and PPE . Our findings strongly suggest that Flk-1 may be a crucial determinant of baseline peritoneal transport characteristics . Further interventional studies are needed .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22563920"}
{"sentence": "BACKGROUND Engineered zinc-finger nucleases ( ZFN ) represented an innovative method for the genome manipulation in vertebrates . ZFN introduced targeted DNA double strand breaks ( DSB ) and initiated non-homologous end joining ( NHEJ ) after pronuclear or cytoplasmatic microinjection into zygotes . Resulting frame shift mutations led to functional gene ablations in zebra fish , mice , pigs and also in laboratory rats . Therefore , we targeted the rat Rag1 gene essential for the V(D)J recombination within the immunoglobulin production process and for the differentiation of mature B and T lymphocytes to generate an immunodeficient rat model in the LEW/Ztm strain . RESULTS After microinjection of Rag1 specific ZFN mRNAs in 623 zygotes of inbred LEW/Ztm rats 59 offspring were born from which one carried a 4 bp deletion . This frame shift mutation led to a premature stop codon and a subsequently truncated Rag1 protein confirmed by the loss of the full-length protein in Western Blot analysis . Truncation of the Rag1 protein was characterized by the complete depletion of mature B cells . The remaining T cell population contained mature CD4+/CD3+/TCR\\u03b1\\u03b2+ as well as CD8+/CD3+/TCR\\u03b1\\u03b2+ positive lymphocytes accompanied by a compensatory increase of natural killer cells in the peripheral blood . Reduction of T cell development in Rag1 mutant rats was associated with a hypoplastic thymus that lacked follicular structures . Histological evaluation also revealed the near-complete absence of lymphocytes in spleen and lymph nodes in the immunodeficient Rag1 mutant rat . CONCLUSION The Rag1 mutant rat will serve as an important model for transplantation studies . Furthermore , it may be used as a model for reconstitution experiments related to the immune system , particularly with respect to different populations of human lymphocytes , natural killer cells and autoimmune phenomena .", "label": [0, 1, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23136839"}
{"sentence": "The present study was designed to investigate the protective efficacy of eugenol against skin cancer and probe into the mechanistic aspects . Skin tumors were initiated by applying 160 nmol DMBA and promoted by twice weekly applications of 8.5 nmol TPA for 28 wk . All mice developed tumors by 13 wk of promotion . However , in mice pretreated with 30 microL eugenol , no tumors were detected until 8 wk ( following anti-initiation protocol ) and until 14 wk ( following antipromotion protocol ) of tumor promotion . PCNA and TUNEL immunohistochemistry of tumors revealed eugenol to ameliorate cell proliferation and elevate apoptosis respectively . The effect of eugenol was assessed on specific stages of carcinogenesis . Initiation with DMBA led to a significant upregulation of p53 expression with a concomitant increase in p21(WAF1) levels in epidermal cells indicating induction of damage to the DNA . However , pretreatment with eugenol led to overexpression of these genes , which probably helped stimulate apoptosis of the initiated cells . To ascertain the molecular mechanisms implicated in the antitumor promoting activity of eugenol , its effect was investigated on markers of tumor promotion and inflammation : ODC activity and iNOS and COX-2 expression , and on levels of proinflammatory cytokines ( IL-6 , TNF-alpha , and PGE(2) ) . Eugenol markedly inhibited all . Eugenol also inhibited the upstream signaling molecule : NF-kappaB , which regulates the expression of these genes . TPA-induced depletion of cutaneous GSH and antioxidant enzymes armory was also precluded by eugenol . From these results , it could be concluded that eugenol markedly protects against chemically induced skin cancer and acts possibly by virtue of its antiproliferative , anti-inflammatory , and antioxidant activities .", "label": [0, 0, 0, 0, 1, 1, 0, 1, 1, 1], "id": "20043298"}
{"sentence": "INTRODUCTION AND AIMS The survival of pancreatic cancer patients with portal vein resection is extremely poor due to the high incidence of liver metastasis . The occurrence of liver metastasis is decreased by locoregional arterial infusion after pancreatic surgery . Chemosensitivity tests can provide the basis for individualized chemotherapy in each patient and predict the clinical response . Therefore , the current study was designed to clarify whether locoregional chemotherapy based on the results of chemosensitivity tests has the clinical effects of preventing liver metastasis and improving survival for patients with portal vein resection . METHODOLOGY The resected specimens from 40 of 47 patients with resection of pancreatic cancer were assessed for chemosensitivity to various anticancer drugs . Fourteen patients underwent portal vein resection due to direct invasion , and nine of these patients received intra-arterial adjuvant chemotherapy on the basis of the results of MTT assay to prevent liver metastasis . The remaining five patients received no chemotherapy . RESULTS None of the patients who received intra-arterial chemotherapy had liver metastasis , and this group of patients had improved survival . The mean survival of patients with intra-arterial chemotherapy was significantly longer than that of patients without chemotherapy ( 25.6 months with chemotherapy versus 9.4 months without chemotherapy ) . CONCLUSION A pilot study of postoperative intra-arterial chemotherapy showed the reduction of liver metastasis and improvement of survival among pancreatic cancer patients with portal vein resection .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12409831"}
{"sentence": "PURPOSE BMP-6 , which belongs to the TGF-\u03b2 superfamily , is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis . Our recent research has implied that BMP-6 may suppress breast cancer metastasis . In the present study , we extended to elucidate the molecular mechanism by which BMP-6 exerts its anti-tumorigenic effect . METHODS The Boyden chamber assay was used to examine the ability of BMP-6 and HO-1 in MCF-7 malignant progress . RT-PCR , western blot , luciferase assay , and quantitative CHIP were used to determine the potential mechanism and signaling pathways by which BMP-6 and HO-1 function as anti-metastatic factors in MCF-7 cells . RESULTS The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MCF-7 cells , which effect was significantly deprived by knockdown of HO-1 . We further demonstrated that BMP-6 treatment resulted in an activation of HO-1 transcription through the recruitment of Smad1/5 to the Smad-responsive element on its promoter . In addition , BMP-6-induced up-regulation of HO-1 exhibited an inhibitory effect on MMP-9 secretion in a paracrine action in MCF-7 cells . Overexpression of BMP-6 and HO-1 synergistically suppressed MMP-9 transcription , which effect was specifically mediated via the MAPK/p38/AP-1 signaling . However , blockade of HO-1 using ZnPPIX totally abolished BMP-6-regulated MMP-9 activation in MCF-7 cells . CONCLUSIONS These observations suggest a novel role of BMP-6/HO-1 cascade to relieve breast cancer metastasis by regulating the secretion of growth factors in tumor microenvironment .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21136273"}
{"sentence": "HM781-36B is an orally administered pan-human epidermal growth factor receptor ( HER ) inhibitor . To explore the role of pan-HER inhibitor in breast cancer , we investigated the antitumor effect and mechanisms of HM781-36B in breast cancer cell lines . Six breast cancer cell lines ( BT474 , MDA-MB-453 , SK-BR-3 , T47D , MCF-7 , and MDA-MB-231 ) were tested . The growth inhibitory effect was assessed using the tetrazolium bromide [ 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide ] assay . The cell cycle at various concentrations of HM781-36B was analyzed by flow cytometry , and analysis of downstream molecules was performed by western blot analysis . Interaction of HM781-36B with cytotoxic chemotherapeutic agents was analyzed by combination index using CalcuSyn . The HER2-amplified cells ( SK-BR-3 , BT474 , and MDA-MB-453 ) were sensitive to HM781-36B ( IC50=0.001 \u03bcmol/l , 0.0012 \u03bcmol/l , and 0.0095 \u03bcmol/l , respectively ) . HM781-36B induced G1 arrest and resulted in apoptosis . It reduced the level of p-HER2 , p-AKT , p-ERK , and p-STAT3 . HM781-36B combined with 5-fluorouracil , cisplatin , paclitaxel , or gemcitabine showed a synergistic inhibitory effect on the HER2-amplified and on some of the HER2-nonamplified breast cancer cells . HM781-36B could be a promising treatment for HER2-amplified breast cancer as a single agent or in combination with cytotoxic agents and can be a candidate for treatment of HER2-nonamplified breast cancer in combination with cytotoxic agents .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23422737"}
{"sentence": "The NF-\u03baB is best known for its role in inflammation . Here we show that constitutive NF-\u03baB activity in cancer cells promotes the biosynthesis of redox scavenger glutathione ( GSH ) , which in turn confers resistance to oxidative stress . Inhibition of NF-\u03baB significantly decreases GSH in several lines of human leukemia and prostate cancer cells possessing high or moderate NF-\u03baB activities . Concomitantly , NF-\u03baB inhibition by pharmacological and molecular means sensitizes \" NF-\u03baB positive \" cancer cells to chemically-induced oxidative stress and death . We propose that inhibition of NF-\u03baB can reduce intracellular GSH in \" NF-\u03baB-positive \" cancers thereby improving the efficacy of oxidative stress-based anti-cancer therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20810208"}
{"sentence": "A new line of human ovarian serous adenocarcinoma cells , TU-OS-4 , was established and characterized . The cells showed a short , spindle-shaped morphology and grew in monolayers without contact inhibition while forming an arrangement resembling a jigsaw puzzle . Chromosome numbers ranged from 55 to 73 . The proliferation rate was lower than other serous adenocarcinoma cell lines tested ( KF , SHIN-3 , and SK-OV-3 ) , and the doubling time was 53.3 h . Western blot analysis showed that TU-OS-4 cells overexpressed epidermal growth factor receptor , human epidermal growth factor receptor ( HER ) 2 , and phosphorylated HER2 protein . The IC(50) values to cisplatin , paclitaxel , and lapatinib were 25.8 \\u03bcM , 686 nM , and 183 nM , respectively . Heterotransplantation in nude mice reflected the original tumor of the cells . These results suggested that this cell line would be useful to study chemoresistant mechanisms and contribute to establishing novel treatment strategies for patients with ovarian cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23274876"}
{"sentence": "OBJECTIVE To clarify the relationship between the expression of pol beta and DNA damage /repair induced by Benzo(a)pyrene ( BaP ) . METHODS pol beta wild-type cells ( pol beta +/+ ) , pol beta null cells ( pol beta -/- ) and wild-type pol beta overexpressed cells ( pol beta oe ) which had the same genetic background were studied . Firstly , RT-PCR and Western blot targeting to pol beta were carried out to measure the expression of pol beta mRNA and protein in above three kinds of cells , then MTT test and single cell gel electrophoresis ( comet assay ) were used to compare cell viability and DNA damage/repair of the three kinds of cells when exposed to BaP . RESULTS There was pol beta deletion in pol beta -/- cells and the level of pol beta mRNA and protein in pol beta oe cells was twice higher than that in pol beta +/+ cells . BaP could induce DNA damage and reduce cell viability , when compared with pol beta +/+ cells , IC50 of pol beta -/- cells was remarkably lower , DNA was prone to damage and more difficult to be repaired , on the other hand , IC50 of pol beta oe cells was obviously higher and the damage effect on DNA was weaker and prone to be repaired . CONCLUSION Pol beta played an important role in the repair of DNA damage induced by BaP , deficiency of pol beta could decrease the DNA repair capability of cells , and overexpression of pol beta could help cells response to DNA damage and protect cells from death in a certain degree .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20364579"}
{"sentence": "Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism . Defective autophagy is implicated in human pathology , as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation , oxidative stress , genomic damage , and inflammation . We previously showed that autophagy-defective immortalized mouse mammary epithelial cells are susceptible to metabolic stress , DNA damage , and genomic instability . We now report that autophagy deficiency is associated with endoplasmic reticulum ( ER ) and oxidative stress , and with deregulation of p62-mediated keratin homeostasis in mammary cells , allograft tumors , and mammary tissues from genetically engineered mice . In human breast tumors , high phospho(Ser73)-K8 levels are inversely correlated with Beclin 1 expression . Thus , autophagy preserves cellular fitness by limiting ER and oxidative stress , a function potentially important in autophagy-mediated suppression of mammary tumorigenesis . Furthermore , autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism . High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and , as such , could have therapeutic implications for breast cancer patients .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20530580"}
{"sentence": "In lung cancer , platelet-derived growth factor receptor \u03b1 ( PDGFR\u03b1 ) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors . We sought to determine the effect of targeting stromal PDGFR\u03b1 in preclinical lung tumor xenograft models ( human tumor , mouse stroma ) . Effects of anti-human ( IMC-3G3 ) and anti-mouse ( 1E10 ) PDGFR\u03b1 monoclonal antibodies ( mAb ) on proliferation and PDGFR\u03b1 signaling were evaluated in lung cancer cell lines and mouse fibroblasts . Therapy studies were conducted using established PDGFR\u03b1-positive H1703 cells and PDGFR\u03b1-negative Calu-6 , H1993 , and A549 subcutaneous tumors in immunocompromised mice treated with vehicle , anti-PDGFR\u03b1 mAbs , chemotherapy , or combination therapy . Tumors were analyzed for growth and levels of growth factors . IMC-3G3 inhibited PDGFR\u03b1 activation and the growth of H1703 cells in vitro and tumor growth in vivo , but had no effect on PDGFR\u03b1-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFR\u03b1 activation of mouse fibroblasts , but had no effect on human cancer cell lines in vitro . In vivo , 1E10-targeted inhibition of murine PDGFR\u03b1 reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells . We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFR\u03b1 targeting . We conclude that stromal PDGFR\u03b1 inhibition represents a means for enhancing control of lung cancer growth in some cases , independent of tumor cell PDGFR\u03b1 expression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22933705"}
{"sentence": "BACKGROUND Apigenin , a natural plant flavone , may have chemopreventive and therapeutic potentials for anti-inflammatory , antioxidant , and anti-cancer . Nevertheless , the anti-tumor effect of apigenin on human head and neck squamous cell carcinoma ( HNSCC ) is not fully understood . METHODS The antioxidant capacity and protective effects of apigenin against oxidative stress in murine normal embryonic liver BNLCL2 cells are examined . Cell viability , morphologic change , clonogenic survival , cell cycle distribution , reactive oxygen species ( ROS ) production , glutathione formation , and death receptors- and Bcl-2-mediated caspase pathways of HNSCC SCC25 cells and A431 cells with apigenin are investigated . RESULTS Apigenin inhibits the growth of SCC25 and A431 cells and induces cell cycle arrest in the G2/M phase . Apigenin has an antioxidant capacity as well as the ability to inhibit lipid peroxidation . It protects BNLCL2 cells against oxidative damage , and is potentially able to prevent cancer . Apigenin increases intracellular ROS levels and reduces levels of glutathione ; it also induces cell apoptosis via tumor necrosis factor receptor ( TNF-R)- , TNF-related apoptosis-inducing ligand receptor ( TRAIL-R)- , and Bcl-2-mediated caspase-dependent cell death pathways in SCC25 cells . The combination of apigenin with 5-fluorouracil ( 5-Fu ) or cisplatin induces the dramatic death of SCC25 cells . CONCLUSIONS Apigenin induces SCC25 cell apoptosis via the up-regulation of both TNF-R and TRAIL-R signaling pathways , and has a synergistic effect on the inhibition of cell proliferation in combination with 5-Fu or cisplatin . GENERAL SIGNIFICANCE These analytical findings suggest that apigenin may be a good therapeutic agent against HNSCC cells .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 1, 1], "id": "22554915"}
{"sentence": "Changes at the invariable donor splice site +1 guanine , relatively frequent in human genetic disease , are predicted to abrogate correct splicing , and thus are classified as null mutations . However , their ability to direct residual expression , which might have pathophysiological implications in several diseases , has been poorly investigated . As a model to address this issue , we studied the IVS6+1G>T mutation found in patients with severe deficiency of the protease triggering coagulation , factor VII ( FVII ) , whose absence is considered lethal . In expression studies , the IVS6+1G>T induced exon 6 skipping and frame-shift , and prevented synthesis of correct FVII transcripts detectable by radioactive/fluorescent labelling or real-time RT-PCR . Intriguingly , the mutation induced the activation of a cryptic donor splice site in exon 6 and production of an in-frame 30bp deleted transcript ( 8 \u00b1 2% ) . Expression of this cDNA variant , lacking 10 residues in the activation domain , resulted in secretion of trace amounts ( 0.2 \u00b1 0.04% ) of protein with appreciable specific activity ( 48 \u00b1 16% of wt-FVII ) . Altogether these data indicate that the IVS6+1G>T mutation is compatible with the synthesis of functional FVII molecules ( of normal , 1pM ) , which could trigger coagulation . The low but detectable thrombin generation ( 352 \u00b1 55nM ) measured in plasma from an IVS6+1G>T homozygote was consistent with a minimal initiation of the enzymatic cascade . In conclusion , we provide experimental clues for traces of FVII expression , which might have reverted an otherwise perinatally lethal genetic condition .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22426302"}
{"sentence": "Breast cancer includes high number of molecular entities targetable by specific agents . In this study , array CGH and PIK3CA/AKT1 mutations were used to drive patients into targeted therapy . A prospective molecular analysis was offered to metastatic breast cancer patients for whom samples were collected prospectively or retrospectively either from frozen or paraffin-embedded tissue . Analyses were performed using array CGH ( Agilent platform ) and PIK3CA ( exon 10 and 21 ) and AKT1 mutations were explored by standard Sanger sequencing . One hundred and eight patients were included . Good quality CGH was obtained in 79% cases and was better for frozen samples . Genomic alterations were identified in 50% of patients including 11 PIK3CA and 8 AKT1 mutations . Eighteen treatments ( 17 patients ) were administered according to their molecular profile with evidence of activity in nine . Reasons for not providing a genomic-driven treatment included absence of progressive disease ( 38% ) , investigator's choice ( 9% ) , rapid PD ( 19% ) , and no drug access ( 21% ) . Array CGH correctly identified Her2 status in 97% cases ; failures were related to low % of tumour cells . Our study showed that array CGH is feasible in the context of daily practice and , in combination with PIK3CA/AKT1 mutations , identifies a significant number of actionable molecular alterations that allow driving patients into specific targeted agents .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22840369"}
{"sentence": "Ruthenium(II) methylimidazole complexes , with the general formula [ Ru(MeIm)(4)(N\u2322N)](2+) ( N\u2322N=tip ( RMC1 ) , iip ( RMC2 ) , dppz ( RMC3 ) , dpq ( RMC4 ) ; MeIm=1-methylimidazole , tip=2-(thiophene-2-yl)-1H-imidazo [ 4,5-f ] [ 1,10]phenanthroline , iip=2-(1H-imidazol-4-yl)-1H-imidazo [ 4,5-f ] [ 1,10]phenanthroline , dppz=dipyrido[3,2-a:2',3'-c]phenazine , dpq=pyrazino [ 2,3-f ] [ 1,10]phenanthroline ) , were synthesized and characterized . As determined by MTT ( 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ) assay , these complexes displayed potent anti-proliferation activity against various cancer cells . RMC1 inhibited the growth of A549 ( human lung adenocarcinoma ) lung cells through induction of apoptotic cell death , as evidenced by the accumulation of cell population in sub-G1 phase . RMC1 also induced the depletion of mitochondrial membrane potential in A549 cells by regulating the expression of pro-survival and pro-apoptotic Bcl-2 family members . Another experiment showed that Bid protein was also activated by RMC1 , which implied that RMC1 could existed two pathways crosstalk , namely , have exogenous death receptor signaling pathway . These results demonstrated that RMC1 induced cancer cell death by acting on both mitochondrial and death receptor apoptotic pathways , suggesting that RMC1 could be a candidate for further evaluation as a chemotherapeutic agent against human cancers .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21816206"}
{"sentence": "The ubiquitin-proteasome system ( UPS ) promotes the timely degradation of short-lived proteins with key regulatory roles in a vast array of biological processes , such as cell cycle progression , oncogenesis and genome integrity . Thus , abnormal regulation of UPS disrupts the protein homeostasis and causes many human diseases , particularly cancer . Indeed , the FDA approval of bortezomib , the first class of general proteasome inhibitor , for the treatment of multiple myeloma , demonstrated that the UPS can be an attractive anti-cancer target . However , normal cell toxicity associated with bortezomib , resulting from global inhibition of protein degradation , promotes the focus of drug discovery efforts on targeting enzymes upstream of the proteasome for better specificity . E3 ubiquitin ligases , particularly those known to be activated in human cancer , become an attractive choice . Cullin-RING Ligases ( CRLs ) with multiple components are the largest family of E3 ubiquitin ligases and are responsible for ubiquitination of of cellular proteins degraded through UPS . Activity of CRLs is dynamically regulated and requires the RING component and cullin neddylation . In this review , we will introduce the UPS and CRL E3s and discuss the biological processes regulated by each of eight CRLs through substrate degradation . We will further discuss how cullin neddylation controls CRL activity , and how CRLs are being validated as the attractive cancer targets by abrogating the RING component through genetic means and by inhibiting cullin neddylation via MLN4924 , a small molecule indirect inhibitor of CRLs , currently in several Phase I clinical trials . Finally , we will discuss current efforts and future perspectives on the development of additional inhibitors of CRLs by targeting E2 and/or E3 of cullin neddylation and CRL-mediated ubiquitination as potential anti-cancer agents .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23151137"}
{"sentence": "BACKGROUND Detection of disease-causing mutations using Deep Sequencing technologies possesses great challenges . In particular , organizing the great amount of sequences generated so that mutations , which might possibly be biologically relevant , are easily identified is a difficult task . Yet , for this assignment only limited automatic accessible tools exist . FINDINGS We developed GenomeGems to gap this need by enabling the user to view and compare Single Nucleotide Polymorphisms ( SNPs ) from multiple datasets and to load the data onto the UCSC Genome Browser for an expanded and familiar visualization . As such , via automatic , clear and accessible presentation of processed Deep Sequencing data , our tool aims to facilitate ranking of genomic SNP calling . GenomeGems runs on a local Personal Computer ( PC ) and is freely available at http://www.tau.ac.il/ CONCLUSIONS GenomeGems enables researchers to identify potential disease-causing SNPs in an efficient manner . This enables rapid turnover of information and leads to further experimental SNP validation . The tool allows the user to compare and visualize SNPs from multiple experiments and to easily load SNP data onto the UCSC Genome browser for further detailed information .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22748151"}
{"sentence": "Bone is the second most common metastatic site in patients with renal cell carcinoma presenting with metastases ( mRCC ) at diagnosis . Complications of metastatic bone disease , including bone pain , fractures , spinal cord compression , and hypercalcaemia , are the primary cause of decline in the quality of life of patients with mRCC . Currently , treatment for mRCC bone metastases is generally palliative . Bisphosphonates are also used ; however , the efficacy of bisphosphonates in conjunction with targeted agents is currently unknown . As growth factors play a critical role in the development of bone metastases , there is a biological rationale for the use of targeted agents to treat them . We report here the case of two patients with mRCC with surgically unresectable sacral bone metastases treated with sunitinib , who are still alive with long-term stabilization of metastases of 48 and 31 months . Results suggest targeted agents such as sunitinib may be an effective treatment for bone metastases .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21187506"}
{"sentence": "OBJECTIVE To investigate the expression profiles of serum Golgi protein-73 ( GP73 ) in liver cirrhosis and primary hepatic carcinoma ( PHC ) and determine its clinical value for differential diagnosis . METHODS Serum protein expressions of GP73 and alpha-fetoprotein ( AFP ) were detected by enzyme-linked immunosorbent assay and chemiluminescence assay , respectively , in patients with PHC ( n=80 ) , liver cirrhosis ( n=65 ) , and healthy controls ( n=50 ) . Inter-group changes were assessed by Kruskal-Wallis test , and significance of these differences was assessed by Mann- Whitney test . A receiver operating characteristic ( ROC ) curve was plotted to evaluate the diagnostic efficiency and determine the cut-off values for GP73 and AFP . Sensitivity and specificity were compared by the Chi-squared test . Correlation between serum GP73 expression and clinical parameters was determined by Spearman's rank correlation analysis . RESULTS The PHC group showed significantly higher serum GP73 ( 282.0 mug/L ) than the liver cirrhosis group ( 211.8 mug/L ) and control group ( 58.3 mug/L ) ( H = 93.30 , P less than 0.01 ) . For differential diagnosis of PHC and liver cirrhosis , the cut-off value was 318.1 mug/L for GP73 and 13.4 mug/L for AFP . Sensitivity of GP73 was lower than AFP ( 45% ( 36/80 ) vs. 65% ( 52/80 ) ; X2 = 8.02 , P less than 0.05 ) . Specificity of GP73 was lower than AFP but no significance was found ( 83.1% ( 54/65 ) vs. 87.7% ( 57/65 ) ; X2=0.27 , P more than 0.05 ) . The areas under the ROC curves were not significantly different between GP73 and AFP ( 0.65 ( 95% confidence interval ( CI ) : 0.54 vs. 0.75 ( 95% CI : 0.67 Z = 1.88 , P more than 0.05 ) . The area under the ROC curves increased but not significantly ( 0.80 ( 95% CI : 0.73 vs. 0.75 ( 95% CI : 0.67 Z=2.61 , P more than 0.05 ) . Serum GP73 was correlated with liver cirrhosis ( r=0.27 ) , vascular invasion ( r=0.29 ) , and TNM staging ( r=0.27 ) ( all P less than 0.05 ) , but not with sex ( r=0.13 ) , age ( r=0.10 ) , enhanced AFP ( > 13.4 mug/L ; r=0.03 ) , tumor size ( r=0.18 ) , or distant metastasis ( r=0.04 ) , all P less than 0.05 . CONCLUSION Serum GP73 and AFP have comparable diagnostic efficiency , but the sensitivity of AFP is superior for differential diagnosis of liver cirrhosis and primary hepatic carcinoma . Elevated serum GP73 may be correlated with liver tumor load and aggressiveness .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23522254"}
{"sentence": "Breast cancer incidence is increased in women receiving menopausal hormone therapy with estrogen plus progestin but not with estrogen alone . The use of a tissue-selective estrogen complex ( TSEC ) has been proposed as a novel menopausal hormone therapy strategy to eliminate the requirement for a progestogen . Combination of bazedoxifene ( BZA ) with conjugated estrogens ( CEs ) , the first TSEC , has shown beneficial effects . Whether it would exert antiestrogenic effects on breast cancer is not clear . To address this issue , we compared estradiol ( E(2) ) and CE alone on proliferation and apoptosis in MCF-7 breast cancer cells . CE stimulated growth of MCF-7 cells at a peak concentration 10-fold higher than required for E(2) . Both CE and E(2) alone increased DNA synthesis and reduced apoptosis with activation of MAPK , Akt , and p70S6K and up-regulation of antiapoptotic factors survivin , Bcl-2 , and X-linked inhibitor of apoptosis protein , These effects could be completely blocked by BZA . Gene expression studies demonstrated that CE and E(2) were equally potent on expression of cMyc , pS2 , and WNT1 inducible signaling pathway protein 2 , whereas the stimulatory effects of CE on progesterone receptor and amphiregulin expression were weaker than E(2) . BZA effectively blocked each of these effects and showed no estrogen agonistic effects when used alone . Our results indicate that the stimulatory effects of E(2) or CE on breast cancer cells could be completely abrogated by BZA . These studies imply that the CE/BZA , TSEC , exerts antiestrogenic effects on breast cancer cells and might block the growth of occult breast neoplasms in postmenopausal women , resulting in an overall reduction in tumor incidence .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23254198"}
{"sentence": "Plitidepsin ( Aplidin ) , an antitumor agent of marine origin , presently is undergoing phase II/III clinical trials , and has shown promise for the treatment of lymphoma . Here , we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death . Several Diffuse Large Cell Lymphoma ( DLCL ) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituximab . All DLCL and Burkitt lymphoma cell lines were inhibited by plitidepsin in nanomolar concentrations , while rituximab sensitivity varied among different cell lines . Ramos and the RL cell lines proved sensitive to rituximab and were used to test the effects of each of the two drugs . The two agents exhibited synergism at all tested concentrations . For in vivo studies , irradiated athymic nude mice were engrafted with the Ramos lymphoma . Treatment was initiated when the tumors were cm in diameter , and toxic and therapeutic effects were monitored . In the in vivo study , additive effects of the combined two drugs , was demonstrated without an increase in host toxicity . The in vitro synergy and the in vivo additive antitumor effects without an increase in host toxicity with two relatively non-marrow suppressive agents encourages further development of this combination for treatment of aggressive B-cell lymphomas .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22336911"}