{"sentence": "Hypoxic events frequently occur in the aquatic environment in association with micro pollutants , including heavy metals . Only a few studies are however available on the uptake and biological responses of heavy metals under hypoxic conditions . To elucidate the phenomenon , mirror carp Cyprinus carpio L . ( 16.13-16.22 g ) were exposed chronically to dietary copper ( Cu ; 250 and 500 mg kg dry wt.(-1) ) for 30 d under normoxic ( 8.25 mg O(2) L(-1) ) and hypoxic ( mg O(2) L(-1) ) conditions and adopting an integrated approach , sub-lethal biomarker responses were determined at different levels of biological organisation . Level of oxidative DNA damage ( as determined by modified Comet assay ) showed strong significant difference following exposure to dietary Cu level under normoxic ( 1.6-fold ) as well as under hypoxic condition at both Cu levels ( 2.1 and 2.5-folds respectively ) . Significant difference was also observed for haematological parameters ( i.e. increased red and white blood cells , haematocrit value and haemoglobin concentration ) . Quantitative histology revealed alterations in tissues ( i.e. liver and gills ) for hypoxic and all dietary Cu treatment groups under both normoxic and hypoxic conditions suggesting a compensatory response to these organs ( p<0.05 ) . The order of Cu accumulation in tissues ( as determined by ICP-OES ) was liver>intestine>kidney>gill . Interestingly , SGR under both normoxic and hypoxic conditions reduced with elevating Cu levels ( p=0.019 ) . Overall , the results provide evidence for enhanced toxicological responses in fish following exposure to Cu either alone or in combination with hypoxic condition and lends support to the evolving viewpoint that many water quality guidelines should be revisited in terms of new ecotoxicological criteria .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22239943"}
{"sentence": "A 51-year-old previously healthy man , an ex-smoker , was admitted to the authors ' medical department with a 3-month history of dry cough ; intermittent fever ; painless , ulcerated cutaneous lesions over the trunk and limbs ( Figure 1 ) ; and progressive weight loss . He was of Greek descent . His medical history was remarkable for nasal polyps , which were surgically removed 15 years earlier . Initially , he had been treated with antibiotics , without improvement . Several days before admission , chest radiography revealed pulmonary infiltrates in the left lower lobe . On admission , physical examination revealed a well-orientated man in mild distress , with inspiratory rhonchi at the lower part of the left lung and scattered erythematous nodules of variable size , some of which were ulcerated . Laboratory values were notable for leukopenia , 3.3 x 10(9)/L ; total protein , 5.9 g/dL ; globulin , 2.2 g/dL ; serum glutamic oxaloacetic transaminase , 86 IU/L ; serum glutamic pyruvic transaminase , 71 IU/L ; and lactate dehydrogenase , 519 U/L . Computed tomograph ( CT ) of the chest showed multiple alveolar opacities bilaterally ( Figure 2 ) . Fiberoptic bronchoscopy did not reveal any important pathologic findings . Results of bronchial biopsy , cytology of bronchoalveolar lavage , washing , brushing , and sputum following bronchoscopy were negative . CT of the brai and sinonasal area revealed an abnormal low-density mass in the left nasal area . CT findings of the abdomen were negative , as were results of a bone marrow biopsy . There was no evidence of immunosuppression . The differential diagnosis , considering the evidence described , included granulomatous or infectious diseases , angiocentric lymphoproliferative lesions , and lymphomas . Biopsy of a skin lesion showed lymphoproliferative infiltration of the dermis with a follicular and angiocentric growth pattern and regional epidermal necrosis . Immunohistochemical stains showed that the tumor cell were positive for CD56 and CD3 ( cytoplasmic positivity ) and expressed the cytotoxic proteins T-cell intracellular antigen and granzyme B ( Figure 3 ) They lacked TdT , CD34 , CD7 , CD8 , TCL-1 , and CD123 . Findings from an in situ hybridization study for Epstein-Barr virus were negative . Give this result , molecular analysis ofT-cell receptor ( TCR ) gene rearrangements was performed using polymerase chain reaction-based TCR-gamma gene , wit negative results . The morphology and the immunophenotype were consistent with natural killer/T-cell lymphoma , nasal-type . Nasal involvement must be first excluded to proceed to the diagnosis of nasal-type natural killer-cell lymphoma . Indeed , histologic examination of the nasal mass revealed its polypoid nature . Thus , the authors were led to the diagnosis of extranodal extranasal natural killer/T-cell lymphoma , nasal-type , CD56-positive , Ep stein-Barr virus-negative , TCR-negative . The patient received combination chemotherapy and completed 4 cycles of cyclophosphamide , doxorubicin vincristine , and prednisone every 14 days for 2 months . Skin lesions improved , and there was no fever soon after the initiation of therapy . Reevaluatio after the fourth cycle , however , disclosed pulmonary infiltrations as well as leukemic infiltration of the central nervous system . The patient had receive systemic salvage chemotherapy and intrathecal infusions of methotrexate . Although the lung lesions had diminished at that time , the patient develope paraplegia , his clinical course rapidly deteriorated , and he eventually died .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20839428"}
{"sentence": "MicroRNAs ( miRs ) are small non-coding RNAs that recently emerged as potent regulators of gene expression . The members of the miR-17-92 cluster have been shown to control endothelial cell functions and neovascularization ; however , the regulation and function of the cluster in endothelial cell lineage commitment has not been explored . This project aimed to test the role of the miR-17-92 cluster during endothelial differentiation . We demonstrate that miR-17 , miR-18 , miR-19 and miR-20 are increased upon the induction of endothelial cell differentiation of murine embryonic stem cells or induced pluripotent stem cells . In contrast , miR-92a and the primary miR-17-92 transcript were downregulated . The inhibition of each individual miR of the cluster by cholesterol-modified antagomirs did not affect endothelial marker gene expression . Moreover , the combination of all antagomirs had no effect . These findings illustrate that although the miR-17-92 cluster regulates vascular integrity and angiogenesis , none of the members has a significant impact on the endothelial differentiation of pluripotent stem cells .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22797777"}
{"sentence": "The solution structure of the complex of enzyme IIA of the N,N'-diacetylchitobiose ( Chb ) transporter with the histidine phosphocarrier protein HPr has been solved by NMR . The IIA(Chb)-HPr complex completes the structure elucidation of representative cytoplasmic complexes for all four sugar branches of the bacterial phosphoryl transfer system ( PTS ) . The active site His-89 of IIA(Chb) was mutated to Glu to mimic the phosphorylated state . IIA(Chb)(H89E) and HPr form a weak complex with a K(D) of mM . The interacting binding surfaces , concave for IIA(Chb) and convex for HPr , complement each other in terms of shape , residue type , and charge distribution , with predominantly hydrophobic residues , interspersed by some uncharged polar residues , located centrally , and polar and charged residues at the periphery . The active site histidine of HPr , His-15 , is buried within the active site cleft of IIA(Chb) formed at the interface of two adjacent subunits of the IIA(Chb) trimer , thereby coming into close proximity with the active site residue , H89E , of IIA(Chb) . A His89-P-His-15 pentacoordinate phosphoryl transition state can readily be modeled without necessitating any significant conformational changes , thereby facilitating rapid phosphoryl transfer . Comparison of the IIA(Chb)-HPr complex with the IIA(Chb)-IIB(Chb) complex , as well as with other cytoplasmic complexes of the PTS , highlights a unifying mechanism for recognition of structurally diverse partners . This involves generating similar binding surfaces from entirely different underlying structural elements , large interaction surfaces coupled with extensive redundancy , and side chain conformational plasticity to optimize diverse sets of intermolecular interactions .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22593574"}
{"sentence": "Immunosuppression of humoral and cellular responses following chronic oral exposure to 1 , 5 , 10 , and 20 ppm N-nitrosodimethylamine ( NDMA ) was examined in CD-1 mice . Monitoring of cumulative mortality and the incidence of peritoneal ascites in animals showed an NDMA dose-related mortality and hepatotoxicity . No visible changes in immunological parameters were noted at the 1 ppm NDMA dose . Immunosuppression of immunoglobulin M ( IgM ) antibody response by NDMA to sheep red blood cells ( SRBC ) was time-related , dose-related , and could be reversed within 30 d by removal of the chemical from the drinking water . Cellular immune response , monitored by allogeneic stimulation of cells in mixed lymphocyte reaction ( MLR ) , was markedly suppressed by 10 and 20 ppm NDMA . Thus , chronic exposure to NDMA , except for the low-hepatotoxic doses of nitrosamine , resulted in a marked and persistent immunosuppression of cellular and humoral responses in CD-1 mice . In conclusion , chronic exposure to the hepatotoxic ( ascite-inducing ) doses of NDMA suppressed humoral and cellular immunity . The persistent immunosuppression could be reversed after the removal of NDMA from the drinking water . Although no direct NDMA-related cancer was reported in humans , our data point to a potential epigenetic carcinogenicity of nitrosamines due to chronic immunosuppression .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1433375"}
{"sentence": "AIMS Tumour cell growth results from a disturbance in the balance between the rate of proliferation and cell death . In this study , proteins involved in the regulation of cell cycle arrest and apoptosis were studied as possible factors responsible for uncontrolled cell growth in colorectal cancer . METHODS The expression of proteins involved in these processes was investigated in 48 metastases from patients with colorectal cancer and compared with eight normal colon mucosa samples and 14 primary tumours . Both primary tumours and metastases were obtained from eight patients . The expression of thymidylate synthase ( TS ) , p53 , retinoblastoma protein ( Rb ) , Fas receptor , Fas ligand , bcl-2 , mcl-1 , bax , and bcl-x was measured using immunohistochemistry . Proliferation was determined by Ki67 staining , whereas apoptosis was assessed by M30 immunostaining , which recognises cleaved cytokeratin 18 . RESULTS In the limited number of cases in which paired comparisons were possible , the expression of TS and Ki67 was significantly higher in metastases than in the matched primary tumour samples ( p = 0.014 and 0.016 , respectively ) , whereas Rb expression was lower in metastases than in primary tumours ( p = 0.024 ) . Fas receptor expression was high in normal mucosa but absent in primary tumours and metastases , whereas the opposite was seen for p53 . The expression of bax , mcl-1 , and bcl-x in normal mucosa was more apical than that seen in malignant cells , where a more diffuse expression pattern was seen ( p < 0.04 ) . Apoptosis was more abundant in primary tumours than in metastases . CONCLUSIONS These results demonstrate that proliferation and apoptosis are disturbed during colorectal cancer progression , and this is accompanied by loss of Rb and Fas expression , the accumulation of p53 and TS , and changes in the expression patterns of bax , mcl-1 , and bcl-xl .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "11896073"}
{"sentence": "The radioprotective effects of dimethyl sulfoxide ( DMSO ) have been known for many years , and the suppression of hydroxyl ( OH ) radicals induced by ionizing radiation has been thought to be the main cause of this effect . However , the DMSO concentration used was very high , and might be toxic , in earlier studies . In the present study , we administered a lower , non-toxic concentration ( 0.5% , i.e. , 64 mM ) of DMSO before irradiation and examined its radioprotective effects . Colony formation assay and micronucleus assay showed significant radioprotective effects in CHO , but not in xrs5 , which is defective in the repair function of DNA double-strand breaks . The levels of phosphorylated H2AX and the formation of 53BP1 foci 15 minutes after irradiation , which might reflect initial DNA double-strand breaks , in DMSO-treated CHO cells were similar to those in non-treated cells , suggesting that the radioprotective effects were not attributable to the suppression of general indirect action in the lower concentration of DMSO . On the other hand , 2 hours after irradiation , the average number of 53BP1 foci , which might reflect residual DNA double-strand breaks , was significantly decreased in DMSO-treated CHO cells compared to non-treated cells . The results indicated that low concentration of DMSO exerts radioprotective effects through the facilitation of DNA double-strand break repair rather than through the suppression of indirect action .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21116101"}
{"sentence": "Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases . However , the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood . In this study , we have determined that androgens regulate overall cell metabolism and cell growth , in part , by increasing autophagy in prostate cancer cells . Importantly , inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogated androgen-induced prostate cancer cell growth . Mechanistically , androgen-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation , an effect previously demonstrated to be necessary for prostate cancer cell growth . Further , autophagy and subsequent cell growth is potentiated , in part , by androgen-mediated increases in reactive oxygen species . These findings demonstrate a role for increased fat metabolism and autophagy in prostatic neoplasias and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23250485"}
{"sentence": "Cis-diamminedichloroplatinum ( II ) ( cisplatin ) is a well characterized antitumor drug used for the treatment of a variety of human cancers . The cytotoxicity of cisplatin is mainly mediated through the formation of DNA adducts , which are also believed to be responsible for the secondary malignancies produced by the drug . The aim of this study was to determine the in vivo mutagenic activity of cisplatin in the lacZ plasmid-based transgenic mouse model . The mutant frequency ( MF ) and the spectrum of mutations induced by cisplatin in the mouse liver were analyzed and compared to controls . The mean MF in the lacZ gene was increased 2-fold in mice treated with a single 6 mg/kg body weight dose of cisplatin and sacrificed after 17 and 28 days ( P = 0.001 and P < 0.0001 ) . Restriction analysis and sequencing of mutant DNA showed that cisplatin was able to induce both large deletions and point mutations . A specific profile of base substitution and frameshift mutations was identified in treated mice , consisting primarily of G:C-->A:T transitions at GpG and ApG sites , the preferential DNA binding sites of cisplatin , and single basepair deletions/insertions . The present results provide the first evidence that cisplatin has mutagenic activity in vivo and induces a characteristic pattern of mutations in the mouse liver . This mutagenicity may be responsible for its tumorigenic activity .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12489119"}
{"sentence": "A prominent feature of inflammatory diseases is endothelial dysfunction . Factors associated with endothelial dysfunction include proinflammatory cytokines , adhesion molecules , and matrix degrading enzymes . At the transcriptional level , they are regulated by the histone deacetylase sirtuin ( SIRT ) 1 via its actions on the proinflammatory transcription factor nuclear factor-\u03baB ( NF-\u03baB ) . The role of SIRT6 , also a histone deacetylase , in regulating inflammation in endothelial cells is not known . The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells ( HUVECs ) in the presence of lipopolysaccharide ( LPS ) . LPS decreased expression of SIRT6 in HUVECs . Knockdown of SIRT6 increased the expression of proinflammatory cytokines ( IL-1\u03b2 , IL-6 , IL-8 ) , COX-prostaglandin system , ECM remodelling enzymes ( MMP-2 , MMP-9 and PAI-1 ) , the adhesion molecule ICAM-1 , and proangiogenic growth factors VEGF and FGF-2 ; cell migration ; cell adhesion to leukocytes . Loss of SIRT6 increased the expression of NF-\u03baB , whereas overexpression of SIRT6 was associated with decreased NF-\u03baB transcriptional activity . Taken together , these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation , vascular remodelling , and angiogenesis . SIRT6 may be a potential pharmacological target for inflammatory vascular diseases .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23132960"}
{"sentence": "MicroRNAs ( miRNAs ) are small noncoding RNAs , 19-24 nucleotides in length , that regulate gene expression and are expressed aberrantly in most types of cancer . MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers . It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs . Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism , by binding as ligands to receptors of the Toll-like receptor ( TLR ) family , murine TLR7 and human TLR8 , in immune cells , triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis . Thus , by acting as paracrine agonists of TLRs , secreted miRNAs are key regulators of the tumor microenvironment . This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread , thus representing a possible target for cancer treatment .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22753494"}
{"sentence": "The aim of the present study was to isolate endothelial cells from tooth buds ( unerupted deciduous teeth ) of miniature swine . Mandibular molar tooth buds harvested from swine fetuses at fetal days90-110 were cultured in growth medium supplemented with 15% fetal bovine serum in 100-mm culture dishes until the primary cells outgrown from the tooth buds reached confluence . A morphologically defined set of pavement-shaped primary cells were picked up manually with filter paper containing trypsin/ethylenediamine tetraacetic acid solution and transferred to a separate dish . A characterization of the cellular characteristics and a functional analysis of the cultured cells at passages 3 to 5 were performed using immunofluorescence , a reverse transcriptase polymerase chain reaction assay , a tube formation assay , and transmission electron microscopy . The isolated cells grew in a pavement arrangement and showed the characteristics of contact inhibition upon reaching confluence . The population doubling time was at passage 3 . As shown by immunocytostaining and western blotting with specific antibodies , the cells produced the endothelial marker proteins such as vascular endothelial cadherin , von Willebrand factor , and vascular endothelial growth factor receptor-2 . Observation with time-lapse images showed that small groups of cells aggregated and adhered to each other to form tube-like structures . Moreover , as revealed through transmission electron microscopy , these adherent cells had formed junctional complexes . These endothelial cells from the tooth buds of miniature swine are available as cell lines for studies on tube formation and use in regenerative medical science .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23435856"}
{"sentence": "Glioma tumors are refractory to conventional treatment . Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans . In this study , we introduce oxidative stress-energy depletion ( OSED ) therapy as a new suggested treatment for glioblastoma . OSED utilizes D-amino acid oxidase ( DAO ) , which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide ( H2O2 ) . OSED combines DAO with 3-bromopyruvate ( 3BP ) , a hexokinase II ( HK II ) inhibitor that interferes with Warburg effect , a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis . Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action . C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation , clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes . DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley ( SD ) rats , especially after combination with 3BP . OSED treatment was safe and tolerable in SD rats . OSED therapy may be a promising therapeutic modality for glioma .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "21921941"}
{"sentence": "Solar ultraviolet radiation is considered to be injurious rather than necessary for most organisms living on the earth . It is reported that the risk of skin cancer in humans increases by the depletion of the ozone layer . We have examined the genotoxicity of solar ultraviolet , especially the longer wavelength light , using Drosophila . Recently , we have demonstrated that light of wavelength up to 340 nm is mutagenic on Drosophila larvae . Using an excision repair-deficient Drosophila strain ( mus201 ) , we have obtained results suggesting that the lesion caused in larvae by the 320 nm-light irradiation may be similar to the damage induced by irradiation at 310 nm , and that light of 330 and 340 nm may induce damage different from that induced by 310 and 320 nm-light . To examine the difference in DNA damage induced by light of a particular wavelength , we performed monochromatic irradiation on larvae of two Drosophila strains ; one excision repair-deficient ( mei-9 ) and another postreplication repair-deficient ( mei-41). 310 and 320 nm-light was more mutagenic in the mei-9 strain than in mei-41 , whereas 330 and 340 nm-light was more mutagenic in mei-41 than in mei-9 . It is demonstrated that the mei-41 gene is a homologue of the human atm gene which is responsible for a cell cycle checkpoint . This result suggests that 310-320 nm-light induces DNA damage that is subject to nucleotide excision repair ( NER ) and that 330-360 nm-light causes damage to be recognized by the cell cycle checkpoint but it is not repairable by NER .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "12659514"}
{"sentence": "Genetic immunotherapy with tumor antigen gene-modified dendritic cells ( DC ) generates robust immunity , although antitumor protection is not complete in all models . Previous experience in a model in which C57BL/6 mice immunized with DC transduced with adenoviral vectors expressing MART-1 demonstrated a 20-40% complete protection to a tumor challenge with B16 melanoma cells . Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in na\ufffdve mice . In the present study , we wished to determine if the supraphysiological production of the Th1-skewing cytokine interleukin-12 ( IL-12 ) could enhance immune activation and antitumor protection in this model . In a series of experiments immunizing mice with DC cotransduced with MART-1 and IL-12 , antitumor protection and antigen-specific splenocyte cytotoxicity and interferon gamma production inversely correlated with the amount of IL-12 produced by DC . This adverse effect of IL-12 could not be explained by a direct cytotoxic effect of natural killer cells directed towards DC , nor the production of nitric oxide leading to down-regulation of the immune response - the two mechanisms previously recognized to explain immune-suppressive effects of IL-12-based vaccine therapy . In conclusion , in this animal model , IL-12 production by gene-modified DC leads to a cytokine-induced dose-dependent inhibition of antigen-specific antitumor protection .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12386826"}
{"sentence": "Recently , the use of gold nanoparticles as potential tumor selective radiosensitizers has been proposed as a breakthrough in radiotherapy . Experiments in living cells and in vivo have demonstrated the efficiency of the metal nanoparticles when combined with low energy x-ray radiations ( below conventional 1 MeV Linac radiation ) . Further studies on DNA have been performed in order to better understand the fundamental processes of sensitization and to further improve the method . In this work , we propose a new strategy based on the combination of platinum nanoparticles with irradiation by fast ions effectively used in hadron therapy . It is observed in particular that nanoparticles enhance strongly lethal damage in DNA , with an efficiency factor close to 2 for double strand breaks . In order to disentangle the effect of the nano-design architecture , a comparison with the effects of dispersed metal atoms at the same concentration has been performed . It is thus shown that the sensitization in nanoparticles is enhanced due to auto-amplified electronic cascades inside the nanoparticles , which reinforces the energy deposition in the close vicinity of the metal . Finally , the combination of fast ion radiation ( hadron therapy ) with platinum nanoparticles should strongly improve cancer therapy protocols .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20101074"}
{"sentence": "Over the past two decades , bioactive natural compounds have been shown to be a plausible adjunct to the treatment of breast cancer , the second leading cause of cancer death among American women . This study was designed to investigate the effects of ursolic acid ( UA ) , a pentacyclic triterpene found in many foods and herbs , in a model of postmenopausal breast cancer . Ovariectomized C57BL/6 mice ( n = 40 ) were randomized to receive control diet ( AIN-93G ) or diet supplemented with UA at 1 of 3 doses ( wt/wt ) : 0.05% , 0.10% , or 0.25% ( \u224854 , 106 , or 266 mg/kg body weight/day , respectively ) . After 3 wk , syngeneic MMTV-Wnt-1 mammary tumor cells were injected in the mammary fat pad , and mice continued on their respective diets for 5 more wk . All UA doses decreased tumor cell proliferation , as assessed by Ki67 immunostaining ; nevertheless , UA at 0.10% was most effective in inhibiting tumor take and decreasing tumor final tumor size . Modulation of Akt/mTOR signaling and induction of apoptosis appeared to mediate these effects on tumor growth . UA potently disrupted cell cycle progression and induced necrosis in a clonal MMTV-Wnt-1 mammary tumor cell line in vitro . This study supports the potential of UA as an antitumorigenic agent .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21058195"}
{"sentence": "BACKGROUND : The immune system has been shown to play an important role in gastrointestinal stromal tumor ( GIST ) . The neutrophil-to-lymphocyte ratio ( NLR ) in blood is an easily assessable parameter of systemic inflammatory response . The aim of this study was to determine whether the NLR is prognostic in GIST . METHODS : A total of 339 previously untreated patients with primary , localized GIST operated at our institution between 1995 and 2010 were identified from a prospectively collected sarcoma database . NLR was assessed preoperatively . Patients who received adjuvant imatinib treatment were excluded from the analysis ( n=64 ) . Cox regression models were calculated and correlation analyses were performed . RESULTS : On univariate analysis , NLR was associated with recurrence-free survival ( RFS ) ( P=0.003 , hazard ratio 3.3 , 95% confidence interval 1.5-7.4 ) . Patients with a low NLR had a 1- and 5-year RFS of 98 and 91% , compared with 89 and 76% in those with a high NLR . The median RFS was not reached . Positive correlations were found between NLR and mitotic rate ( Pearson correlation coefficient [ r]=0.15 , P=0.03 ) , and NLR and tumor size ( r=0.36 , P=0.0001 ) . RFS in patients with a GIST>5cm with low NLR was significantly longer compared to patients with high NLR ( P=0.002 ) . Flow cytometry analysis of freshly obtained GISTs revealed that neutrophils constituted a minimal percentage of intratumoral immune cells . CONCLUSIONS : NLR is a surrogate for high-risk tumor features . Elevated blood NLR appears to represent systemic inflammation in patients with high-risk GIST .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23054118"}
{"sentence": "A fully intact immune system would be expected to hinder the efficacy of oncolytic virotherapy by inhibiting viral replication . Simultaneously , however , it may also enhance antitumor therapy through initiation of proinflammatory , antiviral cytokine responses at the tumor site . The aim of this study was to investigate the role of a fully intact immune system on the antitumor efficacy of an oncolytic virus . In this respect , injection of oncolytic vesicular stomatitis virus ( VSV ) into subcutaneous B16ova melanomas in C57Bl/6 mice leads to tumor regression , but it is not associated with viral replicative burst in the tumor . In contrast , intratumoral delivery of VSV induces an acute proinflammatory reaction , which quickly resolves concomitantly with virus clearance . Consistent with the hypothesis that therapy may not be dependent on the ability of VSV to undergo progressive rounds of replication , a single-cycle VSV is equally effective as a fully replication-competent VSV , whereas inactivated viruses do not generate therapy . Even though therapy is dependent on host CD8+ and natural killer cells , these effects are not associated with interferon-gamma-dependent responses against either the virus or tumor . There is , however , a strong correlation between viral gene expression , induction of proinflammatory reaction in the tumor and in vivo therapy . Overall , our results suggest that acute innate antiviral immune response , which rapidly clears VSV from B16ova tumors , is associated with the therapy observed in this model . Therefore , the antiviral immune response to an oncolytic virus mediates an intricate balance between safety , restriction of oncolysis and , potentially , significant immune-mediated antitumor therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20016540"}
{"sentence": "Liver cancer ranks as the fifth most prevalent malignancy of all cancers worldwide . According to the principles of traditional Chinese medicine , liver Yin deficiency is a common clinical syndrome of liver cancer , and tonifying liver Yin is a common treatment method for liver cancer . However , no hepatocarcinoma-specific liver Yin tonifying formula has yet been established . In the present study , we established a liver cancer-specific combination of herbs , which we term liver Yin tonifying formula ( LYTF ) . We found that LYTF inhibits the proliferation of Bel-7402 cells in a dose- and time-dependent manner . LYTF induces apoptosis in Bel-7402 cells , which is accompanied by activation of caspases-8 , -9 and -3 . Pan-caspase blocking completely abrogates LYTF-induced apoptosis and partially abrogates LYTF-induced proliferation inhibition . LYTF also induces cell senescence , as indicated by a large and flattened morphology , senescence-activated \u03b2-galactosidase-positive staining and G0/G1 cell cycle arrest , accompanied by the up-regulation of p16 and p21 and the down-regulation of retinoblastoma protein phosphorylation . These findings suggest that LYTF is effective in inhibiting the growth and survival of hepatocarcinoma cells through the induction of apoptosis and cell senescence . Our study also provides insight into traditional Chinese medicine methods used for the treatment of liver cancer .", "label": [0, 0, 0, 1, 1, 0, 0, 1, 0, 0], "id": "22969849"}
{"sentence": "We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis . In this model , cancer cells secrete hydrogen peroxide ( H2O2 ) , initiating oxidative stress and aerobic glycolysis in the tumor stroma . This , in turn , drives L-lactate secretion from cancer-associated fibroblasts . Secreted L-lactate then fuels oxidative mitochondrial metabolism ( OXPHOS ) in epithelial cancer cells , by acting as a paracrine onco-metabolite . We have previously termed this type of two-compartment tumor metabolism the \" Reverse Warburg Effect, \" as aerobic glycolysis takes place in stromal fibroblasts , rather than epithelial cancer cells . Here , we used MCT4 immuno-staining of human breast cancer tissue microarrays ( TMAs ; > 180 triple-negative patients ) to directly assess the prognostic value of the \" Reverse Warburg Effect. \" MCT4 expression is a functional marker of hypoxia , oxidative stress , aerobic glycolysis , and L-lactate efflux . Remarkably , high stromal MCT4 levels ( score = 2 ) were specifically associated with decreased overall survival ( < 18% survival at 10 y post-diagnosis ) . In contrast , patients with absent stromal MCT4 expression ( score = 0 ) , had 10-y survival rates of ( p-value < 10 ( -32 ) ) . High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 ( p-value < 10 ( -14 ) ) , a known marker of early tumor recurrence and metastasis . In fact , the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients , consistent with the goal of individualized risk-assessment and personalized cancer treatment . However , epithelial MCT4 staining had no prognostic value , indicating that the \" conventional \" Warburg effect does not predict clinical outcome . Thus , the \" Reverse Warburg Effect \" or \" parasitic \" energy-transfer is a key determinant of poor overall patient survival . As MCT4 is a druggable-target , MCT4 inhibitors should be developed for the treatment of aggressive breast cancers , and possibly other types of human cancers . Similarly , we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors ( such as , AR-C155858 , AR-C117977 , and AZD-3965 ) .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22313602"}
{"sentence": "Mps one binder 1a ( MOB1A ) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers . Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a(\\u0394/\\u0394)1b(tr/+) or Mob1a(\\u0394/+)1b(tr/tr) mice results in tumor development . Because most of these cancers resembled trichilemmal carcinomas , we generated double-mutant mice bearing tamoxifen-inducible , keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b ( kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation , apoptotic resistance , impaired contact inhibition , enhanced progenitor self renewal , and increased centrosomes . Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1 . Similarly , YAP1 was activated in some human trichilemmal carcinomas , and some of these also exhibited MOB1A/1B inactivation . Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis , and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23143302"}
{"sentence": "OBJECTIVES/HYPOTHESIS Head and neck squamous cell carcinoma ( HNSCC ) is a complex disease process involving interactions with carcinoma-associated fibroblasts and endothelial cells . We further investigated these relationships by suppressing stromal cell growth through the inhibition of fibroblast growth factor receptor ( FGFR ) . STUDY DESIGN Preclinical investigation . METHODS HNSCC cell lines ( FADU , OSC19 , Cal27 , SCC1 , SCC5 , SCC22A ) , fibroblast ( HS27 ) , and endothelial cells ( human umbilical vascular endothelial cell ) were cultured individually or in coculture . Proliferation was assessed following treatment with a range of physiologic concentrations of FGFR inhibitor PD173074 . Mice bearing established HNSCC xenografts were treated with PD173074 ( 12 mg/kg ) , and tumor histology was analyzed for stromal composition , proliferation ( Ki67 staining ) , and apoptosis ( TUNEL [ terminal deoxynucleotidyl transferase dUTP nick end labeling ] staining ) . RESULTS In vitro , inhibition of FGFR with PD173074 dramatically reduced proliferation of fibroblasts and endothelial cells compared to untreated controls . However , HNSCC cell proliferation was not affected by inhibition of FGFR . When cocultured with fibroblasts , HNSCC cells proliferation increased by 15% to 80% ( P < .01 ) . Furthermore , this fibroblast-enhanced tumor cell growth was suppressed by FGFR inhibition . Additionally , treatment of mice bearing HNSCC xenografts with PD173074 resulted in significant growth inhibition ( P < .001 ) . Additionally , those tumors from mice treated with PD173074 had a smaller stromal component , decreased proliferation , and increased apoptosis . CONCLUSIONS Targeting the FGFR pathway in head and neck cancer acts through the stromal components to decrease HNSCC growth in vivo and in vitro .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22460537"}
{"sentence": "There are contradictory observations about the different radiosensitivities of cancer stem cells and cancer non-stem cells . To resolve these contradictory observations , we studied radiosensitivities by employing breast cancer stem cell ( CSC)-like MDA-MB231 and MDA-MB453 cells as well as their corresponding non-stem cells . CSC-like cells proliferate without differentiating and have characteristics of tumor-initiating cells [ 1 ] . These cells were exposed to \\u03b3-rays ( 1.25-8.75 Gy ) and survival curves were determined by colony formation . A final slope , D(0) , of the survival curve for each cell line was determined to measure radiosensitivity . The D(0) of CSC-like and non-stem MDA-MB-453 cells were 1.16 Gy and 1.55 Gy , respectively . Similar results were observed in MDA-MB-231 cells ( 0.94 Gy vs. 1.56 Gy ) . After determination of radiosensitivity , we investigated intrinsic cellular determinants which influence radiosensitivity including cell cycle distribution , free-radical scavengers and DNA repair . We observed that even though cell cycle status and antioxidant content may contribute to differential radiosensitivity , differential DNA repair capacity may be a greater determinant of radiosensitivity . Unlike non-stem cells , CSC-like cells have little/no sublethal damage repair , a low intracellular level of ataxia telangiectasia mutated ( ATM ) and delay of \\u03b3-H2AX foci removal ( DNA strand break repair ) . These results suggest that low DNA repair capacity is responsible for the high radiosensitivity of these CSC-like cells .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23185620"}
{"sentence": "Hormone replacement therapy , which is a common menopausal treatment , is contraindicated in women with breast cancers due to concerns regarding the potential for breast cell proliferation . As such , there is a need for alternative methods for treating menopausal symptoms . To determine the influence of one such alternative , black cohosh ( Cimicifuga racemosa [ CR] ) , on estrogen-dependent mammary cancers , we conducted an in vitro investigation of the effect of an isopropanolic CR-extract on the proliferation of estrogen receptor-positive breast cancer cells . The experiments were performed using the human breast adenocarcinoma ( MCF-7 ) cell test system , an established in vitro model for estrogen-dependent tumors . The influence of CR-extract on the proliferation of the MCF-7 cells was determined by measuring the incorporation of radioactively labeled thymidine . Under estrogen-deprived conditions , the CR-extract ( 10(-3)-10(-5) dilutions ) significantly inhibited MCF-7 cell proliferation . Additionally , application of the CR-extract inhibited estrogen-induced proliferation of MCF-7 cells . Moreover , the proliferation-inhibiting effect of tamoxifen was enhanced by the CR-extract . Such data that suggest a non-estrogenic , or estrogen-antagonistic effect of CR on human breast cancer cells lead to the conclusion that CR treatment may be a safe , natural remedy for menopausal symptoms in breast cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12408370"}
{"sentence": "We have recently developed surface-shielded transferrin-polyethylenimine ( Tf-PEI)/DNA delivery systems that target reporter gene expression to distant tumors after systemic application . In the present study , we used surface-shielded Tf-PEI/DNA complexes for delivering the gene for a highly potent cytokine , tumor necrosis factor-alpha ( TNFalpha ) . TNFalpha is known for its ability to induce hemorrhagic tumor necrosis and tumor regression . However , the therapeutic application of TNFalpha is hampered by its high systemic toxicity dictating the need to target TNFalpha activity to the tumor . Systemic application of surface-shielded Tf-PEI complexes with the TNFalpha gene resulted in preferential expression of TNFalpha in the tumor without detectable TNFalpha serum levels , in contrast to the application of nontargeted complexes . Tumor-targeted TNFalpha gene delivery induced pronounced hemorrhagic tumor necrosis and inhibition of tumor growth in three murine tumor models of different tissue origins , Neuro2a neuroblastoma , MethA fibrosarcoma , and M-3 melanoma , with complete tumor regressions observed in the MethA model . No systemic TNF-related toxicity was observed due to the localization of the TNFalpha activity to the tumor . Targeted gene therapy may be an attractive strategy applicable to highly active , yet toxic , molecules such as TNFalpha .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12136428"}
{"sentence": "Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis . The possibility was tested that interleukin-8 ( IL-8 ) , which is a cytokine that is chemotactic for lymphocytes and neutrophils , is also angiogenic . Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells . Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha . An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity . These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis , tumor growth , and wound repair .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "1281554"}
{"sentence": "We have observed previously that treatment of plateau-phase L5178Y murine lymphoblasts in vitro with 2'-deoxycoformycin plus deoxyadenosine ( dCF/dAdo ) can inhibit the repair of X-irradiation-induced DNA single-strand breaks ( SSB ) in these cells and that this effect is associated with synergistic cell kill . In this study we examined the effect of a combination treatment of plateau-phase L5178Y cells with bleomycin ( BLM ) plus dCF/dAdo . Incubation of BLM-treated cells with dCF/dAdo resulted in significant inhibition of the repair of BLM-induced DNA SSB . However , an additive , but not a synergistic , increase in cell kill was observed when cells were treated with a combination of BLM plus dCF/dAdo .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "1282003"}
{"sentence": "Src kinase is elevated in breast tumors that are ER/PR negative and do not overexpress HER2 , but clinical trials with Src inhibitors have shown little activity . The present study evaluated preclinical efficacy of a novel peptidomimetic compound , KX-01 ( KX2-391 ) , that exhibits dual action as an Src and pretubulin inhibitor . KX-01 was evaluated as a single-agent and in combination with paclitaxel in MDA-MB-231 , MDA-MB-157 , and MDA-MB-468 human ER/PR/HER2-negative breast cancer cells . Treatments were evaluated by growth/apoptosis , isobologram analysis , migration/invasion assays , tumor xenograft volume , metastasis , and measurement of Src , focal adhesion kinase ( FAK ) , microtubules , Ki67 , and microvessel density . KX-01 inhibited cell growth in vitro and in combination with paclitaxel resulted in synergistic growth inhibition . KX-01 resulted in a dose-dependent inhibition of MDA-MB-231 and MDA-MB-157 tumor xenografts ( 1 and 5 mg/kg , twice daily ) . KX-01 inhibited activity of Src and downstream mediator FAK in tumors that was coincident with reduced proliferation and angiogenesis and increased apoptosis . KX01 also resulted in microtubule disruption in tumors . Combination of KX-01 with paclitaxel resulted in significant regression of MDA-MB-231 tumors and reduced metastasis to mouse lung and liver . KX-01 is a potently active Src/pretubulin inhibitor that inhibits breast tumor growth and metastasis . As ER/PR/HER2-negative patients are candidates for paclitaxel therapy , combination with KX-01 may potentiate antitumor efficacy in management of this aggressive breast cancer subtype .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "22784709"}
{"sentence": "PURPOSE Overproduction of reactive oxygen species ( ROS ) intermediates above the functional capability of cellular antioxidants may result in instability of important macromolecules and represents the molecular basis of many diseases including inflammation processes , cardiovascular alterations , cancer etc . The purpose of this study was to determine plasma level of superoxide anion , hydrogen-peroxide and malondialdehyde ( MDA ) as markers of oxidative stress and activities of superoxide dismutase ( SOD ) , catalase ( CAT ) and glutathione peroxidase ( GPx ) as antioxidant enzymes in B-chronic lymphocytic leukemia ( B-CLL ) patients . METHODS The study included 29 untreated B-CLL patients in stage A , and 21 in stages B and C , classified according to the Binet system ; 31 healthy volunteers formed the control group . After centrifugation of heparinized peripheral blood , plasma levels of all investigated parameters were determined using spectrophotometric methods . RESULTS Plasma CAT activity was increased in B-CLL patients compared with control subjects ; also , progression of disease was related with significantly higher plasma activity of CAT . Also , B-CLL patients showed significantly higher plasma concentration of MDA compared with controls . No statistically significant differences of superoxide anion and hydrogen peroxide as well as plasma activity of SOD and GPx between the tested groups were noted . CONCLUSION Increase of CAT activity in B-CLL patients indicates that there is stimulation of the antioxidant enzyme system , while the increase of MDA concentration shows increased lipid peroxidation level . According to these results it could be concluded that an imbalance exists between oxidants and antioxidants in the plasma of B-CLL patients .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20658731"}
{"sentence": "Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica . Rats were exposed to crystalline silica by inhalation ( 15 mg m(-3) , 6 h per day , 5 days ) and global gene expression profile was determined in the lungs by microarray analysis at 1 , 2 , 4 , 8 and 16 weeks following termination of silica exposure . The number of significantly differentially expressed genes ( >1.5-fold change and <0.01 false discovery rate P-value ) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats . Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings . The number of biological functions , canonical pathways and molecular networks significantly affected by silica exposure , as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post-exposure time intervals , also exhibited a steady increase similar to the silica-induced pulmonary toxicity . Genes involved in oxidative stress , inflammation , respiratory diseases , cancer , and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs ; however , unresolved inflammation was the single most significant biological response to pulmonary exposure to silica . Excessive mucus production , as implicated by significant overexpression of the pendrin coding gene , SLC26A4 , was identified as a potential novel mechanism for silica-induced pulmonary toxicity . Collectively , the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat . Published 2012 . This article is a US Government work and is in the public domain in the USA .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22431001"}
{"sentence": "Neutrophils have become recognised as important contributors to the effectiveness of tumour eradication by photodynamic therapy ( PDT ) . In this study , we have used the mouse SCCVII squamous cell carcinoma model to investigate the activity of neutrophils in tumours treated by PDT . Tumour levels of neutrophilic myeloperoxidase ( MPO ) demonstrated not only a massive and sustained sequestration of these cells in PDT-treated tumours but also revealed their activated state evidenced by the presence of released MPO . Among the adhesion molecules expressed on tumour vascular endothelium , ICAM-1 appears to be of primary importance in the invasion of neutrophils into PDT-treated tumours , because its functional blocking with monoclonal antibodies reduced the tumour cure rate . A marked upregulation of its ligands CD11b/CD18 and CD11c/CD18 found on neutrophils associated with PDT-treated tumours supports this assumption . To evaluate the role of inflammatory cytokines regulating neutrophil activity , neutralising antibodies were given to mice before PDT treatment . The results suggest that IL-1beta activity is critical for the therapeutic outcome , since its neutralisation diminished the cure rates of PDT-treated tumours . No significant effect was observed with anti-IL-6 and anti-TNF-alpha treatment . Further flow cytometry-based examination of neutrophils round in PDT-treated tumours revealed that these cells express MHC class II molecules , which suggests their engagement as antigen-presenting cells and involvement in the development of antitumour immune response .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "12665307"}
{"sentence": "There is increasing evidence for the implication of tumor-derived angiogenic and anti-angiogenic factors in controlling tumor growth in vivo . In this study , we documented the production of inhibitors of angiogenesis by pancreatic cancer cells and examined how changes in the balance between pro- and anti-angiogenic factors regulate tumor growth in vivo . The human pancreatic cancer cell line Hs-776T ( HS-W ) produces slow-growing tumors in SCID mice . Cells of a variant form ( HS-R ) of Hs-776T produced faster-growing tumors compared to HS-W . Characterization of HS-W and HS-R cells in vitro showed similar proliferation rates and production of the angiogenic factors vascular endothelial growth factor ( VEGF ) and basic fibroblast growth factor ( bFGF ) . Analyzes of anti-angiogenic factors showed comparable levels of angiostatin and thrombospondin 1 and 2 , but endostatin was only detected in conditioned media of HS-W cells and was absent in HS-R . Cell proliferation was similar in both tumor types in vivo , whereas HS-W tumors demonstrated increased apoptosis with a high percentage of apoptotic endothelial cells ( EC ) . Subsequently , VEGF was over-expressed in Hs-776T cells ( HS-VF ) , resulting in rapidly growing tumors and lowering tumor and EC apoptosis . Collectively , our study confirms that tumor growth is dependent on its ability to increase the angiogenic stimulus or to reduce the amounts of endogenous anti-angiogenic factors .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "12831059"}
{"sentence": "AIM To compare the value of intravenous contrast-enhanced ultrasonography ( US ) , intravenous contrast-enhanced computed tomography ( CT ) , and magnetic resonance imaging ( MRI ) in the diagnosis of hepatic hemangiomas . MATERIAL AND METHODS The study enrolled 48 patients , aged between 20 and 79 years ( 35 [ 72.9% ] women , 13 [ 27.1% ] men ; mean age , 53.5+/-12.855 years ) , who were examined and treated in the Departments of Gastroenterology , Surgery , and Oncology , Hospital of Kaunas University of Medicine , in the year 2007 . All patients underwent intravenous contrast-enhanced US , intravenous contrast-enhanced CT , and MRI and were diagnosed with hepatic hemangioma according to the findings of these examinations . RESULTS The size of hemangiomas was < or =2.0 cm in 20 cases ( 41.7% ) and >2.0 cm in 28 ( 58.3% ) . No association between hepatic hemangioma and patient's age was found ( chi(2)=0.547 , df=2 , P=0.761 ) . Nearly one-third of hemangiomas were located in the segment IV of the left hepatic lobe . There were a few complicated hemangiomas in the study sample : 2 with calcification and 1 with necrosis . The sensitivity of CT in the diagnosis of hepatic hemangioma was 76.92% ; specificity , 33.3% ; positive prognostic value , 83.3% ; and negative prognostic value , 25.0% . The sensitivity of intravenous contrast-enhanced US in the diagnosis of hepatic hemangioma was 77.8% ; specificity , 100% ; positive prognostic value , 100% ; and negative prognostic value , 23.1% . CONCLUSIONS Intravenous contrast-enhanced US is more specific than intravenous contrast-enhanced CT in the diagnosis of hepatic hemangioma ( P=0.0005 ) and has a higher positive prognostic value ( P=0.001 ) .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20679748"}
{"sentence": "BACKGROUND Angiogenic factors following oncological surgery is important in tumor recurrence . Vascular endothelial growth factor ( VEGF ) , angiopoietin 1 ( Ang-1 ) , Ang-2 , soluble VEGF-receptor 1 ( sVEGFR1 ) and sVEGFR2 may influence angiogenesis . This prospective study examined the influence of open and video-assisted thoracic surgery ( VATS ) lung resections for early stage non-small cell lung cancer ( NSCLC ) on postoperative circulating angiogenic factors . METHODS Forty-three consecutive patients underwent major lung resection through either VATS ( n = 23 ) or Open thoracotomy ( n = 20 ) over an 8-month period . Blood samples were collected preoperatively and postoperatively on days ( POD ) 1 and 3 for enzyme linked immunosorbent assay determination of angiogenic factors . RESULTS Patient demographics were comparable . For all patients undergoing major lung resection , postoperative Ang-1 and sVEGFR2 levels were significantly decreased , while Ang-2 and sVEGFR1 levels markedly increased . No significant peri-operative changes in VEGF levels were observed . Compared with open group , VATS had significantly lower plasma levels of VEGF ( VATS 170 \u00b1 93 pg/mL ; Open 486 \u00b1 641 pg/mL ; P = 0.04 ) and Ang-2 ( VATS 2484 \u00b1 1119 pg/mL ; Open 3379 \u00b1 1287 pg/mL ; P = 0.026 ) on POD3 . CONCLUSIONS Major lung resection for early stage NSCLC leads to a pro-angiogenic status , with increased Ang-2 and decreased Ang-1 productions . VATS is associated with an attenuated angiogenic response with lower circulating VEGF and Ang-2 levels compared with open . Such differences in angiogenic factors may be important in lung cancer biology and recurrence following surgery .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23024612"}
{"sentence": "BACKGROUND Prostate cancer ( PCa ) progression is often associated with transactivation of the androgen receptor ( AR ) by endogenous hormones/growth factors . One such factor affecting growth , proliferation , and apoptostis ( pro-/anti- ) in various cancers is the adipokine leptin . This research studied leptin-induced signaling and apoptosis in androgen sensitive ( LNCaP , PC3/AR ) and insensitive ( PC3 , DU145 ) PCa cell lines . METHODS Signaling was studied by immunoblotting in cells overexpressing leptin receptors ( LRb ) , Janus kinase 2 ( JAK2 ) , and kinase negative-HER2-YFP cDNAs . Apoptosis was measured by immunoblotting of apoptotic proteins and by Hoechst staining of condensed DNA . RESULTS Leptin rapidly induced activation of JAK2 , STAT3 , and MAPK ( ERK1/2 ) signaling cascades ; it may also induce HER2 transactivation via leptin-induced phospho-JAK2 . Leptin was then shown to exert clear pro-apoptotic effects , increasing levels of caspase 3 , cleavage of its substrate , poly ( ADP-ribose ) polymerase ( PARP ) to cleaved PARP(89) , levels of CK 18 , a cytoskeletal protein formed during apoptosis , and DNA condensation . Kinase inhibitors indicated that leptin-induced apoptosis is probably mediated by balanced activation of JAK2/STAT3 , p38 MAPK , and PKC pathways in PCa cells . A human leptin mutein LRb antagonist , L39A/D40A/F41A , fully inhibited leptin-induced phosphorylation of JAK2 , ERK1/2 , and Akt/PKB , and partially abrogated effects on apoptotic proteins . In LNCaP and PC3/AR cells , leptin increased AR protein levels in correlation with raised apoptotic markers . Thus , AR may mediate , at least partly , the leptin-induced apoptotic response . CONCLUSIONS Leptin can clearly induce apoptosis in human PCa cell lines . These findings could lead to development of new leptin agonists with enhanced pro-apoptotic effects and targeted for use in human PCa .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21541970"}
{"sentence": "Novel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer . Here , we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger ( SDGE ) are potent inhibitors of proliferation of endometrial cancer cells . SDGE , isolated from six different batches of ginger rhizomes , consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC(50) of 1.25 \ufffdg/ml . SDGE also enhanced the anti-proliferative effect of radiation and cisplatin . Decreased proliferation of Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3 . GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE , with the isomers neral and geranial constituting 30-40% . Citral , a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an IC(50) 10 \ufffdM ( 2.3 \ufffdg/ml ) . Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells . SDGE was more effective in inducing cancer cell death than citral , suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death . SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20-40% decrease in the mitochondrial membrane potential . Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE . This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax . Inhibitor of p53 , pifithrin-\u03b1 , attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53(neg) SKOV-3 cells . Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23300887"}
{"sentence": "Inflammatory responses and associated products have been implicated in cancer metastasis . However , the relationship between these two processes is uncertain due to the lack of a suitable model . Taking advantage of localized and controllable inflammatory responses induced by biomaterial implantation and the capability of tissue scaffolds to release a wide variety of chemokines , we report a novel system for studying the molecular mechanisms of inflammation-mediated cancer metastasis . The animal model is comprised of an initial subcutaneous implantation of biomaterial microspheres which prompt localized inflammatory responses , followed by the transplantation of metastatic cancer cells into the peritoneal cavity or blood circulation . Histological results demonstrated that substantial numbers of B16F10 cells were recruited to the site nearby biomaterial implants . There was a strong correlation between the degree of biomaterial-mediated inflammatory responses and number of recruited cancer cells . Inflammation-mediated cancer cell migration was inhibited by small molecule inhibitors of CXCR4 but not by neutralizing antibody against CCL21 . Using chemokine-releasing scaffolds , further studies were carried out to explore the possibility of enhancing cancer cell recruitment . Interestingly , erythropoietin ( EPO ) releasing scaffolds , but not stromal cell-derived factor-1\u03b1-releasing scaffolds , were found to accumulate substantially more melanoma cells than controls . Rather unexpectedly , perhaps by indirectly reducing circulating cancer cells , mice implanted with EPO-releasing scaffolds had longer life span than other groups . These results suggest that chemokine-releasing scaffolds may potentially function as implantable cancer traps and serve as powerful tools for studying cancer distraction and even selective annihilation of circulating metastatic cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22019117"}
{"sentence": "It is well known that cell-mediated immunity is suppressed in patients with neoplastic diseases . We have reported that soluble receptors for interleukin-2 ( sIL-2R ) and tumor necrosis factor ( sTNF-R1 ) are elevated in the serum of patients with advanced colorectal cancer . The presence of these soluble receptors and immunosuppressive cytokines , including interleukin-10 ( IL-10 ) , might be important in the mechanisms of immunosuppression. cis-Diaminedichloroplatinum ( cisplatin ) has been reported to immunomodulate , especially when used in low dose in combination with 5-Fluorouracil ( 5-FU ) . In this study , cisplatin and UFT , a form of uracil and tegafur which is a prodrug of 5-FU , were administered with immunomodulator Polysaccharide K ( PSK ) to ten patients with colorectal cancer , who showed distant metastasis in the liver or lung , and the serum levels of sIL-2R and sTNF-R1 and the production of gamma-interferon ( gamma-INF ) and interleukin-10 by peripheral blood mononuclear cells were measured . The serum concentrations of sIL-2R and the production of IL-10 were reduced ( p < 0.05 ) after 2 months of treatment . Thus , this combination appeared to have immunomodulative potential in patients with advanced colorectal cancer .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "11901535"}
{"sentence": "MicroRNAs ( miRNAs ) are small non-coding RNAs of nucleotides that function as negative regulators of gene expression by either inhibiting translation or inducing deadenylation-dependent degradation of target transcripts . Notably , deregulation of miRNAs expression is associated with the initiation and progression of human cancers where they act as oncogenes or tumor suppressors contributing to tumorigenesis . Abnormal miRNA expression may provide potential diagnostic and prognostic tumor biomarkers and new therapeutic targets in cancer . Recently , several miRNAs have been shown to initiate invasion and metastasis by targeting multiple proteins that are major players in these cellular events , thus they have been denominated as metastamiRs . Here , we present a review of the current knowledge of miRNAs in cancer with a special focus on metastamiRs . In addition we discuss their potential use as novel specific markers for cancer progression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22408395"}
{"sentence": "An acquired mutation ( T790M ) in the epidermal growth factor receptor ( EGFR ) accounts for half of all relapses in non-small cell lung cancer ( NSCLC ) patients who initially respond to EGFR kinase inhibitors . In this study , we demonstrated for the first time that EGFR-T790M interacts with the cytoskeletal components , myosin heavy chain 9 ( MYH9 ) and \u03b2-actin , in the nucleus of H1975 cells carrying the T790M-mutant EGFR . The interactions of EGFR with MYH9 and \u03b2-actin were reduced in the presence of blebbistatin , a specific inhibitor for the MYH9-\u03b2-actin interaction , suggesting that the EGFR interaction with MYH9 and \u03b2-actin is affected by the integrity of the cytoskeleton . These physical interactions among MYH9 , \u03b2-actin , and EGFR were also impaired by CL-387,785 , a kinase inhibitor for EGFR-T790M . Furthermore , CL-387,785 and blebbistatin interacted in a synergistic fashion to suppress cell proliferation and induce apoptosis in H1975 cells . The combination of CL-387,785 and blebbistatin enhanced the down-regulation of cyclooxygenase-2 ( COX-2 ) , a transcriptional target of nuclear EGFR . Overall , our findings demonstrate that disrupting EGFR interactions with the cytoskeletal components enhanced the anti-cancer effects of CL-387,785 against H1975 cells , suggesting a novel therapeutic approach for NSCLC cells that express the drug-resistant EGFR-T790M .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22366308"}
{"sentence": "The results of experimental studies have indicated the pleiotropic effects of statins in organism , e.g. the influence on cell cycle , apoptosis or angiogenesis . In this study , the effects of simvastatin on selected parameters of apoptosis and proliferation in chemocarcinogen-induced mammary tumorigenesis in female rats were determined . Simvastatin was administered dietary at a dose of 18 mg/kg and highly effective dose of 180 mg/kg the entire experiment ( 18 weeks ) . At autopsy mammary tumors were removed and prepared for immunohistochemical and histomorphological analysis . In treated animals ( simvastatin 180 mg/kg ) , significant decrease by 12% in Bcl-2 protein expression and non-significant decrease by 27% of Ki67 protein expression in tumor cells compared to tumor cells in control animals were observed after semiquantitative evaluation . Morphometrical analysis has shown significant proapototic shift in Bcl-2/Bax ratio in tumor cells . In high grade control carcinoma cells , the expression of Ki67 increased by 37% ( non-significantly ) in comparison with control low grade carcinomas . A histomorphological analysis of malignant tumors has revealed a shift from high grade to low grade carcinomas after simvastatin treatment . The noticeable decrease of mammary tumor frequency and incidence in rats after simvastatin treatment was accompanied with antiapoptotic Blc-2 protein decrease and proapoptotic Bax protein increase in this experiment .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22668016"}
{"sentence": "Estrogen receptor ( ER ) and NF-\u03baB are transcription factors with profound effects on breast cancer cell proliferation and survival . While many studies demonstrate that ER and NF-\u03baB can repress each other , we previously identified a gene signature that is synergistically upregulated by these two factors in more aggressive luminal B breast tumors . Herein , we examine a novel mechanism of cross talk between ER and NF-\u03baB that results in the upregulation of the antiapoptotic gene BIRC3 ( also known as cIAP2 ) . We demonstrate that NF-\u03baB , acting through two response elements , is required for ER recruitment to an adjacent estrogen response element ( ERE ) in the BIRC3 promoter . This effect is accompanied by a major increase in NF-\u03baB-dependent histone acetylation around the ERE . Interestingly , CBP , a histone acetyltransferase previously implicated in repressive interactions between ER and NF-\u03baB , plays a permissive role by promoting histone acetylation and ER recruitment , as well as enhanced expression of BIRC3 . These findings suggest a new gene regulatory mechanism by which inflammation and NF-\u03baB activation can influence ER recruitment to inherently inactive ER binding sites . This fine-tuning mechanism may explain how two factors that generally repress each other's activity may work together on certain genes to promote breast cancer cell survival and tumor progression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "22083956"}
{"sentence": "We investigated the mode of cell death induced by the anthracyclines , aclarubicin , doxorubicin and daunorubicin in the human leukemia cell lines , HL60 and Jurkat . The cells were incubated with drug concentrations up to 500 nM for periods between 3 and 24 hours , followed by morphological and biochemical analyses . All three substances induced DNA fragmentation , evident as DNA laddering and appearance of cells with hypodiploid DNA content , externalization of phosphatidyl serine , activation of caspases and degradation of the apoptosis-specific endonuclease inhibitor DFF45 . However , concentrations and times necessary for these effects to occur were different , aclarubicin being the quickest acting drug with a lag phase of 3 h , followed by daunorubicin with 6 h and doxorubicin with 24 h . More importantly , aclarubicin induced these effects while the cell membrane was intact , whereas doxorubicin and daunorubicin led to immediate loss of membrane integrity . Programmed cell death is characterised by preservation of membrane integrity in order to allow removal of apoptotic bodies , whereas cell rupture is an early event in necrosis . We therefore suggest that , in our experimental settings , doxorubicin- and daunorubicin-induced cell death occurs by necrosis , while aclarubicin induces programmed cell death .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12370496"}
{"sentence": "BACKGROUND & OBJECTIVE Usually pituitary adenomas are histological benign and grow slowly , but a proportion of them will become locally aggressive , and develop into invasive pituitary adenomas . The reasons for these differences in tumor behavior are poorly understood . Pituitary adenomas are abounding blood vessels . Angiogenesis and tumor invasion both require degradation of the extracellular matrix components to allow cell migration . The matrix metalloproteinases ( MMPs ) and their nature inhibitors-the tissue inhibitors of metalloproteinases ( TIMPs ) may play a central role in these processes . The aggressive mechanism of pituitary adenomas was studied through investigating the expression of MMP-9 , MMP-2 , TIMP-1 , and TIMP-2 in both invasive and non-invasive adenomas . METHODS Sixty-one surgical removed pituitary adenomas ( forty-nine cases invasive and twelve non-invasive adenomas ) were investigated . Immunohistochemistry staining ( SP method ) was used to detect the expression of MMP-9 , MMP-2 , TIMP-1 , and TIMP-2 in two groups . The results were treated with semi-quantitative method and analyzed by using non-parameter rank sum test . RESULTS Immunohistochemical staining of tumor cells for MMP-9 , TIMP-1 , MMP-2 , and TIMP-2 were noted 95.9% ( 47/49 ) , 57.1% ( 28/49 ) , 75.5% ( 37/49 ) and 89.8% ( 44/49 ) in invasive adenomas , and 100% ( 12/12 ) , 91.7% ( 11/12 ) , 66.7% ( 8/12 ) , and 91.7% ( 11/12 ) in non-invasive adenomas , respectively . Invasive tumors were significantly less expressing TIMP-1 and TIMP-2 ( P < 0.05 ) . There was no significant difference for MMP-9 or MMP-2 between invasive and non-invasive groups ( P > 0.05 ) . CONCLUSIONS TIMP-1 and TIMP-2 may play a key role in invasive pituitary adenomas to biological behavior .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12508658"}
{"sentence": "The biological activities of tocotrienols are receiving increasing attention . Herein , we report the efficacy of a mixed-tocotrienol diet against prostate tumorigenesis in the transgenic adenocarcinoma mouse prostate ( TRAMP ) mouse model . Male TRAMP mice , 8 wk old , were fed 0.1% , 0.3% , or 1% mixed tocotrienols in AIN-76A diet up to 24 wk old . Likewise , a positive control group consisting of male TRAMP mice and a negative control group consisting of wild-type nontransgenic mice were fed regular AIN-76A diet up to 24 wk old . Our results show that mixed-tocotrienol-fed groups had a lower incidence of tumor formation along with a significant reduction in the average wet weight of genitourinary apparatus . Furthermore , mixed tocotrienols significantly reduced the levels of high-grade neoplastic lesions as compared to the positive controls . This decrease in levels of high-grade neoplastic lesions was found to be associated with increased expression of proapoptotic proteins BAD ( Bcl(2) antagonist of cell death ) and cleaved caspase-3 and cell cycle regulatory proteins cyclin dependent kinase inhibitors p21 and p27 . In contrast , the expression of cyclins A and E were found to be decreased in mixed-tocotrienol groups . Taken together , our results show that by modulating cell cycle regulatory proteins and increasing expression of proapoptotic proteins , mixed tocotrienols suppress prostate tumorigenesis in the TRAMP mice .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20661828"}
{"sentence": "Many viruses subvert the host cell's ability to mount and complete various DNA damage responses ( DDRs ) after infection . HCMV infection of permissive fibroblasts activates host DDRs at the time of viral deposition and during replication , but the DDRs remain uncompleted without arrest or apoptosis . We believe this was in part due to partitioning of the damage response and double strand break repair components . After extraction of soluble proteins , the localization of these components fell into three groups : specifically associated with the viral replication centers ( RCs ) , diffused throughout the nucleoplasm and excluded from the RCs . Others have shown that cells are incapable of processing exogenously introduced damage after infection . We hypothesized that the inability of the cells to process damage might be due to the differential association of repair components within the RCs and , in turn , potentially preferential repair of the viral genome and compromised repair of the host genome . To test this hypothesis we used multiple strategies to examine repair of UV-induced DNA damage in mock and virus-infected fibroblasts . Comet assays indicated that repair was initiated , but was not completed in infected cells . Quantitative analysis of immunofluorescent localization of cyclobutane pyrimidine dimers ( CPDs ) revealed that after 24 h of repair , CPDs were significantly reduced in viral DNA , but not significantly changed in the infected host DNA . To further quantitate CPD repair , we developed a novel dual-color Southern protocol allowing visualization of host and viral DNA simultaneously . Combining this Southern methodology with a CPD-specific T4 endonuclease V alkaline agarose assay to quantitate repair of adducts , we found efficient repair of CPDs from the viral DNA but not host cellular DNA . Our data confirm that NER functions in HCMV-infected cells and almost exclusively repairs the viral genome to the detriment of the host's genome .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23209410"}
{"sentence": "Airway mucin secretion and MC ( mast cell ) degranulation must be tightly controlled for homoeostasis of the lungs and immune system respectively . We found the exocytic protein Munc18b to be highly expressed in mouse airway epithelial cells and MCs , and localized to the apical pole of airway secretory cells . To address its functions , we created a mouse with a severely hypomorphic Munc18b allele such that protein expression in heterozygotes was reduced by Homozygous mutant mice were not viable , but heterozygotes showed a reduction in stimulated release of mucin from epithelial cells and granule contents from MCs . The defect in MCs affected only regulated secretion and not constitutive or transporter-mediated secretion . The severity of passive cutaneous anaphylaxis was also reduced by showing that reduction of Munc18b expression results in an attenuation of physiological responses dependent on MC degranulation . The Munc18b promoter is controlled by INR ( initiator ) , Sp1 ( specificity protein 1 ) , Ets , CRE ( cAMP-response element ) , GRE ( glucocorticoid-response element ) , GATA and E-box elements in airway epithelial cells ; however , protein levels did not change during mucous metaplasia induced by allergic inflammation . Taken together , the results of the present study identify Munc18b as an essential gene that is a limiting component of the exocytic machinery of epithelial cells and MCs .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22694344"}
{"sentence": "Chromated copper arsenate , which is used worldwide as a wood preservative , can adversely affect human health . Accumulating evidence suggests that chromium ( Cr ) and arsenic ( As ) can potentially disrupt the redox balance and cause respiratory diseases and cancer in humans . The present study was designed to determine the combined toxic effects of these metals in the lungs and to clarify the specific molecules that are stimulated by combined exposure to both metals . Male C57BL/6J mice were intratracheally instilled with arsenate [ As(V) ] , hexavalent chromium [ Cr(VI) ] , or a combination of both metals . Mice were sacrificed 2 days after treatment to collect bronchoalveolar lavage fluid and lung tissue samples . Inflammation , cytotoxicity , apoptosis , and oxidative stress markers were measured . Our results indicated that administration of Cr(VI) alone or in combination with As(V) induced neutrophil-dominant inflammation as well as phosphorylation of mitogen-activated protein kinases ; effects of treatment with As(V) alone were comparatively less potent . By analyzing the production of interleukin-6 and activity of lactate dehydrogenase and caspase , we confirmed that co-treatment intensified pulmonary injury and that it was accompanied by oxidative stress , as confirmed by marked increases in the production of reactive oxygen species , reduced glutathione content , and thioredoxin reductase ( TRXRD ) activity . Expressed mRNA levels of heme oxygenase-1 , glutamylcysteine ligase , glutathione peroxidase 2 , thioredoxin ( TRX ) 1 , and TRXRD1 were also enhanced by co-treatment , whereas treatment with As(V) alone reduced the mRNA expression level of TRX2 . Our data suggest that co-treatment with As(V) exacerbated Cr(VI)-induced pulmonary injury and that this effect may be exerted through a disruption in the balance among several antioxidant genes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19895865"}
{"sentence": "The role of estrogen receptor beta ( ER\u03b2 ) in breast cancer is unclear . ER\u03b2 is considered to have a protective role in breast cancer development based on findings demonstrating that ER\u03b2 expression inhibits ER\u03b1-mediated proliferation of breast cancer cells . We previously demonstrated that ER\u03b2 causes a ligand independent G2 cell cycle arrest in MCF-7 cells . To study the mechanisms of the ER\u03b2-mediated G2 cell cycle arrest , we investigated its effects on the regulatory pathways responsible for the G2/M phase transition . We found that ER\u03b2 inhibits CDK1 activity , which is the critical determinant of the G2/M progression . CDK1 activity is modulated by both stimulatory and inhibitory factors . Cyclin B1 is the major activator of CDK1 . ER\u03b2 inhibited the cell cycle-dependent stimulation of cyclin B1 mRNA and protein . GADD45A and BTG2 are two major inhibitors of CDK1 , which have been implicated in breast tumor formation . Based on these findings , we explored if the expression pattern of GADD45A and BTG2 is affected by ER\u03b2 . We found that ER\u03b2 stimulates GADD45A and BTG2 mRNA levels . The induction of these two genes is caused by ER\u03b2 binding directly to these genes and recruiting c-jun and NCOA2 . Our findings demonstrated that unliganded ER\u03b2 causes a G2 cell cycle arrest by inactivating CDK1 through the repression of cyclin B1 and stimulation of GADD45A and BTG2 expression . These results provide evidence that drugs that stimulate the production of unliganded ER\u03b2 may be effective new therapies to prevent breast cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21120602"}
{"sentence": "OBJECTIVE To investigate the effects of CdTe QDs ( cadmium telluride quantum dots ) on oxidative stress and DNA damage of liver cells in mice . METHODS Thirty ICR male mice were randomly divided into 5 groups : one negative control ( normal saline ) group . Three CdTe QDs groups ( exposed by intravenous injection of 0.2 ml of CdTe QDs at the concentration of 3.75 , 37.5 and 375 nmol/ml respectively ) for electron paramagnetic resonance ( EPR ) test , and another positive control group ( exposed by intravenous injection of 0.2 ml of cyclophosphamide 20 mg/ml ) for single cell gel electrophoresis ( SCGE ) test . All mice were decapitated 24h after the injection , free radicals and DNA damage of liver cells were detected by EPR and SCGE . RESULTS The levels of oxygen free radicals detected by EPR were increased with the increase of CdTe QDs . The tail length , olive tail moment , tail DNA ( % ) and the ratio of tail/head examined by SCGE were also increased with the increase of the dosage of CdTe QDs ( P < 0.01 ) . CONCLUSION CdTe QDs could induce oxidative stress and DNA damage of liver cells in mice with a dose-effect relationship .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "22443054"}
{"sentence": "Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity . Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled . Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures . We genomically characterized mammary adenocarcinomas from these mice to identify cancer-causing genomic events that overlap common alterations in human breast cancer . Chaos3 tumors underwent recurrent copy number alterations ( CNAs ) , particularly deletion of the RAS inhibitor Neurofibromin 1 ( Nf1 ) in nearly all cases . These overlap with human CNAs including NF1 , which is deleted or mutated in 27.7% of all breast carcinomas . Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors . These results indicate that spontaneous NF1 loss can drive breast cancer . This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22851646"}
{"sentence": "Prohibiting angiogenesis is an important therapeutic approach for fighting cancer and other angiogenic related diseases . Research focused on proteins that regulate abnormal angiogenesis has attracted intense interest in both academia and industry . Such proteins are able to target several angiogenic factors concurrently , thereby increasing the possibility of therapeutic success . Aquaporin-1 ( AQP1 ) is a water channel membrane protein that promotes tumour angiogenesis by allowing faster endothelial cell migration . In this study we test the hypothesis that AQP1 inhibition impairs tumour growth in a mouse model of melanoma . After validating the inhibitor efficacy of two different AQP1 specific siRNAs in cell cultures , RNA interference experiments were performed by intratumoural injections of AQP1 siRNAs in mice . After 6 days of treatment , AQP1 siRNA treated tumours showed a 75 % reduction in volume when compared to controls . AQP1 protein level , in AQP1 knockdown tumours , was around 75 % that of the controls and was associated with a significant 40 % reduced expression of the endothelial marker , Factor VIII . Immunofluorescence analysis of AQP1 siRNA treated tumours showed a significantly lower microvessel density . Time course experiments demonstrated that repeated injections of AQP1 siRNA over time are effective in sustaining the inhibition of tumour growth . Finally , we have confirmed the role of AQP1 in sustaining an active endothelium during angiogenesis and we have shown that AQP1 reduction causes an increase in VEGF levels . In conclusion , this study validates AQP1 as a pro-angiogenic protein , relevant for the therapy of cancer and other angiogenic-related diseases such as psoriasis , endometriosis , arthritis and atherosclerosis .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23197380"}
{"sentence": "The Alternative Lengthening of Telomeres ( ALT ) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines . ALT is thought to involve templated extension of telomeres through homologous recombination , but the genetic or epigenetic changes that unleash ALT are not known . Recently , mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers , pediatric glioblastomas , and other tumors of the central nervous system , suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers . We have taken a comprehensive approach to deciphering ALT by applying genomic , molecular biological , and cell biological approaches to a panel of 22 ALT cell lines , including cell lines derived in vitro . Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines . In addition , ALT is associated with extensive genome rearrangements , marked micronucleation , defects in the G2/M checkpoint , and altered double-strand break ( DSB ) repair . These attributes will facilitate the diagnosis and treatment of ALT positive human cancers .", "label": [0, 0, 0, 1, 1, 1, 0, 0, 0, 0], "id": "22829774"}
{"sentence": "BACKGROUND AND AIMS breast reconstruction with silicone prosthesis following nipple-sparing mastectomy has become widely accepted as a reconstruction option in women requiring mastectomy for cancer . The purpose of this study was to evaluate the incidence and some factors influencing early local complications in patients undergoing NSM with immediate implant reconstruction . MATERIAL AND METHODS prospective study was performed on a consecutive series of 214 breast reconstructions in 205 patients . All complications during the six weeks after surgery were recorded. 42 prostheses were implanted after neoadjuvant chemotherapy , 27 patients previously had radiotherapy due to breast conserving surgery and in all other cases surgery was the pri-mary treatment for cancer . RESULTS the overall six-week complication rate was 16% ( 35 ) and included : major skin flap necrosis ( 4% , 9 procedures ) , minor skin necrosis ( 3% , 7 ) , major infection ( 2% , 5 ) , minor infection ( 3% , 7 ) , prolonged seroma formation ( 3% , 6 ) , haematoma ( 1% , 2 ) and epidermolysis ( 1% , 2 ) . In 6% ( 12 ) reconstruction procedures explantation of prosthesis was done . Neoadjuvant chemo-therapy and radiotherapy were not associated with higher rate of complications . CONCLUSION nipple-sparing mastectomy with immediate implant reconstruction has acceptable morbidity rate in the hand of experienced oncoplastic surgeon and therefore should be considered as treatment option to women requiring mastectomy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21044925"}
{"sentence": "Exposure of cells to UV light from the sun causes the formation of pyrimidine dimers in DNA that have the potential to lead to mutation and cancer . In humans , pyrimidine dimers are removed from the genome in the form of nt-long oligomers by concerted dual incisions . Though nearly 50 y of excision repair research has uncovered many details of UV photoproduct damage recognition and removal , the fate of the excised oligonucleotides and , in particular , the ultimate fate of the chemically very stable pyrimidine dimers remain unknown . Physiologically relevant UV doses introduce hundreds of thousands of pyrimidine dimers in diploid human cells , which are excised from the genome within h . Once removed from the genome , \" where do all the dimers go? \" In a recent study we addressed this question . Although our study did not determine the fate of the dimer itself , it revealed that the excised is released from the duplex in a tight complex with the transcription/repair factor TFIIH . This finding combined with recent reports that base and oligonucleotide products of the base and double-strand break repair pathways also make stable complexes with the cognate repair enzymes , and that these complexes activate the MAP kinase and checkpoint signaling pathways , respectively , raises the possibility that TFIIH-30-mer excision complexes may play a role in signaling reactions in response to UV damage .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22825251"}
{"sentence": "We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism . In this model , glycolytic stromal cells produce mitochondrial fuels ( L-lactate and ketone bodies ) that are then transferred to oxidative epithelial cancer cells , driving OXPHOS and mitochondrial metabolism . Thus , stromal catabolism fuels anabolic tumor growth via energy transfer . We have termed this new cancer paradigm the \" reverse Warburg effect, \" because stromal cells undergo aerobic glycolysis , rather than tumor cells . To assess whether this mechanism also applies during cancer cell metastasis , we analyzed the bioenergetic status of breast cancer lymph node metastases , by employing a series of metabolic protein markers . For this purpose , we used MCT4 to identify glycolytic cells . Similarly , we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity , respectively . Consistent with the \" reverse Warburg effect, \" our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism ( OXPHOS ) and that adjacent stromal cells are glycolytic and lack detectable mitochondria . Glycolytic stromal cells included cancer-associated fibroblasts , adipocytes and inflammatory cells . Double labeling experiments with glycolytic ( MCT4 ) and oxidative ( TO MM20 or COX ) markers directly shows that at least two different metabolic compartments co-exist , side-by-side , within primary tumors and their metastases . Since cancer-associated immune cells appeared glycolytic , this observation may also explain how inflammation literally \" fuels \" tumor progression and metastatic dissemination , by \" feeding \" mitochondrial metabolism in cancer cells . Finally , MCT4(+) and TO MM20(-) \" glycolytic \" cancer cells were rarely observed , indicating that the conventional \" Warburg effect \" does not frequently occur in cancer-positive lymph node metastases .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "22395432"}
{"sentence": "A distinct group of breast cancers , called \" basal \" or \" triple-negative \" ( TN ) cancers express both basal cytokeratins and the epidermal growth factor receptor , but fail to express estrogen receptors , progesterone receptors or HER2 and have stem-like or mesenchymal features . They are particularly aggressive , are frequently chemo-resistant , with p53 mutation , up-regulation of IL-6 and Stat3 . Because TN cells are particularly sensitive to the anti-diabetic agent metformin , we hypothesized that it may target JAK2/Stat3 signaling . The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines . Metformin's effects were also studied in sublines with forced over-expression of constitutively active ( CA ) Stat3 , as well as lines with stable knockdown of Stat3 . Metformin inhibited Stat3 activation ( P-Stat3 ) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines . CA-Stat3 transfection attenuated , whereas Stat3 knockdown enhanced , the effects of metformin upon growth inhibition and apoptosis induction . A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis . An mTOR inhibitor showed no significant interaction with metformin . In summary , Stat3 is a critical regulator of metformin action in TN cancer cells , providing the potential for enhancing metformin's efficacy in the clinical setting .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22189713"}
{"sentence": "AIMS Currently , testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies ( MLH1 , PMS2 , MSH2 and MSH6 ) . If any one of these stains is negative the tumour is considered microsatellite unstable and , if clinical circumstances warrant it , the patient is offered genetic testing for Lynch's syndrome . Due to the binding properties of the mismatch repair heterodimer complexes , gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6 , respectively , but the converse is not true . We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies . METHODS The electronic database of the department of Anatomical Pathology , Royal North Shore Hospital , Sydney , Australia , was searched for all colorectal carcinomas on which a four panel immunohistochemical microsatellite instability screen was performed . An audit of the slides for concordant loss of MLH1-PMS2 and MSH2-MSH6 was then undertaken . Unusual or discordant cases were reviewed and , in some cases , re-stained to confirm the staining pattern . RESULTS Of 344 cases of colorectal cancer which underwent four antibody immunohistochemistry , 104 displayed loss of at least one mismatch repair protein . Of these , 100 showed concordant mismatch repair loss ( i.e. , loss of MLH1 and PMS2 or loss of MSH2 and MSH6 ) . The four discordant cases comprised two single negative cases ( 1 MSH6 negative/MSH2 positive case , 1 PMS2 negative/MLH1 positive ) and two triple negative ( both MLH1/PMS2/MSH6 negative ) . The microsatellite instability ( MSI ) group showed a relatively high median age ( 69.3 years ) due to the departmental policy of testing all cases with possible MSI morphology regardless of age . CONCLUSIONS The sensitivity and specificity of a two panel test comprised of PMS2 and MSH6 , compared to a four panel test , is 100% . No false negatives or positives were identified . We conclude that the two panel test should replace a four panel protocol for immunohistochemical screening for mismatch repair deficiency .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20632815"}
{"sentence": "Lipoprotein lipase ( LPL ) plays a central role in normal lipid metabolism as the key enzyme involved in the hydrolysis of triglycerides present in chylomicrons and very low density lipoproteins . LPL is a member of a family of hydrolytic enzymes that include hepatic lipase and pancreatic lipase . Based on primary sequence homology of LPL to pancreatic lipase , Ser-132 , Asp-156 , and His-241 have been proposed to be part of a domain required for normal enzymic activity . We have analyzed the role of these potential catalytic residues by site-directed mutagenesis and expression of the mutant LPL in human embryonic kidney-293 cells . Substitution of Ser-132 , Asp-156 , and His-241 by several different residues resulted in the expression of an enzyme that lacked both triolein and tributyrin esterase activities . Mutation of other conserved residues , including Ser-97 , Ser-307 , Asp-78 , Asp-371 , Asp-440 , His-93 , and His-439 resulted in the expression of active enzymes . Despite their effect on LPL activity , substitutions of Ser-132 , Asp-156 , and His-241 did not change either the heparin affinity or lipid binding properties of the mutant LPL . In summary , mutation of Ser-132 , Asp-156 , and His-241 specifically abolishes total hydrolytic activity without disrupting other important functional domains of LPL . These combined results strongly support the conclusion that Ser-132 , Asp-156 , and His-241 form the catalytic triad of LPL and are essential for LPL hydrolytic activity .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1371284"}
{"sentence": "A 34-year-old Japanese woman presented with left supraclavicular lymph node swelling . Computed tomography scans revealed a mass on the left lower lobe , pulmonary nodules , and pleural effusion . A lymph node biopsy revealed large-cell carcinoma with an epidermal growth factor receptor ( EGFR ) deletion mutation , L747-T751 in exon 19 . Although malignant pleural effusions carried the same EGFR mutation , progressive pleural effusions after treatment with chemotherapy , gefitinib , and erlotinib did not show any EGFR mutation . A cell line established from the pleural effusion 3 days before the patient expired also did not harbor the EGFR mutation . Histological sections of the lymph node of the patient were similar to those of the xenograft tumor of the cell line . There may be genetic heterogeneity in EGFR mutant tumors .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22835516"}
{"sentence": "BACKGROUND Hepatocellular carcinoma ( HCC ) is the most common liver cancer . Therapeutic results are usually unsatisfactory because liver tumors recur often . Immunologic factors may be related to the recurrence of HCC ; however , this possibility is mentioned only rarely . METHODS Thirty HCC patients undergoing hepatectomies were divided into 3 groups according to the diameters of their HCCs : group A ( n = 8 ) , diameter \u22643 cm ; group B ( n = 8 ) , diameter >3 cm and \u22645 cm ; and group C ( n = 14 ) , diameter >5 cm . T-lymphocytes from peripheral blood , nontumor liver tissue , and the HCC were analyzed . RESULTS The percentage of CD25+ in the CD4+ T cells did not differ between the peripheral blood and the nontumor liver tissue among the 3 groups . CD25+ cells were increased in the tumor tissue in group C patients ( range , 6-41% ; median , 22.9% ; P = .003 ) , compared to group A patients . The percentage of CD25+ in the CD4+ T cells in tumor tissue was positively correlated with tumor sizes ( r = 0.556 ) . These CD4+ CD25+ lymphocytes produced transforming growth factor-\u03b2 and interferon-\u03b3 but not interleukin-10 , and were anergic to plate-coated monoclonal antibodies ( anti-CD3/anti-CD28 ) . The characteristics of these antibodies were comparable to those of regulatory T cells . When the infiltration lymphocytes including CD4+ CD25+ T cells were added to the mixed lymphocyte reaction activated by autologous tumor lysate-pulsed dendritic cells , the proliferation of lymphocytes was inhibited . CONCLUSION The increase of CD4+ CD25+ T cells in the tumor microenvironment correlates with tumor sizes . These CD4+ CD25+ regulatory T cells appeared to suppress the immune response activated by dendritic cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21975289"}
{"sentence": "Topoisomerase inhibitors such as camptothecin and etoposide are used as anti-cancer drugs and induce double-strand breaks ( DSBs ) in genomic DNA in cycling cells . These DSBs are often covalently bound with polypeptides at the 3 ' and 5 ' ends . Such modifications must be eliminated before DSB repair can take place , but it remains elusive which nucleases are involved in this process . Previous studies show that CtIP plays a critical role in the generation of 3 ' single-strand overhang at \" clean \" DSBs , thus initiating homologous recombination ( HR)-dependent DSB repair . To analyze the function of CtIP in detail , we conditionally disrupted the CtIP gene in the chicken DT40 cell line . We found that CtIP is essential for cellular proliferation as well as for the formation of 3 ' single-strand overhang , similar to what is observed in DT40 cells deficient in the Mre11/Rad50/Nbs1 complex . We also generated DT40 cell line harboring CtIP with an alanine substitution at residue Ser332 , which is required for interaction with BRCA1 . Although the resulting CtIP(S332A/-/-) cells exhibited accumulation of RPA and Rad51 upon DNA damage , and were proficient in HR , they showed a marked hypersensitivity to camptothecin and etoposide in comparison with CtIP(+/-/-) cells . Finally , CtIP(S332A/-/-)BRCA1(-/-) and CtIP(+/-/-)BRCA1(-/-) showed similar sensitivities to these reagents . Taken together , our data indicate that , in addition to its function in HR , CtIP plays a role in cellular tolerance to topoisomerase inhibitors . We propose that the BRCA1-CtIP complex plays a role in the nuclease-mediated elimination of oligonucleotides covalently bound to polypeptides from DSBs , thereby facilitating subsequent DSB repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20107609"}
{"sentence": "Nonmelanoma skin cancer ( NMSC ) is by far the most frequent type of cancer in humans . NMSC includes several types of malignancies with different clinical outcomes , the most frequent being basal and squamous cell carcinomas . We have used the Sleeping Beauty transposon/transposase system to identify somatic mutations associated with NMSC . Transgenic mice bearing multiple copies of a mutagenic Sleeping Beauty transposon T2Onc2 and expressing the SB11 transposase under the transcriptional control of regulatory elements from the keratin K5 promoter were treated with TPA , either in wild-type or Ha-ras mutated backgrounds . After several weeks of treatment , mice with transposition developed more malignant tumors with decreased latency compared with control mice . Transposon/transposase animals also developed basal cell carcinomas . Genetic analysis of the transposon integration sites in the tumors identified several genes recurrently mutated in different tumor samples , which may represent novel candidate cancer genes . We observed alterations in the expression levels of some of these genes in human tumors . Our results show that inactivating mutations in Notch1 and Nsd1 , among others , may have an important role in skin carcinogenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22832494"}
{"sentence": "Pterostilbene , a polyphenolic compound present in grapes and other fruits , has been demonstrated to inhibit growth and induce apoptosis and autophagy in some cancer cell types . We found that pterostilbene at the IC90 concentration of 44 \ufffdM inhibited proliferation and induced apoptosis in MOLT4 human leukemia cells . Treatment with pterostilbene resulted in a transient accumulation of cells in the G0/G1-cell cycle phase followed by the S-phase arrest . Pterostilbene-induced apoptotic death of MOLT4 cells was mediated by caspase-3 activation and was accompanied by the disruption of mitochondrial membrane potential , phosphatidylserine externalization and internucleosomal DNA fragmentation . Our results suggest that pterostilbene could serve as a potential additional chemotherapeutic agent for the treatment of leukemia .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23264221"}
{"sentence": "The innate immune response involves a variety of inflammatory reactions that can result in inflammatory disease and cancer if they are not resolved and instead are allowed to persist . The effective activation and resolution of innate immune responses relies on the production and posttranscriptional regulation of mRNAs encoding inflammatory effector proteins . The RNA-binding protein HuR binds to and regulates such mRNAs , but its exact role in inflammation remains unclear . Here we show that HuR maintains inflammatory homeostasis by controlling macrophage plasticity and migration . Mice lacking HuR in myeloid-lineage cells , which include many of the cells of the innate immune system , displayed enhanced sensitivity to endotoxemia , rapid progression of chemical-induced colitis , and severe susceptibility to colitis-associated cancer . The myeloid cell-specific HuR-deficient mice had an exacerbated inflammatory cytokine profile and showed enhanced CCR2-mediated macrophage chemotaxis . At the molecular level , activated macrophages from these mice showed enhancements in the use of inflammatory mRNAs ( including Tnf , Tgfb , Il10 , Ccr2 , and Ccl2 ) due to a lack of inhibitory effects on their inducible translation and/or stability . Conversely , myeloid overexpression of HuR induced posttranscriptional silencing , reduced inflammatory profiles , and protected mice from colitis and cancer . Our results highlight the role of HuR as a homeostatic coordinator of mRNAs that encode molecules that guide innate inflammatory effects and demonstrate the potential of harnessing the effects of HuR for clinical benefit against pathologic inflammation and cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22201685"}
{"sentence": "Therapy-induced cellular senescence ( TCS ) , characterized by prolonged cell cycle arrest , is an in vivo response of human cancers to chemotherapy and radiation . Unfortunately , TCS is reversible for a subset of senescent cells , leading to cellular reproliferation and ultimately tumor progression . This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer . We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome . In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape , we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry . We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS . These polyploid senescent cells represent important transition states through which escape preferentially occurs . The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS . Altogether , these studies underscore the importance of TCS in cancer therapeutics .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "22945332"}
{"sentence": "PURPOSE We describe the anticancer activity of ganetespib , a novel non-geldanamycin heat shock protein 90 ( HSP90 ) inhibitor , in non-small cell lung cancer ( NSCLC ) models . EXPERIMENTAL DESIGN The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays , cell lines , and xenografts , and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model . RESULTS Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone , p23 , more potently than 17-AAG . In genomically defined NSCLC cell lines , ganetespib caused depletion of receptor tyrosine kinases , extinguishing of downstream signaling , inhibition of proliferation and induction of apoptosis with IC(50) values ranging 2 to 30 nmol/L , substantially lower than those required for 17-AAG ( 20-3,500 nmol/L ) . Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants . In mice bearing NCI-H1975 ( EGFR L858R/T790M ) xenografts , ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t(1/2) 58.3 hours , supporting once-weekly dosing experiments , in which ganetespib produced greater tumor growth inhibition than 17-AAG . However , after a single dose , reexpression of mutant EGFR occurred by 72 hours , correlating with reversal of antiproliferative and proapoptotic effects . Consecutive day dosing resulted in xenograft regressions , accompanied by more sustained pharmacodynamic effects . Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA . CONCLUSIONS Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets , including those harboring EGFR or ERBB2 mutation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22806877"}
{"sentence": "Breast cancer causes death due to distant metastases in which tumor cells produce matrix metalloproteinase ( MMP ) enzymes which facilitate invasion . Oleuropein , the main olive oil polyphenol , has anti-proliferative effects . This study aimed to investigate the effect of oleuropein on the metastatic and anti-metastatic gene expression in the MDA human breast cancer cell line . We evaluated the MMPs and TIMPs gene expression by semi-quantitative reverse transcriptase polymerase chain reaction ( RT-PCR ) in treated and untreated cells . This study demonstrated that OL may induce anti-metastatic effects on human breast cancer cells . We found that TIMP1,-3 , and -4 were over-expressed after all periods of incubation in treated cancer cells compared to untreated cells , while MMP2 and MMP9 genes were down-regulated , at least initially . Treatment of breast cancer cells with oleuropein could help in prevention of cancer metastasis by increasing the TIMPs and suppressing the MMPs gene expressions .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23167379"}
{"sentence": "Modeling the behavior of mammalian arachnoid cells is critical to understand hydrocephalus and other brain disorders involving abnormal flow of cerebrospinal fluid , yet relatively little is known about the physiology of arachnoid cells due to lack of a robust three-dimensional model system . Explanted primary cultures have been the only option to study transport across arachnoid cell membranes , but practical limitations of primary culture include slow growth , early senescence , and poor reproducibility . The purpose of this study was to create immortalized rat arachnoid cell lines to permit in vitro study of arachnoid granulations and properties of cerebrospinal fluid ( CSF ) flow . We established and partially characterized two immortalized cell lines generated from primary rat arachnoid cells , using retroviral gene transfer of SV40 large T antigen ( SV40 LTAg ) either with or without human telomerase ( hTERT ) . The established cell lines stably express either SV40 LTAg alone , or SV40 LTAg and hTERT , and demonstrate high proliferative rate , contact inhibition at confluence , and stable expression of protein markers characteristic of native arachnoid cells over more than 160 passages .", "label": [0, 0, 0, 1, 1, 0, 0, 0, 0, 0], "id": "21195136"}
{"sentence": "Chromosomal translocations typically impair cell differentiation and often require secondary mutations for malignant transformation . However , the role of a primary translocation in the development of collaborating mutations is debatable . To delineate the role of leukemic translocation NUP98-HOXD13 ( NHD13 ) in secondary mutagenesis , DNA break and repair mechanisms in stimulated mouse B lymphocytes expressing NHD13 were analyzed . Our results showed significantly reduced expression of non-homologous end joining ( NHEJ)-mediated DNA repair genes , DNA Pkcs , DNA ligase4 , and Xrcc4 leading to cell cycle arrest at G2/M phase . Our results showed that expression of NHD13 fusion gene resulted in impaired NHEJ-mediated DNA break repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "23131583"}
{"sentence": "The tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation . Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 ( LCD1 and LCD2 ) , which may be important for Lats1/2-specific functions . Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 ( Lats1(\\u0394N/\\u0394N) ) . Some Lats1(\\u0394N/\\u0394N) mice were born safely and grew normally . However , mouse embryonic fibroblasts ( MEFs ) from Lats1(\\u0394N/\\u0394N) mice displayed mitotic defects , centrosomal overduplication , chromosomal misalignment , multipolar spindle formation , chromosomal bridging and cytokinesis failure . They also showed anchorage-independent growth and continued cell cycles and cell growth , bypassing cell-cell contact inhibition similar to tumor cells . Lats1(\\u0394N/\\u0394N) MEFs produced tumors in nude mice after subcutaneous injection , although the tumor growth rate was much slower than that of ordinary cancer cells . Yap , a key transcriptional coactivator of the Hippo pathway , was overexpressed and stably retained in Lats1(\\u0394N/\\u0394N) MEFs in a cell density independent manner , and Lats2 mRNA expression was downregulated . In conclusion , N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation , leading to chromosomal instability and tumorigenesis .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 1, 0], "id": "23230145"}
{"sentence": "The G protein-coupled human gastrin-releasing peptide receptor ( hGRP-R ) is frequently found aberrantly expressed in human cancers of the colon , stomach , and lung , and its ligand-specific activation has been implicated in cell proliferation and differentiation . Here , we demonstrated hGRP-R activation stimulated sustained cyclic AMP response element binding protein ( CREB ) phosphorylation and transactivation in duodenal cancer cells through a protein kinase C and partially p38 mitogen-activated protein kinase-dependent pathway . In contrast , intracellular calcium , ERK1/2 , protein kinase A , and PI3 kinase were not involved . This novel signaling mechanism might be of importance for regulation of CREB-dependent gene expression in human cancer expressing functional hGRP-R .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12220644"}
{"sentence": "Cardiac \\u03b1-tropomyosin ( Tm ) single-site mutations D175N and E180G cause familial hypertrophic cardiomyopathy ( FHC ) . Previous studies have shown that these mutations increase both Ca(2+) sensitivity and residual contractile activity at low Ca(2+) concentrations , which causes incomplete relaxation during diastole resulting in hypertrophy and sarcomeric disarray . However , the molecular basis for the cause and the difference in the severity of the manifested phenotypes of disease are not known . In this work we have ( 1 ) used ATPase studies using reconstituted thin filaments in solution to show that these FHC mutants result in an increase in Ca(2+) sensitivity and an increased residual level of ATPase , ( 2 ) shown that both FHC mutants increase the rate of cleavage at R133 , residues N-terminal to the mutations , when free and bound to actin , ( 3 ) shown that for Tm-E180G , the increase in the rate of cleavage is greater than that for D175N , and ( 4 ) shown that for E180G , cleavage also occurs at a new site 53 residues C-terminal to E180G , in parallel with cleavage at R133 . The long-range decreases in dynamic stability due to these two single-site mutations suggest increases in flexibility that may weaken the ability of Tm to inhibit activity at low Ca(2+) concentrations for D175N and to a greater degree for E180G , which may contribute to differences in the severity of FHC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22794249"}
{"sentence": "The authors examined nutritional risk factors for prostate cancer among 9,559 participants in the Prostate Cancer Prevention Trial ( United States and Canada , 1994-2003 ) . The presence or absence of cancer was determined by prostate biopsy , which was recommended during the trial because of an elevated prostate-specific antigen level or an abnormal digital rectal examination and was offered to all men at the trial's end . Nutrient intake was assessed using a food frequency questionnaire and a structured supplement-use questionnaire . Cancer was detected in 1,703 men ; 127 cancers were high-grade ( Gleason score 8-10 ) . There were no associations of any nutrient or supplement with prostate cancer risk overall . Risk of high-grade cancer was associated with high intake of polyunsaturated fats ( quartile 4 vs. quartile 1 : odds ratio = 2.41 , 95% confidence interval ( CI ) : 1.33 , 4.38 ) . Dietary calcium was positively associated with low-grade cancer but inversely associated with high-grade cancer ( for quartile 4 vs. quartile 1 , odds ratios were 1.27 ( 95% CI : 1.02 , 1.57 ) and 0.43 ( 95% CI : 0.21 , 0.89 ) , respectively ) . Neither dietary nor supplemental intakes of nutrients often suggested for prostate cancer prevention , including lycopene , long-chain n-3 fatty acids , vitamin D , vitamin E , and selenium , were significantly associated with cancer risk . High intake of n-6 fatty acids , through their effects on inflammation and oxidative stress , may increase prostate cancer risk .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20693267"}
{"sentence": "DNA double-strand breaks ( DSBs ) in embryonic stem ( ES ) cells are repaired primarily by homologous recombination ( HR ) . The mechanism by which HR is regulated in these cells , however , remains enigmatic . To gain insight into such regulatory mechanisms , we have asked how protein levels of Rad51 , a key component of HR , are controlled in mouse ES cells and mouse embryo fibroblasts ( MEFs ) . The Rad51 protein level is about 15-fold higher in ES cells than in MEFs . The level of Rad51 mRNA , however , is only higher , indicating that the differences in mRNA levels due to rates of transcription or mRNA stability are not sufficient to account for the large difference in the abundance of Rad51 protein . Comparison of Rad51 half-lives between ES cells and MEFs also did not explain the elevated level of Rad51 protein in the ES cells . A comparative assessment of the Rad51 translation level demonstrated that it is translated with much greater efficacy in ES cells than in MEFs . To determine whether this high level of translation in ES cells is a general phenomenon in these cells or whether it is a characteristic of specific proteins , such as those involved with recombination and cell cycle progression , we compared mechanisms that regulate the level of Pcna in ES cells with those that regulate Rad51 . The half-life of Pcna and its rate of synthesis were considerably different from those of Rad51 in ES cells , demonstrating that regulation of Rad51 abundance cannot be generalized to other ES cell proteins and not to proteins involved in DNA replication and cell cycle control . Finally , we show that only a small proportion of the abundant Rad51 protein population is activated under basal conditions in ES cells and recruited to DNA DSBs and/or stalled replication forks .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22705496"}
{"sentence": "MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion . The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined . Previous reports have suggested that MDSC may contribute to Treg induction in cancer . Herein , we provide evidence that tumor-induced gr-MDSCs , endowed with the potential of suppressing conventional T Lc , surprisingly impair TGF-\u03b21-mediated generation of CD4(+)CD25(+)FoxP3(+) iTregs . Furthermore , gr-MDSCs impede the proliferation of nTregs without , however , affecting FoxP3 expression . Suppression of iTreg differentiation from na\ufffdve CD4(+) cells by gr-MDSC occurs early in the polarization process , requires inhibition of early T cell activation , and depends on ROS and IDO but does not require arginase 1 , iNOS , NO , cystine/cysteine depletion , PD-1 and PD-L1 signaling , or COX-2 . These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22891289"}
{"sentence": "Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer . Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination , we have measured telomere length , telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5 . In all mortal populations , telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures . When transformed cells reached crisis , the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed . In immortal cells , telomere length and frequency of dicentric chromosomes stabilized after crisis . Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations . These results suggest that chromosomes with short ( TTAGGG)n tracts are recombinogenic , critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1582420"}
{"sentence": "Ceramide induces cell cycle arrest and apoptotic cell death associated with increased levels of p27(kip1) . The aim of this study was to examine the effects of ceramide on p27(kip1) protein levels as a measure of cell cycle arrest and apoptosis . Results showed that ceramide increased p27(kip1) protein levels through activation of protein phosphatase 2A ( PP2A ) in PC-3 prostate cancer cells . Treatment of cells with the PP2A inhibitor okadaic acid or with PP2A-C\u03b1 siRNA inhibited ceramide-induced enhanced p27(kip1) protein expression and Akt dephosphorylation , and prevented Skp2 downregulation . Overexpression of constitutively active Akt attenuated ceramide-induced Skp2 downregulation and p27(kip1) upregulation . In addition , ceramide stimulated binding of the PP2A catalytic subunit PP2A-C\u03b1\u03b2 to Akt as assessed by immunoprecipitation experiments , indicating that PP2A is involved in the induction of p27(kip1) via inhibition of Akt pathway . Finally , whether PP2A can regulate p27(kip1) expression independently of Akt pathway was determined . Knockdown of PP2A-C\u03b1 with siRNA reduced p27(kip1) levels in the presence of Akt inhibitor . These data reveal that PP2A is a regulator of ceramide-induced p27(kip1) expression via Akt-dependent and Akt-independent pathways .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20954073"}
{"sentence": "Tumor invasion and metastasis are the primary causes of cancer patient mortality , underscoring the need for identification of novel genes and signaling pathways that mediate these prognosis-determining phenomena . To identify and characterize novel lung adenocarcinoma genes associated with lung cancer progression , we created a bioinformatics-based approach that focuses on human cell-cycle-regulated genes that have evolved only in higher organisms but not in lower eukaryotic cells . In siRNA experiments in lung cancer cells , FLJ10540 was identified as one of several novel targets involved in cell migration and invasion . Here , we demonstrate that PI3K inhibition affects FLJ10540-mediated cell migration and invasion and further , that FLJ10540 knockdown ablates AKT-Ser(473) phosphorylation . Taken together , these findings indicate that the FLJ10540/PI3K/AKT pathway may harbor new therapeutic targets for treating invasive lung adenocarcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20217555"}
{"sentence": "Steroid hormone receptors , including estrogen receptor-alpha ( ERalpha ) , are ligand-activated transcription factors , and hormone binding leads to depletion of receptor levels via preteasome-mediated degradation . NEDD8 ( neural precursor cell-expressed developmentally down-regulated ) is an ubiquitin-like protein essential for protein processing and cell cycle progression . We recently demonstrated that ubiquitin-activating enzyme ( Uba)3 , the catalytic subunit of the NEDD8-activating enzyme , inhibits ERalpha transcriptional activity . Here we report that Uba3-mediated inhibition of ERalpha transactivation function is due to increased receptor protein turnover . Coexpression of Uba3 with ERalpha increased receptor degradation by the 26S proteasome . Inhibition of NEDD8 activation and conjugation diminished polyubiquitination of ERalpha and blocked proteasome-mediated degradation of receptor protein . The antiestrogen ICI 182,780 is known to induce ER degradation . In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway , ICI 182,780 degradation of ERalpha was impaired , and the antiestrogen was ineffective at inhibiting cell proliferation . This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system , suggesting that the two pathways can act together to modulate ERalpha turnover and cellular responses to estrogens . Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERalpha positive breast cancer cells , we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERalpha .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12554766"}
{"sentence": "The mechanisms by which tumour cells metastasize and the role that cell polarity proteins play in this process are not well understood . We report that partitioning defective protein 3 ( Par3 ) is dysregulated in metastasis in human breast cancer , and is associated with a higher tumour grade and ErbB2-positive status . Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo . Interestingly , the metastatic behaviour was not associated with an overt mesenchymal phenotype . However , loss of Par3 inhibited E-cadherin junction stability , disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a manner dependent on the Tiam1/Rac-GTP pathway . Inhibition of this pathway restored E-cadherin junction stability and blocked invasive behaviour of cells lacking Par3 , suggesting that loss of Par3 promotes metastatic behaviour of ErbB2-induced tumour epithelial cells by decreasing cell-cell cohesion .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23263278"}
{"sentence": "Pyruvate kinase M2 ( PKM2 ) is a key player in the Warburg effect of cancer cells . However , the mechanisms of regulating PKM2 are not fully elucidated . Here , we identified the protein-serine/threonine kinase PIM2 , a known oncogene , as a novel binding partner of PKM2 . The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells . Importantly , we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue , resulting in an increase of PKM2 protein levels . Compared with wild type , PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis , co-activating HIF-1\\u03b1 and \\u03b2-catenin , and cell proliferation , while enhancing mitochondrial respiration of cancer cells . These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer , highlighting PIM2 as a potential therapeutic target .", "label": [0, 0, 1, 0, 0, 1, 0, 0, 0, 0], "id": "24142698"}
{"sentence": "Approximately 50% of human tumors have a mutation in TP53 . The pattern and spectra of TP53 mutations often differ between cancer types , perhaps due to different etiological factors . The Hupki ( human TP53 knock-in ) mouse embryo fibroblast ( HUF ) immortalization assay is useful for studying mutagenesis in the human TP53 gene by environmental carcinogens . Prior to initiating an immortalization assay , carcinogen treatment conditions must be optimized , which can require a large number of cells . As primary HUF cultures senesce within 2 weeks , restricting their use , we investigated whether immortalized HUFs retaining wild-type TP53 can be surrogates for primary HUFs in initial treatment optimization . DNA damage by eight compounds found in diesel exhaust , benzo[a]pyrene , 3-nitrobenzanthrone , 1-nitropyrene , 1,3-dinitropyrene , 1,6-dinitropyrene , 1,8-dinitropyrene , 6-nitrochrysene , and 3-nitrofluorene , was assessed by ( 32 ) P-postlabeling and the alkaline comet assay in primary HUFs and in an immortal HUF cell line J201 . For most compounds , higher levels of DNA adducts accumulated in J201 cells than in primary HUFs . This difference was not reflected in the comet assay or by cell viability changes . Experiments in three additional immortal HUF cell lines ( AAI49 , U56 , and E2-143 ) confirmed strong differences in DNA adduct levels compared with primary HUFs . However , these did not correlate with the protein expression of Nqo1 or Nat1/2 , or with gene expression of Cyp1a1 or Cyp1b1 . Our results show that using immortal HUFs as surrogates for primary HUFs in genotoxicity screening has limitations and that DNA adduct formation is the best measure of genotoxicity of the nitro-polycyclic aromatic hydrocarbons tested in HUFs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22351035"}
{"sentence": "SWAP-70 , a phosphatidylinositol trisphosphate ( PtdIns(3,4,5)P(3) ) binding protein , has been suggested to be involved in transformation of mouse embryo fibroblasts ( MEFs ) as well as membrane ruffling after growth factor stimulation of the cells . A mutant , SWAP-70-374 , was found to be able to bind to F-actin in vitro , whereas wild-type SWAP-70 failed to do so . This mutant was present at the plasma membrane without any stimulation while the wild-type protein was present only in the cytosol unless cells were stimulated with EGF . Expression of this mutant in MEFs resulted in morphologic transformation , fast growth , and loss of contact inhibition , suggesting that SWAP-70 with this mutation can transform the cells . ERK1/2 was activated in SWAP-70-374-transformed cells . Use of MEK inhibitors revealed that the ERK1/2 pathway does not affect the cell growth of MEFs but is responsible for loss of contact inhibition . To investigate the function of SWAP-70 further , drugs that can inhibit SWAP-70-dependent cell responses were screened . Among various drugs , sanguinarine was found to inhibit transformation of MEFs by SWAP-70-374 . This drug was able to inhibit SWAP-70-mediated membrane ruffling as well , suggesting that its effect was closely related to the SWAP-70 signaling pathway . These results suggest that SWAP-70-374 can activate some signaling pathways , including the ERK1/2 pathway , to transform MEFs .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21152038"}
{"sentence": "Extensive biochemical and structural analyses have been performed on the putative DNA repair proteins of hyperthermophilic archaea , in contrast to the few genetic analyses of the genes encoding these proteins . Accordingly , little is known about the repair pathways used by archaeal cells at high temperature . Here , we attempted to disrupt the genes encoding the potential repair proteins in the genome of the hyperthermophilic archaeon Thermococcus kodakaraensis . We succeeded in isolating null mutants of the hjc , hef , hjm , xpb , and xpd genes , but not the radA , rad50 , mre11 , herA , nurA , and xpg/fen1 genes . Phenotypic analyses of the gene-disrupted strains showed that the xpb and xpd null mutants are only slightly sensitive to ultraviolet ( UV ) irradiation , methyl methanesulfonate ( MMS ) and mitomycin C ( MMC ) , as compared with the wild-type strain . The hjm null mutant showed sensitivity specifically to mitomycin C. On the other hand , the null mutants of the hjc gene lacked increasing sensitivity to any type of DNA damage . The Hef protein is particularly important for maintaining genome homeostasis , by functioning in the repair of a wide variety of DNA damage in T. kodakaraensis cells . Deletion of the entire hef gene or of the segments encoding either its nuclease or helicase domain produced similar phenotypes . The high sensitivity of the \u0394hef mutants to MMC suggests that Hef performs a critical function in the repair process of DNA interstrand cross-links . These damage-sensitivity profiles suggest that the archaeal DNA repair system has processes depending on repair-related proteins different from those of eukaryotic and bacterial DNA repair systems using homologous repair proteins analyzed here .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21178304"}
{"sentence": "PRL induces quiescent Nb2 rat T-lymphoma cells to undergo mitogenesis . Upon PRL stimulation , the transcription factor interferon regulatory factor-1 ( IRF-1 ) is induced as a novel T-cell activation gene in Nb2 cells . Surprisingly , IRF-1 is expressed twice during a single PRL-induced growth cycle : first during the early G1 phase , in an immediate transient peak from 15 min to 2 h , and second during the G1/S phase transition , in a broader peak beginning at 8 h . The unusual biphasic expression of IRF-1 mRNA is accompanied both times by de novo IRF-1 protein synthesis . However , the rate of IRF-1 protein turnover appears to be different in G1 and S phases . IRF-1 protein expressed in G1 exhibits a half-life of about 25 min , whereas in the S phase , the half-life is about 60 min . By washing out PRL at various times during G1 , we found a direct correlation among the length of PRL exposure , the second peak of IRF-1 mRNA expression , and DNA synthesis . Our data suggest that PRL and one putative nuclear mediator , IRF-1 , may be important in two distinct phases of the cell cycle : first in cell cycle activation , and then in S phase progression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1491701"}
{"sentence": "The cyclin-dependent kinase ( CDK ) inhibitor p21(Waf1/Cip1/Sdi1) was identified initially as a gene induced in senescent cells and itself has been shown to cause permanent growth arrest/senescence . Reactive oxygen species ( ROS ) , a byproduct of oxidative processes , can also induce an irreversible growth arrest similar to senescence . Here we show that p21 increased intracellular levels of ROS both in normal fibroblasts and in p53-negative cancer cells . N-acetyl-L-cysteine , an ROS inhibitor , rescued p21-induced senescence , showing that ROS elevation is necessary for induction of the permanent growth arrest phenotype. p16(Ink4a) , a CDK4- and CDK6-specific inhibitor , failed to increase ROS levels , and cell cycle arrest induced by p16 was reversible following its down-regulation , demonstrating the specificity of this p21 effect . A p21 mutant that lacked the ability to bind proliferating cell nuclear antigen ( PCNA ) retained the ability to induce both ROS and permanent growth arrest . All of these findings establish that p21 mediates senescence by a mechanism involving ROS accumulation which does not require either its PCNA binding or the CDK inhibitory functions shared with p16 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "11980715"}
{"sentence": "Epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor 2 ( HER2 ) amplification occurs in over 30% of esophageal carcinomas . Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer . We evaluated the antitumor effects of lapatinib , a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2 , 5-fluorouracil ( 5-Fu ) alone and in combination on esophageal cancer cells . The antiproliferative activity of lapatinib , 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index ( CI ) values were calculated . Additionally , cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis . AnnexinV-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination . The EGFR and HER2 activated signaling pathways were monitored by western blotting . The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells . The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2 , and inhibited the activation of downstream signaling molecules , such as AKT and ERK . A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib , however , combination with 5-Fu did not enhance G1 arrest . These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22293713"}
{"sentence": "BACKGROUND Neuroblastoma ( NBL ) is a common pediatric solid tumor , and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment . Chemotherapy resistance at relapse contributes heavily to treatment failure . The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms . On the basis of previous work and on data from publicly available studies , the authors hypothesized that human epidermal growth factor receptor 4 ( Her4 ) contributes to resistance . METHODS Her4 expression was reduced with small-hairpin RNA ( shRNA ) to over express intracellular HER4 , and the authors tested its impact on tumor cell survival under various culture conditions . The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA ( mRNA ) array . RESULTS HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture . With HER4 knockdown , NBL cells became less resistant to anoikis and serum starvation . Moreover , HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin , doxorubicin , etoposide , and activated ifosfamide . In mRNA array analysis , HER4 knockdown predominately altered genes related to cell cycle regulation . In NBL spheres compared with monolayers , cell proliferation was decreased , and cyclin D expression was reduced . HER4 knockdown reversed cyclin D suppression . Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance . CONCLUSIONS The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli , including anoikis , nutrient deficiency , and cytotoxic chemotherapy . The intracellular fragment of HER4 was sufficient to confer this phenotype . HER4 functions as a cell cycle suppressor , maintaining resistance to cellular stress . The current findings indicate that HER4 overexpression may be associated with refractory disease , and HER4 may be an important therapeutic target .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "22415601"}
{"sentence": "Escherichia coli pol V ( UmuD'(2)C ) , the main translesion DNA polymerase , ensures continued nascent strand extension when the cellular replicase is blocked by unrepaired DNA lesions . Pol V is characterized by low sugar selectivity , which can be further reduced by a Y11A \" steric-gate \" substitution in UmuC that enables pol V to preferentially incorporate rNTPs over dNTPs in vitro . Despite efficient error-prone translesion synthesis catalyzed by UmuC_Y11A in vitro , strains expressing umuC_Y11A exhibit low UV mutability and UV resistance . Here , we show that these phenotypes result from the concomitant dual actions of Ribonuclease HII ( RNase HII ) initiating removal of rNMPs from the nascent DNA strand and nucleotide excision repair ( NER ) removing UV lesions from the parental strand . In the absence of either repair pathway , UV resistance and mutagenesis conferred by umuC_Y11A is significantly enhanced , suggesting that the combined actions of RNase HII and NER lead to double-strand breaks that result in reduced cell viability . We present evidence that the Y11A-specific UV phenotype is tempered by pol IV in vivo . At physiological ratios of the two polymerases , pol IV inhibits pol V-catalyzed translesion synthesis ( TLS ) past UV lesions and significantly reduces the number of Y11A-incorporated rNTPs by limiting the length of the pol V-dependent TLS tract generated during lesion bypass in vitro . In a recA730 lexA(Def) \\u0394umuDC \\u0394dinB strain , plasmid-encoded wild-type pol V promotes high levels of spontaneous mutagenesis . However , umuC_Y11A-dependent spontaneous mutagenesis is only of that observed with wild-type pol V , but increases to of wild-type levels in an isogenic \\u0394rnhB strain and of wild-type levels in a \\u0394rnhA \\u0394rnhB double mutant . Our observations suggest that errant ribonucleotides incorporated by pol V can be tolerated in the E. coli genome , but at the cost of higher levels of cellular mutagenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23144626"}
{"sentence": "The c-Jun NH(2)-terminal kinase ( JNK ) signaling cascade has been implicated in a wide range of diseases , including cancer . It is unclear how different JNK proteins contribute to human cancer . Here , we report that JNK2 is activated in more than 70% of human squamous cell carcinoma ( SCC ) samples and that inhibition of JNK2 pharmacologically or genetically impairs tumorigenesis of human SCC cells . Most importantly , JNK2 , but not JNK1 , is sufficient to couple with oncogenic Ras to transform primary human epidermal cells into malignancy with features of SCC . JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor p16 and the activation of NF-kappaB . On the other hand , JNK , along with phosphoinositide 3-kinase , is essential for Ras-induced glycolysis , an energy-producing process known to benefit cancer growth . These data indicate that JNK2 collaborates with other oncogenes , such as Ras , at multiple molecular levels to promote tumorigenesis and hence represents a promising therapeutic target for cancer .", "label": [0, 0, 1, 1, 0, 0, 0, 0, 0, 0], "id": "20354187"}
{"sentence": "A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellular carcinoma . However , the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined . Here , using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis , we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis , proliferation , liver inflammation , and the eventual development of hepatocellular carcinoma . The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis . This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "12391022"}
{"sentence": "Gadd45a , the first well-defined p53 downstream gene , can be induced by multiple DNA-damaging agents , which plays important roles in the control of cell cycle checkpoint , DNA repair process and signaling transduction . Our previous findings suggested that Gadd45a maintains cell-cell adhesion and cell contact inhibition . However , little is known about how Gadd45a participates in the suppression of malignancy in human cancer cells . To examine the functions of Gadd45a in cell invasion and metastasis , we performed the adhesion , wound-healing and transwell assays in Gadd45a ( +/+ ) and Gadd45a ( -/- ) MEF cell lines . We found the adhesion , migration and invasive abilities were much higher in Gadd45a deficient cells . We furthermore applied high-throughput cDNA microarray analysis and bioinformatics analysis to analyze the mechanisms of Gadd45a gene in invasion and metastasis . Compared with the Gadd45a wild type cells , the Gadd45a deficient cells showed a wide range of transcripts alterations . The altered gene pathways were predicted by the MAS software , which indicated focal adhesion,cell communication,ECM-receptor interaction as the three main pathways . Real-time PCR was employed to validate the differentially expressed genes . Interestingly , we figured out that the deregulations of these genes are caused neither by genomic aberrations nor methylation status . These findings provided a novel insight that Gadd45a may involve in tumor progression by regulating related genes expressions .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22825327"}
{"sentence": "The glutathione peroxidases , a family of selenocysteine-containing redox enzymes , play pivotal roles in balancing the signaling , immunomodulatory , and deleterious effects of reactive oxygen species ( ROS ) . The glutathione peroxidase GPX3 is the only extracellular member of this family , suggesting it may defend cells against ROS in the extracellular environment . Notably , GPX3 hypermethylation and underexpression occur commonly in prostate , gastric , cervical , thyroid , and colon cancers . We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic tumorigenesis , a process characterized by oxidative stress and inflammation , comparing Gpx3(-/-) mice in an established two-stage model of inflammatory colon carcinogenesis . Gpx3-deficient mice exhibited an increased tumor number , though not size , along with a higher degree of dysplasia . In addition , they exhibited increased inflammation with redistribution toward protumorigenic M2 macrophage subsets , increased proliferation , hyperactive WNT signaling , and increased DNA damage . To determine the impact of acute gene loss in an established colon cancer line , we silenced GPX3 in human Caco2 cells , resulting in increased ROS production , DNA damage and apoptosis in response to oxidative stress , combined with decreased contact-independent growth . Taken together , our results suggested an immunomodulatory role for GPX3 that limits the development of colitis-associated carcinoma .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 1], "id": "23221387"}
{"sentence": "The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers . Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a -G*CN- sequence context , in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl ( FABP ) , 2-aminofluorene ( FAF ) or 2-acetylaminofluorene ( FAAF ) , and N is either dA or dT . The FABP and FAF lesions exist in a simple mixture of ' stacked ' ( S ) and ' B-type ' ( B ) conformers , whereas the N-acetylated FAAF also samples a ' wedge ' ( W ) conformer . FAAF is repaired three to four times more efficiently than FABP and FAF . A simple A- to -T polarity swap in the G*CA/G*CT transition produced a dramatic increase in syn-conformation and resulted in 2- to 3-fold lower nucleotide excision repair ( NER ) efficiencies in Escherichia coli . These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor , more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts . This work represents a novel 3'-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23180767"}
{"sentence": "Carboxypeptidase M ( CPM ) targets the basic amino acids arginine and lysine present at the C-terminus of peptides or proteins . CPM is thought to be involved in inflammatory processes . This is corroborated by CPM-mediated trimming and modulation of inflammatory factors , and expression of the protease in inflammatory environments . Since the function of CPM in and beyond inflammation remains mainly undefined , the identification of natural substrates can aid in discovering the ( patho)physiological role of CPM . CCL1/I-309 , with its three C-terminal basic amino acids , forms a potential natural substrate for CPM . CCL1 plays a role not only in inflammation but also in apoptosis , angiogenesis and tumor biology . Enzymatic processing differently impacts the biological activity of chemokines thereby contributing to the complex regulation of the chemokine system . The aim of the present study was to investigate whether ( i ) CCL1/I-309 is prone to trimming by CPM , and ( ii ) the biological activity of CCL1 is altered after C-terminal proteolytic processing . CCL1 was identified as a novel substrate for CPM in vitro using mass spectrometry . C-terminal clipping of CCL1 augmented intracellular calcium release mediated by CCR8 but reduced the binding of CCL1 to CCR8 . In line with the higher intracellular calcium release , a pronounced increase of the anti-apoptotic activity of CCL1 was observed in the BW5147 cellular model . CCR8 signaling , CCR8 binding and anti-apoptotic activity were unaffected when CPM was exposed to the carboxypeptidase inhibitor DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid . The results of this study suggest that CPM is a likely candidate for the regulation of biological processes relying on the CCL1-CCR8 system .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22479563"}
{"sentence": "Cellular senescence is considered as a tumor suppressive mechanism . Recent evidence indicates however that senescent cells secrete various growth factors and cytokines , some of which may paradoxically promote cancer progression . This phenomenon termed senescence-associated secretory phenotype ( SASP ) must be inhibited in order for anti-proliferative agents to be effective . The present study was designed to determine whether the \u03b2-catenin destruction complex ( BCDC ) , known to integrate the action of various growth factors and cytokines , would represent a suitable target to inhibit the activity of SASP components . For this , we carried out experiments to determine the effect of drug-induced senescence on secretion of SASP , \u03b2-catenin transactivation , and the relationship between these processes . Moreover , genetic and pharmacological approaches were used to define the implication of BCDC in mediating the effects of SASP components on cell migration and resistance to drugs . The findings indicate that drug-induced senescence was associated with expression of various Wnt ligands in addition to previously known SASP components . Beta catenin transactivation and expression of genes implicated in epithelial-mesenchymal transition ( EMT ) also increased in response to drug-induced SASP . These effects were prevented by Pyrvinium , a recently described activator of BCDC . Pyrvinium also suppressed the effects of SASP on cell migration and resistance to doxorubicin . Together , these findings provide insights on the potential role of BCDC in mediating the effects of drug-induced SASP on cancer cell invasion and resistance to therapy , and suggest that targeting this pathway may represent an effective approach to enhance the activity of current and prospective anti-cancer therapeutics .", "label": [1, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23272224"}
{"sentence": "To elucidate role of the three enzymes in hepatocarcinogenesis , hMTH1 , hOGG1 and hMYH , mRNA expression were examined by using RT/semi-quantitative real-time PCR and 8-O-HdG levels was studied by HPLC/ECD in HCC and non-tumorous liver tissue of 21 patients with hepatocellular carcinoma ( HCC ) . It was found that the 8-OHdG level in non-tumourous liver tissue was significantly higher than in HCC tissue ( P = 0.006 ) , and this was correlated with the degree of inflammation . The hMTH1 expression in HCC tissue was significantly higher than in non-tumorous liver tissue ( P = 0.014 ) . Inversely , The hMYH alpha expression was significantly increased ( P = 0.039 ) in non-tumorous liver tissue . No difference was seen in hOGG1 expression in non-tumorous liver and HCC tissue . A significant linear correlation between hMTH1 and hOGG1 expression was found both in HCC tissue ( r = 0.809 , P < 0.001 ) and in non-tumorous liver tissue ( r = 0.883 , P < 0.001 ) . Our findings suggested a reactive rather than pathogenic role of the DNA repair enzymes in the hepatocarcinogenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12658805"}
{"sentence": "The UT-7 cell line was established from a patient with a megakaryoblastic leukemia ( Komatsu et al , Cancer Res 51 : 341 , 1991 ) . Its proliferation is strictly dependent on the presence of hematopoietic growth factors including erythropoietin ( Epo ) , granulocyte-macrophage colony-stimulating factor ( GM-CSF ) , and interleukin-3 ( IL-3 ) . We investigated the differentiation capacities of this cell line under the action of several growth factors , using immunomarkers , flow cytometry , and ultrastructural techniques . In the presence of GM-CSF and IL-3 , eosinophil and basophil promyelocytes were detected , as well as a few cells with erythroid and megakaryocytic ( MK ) differentiation features . In contrast , Epo induced a marked erythroid differentiation with an increase of glycophorin A expression , accompanied by a few hemoglobinized cells . Differentiation induced by the growth factors took 24 to 48 hours to begin , and increased with cell passages to a plateau at 2 weeks of culture . However , this was not only due to a cell selection because the differential effects of Epo and GM-CSF were observed from a single cell clone and the phenotype could be reversed by opposite growth factors , even after a long period of culture . We subsequently investigated the phenotype of UT-7 in the presence of combinations of Epo , IL-3 , and GM-CSF , and showed that GM-CSF and IL-3 act predominantly over Epo . This effect was mediated by a rapid downmodulation of Epo receptors by GM-CSF at messenger RNA and binding sites levels , without a change in receptor affinities . On the other hand , Epo had no effect on number and affinity of GM-CSF receptors . This study shows that UT-7 is a growth factor-dependent pluripotent cell line in which commitment may be directed by a hierarchical action of growth factors through an early and rapid transmodulation of growth factor receptors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1467515"}
{"sentence": "Signal transducers and activators of transcription 3 ( Stat3 ) is activated by cytokines and growth factors in lung cancers and regulates expression of genes implicated in cell growth , survival , and transformation . Previously , we found that mice with a deletion of the G protein-coupled receptor , family C , group 5 , member a ( Gprc5a ) gene develop lung tumors , indicating that Gprc5a is a tumor suppressor . Herein , we show that epithelial cells from Gprc5a knockout mouse lung ( Gprc5a(-/-) cells ) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semisolid medium than their counterparts from wild-type mice ( Gprc5a(+/+) cells ) . Stat3 tyrosine 705 phosphorylation and expression of several Stat3-regulated antiapoptotic genes were higher in Gprc5a(-/-) than in Gprc5a(+/+) cells . Both cell types secreted leukemia inhibitory factor ( Lif ) ; however , whereas Stat3 activation was persistent in Gprc5a(-/-) cells , it was transient in Gprc5a(+/+) cells . Lung adenocarcinoma cells isolated from Gprc5a(-/-) mice also exhibited autocrine Lif-mediated Stat3 activation . The level of Socs3 , the endogenous Stat3 inhibitory protein , was higher in Gprc5a(+/+) than in Gprc5a(-/-) cells , and expression of the tumor suppressor stabilized Socs3 . Inhibition of Stat3 signaling in Gprc5a(-/-) normal and cancer cells by the Janus-activated kinase 2 inhibitor AG490 or by a dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited colony formation . These results show that persistent Stat3 activation is important for the survival and transformation of Gprc5a(-/-) lung cells and suggest that the tumor suppressive effects of Gprc5a are mediated , at least in part , by inhibition of Stat3 signaling through Socs3 stabilization .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20959490"}
{"sentence": "The Ras-assocation domain family ( RASSF ) of tumor suppressor proteins until recently contained six proteins named RASSF1-6 . Recently , four novel family members , RASSF7-10 , have been identified by homology searches for RA-domain-containing proteins . These additional RASSF members are divergent and structurally distinct from RASSF1-6 , containing an N-terminal RA domain and lacking the Sav/RASSF/Hpo ( SARAH ) domain . Here , we show that RASSF8 is ubiquitously expressed throughout the murine embryo and in normal human adult tissues . Functionally , RNAi-mediated knockdown of RASSF8 in non-small-cell lung cancer ( NSCLC ) cell lines , increased anchorage-independent growth in soft agar and enhanced tumor growth in severe combined immunodeficiency ( SCID ) mice . Furthermore , EdU staining of RASSF8-depleted cells showed growth suppression in a manner dependent on contact inhibition . We show that endogenous RASSF8 is not only found in the nucleus , but is also membrane associated at sites of cell-cell adhesion , co-localizing with the adherens junction ( AJ ) component beta-catenin and binding to E-cadherin . Following RASSF8 depletion in two different lung cancer cell lines using alternative small interfering RNA ( siRNA ) sequences , we show that AJs are destabilized and E-cadherin is lost from the cell membrane . The AJ components beta-catenin and p65 are also lost from sites of cell-cell contact and are relocalized to the nucleus with a concomitant increase in beta-catenin-dependent and nuclear factor-kappaB ( NF-kappaB)-dependent signaling following RASSF8 depletion . RASSF8 may also be required to maintain actin -cytoskeletal organization since immunofluorescence analysis shows a striking disorganization of the actin- cytoskeleton following RASSF8 depletion . Accordingly , scratch wound healing studies show increased cellular migration in RASSF8-deficient cells . These results implicate RASSF8 as a tumor suppressor gene that is essential for maintaining AJs function in epithelial cells and have a role in epithelial cell migration .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20514026"}
{"sentence": "OBJECTIVE Lung cancer is a deadly cancer , whose kills more people worldwide than any other malignancy . SLUG ( SNAI2 , Snail2 ) is involved in the epithelial mesenchymal transition in physiological and in pathological contexts and is implicated in the development and progression of lung cancer . METHODS We constructed a lentivirus vector with SLUG shRNA ( LV-shSLUG ) . LV-shSLUG and a control lentivirus were infected into the non-small cell lung cancer cell A549 and real-time PCR , Western blot and IHC were applied to assess expression of the SLUG gene . Cell proliferation and migration were detected using MTT and clony formation methods . RESULTS Real-time PCR , Western Blot and IHC results confirmed down-regulation of SLUG expression by its shRNA by about 80% at both the mRNA and protein levels . Knockdown of SLUG significantly suppressed lung cancer cell proliferation . Furthermore , knockdown of SLUG significantly inhibited lung cancer cell invasion and metastasis . Finally , knockdown of SLUG induced the down-regulation of Bcl-2 and up-regulation of E-cadherin . CONCLUSION These results indicate that SLUG is a newly identified gene associated with lung cancer growth and metastasis . SLUG may serve as a new therapeutic target for the treatment of lung cancer in the future .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23244088"}
{"sentence": "BACKGROUND Cancer of the thyroid gland is rare in children and adolescents . A history of neck irradiation is a well-established risk factor for tumor development , and most previous reports focused on cases that were induced by radiation exposure . We present here a retrospective review of the clinical features , treatment , and long-term outcome of children and adolescents with papillary thyroid cancer ( PTC ) without a history of radiation exposure who were treated at our institution over a period of METHODS We retrospectively investigated 142 PTC patients without an irradiation history who were younger than 20years of age when treated from 1961 to 2005 ( 17 males and 125 females ; mean age=16.3\u00b12.7years ; follow-up=21.8\u00b112.0years ) . The clinicopathological results were evaluated using the medical records . Disease-free survival ( DFS ) and cause-specific survival ( CSS ) were assessed with the Kaplan-Meier method and compared with the log-rank test . Parametric analyses were performed using Student's t test and nonparametric analyses were performed using the Mann-Whitney U test . RESULTS At diagnosis , three patients had distant lung metastasis and 33 had gross neck lymph node ( LN ) metastasis . All patients were treated with surgery ( hemi/partial thyroidectomy in 45 patients , subtotal thyroidectomy in 85 , total thyroidectomy in 12 , no LN dissection in 50 , central compartment dissection in 20 , and modified radical neck dissection in 72 ) , and postoperative external beam radiation therapy was administered to 59 . Postoperative ablative therapy using I(131) was not performed in this series . Recurrence was found for regional LN ( n=25 ) , lung ( n=9 ) , remnant thyroid ( n=5 ) , and others ( n=4 ) . DFS and CSS at 40years were 74.1 and 97.5% , respectively . DFS was significantly worse in patients aged <16years with a family history of thyroid cancer , preoperative neck gross LN metastasis , maximum tumor diameter , and extrathyroidal invasion . Preoperative gross neck LN metastasis and distant metastasis at diagnosis were significant factors for CSS . No other factors contributed to DFS and CSS . When the clinical features of children and adolescents were compared , the incidence of preoperative gross neck LN metastasis and distant metastasis at diagnosis and tumors with a maximum diameter >10mm were significantly higher in the children group than in the adolescent group . DFS was significantly shorter in the children group than in the adolescent group , but no significant difference was found in CSS between these two groups . CONCLUSIONS The prognosis of PTC in children and adolescents is excellent , regardless of the extent of thyroidectomy and LN dissection . We recommend that only children or adolescents with preoperative gross neck LN metastasis and distant metastasis at diagnosis should be subjected to postoperative ablative therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22411092"}
{"sentence": "OBJECTIVE To sort and identify side population ( SP ) cancer stem cells ( CSC ) in human prostate cancer ( PCa ) cell lines . METHODS Stem-like cells were isolated from five PCa cell lines Du145 , IA8 , LNCaP , TSU-Pr and PC-3 using FACS based on CD133+ CD44+ immunophenotype and SP in Hoechst staining . The in vitro growth pattern and tumorigenicity of SP stem cells were verified by soft agar colony-formation trial . LNCaP/SP cells were selected for further identification of stem cell properties using immunostaining , proliferation and invasion assay . Eventually , tumorigenicity and metastasis ability of LNCaP/SP were confirmed by xenograft experiments . RESULTS The percentages of CSCs of the CD133 CD44 + immunophenotype were extremely low in the five PCa cell lines . On the contrary , the percentages of the isolated SP cells were significantly higher in Du145 ( [ 0.15 +/- 0.02]% ) , IA8 ( [ 0.60 +/- 0.07 ]% ) , LNCaP ( [ 0.8 +/- 0.1]% ) and TSU-PrL ( [ 2.0 +/- 0.4]% ) , but none was detected in PC-3 . Besides , IA8/SP , LNCaP/SP and TSU-PrL/SP cells showed a significantly greater colony-forming efficiency than non-side population ( NSP ) cells ( P < 0.05 ) . Compared with LNCaP/NSP cells , LNCaP/SP cells exhibited high expressions of integrin alpha2 , Nanog , CD44 , OCT4 and ABCG2 , remarkably enhanced invasive and proliferative potentials in vitro , and markedly increased tumorigenicity and metastasis ( P < 0.01 ) . CONCLUSION SP sorting is more suitable than CD133+ CD44+ selection for enriching CSCs from PCa cell lines , and LNCaP/ SP represents a typical CSC population .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23405783"}
{"sentence": "TP53 mutations compromising p53 transcriptional function occur in more than 50% of human cancers , including pancreatic adenocarcinoma , and render cancer cells more resistant to conventional therapy . In the last few years , many efforts have been addressed to identify p53-reactivating molecules able to restore the wild-type transcriptionally competent conformation of the mutated proteins . Here , we show that two of these compounds , CP-31398 and RITA , induce cell growth inhibition , apoptosis , and autophagy by activating p53/DNA binding and p53 phosphorylation ( Ser15 ) , without affecting the total p53 amount . These effects occur in both wild-type and mutant p53 pancreatic adenocarcinoma cell lines , whereas they are much less pronounced in normal human primary fibroblasts . Furthermore , CP-31398 and RITA regulate the axis SESN1-2/AMPK/mTOR by inducing AMPK phosphorylation on Thr172 , which has a crucial role in the autophagic response . The protective role of autophagy in cell growth inhibition by CP-31398 and RITA is supported by the finding that the AMPK inhibitor compound C or the autophagy inhibitors chloroquine or 3-methyladenine sensitize both pancreatic adenocarcinoma cell lines to the apoptotic response induced by p53-reactivating molecules . Our results demonstrate for the first time a survival role for autophagy induced by p53-reactivating molecules , supporting the development of an anti-cancer therapy based on autophagy inhibition associated to p53 activation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23238993"}
{"sentence": "This study aimed to analyze the role of endothelial progenitor cell ( EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor ( MIF)/chemokine receptor axis . Primary murine and murine embryonic EPCs ( eEPCs ) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis , focusing on the influence of hypoxic versus normoxic stimulation . Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12 , CXCL1 , MIF , and vascular endothelial growth factor ( VEGF ) . These factors stimulated the transmigration activity and adhesive capacity of EPCs , with MIF and VEGF exhibiting the strongest effects under hypoxia . MIF- , VEGF- , CXCL12- , and CXCL1-stimulated EPCs enhanced tube formation , with MIF and VEGF exhibiting again the strongest effect following hypoxia . Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF . Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12 , whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell ( SMC ) phenotype , indicating an angiogenic and differentiation capacity in vivo . Surprisingly , CXCL12 , a chemoattractant for smooth muscle progenitor cells , inhibited SMC differentiation . We have identified a role for EPC-derived proangiogenic MIF , VEGF and MIF receptors in EPC recruitment following hypoxia , EPC differentiation and subsequent tube and vessel formation , whereas CXCL12 , a mediator of early EPC recruitment , does not contribute to the remodeling process . By discerning the contributions of key angiogenic chemokines and EPCs , these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors , EPCs , and the angiogenic target tissue .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23184390"}
{"sentence": "DYT1 is caused by a partly penetrant dominant mutation in TOR1A that leads to a glutamic acid deletion ( \\u0394E ) in torsinA . Identifying environmental factors that modulate disease pathogenesis and penetrance could help design therapeutic strategies for dystonia . Several cell-based studies suggest that expression of torsinA(\\u0394E) increases the susceptibility of neuronal cells to challenges to their oxidative/energy metabolism . Based on those reports , we hypothesized that mice expressing torsinA(\\u0394E) would be more susceptible than control littermates to the effects of oxidative stress and ATP deficits caused by disruption of the mitochondrial respiratory chain in neurons . To test this hypothesis , we administered 20 or 50 mg/kg/day of the irreversible complex-II inhibitor 3-nitropropionic acid ( 3-NP ) intraperitoneally for 15 consecutive days to young heterozygote DYT1 knock-in ( KI ) mice and wild type littermates . Repeated phenotypic assessments were performed at baseline , during and after the injections . Animals were then sacrificed and their brains processed for protein analysis . The administration of 20 mg/kg 3-NP led to increased levels of torsinA in the striatum , the main target of 3-NP , but did not cause motor dysfunction in DYT1 KI or control mice . The administration of 50 mg/kg/day of 3-NP caused the death of of wild type animals . Interestingly , DYT1 KI animals showed significantly reduced mortality . Surviving animals exhibited abnormal motor behavior during and right after the injection period , but recovered by 4 weeks postinjection independent of genotype . In contrast to the findings reported in cultured cells , these studies suggest the DYT1 mutation does not sensitize central neurons against the toxic effects of oxidative stress and energy deficits .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22880064"}
{"sentence": "OBJECTIVE The signalling molecule protein kinase B ( Akt ) modulates many cellular processes . Phosphatidylinositol 3-kinase ( PI3K)/Akt signalling pathways play important roles in tumour angiogenesis . The aim of this study was to determine the role of phosphorylated Akt ( pAkt ) in angiogenesis and its correlation with vascular endothelial growth factor ( VEGF)-A in gastric adenocarcinoma . METHODS Tumour tissue and matched healthy gastric mucosa were obtained from patients undergoing surgical resection of gastric adenocarcinoma . Akt and pAkt were detected via Western blotting . VEGF-A , pAkt and CD34 were examined by immunohistochemistry . RESULTS Akt and pAkt protein levels were significantly higher in gastric cancer tissue than in normal tissue ( n = 48 patients ) . Positive VEGF-A immunostaining was significantly associated with pAkt immunostaining . Microvessel density was correlated with both VEGF-A and pAkt positivity . CONCLUSIONS Phosphorylated Akt and VEGF-A are involved in angiogenesis of gastric adenocarcinoma , and Akt activation may contribute to angiogenesis via VEGF-A upregulation . The PI3K/Akt/VEGF signalling pathway may be involved in gastric adeno carcinoma .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23321169"}
{"sentence": "Gene therapy vectors based on the adeno-associated virus ( AAV ) are extremely efficient for gene transfer into post-mitotic cells of heart , muscle , brain , and retina . The reason for their exquisite tropism for these cells has long remained elusive . Here , we show that upon terminal differentiation , cardiac and skeletal myocytes downregulate proteins of the DNA damage response ( DDR ) and that this markedly induces permissivity to AAV transduction . We observed that expression of members of the MRN complex ( Mre11 , Rad50 , Nbs1 ) , which bind the incoming AAV genomes , faded in cardiomyocytes at weeks after birth , as well as upon myoblast differentiation in vitro ; in both cases , withdrawal of the cells from the cell cycle coincided with increased AAV permissivity . Treatment of proliferating cells with short-interfering RNAs ( siRNAs ) against the MRN proteins , or with microRNA-24 , which is normally upregulated upon terminal differentiation and negatively controls the Nbs1 levels , significantly increased permissivity to AAV transduction . Consistently , delivery of these small RNAs to the juvenile liver concomitant with AAV markedly improved in vivo hepatocyte transduction . Collectively , these findings support the conclusion that cellular DDR proteins inhibit AAV transduction and that terminal cell differentiation relieves this restriction .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22850678"}
{"sentence": "Carbon nanotubes have a wide range of applications in various industries and their use is likely to rise in the future . Currently , a major concern is that with the increasing use and production of these materials , there may be increased health risks to exposed workers . Long ( > 15 microm ) straight nanotubes may undergo frustrated phagocytosis which is likely to result in reduced clearance . We examine here the effects of multiwalled carbon nanotubes of different sizes on monocytic THP-1 cells , with regard to their ability to stimulate increased expression of the HO-1 and GST genes and their ability to produce nuclear translocation of the transcription factor , Nrf2 , as well as the release of several pro-inflammatory cytokines and mediators of inflammation . Our results suggest that long ( 50 microm ) carbon nanotubes ( 62.5 microg/ml for 4 hours ) produce increased nuclear translocation of Nrf2 and increased HO-1 gene expression compared with shorter entangled nanotubes . There was no increased gene expression for GST . The long nanotubes ( NT1 ) caused increased release of the proinflammatory cytokine IL-1beta , an effect which was diminished by the antioxidant trolox , suggesting a role of oxidative stress in the upregulation of this cytokine . Tentatively , our study suggests that long carbon nanotubes may exert their effect in THP-1 cells in part via an oxidative stress mechanism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21179939"}
{"sentence": "Metformin is a well-established diabetes drug that prevents the onset of most types of human cancers in diabetic patients , especially by targeting cancer stem cells . Metformin exerts its protective effects by functioning as a weak \" mitochondrial poison, \" as it acts as a complex I inhibitor and prevents oxidative mitochondrial metabolism ( OXPHOS ) . Thus , mitochondrial metabolism must play an essential role in promoting tumor growth . To determine the functional role of \" mitochondrial health \" in breast cancer pathogenesis , here we used mitochondrial uncoupling proteins ( UCPs ) to genetically induce mitochondrial dysfunction in either human breast cancer cells ( MDA-MB-231 ) or cancer-associated fibroblasts ( hTERT-BJ1 cells ) . Our results directly show that all three UCP family members ( UCP-1/2/3 ) induce autophagy and mitochondrial dysfunction in human breast cancer cells , which results in significant reductions in tumor growth . Conversely , induction of mitochondrial dysfunction in cancer-associated fibroblasts has just the opposite effect . More specifically , overexpression of UCP-1 in stromal fibroblasts increases \u03b2-oxidation , ketone body production and the release of ATP-rich vesicles , which \" fuels \" tumor growth by providing high-energy nutrients in a paracrine fashion to epithelial cancer cells . Hence , the effects of mitochondrial dysfunction are truly compartment-specific . Thus , we conclude that the beneficial anticancer effects of mitochondrial inhibitors ( such as metformin ) may be attributed to the induction of mitochondrial dysfunction in the epithelial cancer cell compartment . Our studies identify cancer cell mitochondria as a clear target for drug discovery and for novel therapeutic interventions .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23257779"}
{"sentence": "The development of targeted therapies and immunotherapies has markedly advanced the treatment of metastasized melanoma . While treatment with selective BRAF(V600E) inhibitors ( like vemurafenib or dabrafenib ) leads to high response rates but short response duration , CTLA-4 blocking therapies induce sustained responses , but only in a limited number of patients . The combination of these diametric treatment approaches may further improve survival , but pre-clinical data concerning this approach is limited . We investigated , using Tyr::CreER(T2)PTEN(F-/-)BRAF(F-V600E/+) inducible melanoma mice , whether BRAF(V600E) inhibition can synergize with anti-CTLA-4 mAb treatment , focusing on the interaction between the BRAF(V600E) inhibitor PLX4720 and the immune system . While PLX4720 treatment strongly decreased tumor growth , it did not induce cell death in BRAF(V600E)/PTEN(-/-) melanomas . More strikingly , PLX4720 treatment led to a decreased frequency of tumor-resident T cells , NK-cells , MDSCs and macrophages , which could not be restored by the addition of anti-CTLA-4 mAb . As this effect was not observed upon treatment of BRAF wild-type B16F10 tumors , we conclude that the decreased frequency of immune cells correlates to BRAF(V600E) inhibition in tumor cells and is not due to an off-target effect of PLX4720 on immune cells . Furthermore , anti-CTLA-4 mAb treatment of inducible melanoma mice treated with PLX4720 did not result in enhanced tumor control , while anti-CTLA-4 mAb treatment did improve the effect of tumor-vaccination in B16F10-inoculated mice . Our data suggest that vemurafenib may negatively affect the immune activity within the tumor . Therefore , the potential effect of targeted therapy on the tumor-microenvironment should be taken into consideration in the design of clinical trials combining targeted and immunotherapy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22934253"}
{"sentence": "Advanced or metastatic prostate cancer is treated by androgen deprivation ; however , patients inevitably relapse with castration-resistant prostate cancer ( CRPC ) . CRPC remains dependent on androgen receptor ( AR ) signaling , which may include constitutive , ligand-independent action of naturally occurring AR splice variants . For example , the AR splice variant AR3 ( also termed AR-V7 ) is expressed in CRPC and is linked to poor prognosis . Vav3 , a Rho GTPase guanine nucleotide exchange factor , is an AR coactivator that is up-regulated in human prostate cancer compared with benign tissue and in preclinical models of CRPC . Vav3 confers castration-resistant growth to androgen-dependent human prostate cancer cells . Despite the importance of AR coactivators in promoting CRPC , the potential role of these regulatory proteins in modulating AR splice variant activity is unknown . We examined the contributions of Vav3 to AR activity in two CRPC cell lines that naturally express relatively high levels of Vav3 and AR3 . Vav3 or AR3 knockdown greatly attenuated cell proliferation , soft agar growth , and ligand-independent AR activity . Vav3 potently enhanced the transcriptional activity of AR3 and another clinically relevant AR splice variant , ARv567es . Vav3 knockdown resulted in lowered nuclear AR3 levels , whereas total AR3 levels remained similar . Conversely , overexpression of Vav3 resulted in increased nuclear AR3 . Coimmunoprecipitation revealed that AR3 and Vav3 interact . These novel data demonstrating physical and functional interactions between Vav3 , a unique AR coactivator , and an AR splice variant provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to CRPC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23023561"}
{"sentence": "Glioblastoma is one of the most lethal and common malignant human brain tumors , with aggressive proliferation and highly invasive properties . Honokiol derived from Magnolia officinalis is able to cross the blood-brain barrier ( BBB ) and the blood-cerebrospinal fluid barrier ( BCSFB ) , suggesting a strong possibility that it could be an effective drug for the treatment of brain tumors , including glioblastoma . Thus , we investigated the effects of honokiol on the expression of adhesion molecules in TNF-\u03b1-stimulated endothelial cells , and cancer growth and invasion were determined in T98G human glioblastoma cells . Honokiol dose-dependently inhibited the expression of intercellular adhesion molecule-1 ( ICAM-1 ) and vascular cell adhesion molecule-1 ( VCAM-1 ) in human umbilical vein endothelial cells ( HUVECs ) stimulated with TNF-\u03b1 for 6 h . Pretreatment with honokiol significantly reduced the adhesion of T98G cells to HUVECs . Moreover , honokiol inhibited the invasion of T98G cells , suggesting that honokiol has an anti-metastatic effect . In addition , honokiol increased the cytotoxicity of T98G cells in a dose- and time-dependent manner as assayed by MTT . TUNEL assay showed that honokiol significantly induced apoptosis in T98G cells at doses of 10 \ufffdM or more . The induction of apoptotic cell death was mediated by the downregulation of the anti-apoptotic protein Bcl-2 and the upregulation of the pro-apoptotic protein Bax . Taken together , the results of this study suggest that honokiol exerts an anticancer effect by preventing metastasis and inducing apoptotic cell death of brain tumor cells .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22895699"}
{"sentence": "BACKGROUND Adult human mesenchymal stem cells ( hMSC ) have been shown to home to sites of carcinoma and affect biological processes , including tumour growth and metastasis . Previous findings have been conflicting and a clear understanding of the effects of hMSCs on cancer remains to be established . Therefore , we set out to investigate the impact of hMSCs on the oestrogen receptor positive , hormone-dependent breast carcinoma cell line MCF-7 . RESULTS In this study , we show the effects of hMSCs on cancer cells are mediated through a secreted factor(s) which are enhanced by cancer cell-hMSC contact/communication . In addition to enhanced proliferation when in co-culture with hMSCs , MCF-7 cells were found to have increased migration potential in vitro . Inhibition of ER signalling by the pure anti-oestrogen ICI 182,780 decreased the effect of hMSCs on MCF-7 cell proliferation and migration supporting a role for ER signalling in the hMSC/MCF-7 cell interaction . Additionally , hMSCs have been shown to secrete a wide variety of growth factors and chemokines including stromal cell-derived factor-1 ( SDF-1 ) . This coupled with the knowledge that SDF-1 is an ER-mediated gene linked with hormone-independence and metastasis led to the investigation of the SDF-1/CXCR4 signalling axis in hMSC-MCF-7 cell interaction . Experiments revealed an increase in SDF-1 gene expression both in vivo and in vitro when MCF-7 cells were cultured with hMSCs . SDF-1 treatment of MCF-7 cells alone increased proliferation to just below that seen with hMSC co-culture . Additionally , blocking SDF-1 signalling using a CXCR4-specific inhibitor decreased hMSC induced proliferation and migration of MCF-7 . However , the combined treatment of ICI and AMD3100 reduced MCF-7 cell proliferation and migration below control levels , indicating targeting both the ER and CXCR4 pathways is effective in decreasing the hMSCs induction of MCF-7 cell proliferation and migration . CONCLUSIONS The sum of these data reveals the relationship between tumour microenvironment and tumour growth and progression . Better understanding of the mechanisms involved in this tumour stroma cell interaction may provide novel targets for the development of treatment strategies for oestrogen receptor positive , hormone-independent , and endocrine-resistant breast carcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21087507"}
{"sentence": "Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells ( Treg ) and plasmacytoid dendritic cells ( pDC ) that facilitate immune escape and correlate with poor prognosis . Here , we report that inducible costimulatory molecule ( ICOS ) , a T cell costimulatory molecule of the CTLA4/PD1/CD28 family , is expressed mostly by tumor-associated Treg in primary breast tumors . A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC . Indeed , tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal . In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells , establishing a pivotal role for ICOS in this process . Supporting these findings , the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis . Together , our results highlight an important relationship between Treg and pDC in breast tumors , and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells . These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer . Cancer Res ; 72(23) ; 6130-41. \ufffd2012 AACR .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23026134"}
{"sentence": "Cytokine-dependent cell lines have been used to analyze the cytokine-induced cellular signaling and the mechanism of oncogenesis . In the current study , we analyzed MOTN-1 and PLT-2 cell lines established from different stages of a T-cell large granular lymphocyte leukemia patient ( Daibata et al. 2004 ) . MOTN-1 is IL-2-dependent derived from the chronic phase , whereas IL-2-independent PLT-2 is from the aggressive and terminal stage . They shared considerable chromosome abnormalities and the pattern of T-cell receptor rearrangement , presuming that the cytokine independence of PLT-2 was due to the additive genetic abnormality . Besides IL-2 , IL-15 supported MOTN-1 cell growth , because these receptors share beta- and gamma-subunits . IL-2 activated ERK , AKT and STAT pathway of MOTN-1 . STAT3 pathway of PLT-2 was also activated by IL-2 , suggesting intact IL-2 induces signal transduction of PLT-2 . However , ERK1/2 but not AKT , was continuously activated in PLT-2 , consistent with the increased Ras-activity of PLT-2 . Sequence analysis revealed KRAS G12A mutation but not NRAS and HRAS mutation of PLT-2 but not MOTN-1 . Another signaling molecule affecting Ras-signaling pathway , SHP2 , which has been frequently mutated in juvenile myelomonocytic leukemia ( JMML ) , did not show mutation . Moreover , MEK inhibitor , PD98059 , as well as farnesylation inhibitor inhibited PLT-2 cell growth . Using NIH3T3 and MOTN-1 , ERK activation , increased cell proliferation and survival by KRAS G12A were shown , suggesting the important role of KRAS G12A in IL-2-independent growth of PLT-2 . Taken together , KRAS G12A is important for IL-2-independent growth of PLT-2 cells and suggests the possibility of involvement of KRAS mutation with disease progression .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23092099"}
{"sentence": "Nasopharyngeal carcinoma ( NPC ) is an endemic malignant disease of the head and neck region with unique features including striking ethnic and geographic variations as well as multifactorial etiology . Previous studies have demonstrated the anticancer properties of genistein , the major soy isoflavonoid , in several human cancer cells such as breast , prostate , colon , gastric , lung , and hepatoma . However , the action of genistein in NPC cells has not been determined . In this study , we investigated the inhibitory effects of genistein on NPC cells and its possible underlying mechanisms . We found that genistein dose-dependently inhibited the proliferation of human NPC cell line CNE2 cells . DNA flow cytometric analysis revealed that 30 to 120 microM genistein induced dramatic G2/M phase arrest in NPC cells . The mRNA expression levels , as shown by gene expression array and quantitative real-time polymerase chain reaction , and the protein expression levels of the cell cycle regulators p21(Cip1) and ATR ( Ataxia telangiectasia and Rad3 related ) were elevated following genistein treatment . Interestingly , we also observed concomitant induction of p15(Ink4b) in genistein induced inhibitory effects in NPC cells . Moreover , selective estrogen receptor modulators did not affect genistein induced growth inhibition . These findings provide new insights into the potential intervention of NPC with genistein .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20574925"}
{"sentence": "BACKGROUND : Although quiescence ( reversible cell cycle arrest ) is a key part in the life history and fate of many mammalian cell types , the mechanisms of gene regulation in quiescent cells are poorly understood . We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts . RESULTS : Using microarrays , we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts . Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles , indicating common changes induced by distinct quiescence signals . By analyzing the gene expression patterns of microRNA target genes with quiescence , we discovered a strong regulatory function for miR-29 , which is downregulated with quiescence . Using microarrays and immunoblotting , we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence . In addition , overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence . We also found that let-7 and miR-125 were upregulated in quiescent cells . Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence , while the combination of both together slowed cell cycle re-entry even further . CONCLUSIONS : microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles , in particular , the induction of extracellular matrix proteins in quiescent fibroblasts .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23259597"}
{"sentence": "Luteolin is a plant flavonoid which exhibits anti-oxidative , anti-inflammatory and anti-tumor effects . However , the antiproliferative potential of luteolin is not fully understood . In this study , we investigated the effect of luteolin on cell cycling and apoptosis in human esophageal squamous carcinoma cell line Eca109 cells . MTT assays showed that luteolin had obvious cytotoxicity on Eca109 with an IC50 of 70.7\ufffd1.72 \u03bcM at 24 h . Luteolin arrested cell cycle progression in the G0/G1 phase and prevented entry into S phase in a dose- and time-dependent manner. as assessed by FCM . Luteolin induced apoptosis of Eca109 cells was demonstrated by AO/EB staining assay and annexin V-FITC/PI staining . Moreover , luteolin downregulated the expression of cyclin D1 , survivin and c-myc , and it also upregulated the expression of p53 , in line with the fact that luteolin was able to inhibit Eca109 cell proliferation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23317200"}
{"sentence": "BACKGROUND As a highly conserved system , the activation of the Notch pathway has been implicated in the tumorigenesis of various hematologic diseases , including leukemias , lymphomas , and multiple myeloma . The Notch3 receptor is frequently expressed in T-cell acute lymphoblastic leukemia ( T-ALL ) . METHODS To explore its possibility as a therapeutic target for T-ALL , we investigated the effect of Notch3 silencing on Jurkat and SupT1 cells using a novel tumor-specific short hairpin RNA ( shRNA ) driven by survivin promoters . RESULTS We found that downregulated expression of Notch3 correlated with significant apoptosis and inhibition of proliferation . CONCLUSION These facts suggest that downregulating expression of Notch3 could attenuate the Notch signaling activity in T-ALL . All these results indicate that inhibition of Notch3 expression can result in potent antitumor activity in T-ALL .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21940234"}
{"sentence": "PURPOSE Osteosarcoma is an aggressive primary bone cancer characterized by expression of platelet-derived growth factor ( PDGF ) and its cognate receptor . Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms . It has been reported previously that STI571 has specific activity in inhibiting select tyrosine kinase receptors , including PDGF and c-Kit . Osteosarcomas express low levels of c-Kit but abundant levels of PDGF receptor ( PDGFR ) . EXPERIMENTAL DESIGN To investigate the potential of STI571 as therapy for osteosarcoma , we studied its effects on PDGF-mediated cell growth in vitro and in an in vivo mouse model . RESULTS PDGF acted as a potent mitogen in a dose-dependent manner in two osteosarcoma cell lines . STI571 ( 1.0 micro M ) inhibited both PDGFR-alpha and PDGFR-beta phosphorylation and the downstream phosphorylation targets extracellular signal-regulated kinase and Akt . STI571 also inhibited PDGF-mediated growth and induced apoptosis in vitro as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated nick end labeling staining . To study the effect of STI571 alone or in combination with Taxol in an in vivo model , an osteosarcoma cell line ( KRIB ) was transplanted into the tibia of athymic nude mice . Mice were treated with STI571 ( 50 mg/kg p.o. q M-F ) , Taxol ( 8 mg/kg i.p. weekly ) , or STI571 plus Taxol for 6 weeks . There was no significant difference in tumor size between treatment and control mice . Aberrant signaling pathways downstream of the PDGFR in the v-Ki-ras oncogene-transformed KRIB cell line may in part explain this finding . CONCLUSIONS Our data demonstrate that STI571 inhibits PDGF-mediated growth and leads to apoptosis of osteosarcoma cells in vitro by selective inhibition of the PDGFR tyrosine kinase . The effectiveness of STI571 in our studies suggests targeting of PDGFRs as a novel treatment for osteosarcoma .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12429650"}
{"sentence": "BACKGROUND Autotaxin ( ATX ) is an extracellular lysophospholipase D that generates lysophosphatidic acid ( LPA ) from lysophosphatidylcholine ( LPC ) . Both ATX and LPA have been shown to be involved in many cancers . However , the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma ( HCC ) remain elusive . RESULTS In this study , ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects . ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis . In addition , ATX expression was examined in normal human hepatocytes and liver cancer cell lines . Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did . Proinflammtory cytokine tumor necrosis factor alpha ( TNF-alpha ) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells , which led to a corresponding increase in lysophospholipase-D activity . Moreover , we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B ( NF-kappaB ) in basal and TNF-alpha induced ATX expression . Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion . CONCLUSIONS This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC . Our observation that links the TNF-alpha/NF-kappaB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20356387"}
{"sentence": "Histone H3 methylation at lysine 4 ( K4 ) is associated with euchromatic regions and is thought to be important for the transcriptional activation of genes during differentiation . In this study , we found that di- and tri-methylation of histone H3 at K4 and acetylation of histones H3 and H4 from the promoter/enhancer to the transcribed region close to the transcription initiation site of the solute carrier family 2 , member 5 ( SLC2A5 ) gene , and its expression , were induced by differentiation of intestine-like Caco-2 cells . These effects were accompanied by contact inhibition of cell growth of these cells . Furthermore , these modifications were induced by co-treatment with a synthetic glucocorticoid hormone dexamethasone and a p44/42 mitogen-activated protein kinase inhibitor PD89059 . Our results suggest that methylation of histone H3 at K4 and acetylation of histones H3 and H4 are involved in SLC2A5 gene induction associated with intestinal differentiation of Caco-2 cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20043883"}
{"sentence": "Stannous chloride ( SnCl(2) ) and UVA induce DNA lesions through ROS . The aim of this work was to study the toxicity induced by UVA preillumination , followed by SnCl(2) treatment . E. coli BER mutants were used to identify genes which could play a role in DNA lesion repair generated by these agents . The survival assays showed ( i ) The nfo mutant was the most sensitive to SnCl(2) ; ( ii ) lethal synergistic effect was observed after UVA pre-illumination , plus SnCl(2) incubation , the nfo mutant being the most sensitive ; ( iii ) wild type and nfo mutants , transformed with pBW21 plasmid ( nfo(+) ) had their survival increased following treatments . The alkaline agarose gel electrophoresis assays pointed that ( i ) UVA induced DNA breaks and fpg mutant was the most sensitive ; ( ii ) SnCl(2)-induced DNA strand breaks were higher than those from UVA and nfo mutant had the slowest repair kinetics ; ( iii ) UVA + SnCl(2) promoted an increase in DNA breaks than SnCl(2) and , again , nfo mutant displayed the slowest repair kinetics . In summary , Nfo protects E. coli cells against damage induced by SnCl(2) and UVA + SnCl(2) .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20300433"}
{"sentence": "PURPOSE This study aims to investigate the role of the aberrant expression of Transkelolase-like 1 ( TKTL1 ) in head and neck squamous cell carcinoma ( HNSCC ) tumorigenesis and to characterize TKTL1 contribution to HNSCC tumorigenesis through aerobic glycolysis and HIF1alpha stabilization . EXPERIMENTAL DESIGN TKTL1 promoter hypomethylation and mRNA/protein aberrant expression were studied in human HNSCC tumor samples and normal mucosas . Oncogenic functions of TKTL1 were examined in HNSCC cell line panels and tumor xenograft models with TKTL1 expression construct . The metabolite levels of fructose-6-phosphate , glyceraldehydes-3-phosphate , pyruvate , lactate , and the levels of HIF1alpha protein and its downsteam glycolytic targets were compared between the TKTL1-expressing and vehicle-expressing HNSCC cells . Meanwhile , the effects of HIF1alpha/glycolytic inhibitors were evaluated on the TKTL1 transfectants . RESULTS TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal mucosas , correlating with its overexpression in HNSCC . Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo . Overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate , in turn elevating the production of pyruvate and lactate , resulting in the normoxic stabilization of the malignancy-promoting transcription factor HIF1alpha and the upregulation of downstream glycolytic enzymes . Notably , the reduction of TKTL1 expression decreased HIF1alpha accumulation and inhibition with HIF1alpha and/or the glycolysis inhibitor could abrogate the growth effects mediated by TKTL1 overexpression . CONCLUSION TKTL1 is a novel candidate oncogene that is epigenetically activated by aberrant hypomethlation and contributes to a malignant phenotype through altered glycolytic metabolism and HIF1alpha accumulation .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20103683"}
{"sentence": "The progression of prostate cancers ( PCs ) to locally invasive , androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse . The present study was undertaken to establish the possibility of using a combination of specific oncogenic products , including epidermal growth factor receptor ( EGFR ) , pAkt , nuclear factor-kappaB ( NF-\u03baB ) and macrophage inhibitory cytokine-1 ( MIC-1 ) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages . The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR , Ser(473)-pAkt , NF-\u03baB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133(+) PC cells and the bulk tumor mass of CD133(-) PC cells . Importantly , all of these biomarkers were also overexpressed in 80-100% of 30 PC metastasis bone tissue specimens . Moreover , the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population ( SP ) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells . Of therapeutic interest , the targeting of EGFR , pAkt , NF-\u03baB or MIC-1 was also effective at suppressing the basal and EGF-promoted prostasphere formation by SP WPE1-NB26 cells , inducing disintegration of SP cell-derived prostaspheres and decreasing the viability of SP and non-SP WPE1-NB26 cell fractions . Also , the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel . These findings suggest that the combined use of EGFR , pAkt , NF-\u03baB and/or MIC-1 may represent promising strategies for improving the accuracy of current diagnostic and prognostic methods and efficacy of treatments of PC patients in considering the disease heterogeneity , thereby preventing PC progression to metastatic and lethal disease states .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22384099"}
{"sentence": "Melittin ( 1 ) is a major polypeptide in honey bee venom that has been used traditionally against chronic inflammation and cancer . However , its molecular mechanism has not been determined . In this study , the antitumor effect of 1 was compared with that of NS398 , a cyclooxygenase-2 ( COX-2 ) inhibitor , in vivo and in vitro . Subcutaneous injection of 1 at 0.5 and 5 mg/kg suppressed significantly vascular endothelial growth factor ( VEGF)-A-transfected highly metastatic Lewis lung cancer ( VEGF-A-hm LLC ) tumor growth by 25% and 57% , respectively . Also , 1 inhibited significantly the number of vessels around VEGF-A-hm LLC cells . The results were superior to those obtained in the mice treated with NS398 . Compound 1 dose-dependently inhibited proliferation and tube formation in human umbilical vein endothelial cells ( VEGF-A-HUVECs ) , without affecting cell viability in native HUVECs . In addition , 1 decreased the expression of VEGF receptor-2 ( VEGFR-2 ) , COX-2 , and prostaglandin E(2) ( PGE(2) ) in VEGF-A-transfected HUVECs . These effects were accompanied by a reduction of the phosphorylation of extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase , whereas it increased the phosphorylation of p38 mitogen-activated protein kinase ( MAPK ) . SB203580 abolished the downregulation of COX-2 and VEGFR-2 and the inhibition of cell proliferation by 1 . The antitumor activity of 1 may be associated with antiangiogenic actions via inhibiting VEGFR-2 and inflammatory mediators involved in the MAPK signaling pathway .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23110475"}
{"sentence": "In patients with advanced bladder cancer , glucocorticoids are frequently given to reduce acute toxicity , particularly hyperemesis , during chemotherapy , as well as to improve cachectic conditions . However , it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer through the glucocorticoid receptor pathway . Glucocorticoid receptor expression was first investigated in human bladder cancer lines and tissue microarrays . Then , the effects of dexamethasone on glucocorticoid receptor transcription , cell proliferation , apoptosis/cell cycle , and invasion were examined in bladder cancer lines . Finally , mouse xenograft models for bladder cancer were used to assess the efficacy of dexamethasone on tumor progression . All the cell lines and tissues examined were found to express glucocorticoid receptor . Dexamethasone increased glucocorticoid receptor-mediated reporter activity and cell proliferation , and inhibited apoptosis in the presence or absence of cisplatin . In contrast , dexamethasone suppressed cell invasion , the expression of its related genes [ MMP-2/MMP-9 , interleukin ( IL)-6 , VEGF ] , and the activity of MMP-2/MMP-9 , and also induced mesenchymal-to-epithelial transition . In addition , dexamethasone increased I\u03baB\u03b1 protein levels and cytosolic accumulation of NF-\u03baB . In xenograft-bearing mice , dexamethasone slightly augmented the growth of the inoculated tumors but completely prevented the development of bloody ascites , suggestive of peritoneal dissemination of tumor cells , and actual metastasis . In all these assays , dexamethasone effects were abolished by a glucocorticoid receptor antagonist or glucocorticoid receptor knockdown via RNA interference . Thus , glucocorticoid receptor activation resulted in promotion of cell proliferation via inhibiting apoptosis yet repression of cell invasion and metastasis . These results may provide a basis of developing improved chemotherapy regimens , including or excluding glucocorticoid receptor agonists/antagonists , for urothelial carcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23033490"}
{"sentence": "The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines . Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men . In spite of the current therapeutic options for this cancer entity , many patients die due to metastases in distant organs and acquired chemotherapy resistance . Thus , approaches to provide improvements in outcome and quality of life for such patients are urgently needed . Recently , the polyisoprenylated benzophenone 7-epi-nemorosone , originally collected by honeybees from Clusia rosea and Clusia grandiflora ( Clusiaceae ) , has been described to be a potent antitumoral agent . Here , its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques . Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1(+) sub-line . No cross-resistance was detected . FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1 , G1 , and depletion in the S phase populations . A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot . Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events . Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug . ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2 . Additionally , Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2 . Here , we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22981203"}
{"sentence": "Although tumor-associated macrophages ( TAMs ) are involved in tumor growth and metastasis , the mechanisms controlling their pro-tumoral activities remain largely unknown . The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors . In this study , we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice , which lack c-Myc in macrophages , to investigate the role of macrophage c-MYC expression in cancer . Under steady-state conditions , immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal , including the abundance of different subsets of bone marrow hematopoietic stem cells , precursors and circulating cells , macrophage density , and immune organ structure . In a model of melanoma , however , TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions ( e.g. , reduced expression of VEGF , MMP9 , and HIF1\u03b1 ) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice . Macrophage c-Myc deletion also diminished fibrosarcoma growth . These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23028984"}
{"sentence": "OBJECTIVE To explore the clinical significance of miRNA-216a expression in pancreatic cancer . METHODS Fourteen patients with pancreatic cancer undergoing pancreaticoduodenectomy and 6 patients with benign pancreas lesions were examined for miR-216a expressions in the tumor or lesion tissues using Agilent Human miRNA Microarray ( V12.0 ) . The relationship between miR-216a expressions and the clinicopathological features of the patients was analyzed . RESULTS The expression of miRNA-216a was significantly lower in pancreatic cancer than in benign pancreas lesions ( P=0.000 ) . The expression of miRNA-216a was significantly correlated with the T stage of the tumor ( P=0.002 ) , but not with the patients ' age , gender , smoking status , tumor stage , lymph node metastases , distant metastasis , tumor differentiation , nerve invasion , vessel invasion or serum CA19-9 level ( P>0.05 ) . CONCLUSIONS The down-regulated expression of miR-216a in pancreatic cancer suggests the involvement of miR-216a in the tumorigenesis and development of pancreatic cancer. miR-216a may potentially serve as a novel tumor marker and also a prognostic factor for pancreatic cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23174591"}
{"sentence": "The flow of interstitial fluid and the associated interstitial fluid pressure ( IFP ) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization . Both experimental and theoretical studies have shown that tumors may present elevated IFP , which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor . Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues . These studies have helped to understand both biochemical signaling and treatment prognosis . Building upon previous work , here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model . We include fluid/oxygen extravasation as well as a continuous lymphatic field , and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow , transcapillary fluid flux , interstitial fluid flow , and lymphatic drainage . We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors . In particular , we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux , thus decreasing the rate of tumor growth . We also investigate the effect of tumor vascular pathologies , including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences , on the fluid flow across the tumor capillary bed , the lymphatic drainage , and the IFP . Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor , which have been observed in experiments , and contributes to a more uniform distribution of oxygen , solid tumor pressure and a broad-based collapse of the tumor lymphatics . We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor . We discuss the implications of these results on microenvironmental transport barriers , and the tumor invasive and metastatic potential . Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23220211"}
{"sentence": "BACKGROUND Tissue factor ( TF ) , an initiator of blood coagulation , participates in cancer progression and metastasis . We recently found that inhibition of MAPK/ERK upregulated both full length TF ( flTF ) and soluble isoform TF ( asTF ) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells . We explored the possible mechanisms , especially the possible interaction with EGFR and PI3K/Akt pathways . METHODS A plasmid containing TF promoter -2174\u2009 plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity . In order to study the interaction of these pathways , ERK inhibitor ( PD98059 ) , PI3K inhibitors ( LY294002 , wortmannin ) , Akt inhibitor ( A6730 ) , and EGFR inhibitor ( erlotinib ) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells , and ovarian cancer OVCAR-3 and SKOV-3 cells . Quantitative PCR and western blot were used to determine TF expression . One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells . RESULTS We show that PI3K inhibitors LY294002 , wortmannin and A6730 significantly inhibited TF promoter activity , and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation . In contrast , ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells . The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors . Most interestingly , the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression . Similar results were found with ovarian cancer cells SKOV-3 and OVCAR-3 . Furthermore , in MDA-MB-231 , mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment . CONCLUSIONS This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt-mediated TF expression in breast cancer MDA-MB-231 cells . The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells . Interestingly , we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231 . As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells , targeting these signaling components is expected to potentially inhibit TF expression-associated tumor progression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22534171"}
{"sentence": "Vitexicarpin ( 3 ' , 5-dihydroxy-3 , 4 ' , 6 , 7-tetramethoxyflavone ) , a polymethoxyflavone isolated from Viticis Fructus ( Vitex rotundifolia Linne fil. ) , has long been used as an anti-inflammatory herb in traditional Chinese medicine . It has also been reported that vitexicarpin can inhibit the growth of various cancer cells . However , there is no report elucidating its effect on human prostate carcinoma cells . The aim of the present study was to examine the apoptotic induction activity of vitexicarpin on PC-3 cells and molecular mechanisms involved . MTT studies showed that vitexicarpin dose-dependently inhibited growth of PC-3 cells with an IC50 \u03bcM . Hoechst 33258 staining further revealed that vitexicarpin induced apoptotic cell death . The effect of vitexicarpin on PC-3 cells apoptosis was tested using prodium iodide ( PI)/Annexin V-FITC double staining and flow cytometry . The results indicated that vitexicarpin induction of apoptotic cell death in PC-3 cells was accompanied by cell cycle arrest in the G2/M phase . Furthermore , our study demonstrated that vitexicarpin induction of PC-3 cell apoptosis was associated with upregulation of the proapoptotic protein Bax , and downregulation of antiapoptotic protein Bcl-2 , release of Cytochrome c from mitochondria and decrease in mitochondrial membrane potential . Our findings suggested that vitexicarpin may become a potential leading drug in the therapy of prostate carcinoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23464460"}
{"sentence": "Each year , more than 700,000 people undergo cancer surgery in the United States . However , more than 40% of those patients develop recurrences and have a poor outcome . Traditionally , the medical community has assumed that recurrent tumors arise from selected tumor clones that are refractory to therapy . However , we found that tumor cells have few phenotypical differences after surgery . Thus , we propose an alternative explanation for the resistance of recurrent tumors . Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate small pockets of residual disease quickly . Recurrent tumors and draining lymph nodes are infiltrated with M2 ( CD11b(+)F4/80(hi)CD206(hi) and CD11b(+)F4/80(hi)CD124(hi) ) macrophages and CD4(+)Foxp3(+) regulatory T cells . This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size , an intact antitumor immune response , and unaltered cancer cells . Therapeutic strategies coupling antitumor agents with inhibition of immunosuppressive cells potentially could impact the outcomes of more than 250,000 people each year .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23271806"}
{"sentence": "Gliomas are aggressive and almost incurable glial brain tumors which frequently display abnormal platelet-derived growth factor ( PDGF ) signaling . Evidence gained from studies on several in vivo animal models has firmly established a causal connection between aberrant PDGF signaling and the formation of some gliomas . However , only recently has significant knowledge been gained regarding crucial issues such as the glioma cell of origin and the relationship between the transforming stimulus and the cellular characteristics of the resulting tumor . Based on recent evidence , we propose that PDGF can bias cell-fate decisions , driving the acquisition of cell type-specific features by the progeny of multipotent neural progenitors , thus determining the shape and direction of the transformation path . Furthermore , recent data about the cellular mechanisms of PDGF-driven glioma progression and maintenance indicate that PDGF may be required , unexpectedly , to override cell contact inhibition and promote glioma cell infiltration rather than to stimulate cell proliferation .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "19832839"}
{"sentence": "Onconase ( Onc ) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines . It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials . In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs . Intriguingly , repeated infusions of this protein do not cause apparent immunological reactions in patients . The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin ( PHA ) , and in mixed allogeneic lymphocyte cultures . Unexpectedly , we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc . Apoptosis was measured by flow cytometry using markers that detect activation of caspases , the in situ presence of DNA strand breaks , and loss of fragmented DNA ( 'sub-G1 ' cell subpopulation ) . The enhancement of frequency of activation-induced apoptosis ( up to 244% ) was observed at 4.2-83 nM Onc concentration , which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines . The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration . Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance , the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients . The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent , e.g. , to suppress transplant rejection or treat autoimmune diseases .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12429974"}
{"sentence": "The thyroid hormone ( T3 ) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that overexpress the beta 1 isoform of the T3 receptor . An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3 . The hormone also causes a decrease of cyclin D1 gene transcription , and is able to antagonize the activation of the cyclin D1 promoter by Ras . In addition , a strong and sustained increase of the levels of the cyclin kinase inhibitor ( CKI ) p27(Kip1) are found in T3-treated cells . The increased levels of p27(Kip1) lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes . As a consequence of these changes , retinoblastoma proteins are hypophosphorylated in T3-treated N2a-beta cells , and progression through the restriction point in the cell cycle is blocked .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12505306"}
{"sentence": "We have used a combination of vitamin A ( all-trans-retinyl palmitate ) , 5-fluorouracil ( 5-FU ) and radiation to treat human head and neck squamous cell carcinoma ( HNSCC ) . This chemoradiotherapy is called \" FAR therapy. \" In this study we examined the effects of all-trans-retinoic acid ( ATRA ) , the active metabolite of vitamin A , and ATRA plus 5-FU on two HNSCC cell lines ( YCU-N861 and YCU-H891 ) to gain insight into the molecular mechanisms of FAR therapy . ATRA at 1 mM ( the order of concentration found in HNSCC tumors treated with FAR therapy ) inhibited cell proliferation and caused G1 cell cycle arrest in both cell lines . This was associated with a decrease in cyclin D1 , an increase in p27(Kip1) and a reduction in the hyperphosphorylated form of retinoblastoma protein ( pRB ) . With YCU-N861 cells , ATRA also caused a decrease in Bcl-2 and Bcl-X(L) and an increase in Bax . Both ATRA and 5-FU activated c-Jun N-terminal kinase ( JNK ) 1 and the combination of both agents resulted in additive or synergistic activation of JNK1 , and also enhanced the induction of apoptosis . The YCU-H891 cells , in which the epidermal growth factor receptor ( EGFR)-signal transducer and activator of transcription 3 ( Stat3 ) pathway is constitutively activated , were more resistant to treatments with ATRA , 5-FU and the combination of both agents than YCU-N861 cells . A dominant negative Stat3 construct strongly enhanced the cellular sensitivity of this cell line to 5-FU but not to ATRA . In addition there is evidence that activation of Stat3 is associated with cellular resistance to radiation in HNSCC . Therefore , the addition to FAR therapy of agents that inhibit activation of the Stat3 pathway may enhance the clinical response of patients with HNSCC to FAR therapy .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "11927016"}
{"sentence": "OBJECTIVE : Emerging evidences implicate long noncoding RNAs ( lncRNAs ) are deregulated in cancer development . The purpose of the current study is to investigate the role of new lncRNA , named PlncRNA-1 , in prostate cancer ( CaP ) pathogenesis . MATERIALS AND METHODS : In this study , real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues , 14 pairs CaP tissues and BPH tissues , 4 CaP cell lines , including LNCaP , LNCaP-AI , PC3 , and C4-2 , and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E . After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines , cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling ( TUNEL ) . After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines , real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR . RESULTS : We showed that expression PlncRNA-1 , was significantly higher in CaP cells relative to normal prostate epithelial cells , as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia ( BPH ) . Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI . Mechanistically , PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor ( AR ) mRNA , protein and AR downstream target . Of note , blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines . CONCLUSIONS : Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22264502"}
{"sentence": "BACKGROUND Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia ( BPH ) and prostate carcinoma . The prostate is comprised of a functional secretory epithelium , a basal epithelium , and a supporting stroma comprised of structural elements , and a spectrum of cell types that includes smooth muscle cells , fibroblasts , and inflammatory cells . As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions , discordance within the stroma could permit or promote disease processes . In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology . METHODOLOGY/PRINCIPAL FINDINGS We quantitated transcript levels in microdissected glandular-adjacent stroma from young ( age 4 months ) and old ( age 20-24 months ) C57BL/6 mice , and identified a significant change in the expression of 1259 genes ( p<0.05 ) . These included increases in transcripts encoding proteins associated with inflammation ( e.g. , Ccl8 , Ccl12 ) , genotoxic/oxidative stress ( e.g. , Apod , Serpinb5 ) and other paracrine-acting effects ( e.g. , Cyr61 ) . The expression of several collagen genes ( e.g. , Col1a1 and Col3a1 ) exhibited age-associated declines . By histology , immunofluorescence , and electron microscopy we determined that the collagen matrix is abundant and disorganized , smooth muscle cell orientation is disordered , and inflammatory infiltrates are significantly increased , and are comprised of macrophages , T cells and , to a lesser extent , B cells . CONCLUSION/SIGNIFICANCE These findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20824135"}
{"sentence": "MicroRNAs ( miRNAs ) are considered to be regulators of various biological processes in cancers , including the epithelial to mesenchymal transition ( EMT ) , which is a key factor in cancer metastasis . In this study , we aimed to clarify the potential roles of miR-490-3p in hepatocellular carcinoma ( HCC ) cells . Using real-time quantitative RT-PCR , we discovered that miR-490-3p was up-regulated in HCC tissues and cells compared with the adjacent non-tumor tissues and normal cells . We also found that overexpression of miR-490-3p led to an increase in cell proliferation , migration , and invasion abilities and that it contributed to EMT . The inhibition of miR-490-3p had the opposite effect on the cells . We identified ERGIC3 ( endoplasmic reticulum-Golgi intermediate compartment protein 3 ) as a direct target gene for miR-490-3p . Unlike most miRNA-mRNA interactions , miR-490-3p increased ERGIC3 mRNA and protein levels as well as the intensity of expression of the EGFP reporter gene controlled by the 3'-UTR of ERGIC3 mRNA . The up-regulation by miR-490-3p also required the participation of Ago2 . The inhibition of miR-490-3p reduced the expression of ERGIC3 . Overexpression of ERGIC3 led to the same effect on HCC cells as miR-490-3p overexpression , including EMT . Importantly , silencing ERGIC3 reversed the cellular responses mediated by miR-490-3p overexpression . In conclusion , our study indicated for the first time that miR-490-3p functioned like an oncogenic miRNA in HCC cells and that the inhibition of miR-490-3p might provide an potential treatment approach for HCC patients .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23212913"}
{"sentence": "Toll-like receptor 2 ( TLR2 ) is a target for immune system stimulation during cancer immunotherapy and a cell-surface marker for pancreatic cancer . To develop targeted agents for cancer imaging and therapy , we designed , synthesized , and characterized 13 novel , fully synthetic high affinity TLR2 agonists . Analogue 10 had the highest agonist activity ( NF-\u03baB functional assay , EC(50) = 20 nM ) and binding affinity ( competitive binding assay , K(i) = 25 nM ) . As an immune adjuvant , compound 10 stimulated the immune system in vivo by generation and persistence of antigen-specific CD8+ T cells indicating its potential use in cancer immunotherapy . After conjugation of near-infrared dye to 10 , agonist activity ( EC(50) = 34 nM ) and binding affinity ( K(i) = 11 nM ) were retained in 13 . Fluorescence signal was present in TLR2 expressing pancreatic tumor xenografts 24 h after injection of 13 , while an excess of unlabeled ligand blocked 13 from binding to the tumor , resulting in significantly decreased signal ( p < 0.001 ) demonstrating in vivo selectivity .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23098072"}
{"sentence": "Approximately 50% of melanomas require oncogenic B-RAF(V600E) signaling for proliferation , survival , and metastasis , and the use of highly selective B-RAF inhibitors has yielded remarkable , although short-term , clinical responses . Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors , and the identification of B-RAF targets may therefore provide new strategies for managing melanoma . In this report , we applied whole-genome expression analyses to reveal that oncogenic B-RAF(V600E) regulates genes associated with epithelial-mesenchymal transition in normal cutaneous human melanocytes . Most prominent was the B-RAF-mediated transcriptional repression of E-cadherin , a keratinocyte-melanoma adhesion molecule whose loss is intimately associated with melanoma invasion and metastasis . Here we identify a link between oncogenic B-RAF , the transcriptional repressor Tbx3 , and E-cadherin . We show that B-RAF(V600E) induces the expression of Tbx3 , which potently represses E-cadherin expression in melanocytes and melanoma cells . Tbx3 expression is normally restricted to developmental embryonic tissues and promoting cell motility , but it is also aberrantly increased in various cancers and has been linked to tumor cell invasion and metastasis . We propose that this B-RAF/Tbx3/E-cadherin pathway has a critical role in promoting the metastasis of B-RAF-mutant melanomas .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23190890"}
{"sentence": "Cellular redox changes have emerged as a pivotal and proximal event in cancer . PKI 166 is used to determine the effects of redox sensitive inhibition of EGFR , metastasis and apoptosis in epidermoid carcinoma . Cytotoxicity study of PKI 166 ( IC50 1.0 microM ) treated A431 cells were performed by MTT assay for 48 and 72 hrs . Morphological analysis of PKI 166 treated A431 cells for 48 hrs. revealed the cell shrinkage , loss of filopodia and lamellipodia by phase contrast and SEM images in dose dependent manner . It has cytotoxic effects through inhibiting cellular proliferation , leads to the induction of apoptosis , as increased fraction of sub-G1 phase of the cell cycle , chromatin condensation and DNA ladder . It inhibited cyclin-D1 and cyclin-E expression and induced p53 , p21 expression in dose dependent manner . Consequently , an imbalance of Bax/Bcl-2 ratio triggered caspase cascade and subsequent cleavage of PARP , thereby shifting the balance in favour of apoptosis . PKI 166 treatment actively stimulated reactive oxygen species ( ROS ) and mitochondrial membrane depolarization . It inhibited some metastatic properties of A431 cells supressing colony formation by soft agar assay and inhibition of MMP 9 activity by gelatin zymography and western blot analysis . PKI 166 inhibited growth factor induced phosphorylation of EGFR , Akt , MAPK , JNK and colony formation in A431 cells . Thus the inhibition of proliferation was associated with redox regulation of the caspase cascade , EGFR , Akt/PI3K , MAPK/ ERK and JNK pathway . On the other hand , increased antioxidant activity leads to decreased ROS generation inhibit the anti-proliferative and apoptotic properties of PKI 166 in A431 cells . These observations indicated PKI 166 induced redox signalling dependent inhibition of cell proliferation , metastatic properties and induction of apoptotic potential in epidermoid carcinoma .", "label": [1, 0, 0, 0, 1, 0, 0, 1, 1, 1], "id": "23350354"}
{"sentence": "Schizophrenia is a complex mental disorder with high degree of genetic influence in its etiology . Several recent studies revealed that copy number variations ( CNVs ) of genomic DNA contributed significantly to the genetic architecture of sporadic schizophrenia . This study aimed to investigate whether CNVs also contribute to the familial forms of schizophrenia . Using array-based comparative genomic hybridization technology , we searched for pathogenic CNV associated with schizophrenia in a sample of 60 index cases from multiplex schizophrenia families . We detected three inherited CNVs that were associated with schizophrenia in three families , including a microdeletion of at chromosome 6q12-q13 , a microduplication of at chromosome 18q12.3 , and an interstitial duplication of at chromosome 15q11.2-q13.1 . Our data indicate that CNVs contribute to the genetic underpinnings of the familial forms of schizophrenia as well as of the sporadic form . As 15q11-13 duplication is a well-known recurrent CNV associated with autism in the literature , the detection of the 15q11.2-q13.1 duplication in our schizophrenia patients provides additional support to other studies reporting that schizophrenia is part of the clinical spectrum of 15q11-q13 duplication syndrome .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22682706"}
{"sentence": "The effects of deoxycholic acid ( DCA ) and ursodeoxycholic acid ( UDCA ) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP)-induced aberrant crypt foci ( ACF ) in the rat colon were examined . The effect of these bile acids on DNA adduct formation by PhIP in the colon was then analyzed , since the main action of PhIP is the formation of DNA adducts and subsequent gene mutations . For the ACF study , male F344 rats were administered PhIP-HCl ( 75 mg/kg , 10 doses ) by gavage , and a diet containing bile acid ( 0.4% DCA or UDCA ) was provided from 3 days before the first dose of PhIP for 8 weeks . The mean number of ACF per colon of DCA , UDCA and controls were 9.9 , 2.4 and 5.5 , respectively . The ACF number was significantly increased by DCA and decreased by UDCA ( P<0.001 ) . To examine the effect of bile acids on DNA adduct formation , male F344 rats were fed a diet supplemented with bile acids ( 0.1 or 0.4% of DCA and UDCA ) 7 days prior to the PhIP administration . All rats were administered a single dose of PhIP-HCl ( 50 mg/kg ) by gavage and sacrificed 48 hours later . DNA adduct levels of the 0.1% UDCA , 0.1% DCA and controls were 2.93 ( adducts/10(7) nucleotides ) , 2.65 and 1.10 , respectively . Those of 0.4% UDCA , 0.4% DCA and controls were 1.64 , 1.30 and 1.00 , respectively . The PhIP-DNA adduct level was significantly increased by administration of 0.1% UDCA , 0.1% DCA ( P<0.05 ) and 0.4% UDCA ( P<0.01 ) . The increasing effect of both DCA and UDCA on PhIP-induced DNA adduct formation was unexpected , and was not directly associated with ACF formation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12636105"}
{"sentence": "OBJECTIVE As we previously demonstrated , the inhibitory effect of iodine on thyroid cell growth is mediated by iodolactones , especially 6-iodo-5-hydroxy-eicosatrienoic acid ( delta-iodolactone ) . In this communication we compare the effect of iodide , molecular iodine and delta-iodolactone on growth inhibition and apoptosis on three human thyroid carcinoma cell lines ( B-CPAP cells , FTC-133 cells and 8505C cells ) as well as on human breast cancer cells ( MCF 7 ) . METHODS Thyroid carcinoma cells were cultured in Dulbecco's modified Eagle's medium ( DMEM ) and MCF 7 cells in Rowswell Park Memorial Institute ( RPMI ) culture medium , both containing 10% ( v/v ) Fetal Calf Serum ( FCS ) , until they were confluent . Around 2000 cells were then distributed in 12-well plates and grown for 48 h in either DMEM ( thyroid cancer cells ) or in RPMI medium ( MCF 7 cells ) both containing 5% FCS . Thereafter , different concentrations of iodide , iodine or delta-iodolactone were added for 24 h . Growth rate was estimated by cell counting in a Coulter Counter adapted for epithelial cells . Apoptosis was determined by a mitochondrial potential assay . RESULTS The growth rate of B-CPAP cells was unaffected by iodide , but was reduced by high concentreations of molecular iodine ( 100 and 500 microM ) . However , delta-iodolactone significantly reduced cell proliferation already with low concentrations ( 5 microM and 10 microM ) and further in a dose-dependent manner up to 82% . FTC-133 and 8505C cells were unaffected by iodide , iodine or delta-iodolactone . In contrast , in MCF 7 cells , molecular iodine ( 100 microM ) inhibited growth from 100% to 83% but delta-iodolactone ( 1 , 5 and 10 microM ) dose-dependently decreased growth rate from 100% to 82% and 62% , respectively . The inhibition of growth was through apoptosis , and not necrosis , as the amount of apoptotic cells corresponded to the growth inhibition . CONCLUSION delta-Iotaodolactone seems to be the main iodocompound which can inhibit growth and induce apoptosis in B-CPAP cells as well as in MCF 7 breast cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20363723"}
{"sentence": "Integrin \\u03b1v\\u03b23 plays a role in insulin-like growth factor 1 ( IGF1 ) signaling ( integrin-IGF1 receptor ( IGF1R ) cross-talk ) in non-transformed cells in anchorage-dependent conditions . We reported previously that IGF1 directly binds to \\u03b1v\\u03b23 and induces \\u03b1v\\u03b23-IGF1-IGF1R ternary complex formation in these conditions . The integrin-binding defective IGF1 mutant ( R36E/R37E ) is defective in inducing ternary complex formation and IGF signaling , whereas it still binds to IGF1R . We studied if IGF1 can induce signaling in anchorage-independent conditions in transformed Chinese hamster ovary cells that express \\u03b1v\\u03b23 ( \\u03b23-CHO ) cells . Here we describe that IGF1 signals were more clearly detectable in anchorage-independent conditions ( polyHEMA-coated plates ) than in anchorage-dependent conditions . This suggests that IGF signaling is masked by signals from cell-matrix interaction in anchorage-dependent conditions . IGF signaling required \\u03b1v\\u03b23 expression , and R36E/R37E was defective in inducing signals in polyHEMA-coated plates . These results suggest that \\u03b1v\\u03b23-IGF1 interaction , not \\u03b1v\\u03b23-extracellular matrix interaction , is essential for IGF signaling . Inhibitors of IGF1R , Src , AKT , and ERK1/2 did not suppress \\u03b1v\\u03b23-IGF-IGF1R ternary complex formation , suggesting that activation of these kinases are not required for ternary complex formation . Also , mutations of the \\u03b23 cytoplasmic tail ( Y747F and Y759F ) that block \\u03b23 tyrosine phosphorylation did not affect IGF1R phosphorylation or AKT activation . We propose a model in which IGF1 binding to IGF1R induces recruitment of integrin \\u03b1v\\u03b23 to the IGF-IGF1R complex and then \\u03b23 and IGF1R are phosphorylated . It is likely that \\u03b1v\\u03b23 should be together with the IGF1-IGF1R complex for triggering IGF signaling .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "23243309"}
{"sentence": "It is crucial for organ homeostasis that epithelia have effective mechanisms to restrict motility and cell proliferation in order to maintain tissue architecture . On the other hand , epithelial cells need to rapidly and transiently acquire a more mesenchymal phenotype , with high levels of cell motility and proliferation , in order to repair epithelia upon injury . Cross talk between cell-cell and cell-matrix signaling is crucial for regulating these transitions . The Pak1-betaPIX-GIT complex is an effector complex downstream of the small GTPase Rac1 . We previously showed that translocation of this complex from cell-matrix to cell-cell adhesion sites was required for the establishment of contact inhibition of proliferation . In this study , we provide evidence that this translocation depends on cadherin function . Cadherins do not recruit the complex by direct interaction . Rather , we found that inhibition of the normal function of cadherin or Pak1 leads to defects in focal adhesion turnover and to increased signaling by phosphatidylinositol 3-kinase . We propose that cadherins are involved in regulation of contact inhibition by controlling the function of the Pak1-betaPIX-GIT complex at focal contacts .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20154149"}
{"sentence": "INTRODUCTION I\u03baB Kinase \u03b5 ( IKK\u03b5 ) is a member of the IKK family which plays an important role in the activation of nuclear factor-\u03baB ( NF-\u03baB ) . Overexpressed in over 30% of breast cancers , IKK\u03b5 has been recently identified as a potential breast cancer oncogene . The purpose of this study is to examine the therapeutic potential of IKK\u03b5 siRNA on human breast cancer cells . METHODS Eight siRNAs targeting different regions of the IKK\u03b5 mRNA were designed , and the silencing effect was screened by quantitative real time RT-PCR . The biological effects of synthetic siRNAs on human breast cancer cells were investigated by examining the cell proliferation , migration , invasion , focus formation , anchorage-independent growth(via soft agar assay ) , cell cycle arrest , apoptosis ( via annexing binding ) , NF-\u03baB basal level , and NF-\u03baB related gene expressions upon the IKK\u03b5 silencing . RESULTS Silencing of IKK\u03b5 in human breast cancer cells resulted in decrease of focus formation potential and clonogenicity as well as in vitro cell migration/invasion capabilities . Moreover , knockdown of IKK\u03b5 suppressed cell proliferation . Cell cycle assay showed that the anti-proliferation effect of IKK\u03b5 siRNA was mediated by arresting cells in G(0)/G(1) phase , which was caused by down-regulation of cyclin D(1) . Furthermore , we demonstrated that silencing of IKK\u03b5 inhibited the NF-\u03baB basal activity as well as the Bcl-2 expression . Significant apoptosis was not observed in breast cancer cells upon the silencing of IKK\u03b5 . The present study provided the first evidence that silencing IKK\u03b5 using synthetic siRNA could inhibit the invasiveness properties and proliferation of breast cancer cells . CONCLUSIONS Our results suggested that silencing IKK\u03b5 using synthetic siRNA may offer a novel therapeutic strategy for breast cancer .", "label": [1, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20863366"}
{"sentence": "Insulin-like growth factor ( IGF)-I receptor ( IGF-IR ) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas ( BTC ) . We investigated the immunohistochemical expression of elements of the IGF axis , matrilysin , overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC . We also assessed the effect of IGF-IR blockade on signal transduction , proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor , BMS-536924 , and dominant negative IGF-IR ( IGF-IR/dn ) . The effects of IGF-IR blockade was also studied in nude mouse xenograft models . IGF-I was expressed in 60% and IGF-II in 50% of tumors . High expression was associated with tumor size . IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression . Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression . BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin . BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion . This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion . Moreover , IGF-IR blockade was effective against tumors in mice . IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease . BMS-536924 might have significant therapeutic utility .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22044563"}
{"sentence": "PURPOSE The ability to accurately predict the likelihood of expansion of the CGG repeats in the FMR1 gene to a full mutation is of critical importance for genetic counseling of women who are carriers of premutation alleles ( 55-200 CGG repeats ) and who are weighing the risk of having a child with fragile X syndrome . The presence of AGG interruptions within the CGG repeat tract is thought to decrease the likelihood of expansion to a full mutation during transmission , thereby reducing risk , although their contribution has not been quantified . METHODS We retrospectively analyzed 267 premutation alleles for number and position of AGG interruptions , length of pure CGG repeats , and CGG repeat lengths present in the offspring of the maternal transmissions . In addition , we determined the haplotypes of four markers flanking the 5'-UTR locus in the premutation mothers . RESULTS We found that the presence of AGG interruptions significantly increased genetic stability , whereas specific haplotypes had a marginal association with transmission instability . CONCLUSION The presence of AGG interruptions reduced the risk of transmission of a full mutation for all maternal ( premutation ) repeat lengths below CGG repeats , with a differential risk ( 0 vs. 2 AGG ) exceeding 60% for alleles in the 70- to 80-CGG repeat range .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22498846"}
{"sentence": "The involvement of PRL in regulating monocyte/macrophage functions is suggested by the presence of PRL-Rs in these cells . Here , we show that PRL , though it failed to activate mouse peritoneal resident macrophages ( RMs ) , acted as a second signal and activated mouse peritoneal inflammatory macrophages ( EMs ) to a tumoricidal state . The cytotoxicity of mouse tumor-associated macrophages ( TAMs ) isolated at day 1 of tumor ( Ehrlich ascites carcinoma , EAC ) growth was enhanced by PRL . However , with progression of tumor growth , TAMs became nonresponsive to the hormone . PRL-induced killing of P815 target cells by EMs and TAMs was independent of TNF but correlated with the hormone-induced augmentation of NO2(-) and O2(-) release in these macrophages . Administration of PRL in vivo inhibited EAC growth and augmented NO2(-) release by TAMs . PRL synergized with the TH1 cytokine IFN-gamma , a known activator of macrophages , in inducing tumor killing and release of NO2(-) from EMs and TAMs . The hormone might activate macrophages at least partially , through the release of IFN-gamma as anti-IFN-gamma blocked IFN-gamma- as well as PRL-induced cytotoxicity in EMs . The TH2 cytokine IL-4 suppressed PRL-induced activation of macrophages . PRL induced release of IL-12 from EMs also , which suggested that the hormone might drive the TH1 response through IL-12 . Our observations further suggest that PRL alone and in synergy with IFN-gamma , released through induction of IL-12 , may generate tumoricidal macrophages and thus regulate the antitumor immune response of tumor hosts .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "11802212"}
{"sentence": "Rhabdoid tumors have been reported in many different anatomic sites as an aggressive tumor and usually present with a rhabdoid tumor component ( a composite tumor ) rather than a pure rhabdoid tumor . Rhabdoid tumor in the prostate has been described only once in the prostatic region as a possible epithelial origin . Rhabdoid features in prostatic stromal sarcomas ( PSSs ) have never been described in the literature . Here , we report a case of a PSS with rhabdoid features . A 31-year-old man presented with a 4-month history of voiding difficulty and anal pain . Computed tomography of the abdomen revealed an ovoid mass in the prostate invading rectum and urinary bladder . A needle biopsy was diagnosed as an unclassified spindle cell sarcoma , and 2 cycles of adriamycin-based neoadjuvant chemotherapy were given , followed by radical prostatectomy . The prostatectomy specimen revealed a high-grade sarcoma with fascicles of highly cellular spindle cells and numerous mitoses with hemorrhage and necrosis . In areas , the tumor also contained sheets of loosely cohesive epithelioid cells with rhabdoid tumor component . Both spindle and rhabdoid tumor cells were positive for vimentin , CD34 , and progesterone receptor and negative for desmin and cytokeratin immunostainings . The rhabdoid tumor cells retained INI1 expression . The tumor recurred in the bladder , and the patient died of sepsis . To the best of our knowledge , this is the first case of PSS with rhabdoid features . The tumor showed an aggressive clinical behavior with a short-term survival ( 7 months after diagnosis ) .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21074696"}
{"sentence": "The relationship between DNA damage and repair of peripheral blood leukocytes , liver , kidney and brain cells was investigated in Swiss albino mice ( Mus musculus L. ) after exposure to sevoflurane ( 2.4 vol% for 2 h daily , for 3 days ) . Genetic damage of mouse cells was investigated by the comet assay and micronucleus test . To perform the comet assay , mice were divided into a control group and 4 groups of exposed mice sacrificed on day 3 of the experiment , at 0 , 2 , 6 or 24 h after the last exposure to sevoflurane . Mean tail length ( TL ) , tail moment ( TM ) , and tail intensity ( TI ) values were significantly higher in exposed mice ( all examined organs ) than in the control group . Significant DNA damage immediately after exposure to sevoflurane was observed in leukocytes . Damage induction in the liver , kidney , and brain occurred 6 h later than in leukocytes , as expected according to the toxicokinetics of the drug , where blood is the first compartment to absorb sevoflurane . However , none of the tested tissues revealed signs of repair until 24 h after the exposure . To distinguish the unrepaired genome damage in vivo , the micronucleus test was applied . Number of micronuclei in reticulocytes showed a statistically significant increase , as compared with the control group at all observed times after the treatment .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20145304"}
{"sentence": "Although it has been demonstrated that discrete origins of DNA replication exist in eukaryotic cellular chromosomes , the detailed organization of a eukaryotic cellular origin remains to be determined . Linker substitution mutations were constructed across the entire Saccharomyces cerevisiae chromosomal origin , ARS1 . Functional studies of these mutants revealed one essential element ( A ) , which includes a match to the ARS consensus sequence , and three additional elements ( B1 , B2 , and B3 ) , which collectively are also essential for origin function . These four elements arranged exactly as in ARS1 , but surrounded by completely unrelated sequence , functioned as an efficient origin . Element B3 is the binding site for the transcription factor-origin binding protein ABF1 . Other transcription factor binding sites substitute for the B3 element and a trans-acting transcriptional activation domain is required . The multipartite nature of a chromosomal replication origin and the role of transcriptional activators in its function present a striking similarity to the organization of eukaryotic promoters .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1536007"}
{"sentence": "Cellular senescence forms a barrier that inhibits the acquisition of an immortal phenotype , a critical feature in tumorigenesis . The inactivation of multiple pathways that positively regulate senescence are required for immortalization . To identify these pathways in an unbiased manner , we performed DNA microarray analyses to assess the expression of 20,000 genes in human prostate epithelial cells ( HPECs ) passaged to senescence . These gene expression patterns were then compared with those of HPECs immortalized with the human Papillomavirus 16 E7 oncoprotein . Senescent cells display gene expression patterns that reflect their nonproliferative , differentiated phenotype and express secretory proteases and extracellular matrix components . A comparison of genes transcriptionally up-regulated in senescence to those in which expression is significantly down-regulated in immortalized HPECs identified three genes : the chemokine BRAK , DOC1 , and a member of the insulin-like growth factor axis , IGFBP-3 . Expression of these genes is found to be uniformly lost in human prostate cancer cell lines and xenografts , and previously , their inactivation was documented in tumor samples . Thus , these genes may function in novel pathways that regulate senescence and are inactivated during immortalization . These changes may be critical not only in allowing cells to bypass senescence in vitro but in the progression of prostate cancer in vivo .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "11836256"}
{"sentence": "Free radical-induced cellular stress contributes to cancer during chronic inflammation . Here , we investigated mechanisms of p53 activation by the free radical , NO . NO from donor drugs induced both ataxia-telangiectasia mutated ( ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications , leading to an increase in p53 transcriptional targets and a G(2)M cell cycle checkpoint . Such modifications were also identified in cells cocultured with NO-releasing macrophages . In noncancerous colon tissues from patients with ulcerative colitis ( a cancer-prone chronic inflammatory disease ) , inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels . Immunostaining of HDM-2 and p21(WAF1) was consistent with transcriptionally active p53 . Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 1], "id": "12518062"}
{"sentence": "Vascular endothelial growth factor ( VEGF ) , also known as vascular permeability factor or vasculotropin , is a recently characterized endothelial-specific mitogen which is angiogenic in vivo . Here we demonstrate that VEGF is angiogenic in vitro : when added to microvascular endothelial cells grown on the surface of three-dimensional collagen gels , VEGF induces the cells to invade the underlying matrix and to form capillary-like tubules , with an optimal effect at approximately 2.2nM ( 100ng/ml ) . When compared to basic fibroblast growth factor ( bFGF ) at equimolar ( 0.5nM ) concentrations , VEGF was about half as potent . The most striking effect was seen in combination with bFGF : when added simultaneously , VEGF and bFGF induced an in vitro angiogenic response which was far greater than additive , and which occurred with greater rapidity than the response to either cytokine alone . These results demonstrate that like bFGF , VEGF induces an angiogenic response via a direct effect on endothelial cells , and that by acting in concert , these two cytokines have a potent synergistic effect on the induction of angiogenesis in vitro . We suggest that the synergism between VEGF and bFGF plays an important role in the control of angiogenesis in vivo .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "1281999"}
{"sentence": "Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma ( LGNPPA ) is extremely rare ; only four cases have been reported . Herein are presented the case reports of two Japanese male patients with thyroid-like LGNPPA . Macroscopically , these tumors were pedunculated polypoid masses on the roof of the nasopharynx . Microscopically , they were characterized by papillary and glandular epithelial proliferation . The papillae were complex and tightly packed with hyalinized fibrovascular cores and lined by columnar and pseudostratified cells with intervening spindle-shaped cells . Both cell types had round to oval vesicular nuclei with tiny nucleoli and mildly eosinophilic cytoplasm . Mitotic figures were not evident and necrosis was not observed . Psammoma bodies were seen focally in one of the patients . Transition from normal surface epithelium to tumor cells was identified in both cases . On immunohistochemistry the tumor cells were positive for cytokeratin ( CK)7 , CK19 , thyroid transcription factor-1 ( TTF-1 ) and vimentin . They were negative for CK5/6 , CK20 , thyroglobulin , S-100 protein and CD15 . In situ hybridization for EBV was negative . Nasopharyngeal tumors with similar morphological appearance should be examined for TTF-1 immunoreactivity , and patients should be clinically followed to determine the course of this unusual disease and the significance of TTF-1 expression .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20398195"}
{"sentence": "BACKGROUND The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis . By using a specific antagonist that binds the C-terminal tail of nucleolin , the HB-19 pseudopeptide , we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity . METHODS The in vivo antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model . Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days . In parallel , the molecular basis for the action of HB-19 was investigated on a melanoma cell line ( called TIII ) derived from a cutaneous nodule of a RET mouse . RESULTS HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors , several-months delay in the incidence of large tumors , a lower frequency of cutaneous nodules , and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue . Moreover , microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls . Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition , impair anchorage-independent growth , and reduce their tumorigenic potential in mice . Moreover , HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9 , and tumor necrosis factor-alpha in the TIII cells and in melanoma tumors of RET mice . CONCLUSIONS Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice , it delayed for several months the onset and frequency of cutaneous tumors , and exerted a significant inhibitory effect on visceral metastasis . Consequently , HB-19 could provide a novel therapeutic agent by itself or as an adjuvant therapy in association with current therapeutic interventions on a virulent cancer like melanoma .", "label": [1, 0, 0, 0, 1, 0, 1, 0, 0, 0], "id": "20573279"}
{"sentence": "During the course of inflammation and its resolution , macrophages are exposed to various cytotoxic materials , including reactive oxygen species . Thus , macrophages require a protective machinery against oxidative stress to survive at the inflammatory site . Here , we showed that xCT , a component of transport system x(c)(-) , was significantly up-regulated in activated infiltrating cells , including macrophages and neutrophils at the inflammatory site . System x(c)(-) mediates the uptake of extracellular L-cystine and is consequently responsible for maintenance of intracellular glutathione levels . We established a loss-of-function mouse mutant line of xCT by N-ethyl-N-nitrosourea mutagenesis . Macrophages from xCT(mu/mu) mice showed cell death in association with the excessive release of high mobility group box chromosomal protein 1 upon stimulation with LPS , suggesting that xCT deficiency causes unremitting inflammation because of the impaired survival of activated macrophages at the inflammatory site . Subcutaneous injection of 3-methylcholanthrene ( 3-MCA ) induced the generation of fibrosarcoma in association with inflammation . When 3-MCA was injected s.c. into mice , xCT mRNA was up-regulated in situ . In xCT(mu/mu) mice , inflammatory cytokines ( such as IL-1beta and TNFalpha ) were overexpressed , and the generation of 3-MCA-induced fibrosarcoma was accelerated . These results clearly indicate that the defect of the protective system against oxidative stress impaired survival of activated macrophages and subsequently enhanced tumorigenecity .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20308543"}
{"sentence": "DNA double strand breaks ( DSBs ) arise from spontaneous DNA damage due to metabolic activities or from direct and indirect damaging effects of stress . DSBs are also formed transiently during such processes as replication , transcription , and DNA repair . The level of DSBs positively correlates with the activities of homologous and nonhomologous DNA repair pathways , which in turn inversely correlate with methylation levels and chromatin structure . Thus , measurement of strand breaks can provide an informative picture of genome stability of a given cell . The use of random oligonucleotide-primed synthesis for the analysis of DSB levels is described . Applications of the assay for quantitative detection of 3'OH , 3'P , or DNA strand breaks at a cleavage site of the deoxyribose residue are discussed .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20204879"}
{"sentence": "Congenital gonadotropin-releasing hormone ( GnRH ) deficiency manifests as absent or incomplete sexual maturation and infertility . Although the disease exhibits marked locus and allelic heterogeneity , with the causal mutations being both rare and private , one causal mutation in the prokineticin receptor , PROKR2 L173R , appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins . To track the genetic ancestry of PROKR2 L173R , haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives . The mutation's age was estimated using a haplotype-decay model . Thirteen subjects were informative and in all of them the mutation was present on the same kb haplotype whose population frequency is \\u226410% . Thus , PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years . Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers , influenced by additional mutations in the other PROKR2 allele ( recessive inheritance ) or another gene ( digenicity ) . The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection , including potential selective advantages of mutation carriers in genes affecting reproduction .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22773735"}
{"sentence": "OBJECTIVE To study the relationship between clinical pathologic characteristics , treatment modalities and prognostic factors in HER-2 ( Human Epidermal growth factor Receptor-2 ) overexpressed breast carcinoma . MATERIALS AND METHODS Major clinico-pathological factors including therapeutic modalities and survival status of 371 breast cancer patients with HER2 over-expression , teated at Yantai Yuhuangding Hospital from March of 2002 to December of 2010 were retrospectively studied , with special attention focused on survival-related factors . RESULTS The median age of the total 371 patients in this study was 48 years at time of diagnosis , among which , the leading pathological type was infiltrating ductal carcinoma ( 92.5% ) ; 62.8% presented with a primary tomor larger than 2 cm in diameter at diagnosis , 51.0% had axillary lymph node ( ALN ) metastases ; ER ( Estrogen receptor ) /PR ( Progesterone receptor ) double negative occured in 52.8% of cases , and PCNA ( proliferation cell nuclear antigen ) ( + + + ) was found in 55.1% . HER-2 overexpressed patients were usually in advanced stage when the diagnosis was made ( 72.8% at stages IIA The prognosis and survival were assessed in 259 patients with complete follow-up data. 5-year DFS ( disease-free survival ) and OS ( overall survival ) rate was 68.0% and 78.0% respectively . Univariate analysis revealed that age , tumor size , ALN metastases , LVSI ( lymph-vascular space involvement ) , PCNA status , hormonal therapy , chemotherapy cycles , and HER-2 overexpression , correlated closely with the prognosis . ALN metastases , LVSI , PCNA status and chemotherapy cycles were independent predictors of survival . CONCLUSIONS HER-2 overexpressed breast cancer has special clinical and pathological characteristics , with advanced clinical stages and high rate of ER/PR double negative . Lymph node metastases , LVSI , PCNA and chemotherapy cycles are independent predictors of prognosis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22799305"}
{"sentence": "The effect of peptides released during the fermentation of milk on the humoral immune system and on fibrosarcoma growth was studied . Lactobacillus helveticus was able to release peptidic compounds during milk fermentation due to its high proteolytic activity , as was shown by the degree of proteolysis and size-exclusion HPLC elution profiles . Three fractions of these compounds were separated and fed to mice during different periods ( 2 , 5 , and 7 d ) . The humoral immune response was assessed by following the number of IgA-secreting cells , and the antitumor activity was monitored by studying the regression of subcutaneously implanted fibrosarcomas . Feeding during 2 and 7 d with the medium-sized fraction ( Fraction II ) significantly increased the IgA-producing cells in the intestines , whereas feeding with the large compound fraction ( Fraction I ) during 5 d and the small compound fraction ( Fraction III ) during all three feeding periods provided similar increases . A double dose of Fraction II showed the highest IgA-producing cell count . The increase by Fraction III was shown to be caused by the presence of L-Tryptophan . Fraction II significantly decreased the size of fibrosarcoma when previously fed during 7 d , and feeding with Fraction I during 5 d decreased significantly its size after 35 d of growth . Although the mechanisms by which lactic acid bacteria enhance the immune system are not clear , this study clearly shows that bioactive compounds released in fermented milks contribute to the immunoenhancing and antitumor properties of these products . The release of bioactive peptides by lactic acid bacteria can have important implications on the modulation of the cellular immune response .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12487440"}
{"sentence": "Designed from a high throughput screened hit compound , novel 2-amino-1-thiazolyl imidazoles were synthesized and demonstrated cytotoxicity against human cancer cells. 1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-imidazol-2-amine ( compound 2 ) , a 2-amino-1-thiazolyl imidazole , inhibited tubulin polymerization , interacted with the colchicine-binding sites of tubulins , and caused cell cycle arrest at the G(2)/M phase in human gastric cancer cells . Disruption of the microtubule structure in cancer cells by compound 2 was also observed . Compound 2 concentration-dependently inhibited the proliferation of cancer cells in histocultured human gastric and colorectal tumors . Given orally , compound 2 prolonged the lifespans of leukemia mice intraperitoneally inoculated with the murine P388 leukemic cells . We report 2-amino-1-thiazolyl imidazoles as a novel class of orally active microtubule-destabilizing anticancer agents .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20890633"}
{"sentence": "BACKGROUND Special AT-rich binding protein-1 ( SATB1 ) reprograms chromatin organization and transcription profiles to promote tumour growth and metastasis . AIMS This study aimed to confirm the effects of SATB1 on the growth and metastasis of liver cancer and its specific regulation mechanism . METHODS SATB1 expression was evaluated in human hepatoma tissue , adjacent noncancerous tissue and seven kinds of liver cancer cell lines . Cell cycle , cell proliferation , apoptosis and epithelial-mesenchymal transition ( EMT ) was investigated after enhanced or silenced expression of SATB1 . The regulatory action of SATB1 on the expression of genes that are known to regulate cell cycle progression , apoptosis and EMT and the specific apoptotic pathway on which it acts were further analysed . Nude mice that received subcutaneous implantation were used to study the effects of SATB1 on tumour growth in vivo . RESULTS Our data show that the high expression of SATB1 was observed in the human hepatocellular carcinoma tissue ( 26/45 ) and liver cancer cell lines with high metastatic potential . SATB1 upregulated CDK4 and downregulated p16 ( INK ) ( 4A ) to promote cell cycle progression and cell proliferation and prevented apoptosis by inhibiting the FADD-caspase-8-caspase-3 death receptor-mediated apoptosis pathway . SATB1 also induced EMT concomitant with increased expression of Snail1 , Slug , Twist and vimentin and decreased expression of E-cadherin , tight junction protein ZO-1 and desmoplakin . SATB1 promoted the growth of tumour in vivo . CONCLUSION These data suggest that the SATB1 gene may play an important role in the development and progression of liver cancer by regulation of genes related to cell cycle progression , apoptosis and EMT .", "label": [1, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "22583549"}
{"sentence": "CDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers , including hepatocellular carcinoma ( HCC ) ; however , little is known regarding the role of CDKN1C/P57 and its regulation in HCC . In this study , we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation , CDKN1C/P57 up-regulation , and reduced cell growth . In line with these data , we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector , Hes1 . We found that the up-regulation of CDKN1C/P57 by cDNA transfection decreased tumor growth , as determined by growth curve , flow cytometry analysis , and cyclin D1 down-regulation , without affecting the apoptosis machinery . Indeed , the expression of Bax , Noxa , PUMA , BNIP(3) , and cleaved caspase-3 was not affected by CDKN1C/P57 induction . Morphologically CDKN1C/p57-induced HCC cells became flat and lengthened in shape , accumulated the senescence-associated \u03b2-galactosidase marker , and increased P16 protein expression . Evaluation of senescence in cells depleted both for Hes1 and CDKN1C/P57 revealed that the senescent state really depends on the accumulation of CDKN1C/p57 . Finally , we validated our in vitro results in primary HCCs , showing that Hes1 protein expression inversely correlates with CDKN1C/P57 mRNA levels . In addition , reduced Hes1 protein expression is accompanied by a shorter time to recurrence after curative resection , suggesting that Hes1 may represent a biomarker for prediction of patients with poor prognosis .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "22705236"}
{"sentence": "BACKGROUND & OBJECTIVE There is little ideal predictor available on evaluating the lymph node metastatic potential of breast carcinoma . This study was designed to determine the expression of gene products of E-cadherin ( epithelial ) , N-cadherin ( nerve ) , and matrix metalloproteinase-9 ( MMP-9 ) in breast carcinoma tissue and investigate their association with the invasion and metastasis of breast carcinoma . METHODS The authors examined the expressions of E-cadherin , N-cadherin , and MMP-9 in 72 cases of breast carcinoma(39 cases with lymph node metastasis and 33 cases without lymph node metastasis ) by immunohistochemistry . Multivariable Cox proportional hazards model was used to analyze the patients ' prognosis . RESULTS The average ranks of E-cadherin in lymph node metastasis group and no lymph node metastasis group were 29.19 and 45.14 , respectively , with significant difference ( P < 0.001 ) . The expression of E-cadherin was correlated inversely with the metastasis of breast carcinoma . The average ranks of N-cadherin and MMP-9 were 40.04 and 42.97 in lymph node metastasis group , and 32.32 and 28.85 in no lymph node metastasis group , both with significant difference ( P < 0.05 ) , and these expressions were positively correlated with the lymph node metastasis of breast carcinoma . The patients who had high expression of E-cadherin had a longer survival time . CONCLUSION Expression of E-cadherin , N-cadherin , and MMP-9 are associated strongly with lymph node metastasis of breast carcinoma . These proteins are indicators of metastasis potential and prognosis of breast carcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12508543"}
{"sentence": "AIM To assess the prognostic significance of nuclear factor-\u03baB ( NF-\u03baB ) and its target genes in gastric cancer . METHODS The tumor tissues of 115 patients with gastric cancer were immunohistochemically evaluated using monoclonal antibodies against NF-\u03baB RelA . Preoperative serum levels of vascular endothelial growth factor ( VEGF ) , interleukin-6 ( IL-6 ) were assessed via enzyme-linked immuno-sorbent assay . C-reactive protein ( CRP ) and serum amyloid A ( SAA ) were measured via immunotrubidimetry . RESULTS Positive rate of NF-\u03baB RelA was 42.6% . NF-\u03baB RelA expression in tumor tissues was also related to serum levels of IL-6 ( P = 0.044 ) and CRP ( P = 0.010 ) . IL-6 , SAA , CRP were related to depth of invasion , VEGF and SAA were correlated with lymph node metastasis . IL-6 , VEGF , SAA and CRP were related to the stage . Univariate analysis demonstrated that immunostaining of NF-\u03baB RelA , levels of IL-6 , VEGF , SAA were significantly related with both disease free survival and overall survival ( OS ) . Multivariate analysis verified that NF-\u03baB RelA [ hazard ratio ( HR ) : 3.40 , P = 0.024 ] and SAA ( HR : 3.39 , P = 0.045 ) were independently associated with OS . CONCLUSION Increased expression of NF-\u03baB RelA and high levels of serum SAA were associated with poor OS in gastric cancer patients .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23002344"}
{"sentence": "At present , isoniazid ( INH ) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer , although it is not clear whether or not this reduces the antitumor efficacy of BCG . In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs . INH was given on the 3 days around each BCG instillation . We found that the administration of INH severely impaired the immunological effects of BCG . The induction of mononuclear cell infiltration in the bladder wall was reduced . Enlargement of the regional lymph nodes ( weight and number of cells ) , and increase of MHC Class II expression on the lymph node cells , normally observed after intravesical BCG administration , were inhibited by INH . Systemic immunity , measured by the DTH reaction in the skin to PPD , was also diminished due to the combined treatment of BCG with INH . When INH was administered during the last 4 of 6 BCG instillations , the immune response to BCG was still impaired . A five-fold increase of the dose of BCG did not overcome the effect of INH . INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced . Although INH concentrations in the urine were high at the onset of the instillation , in vitro experiments indicated that the effect of INH may not be caused by killing of the BCG organisms shortly after application in the bladder . In conclusion , our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG . As this response may be important for the antitumor effect of BCG , urologists should be cautious with the prophylactic use of INH . The influence on the antitumor efficacy is now investigated in man .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1433571"}
{"sentence": "In a screen for thoracic malignancy-associated markers , thyroid stimulating hormone receptor ( TSHR ) was identified as a candidate as it binds to the previously-characterized lung cancer marker NKX2-1 . We screened for mutations in all coding regions of the TSHR gene in 96 lung adenocarcinoma samples and their matched adjacent normal lung samples . We found one patient with a somatic mutation at codon 458 ( exon 10 ) , which is located at the transmembrane domain where most TSHR mutations have been found in thyroid-related diseases . This patient had lung adenocarcinoma with BAC ( bronchioloalveolar carcinoma ) features in the setting of a prior medical history significant for carotid stenosis and severe chronic obstructive pulmonary disease ( COPD ) . In order to characterize the genetic features of TSHR in lung cancer , we checked for TSHR expression and copy number in the 96 lung cancer tissues . TSHR protein expression was generally overexpressed in multiple thoracic malignancies ( adenocarcinoma , squamous cell carcinoma and malignant pleural mesothelioma ) by immunohistochemistry . Our data suggest that aberrant TSHR function may contribute to lung cancer development or a subgroup of lung cancer with specific clinical phenotypes .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22842620"}
{"sentence": "The evidence that androgen blockade-resistant prostate cancer , termed castration resistant , remains androgen receptor ( AR ) dependent is compelling . AR is re-activated through multiple mechanisms including expression of constitutively active splice variants that lack hormone binding domains ( HBDs ) . This highlights need to develop therapies that target regions other than the HBD . Because the p160 coactivators interact most strongly with the amino-terminus of AR , we examined the consequences of disrupting this interaction . We identified two overlapping SRC-1 peptides that interact with AR , but not with progesterone receptor . These peptides reduce AR and AR variant AR-V7 dependent induction of an AR responsive reporter . Using mammalian two hybrid assays , we found that the peptides interrupt the AR/SRC-1 , AR/SRC-2 and AR N/C interactions , but not SRC-1/CARM-1 interactions . Consistent with the SRC-1 dependence of induced , but not repressed genes , in LNCaP cells , the peptides inhibited hormone dependent induction of endogenous target genes including PSA and TMPRSS2 , but did not block AR dependent repression of UGT2B17 or inhibit vitamin D receptor activity . Simultaneous detection of SRC-1 peptides and PSA by double immunofluorescence in transfected LNCaP cells clearly demonstrated a strong reduction in PSA levels in cells expressing the peptides . The peptides also inhibited the AR dependent expression of PSA in castration resistant C4-2 cells . Moreover they inhibited androgen dependent proliferation of LNCaP cells and proliferation of C4-2 cells in androgen depleted medium without affecting AR negative PC-3 cells . Thus , the p160 coactivator binding site is a novel potential therapeutic target to inhibit AR activity .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23270728"}
{"sentence": "The ras oncogenes alone fully transform established ( immortalized ) rodent fibroblasts in a few days , but generally transform early-passage fibroblasts only partially , unless their action is complemented by that of a nuclear , immortalizing , oncogene . Here we show that transfection of second-passage Syrian hamster embryo fibroblasts ( HEFs ) by the EJ-H-ras oncogene coupled to the neo gene , followed by selection with G418 , gives rise to apparently normal , or only slightly transformed , clonal colonies , only a few of which become established . The study of two established clonal lines showed that they acquired only after some weeks , and stepwise , the main characteristics of full neoplastic transformation , i.e. anchorage independence , reduced requirement for serum growth factors and tumorigenicity . Later both clonal lines became increasingly tumorigenic and completely independent of exogenous growth and attachment factors , without increase in the expression of the H-ras oncogene . Transfection of one of the clones , early after its isolation , with a truncated derivative of the nuclear v-myb oncogene devoid of its transcriptional negative regulatory domain and able to partially transform chicken embryo fibroblasts [ (myb(KXANM) ] gave rise to more transformed cells , expressing both EJ-H-ras and myb(KXANM) , which became tumorigenic earlier than the controls and remained more tumorigenic later on . With more efficient transfection techniques , numerous foci of fully transformed cells were subsequently obtained , in a few days , in cultures transfected sequentially with EJ-H-ras(neo) and myb(KXANM) and in cultures co-transfected with the two oncogenes . Highly tumorigenic , serum-independent and immortalized clones expressing both oncogenes were obtained from these cultures . Hence , the truncated myb(KXANM) oncogene accelerate the stepwise transformation of unestablished HEFs by the EJ-HH-ras oncogene and , together with this oncogene , fully transforms these same cells in a single step . The two oncogenes acting in cooperation also induce cell immortalization , but myb(KXANM) , by itself , is not an immortalizing oncogene . No cooperation was observed between EJ-H-ras(neo) and the unaltered v-myb oncogene .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1408144"}
{"sentence": "Liver cancer , predominantly hepatocellular carcinoma ( HCC ) , represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation . Due to dismal prognosis and limited therapeutic intervention , chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC . Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties . We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine ( DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 ( Nrf2)-mediated antioxidant mechanisms . Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB ( NF-\u03baB)-regulated inflammatory pathway , our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion ( PE ) during DENA-induced rat hepatocarcinogenesis . Rats were administered with PE ( 1 or 10 g/kg ) 4 weeks before and 18 weeks following DENA initiation . There was a significant increase in hepatic expressions of inducible nitric oxide synthase , 3-nitrotyrosine , heat shock protein 70 and 90 , cyclooxygenase-2 and NF-\u03baB in DENA-exposed rat livers . PE dose-dependently suppressed all aforementioned elevated inflammatory markers . A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography . Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-\u03baB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis . Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits , namely , Nrf2-mediated redox signaling and NF-\u03baB-regulated inflammatory pathway , by pomegranate phytoconstituents to achieve chemoprevention of HCC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22841394"}
{"sentence": "Proliferation of non-transformed cells is regulated by cell-cell contacts , which are referred to as contact-inhibition . Vice versa , transformed cells are characterised by a loss of contact-inhibition . Despite its generally accepted importance for cell-cycle control , little is known about the intracellular signalling pathways involved in contact-inhibition . Unravelling the molecular mechanisms of contact-inhibition and its loss during tumourigenesis will be an important step towards the identification of novel target genes in tumour diagnosis and treatment . To better understand the underlying molecular mechanisms we identified the transcriptional programme of contact-inhibition in NIH3T3 fibroblast using high-density microarrays . Setting the cut off : >or=1.5-fold , P <or= 0.05 , 853 genes and 73 cDNA sequences were differentially expressed in confluent compared to exponentially growing cultures . Importing these data into GenMAPP software revealed a comprehensive list of cell-cycle regulatory genes mediating G0/G1 arrest , which was confirmed by RT-PCR and Western blot . In a narrow analysis ( cut off : >or=2-fold , P <or= 0.002 ) , we found 110 transcripts to be differentially expressed representing 107 genes and 3 cDNA sequences involved , for example , in proliferation , signal transduction , transcriptional regulation , cell adhesion and communication . Interestingly , the majority of genes was upregulated indicating that contact-inhibition is not a passive state , but actively induced . Furthermore , we confirmed differential expression of eight genes by semi-quantitative RT-PCR and identified the potential tumour suppressor transforming growth factor-beta ( TGF-beta)-1-induced clone 22 ( TSC-22 ; tgfb1i4 ) as a novel protein to be induced in contact-inhibited cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20564218"}
{"sentence": "OBJECTIVE To investigate the expression and mutation of MTA1 , nm23H1 and E-cadherin(E-cad) genes in ovarian carcinoma ( OC ) in relation to lymph node ( LN ) metastasis . METHODS A panel of normal ovarian tissues , primary OC specimens and corresponding LNS was examined for mRNA expression and mutation of MTA1 and nm23H1 and protin expression of E-cad genes by using RT-PCR , RT-PCR-SSCP and immunohistochemistry . RESULTS The frequency of MTA1 over expression was 100%(7/7) in primary OC with metastasis but only 38.5%(5/13) in those without metastasis ( P = 0.0103 ) . Overexpression of MTA1 was observed in 87.5%(6/7) of LNS with metastasis but in only 23%(3/13) of LNS without metastasis ( P = 0.0118 ) . In contrast with MTA1 , low expression of nm23H1 mRNA was seen in 7 of 7 OC with metastasis but only in 4 of 13(30%) of those without metastasis ( P = 0.0043 ) . Low nm23H1 expression was also seen in 7 of 7 LNS with metastasis but only in 5 of 13 ( 38.5% ) nonmetastatic LNS ( P = 0.0102 ) . Meantime , no expression of E-cad protein was observed in 7 of 7 OC with metastasis but in 6 of 13(46.2%) of those without metastasis ( P = 0.044 ) . In correlation analysis of the three genes , MTA1 reversely correlated with nm23H1 and E-cad respectively ( r = -0.903 , -0.803 ) , and positive correlation existed between nm23H1 and E-cad ( r = 0.724 ) . No mutation of MTA1 , nm23H1 and was found by SSCP analysis . CONCLUSION The mRNA expression of MTA1 , nm23H1 and E-cad is positively and negatively correlated with LN metastasis . The expression abnormalities but not the mutations of the three genes are frequent events related to LN metastasis of ovarian cancer .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12599421"}
{"sentence": "BACKGROUND AND AIMS : Impairment of the immune system may contribute to the risk for having cancer as Toll-like receptors are important for innate immunity . We examined the association between candidate disease-susceptibility polymorphisms in the single nucleotide polymorphism ( SNPs ) like TLR2 ( -196 to-174del ) , TLR3 ( C1377T ) , TLR4 ( Thr399Ile ) and TLR9 ( G2848A ) genes in patients with bladder cancer in a North Indian population . METHODS : SNPs were comprised of TLR2 ( -196 to -174 Del ) , TLR3(C1377T) , TLR4 ( Thr399Ile ) and TLR9 ( G2848A ) genes . Allelic and genotypic frequencies of these TLRs SNP from histopathologically confirmed patients of bladder cancer ( n=200 ) and unrelated healthy controls of similar ethnicity ( n=200 ) were genotyped by polymerase chain reaction restriction fragment length polymorphism ( PCR-RFLP ) analysis . RESULTS : In TLR2 I/D gene polymorphism , the combination of ID+DD showed a significant 3-fold increased risk ( p=0.001 ) . TLR2 with heterozygous genotype ID showed a 3-fold risk and combination of heterozygous and variant genotype ( ID+DD ) also showed a 5-fold risk with tumor stage/grade of patients with bladder cancer . The other genotypes of TLR3 , 4 and 9 did not exhibit any significant association with bladder cancer risk . CONCLUSIONS : Our results suggested the involvement of TLR2 ( -196 to-174 del ) in bladder cancer susceptibility ; however , TLR3 , 4 and 9 genes were not associated with risk of bladder cancer , implicating that polymorphisms in these tested TLRs genes are not likely to be associated with increased risk for developing bladder cancer . Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for the etiology of bladder cancer .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23142523"}
{"sentence": "BACKGROUND To investigate the dynamics of inter- and intratumoral molecular alterations during tumor progression in recurrent gliomas . METHODOLOGY/PRINCIPAL FINDINGS To address intertumoral heterogeneity we investigated non-microdissected tumor tissue of 106 gliomas representing 51 recurrent tumors . To address intratumoral heterogeneity a set of 16 gliomas representing 7 tumor pairs with at least one recurrence , and 4 single mixed gliomas were investigated by microdissection of distinct oligodendroglial and astrocytic tumor components . All tumors and tumor components were analyzed for allelic loss of 1p/19q ( LOH 1p/19q ) , for TP53- mutations and for R132 mutations in the IDH1 gene . The investigation of non-microdissected tumor tissue revealed clonality in 75% ( 38/51 ) . Aberrant molecular alterations upon recurrence were detected in 25% ( 13/51). 64% ( 9/14 ) of these were novel and associated with tumor progression . Loss of previously detected alterations was observed in 36% ( 5/14 ) . One tumor pair ( 1/14 ; 7% ) was significant for both . Intratumoral clonality was detected in 57% ( 4/7 ) of the microdissected tumor pairs and in 75% ( 3/4 ) of single microdissected tumors. 43% ( 3/7 ) of tumor pairs and one single tumor ( 25% ) revealed intratumoral heterogeneity . While intratumoral heterogeneity affected both the TP53- mutational status and the LOH1p/19q status , all tumors with intratumoral heterogeneity shared the R132 IDH1- mutation as a common feature in both their microdissected components . CONCLUSIONS/SIGNIFICANCE The majority of recurrent gliomas are of monoclonal origin . However , the detection of divertive tumor cell clones in morphological distinct tumor components sharing IDH1- mutations as early event may provide insight into the tumorigenesis of true mixed gliomas .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22844452"}
{"sentence": "Retinoic acid ( RA)-induced differentiation therapy is partially successful in neuroblastoma treatment . We found that a novel combination of vanadium-based PTP inhibitors with RA induced extensive differentiation in neuroblastoma cells . In contrast to RA alone , this led to either permanent differentiation or senescence after 14days of combined treatment followed by chemical removal . Senescence was dependent in part on synergistic AKT and ERK activation. p21 was also strongly induced , but in contrast to oncogene-induced senescence , p53 was not activated . Vanadium-based inhibitors thus serve strongly to enhance RA's ability to drive differentiation and a novel form of senescence in neuroblastoma cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23022267"}
{"sentence": "A simple reversed-phase HPLC method for measuring hepatic levels of acetaminophen- ( APAP- ) protein adduct following an overdose of APAP was developed . An aliquot of liver homogenate in phosphate-buffered saline pH 7.4 ( PBS ) was placed on a Nanosep centrifugal device , which was centrifuged to obtain a protein residue . This residue was incubated with a solution of p-aminobenzoic acid ( PABA ) , the internal standard , and bacterial protease in PBS , transferred to a Nanosep centrifugal device , and centrifuged . A 100\\u2009\\u03bcL portion of the filtrate was analyzed on a YMC-Pack ODS-AMQ C18 column , using 100\\u2009mM potassium dihydrogen phosphate-methanol-acetic acid ( 100\\u2009:\\u20090.6\\u2009:\\u20090.1 ) as the mobile phase , a flow rate of 1\\u2009mL/min , and photometric detection at 254\\u2009nm . PABA and APAP-cystein-S-yl ( APAP-Cys ) eluted at and 22.7\\u2009min , respectively . Method linearity , based on on-column concentrations of APAP-Cys , was observed over the range 0.078-40\\u2009\\u03bcg . Recoveries of APAP-Cys from spiked blank liver homogenates ranged from to 91% . Limits of detection and of quantification of APAP-Cys , based on column concentrations , were 0.06\\u2009\\u03bcg and 0.14\\u2009\\u03bcg , respectively . RSD values for interday and intraday analyses of a blank liver homogenate spiked with APAP-Cyst at three levels were , in all cases , \\u22641.0% and <1.5% , respectively . The proposed method was found appropriate for comparing the antidotal properties of N-acetylcysteine and taurine in a rat model of APAP poisoning .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22619591"}
{"sentence": "There is little understanding of the factors controlling the mobilization of blast cells from bone marrow to peripheral blood and tissues . The aim of this study was to evaluate the soluble hepatocyte growth factor ( sHGF ) and vascular endothelial growth factor ( sVEGF ) levels in newly diagnosed patients with acute myeloid leukemia ( AML ) and to correlate these levels with the clinico-pathological features . Sixty-three patients with AML and 15 normal controls were included in this study . The levels of sHGF and sVEGF were determined by enzyme linked immunosorbent assay at diagnosis and after remission induction chemotherapy . Our results revealed significantly increased plasma levels of sHGF and sVEGF at diagnosis when compared to both control and remission levels ( P=0.000 for both ) . The sHGF and sVEGF levels differed between AML FAB subtypes ( P=0.000 ) . The highest concentrations were found in M5 followed by M4 . SHGF and sVEGF were directly correlated with peripheral white cell counts ( WBC ) ( r=0.836 , P=0.000 , r=0.718 ; P=0.000 , respectively ) , but inversely correlated with blast cell distribution ratio ( BCDR ) ( r=-0.785 , P=0.000 , r=-0.664 , P=0.000 , respectively ) . Moreover , both sHGF and sVEGF levels were significantly elevated in AML patients with extra-medullary infiltration as compared to those without ( P=0.000 , 0.006 , respectively ) . The sHGF but not sVEGF levels were significantly elevated in patients who died compared to those who relapsed and to patients in complete remission ( P=0.02 , 0.08 , respectively ) . Logistic regression analysis revealed that the sHGF level at diagnoses is a powerful predictor of the patient outcome , compared to sVEGF . In conclusion : our data support the hypothesis that angiogenic factors play a functional role in blast cell movement from the bone marrow to peripheral tissues . Assessment of sHGF at AML diagnosis is likely to be helpful in predicting patient outcome and selecting optimal therapeutic regimen .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12850814"}
{"sentence": "Investigations toward the understanding of chronic obstructive pulmonary disease ( COPD ) have been directed , so far , to the study of mechanisms leading to the disease . We believe that understanding why of smokers evade COPD and how this evasion is accomplished might be a fruitful endeavour that could advance knowledge of the development of the disease . Since the inflammatory infiltrate smokers develop seems to be the key element leading to the lung destruction in COPD , the understanding of the possible ways inflammation can be dampened , as well as its consequences , ought to be important . We review here some of the mechanisms by which inflammation is controlled : by the post-translational regulons , by the mechanisms preventing full activation of dendritic cells and by the regulatory T-cells . The potential role of the M2 alveolar macrophage phenotype and the newly described myeloid-derived suppressor cells is mentioned . We also point out that evasion comes at a price , as healthy smokers might be immunosuppressed to some extent and unable to prevent the development of cancer , certainly less so than in severe COPD , where immunity is heightened . Probably , the knowledge of the mechanisms of evasion from COPD could add significantly to the understanding of those leading to the disease .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22005915"}
{"sentence": "High resolution oligonucleotide array Comparative Genome Hybridization technology ( array-CGH ) has greatly assisted the recognition of the 1p36 contiguous gene deletion syndrome . The 1p36 deletion syndrome is considered to be one of the most common subtelomeric microdeletion syndromes and has an incidence of in 5000 live births , while respectively the \" pure \" 1p36 microduplication has not been reported so far . We present seven new patients who were referred for genetic evaluation due to Developmental Delay ( DD ) , Mental Retardation ( MR ) , and distinct dysmorphic features . They all had a wide phenotypic spectrum . In all cases previous standard karyotypes were negative . Array-CGH analysis revealed five patients with interstitial 1p36 microdeletion ( four de novo and one maternal ) and two patients with de novo reciprocal duplication of different sizes . These were the first reported \" pure \" 1p36 microduplication cases so far . Three of our patients carrying the 1p36 microdeletion syndrome were also found to have additional pathogenetic aberrations . These findings ( del 3q27.1 ; del 4q21.22-q22.1 ; del 16p13.3 ; dup 21q21.2-q21.3 ; del Xp22.12 ) might contribute to the patients ' severe phenotype , acting as additional modifiers of their clinical manifestations . We review and compare the clinical and array-CGH findings of our patients to previously reported cases with the aim of clearly delineating more accurate genotype-phenotype correlations for the 1p36 syndrome that could allow for a more precise prognosis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22766398"}
{"sentence": "Insulin-like growth factor I ( IGF-I ) and IGF-II stimulate cancer cell proliferation via interaction with the type I IGF receptor ( IGF-IR ) . We put forward the hypothesis that IGF-IR mediates cancer cell growth by regulating amino acid transport , both when sufficient nutrients are present and when key nutrients such as glutamine are in limited supply . We examined the effects of alphaIR3 , the monoclonal antibody recognizing IGF-IR , on cell growth and amino acid transport across the cell membrane in a human neuroblastoma cell line , SK-N-SH . In the presence of alphaIR3 ( 2 micro/ml ) , cell proliferation was significantly attenuated in both control ( 2 mM glutamine ) and glutamine-deprived ( 0 mM glutamine ) groups . Glutamine deprivation resulted in significantly increased glutamate ( system X(AG)(-) ) , MeAIB ( system A ) , and leucine ( system L ) transport , which was blocked by alphaIR3 . Glutamine ( system ASC ) and MeAIB transport was significantly decreased by alphaIR3 in the control group . Addition of alphaIR3 significantly decreased DNA and protein biosynthesis in both groups . Glutamine deprivation increased the IGF-IR protein on the cell surface . Our results suggest that activation of IGF-IR promotes neuroblastoma cell proliferation by regulating trans-membrane amino acid transport .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12031683"}
{"sentence": "We have constructed plasmids pS3G-1 and pSG4 that contain single acetylaminofluorene adducts within contiguous runs of three ( 5'-CCCG1G2G3-3' ) and four ( 5'-CG1GGG4T-3' ) guanine residues , respectively . In Escherichia coli , the frequency of induced -1 frameshift mutations was strongly dependent on the position of modification : pS3G-G3 was approximately 100-fold and 10-fold more mutagenic than pS3G-G1 and pS3G-G2 , respectively ; pSG4-G4 was approximately 600-fold more mutagenic than pSG4-G1 . Mutagenesis was SOS-dependent and was markedly reduced in bacteria that were proficient in nucleotide excision repair as compared to a repair-deficient uvrA6 mutant . DNA sequencing showed that -1 frameshift events in pS3G-1 consisted of either targeted mutations ( greater than 90% of induced mutations ) within the guanine sequence or semitargeted mutations ( greater than 10% ) in the 5 ' flanking repetitive cytosine sequence . Semitargeted events , which were observed when acetylaminofluorene modification was at G1 and G2 , show that a lesion can reduce the fidelity of replication at positions 5 ' to its location on the template strand . No semitargeted frameshifts were observed in plasmid pSG4 , which lacks a repetitive sequence 5 ' to the adduct . Our results are consistent with a model for frameshift mutagenesis in which the acetylaminofluorene adduct ( i ) allows accurate incorporation of cytosine opposite the bulky lesion during DNA synthesis and ( ii ) impedes elongation of primer/template termini formed opposite the adduct or 5 ' to the adduct on the template strand , providing increased opportunity for the formation of slipped frameshift intermediates .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1741385"}
{"sentence": "Deregulation of insulin-like growth factor-1 receptor ( IGF-1R ) is closely associated with malignant transformation and tumor cell survival in various cancers . We found that IGF-1R expression level in leukemia cells positively correlated with the percentage of blast in bone marrow from de novo acute myeloid leukemia ( AML ) patients . Moreover , we showed that NVP-ADW742 , a novel small weight molecular inhibitor of IGF-IR , could induce apoptosis in both HL-60 cell line and primary AML blasts . However , no significant alteration of cell cycle was observed in HL-60 cells . Further studies revealed that NVP-ADW742 induced Akt dephosphorylation , which might subsequently induce p38 phosphorylation and decrease antiapoptotic protein Bcl-2 expression in HL-60 cells . Finally , we demonstrated that NVP-ADW742 could synergize with Ara-C to induce the kill in a subset of drug-resistant AML specimens . We suggested that IGF-lR targeting might be therapeutically beneficial for some AML patients .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "21141739"}
{"sentence": "AMPK is a metabolic sensor that helps maintain cellular energy homeostasis . Despite evidence linking AMPK with tumor suppressor functions , the role of AMPK in tumorigenesis and tumor metabolism isunknown . Here we show that AMPK negatively regulates aerobic glycolysis ( the Warburg effect ) in cancer cells and suppresses tumor growth invivo . Genetic ablation of the \\u03b11 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis . Inactivation of AMPK\\u03b1 in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis , increased allocation of glucose carbon into lipids , and biomass accumulation . These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1\\u03b1 ( HIF-1\\u03b1 ) , as silencing HIF-1\\u03b1 reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPK\\u03b1 signaling . Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23274086"}
{"sentence": "Human CD93 , an epidermal growth factor ( EGF)-like domain containing transmembrane protein , is predominantly expressed in the vascular endothelium . Studies have shown that AA4 , the homolog of CD93 in mice , may mediate cell migration and angiogenesis in endothelial cells . Soluble CD93 has been detected in the plasma of healthy individuals . However , the role of soluble CD93 in the endothelium remains unclear . Recombinant soluble CD93 proteins with EGF-like domains ( rCD93D123 , with domains 1 , 2 , and 3 ; and rCD93D23 , with domains 2 and 3 ) were generated to determine their functions in angiogenesis . We found that rCD93D23 was more potent than rCD93D123 in stimulating the proliferation and migration of human umbilical vein endothelial cells ( HUVECs ) . Production of matrix-metalloproteinase 2 increased after the HUVECs were treated with rCD93D23 . Further , in a tube formation assay , rCD93D23 induced cell differentiation of HUVECs through phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase and extracellular signal-regulated kinases-1/2 signaling . Moreover , rCD93D23 promoted blood vessel formation in a Matrigel-plug assay and an oxygen-induced retinopathy model in vivo . Our findings suggest that the soluble EGF-like domain containing CD93 protein is a novel angiogenic factor acting on the endothelium .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23272129"}
{"sentence": "Polycylic aromatic hydrocarbons ( PAHs ) are ubiquitous contaminants in the marine environment . Their toxicity is mainly linked to the ability of marine species to biotransform them into reactive metabolites . PAHs are thus often detected at trace levels in animal tissues . For biomonitoring purposes , this findings have two main consequences , ( i ) the determination of the PAH tissue concentration is not suitable for the evaluation of individual exposure to PAHs ( ii ) it can explain sometimes the lack of correlations obtained with relevant markers of toxicity such as genotoxicity biomarkers . The aim of the present study was to better investigate the link between PAH exposure and genotoxicity in marine flatfish . During a laboratory experiment , juvenile soles were exposed for four weeks to a mixture of three PAHs , namely benzo[a]pyrene , fluoranthene and pyrene , followed by one week of depuration . Fish were exposed via the trophic route to a daily PAH concentration of 120 \u03bcg/g food . Fish were sampled at different time points . The bioavailability and the biotransformation of PAHs were assessed by the measurement of biliary metabolites using a sensitive UPLC MS/MS method . The 7-ethoxyresorufine-O-deethylase was also measured in liver subcellular fractions as a biomarker of phase I biotransformation activities . Genotoxicity was assessed in parallel by the measurement of DNA strand breaks in fish erythrocytes by the alkaline comet assay . During this study , the high amount of PAH metabolites produced in sole demonstrated the bioavailability of PAHs and their biotransformation by fish enzymes . A positive correlation was observed between the level of hydroxylated PAH metabolites and genotoxicity as measured by the alkaline comet assay .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20417553"}
{"sentence": "We wanted to investigate the effects of gamma radiation on DNA single-strand breaks ( SSB ) and glutathione ( GSH ) levels in mononuclear blood cells ( MNC ) of radiotherapy technicians . DNA SSB in MNC of radiotherapy technicians who use ( 60)Co-gamma source in their works were detected by alkaline filter elution and compared to control subjects . In addition , GSH levels were measured using the enzymatic method in MNC . Blood samples were collected from radiotherapy technicians on Monday and Friday . DNA SSB levels were found to be significantly higher in smoking controls compared to non-smoking controls . Significant increases of 36% and 49% in DNA SSB were detected from Monday to Friday for non-smoking and smoking radiotherapy technicians , respectively . GSH levels were found to be decreased significantly from Monday to Friday . Gamma-radiation resulted in increased DNA SSB levels of MNC in radiotherapy technicians throughout the working week and these breaks have been observed to be repaired at the weekend . Smoking habit caused an additional increase in the SSBs observed in radiotherapy technicians .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "14578017"}
{"sentence": "Dentin matrix protein 1 ( DMP1 ) is a member of the small integrin-binding ligand N-linked glycoprotein ( SIBLING ) family , a group of proteins initially described as mineralized extracellular matrices components . More recently , SIBLINGs have been implicated in several key steps of cancer progression , including angiogenesis . Although proangiogenic activities have been demonstrated for 2 SIBLINGs , the role of DMP1 in angiogenesis has not yet been addressed . We demonstrate that this extracellular matrix protein induced the expression of vascular endothelial cadherin ( VE-cadherin ) , a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate vascular endothelial growth factor receptor 2 ( VEGFR-2 ) activity , the major high-affinity receptor for VEGF . DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell-cycle arrest in human umbilical vein endothelial cells ( HUVECs ) in a CD44-dependent manner . VEGF-induced proliferation , migration , and tubulogenesis responses were specifically blocked on DMP1 pretreatment of HUVECs . Indeed , after VE-cadherin induction , DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling . However , DMP1 did not interfere with basic fibroblast growth factor-induced angiogenesis . In vivo , DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis . These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis .", "label": [0, 0, 0, 0, 1, 0, 1, 0, 0, 0], "id": "21190990"}
{"sentence": "Cyclin-dependent kinases are most extensively studied targets for cancer chemotherapy since the tumor cells exhibit false checkpoints and can proliferate even if the genome is compromised . Cyclin-dependent kinases ensure the tight regulation of the cell cycle execution by mediating phosphorylation of cellular proteins . Deregulation of the cyclin-dependent kinase 2 activity by cellular and external factors leads to many diseases like cancers . Different methods like radiolabeled , fluorescence and luminescence are available for screening of library of compounds against kinases . However , bioluminescent methods offer several advantages like low background and no effect of fluorescent compound interference . Present study is focused on development , optimization and validation of cyclin-dependent kinase 2 assay which is suitable for identification potent and selective , ATP competitive and non-competitive inhibitors of cyclin-dependent kinase 2 . The aim of present investigation was to optimize the assay for cyclin-dependent kinase 2/cylin A and cyclin-dependent kinase 2/cyclin E with use of bioluminescence based biochemical reaction . Both cyclin-dependent kinase 2 which are cyclin-dependent kinase 2/cyclin A and cyclin-dependent kinase 2/cyclin E complexes , have different affinity for ATP . Therefore , both isoform analogs of cyclin-dependent kinase 2 were optimized separately . Optimum cyclin-dependent kinase 2/cyclin A and cyclin-dependent kinase 2/cyclin E concentration were found to be 250 ng/well and 200 ng/well , respectively . Optimum substrate ( histone H1 ) concentration was found to be 2.5 mg/ml for both cyclin-dependent kinase 2 analogs . Optimum reaction time was found to be 20 min for both cyclin-dependent kinase 2/cyclin complexes .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "21188035"}
{"sentence": "It is prevailingly thought that the antiestrogens tamoxifen and ICI 182 , 780 are competitive antagonists of the estrogen-binding site of the estrogen receptor-alpha ( ER-\u03b1 ) . However , a plethora of evidence demonstrated both antiestrogens exhibit agonist activities in different systems such as activation of the membrane-initiated signaling pathways . The mechanisms by which antiestrogens mediate estrogen-like activities have not been fully established . Previously , a variant of ER-\u03b1 , EP-\u03b136 , has been cloned and showed to mediate membrane-initiated estrogen and antiestrogen signaling in cells only expressing ER-\u03b136 . Here , we investigated the molecular mechanisms underlying the antiestrogen signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of endogenous ER-\u03b136 . We found that the effects of both 4-hydoxytamoxifen ( 4-OHT ) and ICI 182 , 780 ( ICI ) exhibited a non-monotonic , or biphasic dose response curve ; antiestrogens at low concentrations , elicited a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations , antiestrogens inhibited cell growth . Antiestrogens at l nM induced the phosphorylation of the Src-Y416 residue , an event to activate Src , while at 5 \ufffdM induced Src-Y527 phosphorylation that inactivates Src . Antiestrogens at 1 nM also induced phosphorylation of the MAPK/ERK and activated the Cyclin D1 promoter activity through the Src/EGFR/STAT5 pathways but not at 5 \ufffdM . Knock-down of ER-\u03b136 abrogated the biphasic antiestrogen signaling in these cells . Our results thus indicated that ER-\u03b136 mediates biphasic antiestrogen signaling in the ER-negative breast cancer cells and Src functions as a switch of antiestrogen signaling dependent on concentrations of antiestrogens through the EGFR/STAT5 pathway .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22276155"}
{"sentence": "Ulcerative colitis ( UC ) is a major form of chronic inflammation that can frequently progress to colon cancer . Several studies have demonstrated massive infiltration of neutrophils and macrophages into the lamina propria and submucosa in the progression of UC-associated colon carcinogenesis . Macrophages contribute to the development of colitis-associated colon cancer ( CAC ) . However , the role of neutrophils is not well understood . To better understand the involvement of tumor-associated neutrophils ( TANs ) in the regulation of CAC , we used a mouse CAC model produced by administering azoxymethane ( AOM ) , followed by repeated dextran sulfate sodium ( DSS ) ingestion . This causes severe colonic inflammation and subsequent development of multiple tumors in mice colon . We observed that colorectal mucosal inflammation became increasingly severe with AOM and DSS treatment . Macrophages infiltrated the lamina propria and submucosa , together with a marked increase in neutrophil infiltration . The chemokine CXCL2 increased in the lamina propria and submucosal regions of the colons of the treated mice , together with the infiltration of neutrophils expressing CXCR2 , a specific receptor for CXCL2 . This process was followed by neoplastic transformation . After AOM and DSS treatment , the mice showed enhanced production of metalloproteinase ( MMP)-9 and neutrophil elastase ( NE ) , accompanied by excessive vessel generation and cell proliferation . Moreover , CXCL2 promoted neutrophil recruitment and induced neutrophils to express MMP-9 and NE in vitro . Furthermore , administration of neutrophil-neutralizing antibodies after the last DSS cycle markedly reduced the number and size of tumors and decreased the expression of CXCR2 , CXCL2 , MMP-9 , and NE . These observations indicate a crucial role for TANs in the initiation and progression of CAC and suggest that the CXCL2-CXCR2 axis might be useful in reducing the risk of UC-associated colon cancer .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23272179"}
{"sentence": "Cancer cells constantly adapt to oxidative phosphorylation ( OXPHOS ) suppression resulting from hypoxia or mitochondria defects . Under the OXPHOS suppression , AMP-activated protein kinase ( AMPK ) regulates global metabolism adjustments , but its activation has been found to be transient . Whether cells can maintain cellular ATP homeostasis and survive beyond the transient AMPK activation is not known . Here , we study the bioenergetic adaptation to the OXPHOS inhibitor oligomycin in a group of cancer cells . We found that oligomycin at 100 ng/ml completely inhibits OXPHOS activity in 1 h and induces various levels of glycolysis gains by 6 h , from which we calculate the bioenergetic organizations of cancer cells . In glycolysis-dominant cells , oligomycin does not induce much energy stress as measured by glycolysis acceleration , ATP imbalance , AMPK activation , AMPK substrate acetyl-CoA carboxylase phosphorylation at Ser(79) , and cell growth inhibition . In OXPHOS-dependent LKB1 wild type cells , oligomycin induces 5-8% ATP drops and transient AMPK activation during the initial 1-2 h . After AMPK activation is completed , oligomycin-induced increase of acetyl-CoA carboxylase phosphorylation at Ser(79) is still detected , and cellular ATP is back at preoligomycin treatment levels by sustained elevation of glycolysis . Cell growth , however , is inhibited without an increase in cell death and alteration in cell cycle distribution . In OXPHOS-dependent LKB1-null cells , no AMPK activation by oligomycin is detected , yet cells still show a similar adaptation . We also demonstrate that the adaptation to oligomycin does not invoke activation of hypoxia-induced factor . Our data suggest that cancer cells may grow and survive persistent OXPHOS suppression through an as yet unidentified regulatory mechanism .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20110356"}
{"sentence": "Certain hexavalent chromium ( Cr(VI) ) compounds are well established occupational respiratory tract carcinogens . However , despite extensive studies , the cellular and molecular mechanisms underlying Cr(VI)-induced lung cancer remain poorly understood . In fact , the models used were often suboptimal and yielded conflicting results that were heavily dependent upon the system and experimental conditions employed . Here , we investigated the effects of chronic subcytotoxic and mildly cytotoxic ( 0.1-2 microM ) Cr(VI) exposures on cultures of human bronchial epithelial cells , the main targets of Cr(VI) carcinogenicity . Our studies with the nontumorigenic BEAS-2B cell line suggest that relatively short exposures ( h ) to sublethal Cr(VI) doses ( 0.1-1 microM ) may render these cells less sensitive to contact inhibition . We have also observed a reduced sensitivity to Cr(VI)-induced apoptosis shortly after the beginning of exposure to a mildly cytotoxic Cr(VI) dose ( 2 microM ) . Further studies are needed to determine whether these two phenotypes are involved in the Cr(VI)-induced carcinogenic process . Additionally , evidence gathered in this study strongly points to a Cr(VI) interference with cell adhesion to the substratum and with cell-cell interactions . Finally , by chronically exposing BEAS-2B cells to mildly cytotoxic Cr(VI) doses ( 1 and 2 microM ) , we were able to induce changes in cell morphology and pattern of growth characteristic of an early phase of pre-malignant progression .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "20336777"}
{"sentence": "A large number of human cancers display alterations in the Ink4a/cyclin D/Cdk4 genetic pathway , suggesting that activation of Cdk4 plays an important role in oncogenesis . Here we report that Cdk4-null mouse embryonic fibroblasts are resistant to transformation in response to Ras activation with dominant-negative ( DN ) p53 expression or in the Ink4a/Arf-null background , judged by foci formation , anchorage-independent growth , and tumorigenesis in athymic mice . Cdk4-null fibroblasts proliferate at normal rates during early passages . Whereas Cdk4(+/+)Ink4a/Arf(-/-) cells are immortal in culture , Cdk4(-/-)Ink4a/Arf(-/-) cells undergo senescence during continuous culture , as do wild-type cells . Activated Ras also induces premature senescence in Cdk4(-/-)Ink4a/Arf(-/-) cells and Cdk4(-/-) cells with DNp53 expression . Thus , Cdk4 deficiency causes senescence in a unique Arf/p53-independent manner , which accounts for the loss of transformation potential . Cdk4-null cells express high levels of p21(Cip1/Waf1) with increased protein stability . Suppression of p21(Cip1/Waf1) by small interfering RNA ( siRNA ) , as well as expression of HPV-E7 oncoprotein , restores immortalization and Ras-mediated transformation in Cdk4(-/-)Ink4a/Arf(-/-) cells and Cdk4(-/-) cells with DNp53 expression . Therefore , Cdk4 is essential for immortalization , and suppression of Cdk4 could be a prospective strategy to recruit cells with inactive Arf/p53 pathway to senescence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12435633"}
{"sentence": "Archaeal and eukaryotic B-family DNA polymerases ( pols ) mainly replicate chromosomal DNA but stall at lesions , which are often bypassed with Y-family pols . In this study , a B-family pol Vent ( exo(-) ) from the euryarchaeon Thermococcus litoralis was studied with three types of DNA lesions-N(2)-alkylG , O(6)-alkylG , and an abasic ( AP ) site-in comparison with a model Y-family pol Dpo4 from Sulfolobus solfataricus , to better understand the effects of various DNA modifications on binding , bypass efficiency , and fidelity of pols . Vent ( exo(-) ) readily bypassed N(2)-methyl(Me)G and O(6)-MeG , but was strongly blocked at O(6)-benzyl(Bz)G and N(2)-BzG , whereas Dpo4 efficiently bypassed N(2)-MeG and N(2)-BzG and partially bypassed O(6)-MeG and O(6)-BzG . Vent ( exo(-) ) bypassed an AP site to an extent greater than Dpo4 , corresponding with steady-state kinetic data . Vent ( exo(-) ) showed 180- , and 300-fold decreases in catalytic efficiency ( k(cat)/K(m) ) for nucleotide insertion opposite an AP site , N(2)-MeG , and O(6)-MeG but and 5000-fold decreases opposite O(6)-BzG and N(2)-BzG , respectively , as compared to G , whereas Dpo4 showed little or only decreases opposite N(2)-MeG and N(2)-BzG but decreases opposite O(6)-MeG , O(6)-BzG , and the AP site . Vent ( exo(-) ) preferentially misinserted G opposite N(2)-MeG , T opposite O(6)-MeG , and A opposite an AP site and N(2)-BzG , while Dpo4 favored correct C insertion opposite those lesions . Vent ( exo(-) ) and Dpo4 both bound modified DNAs with affinities similar to unmodified DNA . Our results indicate that Vent ( exo(-) ) is as or more efficient as Dpo4 in synthesis opposite O(6)-MeG and AP lesions , whereas Dpo4 is much or more efficient opposite ( only ) N(2)-alkylGs than Vent ( exo(-) ) , irrespective of DNA-binding affinity . Our data also suggest that Vent ( exo(-) ) accepts nonbulky DNA lesions ( e.g. , N(2)- or O(6)-MeG and an AP site ) as manageable substrates despite causing error-prone synthesis , whereas Dpo4 strongly favors minor-groove N(2)-alkylG lesions over major-groove or noninstructive lesions .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22793782"}
{"sentence": "OBJECTIVE Chronic generation of inflammatory cytokines and reactive oxygen species are implicated in atherosclerosis , aging , cancers , and other chronic diseases . We hypothesized that zinc induces A20 in premonocytic , endothelial , and cancer cells , and A20 binds to tumor necrosis factor ( TNF)-receptor associated factor , and inhibits I\u03ba kinase-\u03b1 ( IKK-\u03b1)/nuclear factor-\u03baB ( NF-\u03baB ) , resulting in downregulation of TNF-\u03b1 and interleukin-1\u03b2 ( IL-1\u03b2 ) . METHODS To test this hypothesis , we used HL-60 , human umbilical vein endothelial cells , and SW480 cell lines under zinc-deficient and zinc-sufficient conditions in this study . We measured oxidative stress markers , inflammatory cytokines , A20 protein and mRNA , A20-FRAF-1 complex , and IKK-\u03b1/NF-\u03baB signaling in stimulated zinc-deficient and zinc sufficient cells . We also conducted antisense A20 and siRNA studies to investigate the regulatory role of zinc in TNF-\u03b1 and IL-1\u03b2 via A20 . RESULTS We found that zinc increased A20 and A20-tumor necrosis factor-receptor associated factor-1 complex , decreased the IKK-\u03b1/NF-\u03baB signaling pathway , oxidative stress markers , and inflammatory cytokines in these cells compared with zinc-deficient cells . We confirmed that zinc-induced A20 contributes to downregulation of TNF-\u03b1 and IL-1\u03b2 by antisense and short interfering RNA A20 studies . CONCLUSION Our studies suggest that zinc suppresses generation of NF-\u03baB-regulated inflammatory cytokines by induction of A20 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21035309"}
{"sentence": "Monoclonal antibodies ( mAbs ) to HER2 are currently used to treat breast cancer , but low clinical efficacy , along with primary and acquired resistance to therapy , commonly limit clinical applications . We previously reported that combinations of antibodies directed at non-overlapping epitopes of HER2 are endowed with enhanced antitumor effects , probably due to accelerated receptor degradation . Here , we extend these observations to three-dimensional mammary cell models , and compare the effects of single mAbs with the effects of antibody combinations . Collectively , our in vitro assays and computational image analyses indicate that combining mAbs against different epitopes of HER2 better inhibits invasive growth . Importantly , while growth factors are able to reduce intraluminal apoptosis and induce an invasive phenotype , combinations of mAbs better than single mAbs can reverse the growth factor-induced phenotypes of HER2-overexpressing spheroids . In conclusion , our studies propose that mAb combinations negate the biological effects of growth factors on invasive growth of HER2-overexpressing cells . Hence , combining mAbs offers a therapeutic strategy , potentially able to enhance clinical efficacy of existing antireceptor immunotherapeutics .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21132012"}
{"sentence": "In order to determine the in vivo immune response in glioblastoma , monoclonal and polyclonal antibodies specific for inflammatory leukocytes and immunoregulatory products were utilized to stain tissue from four surgical specimens . The more activated the inflammatory cells , the more activated the tumors appeared to be . In the tumor with the largest infiltration ( Case 3 ) , inflammatory cells were stained for interferon-gamma , interleukin-2 , interleukin-1 beta , lymphotoxin , tumor necrosis factor-alpha , and transforming growth factor-beta . The tumor cells also expressed interleukin-1 beta , interleukin-6 , transforming growth factor-beta , tumor necrosis factor-alpha , and prostaglandin E. In contrast , in the tumor with the least inflammatory response ( Case 1 ) , the tumor cells did not express any cytokines . Expression of cytokines by glioma cells was modest in the two cases with modest inflammatory responses . Cellular inflammation , primarily consisting of T cells and macrophages with few or no B cells or natural killer cells , was two- to 15-fold greater outside the tumor than within . In contrast to leukocytes outside the tumor , which were activated and expressing class II major histocompatibility antigens , leukocytes within the tumor parenchyma or at the tumor's edge were negative for these antigens . In the four specimens studied here , the tumor cells themselves were also negative for class II major histocompatibility antigens . These findings , although preliminary , suggest that inflammatory cells within gliomas are inactivated and that glioma cells may increase the expression of immunosuppressive cytokines in response to an increased lymphocyte infiltrate . This observation , if corroborated by more extensive studies , may help to explain the failure of immune treatments in glioblastoma multiforme .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1318961"}
{"sentence": "1,25-Dihydroxyvitamin D(3) ( 1,25D ) , the hormonal form of vitamin D , and several analogs have failed as monotherapies for cancer because of poor efficacy or acquired resistance . However , 1,25D analogs are amenable to bifunctionalization . Preclinical studies have revealed combinatorial effects of 1,25D analogs and histone deacetylase inhibitors ( HDACi ) . Secosteroidal hybrid molecules combining vitamin D receptor ( VDR ) agonism with HDACi displayed enhanced efficacy but are laborious to synthesize . Here , we have developed easily assembled , fully integrated , non-secosteroidal VDR agonist/HDACi hybrids . The most promising are full VDR agonists with lower potency than 1,25D . Structure/function studies revealed that antiproliferative activity against 1,25D-resistant squamous carcinoma cells required VDR agonism and HDACi . Remarkably , modeling and X-ray crystallography reveal non-secosteroidal hybrids bind in the VDR ligand binding domain in the opposite orientation of their secosteroidal counterparts .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22921063"}
{"sentence": "Activated lymphocytes and malignant lymphoma cells derived from them ( Ki-1 positive lymphoma cells ) share similar mechanisms of proliferation . To further examine the inhibitory role of endogenous transforming growth factor beta ( TGF beta ) in Ki-1 positive lymphoma cells , the authors studied anti-TGF beta antibodies and measured their effect on proliferation . A monoclonal antibody ( T1A5 ) prepared against a unique antigenic epitope of high molecular weight Hodgkin's TGF beta and a polyclonal rabbit antibody prepared against highly purified 25,000 D porcine platelet TGF beta 1 were used . Both antibodies are shown here to inhibit the biological activity of Hodgkin's TGF beta and to crossreact with their respective antigens in immunoblotting . DNA synthesis by Ki-1 lymphoma cells was increased 138-fold by anti-TGF beta 1 antibody and 262-fold by anti-Hodgkin's TGF beta . Exogenous TGF beta 1 suppression was completely reversed by anti-TGF beta 1 antibody and IL-2-induced proliferation was markedly potentiated ( 41 fold ) . L-428 Reed-Sternberg cells secrete physiologically active TGF beta but have fewer than 500 TGF beta receptor sites per cell ; no significant proliferative response was measured for either anti-TGF beta 1 or anti-Hodgkin's TGF beta . These results show the suppressive effect of exogenous TGF beta 1 on indolent Ki-1 lymphoma cells and suggest that the endogenous secretion of high molecular weight physiologically active TGF beta is important in maintaining the indolent nature of this low-grade Ki-1 positive lymphoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1312308"}
{"sentence": "In response to DNA double strand breaks , the histone variant H2AX at the break site is phosphorylated at serine 139 by DNA damage sensor kinases such as ataxia telangiectasia-mutated , forming gamma-H2AX . This phosphorylation event is critical for sustained recruitment of other proteins to repair the break . After repair , restoration of the cell to a prestress state is associated with gamma-H2AX dephosphorylation and dissolution of gamma-H2AX-associated damage foci . The phosphatases PP2A and PP4 have previously been shown to dephosphorylate gamma-H2AX . Here , we demonstrate that the wild-type p53-induced phosphatase 1 ( WIP1 ) also dephosphorylates gamma-H2AX at serine 139 in vitro and in vivo . Overexpression of WIP1 reduces formation of gamma-H2AX foci in response to ionizing and ultraviolet radiation and blocks recruitment of MDC1 ( mediator of DNA damage checkpoint 1 ) and 53BP1 ( p53 binding protein 1 ) to DNA damage foci . Finally , these inhibitory effects of WIP1 on gamma-H2AX are accompanied by WIP1 suppression of DNA double strand break repair . Thus , WIP1 has a homeostatic role in reversing the effects of ataxia telangiectasia-mutated phosphorylation of H2AX .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20118229"}
{"sentence": "Thellungiella salsuginea , a close relative of Arabidopsis , represents an extremophile model for abiotic stress tolerance studies . We present the draft sequence of the T. salsuginea genome , assembled based on coverage to seven chromosomes with a coding capacity of at least 28,457 genes . This genome provides resources and evidence about the nature of defense mechanisms constituting the genetic basis underlying plant abiotic stress tolerance . Comparative genomics and experimental analyses identified genes related to cation transport , abscisic acid signaling , and wax production prominent in T. salsuginea as possible contributors to its success in stressful environments .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22778405"}
{"sentence": "In the present study , the question was addressed whether anthocyanins interfere with the topoisomerase I poison irinotecan in vivo . In vivo complexes of enzyme to DNA bioassay was used to detect irinotecan-induced stabilization of topoisomerase I/DNA complexes and single cell gel electrophoresis to determine DNA-strand-break induction in the colon of male Wistar rats . Furthermore , analysis of anthocyanin concentrations in rat plasma and rat colon was included in the testing , demonstrating that anthocyanins reach the colon and the concentrations do not differ between rats that only received anthocyanins and the anthocyanin/irinotecan group . Blackberry extract was found to significantly reduce irinotecan-mediated topoisomerase I/DNA cleavable complex formation . Overall , anthocyanins did not notably increase cleavable complex formation . However , a significant increase of DNA damage was shown after a single dose of irinotecan as well as the single compounds cyanidin ( cy ) and cyanidin-3-glucoside ( cy-3-g ) . Furthermore , a significant reduction of irinotecan-induced DNA-strand breaks after a pretreatment with cy , cy-3-g and blackberry extract was observed . Thus , the question arises whether anthocyanin-rich preparations might interfere with chemotherapy or whether , due to low systemic bioavailability , the preparations might provide protective potential in the gastrointestinal tract .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23275152"}
{"sentence": "MicroRNAs ( miRNAs ) are 19 nt non-coding RNA molecules that regulate expression of target genes at the post-transcriptional level . Evidence indicates that miRNAs play an essential role in physiological and pathological conditions including pulmonary development , inflammation , fibrosis and cancer . The aim of the present study is to investigate the altered miRNAs expression profile in rats with experimental silicosis . We duplicated silicosis rat model , and identify the miRNA expression pattern of silicosis rat with miRNA microarray . Compared with normal lung tissue , fourteen miRNAs were found significantly up-regulated while the other twenty-five down-regulated in silicosis samples . The differential expression of two selected miRNAs was confirmed by stem-loop real-time reverse transcription-polymerase chain reaction . Our results indicate that the 39 altered miRNAs may be involved in lung fibrosis of rats that were exposed to silica dust . Furthermore , the microarray results provide a solid basis for further validation , such as identification of other miRNAs that may be related to inflammation and fibrosis . The findings are paving way for silicosis early prevention , prognosis and possible therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23208435"}
{"sentence": "Metastasis , commonly to the lung , is the major cause of mortality from testicular cancer . The aim of the present study was to examine the effect of a novel nutrient mixture ( NM ) containing ascorbic acid , amino acids and green tea extract on the inhibition of melanoma growth and metastasis using a model of intratesticular inoculation of B16FO cells into nude mice . Male athymic mice ( n=12 ) , 10-12 weeks of age , were inoculated with 5\ufffd10(5) B16FO melanoma cells in 100 \u03bcl of PBS into the right testis , while the left testis was left untreated . Following inoculation , the mice were randomly divided into two groups . The control group ( n=6 ) was fed a regular mouse chow diet and the NM 1% group ( n=6 ) the same diet , but supplemented with 1% NM . Four weeks later the mice were sacrificed and the abdominal cavity was opened . Mice in the control group exhibited extensive metastasis in the peritoneal cavity and severely enlarged right testes and necrotic seminiferous tubules . By contrast , in the NM 1% fed group there was no evidence of peritoneal metastasis in 50% of the animals and mild metastasis in the remaining 50% . The right testes were enlarged and seminiferous tubules in the area of invasion showed evidence of degeneration . No metastasis to the liver , kidney or spleen were evident in either group . However , severe lung metastasis was observed in 2 of 6 mice in the control group and mild metastasis in 2 of 6 mice in the NM 1% group . In conclusion , these results confirm earlier studies and verify the anti-metastatic potential of NM .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23226724"}
{"sentence": "OBJECTIVES : Cigarette smoking is a major risk factor for pancreatic cancer ( PaCa ) . However , the mechanisms of smoking-induced PaCa remain unknown . Here we investigated the effect of smoking compounds on cell death pathways in pancreatic ductal cells , precursors of PaCa . METHODS : Human pancreatic ductal cells ( HPDE6-c7 ) were cultured with cigarette smoke extract ( CSE ) or smoking compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ( NNK ) . Apoptosis and autophagy were assessed by DNA fragmentation and immunofluorescence , respectively . RESULTS : Exposure to CSE or NNK decreased DNA fragmentation and up-regulated BclXL . Akt kinase was activated by smoking compounds through reactive oxygen species-dependent mechanism . Specifically , Akt activation was prevented by inhibition of nicotinamide adenine dinucleotide oxidase . Molecular or pharmacologic inhibitions of Akt prevented the antiapoptotic effect of smoking compounds . Smoking compounds stimulated rapid ( 1 hour ) and transient activation of 5'-adenosine monophosphate-activated protein kinase and formation of autophagic vacuoles , indicating stimulation of autophagy . Repeated exposure to CSE/NNK ( 48 hours or longer ) abolished the early activation of autophagic markers . Inhibition of Akt prevented the antiautophagic effect of long exposure to smoking compounds , indicating that smoking-induced late activation of Akt prevents autophagy . CONCLUSIONS : Long exposure of pancreatic ductal cells to smoking compounds inhibited apoptosis and autophagy . The results revealed a central role for Akt kinase in mediating key procarcinogenic effects of smoking compounds .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23271397"}
{"sentence": "BACKGROUND : To quantify tumour angiogenesis , microvessel density ( MVD ) has been widely used . We here present a novel angiogenesis marker , microvessel proliferation ( MVP ) , based on dual immunohistochemical staining of nestin and Ki-67 . Immature endothelial cells express nestin , and when co-expressed with the proliferation marker Ki-67 , the number of proliferating immature blood vessels can be measured . MATERIALS AND METHODS : Microvessel proliferation was evaluated in 178 breast cancer samples and estimated by vascular proliferation index ( VPI ) , the ratio between the number of vessels containing proliferating endothelial cells and the total number of immature vessels . RESULTS : High VPI was strongly associated with several markers of aggressive breast cancer , such as negative oestrogen receptor ( ER ) status ( p=0.003 ) , high tumour cell proliferation by Ki-67 ( p=0.004 ) , high p53 expression ( p=0.001 ) , and five profiles for the basal-like phenotype ( odds ratios ( OR ) ; range 3.4-6.3 ) . Also , high VPI was significantly associated with interval detected breast cancer compared with screening detected lesions ( p<0.0005 ) , and adverse outcome in univariate and multivariate survival analysis ( p=0.034 and p=0.022 , respectively ) . CONCLUSION : Microvessel proliferation is a novel marker of ongoing angiogenesis and was associated with aggressive tumour features , basal-like phenotypes , interval presentation , and prognosis in this series of breast cancer .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "22840462"}
{"sentence": "Key cellular decisions , such as proliferation or growth arrest , typically occur at spatially defined locations within tissues . Loss of this spatial control is a hallmark of many diseases , including cancer . Yet , how these patterns are established is incompletely understood . Here , we report that physical and architectural features of a multicellular sheet inform cells about their proliferative capacity through mechanical regulation of YAP and TAZ , known mediators of Hippo signaling and organ growth . YAP/TAZ activity is confined to cells exposed to mechanical stresses , such as stretching , location at edges/curvatures contouring an epithelial sheet , or stiffness of the surrounding extracellular matrix . Weidentify the F-actin-capping/severing proteins Cofilin , CapZ , and Gelsolin as essential gatekeepers that limit YAP/TAZ activity in cells experiencing low mechanical stresses , including contact inhibition of proliferation . We propose that mechanical forces are overarching regulators of YAP/TAZ in multicellular contexts , setting responsiveness to Hippo , WNT , and GPCR signaling .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23954413"}
{"sentence": "This study aims to identify significant predictors of survival in pediatric and adolescent colorectal carcinoma . We retrospectively analyzed our experience with 29 histologically verified cases , of which 20 were resected for cure . Variables analyzed as predictors of survival included : ( 1 ) resectability , ( 2 ) regional nodal involvement , ( 3 ) depth of invasion , ( 4 ) grade , and ( 5 ) interval from symptom onset to diagnosis . Signet ring or anaplastic lesions were considered high grade . Survival curves were generated on both the overall group and those resected for cure . Multivariate analysis was performed on the overall group . The median age at diagnosis was 19 years ( range , 10 to 21 ) . Median follow-up in survivors was 4.7 years . Signet ring tumors occurred in 45% and another 24% were poorly differentiated . Seventy-six percent presented with regional lymph node metastases . The median survival for the overall group was 16 months , whereas that for those undergoing complete resection was 33 months . In patients undergoing resection for cure , grade ( P = .005 ) , regional nodal involvement ( P = .007 ) , and depth of invasion ( P = .03 ) were significant predictors of outcome in univariate analysis . In the overall group these variables as well as resectability and distant metastases were significant in univariate analysis . In multivariate analysis high-grade lesions and lymph node involvement were highly correlated , as were resectability and metastases . Thus , either variable ( but not both ) of each pair added information to the multivariate model . In patients resected for cure , positive nodes or high histological grade became the only significant predictors of survival.(ABSTRACT TRUNCATED AT 250 WORDS )", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1403541"}
{"sentence": "The generation and detection of mechanical forces is a ubiquitous aspect of cell physiology , with direct relevance to cancer metastasis(1) , atherogenesis(2) and wound healing(3) . In each of these examples , cells both exert force on their surroundings and simultaneously enzymatically remodel the extracellular matrix ( ECM ) . The effect of forces on ECM has thus become an area of considerable interest due to its likely biological and medical importance(4-7) . Single molecule techniques such as optical trapping(8) , atomic force microscopy(9) , and magnetic tweezers(10,11) allow researchers to probe the function of enzymes at a molecular level by exerting forces on individual proteins . Of these techniques , magnetic tweezers ( MT ) are notable for their low cost and high throughput . MT exert forces in the range of pN and can provide millisecond temporal resolution , qualities that are well matched to the study of enzyme mechanism at the single-molecule level(12) . Here we report a highly parallelizable MT assay to study the effect of force on the proteolysis of single protein molecules . We present the specific example of the proteolysis of a trimeric collagen peptide by matrix metalloproteinase 1 ( MMP-1 ) ; however , this assay can be easily adapted to study other substrates and proteases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22871786"}
{"sentence": "OBJECTIVES Despite the well-defined histological types of non-small cell lung cancer ( NSCLC ) , a given stage is often associated with wide-ranging survival rates and treatment outcomes . This disparity has led to an increased demand for the discovery and identification of new informative biomarkers . METHODS In the current study , we screened 81 NSCLC samples using Illumina whole-genome gene expression microarrays in an effort to identify differentially expressed genes and new NSCLC biomarkers . RESULTS We identified novel genes whose expression was upregulated in NSCLC , including SPAG5 , POLH , KIF23 , and RAD54L , which are associated with mitotic spindle formation , DNA repair , chromosome segregation , and dsDNA break repair , respectively . We also identified several novel genes whose expression was downregulated in NSCLC , including SGCG , NLRC4 , MMRN1 , and SFTPD , which are involved in extracellular matrix formation , apoptosis , blood vessel leakage , and inflammation , respectively . We found a significant correlation between RNA degradation and survival in adenocarcinoma cases . CONCLUSIONS Even though the follow-up time was too limited to draw final conclusions , we were able to show better prediction p values in a group selection based on molecular profiles compared to histology . The current study also uncovered new candidate biomarker genes that are likely to be involved in diverse processes associated with NSCLC development .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21412013"}
{"sentence": "Prostate cancer is responsible for major deaths globally after lung cancer . However , etiology of prostate cancer is still unknown . Individual risk and incidence of prostate cancer may result from the interaction of genetic susceptibility with exposure to environmental factors such as infectious agents , tobacco , occupational exposure , dietary carcinogens , and/or hormonal imbalances leading to injury of the prostate and to the development of chronic inflammation . About 30% of all human cancers are caused by tobacco smoking and inhaled pollutants . Inflammation is now regarded as an important hallmark of cancer . The present study has been aimed to explore the pro-inflammatory levels in prostate carcinoma patients by examining the serum levels of novel cytokine interleukin-18 ( IL-18 ) expression in tobacco exposed population . A total of 578 ( n = 284 biopsy proven prostate cancer patients , n = 294 controls with and without tobacco exposed population ) were recruited . Serum IL-18 ( Interleukin-18 ) level was done by ELISA . The IL-18 levels between cancer patients and controls within same mode tobacco exposure as tobacco smoking ( overall ) showed significant difference ( P < 0.0001 ) and further we compared within stratified group , it significantly differ ( P < 0.0001 ) in bidi and cigarette smoking than control non users . Furthermore , IL-18 levels in tobacco chewers ( overall ) with gutkha and khaini chewers showed significant difference ( P < 0.01 ) than controls non users . Moreover , the IL-18 levels between cancer patients and controls with in of combined mode chewers smokers and alcohol ( CSA ) , smokers with alcohol showed significant difference ( P < 0.01 ) than controls . The IL-18 levels also differed significantly ( P < 0.05 ) with smokers and chewers in higher stages of III and IV , and showed non significant with in lower stages . Tobacco exposure enhance the inflammation in prostate carcinoma patients in stratified group as it have been represented as a risk factors in various cancers , but this study provide further its role that seems to influence inflammation especially in prostate carcinoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23293472"}
{"sentence": "Colorectal cancer represents one of the most challenging diseases . Increasing evidence indicates that aberrant expression of microRNAs ( miRNAs ) is related to pathogenesis of colorectal cancer . Cancer cells reprogram metabolic pathways to sustain higher proliferation rates . Whether mechanisms underlying the role of miRNA in colorectal cancer are involved in metabolic reprogramming and the mechanisms through which miRNAs alter cancer metabolism are as yet unknown . Herein , we show that miR-124 , miR-137 and miR-340 are associated with poor prognosis of colorectal cancer . Expression of these miRNAs inhibits the growth of colorectal cancer cells . PKM ( pyruvate kinase isozyme ) alternative splicing proteins ( PTB1/hnRNAPA1/hnRNAPA2 ) , which control the inclusion of exon 9 ( PKM1 ) or exon 10 ( PKM2 ) , are targeted by miR-124 , miR-137 and miR-340 . Consequently , miR-124 , miR-137 and miR-340 switch PKM gene expression from PKM2 to PKM1 . High ratios of PKM1/PKM2 inhibit the glycolysis rate , but elevate the glucose flux into oxidative phosphorylation . These results demonstrate that miRNAs ( miR-124 , miR-137 and miR-340 ) impair colorectal cancer growth by counteracting the Warburg effect due to regulating alternative splicing of the PKM gene .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22895557"}
{"sentence": "DNA damage checkpoints arrest cell cycle progression to facilitate DNA repair . The ability to survive genotoxic insults depends not only on the initiation of cell cycle checkpoints but also on checkpoint maintenance . While activation of DNA damage checkpoints has been studied extensively , molecular mechanisms involved in sustaining and ultimately inactivating cell cycle checkpoints are largely unknown . Here , we explored feedback mechanisms that control the maintenance and termination of checkpoint function by computationally identifying an evolutionary conserved mitotic phosphorylation network within the DNA damage response . We demonstrate that the non-enzymatic checkpoint adaptor protein 53BP1 is an in vivo target of the cell cycle kinases Cyclin-dependent kinase-1 and Polo-like kinase-1 ( Plk1 ) . We show that Plk1 binds 53BP1 during mitosis and that this interaction is required for proper inactivation of the DNA damage checkpoint. 53BP1 mutants that are unable to bind Plk1 fail to restart the cell cycle after ionizing radiation-mediated cell cycle arrest . Importantly , we show that Plk1 also phosphorylates the 53BP1-binding checkpoint kinase Chk2 to inactivate its FHA domain and inhibit its kinase activity in mammalian cells . Thus , a mitotic kinase-mediated negative feedback loop regulates the ATM-Chk2 branch of the DNA damage signaling network by phosphorylating conserved sites in 53BP1 and Chk2 to inactivate checkpoint signaling and control checkpoint duration .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20126263"}
{"sentence": "OBJECTIVE This study describes a new method used in the clinical laboratory at Hospital Israelita Albert Einstein to detect mutations in exons 8 and 17 of the KIT gene in patients with acute myeloid leukemia . METHODS Genomic DNA extraction was performed on 54 samples of peripheral blood or bone marrow from patients with acute myeloid leukemia . The extracted DNA was amplified by polymerase chain reaction and sequenced , and the fragments were analyzed . RESULTS Within the analyzed samples , we detected four mutations in exon 8 , two mutations in exon 17 , and mutations or a double mutation in one sample . CONCLUSION The tests detecting mutations in exon 8 and 17 on the KIT gene were successfully standardized . The test is now included among the routine diagnostics employed for patients at Hospital Israelita Albert Einstein clinical laboratory .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23386005"}
{"sentence": "A number of cancer chemotherapeutic drugs designed to have cytotoxic actions on tumor cells have recently been shown to also have antiangiogenic activities . Endothelial cell migration and proliferation are key components of tumor angiogenesis , and agents that target the microtubule cytoskeleton can interfere with these processes . In this study , the effect on endothelial cell functions of the microtubule-stabilizing drugs Taxotere and Taxol were evaluated in three in vitro assays : a chemokinetic migration assay , an angiogenesis factor-mediated chemotactic migration assay , and a three-dimensional Matrigel tubule formation assay , using rat fat pad endothelial cells ( RFPECs ) and/or human umbilical vein endothelial cells ( HUVECs ) . Taxotere was active in all three assays at concentrations that were not cytotoxic and did not inhibit endothelial cell proliferation . In the RFPEC chemokinetic migration and in vitro tubule formation assays , the IC50 values were approximately 10(-9) M for both Taxotere and Taxol . HUVEC migration , however , was more sensitive to Taxotere , with an observed IC50 of 10(-12) M in a chemokinetic assay . In a Boyden chamber assay , HUVEC chemotaxis stimulated by either of two angiogenic factors , thymidine phosphorylase or vascular endothelial growth factor , was inhibited by Taxotere with an IC50 of 10(-11) M and was ablated at 10(-9) M. Taxotere was also up to 1000-fold more potent than Taxol in inhibiting either chemokinetic or chemotactic migration . When the microtubule cytoskeleton was visualized using immunofluorescence staining of alpha-tubulin , there were no gross morphological changes observed in HUVECs or RFPECs treated with Taxotere at concentrations that inhibited endothelial cell migration but not proliferation . The effects of Taxotere on migration were associated with a reduction in the reorientation of the cell's centrosome , at concentrations that did not affect gross microtubule morphology or proliferation . Reorientation of the centrosome , which acts as the microtubule organizing center , in the intended direction of movement is a critical early step in the stabilization of directed cell migration . These data indicate that endothelial cell migration correlates more closely with changes in microtubule plasticity than with microtubule gross structure . The antiangiogenic activity of Taxotere in vivo was assessed in a Matrigel plug assay . In this assay , the angiogenic response to fibroblast growth factor 2 was inhibited in vivo by Taxotere with an ID50 of 5.4 mg/kg when injected twice weekly over a 14-day period , and angiogenesis was completely blocked in mice that received 10 mg/kg Taxotere . The in vivo data further suggested that Taxotere had selectivity for endothelial cell migration and/or microvessel formation because infiltration of inflammatory cells into the Matrigel plug was much less sensitive to inhibition by Taxotere . In conclusion , Taxotere is a potent and potentially specific inhibitor of endothelial cell migration in vitro and angiogenesis in vitro and in vivo .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "12479700"}
{"sentence": "Acetyl-11-keto-beta-boswellic acid ( AKBA ) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate from the stem of the tree Boswellia serrata ( frankincense ) . AKBA has been recently identified as a novel , orally active , non-redox and non-competitive 5-lipoxygenase inhibitor that also inhibits topisomerase I and II in vitro . Because natural pentacyclic triterpenes have an antiproliferative effect against different tumor types , we investigated the effects of AKBA on the proliferation of 11 primary cell cultures established from human surgical specimens of meningiomas , common central nervous system tumors . Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2-8 microM . At similar , physiologically achievable concentrations , AKBA rapidly ( within minutes ) and potently inhibited the phosphorylation of extracellular signal-regulated kinase 1 and 2 ( Erk-1 and Erk-2 ) in meningioma cells stimulated with platelet-derived growth factor BB . High expression level of 5-LO was detected in primary meningioma cells and surgical specimens by immunoblotting analysis , suggesting the possible role of 5-LO in meningioma tumorigenesis . Considering the critical importance of the Erk-1/2 signal transduction pathway not only in meningiomas but in other human neoplasms , the interruption of signaling through this evolutionarily conserved pathway might be one of the mechanisms by which AKBA induces suppression of proliferation and apoptosis of different tumor types .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12664615"}
{"sentence": "Tumor necrosis factor related apoptosis-inducing ligand ( TRAIL ) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies . TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways , but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far . In the present work , we analyzed cell viability , DISC formation as well as IL-8 and NF-kappaB activation side by side in responses to TRAIL and agonistic antibodies against DR4 ( mapatumumab ) and against DR5 ( lexatumumab ) in pancreatic ductal adenocarcinoma cells . We found that all three reagents are able to activate cell death and pro-inflammatory signaling . Death-inducing signaling complex ( DISC ) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5 , whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors . Notably , blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4 . Interestingly , inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death . Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "20354842"}
{"sentence": "UNLABELLED ABC transporters like P-glycoprotein ( P-gp/ABCB1 ) are membrane proteins responsible for the transport of toxic compounds out of non-malignant cells and tumor tissue . AIM To investigate the effect of glycolysis and the tissue redox state on P-gp expression in multicellular tumor spheroids derived from prostate adenocarcinoma cells ( DU-145 ) , glioma cells ( Gli36 ) , and the human cervix carcinoma cell line KB-3-1 transfected with a P-gp-EGFP fusion gene that allows monitoring of P-gp expression in living cells . During cell culture of DU-145 , Gli36 , and KB-3-1 tumor spheroids P-gp expression was observed as well as increased lactate and decreased pyruvate levels and expression of glycolytic enzymes . Inhibition of glycolysis for 24 h by either iodoacetate ( IA ) or 2-deoxy-D-glucose ( 2-DDG ) downregulated P-gp expression which was reversed upon coincubation with the radical scavenger ebselen as shown by semi-quantitative immunohistochemisty in DU-145 and Gli36 tumor spheroids , and by EGFP fluorescence in KB-3-1 tumor spheroids . Consequently endogenous ROS generation in DU-145 tumor spheroids was increased in the presence of either IA or 2-DDG , which was abolished upon coincubation with ebselen . Exogenous addition of pyruvate significantly reduced ROS generation , increased P-gp expression as well as efflux of the P-gp substrate doxorubicin . Doxorubicin transport was significantly blunted by 2-DDG and IA , indicating that inhibition of glycolysis reversed the multidrug resistance phenotype . In summary our data demonstrate that P-gp expression in tumor spheroids is closely related to the glycolytic metabolism of tumor cells and can be downregulated by glycolysis inhibitors via mechanisms that involve changes in the cellular redox state .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19950199"}
{"sentence": "The aryl hydrocarbon receptor ( AhR ) is a ligand-activated transcription factor . Recent studies have reported the anti-tumor effects of the AhR in breast cancer . In this study , we investigated the anti-tumor effect of AhR activation based on the cancer stem cell hypothesis . We show that AhR activation suppressed mammosphere formation of MCF-7 cells and decreased the proportion of cells with high ALDH-1 ( aldehyde dehydrogenase 1 ) activity . In addition , we also demonstrate that AhR activation regulates self-renewal signaling by down-regulating Wnt/\u03b2-catenin and Notch .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22123295"}
{"sentence": "Here , we provide the necessary proof of concept , that it is possible to metabolically create a non-permissive or \" hostile \" stromal microenvironment , which actively prevents tumor engraftment in vivo . We developed a novel genetically engineered fibroblast cell line that completely prevents tumor formation in mice , with a 100% protection rate . No host side effects were apparent.This could represent a viable cellular strategy for preventing and treating a variety of human cancers . More specifically , we examined the autocrine and paracrine effects of the cellular delivery of TNF-alpha on breast cancer tumor growth and cancer metabolism . For this purpose , we recombinantly overexpressed TNF-alpha in human breast cancer cells ( MDA-MB-231 ) or human immortalized fibroblasts ( hTERT-BJ1 ) . Our results directly show that TNF-alpha functions as a potent tumor suppressor . Remarkably , TNF-alpha-expressing breast cancer cells were viable , without any significant increases in their basal apoptotic rate . However , after 4 weeks post-implantation , TNF-alpha-expressing breast cancer cells failed to form any tumors in xenografted mice ( 0 tumors/10 injections ) , ultimately conferring 100% protection against tumorigenesis . Similarly , TNF-alpha-overexpressing fibroblasts were also viable , without any increases in apoptosis . Significantly , complete tumor suppression was obtained by co-injecting TNF-alpha expressing stromal fibroblasts with human breast cancer cells , indicating that paracrine cell-mediated delivery of TNF-alpha can also prevent tumor engraftment and growth ( 0 tumors/10 injections ) . Mechanistically , TNF-alpha induced autophagy and mitochondrial dysfunction in both epithelial cancer cells and stromal fibroblasts , preventing energy transfer from the tumor microenvironment , likely \" starving \" the cancer cells to death . In addition , via qRT-PCR analysis of MDA-MB-231 cells , we observed that TNF-alpha mediated the up-regulation of gene transcripts associated with inflammation and senescence [ IL-1-beta , IL-6 , IL-8 , MCP-1 , COX-2 , p21(WAF1/CIP1) ] and downregulated known tumor-promoting genes ( collagen VI and MMP2 ) . Recombinant overexpression of TNF-alpha receptor(s) in MDA-MB-231 cells also significantly reduced tumor growth , but was not as effective as the TNF-alpha ligand itself in preventing tumor growth . Thus , we propose that stromal cell-mediated delivery of TNF-alpha to human tumors [ using transfected fibroblasts or mesenchymal stem cells ( hMSCs) ] may be a novel and effective strategy for the prevention and treatment of human cancers .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 1], "id": "23292149"}
{"sentence": "Diallyl disulfide ( DADS ) is a major organo-sulfur compound derived from garlic ( Allium sativum ) , which inhibits the proliferation of various types of cancer cells . In this study we investigated the effect of DADS on the induction of apoptosis , as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells . Treatment of B16F-10 cells with nontoxic concentrations of DADS resulted in the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner . Cell-cycle analysis revealed that the occurrence of the sub-G1 peak was significantly elevated in DADS-treated cells . DADS treatment also down-reguated Bcl-2 expression and up-regulated p53 , caspase-9 , and caspase-3 expression in B16F-10 melanoma cells . The study also reveals that DADS inhibited the activation and nuclear translocation of p65 , p50 , and c-Rel subunits of nuclear factor ( NF)-B and other transcription factors , such as c-fos , activated transcription factor-2 , and cyclic adenosine monophosphate response element-binding protein , in B16F-10 melanoma cells The pro-inflammatory cytokine production and gene expression of tumor necrosis factor ( TNF)-\u03b1 , interleukin ( IL)-1\u03b2 , IL-6 , and granulocyte-macrophage colony-stimulating factor ( GM-CSF ) were down-regulated in DADS-treated cells compared with control B16F-10 metastatic melanoma cells . DADS induces caspase-dependent apoptosis through a mitochondria-mediated intrinsic pathway in B16F-10 melanoma cells by activating p53 and caspase-3 gene expression and suppressing pro-inflammatory cytokines and NF-B-mediated Bcl-2 activation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "20932246"}
{"sentence": "Piceatannol is a stilbenoid , a metabolite of resveratrol found in red wine . Piceatannol and sera from rats orally given piceatannol were found to dose-dependently suppress both the proliferation and invasion of AH109A hepatoma cells in culture . Its antiproliferative effect was based on cell cycle arrest at lower concentration ( 25 \u03bcM ) and on apoptosis induction at higher concentration ( 100 \u03bcM ) . Piceatannol suppressed reactive oxygen species-potentiated invasive capacity by scavenging the intracellular reactive oxygen species . These results suggest that piceatannol , unlike resveratrol , has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction . They also suggest that the antioxidative property of piceatannol , like resveratrol , may be involved in its anti-invasive action . Subsequently , piceatannol was found to suppress the growth of solid tumor and metastasis in hepatoma-bearing rats . Thus , piceatannol may be a useful anticancer natural product .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22496613"}
{"sentence": "Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors , and recently , it has been shown to be an active agent for the treatment of malignant pheochromocytomas . Previously , we demonstrated that sunitinib directly inhibited mTORC1 signaling in rat pheochromocytoma PC12 cells . Although autophagy is a highly regulated cellular process , its relevance to cancer seems to be complicated . It is of note that inhibition of mTORC1 is a prerequisite for autophagy induction . Indeed , direct mTORC1 inhibition initiates ULK1/2 autophosphorylation and subsequent Atg13 and FIP200 phosphorylation , inducing autophagy . Here , we demonstrated that sunitinib significantly increased the levels of LC3-II , concomitant with a decrease of p62 in PC12 cells . Following sunitinib treatment , immunofluorescent imaging revealed a marked increased punctate LC3-II distribution . Furthermore , Atg13 knockdown significantly reduced its protein level , which in turn abolished sunitinib-induced autophagy . Moreover , inhibition of autophagy by siRNAs targeting Atg13 or by pharmacological inhibition with ammonium chloride , enhanced both sunitinib-induced apoptosis and anti-proliferation . Thus , sunitinib-induced autophagy is dependent on the suppression of mTORC1 signaling and the formation of ULK1/2-Atg13-FIP200 complexes . Inhibition of autophagy may be a promising therapeutic option for improving the anti-tumor effect of sunitinib .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23269235"}
{"sentence": "Keratinocyte growth factor ( KGF , fibroblast growth factor-7 ) is a fibroblast-derived mitogen , which stimulates proliferation of epithelial cells . The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair . However , the role of KGF in cutaneous carcinogenesis and cancer progression is not known . We have examined the role of KGF in progression of squamous cell carcinoma ( SCC ) of the skin . The expression of KGF receptor ( KGFR ) mRNA was lower in cutaneous SCCs ( n = 6 ) than in normal skin samples ( n = 6 ) . Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF . KGF did not stimulate SCC cell proliferation , but it reduced invasion of SCC cells through collagen . Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes , including genes with tumor suppressing properties ( SPRY4 , DUSP4 , DUSP6 , LRIG1 , PHLDA1 ) . KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes , including genes associated with tumor progression ( MMP13 , MATN2 , CXCL10 , and IGFBP3 ) . Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2 . Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression . These results provide evidence , that KGF does not promote progression of cutaneous SCC , but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells , as compared to normal keratinocytes .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22427941"}
{"sentence": "Exosomes are small-membrane vesicles secreted by hematopoietic and malignant epithelial cells as well as trophoblasts . The composition of cancerous exosomes has been proven to play pivotal roles in the maintenance of the microenvironment that is beneficial for the progression of cancer , such as Fas-ligand-triggered lymphocyte apoptosis . We supposed that the immunosuppressive effect of cancerous exosomes might be helpful in the treatment of diseases characterized by overactivation of the immune system and subsequent tissue injury . The aim of this study was to evaluate the protective effect of tumor-derived exosomes in the mice model of lipopolysaccharide ( LPS)-induced inflammation . Tetrazolium ( MTT ) and DNA electrophoresis were used to measure the cytotoxicity of exosomes on lymphocytes . Pathologic observation of tissue sections , serologic analysis of aspartate aminotransferase/alanine aminotransferase ( AST/ALT ) , and urinary analysis of protein were used to assess the protection effect of exosomes in LPS-induced multiorgan damage . In vitro outcomes of MTT and DNA electrophoresis showed the cytotoxicity of exosomes on lymphocytes . Together with the alleviation of organ damages evaluated by urine protein , serum AST/ALT , and pathologic analysis , we confirmed the possibility that pretreatment of mice with exosomes , produced by H22 hepatic tumor cells , resulted in protection against LPS-induced tissue damage , which is caused by overactivation of the immune system and inflammation response . This therapeutic strategy will raise an interesting way to search new therapeutics in pairs of diseases with complementarities in etiology and pathology , namely , a strategy of taking advantage of the mutual complementarities between diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22984881"}
{"sentence": "Although some types of carbon nanotubes ( CNTs ) have been described to induce mesothelioma in rodents and genotoxic effects in various cell systems , there are few previous studies on the genotoxicity of CNTs in mesothelial cells . Here , we examined in vitro DNA damage induction by short multi-wall CNTs ( MWCNTs ; 10-30 nm \u00d7 1-2 \\u03bcm ) and single-wall CNTs ( SWCNTs ; >50% SWCNTs , other CNTs ; <2 nm \u00d7 1-5 \\u03bcm ) in human mesothelial ( MeT-5A ) cells and bronchial epithelial ( BEAS 2B ) cells , using the single cell gel electrophoresis ( comet ) assay and the immunoslot blot assay for the detection of malondialdehyde ( M1dG ) DNA adducts . In BEAS 2B cells , we also studied the induction of micronuclei ( MN ) by the CNTs using the cytokinesis-block method . The cells were exposed to the CNTs ( 5-200 \\u03bcg/cm(2) , corresponding to 19-760 \\u03bcg/ml ) for 24 and 48h in the comet assay and for 48 and 72 h in the MN and M1dG assays . Transmission electron microscopy ( TEM ) showed more MWCNT fibres and SWCNT clusters in BEAS 2B than MeT-5A cells , but no significant differences were seen in intracellular dose expressed as area of SWCNT clusters between TEM sections of the cell lines . In MeT-5A cells , both CNTs caused a dose-dependent induction of DNA damage ( % DNA in comet tail ) in the 48-h treatment and SWCNTs additionally in the 24-h treatment , with a statistically significant increase at 40 \\u03bcg/cm(2) of SWCNTs and ( after 48 h ) 80 \\u03bcg/cm(2) of both CNTs . SWCNTs also elevated the level of M1dG DNA adducts at 1 , 5 , 10 and 40 \\u03bcg/cm(2) after the 48-h treatment , but both CNTs decreased M1dG adduct level at several doses after the 72-h treatment . In BEAS 2B cells , SWCNTs induced a statistically significant increase in DNA damage at 80 and 120 \\u03bcg/cm(2) after the 24-h treatment and in M1dG adduct level at 5 \\u03bcg/cm(2) after 48 h and 10 and 40 \\u03bcg/cm(2) after 72 h ; MWCNTs did not affect the level of DNA damage but produced a decrease in M1dG adducts in the 72-h treatment . The CNTs did not affect the level of MN . In conclusion , MWCNTs and SWCNTs induced DNA damage in MeT-5A cells but showed a lower ( SWCNTs ) or no ( MWCNTs ) effect in BEAS 2B cells , suggesting that MeT-5A cells were more sensitive to the DNA-damaging effect of CNTs than BEAS 2B cells , despite the fact that more CNT fibres or clusters were seen in BEAS 2B than MeT-5A cells . M1dG DNA adducts were induced by SWCNTs but decreased after a 3-day exposure to MWCNTs and ( in MeT-5A cells ) SWCNTs , indicating that CNTs may lead to alterations in oxidative effects within the cells . Neither of the CNTs was able to produce chromosomal damage ( MN ) .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23266321"}
{"sentence": "In both mitotic and meiotic processes , cellular surveillance of the integrity of genetic information transmission from parental cells to their subsequent generations is carried out by a network of proteins primarily involved in cell-cycle regulation , DNA replication , DNA repair , and chromosome segregation . Within this context , the mammalian MRE11 represents an essential multifunctional protein that promotes repair of DNA double-strand breaks and plays a role in the signaling of DNA damage response . Mutations in human hMRE11 gene could contribute to the rare \" AT-like \" disorder . However , at present time the functional roles of hMRE11 in these cellular processes are elusive . In the current study , we provide evidence that hMRE11 interacts physically with the mismatch repair protein hMLH1 through yeast two-hybrid analysis . In addition , we show that recombinant hMRE11 and hMLH1 proteins interact when these two proteins are coexpressed in bacterial cells , and both proteins can be co-immunoprecipitated from human cell extracts . Furthermore , hMRE11 and hMLH1 display similar expression patterns when examined with a human normal/tumor DNA array . Together , these data suggest that hMRE11 and hMLH1 might act in a co-operative fashion during DNA damage detection , signaling , and repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12509276"}
{"sentence": "Abstract The use of immunotherapeutics in melanoma has received much attention , and recent advances to further characterize the regulatory components of the immune system and the importance of co-stimulatory molecules have opened a new area for clinical investigation . Cytotoxic T lymphocyte-associated antigen 4 ( CTLA-4 ) serves as a negative regulator of immunity . Recent trials administering fully human anti-CTLA-4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses . Treatment with CTLA-4 blocking antibodies , however , is not without potential toxicities . Autoimmune side-effects , the most common being colitis-associated diarrhea , are frequently associated with clinical responses . In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA-4 blockade but without significant toxicities , we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor ( GVAX ; Cell Genesys , South San Francisco , CA , USA ) with periodic infusions of CTLA-4 blocking antibodies . This sequential treatment resulted in clinically significant anti-tumor immunity without grade 3 or 4 toxicity in most patients . Pathological analyses following treatment of pre-existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra-tumoral CD8+ effector cells to FoxP3+ regulatory cells ( T(regs) ) . Effective anti-tumor immunity and serious autoimmunity can be disassociated . Further targeting of anti-tumor T(regs)in combinatorial therapy approaches may be a rich avenue of future investigation .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20482528"}
{"sentence": "Environmental carcinogen exposure may play an important role in the incidence of cancer in children . In addition to environmental pollutants , maternal smoking during pregnancy may be a contributing factor . Major carcinogenic components of cigarette smoke and other combustion by-products in the environment include polycyclic aromatic hydrocarbons ( PAH ) . Mouse offspring exposed during midpregnancy to the PAH , benzo[a]pyrene ( B[a]P ) , show significant deficiencies in their immune functions , observed in late gestation which persist for at least 18 months . Tumor incidences in these progeny are 8 to 10-fold higher than in controls . We have demonstrated a significant reduction in thymocytes ( CD4+ CD8+ , CD4+ CD8+ Vbeta8+ , CD4+ CD8+ Vgamma2+ ) from newborn and splenocytes ( CD4+ CD8+ ) from 1-week-old mouse progeny exposed to B[a]P in utero . To investigate possible causes of the observed T cell reduction , we analyzed the thymocytes and splenocytes from progeny and maternal tissues for the presence of B[a]P-DNA adducts . Adducts were detected in maternal , placental and offspring lymphoid tissues at day 19 of gestation , at birth and 1-wk after birth . The presence of B[a]P-DNA adducts in immature T cells may , in part , explain the previously observed T cell immunosuppression and tumor susceptibility in mice exposed to B[a]P in utero . The effects of DNA lesions on progeny T cells may include interference with normal T-cell development . These results provide a possible explanation for the relationship between maternal smoking during pregnancy and childhood carcinogenesis .", "label": [0, 1, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12375734"}
{"sentence": "Imiquimod is a synthetic compound with antitumor properties ; a 5% cream formulation is successfully used to treat skin tumors . The antitumor effect of imiquimod is multifactorial , although its ability to modulate immune responses by triggering TLR7/8 is thought to be key . Among the immune cells suggested to be involved are plasmacytoid DCs ( pDCs ) . However , a direct contribution of pDCs to tumor killing in vivo and the mechanism of their recruitment to imiquimod-treated sites have never been demonstrated . Using a mouse model of melanoma , we have now demonstrated that pDCs can directly clear tumors without the need for the adaptive immune system . Topical imiquimod treatment led to TLR7-dependent and IFN-\u03b1/\u03b2 receptor 1-dependent ( IFNAR1-dependent ) upregulation of expression of the chemokine CCL2 in mast cells . This was essential to induce skin inflammation and for the recruitment of pDCs to the skin . The recruited pDCs were CD8\u03b1+ and induced tumor regression in a TLR7/MyD88- and IFNAR1-dependent manner . Lack of TLR7 and IFNAR1 or depletion of pDCs or CD8\u03b1+ cells from tumor-bearing mice completely abolished the effect of imiquimod . TLR7 was essential for imiquimod-stimulated pDCs to produce IFN-\u03b1/\u03b2 , which led to TRAIL and granzyme B secretion by pDCs via IFNAR1 signaling . Blocking these cytolytic molecules impaired pDC-mediated tumor killing . Our results demonstrate that imiquimod treatment leads to CCL2-dependent recruitment of pDCs and their transformation into a subset of killer DCs able to directly eliminate tumor cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22251703"}
{"sentence": "Dendritic cells ( DCs ) and natural killer ( NK ) cells are central components of innate immunity for controlling tumor growth . The therapeutic effects of certain anti-myeloma drugs are partially mediated by targeting the innate immune response . In addition , novel types of natural compounds have been developed that efficiently modulate the activity of both the cellular and humoral compartments of immunity . MGN-3 is known as an activator of natural killer cells , inducer of apoptosis and cytokine production , and modulator of dendritic cell maturation and differentiation in vitro . We have performed a randomized , placebo-controlled study to examine the effects of MGN-3 on innate immune system parameters in 48 multiple myeloma patients . We performed immunophenotypic analysis of peripheral blood samples , determined NK cell activity , and assessed the cytokine profiles of plasma before and during 3months of treatment . The results demonstrate a clear increase in NK activity in MGN-3-treated patients compared to the placebo group , an increased level of myeloid DCs in peripheral blood , and augmented concentrations of T helper cell type 1-related cytokines . The present study suggests that MGN-3 may represent an immunologically relevant product for activating innate immunity in multiple myeloma patients and warrants further testing to demonstrate clinical efficacy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22941038"}
{"sentence": "Genetic defects in breast cancer ( BC ) susceptibility genes , most importantly BRCA1 and BRCA2 , account for of hereditary BC and ovarian cancer ( OC ) . Little is known about the contribution of constitutive ( soma-wide ) epimutations to the remaining cases . We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM , BRCA1 , BRCA2 , RAD51C , PTEN and TP53 in blood cells . In a second step , patients with \\u22656% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles ( epimutations ) , indicative of epigenetic gene silencing . Altogether we identified nine ( 1.4% ) patients with constitutive BRCA1 and three ( 0.5% ) with RAD51C hypermethylation . Epimutations were found in both sporadic cases , in particular in 2 ( 5.5% ) of 37 patients with early-onset BC , and familial cases , in particular 4 ( 10% ) of 39 patients with OC . Hypermethylation was always confined to one of the two parental alleles in a subset ( 12-40% ) of the analyzed cells . Because epimutations occurred in cell types from different embryonal layers , they most likely originated in single cells during early somatic development . We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development . Because the role of constitutive epimutations in cancer development is likely to be largely underestimated , future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22843497"}
{"sentence": "We studied the effect of oxidative stress induced by hyperoxia , hydrogen peroxide , or menadione on mouse leukemia P388 cells at early ( 4 days ) and late ( 7 days ) stages of tumor growth . Oxidative stress proved to inhibit cell division and to induce apoptosis . Seven-day leukemia cells feature lower proliferative potential and higher sensitivity to oxidative stress and platidiam .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "12561326"}
{"sentence": "Oncostatin M ( OSM ) , an interleukin-6 type cytokine , acts via the gp130 signaling receptor to inhibit proliferation and induce differentiation of breast cancer cells . EGF , a mitogen for breast cells , signals via EGFR/ErbB tyrosine kinase receptors which are implicated in breast cancer pathogenesis . Here we show paradoxically that EGF enhanced the OSM-induced inhibition of proliferation and induction of cellular differentiation in both estrogen receptor positive and negative breast cancer cells . This functional synergism was also seen with heregulin but not SCF , PDGF or IGF-1 , indicating that it was specific to EGF-related growth factors . Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3 . There was a similar association between the OSMRbeta and ErbB-2 . Furthermore , EGF unexpectedly induced tyrosine phosphorylation of gp130 . We show that OSM induced phosphorylation of STAT3 . Both OSM and EGF activated the p42/44 MAP kinases , but while the MEK inhibitor , PD98059 , ablated the OSM-induced inhibition , it only partially ablated the inhibitory effects of OSM plus EGF . Thus , we have demonstrated that the receptors and signalling pathways of two apparently unrelated growth factors were intimately linked , resulting in an unexpected biological effect . This provides a new mechanism for generating signalling diversity and has potential clinical implications in breast cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "11821958"}
{"sentence": "In order to elucidate the mechanisms by which tumour-specific CD4+ T-cell responses are impaired during tumour development , an attempt was made to identify factors which impair CD4+ T-cell responses at a late tumour-bearing stage . Plasma from mice bearing B16 melanoma for 30 days ( plasma d30 ) showed a more profound immunosuppressive effect on the in vitro proliferation of unrelated antigen-specific CD4+ T cells in the presence of both antigen and antigen-presenting cells ( APC ) than plasma from na\ufffdve mice . The level of plasma transforming growth factor ( TGF)- was elevated in mice bearing B16 melanoma for 30 days compared with na\ufffdve mice , and the suppressive effect of plasma d30 was partially diminished by the neutralization of TGF- . Interestingly , immunoglobulin ( IgG)-bound TGF- , but not IgG-unbound TGF- , in plasma d30 was suggested to be responsible for the immunosuppressive activity . In addition , no suppressive effect of plasma d30 was observed when antigen was added as a class II peptide , thus suggesting that the impaired proliferation of CD4+ T cells in the presence of plasma d30 was due to a dysfunction of antigen uptake/processing by APC . Furthermore , dissociation between IgG and TGF- resulted in a loss of the suppressive activity of plasma d30 . Taken together , these results suggest that circulating IgG-bound TGF- is , at least in part , responsible for the impaired responses of CD4+ T cells at the late tumour-bearing stage by suppressing antigen uptake/ processing by APC .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12041507"}
{"sentence": "cDNA microarray-based gene expression analysis has been successfully employed to explore the action mechanism and to validate the targets of several drugs . In the present study , we evaluated anti-angiogenic activity of demethoxycurcumin ( DC ) , a structural analog of curcumin , isolated from Curcuma aromatica , and investigated the effect of DC on genetic reprogramming in cultured human umbilical vein endothelial cells ( HUVECs ) using cDNA microarray analysis . Of 1024 human cancer-focused genes arrayed , 187 genes were up-regulated and 72 genes were down-regulated at least 2-fold by DC . Interestingly , 9 angiogenesis-related genes were down-regulated over 5-fold in response to DC , suggesting that the genetic reprogramming was crucially involved in anti-angiogenesis by the compound . To verify the results obtained from cDNA microarray analysis , matrix metalloproteinase-9 ( MMP-9 ) , the product of one of the angiogenesis-related genes down-regulated over 5-fold by DC , was investigated using gelatin zymography . DC potently inhibited the expression of MMP-9 , yet showed no direct effect on its activity . These data show that gene expressional change of MMP-9 is a major mediator for angiogenesis inhibition by DC . All genes identified and microarray data are available on the web at http://dasan.sejong.ac.kr/", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12495478"}
{"sentence": "Whereas estrogen-estrogen receptor \u03b1 ( ER ) signaling plays an important role in breast cancer growth , it is also necessary for the differentiation of normal breast epithelial cells . How this functional conversion occurs , however , remains unknown . Based on a genome-wide sequencing study that identified mutations in several breast cancer genes , we examined some of the genes for mutations , expression levels , and functional effects on cell proliferation and tumorigenesis . We present the data for C1orf64 or ER-related factor ( ERRF ) from 31 cell lines and 367 primary breast cancer tumors . Whereas mutation of ERRF was infrequent ( 1 of 79 or 1.3% ) , its expression was up-regulated in breast cancer , and the up-regulation was more common in lower-stage tumors . In addition , increased ERRF expression was significantly associated with ER and/or progesterone receptor ( PR ) positivity , which was still valid in human epidermal growth factor receptor 2 ( HER2)-negative tumors . In ER-positive tumors , ERRF expression was inversely correlated with HER2 status . Furthermore , higher ERRF protein expression was significantly associated with better disease-free survival and overall survival , particularly in ER- and/or PR-positive and HER2-negative tumors ( luminal A subtype ) . Functionally , knockdown of ERRF in two ER-positive breast cancer cell lines , T-47D and MDA-MB-361 , suppressed cell growth in vitro and tumorigenesis in xenograft models . These results suggest that ERRF plays a role in estrogen-ER-mediated growth of breast cancer cells and could , thus , be a potential therapeutic target .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22341523"}
{"sentence": "Proliferating cells consume more glucose to cope with the bioenergetics and biosynthetic demands of rapidly dividing cells as well as to counter a shift in cellular redox environment . This study investigates the hypothesis that manganese superoxide dismutase ( MnSOD ) regulates cellular redox flux and glucose consumption during the cell cycle . A direct correlation was observed between glucose consumption and percentage of S-phase cells in MnSOD wild-type fibroblasts , which was absent in MnSOD homozygous knockout fibroblasts . Results from electron paramagnetic resonance spectroscopy and flow cytometric assays showed a significant increase in cellular superoxide levels in S-phase cells , which was associated with an increase in glucose and oxygen consumption , and a decrease in MnSOD activity . Mass spectrometry results showed a complex pattern of MnSOD-methylation at both lysine ( 68 , 89 , 122 , and 202 ) and arginine ( 197 and 216 ) residues . MnSOD protein carrying a K89A mutation had significantly lower activity compared with wild-type MnSOD . Computational-based simulations indicate that lysine and arginine methylation of MnSOD during quiescence would allow greater accessibility to the enzyme active site as well as increase the positive electrostatic potential around and within the active site . Methylation-dependent changes in the MnSOD conformation and subsequent changes in the electrostatic potential around the active site during quiescence versus proliferation could increase the accessibility of superoxide , a negatively charged substrate . These results support the hypothesis that MnSOD regulates a \" metabolic switch \" during progression from quiescent through the proliferative cycle . We propose MnSOD as a new molecular player contributing to the Warburg effect .", "label": [0, 0, 1, 0, 0, 1, 0, 0, 1, 0], "id": "22710435"}
{"sentence": "PURPOSE Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies . The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks , which can potentially contribute to its genotoxic effects [ Celik , H. , Arin\u00e7 , E. , Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect . J Pharm Pharm Sci , 11(4):68-82 , 2008 ] . In the current study , our aim was to investigate the possible protective effects of several phenolic antioxidants , quercetin , rutin , naringenin , resveratrol and trolox , against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation . METHODS DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method . RESULTS Our results indicated that , among the compounds tested , quercetin was the most potent antioxidant in preventing DNA damage . Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner ; 100 microM of quercetin almost completely inhibited the DNA strand breakage . Unlike quercetin , its glycosidated conjugate rutin , failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested ( 2 mM ) . The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations . Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C. CONCLUSION We conclude that quercetin , one of the most abundant flavonoids in the human diet , is highly effective in reducing the DNA damage caused by the antitumor agents , idarubicin and mitomycin C , following bioactivation by P450 reductase .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20816008"}
{"sentence": "Colon cancer is a leading cause of morbidity and mortality in Western countries . Basic fibroblast growth factor ( bFGF ) was up-regulated in patients with colon cancer and was considered as a potential therapeutic target . In this study , we first demonstrated that a novel bFGF-binding peptide ( named P7 ) inhibited proliferation of several colon cancer cell lines including HT-29 , LoVo , and Caco2 cells stimulated by bFGF . Further investigations with HT-29 cells indicated that P7 arrested the cell cycle at the G0/G1 phase of bFGF-stimulated cells , reduced the levels of phospho-Erk1/Erk2 induced by bFGF , and caused significant changes in the expression of proteins related to proliferation , cell cycle , and cancer . Our results suggested that the bFGF-binding peptide has a potential antitumor effect on colon cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20331620"}
{"sentence": "SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM , ATR , and DNA-PK , proteins with known roles in DNA damage and cellular stress responses . SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response , resistance to oxidative stress , regulation of hypoxic responses , and apoptosis . To understand the roles of SMG1 further , we generated a Genetrap Smg1 mouse model . Smg1 homozygous KO mice were early embryonic lethal , but Smg1 heterozygous mice showed a predisposition to a range of cancers , particularly lung and hematopoietic malignancies , as well as development of chronic inflammation . These mice did not display deficiencies in known roles of SMG1 , including nonsense-mediated decay . However , they showed elevated basal tissue and serum cytokine levels , indicating low-level inflammation before the development of tumors . Smg1 heterozygous mice also showed evidence of oxidative damage in tissues . These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23277562"}
{"sentence": "Extracellular respiration of solid-phase electron acceptors in some microorganisms requires a complex chain of multiheme c-type cytochromes that span the inner and outer membranes . In Shewanella species , MtrA , an periplasmic decaheme c-type cytochrome , is an essential component for extracellular respiration of iron(III) . The exact mechanism of electron transport has not yet been resolved , but the arrangement of the polypeptide chain may have a strong influence on the capability of the MtrA cytochrome to transport electrons . The iron hemes of MtrA are bound to its polypeptide chain via proximal ( CXXCH ) and distal histidine residues . In this study , we show the effects of mutating histidine residues of MtrA to arginine on protein expression and extracellular respiration using Shewanella sp. strain ANA-3 as a model organism . Individual mutations to six out of nine proximal histidines in CXXCH of MtrA led to decreased protein expression . However , distal histidine mutations resulted in various degrees of protein expression . In addition , the effects of histidine mutations on extracellular respiration were tested using ferrihydrite and current production in microbial fuel cells . These results show that proximal histidine mutants were unable to reduce ferrihydrite . Mutations to the distal histidine residues resulted in various degrees of ferrihydrite reduction . These findings indicate that mutations to the proximal histidine residues affect MtrA expression , leading to loss of extracellular respiration ability . In contrast , mutations to the distal histidine residues are less detrimental to protein expression , and extracellular respiration can proceed .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22923588"}
{"sentence": "BACKGROUND Astaxanthin modulates immune response , inhibits cancer cell growth , reduces bacterial load and gastric inflammation , and protects against UVA-induced oxidative stress in in vitro and rodent models . Similar clinical studies in humans are unavailable . Our objective is to study the action of dietary astaxanthin in modulating immune response , oxidative status and inflammation in young healthy adult female human subjects . METHODS Participants ( averaged 21.5 yr ) received 0 , 2 , or 8 mg astaxanthin ( n = 14/diet ) daily for 8 wk in a randomized double-blind , placebo-controlled study . Immune response was assessed on wk 0 , 4 and 8 , and tuberculin test performed on wk 8 . RESULTS Plasma astaxanthin increased ( P < 0.01 ) dose-dependently after 4 or 8 wk of supplementation . Astaxanthin decreased a DNA damage biomarker after 4 wk but did not affect lipid peroxidation . Plasma C-reactive protein concentration was lower ( P < 0.05 ) on wk 8 in subjects given 2 mg astaxanthin . Dietary astaxanthin stimulated mitogen-induced lymphoproliferation , increased natural killer cell cytotoxic activity , and increased total T and B cell subpopulations , but did not influence populations of Thelper , Tcytotoxic or natural killer cells . A higher percentage of leukocytes expressed the LFA-1 marker in subjects given 2 mg astaxanthin on wk 8 . Subjects fed 2 mg astaxanthin had a higher tuberculin response than unsupplemented subjects . There was no difference in TNF and IL-2 concentrations , but plasma IFN-gamma and IL-6 increased on wk 8 in subjects given 8 mg astaxanthin . CONCLUSION Therefore , dietary astaxanthin decreases a DNA damage biomarker and acute phase protein , and enhances immune response in young healthy females .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20205737"}
{"sentence": "The suppression of MAPK and oxidative stress could be an important anti-inflammatory mechanism . Fucoidan regulates MAPK activity in several cell lines . However , the mechanism for the anti-inflammatory and oxidative stress effect of low molecular weight fucoidan ( LMWF ) is poorly understood in RAW264.7 cells . The objective of this study was to examine the critical role of LMWF during LPS-induced inflammation in RAW264.7 cells . To determine the potential role of LMWF , we analysed pro-inflammatory cytokine , transcription factor , inflammation-related and oxidative stress related protein expression in vitro during LPS-induced inflammation in RAW264.7 cells . In this study , we demonstrated the anti-inflammatory effects of LMWF on LPS-induced inflammation in macrophages through the regulation of signalling pathways , including its effect on the attenuation of inflammatory cytokines , such as IL-1\u03b2 , IL-1 and TNF-\u03b1 , and the degradation of phosphorylated p38 MAPK , ERK1/2 and JNK . This study also demonstrates that LMWF might block NO as well as the expression of reactive oxygen species ( ROS ) , which subsequently inhibits the iNOS and COX-2 expression induced by LPS . Based on these findings , we suggest that LMWF might have great potential as an external pathogen prevention and intervention agent for inflammatory diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23006539"}
{"sentence": "Although prostate cancer ( CaP ) is the most frequently diagnosed malignant tumor in American men , the mechanisms underlying the development and progression of CaP remain largely unknown . Recent studies have shown that downregulation of the microRNA miR-124 occurs in several types of human cancer , suggesting a tumor suppressive function of miR-124 . Until now , however , it has been unclear whether miR-124 is associated with CaP . In the present study , we completed a series of experiments to understand the functional role of miR-124 in CaP . We detected the expression level of miR-124 in clinical CaP tissues , evaluated the influence of miR-124 on the growth of CaP cells and investigated the mechanism underlying the dysregulation of miR-124 . We found that ( i ) miR-124 directly targets the androgen receptor ( AR ) and subsequently induces an upregulation of p53 ; ( ii ) miR-124 is significantly downregulated in malignant prostatic cells compared to benign cells , and DNA methylation causes the reduced expression of miR-124 ; and ( iii ) miR-124 can inhibit the growth of CaP cells in vitro and in vivo . Data from this study revealed that loss of miR-124 expression is a common event in CaP , which may contribute to the pathogenesis of CaP . Our studies also suggest that miR-124 is a potential tumor suppressive gene in CaP , and restoration of miR-124 expression may represent a novel strategy for CaP therapy.Oncogene advance online publication , 15 October 2012 ; doi:10.1038/onc.2012.425 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23069658"}
{"sentence": "BACKGROUND Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis . We postulated that therapeutic concentrations of aspirin and pravastatin , especially in combination , may suppress oxidative stress and inflammation in endothelial cells , and this concept was examined in human coronary artery endothelial cells ( HCAECs ) . METHODS Human coronary artery endothelial cells were cultured and treated with oxidized-low density lipoprotein ( ox-LDL , 60 microg/ml for 24 hours ) alone , or pre-treated with aspirin ( 1 , 2 or 5 mmol/L ) , pravastatin ( 1 , 5 or 10 micromol/L ) or their combination ( 1 mmol/L aspirin and 5 micromol/L pravastatin ) , followed by ox-LDL treatment . After respective treatment , superoxide anion production , p38 mitogen activated protein kinase and transcription factor NF-kappaB activation , protein expression of lectin-like ox-LDL receptor-1 ( LOX-1 ) and adhesion molecules , and monocyte adhesion were measured . RESULTS Ox-LDL treatment greatly elicited its receptor LOX-1 expression , superoxide anion production and inflammatory response , which were minimally affected by low concentration of aspirin ( 1 mmol/L ) or pravastatin ( 5 micromol/L ) , but were markedly decreased by their combination . Activation of p38 mitogen activated protein kinase and NF-kappaB , the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-1 , which were only mildly affected by aspirin or pravastatin alone , were significantly attenuated by their combination . As a consequence , monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents . Well-known anti-oxidants alpha-tocopherol and gamma-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin . CONCLUSIONS These studies point to a positive interaction between aspirin and pravastatin with regard to endothelial biology . Anti-oxidant and subsequent anti-inflammatory effect may be one of the potential underling mechanisms .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20819511"}
{"sentence": "BACKGROUND Modulation of the expression of retinoic acid receptors ( RAR ) alpha and gamma in adult rat prostate by testosterone ( T ) suggests that RAR signaling events might mediate some of the androgen effects on prostate cells . METHOD In this study , we examined the interactions between T and retinoic acid ( RA ) in cell growth of human prostate carcinoma cells , LNCaP , and their relationship with the expression of RAR and epidermal growth factor receptor ( EGF-R ) . RESULTS Both T and RA , when administered alone , stimulated 3H-thymidine incorporation in LNCaP cells in a dose-dependent manner ; the effect of each agent was reciprocally attenuated by the other agent . Testosterone treatment of LNCaP cells also resulted in dose dependent , biphasic increases in RAR alpha and gamma mRNAs ; increases paralleled that of 3H-thymidine incorporation and were attenuated by the presence of 100 nM RA . These results suggest a link between RAR signaling and the effect of T on LNCaP cell growth . Gel electrophoretic mobility shift assays revealed the presence of putative androgen responsive element ( ARE ) in the promoter region of RAR alpha gene , suggesting that a direct AR-DNA interaction might mediate the effects of T on RAR alpha gene . Furthermore , treatment of LNCaP cells with 20 nM T resulted in an increase in EGF-R . In contrast , EGF-R was suppressed by 100 nM RA that also suppressed the effect of T. CONCLUSIONS Current results demonstrate interactions between T and RA in the expression of RARs and cell growth in LNCaP cells . The presence of putative ARE in the promoter of the RAR alpha gene suggests that AR-DNA interaction might mediate the effects of T on RAR alpha gene . The opposite effects of T and RA on the expression of RAR and EGF-R suggest that signal events of these receptors might be involved in the interaction between T and RA in the control of LNCaP cell growth .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12069693"}
{"sentence": "The current study was undertaken to study the effect of a macerated extract of Nigella sativa seeds in normal as well as in tumour bearing mice against gamma radiation-induced cellular damage to normal tissues . This was done to mimic the clinical setting where in , normal tissues of cancer patients undergoing radiotherapy are exposed to the deleterious effects of radiation . The protection of cellular DNA was analysed in peripheral blood leucocytes of whole body irradiated mice following pretreatment with macerated extract of Nigella sativa seeds ( 100 mg/kg ) , using alkaline comet assay , and also estimating biochemical and blood parameters such as levels of antioxidant enzymes superoxide dismutase and catalase , thiobarbituric acid reactive substances and protein oxidation in organs such as spleen , liver , brain and intestine haemoglobin and total leucocyte count , respectively . The results showed that the macerated extract of Nigella sativa seeds protected the liver , spleen , brain and intestines both in normal as well as tumour bearing mice . This study concludes that macerated extract of Nigella sativa seeds has protective effects against radiation-induced damage and biochemical alterations which could be attributed to the ability to scavenge free radicals and its antioxidant properties . Hence macerated extract of Nigella sativa seeds , could be used in combination with radiation to protect against oxidative stress in normal tissues and improving the quality of life of cancer patients by mitigating unwanted side effects of radiation in normal tissues .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23716868"}
{"sentence": "BACKGROUND/AIMS Adenocarcinoma of the gallbladder is a highly malignant neoplasm. p16 is a tumor suppressor gene protein , which is a cyclin-dependent kinase inhibitor that regulates the G1-S phase of the cell cycle . The purpose of the present study was to investigate the expression of p16 in gallbladder carcinoma and its precancerous conditions and to examine the relationship between p16 expression and clinicopathological parameters . METHODOLOGY Formalin-fixed , paraffin-embedded tissue sections from 20 cases of normal gallbladder , 20 cases of chronic cholecystitis , 20 cases of gallbladder adenoma , 20 cases of dysplasia , and 58 cases of adenocarcinoma were examined . The expression of p16 was evaluated by immunohistochemical analysis . RESULTS In normal gallbladder , no expression of p16 was found . In chronic cholecystitis , expression of p16 was not found . In gallbladder adenomas , expression of p16 was found in 20% ( 4/20 ) . In low grade dyspalsias , expression of p16 was not found . In high grade dysplasias , p16 expression was present in 45.0% ( 9/20 ) . In gallbladder adenocarcinomas , p16 expression was found in 27.6% ( 16/58 ) . Expression of p16 correlated significantly with histologic grade ( p < 0.05 ) . No correlation was found between p16 expression and age , gender , tumor size , gross type , location , vascular invasion , lymph node metastasis , and TNM stage , respectively . CONCLUSIONS P16 protein overexpression is an early and relatively common event in carcinogenesis of gallbladder carcinoma . Expression of p16 protein is absent in normal or chronic cholecystitis . Expression of p16 may be an ancillary diagnostic marker of gallbladder carcinoma and its precancerous conditions .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20422865"}
{"sentence": "BACKGROUND Luteolin is a 3',4',5,7-tetrahydroxyflavone found in various fruits and vegetables . We have shown previously that luteolin reduces HT-29 cell growth by inducing apoptosis and cell cycle arrest . The objective of this study was to examine whether luteolin downregulates the insulin-like growth factor-I receptor ( IGF-IR ) signaling pathway in HT-29 cells . METHODS In order to assess the effects of luteolin and/or IGF-I on the IGF-IR signaling pathway , cells were cultured with or without 60 \u03bcmol/L luteolin and/or 10 nmol/L IGF-I . Cell proliferation , DNA synthesis , and IGF-IR mRNA levels were evaluated by a cell viability assay , [ 3H]thymidine incorporation assays , and real-time polymerase chain reaction , respectively . Western blot analyses , immunoprecipitation , and in vitro kinase assays were conducted to evaluate the secretion of IGF-II , the protein expression and activation of IGF-IR , and the association of the p85 subunit of phophatidylinositol-3 kinase ( PI3K ) with IGF-IR , the phosphorylation of Akt and extracellular signal-regulated kinase ( ERK)1/2 , and cell division cycle 25c ( CDC25c ) , and PI3K activity . RESULTS Luteolin ( 0 - 60 \u03bcmol/L ) dose-dependently reduced the IGF-II secretion of HT-29 cells . IGF-I stimulated HT-29 cell growth but did not abrogate luteolin-induced growth inhibition . Luteolin reduced the levels of the IGF-IR precursor protein and IGF-IR transcripts . Luteolin reduced the IGF-I-induced tyrosine phosphorylation of IGF-IR and the association of p85 with IGF-IR . Additionally , luteolin inhibited the activity of PI3K activity as well as the phosphorylation of Akt , ERK1/2 , and CDC25c in the presence and absence of IGF-I stimulation . CONCLUSIONS The present results demonstrate that luteolin downregulates the activation of the PI3K/Akt and ERK1/2 pathways via a reduction in IGF-IR signaling in HT-29 cells ; this may be one of the mechanisms responsible for the observed luteolin-induced apoptosis and cell cycle arrest .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22269172"}
{"sentence": "Ataxia-telangiectasia mutated ( ATM ) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity . However , ATM also has been implicated in metabolic regulation , and ATM deficiency is associated with elevated reactive oxygen species ( ROS ) . ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer , underscoring the importance of cellular pathways involved in redox homeostasis . We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS . We show that in response to elevated ROS , ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy . Importantly , elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin , which also rescues lymphomagenesis in Atm-deficient mice . Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy , identifying an integration node for the cellular damage response with key pathways involved in metabolism , protein synthesis , and cell survival .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "20160076"}
{"sentence": "Ubiquitylation is a reversible post-translational modification that has emerged as a key regulator of most complex cellular processes . It may rival phosphorylation in scope and exceed it in complexity . The dynamic nature of ubiquitylation events is important for governing protein stability , maintaining ubiquitin homeostasis and controlling ubiquitin-dependent signalling pathways . The human genome encodes active deubiquitylating enzymes ( DUBs , also referred to as deubiquitinases ) , which exhibit distinct specificity profiles towards the various ubiquitin chain topologies . As a result of their ability to reverse ubiquitylation , these enzymes control a broad range of key cellular processes . In this Commentary we discuss the cellular functions of DUBs , such as their role in governing membrane traffic and protein quality control . We highlight two key signalling pathways--the Wnt and transforming growth factor \\u03b2 ( TGF-\\u03b2 ) pathways , for which dynamic ubiquitylation has emerged as a key regulator . We also discuss the roles of DUBs in the nucleus , where they govern transcriptional activity and DNA repair pathways .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22357969"}
{"sentence": "BACKGROUND Nucleolin is one of the major proteins of the nucleolus , but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in tumorigenesis and angiogenesis . Emerging evidence suggests that the cell-surface expressed nucleolin is a strategic target for an effective and nontoxic cancer therapy . METHODOLOGY/PRINCIPAL FINDINGS By monitoring the expression of nucleolin mRNA , and by measuring the level of nucleolin protein recovered from the surface and nucleus of cells , here we show that the presence of nucleolin at the cell surface is dependent on the constant induction of nucleolin mRNA . Indeed , inhibitors of RNA transcription or translation block expression of surface nucleolin while no apparent effect is observed on the level of nucleolin in the nucleus . The estimated half-life of surface nucleolin is less than one hour , whereas that of nuclear nucleolin is more than 8 hours . Nucleolin mRNA induction is reduced markedly in normal fibroblasts that reach confluence , while it occurs continuously even in post-confluent epithelial tumor cells consistent with their capacity to proliferate without contact inhibition . Interestingly , cold and heat shock induce nucleolin mRNA concomitantly to enhanced mRNA expression of the heat shock protein 70 , thus suggesting that surface nucleolin induction also occurs in response to an environmental insult . At the cell surface , one of the main functions of nucleolin is to shuttle specific extracellular ligands by an active transport mechanism , which we show here to be calcium dependent . CONCLUSION/SIGNIFICANCE Our results demonstrate that the expression of surface nucleolin is an early metabolic event coupled with tumor cell proliferation and stress response . The fact that surface nucleolin is constantly and abundantly expressed on the surface of tumor cells , makes them a preferential target for the inhibitory action of anticancer agents that target surface nucleolin .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "21203423"}
{"sentence": "The aim of the present study was to investigate the apoptosis of human ovarian cancer cell lines , A2780 and CP70 , induced by a novel curcumin analogue , B19 . The proliferation of cells was detected with methyl thiazolyl tetrazolium ( MTT ) assay and apoptosis was examined by flow cytometry . Reactive oxygen species ( ROS ) were assessed by the fluorescent indicator DCF-DA . The protein expression of the endoplasmic reticulum ( ER ) stress pathways , GRP78 , XBP-1 , ATF-4 and CHOP , was examined with Western blotting . A growth inhibitory effect was observed after treatment with B19 in a dose-dependent manner and with more potential than curcumin . At 20 \ufffdM , B19 induced significant apoptosis in CP70 cells . Furthermore , B19 induced the ER stress response , while curcumin had no effect on ER stress . These results suggest that B19 has more effective antitumor properties than curcumin , and is associated with the activation of ER stress and ROS in ovarian cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22159410"}
{"sentence": "OBJECTIVE To evaluate the Expression and correlation of cyclooxygenase-2 ( COX-2 ) and vascular endothelial growth factor receptor ( VEGF ) in nasopharyngeal carcinoma . METHOD In this study , expression levels of COX-2 , VEGF were examined in 58 patients with nasopharyngeal carcinoma and 38 patients with inflammation in nasopharyngeal mucosa by immunohistochemistry method . RESULT The expression of COX-2 , VEGF were higher in nasopharyngeal carcinoma than those in nasopharyngeal mucosa ( P < 0.05 ) , and they had some correlation with the invasion and lymphatic metastasis and with the clinical stage of nasopharyngeal carcinoma ( P < 0.05 ) . The expression of COX-2 was positively correlated with that of VEGF ( P < 0.05 ) . CONCLUSION The coexpression of COX-2 and VEGF may play animportant role in the carcinogenesis and development of nasopharyngeal carcinoma , and they may prom ( see text ) lymph node metastasis of nasopharyngeal carcinoma .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 1, 1], "id": "22803408"}
{"sentence": "In normal tissues , strict control of tissue size is achieved by regulating cell numbers . The mechanism that controls total cell number is known as contact inhibition of growth and it depends on the NF2/Merlin pathway . Negative regulation of this pathway by deleterious mutations or by oncogenes results in cell transformation and tumor progression . Here we provide evidence that the CD43 sialomucin cooperates with oncogenic signals to promote cell transformation by abrogating the contact inhibition of growth through a molecular mechanism that involves AKT-dependent Merlin phosphorylation and degradation . Accordingly , inhibition of endogenous CD43 expression by RNA interference in lung , cervix and colon human cancer cells impaired tumor growth in vivo . These data underscore a previously unidentified role for CD43 in non-hematopoietic tumor progression .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "24260485"}
{"sentence": "The calcium-calmodulin activated kinase CaMKII mediates many forms of learning and memory . Activity-regulated translocation of CaMKII to synapses is important for its functions in synaptic plasticity . Here , we tested the role of the NMDA receptor subunit GluN2B in recruiting CaMKII\\u03b1 to synapses with different paradigms : global bath stimulation of NMDA receptors , a chemical long term potentiation ( cLTP ) protocol that selectively activates synaptic NMDA receptors , or local stimulation of NMDA receptors at a contiguous set of synapses that triggers a propagating synaptic accumulation of CaMKII . Global or cLTP-induced synaptic accumulation of CaMKII\\u03b1 occurred in wild-type but not sister GluN2B -/- cultured mouse hippocampal neurons . Expression of YFP-GluN2B , but not a similar level of YFP-GluN2A , rescued global and cLTP-induced CaMKII\\u03b1 translocation . Using chimeric constructs , the pore-forming extracellular and membrane domains of GluN2A combined with the cytoplasmic tail of GluN2B were sufficient to rescue CaMKII\\u03b1 translocation , whereas the reverse chimera was ineffective . Furthermore , the dual point mutation R1300Q,S1303D in GluN2B that blocks interaction of this high affinity site with CaMKII abolished rescue . Thus , CaMKII binding to GluN2B is required for global and cLTP-induced synaptic accumulation of CaMKII\\u03b1 . However , surprisingly , locally induced propagating synaptic accumulation of CaMKII\\u03b1 occurred normally in GluN2B -/- neurons , indistinguishably from wild-type . Thus , synaptic trapping of CaMKII during locally induced propagating translocation occurs by different mechanisms and molecular partners compared with global stimulation and cLTP paradigms . These findings underscore the complex regulatory properties and molecular interactions of CaMKII\\u03b1 , a key player in synaptic plasticity .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22902837"}
{"sentence": "Certain components of apples have been shown to prevent cancer growth and impede cancer progression . We hypothesized that extracted apple polysaccharides ( APs ) might , therefore , have anticancer effects , through a mechanism involving the induction of apoptosis in cancer cells , partly via the NF-\u03baB pathway . Two human colorectal cancer ( CRC ) cell lines , HT-29 and SW620 , were exposed to different concentrations of APs ( 0.01 , 0.1 or 1 mg/ml ) . Cell apoptosis was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay by flow cytometry and incorporation of 5'-bromodeoxyuridine ( BrdU ) into DNA to identify the proliferating cell fraction , using fluorescence microscopy in vitro . The protein levels of NF-\u03baB/p65 , I-\u03baB\u03b1 , pI-\u03baB\u03b1 , Bax , Bcl-xl and Bcl-2 were evaluated by western blotting . The target sites of APs on CRC cells were assessed by flow cytometry . At concentrations of 0.1 and 1 mg/ml , APs showed apoptosis-inducing effects , increased expressions of Bax , nuclear p65 and cytoplasmic pI-\u03baB\u03b1 , and decreased expressions of Bcl-2 , Bcl-xl and cytoplasmic I-\u03baB\u03b1 . APs induced apoptosis by slightly activating the NF-\u03baB pathway ; the AP target site could be the Toll-like receptor 4 on the cell membrane . These results demonstrate the potential of APs as agents for clinical prevention and treatment of CRC .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22470124"}
{"sentence": "Autophagy is a catabolic process by which a cell degrades its intracellular materials to replenish itself . Induction of autophagy under various cellular stress stimuli can lead to either cell survival or cell death via apoptotic and/or autophagic ( nonapoptotic ) pathways . The NSAID sulindac sulfide induces apoptosis in colon cancer cells . Here , we show that inhibition of autophagy under serum-deprived conditions resulted in significant reductions of sulindac sulfide-induced apoptosis in HT-29 colon cancer cells . In contrast , inhibition of autophagy under conditions where serum is available significantly increased sulindac sulfide-induced apoptosis in HT-29 cells . We previously showed that the apoptosis inhibitor , survivin , plays a role in regulating NSAID-induced apoptosis and autophagic cell death . Here , we show that survivin protein half-life is increased in the presence of autophagy inhibitors under serum-deprived conditions , but not under conditions when serum is available . Thus , the increased levels of survivin may be a factor contributing to inhibition of sulindac sulfide-induced apoptosis under serum-deprived conditions . These results suggest that whether a cell lives or dies due to autophagy induction depends on the balance of factors that regulate both autophagic and apoptotic processes .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23431290"}
{"sentence": "Histopathological features of the lymph node involvement were studied in 104 patients with thoracic esophageal cancer who underwent subtotal esophagectomy combined with extended radical lymph adenectomy in cervicothoracoabdominal region . Metastatic involvement was found in a total number of 503 lymph nodes from 73 patients by histologic examination . The mean of long and short diameter was found to be less than 5mm in 125 ( 24.9% ) of these 503 nodes . The involved area on the section was less than one third in 149 nodes ( 29.6% ) , and was significantly smaller in mediastinal lymph nodes than those in cervical or abdominal ones . Sixty-seven ( 13.3% ) of 503 nodes were partially invaded by micrometastasis of 1mm or less in diameter . Micrometastasis also more frequently occurred in mediastinal nodes with a statistically significant difference . Extranodal proliferation ( ENP ) of cancer cells was found in 106 nodes ( 21.1% ) , and extranodal lymphatic and/or blood vessel invasion ( ENly , v ) was also recognized in 60 nodes ( 11.9% ) . Micrometastasis and ENP with or without ENly , v were found in 24 ( 32.9% ) and 29 ( 39.7% ) of 73 patients with positive lymph node metastasis , respectively . Postoperative survival rate in patients with micrometastasis and/or ENP with or without ENly , v was inferior to that in patients with neither of them .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1435691"}
{"sentence": "Lung cancer is primarily caused by exposure to tobacco smoke . Tobacco smoke contains numerous carcinogens , including polycyclic aromatic hydrocarbons ( PAH ) . The most common PAH studied is benzo[a]pyrene ( B[a]P ) . B[a]P is metabolically activated through multiple routes , one of which is catalyzed by aldo-keto reductase ( AKR ) to B[a]P-7,8-dione ( BPQ ) . BPQ undergoes a futile redox cycle in the presence of NADPH to generate reactive oxygen species ( ROS ) . ROS , in turn , damages DNA . Studies with a yeast p53 mutagenesis system found that the generation of ROS by PAH o-quinones may contribute to lung carcinogenesis because of similarities between the patterns ( types of mutations ) and spectra ( location of mutations ) and those seen in lung cancer . The patterns were dominated by G to T transversions , and the spectra in the experimental system have mutations at lung cancer hotspots . To address repair mechanisms that are responsible for BPQ induced damage we observed the effect of mutating two DNA repair genes OGG1 and APE1 ( APN1 in yeast ) and tested them in a yeast reporter system for p53 mutagenesis . There was an increase in both the mutant frequency and the number of G:C/T:A transversions in p53 treated with BPQ in ogg1 yeast but not in apn1 yeast . Knocking out APN2 increased mutagenesis in the apn1 cells . In addition , we did not find a strand bias on p53 treated with BPQ in ogg1 yeast . These studies suggest that Ogg1 is involved in repairing the oxidative damage caused by BPQ , Apn1 and Apn2 have redundant functions and that the stand bias seen in lung cancer may not be due to impaired repair of oxidative lesions .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23117049"}
{"sentence": "Ataxia telangiectasia mutated ( ATM ) kinase is a central player in cellular response to DNA damage . Phosphorylation of the histone H2AX by ATM is required for the accumulation of repair proteins at the sites of double-strand breaks . Recently , it was reported that the histone acetyltransferase Tat interactive protein-60 ( IPP60 ) is required to acetylate ATM prior to its activation . The RuvB-like proteins TIP48 and TIP49 are known to be necessary for the assembly and functional activity of the TIP60 acetyltransferase complex . In the present communication , we investigated the requirements of IIP48 and IIP49 for ATM activation by monitoring the cell cycle distribution and H2AX phosphorylation after irradiation of IIP48- and IIP49-depleted cells . We found that neither the cell cycle norgammay-H2AX were affected in IIP48- and IIP49-silenced cells , suggesting that the IIP60 chromatin modification complex is not engaged in DNA damage signaling upstream of ATM .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20355335"}
{"sentence": "Estrogens play essential roles in the progression of mammary and prostatic diseases . The transcriptional effects of estrogens are transduced by two estrogen receptors , ER\u03b1 and ER\u03b2 , which elicit opposing roles in regulating proliferation : ER\u03b1 is proliferative while ER\u03b2 is anti-proliferative . Exogenous expression of ER\u03b2 in ER\u03b1-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo , suggesting that ER\u03b2 might oppose ER\u03b1's proliferative effects via formation of ER\u03b1/\u03b2 heterodimers . Despite biochemical and cellular evidence of ER\u03b1/\u03b2 heterodimer formation in cells co-expressing both receptors , the biological roles of the ER\u03b1/\u03b2 heterodimer remain to be elucidated . Here we report the identification of two phytoestrogens that selectively activate ER\u03b1/\u03b2 heterodimers at specific concentrations using a cell-based , two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity . Using ER\u03b1/\u03b2 heterodimer-selective ligands at defined concentrations , we demonstrate that ER\u03b1/\u03b2 heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms . Furthermore , using Automated Quantitative Analysis ( AQUA ) to examine nuclear expression of ER\u03b1 and ER\u03b2 in human breast tissue microarrays , we demonstrate that ER\u03b1 and ER\u03b2 are co-expressed in the same cells in breast tumors . The co-expression of ER\u03b1 and ER\u03b2 in the same cells supports the possibility of ER\u03b1/\u03b2 heterodimer formation at physio- and pathological conditions , further suggesting that targeting ER\u03b1/\u03b2 heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ER\u03b1 and ER\u03b2 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22347418"}
{"sentence": "The ARF locus is frequently inactivated in human cancer . The oncosuppressor ARF has indeed been described as a general sensor for different situation of cellular stress . We have previously demonstrated that ARF deficiency severely impairs inflammatory responses in vitro and in vivo , establishing a role for ARF in the regulation of innate immunity . The aim of the present work was to get further insights into the immune functions of ARF and to evaluate its possible contribution to the polarization of macrophages toward the M1 or M2 phenotype . Our results demonstrate that resting Arf(-/-) macrophages express high levels of Ym1 and Fizz-1 , two typical markers of alternatively-activated macrophages ( M2 ) . Additionally , Arf(-/-) peritoneal macrophages showed an impaired response to lipopolysaccharide ( a classical inducer of M1 polaryzation ) and a reduced production of pro-inflammatory cytokines/chemokines . Moreover , upon stimulation with interleukin-4 ( IL-4 ) , an inducer of the M2 phenotype , well established M2 markers such as Fizz-1 , Ym1 and arginase-1 were upregulated in Arf(-/-) as compared with wild type macrophages . Accordingly , the cytokine and chemokine profile associated with the M2 phenotype was significantly overexpressed in Arf(-/-) macrophages responding to IL-4 . In addition , multiple pro-angiogenic factors such as VEGF and MMP-9 were also increased . In summary , these results indicate that ARF contributes to the polarization and functional plasticity of macrophages .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23243586"}
{"sentence": "Normal human lung fibroblast diploid cells , WI-38 , become senescent after a definite number of divisions . VA-13 is a line of immortalized cells established by transformation of WI-38 cells by SV40 virus . To determine whether SV40 large T ( SV40-T ) antigen is essential for this immortalization of WI-38 cells we introduced an antisense gene for T antigen into VA-13 . Two morphologically different types of antisense transformant ( VA-AS5-8 and VA-AS37-8 ) were obtained . In both antisense transformants the expression of T antigen was reduced by more than 70% as compared to that in the parent cells . The morphology of the antisense transformants indicated a partial conversion to the senescent phenotype of WI-38 . The relative number of cells in the S phase of the antisense transformants was decreased as compared to that in cultures of VA-13 and about 50% of cells were at G1/0 . The doubling time of the transformants was prolonged to close to the doubling time of WI-38 . The level of expression of retinoblastoma protein ( pRB ) complexed with SV40-T antigen of the antisense transformants was significantly decreased although the level of total pRB was much higher than that in VA-13 . The pRB was present exclusively in the underphosphorylated form . Thus , the decreased level of formation of the complex between SV40-T and pRB or the underphosphorylation of pRB may explain the suppression of growth of antisense transformants . Together , these results show that an antisense gene for SV40-T antigen can efficiently block the cell proliferation and the cell immortalization of VA-13 cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "1338304"}
{"sentence": "BACKGROUND Though an increased efficacy of carmustine and temozolomide ( TMZ ) has been demonstrated by inactivation of O(6)-methylguanine-DNA methyltransferase ( MGMT ) with O(6)-benzyl-guanine ( BG ) in human pancreatic tumors refractive to alkylating agents , the regulatory mechanisms have not been explored . METHODS The effects of TMZ and BG on apoptosis , cell growth , the mitotic index , cell cycle distribution , and protein expression were studied by TUNEL , cell counting , flow cytometry , and Western blot analysis , respectively . RESULTS The wt-p53 human pancreatic tumor cell line Capan-2 and p53-efficient mouse embryonic fibroblasts ( MEFs ) were more responsive to treatment with TMZ + BG than mutant p53 Capan-1 and p53-null MEFs . S phase delay with a subsequent G2/M arrest was observed in Capans in response to BG + TMZ . The G1-to-S transition delay in Capan-2 was associated with p53-dependent apoptosis and was distinctly different from the presumed mismatch repair ( MMR ) killing operative during the G2/M arrest . The effect of p53 on BG + TMZ toxicity was supported by a marked change in apoptosis when p53 function was restored/inactivated . There was an early induction of MMR proteins in p53-efficient lines . CONCLUSION p53 provokes a classic proapoptotic response by delaying G1-to-S progression , but it may also facilitate cell killing by enhancing MMR-related cell cycle arrest and cell death .", "label": [0, 0, 0, 0, 1, 1, 0, 1, 1, 0], "id": "20980775"}
{"sentence": "OBJECTIVE In addition to its effects on cholesterol levels , apoE3 has lipid-independent effects that contribute to cardiovascular protection ; one of these effects is the ability to inhibit cell cycling in VSMCs . The goal of this study was to identify and characterize cell cycle-regulatory mechanisms responsible for the anti-mitogenic effect of apoE . METHODS AND RESULTS Primary VSMCs were stimulated with serum in the absence or presence of apoE3. apoE3 upregulated expression of the cdk inhibitor , p27(kip1) , in primary VSMCs , and this effect required Cox2 and activation of PGI(2)-IP signaling . The microRNA family , miR221/222 has recently been identified as a post-translational regulator of p27 , and apoE3 inhibited miR221/222 expression in a Cox2- and PGI(2)/IP-dependent manner . Moreover , reconstituted miR222 expression was sufficient to override the effects of apoE on p27 expression and S phase entry . The ability to repress expression of miR221/222 is shared by apoE3-containing HDL but is absent from apoA-1 , LDL and apoE-depleted HDL . All three apoE isoforms regulate miR221/222 , and the effect is independent of the C-terminal lipid-binding domain. miR221/222 levels are increased in the aortae of apoE3-null mice and reduced when apoE3 expression is reconstituted by adeno-associated virus infection . Thus , regulation of miR221/222 by apoE3 occurs invivo as well as invitro . CONCLUSIONS ApoE inhibits VSMC proliferation by regulating p27 through miR221/222 . Control of cell cycle-regulatory microRNAs adds a new dimension to the spectrum of cardiovascular protective effects afforded by apoE and apoE-HDL .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23294923"}
{"sentence": "Chromatographic , peptide mapping and mass spectrometric analysis were used to examine hemoglobin ( Hb ) from heavy drinkers and abstainers for alcohol consumption-related modifications . Heavy drinker and abstainer hemoglobin samples contained similar amounts of glycosylated Hb and significantly different ( p < 0.05 ) amounts of \" fast \" hemoglobin . The presence of higher amounts of \" fast \" Hb in heavy drinker relative to abstainer samples suggested the presence of alcohol-consumption related modifications . To further examine Hb for modifications , tryptic peptides of the \" fast \" hemoglobin HbA1c were isolated and analyzed by plasma desorption mass spectrometry ( PDMS). [ 14C]acetaldehyde ( AcH)-Hb was synthesized in vivo for use as a standard . Specific peptides were chosen based on co-migration with radiolabeled peptides from a tryptic digest of the [ 14C]acetaldehyde-Hb . The masses obtained by PDMS for two heavy drinker peptides were identical to two radiolabeled peptides ; the two pairs of peptides co-migrated on HPLC . A comparison of the observed mass for the peptides with the theoretical masses for acetaldehyde-modified Hb peptides suggested that the peptides were AcH-modified alpha and beta chain N-termini of Hb . The modified peptides were found in five of six heavy drinker samples . This is the first description of site-specific AcH-Hb adducts occurring in vivo . The routine detection of such adducts has potential for characterizing usual alcohol intake .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1471764"}
{"sentence": "DNA damage signaling and repair take place in a chromatin context . Consequently , chromatin-modifying enzymes , including adenosine triphosphate-dependent chromatin remodeling enzymes , play an important role in the management of DNA double-strand breaks ( DSBs ) . Here , we show that the p400 ATPase is required for DNA repair by homologous recombination ( HR ) . Indeed , although p400 is not required for DNA damage signaling , DNA DSB repair is defective in the absence of p400 . We demonstrate that p400 is important for HR-dependent processes , such as recruitment of Rad51 to DSB ( a key component of HR ) , homology-directed repair , and survival after DNA damage . Strikingly , p400 and Rad51 are present in the same complex and both favor chromatin remodeling around DSBs . Altogether , our data provide a direct molecular link between Rad51 and a chromatin remodeling enzyme involved in chromatin decompaction around DNA DSBs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23266955"}
{"sentence": "Altered p53 protein is prevalently associated with the pathologic class of triple-negative breast cancers and loss of p53 function has recently been linked to the induction of an epithelial-mesenchymal transition ( EMT ) and acquisition of stemness properties . We explored the association between TP53 mutational status and expression of some genes involved in the canonical TGF-\\u03b2 signaling pathway ( the most potent EMT inducer ) and in two early EMT associated events : loss of cell polarity and acquisition of stemness-associated features . We used a publicly accessible microarray dataset consisting of 251 p53-sequenced primary breast cancers . Statistical analysis indicated that mutant p53 tumors ( especially those harboring a severe mutation ) were consistent with the aggressive class of triple-negative cancers and that , differently from cell cultures , surgical tumors underexpressed some TGF-\\u03b2 related transcription factors known as involved in EMT ( ID1 , ID4 , SMAD3 , SMAD4 , SMAD5 , ZEB1 ) . These unexpected findings suggest an interesting relationship between p53 mutation , mammary cell dedifferentiation , and the concomitant acquisition of stemlike properties ( as indicated by the overexpression of PROM1 and NOTCH1 genes ) , which improve tumor cells aggressiveness as indicated by the overexpression of genes associated with cell proliferation ( CDK4 , CDK6 , MKI67 ) and migration ( CXCR4 , MMP1 ) .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22899882"}
{"sentence": "BACKGROUND Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer . Despite impressive clinical responses initially , the majority of patients eventually develop resistance to Taxol . Lactate dehydrogenase-A ( LDH-A ) is one of the predominant isoforms of LDH expressed in breast tissue , which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism . In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells . RESULTS Taxol-resistant subclones , derived from the cancer cell line MDA-MB-435 , sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not . The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells . The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol . A higher sensitivity to the specific LDH inhibitor , oxamate , was found in the Taxol-resistant cells . Furthermore , treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells . CONCLUSION LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol . This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance . To our knowledge , this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells . This study provides valuable information for the future development and use of targeted therapies , such as oxamate , for the treatment of patients with Taxol-resistant breast cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20144215"}
{"sentence": "Here , we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth . For this purpose , we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors , such as p16(INK4A) , p19(ARF) or p21(WAF1/CIP1) . Interestingly , all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy ( either at baseline or after starvation ) , as well as significant mitochondrial dysfunction . Most importantly , these senescent fibroblasts also dramatically promoted tumor growth ( up to without any comparable increases in tumor angiogenesis . Conversely , we generated human breast cancer cells ( MDA-MB-231 cells ) overexpressing CDK inhibitors , namely p16(INK4A) or p21(WAF1/CIP1) . Senescent MDA-MB-231 cells also showed increased expression of markers of cell cycle arrest and autophagy , including \u03b2-galactosidase , as predicted . Senescent MDA-MB-231 cells had retarded tumor growth , with up to a near 2-fold reduction in tumor volume . Thus , the effects of CDK inhibitors are compartment-specific and are related to their metabolic effects , which results in the induction of autophagy and mitochondrial dysfunction . Finally , induction of cell cycle arrest with specific inhibitors ( PD0332991 ) or cellular stressors [ hydrogen peroxide ( H(2)O(2) ) or starvation ] indicated that the onset of autophagy and senescence are inextricably linked biological processes . The compartment-specific induction of senescence ( and hence autophagy ) may be a new therapeutic target that could be exploited for the successful treatment of human breast cancer patients .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22935696"}
{"sentence": "PURPOSE Genomic complexity is present in approximately 15% to 30% of all chronic lymphocytic leukemia ( CLL ) and has emerged as a strong independent predictor of rapid disease progression and short remission duration in CLL . We conducted this study to advance our understanding of the causes of genomic complexity in CLL . EXPERIMENTAL DESIGN We have obtained quantitative measurements of radiation-induced apoptosis and radiation-induced ATM autophosphorylation in purified CLL cells from 158 and 140 patients , respectively , and have used multivariate analysis to identify independent contributions of various biological variables on genomic complexity in CLL . RESULTS Here , we identify a strong independent effect of radiation resistance on elevated genomic complexity in CLL and describe radiation resistance as a predictor for shortened CLL survival . Furthermore , using multivariate analysis , we identify del17p/p53 aberrations , del11q , del13q14 type II ( invariably resulting in Rb loss ) , and CD38 expression as independent predictors of genomic complexity in CLL , with aberrant p53 as a predictor of approximately 50% of genomic complexity in CLL . Focusing on del11q , we determined that normalized ATM activity was a modest predictor of genomic complexity but was not independent of del11q . Through single nucleotide polymorphism array-based fine mapping of del11q , we identified frequent monoallelic loss of Mre11 and H2AFX in addition to ATM , indicative of compound del11q-resident gene defects in the DNA double-strand break response . CONCLUSIONS Our quantitative analysis links multiple molecular defects , including for the first time del11q and large 13q14 deletions ( type II ) , to elevated genomic complexity in CLL , thereby suggesting mechanisms for the observed clinical aggressiveness of CLL in patients with unstable genomes .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20086003"}
{"sentence": "Here , we identified the milk protein \u03b1-casein as a novel suppressor of tumor growth and metastasis . Briefly , Met-1 mammary tumor cells expressing \u03b1-casein showed a reduction in tumor growth and a near 10-fold decrease in experimental metastasis . To identify the molecular mechanism(s) , we performed genome-wide transcriptional profiling . Interestingly , our results show that \u03b1-casein upregulates gene transcripts associated with interferon/STAT1 signaling and downregulates genes associated with \" stemness. \" These findings were validated by immunoblot and FACS analysis , which showed the upregulation and hyperactivation of STAT1 and a decrease in the number of CD44(+) \" cancer stem cells. \" These gene signatures were also able to predict clinical outcome in human breast cancer patients . Thus , we conclude that a lactation-based therapeutic strategy using recombinant \u03b1-casein would provide a more natural and non-toxic approach to the development of novel anticancer therapies .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23047602"}
{"sentence": "BACKGROUND Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis . In recent studies , we demonstrated the ability of lovastatin , an inhibitor of mevalonate synthesis , to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor ( EGFR ) activation . METHODOLOGY/PRINCIPAL FINDINGS In this study , we evaluated the effects of lovastatin on the activity of the LKB1/AMPK pathway that is activated upon cellular energy shortage and can interact with the above pathways . In the squamous cell carcinoma ( SCC ) cell lines SCC9 and SCC25 , lovastatin treatment ( 1-25 \ufffdM , 24 hrs ) induced LKB1 and AMPK activation similar to metformin ( 1-10 mM , 24 hrs ) , a known inducer of this pathway . Lovastatin treatment impaired mitochondrial function and also decreased cellular ADP/ATP ratios , common triggers of LKB1/AMPK activation . The cytotoxic effects of lovastatin were attenuated in LKB1 null MEFs indicating a role for this pathway in regulating lovastatin-induced cytotoxicity . Of clinical relevance , lovastatin induces synergistic cytotoxicity in combination with the EGFR inhibitor gefitinib . In LKB1 deficient ( A549 , HeLa ) and expressing ( SCC9 , SCC25 ) cell lines , metformin enhanced gefitinib cytotoxicity only in LKB1 expressing cell lines while both groups showed synergistic cytotoxic effects with lovastatin treatments . Furthermore , the combination of lovastatin with gefitinib induced a potent apoptotic response without significant induction of autophagy that is often induced during metabolic stress inhibiting cell death . CONCLUSION/SIGNIFICANCE Thus , targeting multiple metabolic stress pathways including the LKB1/AMPK pathway enhances lovastatin's ability to synergize with gefitinib in SCC cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23029387"}
{"sentence": "Accumulating evidence from epidemiological studies indicates that chronic inflammation and oxidative stress play critical roles in neoplastic development . The aim of this study was to investigate the anti-inflammatory , anti-oxidative stress activities , and differential regulation of Nrf2-mediated genes by tea Chrysanthemum zawadskii ( CZ ) and licorice Glycyrrhiza uralensis ( LE ) extracts . The anti-inflammatory and anti-oxidative stress activities of hexane/ethanol extracts of CZ and LE were investigated using in vitro and in vivo approaches , including quantitative real-time PCR ( qPCR ) and microarray . Additionally , the role of the transcriptional factor Nrf2 ( nuclear erythroid-related factor 2 ) signaling pathways was examined . Our results show that CZ and LE extracts exhibited potent anti-inflammatory activities by suppressing the mRNA and protein expression levels of pro-inflammatory biomarkers IL-1\u03b2 , IL-6 , COX-2 and iNOS in LPS-stimulated murine RAW 264.7 macrophage cells . CZ and LE also significantly suppressed the NO production of LPS-stimulated RAW 264.7 cells . Additionally , CZ and LE suppressed the NF-\u03baB luciferase activity in human HT-29 colon cancer cells . Both extracts also showed strong Nrf2-mediated antioxidant/Phase II detoxifying enzymes induction . CZ and LE induced NQO1 , Nrf2 , and UGT and antioxidant response element ( ARE)-luciferase activity in human hepatoma HepG2 C8 cells . Using Nrf2 knockout [ Nrf2 ( -/-) ] and Nrf2 wild-type ( +/+ ) mice , LE and CZ showed Nrf2-dependent transactivation of Nrf2-mediated antioxidant and phase II detoxifying genes . In summary , CZ and LE possess strong inhibitory effects against NF-\u03baB-mediated inflammatory as well as strong activation of the Nrf2-ARE-anti-oxidative stress signaling pathways , which would contribute to their overall health promoting pharmacological effects against diseases including cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20967519"}
{"sentence": "BACKGROUND Cellular and clinical sensitivity to ionizing radiation ( IR ) is determined by DNA double-strand breaks ( DSB ) repair . Here , we investigate the molecular mechanism underlying the extreme response of a head and neck tumor case ( SKX ) to standard radiotherapy . METHODS Immunofluorescence ( IF ) was used for the assessment of DSB repair , Western blot and real-time PCR for protein and mRNA expression , respectively . RESULTS SKX cells exhibited a pronounced radiosensitivity associated with numerous residual \\u03b3-H2AX foci after IR . This was not associated with lacking canonical repair proteins . SKX cells did not express any ATM protein . Accordingly , immunoblotting revealed no ATM kinase activity toward substrates such as p-SMC1 , p-CHK2 and p-KAP1 . Sequencing of all 66 exons of ATM showed no mutation . ATM mRNA level was moderately reduced , which could be reverted by 5'-Aza-C treatment but without restoring protein levels . Importantly , we demonstrated a post-transcriptional regulation in SKX cells via 6-fold enhanced levels of miR-421 , which targets the 3'-UTR of ATM mRNA . Transfection of SKX cells with either anti-miR-421 inhibitor or a microRNA-insensitive ATM vector recovered ATM expression and abrogated the hyper-radiosensitivity . CONCLUSION This is the first report describing microRNA-mediated down-regulation of ATM leading to clinically manifest tumor radiosensitivity .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23199656"}
{"sentence": "The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor . Therefore , new therapeutic approaches for renal cancer are essential . Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells . This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages . However , little is known about englerin A's mode of action in targeting specifically renal cancer cells . Our study is the first to investigate the biological mechanism of englerin A action in detail . We report that englerin A is specific for renal tumor cells and does not affect normal kidney cells . We find that englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells . We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm . As the first study to analyze the biological effects of englerin A , our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug . It also provides a context in which to identify the specific target or targets of englerin A in renal cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23144724"}
{"sentence": "Hepatocellular carcinoma ( HCC ) is one of the most common malignancies worldwide ; however , the prognosis of HCC patients remains poor . This poor prognosis is mainly attributed to the high rate of intrahepatic and distant metastasis . HCC often occurs in a hypoxic environment and hypoxia can activate metastatic programs , ultimately leading to tumor recurrence or metastasis . Thus , the discovery and subsequent development of novel agents to block HCC invasion and migration are the primary objectives of hepatic cancer research . The Notch1 signaling pathway might be involved in hypoxia-induced carcinoma metastasis . However , the mechanisms by which Notch1 mediates cell metastasis , particularly in hepatocellular carcinoma , are not yet entirely clear . The results of the present study show that hypoxia increases the invasion and migration capacities of different HCC cells . Activation of the Notch1 signaling pathway contributes to hypoxia-induced invasion and migration in HCC cells . The activated Notch1 signaling pathway can regulate Snail/E-cadherin through cyclooxygenase-2 ( COX-2 ) under hypoxic conditions . The above results suggest that the Notch1/COX-2/Snail/E-cadherin pathway is possibly associated with hypoxia-induced invasion and migration in HCC cells . Thus , targeting Notch1 may be useful for devising novel preventive and therapeutic strategies for HCC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23124652"}
{"sentence": "We investigated the direct effects of LH-releasing hormone ( LH-RH ) antagonist , Cetrorelix , on the growth of HTOA human epithelial ovarian cancer cell line . RT-PCR revealed the expression of mRNA for LH-RH and its receptor in HTOA cells . Cetrorelix , at concentrations between 10(-9) and 10(-5) M , exerted a dose-dependent antiproliferative action on HTOA cells , as measured by 5-bromo-2'-deoxyuridine incorporation into DNA . Flow cytometric analysis indicated that Cetrorelix , at 10(-5) M , arrested cell cycle in HTOA cells , at G1 phase , after 24 h of treatment . Western blot analysis of cell cycle-regulatory proteins demonstrated that treatment with Cetrorelix ( 10(-5) M ) for 24 h did not change the steady-state levels of cyclin D1 , cyclin E , and cyclin-dependent kinase ( Cdk)4 but decreased the levels of cyclin A and Cdk2 . The protein levels of p21 ( a Cdk inhibitor ) and p53 ( a suppressor of tumor cell growth and a positive regulator for p21 expression ) were increased by Cetrorelix , but the levels of p27 ( a Cdk inhibitor ) did not change significantly . Flow cytometric analysis and terminal deoxynucleotidyltransferase-mediated deoxyuridine 5-triphosphate nick end labeling staining demonstrated that Cetrorelix ( 10(-5) M ) induced apoptosis in HTOA cells . In conclusion , Cetrorelix directly inhibits the proliferation of human epithelial ovarian cancer cells through mechanisms mediated by LH-RH receptor and involving multiple events in cell cycle progression , including G1 phase cell cycle arrest coupled with down-regulation of cyclin A-Cdk2 complex levels , presumably attributable to an up-regulation of p53 and p21 protein levels and apoptosis .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "12161501"}
{"sentence": "Nuclear factor kappa-B ( NF-\u03baB ) activates multiple genes with overlapping roles in cell proliferation , inflammation and cancer . Using an unbiased approach we identified human CDK6 as a novel kinase phosphorylating NF-\u03baB p65 at serine 536 . Purified and reconstituted CDK6/cyclin complexes phosphorylated p65 in vitro and in transfected cells . The physiological role of CDK6 for basal as well as cytokine-induced p65 phosphorylation or NF-\u03baB activation was revealed upon RNAi-mediated suppression of CDK6 . Inhibition of CDK6 catalytic activity by PD332991 suppressed activation of NF-\u03baB and TNF-induced gene expression . In complex with a constitutively active viral cyclin CDK6 stimulated NF-\u03baB p65-mediated transcription in a target gene specific manner and this effect was partially dependent on its ability to phosphorylate p65 at serine 536 . Tumor formation in thymi and spleens of v-cyclin transgenic mice correlated with increased levels of p65 Ser536 phosphorylation , increased expression of CDK6 and upregulaton of the NF-\u03baB target cyclin D3 . These results suggest that aberrant CDK6 expression or activation that is frequently observed in human tumors can contribute through NF-\u03baB to chronic inflammation and neoplasia .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23300567"}
{"sentence": "Topoisomerase 1 ( Top1)-DNA cleavage complexes induced by camptothecin ( CPT ) cause DNA strand breaks during DNA replication or transcription . Although the cellular responses to replication-mediated DNA double-strand breaks have been well studied , the responses to transcription-mediated DNA strand breaks have not . Here , we show that poly ( ADP-ribose ) polymerase ( PARP ) and cockayne syndrome group B protein ( CSB ) modulate the CPT-induced formation of discrete p53-binding protein 1 ( 53BP1 ) nuclear foci at sites of transcription-mediated DNA strand breaks . Inhibition of PARP activity enhanced the formation of these foci , while knockdown of essential components of the base excision repair ( BER ) pathway did not . These findings suggest that PARP suppresses transcription-mediated 53BP1 foci formation , but that this does not occur through the BER pathway . In addition , knockdown of CSB , one of the key factors of transcription-coupled repair , slowed the kinetics of 53BP1 foci formation . These data suggest that PARP and CSB modulate the formation of 53BP1 foci during the processing of transcription-mediated DNA strand breaks .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23229313"}
{"sentence": "The Warburg effect describes a heightened propensity of tumor cells to produce lactic acid in the presence or absence of O(2) . A generally held notion is that the Warburg effect is related to energy . Using whole-genome , proteomic MALDI-TOF-MS and metabolite analysis , we investigated the Warburg effect in malignant neuroblastoma N2a cells . The findings show that the Warburg effect serves a functional role in regulating acidic pericellular pH ( pHe ) , which is mediated by metabolic inversion or a fluctuating dominance between glycolytic-rate substrate level phosphorylation ( SLP ) and mitochondrial ( mt ) oxidative phosphorylation ( OXPHOS ) to control lactic acid production . The results also show that an alkaline pHe caused an elevation in SLP/OXPHOS ratio ( approximately 98% SLP/OXPHOS ) ; while the ratio was approximately 56% at neutral pHe and approximately 93% in acidic pHe . Acidic pHe paralleled greater expression of mitochondrial biogenesis and OXPHOS genes , such as complex III-V ( Uqcr10 , Atp5 and Cox7c ) , mt Fmc1 , Romo1 , Tmem 173 , Tomm6 , aldehyde dehydrogenase , mt Sod2 mt biogenesis component PPAR-\\u03b3 co-activator 1 adjunct to loss of mt fission ( Mff ) . Moreover , acidic pHe corresponded to metabolic efficiency evidenced by a rise in mTOR nutrient sensor G\\u03b2L , its downstream target ( Eif4ebp1 ) , insulin modulators ( Trib3 and Fetub ) and loss of catabolic ( Hadhb , Bdh1 and Pygl)/glycolytic processes ( aldolase C , pyruvate kinase , Nampt and aldose-reductase ) . In contrast , alkaline pHe initiated loss of mitofusin 2 , complex II-IV ( Sdhaf1 , Uqcrq , Cox4i2 and Aldh1l2 ) , aconitase , mitochondrial carrier triple repeat 1 and mt biosynthetic ( Coq2 , Coq5 and Coq9 ) . In conclusion , the Warburg effect might serve as a negative feedback loop that regulates the pHe toward a broad acidic range by altering lactic acid production through inversion of metabolic systems . These effects were independent of changes in O(2) concentration or glucose supply .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22320183"}
{"sentence": "We compared gadolinium diethylenetriaminepentaacetic acid ( Gd-DTPA ) enhanced T1-weighted images ( T1-Gd ) with the histopathological findings in 13 patients with bone or soft tissue sarcomas . Signal intensity of the viable tumor tissue was increased in T1-Gd in 92% of the patients . The necrotic or cystic areas in the tumor were not enhanced , rendering them distinctly . The degree of enhancement of the edematous area around the tumor was similar to or more marked than that of the tumor in 54% of the patients . Area showing inflammatory cells infiltration and edematous areas in the tumor tissue were also enhanced . Thus , the effect of preoperative chemotherapy in tumor tissues other than necrotic and cystic areas tended to be underestimated in T1-Gd . Its effect should be comprehensively evaluated based on not only T1-Gd but also T2-weighted images and findings of other imaging techniques .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "1485542"}
{"sentence": "Vascular integrity is fundamental to the formation of mature blood vessels and depends on a functional , quiescent endothelial monolayer . However , how endothelial cells enter and maintain quiescence in the presence of angiogenic factors is still poorly understood . Here we identify the fibroblast growth factor ( FGF ) antagonist Sprouty2 ( Spry2 ) as a key player in mediating endothelial quiescence and barrier integrity in mouse aortic endothelial cells ( MAECs ) : Spry2 knockout MAECs show spindle-like shapes and are incapable of forming a functional , impermeable endothelial monolayer in the presence of FGF2 . Whereas dense wild type cells exhibit contact inhibition and stop to proliferate , Spry2 knockout MAECs remain responsive to FGF2 and continue to proliferate even at high cell densities . Importantly , the anti-proliferative effect of Spry2 is absent in sparsely plated cells . This cell density-dependent Spry2 function correlates with highly increased Spry2 expression in confluent wild type MAECs . Spry2 protein expression is barely detectable in single cells but steadily increases in cells growing to high cell densities , with hypoxia being one contributing factor . At confluence , Spry2 expression correlates with intact cell-cell contacts , whereas disruption of cell-cell contacts by EGTA , TNF\u03b1 and thrombin decreases Spry2 protein expression . In confluent cells , high Spry2 levels correlate with decreased extracellular signal-regulated kinase 1/2 ( Erk1/2 ) phosphorylation . In contrast , dense Spry2 knockout MAECs exhibit enhanced signaling by Erk1/2 . Moreover , inhibiting Erk1/2 activity in Spry2 knockout cells restores wild type cobblestone monolayer morphology . This study thus reveals a novel Spry2 function , which mediates endothelial contact inhibition and barrier integrity .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23232625"}
{"sentence": "A number of growth factors have been implicated in the control of the proliferation of breast cancer cells and some have been reported to mediate the proliferative effects of oestradiol . MCF-7 cells were treated with growth factors in the presence and absence of oestradiol . Oestradiol increased the response of cells to the proliferative effects of epidermal growth factor ( EGF ) , transforming growth factor alpha ( TGF-alpha ) and basic fibroblast growth factor ( bFGF ) . Platelet derived growth factor ( PDGF ) and cathepsin D had no effect in the presence or absence of oestradiol while TGF-beta slightly reduced the stimulation by oestradiol . In the absence of oestradiol , there was little effect of combinations of growth factors although the effects of bFGF and IGF-I were additive . In the presence of oestradiol , the effects of bFGF and TGF-alpha were additive whereas bFGF acted as an IGF-I antagonist . Overall , bFGF had the greatest effect on cell proliferation although this was less marked than the previously described effect of the IGFs and insulin . The effects of oestradiol on the sensitivity of cells to the proliferative effects of bFGF did not appear to result from regulation of bFGF receptor expression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1419600"}
{"sentence": "Cav-1 ( -/- ) deficient stromal cells are a new genetic model for myofibroblasts and cancer-associated fibroblasts . Using an unbiased informatics analysis of the transcriptional profile of Cav-1 ( -/- ) deficient mesenchymal stromal cells , we have now identified many of the major signaling pathways that are activated by a loss of Cav-1 , under conditions of metabolic restriction ( with low glucose media ) . Our informatics analysis suggests that a loss of Cav-1 induces oxidative stress , which mimics a constitutive pseudo-hypoxic state , leading to ( 1 ) aerobic glycolysis and ( 2 ) inflammation in the tumor stromal microenvironment . This occurs via the activation of two major transcription factors , namely HIF ( aerobic glycolysis ) and NF\u03baB ( inflammation ) in Cav-1 ( -/- ) stromal fibroblastic cells . Experimentally , we show that Cav-1 deficient stromal cells may possess defective mitochondria , due to the over-production of nitric oxide ( NO ) , resulting in the tyrosine nitration of the mitochondrial respiratory chain components ( such as complex I ) . Elevated levels of nitro-tyrosine were observed both in Cav-1 ( -/- ) stromal cells , and via acute knock-down with siRNA targeting Cav-1 . Finally , metabolic restriction with mitochondrial ( complex I ) and glycolysis inhibitors was synthetically lethal with a Cav-1 ( -/- ) deficiency in mice . As such , Cav-1 deficient mice show a dramatically reduced mitochondrial reserve capacity . Thus , a mitochondrial defect in Cav-1 deficient stromal cells could drive oxidative stress , leading to aerobic glycolysis , and inflammation , in the tumor microenvironment . These stromal alterations may underlie the molecular basis of the \" reverse Warburg effect \" , and could provide the key to targeted anti-cancer therapies using metabolic inhibitors . In direct support of these findings , the transcriptional profile of Cav-1 ( -/- ) stromal cells overlaps significantly with Alzheimer disease , which is characterized by oxidative stress , NO over-production ( peroxynitrite formation ) , inflammation , hypoxia and mitochondrial dysfunction . We conclude that Cav-1 ( -/- ) deficient mice are a new whole-body animal model for an activated lethal tumor microenvironment , i.e. , \" tumor stroma \" without the tumor . Since Cav-1 ( -/- ) mice are also an established animal model for profibrotic disease , our current results may have implications for understanding the pathogenesis of scleroderma ( systemic sclerosis ) and pulmonary fibrosis , which are also related to abnormal mesenchymal stem cell function .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "20519932"}
{"sentence": "Transforming growth factor-beta1 ( TGF-beta1 ) exerts potent immunosuppressive effects . In this study , we investigated the potential role of TGF-beta1 produced by hepatocellular carcinoma ( HCC ) cell lines in immunosuppression mechanisms . Using the Mv1Lu cell-growth inhibition assay and an enzyme-linked immunosorbent assay ( ELISA ) , we detected optimal levels of TGF-beta1 in the culture supernatants conditioned by the HCC cell lines PLC/PRF/5 , Hep3B , and HepG2 . To determine the biological activity of TGF-beta1 in the supernatants , we examined the effects of the culture supernatants on the production of interferon ( IFN)-gamma induced during the culture of peripheral blood mononuclear cells ( PBMCs ) stimulated with interleukin ( IL)-12 . IFN-gamma production of IL-12-stimulated PBMCs in the 1:1 dilution of the acid-activated conditioned medium of PLC/PRF/5 , Hep3B , and HepG2 reduced to 14.7 +/- 0.8 , 17.3 +/- 9.0 , and 35.9 +/- 14.6% , respectively , compared with the value in the culture with control medium ( complete culture medium ) . These results suggest that HCC cells producing TGF-beta1 may reduce the generation or activation of cytotoxic T lymphocytes ( CTL ) and natural killer ( NK ) cells , and thus could enhance their ability to escape immune-mediated surveillance .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12685860"}
{"sentence": "IL-16 is a ligand and chemotactic factor for CD4+ T cells . IL-16 inhibits the CD3 mediated lymphocyte activation and proliferation . The effects of IL-16 on the target cells are dependent on the cell type , the presence of co-activators etc . To understand the regulation function and mechanism of IL-16 on target cells , we used a 130 a.a. recombinant IL-16 to study its effects on the growth of Jurkat T leukemia cells in vitro . We found that the rIL-16 stimulated the proliferation of Jurkat cells at low dose ( 10(-9)M ) , but inhibited the growth of the cells at higher concentration ( 10(-5)M ) . Results showed that 10(-5) M of rIL-16 treatment induced an enhanced apoptosis in Jurkat cells . The treatment blocked the expression of FasL , but up-regulated the c-myc and Bid expression in the cells . Pre-treatment of PKC inhibitor or MEK1 inhibitor markedly increased or decreased the rIL-16 induced growth-inhibiting effects on Jurkat cells , respectively . The results suggested that the rIL-16 might be a regulator for the growth or apoptosis of Jurkat cells at a dose-dependent manner . The growth-inhibiting effects of rIL-16 might be Fas/FasL independent , but , associated with the activation of PKC , up-regulated expression of c-Myc and Bid , and the participation of the ERK signal pathway in Jurkat cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12528894"}
{"sentence": "We report a case of recurrent gastric cancer successfully treated by a combination of CPT-11 and CDDP as the third- line chemotherapy . A 78-year-old man with advanced gastric cancer underwent a curative distal gastrectomy . Three years later , the tumor marker level began to rise and computed tomography ( CT ) revealed lymph node metastasis invading the pancreas resulting in pancreatic duct dilatation . S-1 treatment was initiated but was discontinued because of a systemic exanthem . Paclitaxel was administrated as secondary chemotherapy . But , after 2 courses , a further increase in the tumor marker level and portal vein invasion were observed . Combination therapy of CPT-11 and CDDP was administered as the third-line chemotherapy . After 3 courses , the tumor marker level normalized , tumor size decreased , and the invasion was eliminated . Third-line chemotherapy against recurrent gastric cancer should be considered if patient performance status ( PS ) is maintained .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23268075"}
{"sentence": "CDA-2 ( cell differentiation agent 2 ) , a urinary preparation , has potent anti- proliferative and pro-apoptotic properties in cancer cells . However , the mechanisms of tumor inhibitory action of CDA-2 are far from clear , and especially there was no report on lung cancer . Here we demonstrate that CDA-2 and its main component phenylacetylglutamine ( PG ) reduce the metastatic lung tumor growth , and increases survival time after inoculation with Lewis lung carcinoma ( LLC ) cells in a dose-dependent manner in C57BL6 mice . Proliferative program analysis in cancer cells revealed a fundamental impact of CDA-2 and PG on proliferation and apoptosis , including Bcl-2 , Bcl-XL , cIAP1 , Survivin , PCNA , Ki-67 proteins and TUNEL assays . CDA-2 and PG significantly reduced NF-\u03baB DNA-binding activity in lung cancer cells and in alveolar macrophages of tumor bearing mice and especially decreased the release of inflammatory factors including TNF\u03b1 , IL-6 , and KC . Furthermore , CDA-2 and PG decrease the expressions of TLR2 , TLR6 , and CD14 , but not TLR1 , TLR3 , TLR4 , and TLR9 in bone-marrow-derived macrophages ( BMDM ) of mice stimulated by LLC-conditioned medium ( LLC-CM ) . Over-expressing TLR2 in BMDM prevented CDA-2 and PG from inhibiting NF-\u03baB activation , as well as induction of TNF\u03b1 and IL-6 . TLR2:TLR6 complexes mediate the effect of NF-\u03baB inactivation by CDA-2 . In conclusion , CDA-2 potently inhibits lung tumor development by reduction of the inflammation in lung through suppression of NF-\u03baB activation in myeloid cells , associating with modulation of TLR2 signaling .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23284890"}
{"sentence": "Cancer cells exhibit altered glucose metabolism characterized by a preference for aerobic glycolysis or the Warburg effect , and the cells resist matrix detachment-induced apoptosis , which is called anoikis , a barrier to metastasis . It remains largely unclear whether tumor metabolism influences anoikis and metastasis . Here we show that when detached from the matrix , untransformed mammary epithelial cells undergo metabolic reprogramming by markedly upregulating pyruvate dehydrogenase ( PDH ) kinase 4 ( PDK4 ) through estrogen-related receptor gamma ( ERR\\u03b3 ) , thereby inhibiting PDH and attenuating the flux of glycolytic carbon into mitochondrial oxidation . To decipher the significance of this metabolic response , we found that depletion of PDK4 or activation of PDH increased mitochondrial respiration and oxidative stress in suspended cells , resulting in heightened anoikis . Conversely , overexpression of PDKs prolonged survival of cells in suspension . Therefore , decreased glucose oxidation following cell detachment confers anoikis resistance . Unlike untransformed cells , most cancer cells demonstrate reduced glucose oxidation even under attached conditions , and thus they inherently possess a survival advantage when suspended . Normalization of glucose metabolism by stimulating PDH in cancer cells restores their susceptibility to anoikis and impairs their metastatic potential . These results suggest that the Warburg effect , more specifically , diminished glucose oxidation , promotes anoikis resistance and metastasis and that PDKs are potential targets for antimetastasis therapy .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 1, 0], "id": "22431524"}
{"sentence": "To assess the immune function of microglia and macrophages in brain tumors , the expression of MHC class II and B7 costimulatory molecules in three rodent glioma models was examined . Microglia and macrophages , which accounted for 5-12% of total cells , expressed B7.1 and MHC class II molecules in the C6 and 9L tumors , but not RG2 gliomas . Interestingly , the expression of B7.1 and MHC class II molecules by microglia and macrophage was associated with an increase in the number of tumor-infiltrating lymphocytes in C6 and 9L tumors . B7.2 expression , which was present at low levels on microglia and macrophages in normal brain , did not significantly change in tumors . Interestingly , the expression of all three surface antigens increased after microglia were isolated from intracranial C6 tumors and cultured for a short period of time . We conclude that microglia immune activity may be suppressed in gliomas and directly correlates to the immunogenecity of experimental brain tumors .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12446006"}
{"sentence": "By intravenous ( but not oral ) application of ascorbate , millimolar serum concentrations can be reached , which are preferentially cytotoxic to cancer cells . Cytotoxicity is mediated by transition metal-dependent generation of H(2)O(2) in the interstitial space . In this study , the sensitivity of neuroblastoma cells ( Kelly , SK-N-SH ) to ascorbate and H(2)O(2) and their defense mechanisms against H(2)O(2) were investigated . Since aerobic glycolysis ( the Warburg effect ) is a feature of many tumour cells , their glucose consumption and lactate production were monitored . Furthermore , synthesis and release of ferritin by neuroblastoma cells were analysed in order to examine whether ferritin is possibly an iron source for H(2)O(2) generation . Ascorbate ( 0.6-5.0 mM ) and H(2)O(2) ( 25-100 muM ) were found to be similarly cytotoxic to Kelly and SK-N-SH cells . In each case , cytotoxicity increased if cell concentrations decreased , in accordance with low cell concentrations having lower capacities to detoxify H(2)O(2) . Kelly and SK-N-SH cells produced and released remarkable amounts of lactate and ferritin . We propose the selective cytotoxicity of high dose ascorbate to tumour cells to be due to the preferential generation of H(2)O(2) in the acidic and ferritin-rich tumour microenvironment , combined with reduced defense systems against H(2)O(2) as a consequence of aerobic glycolysis .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20511723"}
{"sentence": "Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression . Using genome-wide chromatin-binding profiles , we describe binding of p53 also to regions located distantly from any known p53 target gene . Interestingly , many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions . We demonstrate that these p53-bound enhancer regions ( p53BERs ) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation . Furthermore , p53BERs produce , ina p53-dependent manner , enhancer RNAs ( eRNAs ) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest . Thus , our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site . Moreover , eRNA production from p53BERs is required for efficient p53 transcription enhancement .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23273978"}
{"sentence": "Osteopontin ( OPN ) , which is highly expressed in malignant glioblastoma ( GBM ) , possesses inflammatory activity that is modulated by proteolytic cleavage by thrombin and plasma carboxypeptidase B2 ( CPB2 ) at a highly conserved cleavage site . Full length OPN ( OPN-FL ) was elevated in cerebrospinal fluid ( CSF ) samples from all cancer patients compared to non-cancer patients . However thrombin-cleaved OPN ( OPN-R ) and thrombin/CPB2-double cleaved OPN ( OPN-L ) levels were markedly increased in GBM and non-GBM gliomas compared to systemic cancer and non-cancer patients . Cleaved OPN constituted and of the total OPN in the GBM and non-GBM CSF samples respectively . OPN-R was also elevated in GBM tissues . Thrombin-antithrombin levels were highly correlated with cleaved OPN , but not OPN-FL , suggesting that the cleaved OPN fragments resulted from increased thrombin and CPB2 in this extracellular compartment . Levels of VEGF and CCL4 were increased in CSF of GBM and significantly correlated with the levels of cleaved OPN . GBM cell lines were significantly more adherent to OPN-R and OPN-L than OPN-FL . Adhesion to OPN altered gene expression , in particular genes involved with cellular processes , cell cycle regulation , death and inflammation . OPN promoted motility of U-87 MG cells and conferred resistance to apoptosis . While functional mutation of the RGD motif in OPN largely abolished these functions , OPN(RAA)-R regained significant cell binding and signaling function , suggesting that the SVVYGLR motif in OPN-R may substitute for the RGD-motif if the latter becomes inaccessible . OPN cleavage contributes to GBM development by allowing more cells to bind in niches in which they acquire anti-apoptotic properties .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23204518"}
{"sentence": "A novel camptothecin derivative ( TLC388 ) with higher efficacy and reduced toxicity has been synthesized and tested as a novel chemoradiosensitizing agent . This study investigated the mechanisms of the chemoradiosensitizing effects of TLC388 on H23 human non-small cell lung cancer ( NSCLC ) cells . Using the TUNEL assay , a significantly higher percentage of apoptotic cells was observed in the group treated with TLC388 plus X-ray radiation than those in groups treated with drug or radiation alone . The sensitizer enhancement ratio ( SER ) was 1.91 . Apoptosis increased with drug concentration and radiation dose , exhibiting dose-dependent pattern . The results suggested that apoptosis could be a main mode of cell death that might underlie the increased chemoradio-sensitization of TLC388 . Treatment with 30 nM of TLC388 plus 4 Gy X-ray also produced up to 42% of necrotic cells that were measured by trypan blue exclusion assay , but with TLC388 alone or 4 Gy radiation alone 9.8% or 11.1% necrotic cells were detected , respectively . An immunofluorescent staining method was employed to determine the levels of gamma-H2AX ( phosphorylated H2AX , a variant of the H2A protein family , which is a component of the histone octomer in nucleosomes and is phosphorylated by kinases like ATM and ATR in the PI3K pathway , as the first step in recruiting and localizing DNA repair proteins ) as a molecular biomarker of DNA double strand breaks ( DSBs ) in cells treated with TLC388 +/-radiation , or radiation alone . The formation of gamma-H2AX foci was observed after TLC388 or radiation exposure and when the cells were treated with 30 nM TLC388 plus radiation at a dose of 2 Gy , the percentage of cells containing gamma-H2AX foci increased significantly . Even more interesting , a markedly higher percentage ( 65.4% ) of mitotic cells displayed gamma-H2AX foci after treatment with 30 nM TLC388 plus 0.5 Gy radiation , compared to only 5.9% or 26.1% of the M-phase cells treated with 30 nM TLC388 alone or 0.5 Gy radiation alone , respectively . It is suggested that mitotic cells become very sensitive to the production of DSBs after TLC388-radiation combined treatment and the formation of DSBs is strongly suggested to lead to the induction of apoptosis at doses lower than 4 Gy and to some necrosis at doses of 4 Gy or above . TLC388 enhances the production of DSBs and inhibits their repair , which contributes to the elucidation of the mechanisms of chemoradiosensitization of TLC388 and its development as a novel chemoradiosensitizing drug for improved radiotherapy .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "20393017"}
{"sentence": "Gamma-radiation , tetrandrine , bistratene A , and cisplatin were all found to induce pronounced morphological changes characteristic of apoptosis and extensive DNA fragmentation in the human BM13674 cell line 8 h after treatment . Apoptosis induced in BM13674 cells by these diverse agents was markedly inhibited by 1 microM okadaic acid , a tumour promoter that inhibits protein phosphatases 1 and 2A . This compound also inhibited the appearance of apoptosis in fresh human leukaemia cells that had been exposed to gamma-radiation . The inhibition of apoptosis was confirmed using fluorescence microscopy and DNA gel electrophoresis . Dephosphorylation of a limited number of proteins was shown to be associated with apoptosis and okadaic acid prevented these dephosphorylations . Previous studies on the BM13674 cell line showed that an inhibitor of protein synthesis failed to prevent apoptosis in these cells . The present data provides further support that posttranslational modification of proteins , in particular , phosphorylation/dephosphorylation status , plays an important role in inhibition/activation of programmed cell death in different human cells after exposure to several cytotoxic agents .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1447316"}
{"sentence": "The mammalian COP9 signalosome ( CSN ) complex is involved in cell transformation , but its molecular mechanism remains undetermined . Here we show that disruption of the fifth component ( CSN5 ) prevented the formation of tumors by p53-null cells transformed with an active form of Ras in subcutaneously injected mice . Depletion of CSN5 suppressed cell proliferation , and induced premature senescence characterized by upregulation of senescence-associated-\u03b2-galactosidase activity and increased expression of CDK inhibitors . CSN5-depleted cells exhibited enhanced activation of the PI3 kinase-Akt pathway , and chemical inhibition of this pathway reduced the level of senescence . Thus , CSN5 is suggested to be a novel target in cancer therapy and for drugs against tumor cells harboring mutated p53 .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "23127558"}
{"sentence": "We found that the human colon cancer cell line SW480 consists of two distinct subpopulations which we have designated E-type ( epithelial ) and R-type ( round ) . Pure cultures of each type were obtained by subcloning , and both have maintained their characteristic phenotypes for at least 1 year ( 40 passages ) . E-type cells are the major ( > 98% ) type in the parental SW480 cell line . They form flat epithelial-like colonies . In contrast , R-type cells , which constitute a minor fraction ( < 2% ) of the parental cell line , have a rounded shape and grow in clusters of piled-up cells . Compared to E-type cells or the parental SW480 cells , isolated R-type cells display decreased doubling time , loss of contact inhibition , less adhesiveness to culture plates , higher anchorage-independent growth in soft agar , and a much more aneuploid karyotype . When injected s.c. into nude mice , R-type cells produce much larger tumors within the same period of time than E-type cells , and the tumors are less differentiated than those produced by the E-type cells . Cell fusion experiments between R-type and E-type cells revealed that the R-type phenotype is dominant , and the results suggest that this is due to one or a few genetic changes . Taken together , these findings suggest that the R-type cells represent a more malignant variant of the E-type cells . They may be useful , therefore , for studying mechanisms involved in tumor progression .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "1458472"}
{"sentence": "Genomic instability drives tumorigenesis , but how it is initiated in sporadic neoplasias is unknown . In early preneoplasias , alterations at chromosome fragile sites arise due to DNA replication stress . A frequent , perhaps earliest , genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus , leading to loss of Fhit protein expression . Because common chromosome fragile sites are exquisitely sensitive to replication stress , it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products . Here , we show in normal , transformed , and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks . Using DNA combing , we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse . The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels ; notably , restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells . Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest , allowing continued cell proliferation and ongoing chromosomal instability . This finding was in accord with in vivo studies , as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci . Furthermore , cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications , including amplification of the Mdm2 gene , suggesting that Fhit loss-induced genome instability facilitates transformation . We propose that loss of Fhit expression in precancerous lesions is the first step in the initiation of genomic instability , linking alterations at common fragile sites to the origin of genome instability .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 1, 0], "id": "23209436"}
{"sentence": "Estrogen affects apoptotic cell death in estrogen-responsive tissues . The purpose of the present study was to examine dynamic changes in apoptotic cell death in the anterior pituitary gland during the estrous cycle and to investigate neuroendocrine regulation of these changes in cycling female rats . Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling ( TUNEL ) for in situ detection of DNA strand breaks revealed that the number of TUNEL-positive anterior pituitary cells was changing during the estrous cycle , with a maximum in the morning of proestrus and a minimum in the morning of estrus . A similar pattern was observed with Bax immunostaining ; however , no difference was observed in Bcl-2 immunostaining . Most of Bax-immunoreactive cells were identified as a subpopulation of gonadotropes . Pentobarbital administered in the afternoon of proestrus attenuated the decrease in TUNEL-positive or Bax-immunoreactive cells in the morning of estrus , although estradiol treatment failed to affect it . This action of pentobarbital was reduced by simultaneous treatment with an ovulation-inducing dose of gonadotropin-releasing hormone ( GnRH ) , but not with progesterone , an ovarian steroid also released after GnRH treatment . These results suggest that anterior pituitary cells , mostly gonadotropes , undergo a cyclic change in apoptotic cell death during the estrous cycle and that the inhibition of apoptosis on estrus is due , at least in part , to the proestrous surge of GnRH secretion .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "12457038"}
{"sentence": "Epidemiological studies exploring the connection between hypertension and cancer incidence find a higher cancer mortality in hypertensive patients , particularly elevated in hypertension associated with a stimulation of the renin-angiotensin-aldosterone system . Primary aldosteronism , with plasma aldosterone levels between 0.5 and 1 nM ( 18-36 ng/dL ) and local aldosterone levels up to 500 nM ( 18,000 ng/dL ) , is now recognised as a more common cause for hypertension . We recently found angiotensin II to be genotoxic due to its induction of oxidative stress . Since aldosterone in higher concentrations also has oxidative effects , its potential genotoxic action in pig LLC-PK1 cells with properties of proximal tubules was analysed . DNA damage was evaluated by two test systems : the comet assay , and the micronucleus frequency test . The results showed that aldosterone concentrations starting from 10 nM ( 360 ng/dL ) caused a significant increase of DNA damage monitored with the comet assay in LLC-PK1 , while there was no change in cell vitality and proliferation . The micronucleus frequency test revealed that 10 nM aldosterone also leads to the formation of micronuclei . Furthermore , the formation of superoxide radicals in the cells by this aldosterone concentration could be detected with the superoxide-specific stain dihydroethidium . Further evidence for oxidative stress-induced DNA damage was its reversibility by the antioxidants tempol and catalase . Addition of the steroidal mineralocorticoid receptor antagonist spironolactone or the novel selective nonsteroidal antagonist ( R)-BR-4628 reduced the DNA damage and the amount of superoxide radicals indicating a receptor-dependent process .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20094972"}
{"sentence": "Polycyclic aromatic hydrocarbons ( PAHs ) are widely distributed immunotoxic and carcinogenic environmental contaminants , known to affect macrophages . In order to identify their molecular targets in such cells , we have analyzed gene expression profile of primary human macrophages treated by the prototypical PAH benzo(a)pyrene ( BaP ) , using pangenomic oligonucleotides microarrays . Exposure of macrophages to BaP for 8 and 24 h resulted in 96 and 1100 genes , differentially expressed by at least a twofold change factor , respectively . Some of these targets , including the chemokine receptor CXCR5 , the G protein-coupled receptor 35 ( GPR35 ) , and the Ras regulator RASAL1 , have not been previously shown to be affected by PAHs , in contrast to others , such as interleukin-1beta and the aryl hydrocarbon receptor ( AhR ) repressor . These BaP-mediated gene regulations were fully validated by reverse transcription-quantitative polymerase chain reaction assays for some selected genes . Their bioinformatic analysis indicated that biological functions linked to immunity , inflammation , and cell death were among the most affected by BaP in human macrophages and that the AhR and p53 signaling pathways were the most significant canonical pathways activated by the PAH . AhR and p53 implications were moreover fully confirmed by the prevention of BaP-related upregulation of some selected target genes by AhR silencing or the use of pifithrin-alpha , an inhibitor of PAH bioactivation-related DNA damage/p53 pathways . Overall , these data , through identifying genes and signaling pathways targeted by PAHs in human macrophages , may contribute to better understand the molecular basis of the immunotoxicity of these environmental contaminants .", "label": [0, 1, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20064835"}
{"sentence": "Colorectal cancer ( CRC ) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor , and thus is an useful model for studying metabolic shift . In the present study , we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry ( GC/MS ) and liquid chromatography tandem mass spectrometry ( LC/MS/MS ) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC . Colonic tissues including tumor , polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study . The metabolic profiles were obtained using GC/MS and LC/MS/MS . Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues . Various amino acids and lipids in the polyps and tumors were elevated , suggesting higher energy needs for increased cellular proliferation . In contrast , significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis . In addition , the accumulation of hypoxanthine and xanthine , and the decrease of uric acid concentration , suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC . Further , there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors . It appears that to gain a growth advantage , cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20147338"}
{"sentence": "Nowadays , tobacco smoking is the cause of million deaths per year , counting 31% and 6% of all cancer deaths ( affecting 18 different organs ) in middle-aged men and women , respectively . Nicotine is the addictive component of tobacco acting on neuronal nicotinic receptors ( nAChR ) . Functional nAChR , are also present on endothelial , haematological and epithelial cells . Although nicotine itself is regularly not referred to as a carcinogen , there is an ongoing debate whether nicotine functions as a ' tumour promoter ' . Nicotine , with its specific binding to nAChR , deregulates essential biological processes like regulation of cell proliferation , apoptosis , migration , invasion , angiogenesis , inflammation and cell-mediated immunity in a wide variety of cells including foetal ( regulation of development ) , embryonic and adult stem cells , adult tissues as well as cancer cells . Nicotine seems involved in fundamental aspects of the biology of malignant diseases , as well as of neurodegeneration . Investigating the biological effects of nicotine may provide new tools for therapeutic interventions and for the understanding of neurodegenerative diseases and tumour biology .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22050423"}
{"sentence": "Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors . Although the full process depends on innate and adaptive immunity , it remains unclear whether innate immunity alone is capable of immunoediting . To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity , we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type , RAG2(-/-) , and RAG2(-/-)x \u03b3c(-/-) mice . We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity . This activity required natural killer ( NK ) cells and interferon \u03b3 ( IFN-\u03b3 ) , which mediated the induction of M1 macrophages . M1 macrophages could be elicited by administration of CD40 agonists , thereby restoring editing activity in RAG2(-/-)x \u03b3c(-/-) mice . Our results suggest that in the absence of adaptive immunity , NK cell production of IFN-\u03b3 induces M1 macrophages , which act as important effectors during cancer immunoediting .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22927549"}
{"sentence": "Ferric nitrilotriacetate ( Fe-NTA ) is a potent nephrotoxicant and a renal carcinogen that induces its effect by causing oxidative stress . The present study was undertaken to explore protective effect of silymarin , a flavonolignan from milk thistle ( Silybum marianum ) , against Fe-NTA mediated renal oxidative stress , inflammation and tumor promotion response along with elucidation of the implicated mechanism(s) . Administration of Fe-NTA ( 10 mg/kg bd wt , i.p. ) to Swiss albino mice induced marked oxidative stress in kidney , evident from augmentation in renal metallothionein ( MT ) expression , depletion of glutathione content and activities of antioxidant and phase II metabolizing enzymes , and enhancement in production of aldehyde products such as 4-hydroxy-2-nonenal . Fe-NTA also significantly activated nuclear factor kappa B ( NFkappaB ) and upregulated the expression of downstream genes : cyclooxygenase 2 and inducible nitric oxide synthase and enhancing the production of proinflammatory cytokines : tumor necrosis factor alpha ( TNF-alpha ) and interleukin-6 ( IL-6 ) . However , feeding of 0.5% and 1% silymarin diet conferred a significant protection against Fe-NTA induced oxidative stress and inflammation . It further augmented MT expression , restored the antioxidant armory , ameliorated NFkappaB activation and decreased the expression of proinflammatory mediators . Silymarin also suppressed Fe-NTA induced hyperproliferation in kidney , ameliorating renal ornithine decarboxylase activity and DNA synthesis . From these results , it could be concluded that silymarin markedly protects against chemically induced renal cancer and acts plausibly by virtue of its antioxidant , anti-inflammatory and antiproliferative activities .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19590824"}
{"sentence": "Inflammatory events have been associated with senile plaques , one of the pathological hallmarks of Alzheimer's disease ( AD ) . It is believed that aggregated beta-amyloid ( betaA ) proteins , which form the core of these plaques , may be responsible for triggering the inflammatory reaction . In the present study , the ability of aluminum ( Al ) to initiate similar inflammatory events was investigated in a human glioblastoma cell line . A 6-day exposure to either lipopolysaccharide ( LPS ) or aluminum sulfate caused a significant increase in the rate of proliferation of the glioblastoma cells . Both treatments also caused activation of the immune-responsive transcription factor NF-kappaB although there were time-related differences . The levels of secreted cytokines , interleukin-6 ( IL-6 ) and tumor necrosis factor alpha ( TNF-alpha ) were both increased by the LPS treatment although exposure to Al decreased the secretion of the former while elevating the levels of the latter . These events may be due to the activation of glial cells and subsequent stress response to either Al complexes or LPS . Although exposure to either stress factor caused a stimulation of inflammatory markers , there were time-dependent differences in the response . This may reflect the ability of the cells to discern different stress factors and thus orchestrate an innate immune response profile distinct to each immunogen .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "11929636"}
{"sentence": "The aim of this study was to extend our previous observations on the soy modulation of biochemical parameters in 7,12-dimethylbenz[a]anthracene ( DMBA)-induced rat mammary tumors , by simultaneously investigating the expression of estrogen receptor-alpha ( ERalpha ) , estrogen receptor-beta ( ERbeta ) , progesterone receptor ( PR ) , apoptosis , neu , and markers of cell proliferation , such as proliferating cell nuclear antigen ( PCNA ) by immunohistochemistry . The percentage of ERalpha positive tumors was 65.8% in masses from control animals , and significantly dropped to 36.8% in tumors from soy treated rats ( P=0.010 ) . The percentage of ERbeta positive tumors was 70.3% in masses from control animals vs. 50.0% in tumors from soy exposed animals ( P=0.066 ) . Moreover , the percentage of cases which were both ERalpha and ERbeta positive was significantly lower ( 17.6% ) in soy treated than in control animals ( 51.3% ) ( P=0.006 ) . The percentage of PR positive tumors was 34.2% in control animals vs. 2.6% in tumors from soy treated rats ( P=0.0006 ) . There were no statistically significant differences in the percentage of tumors positively stained for neu , apoptosis , or PCNA , in control vs. soy treated rats . However , when analyzing the reciprocal correlation among the different biochemical parameters we showed that , in treated animals , the majority of ERalpha positive tumors ( 91.7% ) were also PCNA positive ( P=0.036 ) . The median percentage of PCNA positivity was significantly higher in ERalpha positive than in ERalpha negative tumors ( 25 vs. 5% ) ( P=0.0031 ) . Moreover , an association was found between PCNA and neu status since all neu positive tumors were also PCNA positive ( P=0.011 ) .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12183074"}
{"sentence": "MG132 , as a proteasome inhibitor , can induce apoptotic cell death through formation of reactive oxygen species ( ROS ) . In this study , we investigated the effects of MAPK ( MEK , JNK , and p38 ) inhibitors on MG132-treated A549 lung cancer cells in relation to cell growth , cell death , ROS , and glutathione ( GSH ) levels . Treatment with 10 microM MG132 inhibited the growth of A549 cells at 24 h . MG132 also induced apoptosis , which was accompanied by the loss of mitochondrial membrane potential ( MMP ; deltapsi(m) ) . ROS were not increased in MG132-treated A549 cells . MG132 increased GSH-depleted cell numbers and decreased GSH levels . MEK and JNK inhibitors did not strongly affect cell growth , cell death , ROS , and GSH levels in MG132-treated A549 cells . In contrast , p38 inhibitor reduced cell growth inhibition , apoptosis , and MMP ( deltapsi(m) ) loss by MG132 . However , p38 inhibitor did not change ROS level and GSH content . In conclusion , MG132 inhibited the growth of A549 cells via apoptosis without formation of ROS . Treatment with p38 inhibitor rescued some cells from MG132-induced apotposis , which was not affected by ROS and GSH level changes .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20377132"}
{"sentence": "Jaceosidin , a flavonoid derived from Artemisia princeps ( Japanese mugwort ) , has been shown to inhibit the growth of several human cancer cells , However , the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood . In this study , we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells . We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells . In contrast , jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin . Jaceosidin induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells . Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition . Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2 . Ku55933 , an ATM inhibitor , reversed jaceosidin-induced cell growth inhibition , in part . Moreover , jaceosidin treatment resulted in phosphorylation of ERK , and pretreatment with the ERK inhibitor , PD98059 , attenuated cell growth inhibition by jaceosidin . These data suggest that jaceosidin , isolated from Japanese mugwort , modulates the ERK/ATM/Chk1/2 pathway , leading to inactivation of the Cdc2-cyclin B1 complex , followed by G2/M cell cycle arrest in endometrial cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23274058"}
{"sentence": "5-HT1c receptors have been shown to act as protooncogenes in NIH 3T3 cells , inducing ligand-dependent focus formation . In order to assess their mitogenic and oncogenic potential in a different cell system , we transfected these receptors into CCL39 hamster fibroblasts , a well-characterized growth factor-dependent cell line . Cell clones expressing functional receptors were isolated and tested for ( a ) growth factor dependence of proliferation measuring thymidine incorporation in response to varying doses of serum , ( b ) the response to serotonin alone or in combination with other growth factors , and ( c ) the capacity for anchorage-independent proliferation . In the absence or presence of serotonin , the large majority of the clones isolated showed normal morphology and normal growth factor dependence and was unable to grow in soft agar . None of the clones showed a significant response to serotonin alone in DNA synthesis reinitiation experiments , but synergy was observed between serotonin and the tyrosine kinase activating growth factors EGF and FGF . However , the major part of this effect could be abolished by an antagonist of 5-HT1b receptors , which are endogenous in CCL39 cells . The same receptor was found to mediate a significant mitogenic response to the neurotransmitter in Ha-ras-transfected cells . The fact that 5-HT1c receptors do not readily induce a transformed phenotype in CCL39 cells clearly distinguishes them from strong dominantly acting oncogene products like RAS , SRC , or FMS .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1315291"}
{"sentence": "The mouse polyomavirus encodes a tumor-suppressor gene inactivator in its large T protein and a proto-oncogene activator in its middle T protein . We have used site-directed mutagenesis to selectively inactivate the former function without affecting the latter . Two mutant viruses were constructed to encode altered large T proteins that fail to bind the retinoblastoma tumor-suppressor gene product pRB , along with normal small and middle T proteins . The pRB-binding mutants proved to be defective in immortalization of primary rat embryo fibroblasts by a variety of tests . Yet they proved capable of transforming both primary and established fibroblasts in culture . Most importantly , the inability of these mutants to bind pRB had little effect on their ability to induce tumors in mice . We conclude that induction of multiple tumor types in this system does not depend on large T-pRB interactions but rather on middle T-dependent pathways . In addition , the ability of this virus to immortalize cells in culture is not essential to its ability to induce tumors in the animal .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1328987"}
{"sentence": "p107 Links to cyclin A/CDK2 ( cyclin-dependent kinase 2 ) and cyclin E/CDK2 that are important cell cycle regulators . However , p107 expression remains unclear in almost all kinds of human solid tumours . To clarify the expression of p107 in colorectal tumours , 22 normal mucosae , 9 hyperplastic polyps , 60 adenomas , 198 primary carcinomas , 21 lymph-nodal metastases , and 10 hepatic metastases were immunohistochemically stained for p107 , cyclin A , cyclin E , CDK2 and Ki67 . Results were measured using labelling indices ( LIs). p107 LIs surpassed the highest value in normal tissues in six of nine hyperplastic polyps , 54 of 60 adenomas , 144 of 198 primary cancers , 13 of 21 nodal foci and three of 10 hepatic foci. p107 LIs also apparently rose from normal through hyperplasia and adenoma to early carcinoma . However , they declined in liver-metastatic foci , and in primary cancers showing large size , mucinous type , venous invasion , lymphatic invasion , poorly differentiated type , deep invasion , lymph-nodal metastasis , hepatic metastasis or advanced stage . Low p107 LIs were also linked to a poor survival , particularly in stage-III patients . As the p107 LI gradually rose , the CDK2 ( in primary cancers only ) , cyclin A , cyclin E and Ki67 LIs were elevated concurrently-in both adenomas and primary cancers . Thus , in colorectal tumours , p107 expression rises abnormally and gradually during carcinogenesis and then falls during invasion , and thereby probably perturbs the cell-cycle control and promotes carcinogenesis and invasion . Clinically , reduced p107 may indicate a poorer prognosis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12204665"}
{"sentence": "Objective . The present study was performed to investigate the effect of N-desulfated heparin on basic fibroblast growth factor ( bFGF ) expression , tumor angiogenesis and metastasis of gastric carcinoma . Methods . Human gastric cancer SGC-7901 tissues were orthotopically implanted into the stomach of NOD SCID mice . Twenty mice were randomly divided into two groups which received either intravenous injection of 0.9% NaCl solution ( normal saline group ) or 10\u2009mg/kg N-desulfated heparin ( N-desulfated heparin group ) twice weekly for three weeks . In vitro , human gastric carcinoma SGC-7901 cells were treated with N-desulfated heparin in different concentration ( 0.1\u2009mg/mL , 1\u2009mg/mL , N-desulfated heparin group ) , and treated with medium ( control group ) . Results . In vivo , the tumor metastasis rates were 9/10 in normal saline group and 2/10 in N-desulfated heparin group ( P < 0.05 ) . The intratumoral microvessel density was higher in normal saline group than in N-desulfated heparin group ( P < 0.05). bFGF expression in gastric tissue was inhibited by N-desulfated heparin ( P < 0.05 ) . There was no bleeding in N-desulfated heparin group . In vitro , N-desulfated heparin inhibited significantly bFGF protein and mRNA expression of gastric carcinoma cells ( P < 0.05 ) . Conclusions . N-desulfated heparin can inhibit the metastasis of gastric cancer through inhibiting tumor bFGF expression and tumor angiogenesis with no obvious anticoagulant activity .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22888341"}
{"sentence": "1-Vinylcycloalkenes undergo highly regio- and enantioselective ( >98% ee ) 1,4-hydrovinylation ( HV ) when treated with ethylene ( 1 atm ) at room temperature in the presence of [ (S,S)-2,4-bis-diphenylphosphinopentane ( BDPP)]CoCl(2 ) ( 0.05 equiv ) and methylaluminoxane . The minor 1,2-HV products , seen only in 1-vinylcyclohexene ( and 1-vinylcycloheptene ( 2% ) , are formed as racemic mixtures . The corresponding Ni(II)-catalyzed HV reactions of these substrates give mostly the 1,2-adducts . Racemic 4-tert-butyl-1-vinylcyclohexene , when treated with Co[(S,S)-(BDPP)]Cl(2) and ethylene , undergoes a rare enantiodivergent reaction giving two diastereomers each in >98% ee .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22452442"}
{"sentence": "The aberrant activation of sonic hedgehog ( SHH ) pathway contributes to initiation and progression of various malignancies . However , the roles and underlying mechanisms of SHH signaling pathway in invasion and metastasis of liver cancer have not been well understood . In this study , we found that SHH signaling was activated and correlated with invasion and metastasis in hepatocellular carcinoma ( HCC ) . Enhanced SHH signaling by recombinant human SHH N-terminal peptide ( rSHH-N ) promoted hepatoma cell adhesion , migration and invasion , whereas blockade of SHH signaling with SHH neutralizing antibody or cyclopamine suppressed hepatoma cell adhesion , migration and invasion . Furthermore , matrix metalloproteinase ( MMP)-2 and MMP-9 expressions and activities were upregulated and downregulated by rSHH-N and SHH signaling inhibitor , respectively . The rSHH-N-mediated hepatoma cell migration and invasion was blocked by MMP-specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9 . In addition , phosphorylations of AKT and focal adhesion kinase ( FAK ) were increased and decreased by rSHH-N and SHH signaling inhibitor , respectively . Further investigations showed that activation of AKT and FAK were required for rSHH-N-mediated upregulation of MMP-2 and MMP-9 , cell migration and invasion . Finally , we found that SHH protein expression was positively correlated with phosphorylatd FAK Tyr397 , phosphorylatd AKT Ser473 , MMP-2 and MMP-9 protein expressions in HCC samples . Taken together , our findings suggest that SHH pathway induces cell migration and invasion through FAK/AKT signaling-mediated MMP-2 and MMP-9 production and activation in liver cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22948179"}
{"sentence": "The NOTCH signaling pathway plays important role in the development of multicellular organisms , as it regulates cell proliferation , survival , and differentiation . In adults , it is essential for the T- or B-lymphocyte lineage commitment . NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients . In this study , the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols . In 19 patients ( 22% ) , activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases ( 10% ) demonstrated FBXW7 mutations ( 2 cases had both NOTCH1 and FBXW7 mutations ) . We also analyzed the relationship of the mutation data between the clinical and biological data of the patients . NOTCH1 and FBXW7 , NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype . However , NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20683149"}
{"sentence": "Various endocrine disrupting chemicals ( EDCs ) are exogenous compounds found in the environment and have the potential to interfere with the endocrine system and hormonal regulation . Among EDCs , bisphenolA ( BPA ) and 1,1,1-trichloro-2,2-bis(4-methoxyphenol)-ethane [ methoxychlor ( MXC) ] have estrogenic activity resulting in a variety of dysfunctions in the E2-mediated response by binding to estrogen receptors ( ERs ) , causing human health problems such as abnormal reproduction and carcinogenesis . In this study , we investigated the effects of BPA and MXC on cell proliferation facilitated by ER signaling in human breast cancer cells . MCF-7 cells are known to be ER\u03b1-positive and to be a highly E2-responsive cancer cell line ; these cells are , therefore , a useful invitro model for detecting estrogenic activity in response to EDCs . We evaluated cancer cell proliferation following BPA and MXC treatment using an MTT assay . We analyzed alterations in the expression of genes associated with the cell cycle in MCF-7 cells by semi-quantitative reverse-transcription PCR following treatment with BPA or MXC compared to EtOH . To determine whether BPA and MXC stimulate cancer cell growth though ER signaling , we co-treated the cells with agonists ( propyl pyrazoletriol , PPT ; and diarylpropionitrile , DPN ) or an antagonist ( ICI 182,780 ) of ER signaling and reduced ER\u03b1 gene expression via siRNA in MCF-7 cells before treatment with EDCs . These studies confirmed the carcinogenicity of EDCs invitro . As a result , BPA and MXC induced the cancer cell proliferation by the upregulation of genes that promote the cell cycle and the downregulation of anti-proliferative genes , especially ones affecting the G1/S transition via ER\u03b1 signaling . These collective results confirm the carcinogenicity of these EDCs invitro . Further studies are required to determine whether EDCs promote carcinogenesis invivo .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22307313"}
{"sentence": "BACKGROUND The 235delC mutation of GJB2 gene is considered as a risk factor for the non-syndromic hearing loss ( NSHL ) , and a significant difference in the frequency and distribution of the 235delC mutation has been described world widely . METHODS A systematic review was performed by means of a meta-analysis to evaluate the influence of the 235delC mutation on the risk of NSHL . A literature search in electronic databases using keywords \" 235delC \" , \" GJB2 \" associated with \" carrier frequency \" was conducted to include all papers from January 1999 to June 2011 . A total of 36 papers were included and there contained 13217 cases and 6521 controls derived from Oceania , American , Europe and Asian . RESULTS A remarkable heterogeneity between these studies was observed . The combined results of meta-analysis showed that the 235delC mutant increased the risk of NSHL ( OR = 7.9 , 95%CI 4.77 13.11 , P <0.00001 ) . Meanwhile , heterogeneity of genetic effect was also observed due to the ethnic specificity and regional disparity . Therefore , the stratified meta-analysis was subsequently conducted and the results indicated that the 235delC mutation was significantly correlated with the risk of NHSL in the East Asian and South-east Asian populations ( OR = 12.05 , 95%CI 8.33 P <0.00001 ) , but not significantly in the Oceania and European populations ( OR = 10.36 , 95%CI : 4.68 Z = 1.68 , P >0.05 ) . CONCLUSIONS The 235delC mutation of GJB2 gene increased the risk of NHSL in the East Asian and South-east Asian populations , but non-significantly associated with the NSHL susceptibility in Oceania and European populations , suggesting a significant ethnic specificity of this NSHL-associated mutation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22747691"}
{"sentence": "While human embryonic stem cells ( hESCs ) and human embryonal carcinoma cells ( hECCs ) have been studied extensively at the levels of the genome , transcriptome , proteome and epigenome our knowledge of their corresponding metabolomes is limited . Here , we present the metabolic signatures of hESCs and hESCs obtained by untargeted gas chromatography coupled to mass spectrometry ( GC-MS ) . Whilst some metabolites are common to both cell types , representing the self-renewal and house-keeping signatures , others were either higher ( e.g. , octadecenoic acid , glycerol-3-phosphate , 4-hydroxyproline ) or lower ( e.g. , glutamic acid , mannitol , malic acid , GABA ) in hESCs ( H9 ) compared to hECCs ( NTERA2 ) , these represent cell type specific signatures . Further , our combined results of GC-MS and microarray based gene expression profiling of undifferentiated and OCT4-depleted hESCs are consistent with the Warburg effect which is increased glycolysis in embryonic cells and tumor cells in the presence of O(2) while oxidative phosphorylation ( OXPHOS ) is impaired or even shut down . RNAi-based OCT4 knock down mediated differentiation resulted in the activation of the poised OXPHOS machinery by expressing missing key proteins such as NDUFC1 , UQCRB and COX , increase in TCA cycle activity and decreased lactate metabolism . These results shed light on the metabolite layer of pluripotent stem cells and could potentially establish novel metabolic markers of self renewal and pluripotency .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22768158"}
{"sentence": "Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer . In this context , heparan sulfate proteoglycans ( HSPGs ) emerge as interesting targets , owing to their function as co-receptors of major , pro-angiogenic factors . Accordingly , previous studies have suggested anti-tumor effects of heparin , i.e. over-sulfated HS , and various heparin mimetics ; however , a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties . Here , we have explored the use of human ScFv anti-HS antibodies ( \u03b1HS ) as a more rational approach to target HSPG function in endothelial cells ( ECs). \u03b1HS were initially selected for their recognition of HS epitopes localized preferentially to the vasculature of patient glioblastoma tumors , i.e. highly angiogenic brain tumors . Unexpectedly , we found that these \u03b1HS exhibited potent pro-angiogenic effects in primary human ECs. \u03b1HS were shown to stimulate EC differentiation , which was associated with increased EC tube formation and proliferation . Moreover , \u03b1HS supported EC survival under hypoxia and starvation , i.e. conditions typical of the tumor microenvironment . Importantly , \u03b1HS-mediated proliferation was efficiently counter-acted by heparin and was absent in HSPG-deficient mutant cells , confirming HS-specific effects . On a mechanistic level , binding of \u03b1HS to HSPGs of ECs as well as glioblastoma cells was found to trigger p38 MAPK-dependent signaling resulting in increased proliferation . We conclude that several \u03b1HS that recognize HS epitopes abundant in the tumor vasculature may elicit a pro-angiogenic response , which has implications for the development of antibody-based targeting of HSPGs in cancer .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23152853"}
{"sentence": "Radiation combined with chemotherapy ( neo-CRT ) is increasingly the standard of care for the treatment of esophageal cancer , either as neoadjuvant therapy in multimodal protocols or as primary therapy . Unfortunately , of patients demonstrate little or no response to neo-CRT . Accordingly , understanding the molecular mechanisms of resistance to therapy may underpin significant advances through the identification of nonresponders either before or early in treatment . We previously identified the RNPC1 gene , which is important in stabilizing p21 , as being upregulated in the tumors of esophageal cancer patients who had a poor response to neo-CRT . We hypothesize that RNPC1 contributes to resistance to radiation therapy through a p21-mediated cell cycle accumulation/arrest mechanism . Analysis revealed that p53 and RNPC1 expression were highest in the JH-EsoAd1 cell line and lowest in OE19 cells . This was associated with accumulation of cells in G\u2080/G\u2081. p21 expression , which was highest in OE19 cells and lowest in OE33 cells , was associated with relative intrinsic sensitivity to radiation . OE33 cells were transfected with a plasmid ( pCMV6-AC-GFP ) encoding a C-terminal GFP-tagged RNPC1 , and overexpression was confirmed by qPCR and fluorescence microscopy . Overexpression of RNPC1-GFP resulted in significantly increased levels of the p21 transcript and protein through a direct physical interaction between the RNPC1 protein and the p21 transcript . Furthermore , RNPC1 overexpression led to significant G\u2080/G\u2081 cell cycle accumulation and significantly enhanced cellular resistance to radiation . We conclude that RNPC1 contributes to tumor resistance to radiotherapy , which likely occurs through a p21-mediated G\u2080/G\u2081 accumulation mechanism . Therefore , RNPC1 may represent a potential therapeutic target for enhancing tumor sensitivity to radiation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22214381"}
{"sentence": "Targeting receptor tyrosine kinase ( RTK ) degradation may be an interesting approach to reduce RTK cell signaling in cancer cells . Here we show that increasing E3 ubiquitin ligase casitas B-lineage lymphoma ( c-Cbl ) expression using lentiviral infection decreased osteosarcoma cell replication and survival and reduced cell migration and invasion in murine and human osteosarcoma cells . Conversely , c-Cbl inhibition using short hairpin RNA ( shRNA ) increased osteosarcoma cell growth and survival , as well as invasion and migration , indicating that c-Cbl plays a critical role as a bone tumor suppressor . Importantly , the anticancer effect of increasing c-Cbl expression in osteosarcoma cells was related mainly to the downregulation of epidermal growth factor receptor ( EGFR ) and platelet-derived growth factor receptor alpha ( PDGFR\u03b1 ) . In a murine bone tumor model , increasing c-Cbl expression also reduced RTK expression , resulting in decreased tumor cell proliferation and survival and reduced tumor growth . Interestingly , increasing c-Cbl also markedly reduced lung metastasis in mice . Tissue microarray analysis revealed that low c-Cbl protein expression is associated with elevated EGFR and PDGFR\u03b1 protein levels in human osteosarcoma with poor outcome . This study shows that increasing c-Cbl expression reduces osteosarcoma cell growth , survival , and metastasis in part through downregulation of RTKs , which supports the potential therapeutic interest of targeting c-Cbl in malignant bone diseases involving increased RTK .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22623369"}
{"sentence": "Urokinase plasminogen activator receptor ( uPAR ) activates alpha5beta1 integrin and ERK signaling , inducing in vivo proliferation of HEp3 human carcinoma . Here we demonstrate that EGFR mediates the uPAR/integrin/fibronectin ( FN ) induced growth pathway . Its activation is ligand-independent and does not require high EGFR , but does require high uPAR expression . Only when uPAR level is constitutively elevated does EGFR become alpha5beta1-associated and activated . Domain 1 of uPAR is crucial for EGFR activation , and FAK links integrin and EGFR signaling . Inhibition of EGFR kinase blocks uPAR induced signal to ERK , implicating EGFR as an important effector of the pathway . Disruption of uPAR or EGFR signaling reduces HEp3 proliferation in vivo . These findings unveil a mechanism whereby uPAR subverts ligand-regulated EGFR signaling , providing cancer cells with proliferative advantage .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12124174"}
{"sentence": "It is well established that aberrant production of inflammatory mediators has been associated with most the toxic manifestations and the genesis of different chronic diseases including cancer . The basic aim of the present study is to investigate the effects of soy isoflavones ( SIF ) on 12-O-tetradecanoylphorbol-13-acetate ( TPA)-induced cutaneous inflammatory responses and to explore the underlying molecular mechanisms . We have studied the protective effects of SIF against TPA induced oxidative stress , pro-inflammatory cytokines level , activation of NF-\u03baB , expression of COX-2 and ki-67 in mouse skin . Animals were divided into five groups I-V ( n=6 ) . Groups II , III and IV received topical application of TPA at the dose of 10 nmol/0.2 ml of acetone/animal/day , for 2 days . Animals of the groups III and IV were pre-treated with SIF 1.0 \u03bcg ( D1 ) and 2.0 \u03bcg ( D2 ) topically 30 min prior to each TPA administration , while groups I and V were given acetone ( 0.2 ml ) and SIF ( D2 ) , respectively . We have found that SIF pretreatment significantly inhibited TPA induced oxidative stress , proinflammatory cytokines production and activation of NF-\u03baB . SIF also inhibited the expression of COX-2 and ki-67 . Histological findings further supported the protective effects of SIF against TPA-induced cutaneous damage . Thus , our results suggest that inhibitory effect of SIF on TPA-induced cutaneous inflammation includes inhibition of proinflammatory cytokines , attenuation of oxidative stress , activation of NF-\u03baB and expression of COX-2 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22981962"}
{"sentence": "INTRODUCTION The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood . Apoptosis and induction of inflammation by tumor released cytokines as tumor escape mechanisms have been proposed to play an important role in colorectal carcinogenesis . METHODS Expression of Tumor necrosis factor-alpha ( TNF-\u03b1 ) was analyzed in colorectal cancer specimen and the cancer cell line HT-29 by immunohistochemistry and RT-PCR . TNF-\u03b1 expression on protein and mRNA level were correlated with clinical characteristics and impact on survival . TNFR-1 was co-labelled with TNF-\u03b1 and CD8+ cytotoxic T cells in immunofluorescence double staining experiments . RESULTS 94% ( n=98/104 ) of the patients with CRC expressed TNF-\u03b1 . High TNF-\u03b1 expression was significantly associated with positive lymph node stage and recurrence of the tumor . Multivariate analysis revealed high TNF-\u03b1 expression as an independent prognostic factor . Immunohistochemistry was correlated with RT-PCR results ( \u03c4=0.794 ) . Immunofluorescence double staining experiments revealed increased TNFR-1 expression by CD8+ cells . CONCLUSIONS TNF-\u03b1 expression by tumor cells may be an efficient immunological escape mechanism by inflammation-enhanced metastases and probably by induction of apoptosis in tumor-infiltrating CD8+ immune cells resulting in a down regulation of the tumoral immune response . Our data support the role of tumor-derived TNF-\u03b1 expression as an important promoter of tumoral immune escape mechanisms and malignant progression , and suggest that analysis on either protein ( immunohistochemistry ) or RNA level ( RT-PCR ) can be used effectively in this respect . Targeting TNF-\u03b1 may be a promising option , especially in cases with high TNF-\u03b1 expression and positive lymph node metastases .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20978325"}
{"sentence": "Endocrine gland-derived vascular endothelial growth factor ( EG-VEGF ) has recently been identified as one of the vascular endothelial growth factors , and it is considered that the overexpression of EG-VEGF in colon cancer is related to hepatic metastasis . In this study , we report our recent novel findings of the involvement of EG-VEGF in cell invasion of colon cancer cells . Colon cancer cell lines ( DLD-1 and HCT116 ) with high expression of prokineticin receptor ( PK-R ) 1 and 2 were stimulated with the EG-VEGF protein . Furthermore , Matrigel cell invasion assay was performed to examine the changes in cancer cell invasion . In addition , we investigated the mRNA expression of matrix metalloproteinase ( MMP)-2 , -7 and -9 in cancer cells . Finally , the EG-VEGF receptor on the colon cancer cell membrane was blocked by anti-PK-R1 and -PK-R2 antibodies to study whether cell invasion ability would be altered . In colon cancer cell lines where the expression of PK-R1 and 2 was confirmed , stimulation with EG-VEGF increased cell invasion a maximum of times . Furthermore , an increase in the mRNA and protein expression of MMP-2 , -7 and -9 was observed . We also observed that the cell invasion rate decreased only after exposure to the anti-PK-R2 antibody . The study showed that the EG-VEGF protein may act on MMP-2 , -7 and -9 via PK-R2 to strengthen cell invasion ability in colon cancer cell lines .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23135359"}
{"sentence": "Liver resection is now widely accepted as a potentially curative treatment for colorectal liver metastasis . However , the efficacy of surgical resection for gastric cancer liver metastasis(GLM)remains unclear . Based on our 18-year experience with 64 patients who underwent curative hepatectomy for GLM , we discuss the indication and efficacy of surgical resection for GLM . From January 1993 to January 2011 , 73 patients underwent hepatectomy for GLM in the Department of Gastroenterological Surgery , Cancer Institute Ariake Hospital(Japanese Foundation for Cancer Research ) , Japan . The actuarial1 - , 3- , and 5-year overall survival rates and 1- , 3- , and 5-year recurrence-free survival rates of those 64 patients who achieved curative resections were 84 , 50 , and 37% , and 42 , 27 , and 27% , respectively . By multivariate analysis , serosal invasion of the primary gastric cancer and larger hepatic tumor(>5 cm in diameter)were found to be independent indicators of poor prognosis . Based on the multivariate analysis results , all patients were divided into three groups no poor prognostic factor(n=38) , one poor prognostic factor(n=24) , and two poor prognostic factors(n=2) . The actuarial overall survival rates of each group were 63 , 36 , and 0% at 3 years , and 53 , 15 , and 0% at 5 years . GLM patients having hepatic tumors with the maximum diameter of <5 cm , and without serosalinvasion of the primary gastric cancer , are the best candidates for hepatectomy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23235164"}
{"sentence": "Many tumors contain heterogeneous populations of cells , only some of which exhibit increased tumorigenicity and resistance to anticancer therapies . Evidence suggests that these aggressive cancer cells , often termed \" cancer stem cells \" or \" cancer stem-like cells \" ( CSCs ) , rely upon developmental signaling pathways that are important for survival and expansion of normal stem cells . Here we report that , in analogy to embryonic mammary epithelial biology , estrogen signaling expands the pool of functional breast CSCs through a paracrine FGF/FGFR/Tbx3 signaling pathway . Estrogen or FGF9 pretreatment induced CSC properties of breast cancer cell lines and freshly isolated breast cancer cells , whereas cotreatment of cells with tamoxifen or a small molecule inhibitor of FGFR signaling was sufficient to prevent the estrogen-induced expansion of CSCs . Furthermore , reduction of FGFR or Tbx3 gene expression was able to abrogate tumorsphere formation , whereas ectopic Tbx3 expression increased tumor seeding potential by 100-fold . These findings demonstrate that breast CSCs are stimulated by estrogen through a signaling pathway that similarly controls normal mammary epithelial stem cell biology .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21098263"}
{"sentence": "Triggering tumor necrosis factor receptor-1 ( TNFR1 ) induces apoptosis in various cell lines . In contrast , stimulation of TNFR1 in L929sA leads to necrosis . Inhibition of HSP90 , a chaperone for many kinases , by geldanamycin or radicicol shifted the response of L929sA cells to TNF from necrosis to apoptosis . This shift was blocked by CrmA but not by BCL-2 overexpression , suggesting that it occurred through activation of procaspase-8 . Geldanamycin pretreatment led to a proteasome-dependent decrease in the levels of several TNFR1-interacting proteins including the kinases receptor-interacting protein , inhibitor of kappa B kinase-alpha , inhibitor of kappa B kinase-beta , and to a lesser extent the adaptors NF-kappaB essential modulator and tumor necrosis factor receptor-associated factor 2 . As a consequence , NF-kappa B , p38MAPK , and JNK activation were abolished . No significant decrease in the levels of mitogen-activated protein kinases , adaptor proteins TNFR-associated death domain and Fas-associated death domain , or caspase-3 , -8 , and -9 could be detected . These results suggest that HSP90 client proteins play a crucial role in necrotic signaling . We conclude that inhibition of HSP90 may alter the composition of the TNFR1 complex , favoring the caspase-8-dependent apoptotic pathway . In the absence of geldanamycin , certain HSP90 client proteins may be preferentially recruited to the TNFR1 complex , promoting necrosis . Thus , the availability of proteins such as receptor-interacting protein , Fas-associated death domain , and caspase-8 can determine whether TNFR1 activation will lead to apoptosis or to necrosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12441346"}
{"sentence": "We showed in a previous study that soluble low-molecular-mass tumor-associated antigens ( sTAA ) promote the anti-tumor effect of the anticancer drug cyclophosphamide ( CPA ) on rat mammary carcinogenesis . In this report , we analyzed the possible mechanism underlying this phenomenon . Studies were performed on the bone marrow and thymus from the following groups of rats : i ) control rats , ii ) rats treated with sTAA , iii ) rats treated with CPA , iv ) rats treated with CPA and sTAA . The cellular content of the bone marrow and thymus ( CD4+ and CD8+ lymphocytes ) was analyzed morphometrically and immunohistochemically . In the bone marrow , CPA caused significant substitution of cellular components with fatty tissue whereas sTAA repaired this process . We found that CPA affects mainly the process of myelogenesis whereas sTAA protect the production of lymphocytes . In the thymus , CPA alone or in combination with sTAA repaired the inhibition effect of DMBA on synthesis of CD4+ and CD8+ thymocytes. sTAA further increased the amount of CD8+ T lymphocytes in the medulla of the thymus . Data in the literature as well as the findings presented here demonstrate that the tested treatment , including vaccination with sTAA , actively promotes the generation of the host's antitumor immune response .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12239604"}
{"sentence": "Epidemiological data and animal models have provided evidence that nonsteroidal antiinflammatory drugs ( NSAIDs ) have an anticancer effect . However , the molecular mechanisms underlying these antineoplastic effects are not well understood . We described previously that expression levels of the chemokine receptor , CCR5 , and the beta2-integrin , Mac-1 , were down-regulated on primary monocytes after incubation in supernatants from human carcinoma cell lines , and that this down-regulation resulted in impaired monocyte function with respect to migration and adhesion . We now demonstrate that these impairments are also present in vivo . Monocytes from cancer patients displayed significantly reduced CCR5 levels and migration capacities in comparison to cells from healthy donors . Because migration is necessary for the antitumor activity of monocytes/macrophages , these deficits may contribute to the suppressed immune system seen in cancer patients . In a clinical study , we analyzed the effect of a selective COX-2 inhibitor , Rofecoxib , on the migration of monocytes derived from cancer patients . The results revealed significant improvement in migration equal to those levels seen in healthy donors . We conclude that in patients with cancer , the intake of Rofecoxib for 3 wk leads to significant restoration of monocyte function . These data may , at least in part , help explain the anticancer effects of NSAIDs .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12490541"}
{"sentence": "Interactions of CD70 , a tumor necrosis factor-related cell surface ligand and its receptor , CD27 , are thought to play an important role for T- , B- , and natural killer-cell activation . However , ligation of CD27 can also induce apoptosis . Human glioblastoma is paradigmatic for cancer-associated immunosuppression . We identified CD70 as a radioinducible gene in U87 MG glioma cells . A screening of a panel of human glioma cell lines revealed that 11 of 12 cell lines expressed CD70 mRNA and protein . Two human neuroblastoma cell lines did not express CD70 . CD70 mRNA expression was enhanced by irradiation in 8 of 12 glioma cell lines in a p53-independent manner . No alteration in CD70 expression was observed after glioma cell exposure to cytotoxic drugs such as lomustine . CD70 protein was also detected by immunocytochemistry in 5 of 12 glioblastomas and 3 of 4 anaplastic astrocytomas in vivo . CD27 expression was not detected in any glioma cell line , and there was no evidence for autocrine or backward signaling of the CD70 system in human glioma cells . Unexpectedly , CD70 expressed on glioma cells did not increase the immunogenicity of glioma cells in vitro . In contrast , CD70-positive glioma cells induced apoptosis in peripheral blood mononuclear cells ( PBMCs ) in a CD70-dependent manner . Neutralization of CD70 expressed on glioma cells prevented apoptosis and enhanced the release of tumor necrosis factor-alpha in cocultures of glioma cells and PBMCs . The effects of CD70-expressing glioma cells on PBMCs were mimicked by agonistic CD27 antibodies . Conversely , the shedding of CD27 by PBMCs was identified as a possible escape mechanism from glioma cell-induced CD70-dependent apoptosis . Thus , induction of B-cell and T-cell apoptosis via interactions of CD70 expressed on glioma cells and CD27 expressed on B and T cells may be a novel way for the immune escape of malignant gliomas .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "11980654"}
{"sentence": "ABSTRACT : INTRODUCTION : Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues . Recently , the nuclear retinoic acid receptor ( RAR ) isotypes \u03b1 , \u03b2 and \u03b3 were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues . For instance , RAR\u03b3 appears to be involved in stem cell compartment expansion , while RAR\u03b1 and RAR\u03b2 are implicated in the subsequent cell differentiation . We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer , disrupts the balance between RAR\u03b3 and RAR\u03b1/\u03b2 in favor of RAR\u03b3 . METHODS : The effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium , mammary tumor cells obtained from the MMTV-Myc transgenic mouse model as well as human normal immortalized breast epithelial and breast cancer cell lines . The in vivo effect of the RAR\u03b1-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid ( Am580 ) was examined in the MMTV-Myc mouse model of mammary tumorigenesis . RESULTS : Modulation of the RAR\u03b1/\u03b2 to RAR\u03b3 expression in mammary glands of normal mice , oncomice , and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation , survival and tumor growth . Treatment of MMTV-Myc mice with the RAR\u03b1-selective agonist Am580 led to significant inhibition of mammary tumor growth ( P<0.001 ) , lung metastasis ( P<0.01 ) and extended tumor latency in 63% of mice . Immunocytochemical analysis showed that in these mice , RAR\u03b1 responsive genes such as Cyp26A1 , E-cadherin , cellular retinol-binding protein 1 ( CRBP1 ) and p27 , were up-regulated . In contrast , the mammary gland tumors of mice that responded poorly to Am580 treatment ( 37% ) expressed significantly higher levels of RAR\u03b3 . In vitro experiments indicated that the rise in RAR\u03b3 was functionally linked to promotion of tumor growth and inhibition of differentiation . Thus , activation of the RAR\u03b1 pathway is linked to tumor growth inhibition , differentiation and cell death . CONCLUSIONS : The functional consequence of the interplay between c-Myc oncogene expression and the RAR\u03b3 to RAR\u03b1/\u03b2 balance suggests that prevalence of RAR\u03b3 over-RAR\u03b1/\u03b2 expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RAR\u03b1-isotype-specific agonists and warrant monitoring during clinical trials.See related editorial by Garattini et al http://breast-cancer-research.com/content/14/5/111 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22920668"}
{"sentence": "AIM We studied expression of molecules of the vascular endothelial growth factor ( VEGF ) pathway and its relation to vascularization , cell proliferation and patient outcome in recurring non-anaplastic meningioma . We studied 29 tumor specimens of 8 patients with recurring meningiomas and of 8 age- and gender-matched control patients with non-recurring meningiomas ( including meningothelial , transitional , fibroblastic and atypical subtypes ) using immunohistochemistry and in-situ hybridization . RESULTS VEGF protein , VEGF-mRNA , VEGF receptor ( VEGFR)-1 mRNA , VEGFR-2 mRNA and hypoxia-inducible factor ( HIF)-1-\u03b1 protein were expressed in 27/29 ( 93% ) , 20/27 ( 74% ) , 9/27 ( 33.3% ) , 12/27 ( 44.4% ) and 5/29 ( 17.2% ) specimens , respectively . VEGFR- 2 mRNA expression was found in 6/8 tumors extracted at first operation in patients with recurring tumors and in none of the control cases ( p = 0.007 ) . Microvessel density ( MVD ) and Ki-67 index values were generally higher in meningiomas with expression of angiogenic factors . The association of high Ki-67 index values with VEGF-mRNA expression was significant ( p = 0.04 ) . Time to recurrence was shorter in patients with high MVD than in patients with low MVD ( p = 0.027 ) . CONCLUSIONS High MVD correlates with unfavorable prognosis in our series of recurring meningioma . VEGF and its receptors are frequently expressed in meningiomas and seem important for tumor growth and recurrence . Thus , anti-VEGF therapy in aggressive meningioma seems rational from a pathobiological point of view .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22541785"}
{"sentence": "The concept of targeting new blood vessel formation , or angiogenesis , in tumors is an important advancement in cancer therapy , resulting , in part , from the development of such biologic agents as bevacizumab , a monoclonal antibody directed against vascular endothelial growth factor ( VEGF)-A . The rationale for antiangiogenic therapy is based on the hypothesis that if tumors are limited in their capacity to obtain a new blood supply , so too is their capacity for growth and metastasis . Additional evidence suggests that pruning and/or \" normalization \" of irregular tumor vasculature and reduction of hypoxia may facilitate greater access of cytotoxic chemotherapy ( CT ) to the tumor . Indeed , for metastatic colorectal cancer , bevacizumab in combination with established CT regimens has efficacy superior to that of CT alone . Despite longer progression-free and overall survival times than with CT alone , patients still progress , possibly because of alternative angiogenic \" escape \" pathways that emerge independent of VEGF-A , or are driven by hypoxic stress on the tumor . Other VEGF family members may contribute to resistance , and many factors that contribute to the regulation of tumor angiogenesis function as part of a complex network , existing in different concentrations and spatiotemporal gradients and producing a wide range of biologic responses . Integrating these concepts into the design and evaluation of new antiangiogenic therapies may help overcome resistance mechanisms and allow for greater efficacy over longer treatment periods .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22773560"}
{"sentence": "The submandibular gland-derived tumor cell line SCA-9 is considered a useful tool to study the signaling pathways involved in proliferation , and their regulation , triggered by different stimuli . It is proposed that the non neuronal cholinergic system : acethylcholine , the enzymes that synthesize and degrade it , and the nicotinic and muscarinic receptors , play a key role in tumorigenesis . Here , we investigate the role of muscarinic receptors in SCA-9 cell proliferation , and the modulation of cholinergic signaling pathways exerted by the nuclear transcription factor \u03baB ( NF-\u03baB ) . The activation of cholinergic receptors by carbachol ( 10\u207b\u2079M ) increased cell proliferation ( P<0.001 ) . This was prevented by preincubating cells with the muscarinic antagonist atropine but not by mecamylamine , a nicotinic receptor blocker . Phospholipase C ( PLC)/nitric oxide synthase ( NOS)/arginase pathway is involved in this effect , since carbachol stimulated nitric oxide production , increased NOS2 and NOS3 expressions , urea production , and arginase II expression ( P<0.001 ) . Also , phospholipase A\u2082 ( PLA\u2082)/cyclooxygenase ( COX ) pathway is up-regulated in carbachol-induced SCA-9 cell proliferation , because prostaglandin E\u2082 liberation ( P<0.001 ) is increased and COX-1 expression is turned up ( P<0.001 ) . Interactions between PLC/NOS/arginases and PLA\u2082/COX pathways via its metabolites were detected . SCA-9 cells exhibit a constitutive activation of NF-\u03baB , which regulates carbachol-induced NOS2 and 3 , arginase II and COX-1 expressions . In addition , protein kinase C is involved in the up-regulation of NOS2 and arginase II enzymes induced by carbachol via NF-\u03baB . In conclusion , the activation of cholinergic receptors in SCA-9 tumor cells promotes proliferation via muscarinic effector enzymes , and reveals the participation of NF-\u03baB at this step of tumorigenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22449386"}
{"sentence": "Bilateral spontaneous pneumothorax is a rare occurrence in patients with both primary and metastatic lung cancer . Pneumothorax occurring as a complication of vascular endothelial growth factor receptor ( VEGFR ) inhibitor therapy has not been previously described in the medical literature . Sunitinib malate is a VEGFR inhibitor approved for the treatment of advanced renal cell carcinoma . We present a patient with metastatic renal cell carcinoma manifested as bilateral pulmonary nodules who developed a bilateral spontaneous pneumothorax 3 weeks after initiation of sunitinib therapy . We believe that sunitinib therapy resulted in necrosis of multiple pleural-based pulmonary nodules with central cavernization and ultimately rupture with bronchopleural fistula formation . Based on this experience , we advise that practitioners exercise caution when prescribing anti-VEGFR therapy in patients with pleural-based pulmonary metastases and recognize that the efficacy and toxicity of these agents may be closely linked .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20204363"}
{"sentence": "\u03b3-Tocotrienol and sesamin are phytochemicals that display potent anticancer activity . Since sesamin inhibits the metabolic degradation of tocotrienols , studies were conducted to determine if combined treatment with sesamin potentiates the antiproliferative effects of \u03b3-tocotrienol on neoplastic mouse ( +SA ) and human ( MCF-7 and MDA-MB-231 ) mammary cancer cells . Results showed that treatment with \u03b3-tocotrienol or sesamin alone induced a significant dose-responsive growth inhibition , whereas combination treatment with these agents synergistically inhibited the growth of +SA , MCF-7 and MDA-MB-231 mammary cancer cells , while similar treatment doses were found to have little or no effect on normal ( mouse CL-S1 and human MCF-10A ) mammary epithelial cell growth or viability . However , sesamin synergistic enhancement of \u03b3-tocotrienol-induced anticancer effects was not found to be mediated from a reduction in \u03b3-tocotrienol metabolism . Rather , combined treatment with subeffective doses of \u03b3-tocotrienol and sesamin was found to induce G1 cell cycle arrest , and a corresponding decrease in cyclin D1 , CDK2 , CDK4 , CDK6 , phospho-Rb , and E2F1 levels , and increase in p27 and p16 levels . Additional studies showed that the antiproliferative effect of combination treatment did not initiate apoptosis or result in a decrease in mammary cancer cell viability . Taken together , these findings indicate that the synergistic antiproliferative action of combined \u03b3-tocotrienol and sesamin treatment in mouse and human mammary cancer cells is cytostatic , not cytotoxic , and results from G1 cell cycle arrest .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23266736"}
{"sentence": "22Rv1 is a common prostate cancer cell line used in xenograft mouse experiments as well as in vitro cell culture assays to study aspects of prostate cancer tumorigenesis . Recently , this cell line was shown to harbor multiple copies of a gammaretrovirus , called XMRV , integrated in its genome . While the original prostate cancer xenograft CWR22 is free of any retrovirus , subsequently generated cell lines 22Rv1 and CWR-R1 , carry this virus and additionally shed infectious gammaretroviral particles in their supernatant . Although XMRV most likely was generated by recombination events in cell culture this virus has been demonstrated to infect human cells in vitro and 22Rv1 as well as CWR-R1 cells are now considered biosafety 2 reagents . Here , we demonstrate that 22Rv1 cells with reduced retroviral transcription show reduced tumor angiogenesis and increased necrosis of the primary tumor derived from xenografted cells in scid mice when compared to the parental cell line . The presence of XMRV transcripts significantly increases secretion of osteopontin ( OPN ) , CXCL14 , IL13 and TIMP2 in 22Rv1 cells . Furthermore , these data are supported by in vitro cell invasion and differentiation assays . Collectively , our data suggest that the presence of XMRV transcripts at least partially contributes to 22Rv1 characteristics observed in vitro and in vivo with regard to migration , invasion and tumor angiogenesis . We propose that data received with 22Rv1 cells or equivalent cells carrying xenotropic gammaretroviruses should be carefully controlled including other prostate cancer cell lines tested for viral sequences .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "22848758"}
{"sentence": "Prenatal mortality is a prime concern for commercial swine industry in North America . Fetal losses occur throughout gestation but cluster in early ( and mid ( pregnancy . Adequate vascularization of the attachment site has emerged as a key factor contributing to fetal success . Since Insulin-Like Growth Factor ( IGF ) family members regulate angiogenesis in addition to promoting fetal development and growth , we hypothesized that conceptus success is governed by members of the IGF family . Using quantitative real time PCR , we analyzed expression of IGF family members ( IGF-I , IGF-II , IGF-I Receptor ( IGF-IR ) , IGF-IIR and their binding proteins , IGFBPs ) in matched maternal and fetal tissues of healthy and arresting conceptuses at gestation days ( gd ) 20 and 50 . IGF-II transcripts were 100 fold increased in both maternal and fetal tissues compared to IGF-I , but receptor transcripts were found in similar abundance irrespective of health status and gestation point . IGFBP3 was the most abundantly transcribed of the binding proteins . Using immunohistochemistry we confirmed the expression of IGF family members in maternal luminal and glandular epithelial cells , the endothelium of blood vessels and some scattered stromal cells . Our results suggest that IGF-I and II and their receptors are differentially expressed at the maternal and fetal components of the attachment site .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21685713"}
{"sentence": "Optimal lymphocyte activation requires the simultaneous engagement of stimulatory and costimulatory receptors . Stimulatory immunoreceptors are usually composed of a ligand-binding transmembrane protein and noncovalently associated signal-transducing subunits . Here , we report that alternative splicing leads to two distinct NKG2D polypeptides that associate differentially with the DAP10 and KARAP ( also known as DAP12 ) signaling subunits . We found that differential expression of these isoforms and of signaling proteins determined whether NKG2D functioned as a costimulatory receptor in the adaptive immune system ( CD8+ T cells ) or as both a primary recognition structure and a costimulatory receptor in the innate immune system ( natural killer cells and macrophages ) . This strategy suggests a rationale for the multisubunit structure of stimulatory immunoreceptors .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12426565"}
{"sentence": "Blind mole rats Spalax ( BMR ) are small subterranean rodents common in the Middle East . BMR is distinguished by its adaptations to life underground , remarkable longevity ( with a maximum documented lifespan of 21 y ) , and resistance to cancer . Spontaneous tumors have never been observed in spalacids . To understand the mechanisms responsible for this resistance , we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani . BMR cells proliferated actively for 7-20 population doublings , after which the cells began secreting IFN-\\u03b2 , and the cultures underwent massive necrotic cell death within 3 d . The necrotic cell death phenomenon was independent of culture conditions or telomere shortening . Interestingly , this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat , Heterocephalus glaber , the naked mole rat in which cells display hypersensitivity to contact inhibition . Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death . Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways , and triggered by the release of IFN-\\u03b2 . Thus , we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground .", "label": [0, 0, 0, 1, 1, 0, 0, 1, 0, 0], "id": "23129611"}
{"sentence": "The potential of cytologically reconstructed barley line D-2946 to cope with the major lesions that hamper genome integrity , namely DNA single- and double-strand breaks was investigated . Strand breaks induced by \\u03b3-rays and Li ions were assessed by neutral and alkaline comet assay . Repair capacity after bleomycin treatment was evaluated by agarose gel electrophoresis under neutral and alkaline conditions . Frequencies of radiation-induced chromosome aberrations were also determined . Results indicate that radiation-mediated constitutive rearrangement of the chromosome complement has led to a substantial modulation of the sensitivity of barley genome towards DNA strand breaks , produced by ionising radiation , Li ion implantation and bleomycin in an agent-specific manner , as well as of the clastogenic response to \\u03b3-rays . Based on these findings , reconstructed barley karyotype D-2946 can be considered a candidate radio-sensitive line with reduced ability to maintain genome integrity with respect to both DNA and chromosomal damage .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23221036"}
{"sentence": "The aim of this study was to investigate the inhibitory effects of rutaecarpine on DNA strand breaks and apoptosis induced by hydrogen peroxide ( H2O2 ) in murine Hepa-1c1c7 cells . Oxidative DNA damage was estimated by nuclear condensation assessment , fluorescence-activated cell sorting analysis , and Comet assay . Rutaecarpine inhibited cell death induced by 500 \\u03bcM H2O2 , as assessed by 4',6-diamidino-2-phenylindole ( DAPI ) staining . Treatment with rutaecarpine reduced the number of DNA strand breaks induced by H2O2 , as assessed by DAPI staining and Comet assay , and increased quinone reductase , phosphatidylinositol 3-kinase , and pAkt protein levels , as assessed by western blotting .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "24009839"}
{"sentence": "BARD1 heterodimerizes with BRCA1 , forming an E3 ubiquitin ligase that functions at nuclear foci to repair DNA damage and the centrosome to regulate mitosis . We compared BARD1 recruitment at these structures using fluorescence recovery after photobleaching assays to measure YFP-BARD1 dynamics in live cells . In nuclei at ionizing radiation-induced foci , 20% of the BARD1 pool was immobile and 80% of slow mobility exhibiting a recovery time >500 s . In contrast , at centrosomes 83% of BARD1 was rapidly mobile with extremely fast turnover ( recovery time The faster exchange of BARD1 at centrosomes correlated with BRCA1-independent recruitment . We mapped key targeting sequences to a combination of the N and C-termini , and showed that mutation of the nuclear export signal reduced centrosome localization by 50% , revealing a role for CRM1 . Deletion of the sequence 128-550 increased BARD1 turnover at the centrosome , consistent with a role in transient associations . Conversely , the cancer mutation Q564H reduced turnover by 25% . BARD1 is one of the most highly mobile proteins yet detected at the centrosome , and in contrast to its localization at DNA repair foci , which requires dimerization with BRCA1 , targeting of BARD1 to the centrosome occurs prior to heterodimerization and its rapid turnover may provide a mechanism to regulate dimer formation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21982881"}
{"sentence": "Although interleukin-28A ( IL-28A ) is believed to have an antiviral effect , its role in tumor migration requires further examination . The present study was intended to verify the effect of IL-28A on the migration of UMUC-3 bladder cancer cells . IL-28A and its receptor IL-28AR1 mRNA were detected in UMUC-3 cells . Although exogenous IL-28A showed no effect on cell proliferation , a wound-healing migration assay showed that the migration of UMUC-3 cells was induced by IL-28A . Furthermore , treatment of the cells with IL-28A significantly promoted MMP-9 expression via binding activities of NF-\u03baB and AP-1 . IL-28A also induced the activation of p38MAPK and Jak2-Stat2 signaling . Using the p38MAPK inhibitor SB203580 and the dominant-negative plasmid DN-p38 , we found evidence that the inhibition of p38MAPK signaling suppressed the effects of IL-28A including wound-healing migration and MMP-9 expression by activation of NF-\u03baB and AP-1 binding in UMUC-3 cells . However , Jak-2 inhibition by AG490 did not affect IL-28A-induced migration of UMUC-3 cells . Collectively , we suggest for the first time that the p38MAPK pathway mediates IL-28A-induced cell migration through MMP-9 expression by activating NF-\u03baB and AP-1 binding motifs .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22825757"}
{"sentence": "Tumor-associated macrophages ( TAM ) have been shown to play an important role in tumor angiogenesis . The purpose of this study was to determine whether monocyte recruitment , activation and differentiation mediated by monocyte chemotactic protein-1 ( MCP-1 ) and macrophage colony stimulating factor ( M-CSF ) modulate the expression of the angiogenic factor , Interleukin ( IL)-8 . Isolated human peripheral blood monocytes secreted low basal levels of IL-8 . Incubation of monocytes with M-CSF or MCP-1 resulted in an up-regulation of IL-8 mRNA and protein expression . The differential expression of IL-8 by monocytes following MCP-1 and M-CSF treatments involved activation of the NFkB transcription factor . Further activation with lipopolysaccharide ( LPS ) caused an increase in IL-8 secretion in monocytes but not in monocyte-derived macrophages ( MDM ) . MDM-conditioned media significantly up-regulated IL-8 expression in human malignant melanoma cells in vitro . In summary , we demonstrated that MCP-1 and M-CSF , critical for monocyte recruitment , activation and differentiation , differentially regulate IL-8 expression and may play an important role in monocyte/macrophage-mediated tumor angiogenesis .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12494891"}
{"sentence": "BACKGROUND Colorectal cancer is one of the main cancers in the Western world . About 90% of the deaths arise from formation of distant metastasis . The expression of the newly identified gene metastasis associated in colon cancer 1 ( MACC1 ) is a prognostic indicator for colon cancer metastasis . Here , we analyzed for the first time the impact of single nucleotide polymorphisms ( SNPs ) in the coding region of MACC1 for clinical outcome of colorectal cancer patients . Additionally , we screened met proto-oncogene ( Met ) , the transcriptional target gene of MACC1 , for mutations . METHODS We sequenced the coding exons of MACC1 in 154 colorectal tumors ( stages I , II and III ) and the crucial exons of Met in 60 colorectal tumors ( stages I , II and III ) . We analyzed the association of MACC1 polymorphisms with clinical data , including metachronous metastasis , UICC stages , tumor invasion , lymph node metastasis and patients ' survival ( n = 154 , stages I , II and III ) . Furthermore , we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells . RESULTS We genotyped three MACC1 SNPs in the coding region . Thirteen % of the tumors had the genotype cg ( rs4721888 , L31V ) , 48% a ct genotype ( rs975263 , S515L ) and 84% a gc or cc genotype ( rs3735615 , R804T ) . We found no association of these SNPs with clinicopathological parameters or with patients ' survival , when analyzing the entire patients ' cohort . An increased risk for a shorter metastasis-free survival of patients with a ct genotype ( rs975263 ) was observed in younger colon cancer patients with stage I or II ( P = 0.041 , n = 18 ) . In cell culture , MACC1 SNPs did not affect MACC1-induced cell motility and proliferation . CONCLUSION In summary , the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients ' survival compared to MACC1 expression analysis alone . The ct genotype ( rs975263 ) might be associated with a reduced survival for younger colon cancer patients in early stages . However , further studies with larger sample sizes are needed .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22838389"}
{"sentence": "The use of substrates containing well defined adducts at precise sites , is required to perform a careful analysis of the toxic and mutagenic potential of a lesion . As a first step in this direction the octamer 5'-d(CCGGCGGT) , containing the sequence of the codons 12 d(GGC) and 13 d(GGT) of the human H-ras gene , was reacted with the antitumoral drug cis-diamminedichloroplatinum(II) . The platinated products have been purified by HPLC . A first set of experiments , including enzymatic digestions with nuclease P1 followed by alkaline phosphatase and acid-catalysed hydrolysis , allowed us to determine which bases were engaged in the cis-DDP lesions . Our results indicate that only guanine residues were chelated with cisplatin to yield bifunctional adducts . Furthermore , by performing enzymatic digestions with phosphodiesterases , we have located the adducts with respect to the 5 ' end of the octamer . Among the purified and characterized platinated oligonucleotides , three present a particular interest , since we have shown here that the cis-d(GpG) adduct is precisely situated either at the d(GGC) or at the d(GGT) or at both sites of their sequence .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1480469"}
{"sentence": "ZBP-89 ( ZNF148 ) is a Zinc finger Binding Protein of 89 kDa that binds GC-rich DNA elements . Originally , it was expression cloned using a DNA element mediating EGF regulation of the gastrin promoter . ZBP-89 functions as both a transcriptional activator and repressor . A variety of extracellular regulators including TGFbeta , retinoic acid and butyrate stimulate ZBP-89 gene expression . Butyrate activation of p21WAF1 is potentiated by ZBP-89 through the recruitment of the co-activator p300 , while chronic stimulation by butyrate increases ZBP-89 gene expression correlating with cell differentiation . ZBP-89 stimulates growth arrest and apoptosis through its ability to bind the p21WAF1 promoter or its ability to form protein-protein interactions with p53 . ZBP-89 protein is elevated in a variety of gastrointestinal cancers as well as the pancreas . In particular , ZBP-89 is normally expressed in pancreatic islets and ducts and in about 30% of pancreatic adenocarcinomas .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "12622418"}
{"sentence": "Pilocytic astrocytoma is commonly viewed as a benign lesion . However , disease onset is most prevalent in the first two decades of life , and children are often left with residual or recurrent disease and significant morbidity . The Hedgehog ( Hh ) pathway regulates the growth of higher WHO grade gliomas , and in this study , we have evaluated the activation and operational status of this regulatory pathway in pilocytic astrocytomas . Expression levels of the Hh pathway transcriptional target PTCH were elevated in 45% of tumor specimens analyzed ( ages 1-22 years ) and correlated inversely with patient age . Evaluation of a tissue array revealed oligodendroglioma-like features , pilomyxoid features , infiltration , and necrosis more commonly in specimens from younger patients ( below the median patient age of 10 years ) . Immunohistochemical staining for the Hh pathway components PTCH and GLI1 and the proliferation marker Ki67 demonstrated that patients diagnosed before the age of 10 had higher staining indices than those diagnosed after the age of 10 . A significant correlation between Ki67 and PTCH and GLI1 staining indices was measured , and 86% of Ki67-positive cells also expressed PTCH . The operational status of the Hh pathway was confirmed in primary cell culture and could be modulated in a manner consistent with a ligand-dependent mechanism . Taken together , these findings suggest that Hh pathway activation is common in pediatric pilocytic astrocytomas and may be associated with younger age at diagnosis and tumor growth .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20223881"}
{"sentence": "The immune system has an important role in tumor appearance and spreading . One of the most efficient subpopulations of cytotoxic cells in the destruction of tumors are NK cells . NK cells are activated and increase their cytotoxic potential and modulate their cytokine production after treatment with IFNgamma , IL-12 , TNFalpha and IL-2 . The investigation of the activity of NK cells was performed on peripheral blood lymphocytes ( PBL ) of 16 healthy controls and of 40 patients with metastatic breast carcinoma . Modulation of NK cells was performed with IL-2 , IL-7 , IL-12 , TNFalpha , monoclonal antibodies ( mAb ) for TNFalpha and TNFalpha receptors type I and II , as well as with sera of healthy controls and patients with breast cancer in different clinical stages . Modulating effect of the applied factors after in vitro treatment of PBL was evaluated by the cytotoxic assay using 51chromium . Our results indicate that IL-2 significantly increased the activity of NK cells of controls and breast cancer patients . The sera of patients with advanced breast cancer significantly reduced NK cell activity . IL-7 , IL-12 and mAb for TNFalpha do not significantly change the activity of NK cells . The presence of anti-TNFalpha mAb did not change the inhibitory effect of the sera of breast cancer patients with advanced disease on the activity of NK cells of controls and patients with breast cancer . Blocking of TNFalpha Rcs with mAbs decrease the reactivity of NK cells for IL-2 . The treatment of breast cancer patients with advanced clinical stage of breast cancer with IL-2 , as an additional therapy , could be advantageous , as NK cells after this treatment increase their cytotoxic activity against tumor cells and can improve therapeutical results .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "16078444"}
{"sentence": "BACKGROUND Estrogen receptor \u03b2 ( ER\u03b2 ) is the predominant ER in the colorectal epithelium , whose expression is greatly reduced in colorectal cancer compared with normal colon tissue . Recent in vitro studies suggested that ER\u03b2 may suppress tumor growth . No research was reported whether ER\u03b2 can be used as therapeutic agent for colon cancer . METHODS In this study , ER\u03b2 gene constructed into adenoviral ( Ad ) vectors was used to treat colon cancer HCT-116 cells alone or in combination with raloxifene . In vitro and in vivo studies were conducted to investigate the therapeutic effects of ER\u03b2 and raloxifene in HCT-116 cells . RESULTS Our results indicated that , although Ad-ER\u03b2 alone had no effect on the proliferation of HCT-116 cells , the combination of Ad-ER\u03b2 with raloxifene significantly inhibited the proliferation of HCT-116 cells . The apparently apoptotic induction effects may partly explain the cytotoxicity of the two agents . The results of the study of ER\u03b2 on migration and invasion of HCT-116 cells demonstrated that overexpression of ER\u03b2 significantly decreased cell migration and increased invasion of cells . The antitumor efficacies of ER\u03b2 as well as raloxifene were further investigated on HCT-116 tumor bearing mice . Results demonstrated that both Ad-ER\u03b2 and raloxifene individually inhibited tumor growth . The combination group showed the highest inhibitory efficiency compared with other three groups . CONCLUSION These findings demonstrated that combined administration of Ad-ER\u03b2 with raloxifene represents a promising colon cancer therapeutic strategy .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22398780"}
{"sentence": "Despite insights into the molecular pathways regulating hypoxia-induced gene expression , it is not known which cell types accomplish oxygen sensing during neo-vasculogenesis . We have developed a humanized mouse model of endothelial and mesenchymal progenitor co-transplantation to delineate the cellular compartments responsible for hypoxia response during vasculogenesis . Mesenchymal stem/progenitor cells ( MSPCs ) accumulated nuclear hypoxia-inducible transcription factor ( HIF)-1\u03b1 earlier and more sensitively than endothelial colony forming progenitor cells ( ECFCs ) in vitro and in vivo . Hypoxic ECFCs showed reduced function in vitro and underwent apoptosis within 24h in vivo when used without MSPCs . Surprisingly , only in MSPCs did pharmacologic or genetic inhibition of HIF-1\u03b1 abrogate neo-vasculogenesis . HIF deletion in ECFCs caused no effect . ECFCs could be rescued from hypoxia-induced apoptosis by HIF-competent MSPCs resulting in the formation of patent perfused human vessels . Several angiogenic factors need to act in concert to partially substitute mesenchymal HIF-deficiency . Results demonstrate that ECFCs require HIF-competent vessel wall progenitors to initiate vasculogenesis in vivo and to bypass hypoxia-induced apoptosis . We describe a novel mechanistic role of MSPCs as oxygen sensors promoting vasculogenesis thus underscoring their importance for the development of advanced cellular therapies .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "22970226"}
{"sentence": "Human papillomavirus type 16 ( HPV16 ) E6 and E7 are selectively retained and expressed in HPV16-associated human genital tumors . E6 is active in several cell culture assays , including transformation of NIH 3T3 cells , trans activation of the adenovirus E2 promoter , and cooperation with E7 to immortalize normal human keratinocytes . Biochemically , the HPV16 E6 protein has been shown to bind to tumor suppressor protein p53 in vitro and induce its degradation in a rabbit reticulocyte lysate . To examine the relationship between the various biological activities of E6 and inactivation of p53 , we tested the abilities of dominant negative mutants of p53 to substitute functionally for E6 in the three cell culture assays . While wild-type p53 inhibited keratinocyte proliferation , both mouse and human mutant p53s , in conjunction with E7 , increased proliferation of the keratinocytes , resulting in generation of immortalized lines . However , in contrast to E6 , mutant p53 was unable to induce transformation or trans activate the adenovirus E2 promoter in NIH 3T3 cells . These results suggest that inactivation of wild-type p53 is necessary for HPV-induced immortalization of human keratinocytes and that different or additional activities are required for E6-dependent transformation and trans activation of NIH 3T3 cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1318401"}
{"sentence": "It is well established that blocking the interaction of EGFR with growth factors leads to the arrest of tumor growth , resulting in tumor cell death . ER414 is a human monoclonal antibody ( mAb ) derived by guided selection of the mouse mAb A13 . The ER414 exhibited a lower affinity and , as a result , lower efficacy of inhibition of the EGF-mediated tyrosine phosphorylation of EGFR when compared with mAb A13 and cetuximab . We performed a stepwise in vitro affinity maturation to improve the affinity of ER414 . We obtained a 3D model of ER414 to identify the amino acids in the CDRs that needed to be mutated . Clones were selected from the phage library with randomized amino acids in the CDRs and substitution of amino acids in the HCDR3 and LCDR1 of ER414 led to improved affinity . A clone , H3-14 , with a increased affinity , was selected from the HCDR3 randomized library . Then three clones , ER2 , ER78 and ER79 , were selected from the LCDR1 randomized library based on the H3-14 but did not show further increased affinities compared to that of H3-14 . Of the three , ER2 was chosen for further characterization due to its better expression than others . We successfully performed affinity maturation of ER414 and obtained antibodies with a similar affinity as cetuximab . And antibody from an affinity maturation inhibits the EGF-mediated tyrosine phosphorylation of EGFR in a manner similar to cetuximab .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23091439"}
{"sentence": "BACKGROUND Surgical procedures such as liver resection and liver transplantation are the first-line treatments for hepatocellular carcinoma ( HCC ) patients . However , the high incidence of tumor recurrence and metastasis after liver surgery remains a major problem . Recent studies have shown that hepatic ischemia-reperfusion ( I/R ) injury and endothelial progenitor cells ( EPCs ) contribute to tumor growth and metastasis . We aim to investigate the mechanism of FTY720 , which was originally applied as an immunomodulator , on suppression of liver tumor metastasis after liver resection and partial hepatic I/R injury . METHODOLOGY/PRINCIPAL FINDINGS An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777 . Two weeks after orthotopic liver tumor implantation , the rats underwent liver resection for tumor-bearing lobe and partial hepatic I/R injury . FTY720 ( 2 mg/kg ) was administered through the inferior caval vein before and after I/R injury . Blood samples were taken at days 0 , 1 , 3 , 7 , 14 , 21 and 28 for detection of circulating EPCs ( CD133+CD34+ ) . Our results showed that intrahepatic and lung metastases were significantly inhibited together with less tumor angiogenesis by FTY720 treatment . The number of circulating EPCs was also significantly decreased by FTY720 treatment from day 7 to day 28 . Hepatic gene expressions of CXCL10 , VEGF , CXCR3 , CXCR4 induced by hepatic I/R injury were down-regulated in the treatment group . CONCLUSIONS/SIGNIFICANCE FTY720 suppressed liver tumor metastasis after liver resection marred by hepatic I/R injury in a rat liver tumor model by attenuating hepatic I/R injury and reducing circulating EPCs .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22384233"}
{"sentence": "The conserved eukaryotic DNA replication protein ORC1 is one of the constituents of pre-replication complexes that assemble at or very near origins prior to replication initiation . ORC1 has been shown to be constitutively nuclear in Leishmania major . This study investigates the sequences involved in nuclear localization of ORC1 in Leishmania donovani , the causative agent of visceral leishmaniasis . Nuclear localization signals ( NLSs ) have been reported in only a few Leishmania proteins . Functional analyses have delineated NLSs to regions of amino acids in length in the tyrosyl DNA phosphodiesterase I and type II DNA topoisomerase of L. donovani , and in the L. major kinesin KIN13-1 . Using a panel of site-directed mutations we have identified a sequence essential for nuclear import of LdORC1 . This sequence at the N terminus of the protein comprises residues 2-5 ( KRSR ) , with K2 , R3 and R5 being crucial . Independent mutation of the K2 residue causes exclusion of the protein from the nucleus , while mutating the R5 residue leads to diffusion of the protein throughout the cell . This sequence , however , is insufficient for targeting a heterologous protein ( \\u03b2-galactosidase ) to the nucleus . Analysis of additional ORC1 mutations and reporter constructs reveals that while the highly basic tetra-amino acid sequence at the N terminus is essential for nuclear localization , the ORC1 NLS in its entirety is more complex , and of a distributive character . Our results suggest that nuclear localization signalling sequences in Leishmania nuclear proteins are more complex than what is typically seen in higher eukaryotes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22575896"}
{"sentence": "Ionizing radiation is a potent inducer of DNA damage because it causes single- and double-strand breaks , alkali-labile sites , base damage , and crosslinks . The interest in ionizing radiation is due to its environmental and clinical implications . Single-strand breaks , which are the initial damage induced by a genotoxic agent , can be used as a biomarker of exposure , whereas the more biologically relevant double-strand breaks can be analyzed to quantify the extent of damage . In the present study the effects of 137CS gamma-radiation at doses of 1 , 5 , and 10 Gray on DNA and subsequent repair by C3H10T1/2 cells ( mouse embryo fibroblasts ) were investigated . Two versions of the comet assay , a sensitive method for evaluating DNA damage , were implemented : the alkaline one to detect single-strand breaks , and the neutral one to identify double-strand breaks . The results show a good linear relation between DNA damage and radiation dose , for both single-strand and double-strand breaks . A statistically significant difference with respect to controls was found at the lowest dose of 1 Gy . Heterogeneity in DNA damage within the cell population was observed as a function of radiation dose . Repair kinetics showed that most of the damage was repaired within 2 h after irradiation , and that the highest rejoining rate occurred with the highest dose ( 10 Gy ) . Single-strand breaks were completely repaired 24 h after irradiation , whereas residual double-strand breaks were still present . This finding needs further investigation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12484548"}
{"sentence": "Background . Over the past ten years oncological outcomes achieved by local excision techniques ( LETs ) as the sole treatment for early stages of rectal cancer ( ESRC ) have been often disappointing . The reasons for these poor results lie mostly in the high risk of the disease's diffusion to local-regional lymph nodes even in ESRC . Aims . This study aims to find the correct indications for LET in ESRC taking into consideration clinical-pathological features of tumours that may reduce the risk of lymph node metastasis to zero . Methods . Systematic literature review and meta-analysis of casistics of ESRC treated with total mesorectal excision with the aim of identifying risk factors for nodal involvement . Results . The risk of lymph node metastasis is higher in G \u2265 2 and T \u2265 2 tumours with lymphatic and/or vascular invasion . Other features which have not yet been sufficiently investigated include female gender , TSM stage >1 , presence of tumour budding and/or perineural invasion . Conclusions . Results comparable to radical surgery can be achieved by LET only in patients with T(1) N(0) G(1) tumours with low-risk histological features , whereas deeper or more aggressive tumours should be addressed by radical surgery ( RS ) .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22778940"}
{"sentence": "Telomerase is a ribonucleoprotein consisting of a catalytic subunit , the telomerase reverse transcriptase , TERT , and an integrally associated RNA , TR , which contains a template for the synthesis of short repetitive G-rich DNA sequences at the ends of telomeres . Telomerase can repetitively reverse transcribe its short RNA template , acting processively to add multiple telomeric repeats onto the same DNA substrate . The contribution of enzyme processivity to telomere length regulation in human cells is not well characterized . In cancer cells , under homeostatic telomere length-maintenance conditions , telomerase acts processively , while under nonequilibrium conditions , telomerase acts distributively on the shortest telomeres . To investigate the role of increased telomerase processivity on telomere length regulation in human cells with limited lifespan that are dependent on human TERT ( hTERT ) for lifespan extension and immortalization , we mutated the leucine at position 866 in the reverse transcriptase C motif of hTERT to a tyrosine ( L866Y ) , which is the amino acid found at a similar position in HIV-1 reverse transcriptase . We report that , similar to the previously reported ' gain of function ' Tetrahymena telomerase mutant ( L813Y ) , the human telomerase variant displays increased processivity. hTERT-L866Y , like wild-type hTERT can immortalize and extend the lifespan of limited lifespan cells . Moreover , hTERT-L866Y expressing cells display heterogenous telomere lengths , telomere elongation , multiple telomeric signals indicative of fragile sites and replicative stress , and an increase in short telomeres , which is accompanied by telomere trimming events . Our results suggest that telomere length and homeostasis in human cells may be regulated by telomerase enzyme processivity .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23178942"}
{"sentence": "BACKGROUND The current staging system provides an anatomical classification of lung tumors ; its secondary purpose is to allow the prognostic stratification of patients into homogeneous groups after surgery . In this work , intratumoral perineural invasion , lymphatic and blood vessel invasion together with the necrosis content of the tumor exclusive of the non-small cell cancer staging system were studied . METHODS During a 4-year period , 152 patients operated for non-small cell lung cancer ( NSCLC ) at our hospital were analyzed . Mean age of patients was 55.7 +/- 10.1 years . RESULTS Overall 5-year survival was 42.2 % . Mediastinal lymph node involvement , tumor size , incomplete resection , pneumonectomy , presence of necrosis and perineural invasion were significant prognosticators ( P = 0.03 , 0.04 , 0.0001 , 0.046 , 0.0246 , < 0.0001 , respectively ) . Multivariate analysis revealed that N status , perineural invasion , and the presence of necrosis were independent prognostic factors ( P = 0.006 , P = 0.001 , P = 0.001 , respectively ) . Patients who had stage I tumor with necrosis and perineural invasion had a lower survival rate than those with stage IIIA tumor without these histopathological features ( P = 0.04 ) . The presence of these histopathological characteristics in stage IIIA patients was a sign of a poorer prognosis ( P = 0.0001 ) . CONCLUSIONS Perineural invasion and the presence of necrosis independently indicated a dismal prognosis and their prognostic power is comparable to those of the TNM classification . These factors could be candidates for better survival stratification and the indicators of the need for adjuvant therapy in early stage lung cancer patients .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20333571"}
{"sentence": "Dendritic cells ( DCs ) are key regulators of innate and acquired immunity . The maturation of DCs is directed by signal transduction events downstream of toll-like receptors ( TLRs ) and other pattern recognition receptors . Here , we demonstrate that , in mouse DCs , TLR agonists stimulate a profound metabolic transition to aerobic glycolysis , similar to the Warburg metabolism displayed by cancer cells . This metabolic switch depends on the phosphatidyl inositol 3'-kinase/Akt pathway , is antagonized by the adenosine monophosphate ( AMP)-activated protein kinase ( AMPK ) , and is required for DC maturation . The metabolic switch induced by DC activation is antagonized by the antiinflammatory cytokine interleukin-10 . Our data pinpoint TLR-mediated metabolic conversion as essential for DC maturation and function and reveal it as a potential target for intervention in the control of excessive inflammation and inappropriately regulated immune responses .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "20351312"}
{"sentence": "The telomerase activity and the senescence profile of cultured breast fibroblasts from normal human interstitial and malignant stromal tissue were studied in comparison with their proliferation and differentiation pattern . Fibroblasts were grown either in the presence or absence of a conditioned medium ( CM ) obtained from cultures of the oestrogen receptor-positive breast cancer MCF-7 cell line . At different passages ( from the 2nd up to the 48th ) , fibroblasts were examined for the telomerase activity by the Telomerase Repeats Amplification Protocol ( TRAP ) assay , for proliferation profile by Ki-67 antigen expression , and the myofibroblast or smooth muscle cell-like differentiation pattern by immunofluorescence with monoclonal antibodies specific for smooth muscle markers . Serial passages of fibroblasts from normal or tumour breast reveal that the relationship between the levels of telomerase activity and phenotypic/proliferation profile changes with cell subcultivation in a different manner in the two cell populations . The fibroblasts from normal tissue completed 12 passages in a CM-independent way prior to senescence whereas fibroblasts from tumour stroma senescence were attained after 48 passages . These cells showed a marked decrease of telomerase activity , growth rate and smooth muscle alpha-actin expressing myofibroblasts after the 32nd passage . CM treatment of this fibroblast population induces a decline in the myofibroblast content , which precedes the changes in telomerase activity . Passaged fibroblasts from normal breast tissue can be converted to myofibroblasts upon CM treatment whereas those from tumour stroma were CM-insensitive . Taken together our data suggest that a heterogeneous fibroblast population with different life span is activated/recruited in the breast interstitium and poses the problem of a unique activation/recruitment of fibroblasts in neoplastic conditions .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12814188"}
{"sentence": "Comparative mutagenesis studies of N-(2'-deoxyguanosin-8-yl)-2-acetylaminofluorene ( dG-AAF ) and N-(2'-deoxyguanosin-8-yl)-2-aminofluorene ( dG-AF ) adducts positioned in the Nar I restriction enzyme site were performed using Escherichia coli ( E. coli ) and simian kidney ( COS-7 ) cells . Oligodeoxynucleotides ( (5)(')TCCTCG(1)G(2)CG(3)CCTCTC ) containing a recognition sequence for the Nar I restriction enzyme were modified site-specifically with dG-AAF or dG-AF . Modified and unmodified oligomers inserted into single-stranded phagemid shuttle vectors were used to transform E. coli or to transfect COS-7 cells . Following replication in host cells , progeny plasmids were recovered and analyzed for mutations . In SOS-induced E. coli , dG-AAF primarily induced one- and two-base deletions . The mutational frequency varied , depending on the position modified in the Nar I site ; 91% two-base deletions were observed at G(3) , while 8.4% and 2.8% deletions were detected at G(2) and G(1) , respectively . In contrast , dG-AF at any position in the Nar I site failed to produce deletions , generating primarily G --> T transversions ( mutational frequency , 7.6-8.4% ) . In COS-7 cells , both dG-AAF and dG-AF primarily induced G --> T transversions . Mutation frequencies for dG-AAF were 9.4-24% , the highest values being at G(1) and G(3) . Mutation frequencies for dG-AF were 9.3-21% , the higher value at G(2) . We conclude from this study that the mutation potential of dG-AAF and dG-AF depends on the structure of the adduct , the sequence context of the lesion , and the host cell used for the experiment .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12450390"}
{"sentence": "Recent studies have demonstrated that n-3 polyunsaturated fatty acids such as eicosapentaenoic acid ( EPA ) are able to suppress cell proliferation and inhibit tumor growth . The objective of our study was to investigate the influence of a high dose EPA on the development of the tumor phenotype in ataxia-telangiectasia mutated ( Atm)-deficient mice , a genetic cancer model that is associated with increased levels of oxidative stress . We analyzed toxicity , proliferation , cell-cycle progression , and apoptosis of EPA in vitro and latency to tumorigenesis in vivo . Because of the impact of reactive oxygen species ( ROS ) on the tumor incidence in ataxia telangiectasia ( AT ) , we further analyzed the effect of EPA on the generation of ROS and oxidative DNA damage ( ODD ) . EPA effectively inhibited proliferation , altered cell-cycle progression , and induced apoptosis of tumor cells ( AT-4 ) . EPA showed no effect on the latency to tumorigenesis in Atm-deficient mice . EPA treatment was accompanied by a significant increase of ROS and ODD . Our results demonstrate the antiproliferative effect of EPA on tumor cells by alteration of cell-cycle progression and induction of apoptosis in vitro . On the other hand , EPA treatment of Atm-deficient mice led to the formation of ROS and accumulation of ODD that might have abrogated the anticarcinogenic effect caused by EPA .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20574919"}
{"sentence": "Expression of angiogenic factors is upregulated in hyperplastic mucosa adjacent to colon cancer , and this upregulation is closely associated with cancer growth and metastasis . We investigated the role of histone acetylation in vascular endothelial growth factor ( VEGF ) expression in hyperplastic mucosa adjacent to orthotopic colon cancer in mice . In the hyperplastic mucosa adjacent to KM12SM tumor in the cecum of athymic mice , VEGF upregulation was associated with hypoxia-inducible factor ( HIF)-1alpha induction . The hyperplastic mucosa also showed hypoacetylation of histone H4 and reduction of both p53 and von Hippel-Lindau ( VHL ) proteins . To examine the effects of growth factors and cytokines on histone acetylation and levels of p53 , VHL and HIF-1alpha , the rat intestinal epithelial cell line IEC6 was treated with epidermal growth factor ( EGF ) and interleukin ( IL)-15 for 35 days . Acetylated histone H4 , p53 protein and ubiquitinated protein levels were reduced , whereas HIF-1alpha production was upregulated in EGF- and IL-15-treated IEC6 cells . These findings suggest that EGF- or IL-15-induced histone H4 hypoacetylation is associated with repression of p53 and VHL genes in intestinal epithelial cells . The subsequent suppression of protein ubiquitination leads to upregulation of VEGF production by HIF-1alpha retention .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "12865631"}
{"sentence": "Maintaining the integrity of the cell cycle is critical for ensuring that cells only undergo DNA replication and proliferation under controlled conditions in response to discrete stimuli . One mechanism by which the fidelity of this process is guaranteed is through the activation of cell cycle checkpoints . The mitotic spindle checkpoint , which is regulated by Aurora B kinase , ensures proper kinetochore attachment to chromosomes leading to equal distribution of chromosomes to daughter cells . We demonstrated that the mitogen-activated protein kinase ( MAPK ) cascade regulates mitotic progression and the spindle checkpoint . As demonstrated by immunofluorescence at kinetochores , depletion of Raf Kinase Inhibitory Protein ( RKIP ) , an inhibitor of Raf/MEK/ERK signaling , causes an increase in MAPK activity that inhibits Aurora B kinase activity . By monitoring mitotic index and transit time from nuclear envelope breakdown to anaphase , we demonstrated that RKIP depletion leads to a defective spindle checkpoint and genomic instability , particularly in response to drugs that disrupt microtubule function .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "20812004"}
{"sentence": "BACKGROUND Intracystic papillary carcinoma ( IPC ) of the breast is a rare form of noninvasive breast cancer . An appreciation of associated pathology with IPC may be critical in surgical decision-making . METHODS The medical records of all patients with IPC treated between 1985 and 2001 were retrospectively reviewed . Three patient groups were identified according to the pathologic features of the primary tumor : IPC alone , IPC with associated ductal carcinoma in situ ( DCIS ) , and IPC with associated invasion with or without DCIS . Types of treatment and outcomes were compared between groups . RESULTS Forty patients were treated for IPC during the study period . Fourteen had pure IPC , 13 had IPC with DCIS , and 13 had IPC with invasion . The incidence of recurrence and the likelihood of dying of IPC did not differ between the three groups regardless of the type of surgery ( mastectomy or segmental mastectomy ) performed and whether radiation therapy was administered . The disease-specific survival rate was 100% . CONCLUSIONS When IPC is identified , it is frequently associated with DCIS and or invasion . Standard therapy should be based on associated pathology . The role of radiation therapy in pure IPC remains to be determined .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12383904"}
{"sentence": "Prostate cancer ( PCA ) is the most common histological malignancy and the second leading cause of cancer deaths among North American men . There has been considerable interest in the chemopreventative properties of selenium . In this study , we assessed whether selenium inhibits cell growth and associated cell cycle regulatory proteins . Human PCA cells ( LNCaP , PC3 , PC3-AR2 , and PC3-M ) were incubated with and without selenium ( Seleno-DL-methionine , 150 microM ) for 24 , 48 , and 72 h . Cells were fixed and stained with propidium iodide for flow cytometry analysis . In parallel experiments , total protein was extracted , immunoprecipitated with cyclin E antibody , and analyzed by Western blot for the expression of cell cycle markers . Treatment with selenium caused G1 arrest and an 80% reduction in the S phase of LNCaP with no effect on PC3 . However , PC3 cells transfected with the androgen receptor ( PC3-AR2 ) exhibited a G2/M arrest and a marked reduction ( 57% ) in the S phase during cell cycle progression . In the analysis of cell cycle regulatory molecules , selenium-treated cells demonstrated a significant induction of cyclin-dependent kinase inhibitors Cip1/p21 and Kip1/p27 . These data suggest that selenium possesses strong antiproliferative properties in regard to human PCA . This effect appears to be dependent on the presence of a functioning androgen receptor . This provides a theoretical basis for Phase III studies of selenium in PCA prevention .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "11980647"}
{"sentence": "Previous studies with selenium and/or vitamin E in prostate carcinogenesis animal models have been negative , but these models may not involve oxidative stress mechanisms . In this study , we examined the potential of selenomethionine and alpha-tocopherol to modulate prostate cancer development in the testosterone plus estradiol-treated NBL rat , a model that does involve sex hormone-induced oxidative stress mechanisms and prostatic inflammation . One week following the implantation with hormone-filled Silastic implants , rats were fed diets containing l-selenomethionine ( 1.5 or 3.0 mg/kg ) , DL-alpha-tocopherol acetate ( 2,000 or 4,000 mg/kg ) , or a natural ingredient control diet ( NIH-07 ) . The development of prostate carcinomas was not affected by dietary treatment with either agent . Food intake , body weight , and mortality were also not affected . The high dose of selenomethionine reduced the severity of epithelial dysplasia in the lateral prostate that was not associated with inflammation , and alpha-tocopherol reduced in a dose-related fashion the incidence of marked inflammation and marked epithelial dysplasia in the lateral prostate , regardless of whether these lesions were associated with inflammation. alpha-Tocopherol significantly increased the incidence of adenocarcinomas of the mammary glands at both dietary concentrations . Collectively , our findings suggest that selenomethionine and alpha-tocopherol supplementation does not prevent prostate cancer in rats fed diets with nutritionally adequate levels of selenium and vitamin E. Importantly , the results of the current animal studies and those reported previously were fully predictive of the outcome of the Selenium and Vitamin E Cancer Prevention Trial .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20179302"}
{"sentence": "Human diploid fibroblasts have a limited life span in vitro , and spontaneous immortalization is an extremely rare event . We have used transformation of human diploid fibroblasts by an origin-defective simian virus 40 genome to develop series of genetically matched immortal cell lines to analyze immortalization . Comparison of a preimmortal transformant ( SVtsA/HF-A ) with its uncloned and cloned immortalized derivatives ( AR5 and HAL ) has failed to reveal any major alteration involving the simian virus 40 genome . Karyotypic analysis , however , demonstrated that all of the immortal cell lines in this series have alterations of chromosome 6 involving loss of the portion distal to 6q21 . The karyotypic analysis was corroborated by DNA analyses . Southern analysis demonstrated that only one copy of three proto-oncogene loci ( ros1 , c-myb , and mas1 ) on 6q was retained in immortal cells . Polymerase chain reaction analysis of the microsatellite polymorphism at 6q22 ( D6S87 ) showed loss of heterozygosity . In addition , elevated expression of c-myb ( 6q22-23 ) was observed . We hypothesize that the region at and/or distal to 6q21 plays a role in immortalization , consistent with the presence of a growth suppressor gene .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1373811"}
{"sentence": "Atherosclerosis ( As ) is now widely appreciated to represent a chronic inflammatory reaction of the vascular wall in response to dyslipidemia and endothelial distress involving the inflammatory recruitment of leukocytes and the activation of resident vascular cells . MicroRNAs ( miRNAs ) are a group of endogenous , small ( nucleotides in length ) non-coding RNA molecules , which function specifically by base pairing with mRNA of genes , thereby induce translation repressions of the genes within metazoan cells . Recently , the function of miR-27 , one of the miRNAs , in the initiation and progression of atherosclerosis has been identified . In vivo and in vitro studies suggest that miR-27 may serve as a diagnostic and prognostic marker for atherosclerosis . More recently , studies have identified important roles for miR-27 in angiogenesis , adipogenesis , inflammation , lipid metabolism , oxidative stress , insulin resistance and type 2 diabetes , etc . In this review , we focus on the role of miR-27 in the development of vulnerable atherosclerotic plaques , potential as a disease biomarker and novel therapeutic target in atherosclerosis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22307089"}
{"sentence": "Doxorubicin ( DOX ) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers . However , the clinical use of DOX is restricted due to its severe cardiotoxic side-effects . There has been ongoing search for cardioprotectants against DOX toxicity . Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation . In this review , we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX-induced cardiac cellular damage and dysfunction , based on our recent promising studies in a mouse model of DOX cardiotoxicity . Our data show that chronic oral ingestion of sodium nitrate , at a dose equivalent to of the Acceptable Daily Intake of the World Health Organization , alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage . Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis , tissue lipid peroxidation , and mitochondrial H(2)O(2) generation following DOX treatment . Furthermore , proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme - peroxiredoxin 5 in the nitrate-treated animals . These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process . Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22484629"}
{"sentence": "Hexavalent chromium ( Cr(VI) ) compounds are known human carcinogens associated with the incidence of lung cancer . Although a direct correlation between Cr(VI) exposure and lung cancer has been established , several studies aimed at generating animal models for Cr(VI) have yielded inconsistent data that do not affirmatively support findings from epidemiologic studies . Because the lack of a good animal model has hindered the identification of molecular mechanisms involved in Cr(VI) exposure , we developed an in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis . We report here that long-term exposure to Cr(VI) leads to the malignant transformation of nontumorigenic human lung epithelial cells . Cr(VI)-transformed cells exhibited loss of contact inhibition , colony formation , and increased rates of cell invasion , migration , and proliferation , as compared with passage-matched control cells . Cr(VI)-transformed cells evaded apoptosis by a mechanism involving S-nitrosylation and stabilization of Bcl-2 protein in a nitric oxide-dependent manner . This study establishes an important in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis , and elucidates a novel mechanism that causes apoptosis-resistant malignant transformation of nontumorigenic lung cells in response to a human carcinogen .", "label": [1, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "19556603"}
{"sentence": "Semaphorin 5A , a member of semaphorin family , was originally identified as axonal guidance factor functioning during neuronal development . Previously , we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer . However , its functional roles and mechanism(s) in invasion and metastasis of gastric cancer remain unclear . By using human gastric caner cell lines Parental SGC7901 , SGC7901-siScrambled and SGC7901-siSema 5A , we found that semaphorin 5A significantly promoted the invasive and metastatic abilities of gastric cancer cell in vitro . Semaphorin 5A increased the expression of MMP9 by activating phosphorylated ErK1/2 in gastric cancer cell . Furthermore , MEK inhibitor PD98059 and MMP9 antibody ( Ab ) significantly inhibited in vitro invasive and metastatic abilities induced by semaphorin 5A . Taken together , the present work revealed a novel function of semaphorin 5A that the existence of semaphorin 5A could promote invasion and metastasis of gastric cancer by regulating MMP9 expression , at least partially , via the MEK/ERKs signal transduction pathway . Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22821546"}
{"sentence": "Lowering the threshold of cellular senescence , the process employed by cells to thwart abnormal cell proliferation , though inhibition of CDK2 or Skp2 ( regulator of CDK inhibitors ) has been recently suggested as a potential avenue for cancer treatment . In this study , we employ a published mathematical model of G1/S transition involving the DNA-damage signal transduction pathway to conduct carefully constructed computational experiments to highlight the effectiveness of manipulating cellular senescence in inhibiting damaged cell proliferation . We first demonstrate the suitability of the mathematical model to explore senescence by highlighting the overlap between senescence pathways and those involved in G1/S transition and DNA damage signal transduction . We then investigate the effect of CDK2 deficiency on senescence in healthy cells , followed by effectiveness of CDK2 deficiency in triggering senescence in DNA damaged cells . For this , we focus on the behaviour of CycE , whose peak response indicates G1/S transition , for several reduced CDK2 levels in healthy as well as two DNA-damage conditions to calculate the probability ( \\u03b2 ) or the percentage of CDK2 deficient cells passing G1/S checkpoint ( (1-\\u03b2) indicates level of senescence ) . Results show that 50% CDK2 deficiency can cause senescence in all healthy cells in a fairly uniform cell population ; whereas , most healthy cells ( \\u224867% ) in a heterogeneous population escape senescence . This finding is novel to our study . Under both low- and high-DNA damaged conditions , 50% CDK deficiency can cause 65% increase in senescence in a heterogeneous cell population . Furthermore , the model analyses the relationship between CDK2 and its CKIs ( p21 , p27 ) to help search for other effective ways to bring forward cellular senescence . Results show that the degradation rate of p21 and initial concentration of p27 are effective in lowering CDK2 levels to lower the senescence threshold . Specifically , CDK2 and p27 are the most effective in triggering senescence while p21 having a smaller influence . While receiving experimental support , these findings specify in detail the inhibitory effects of CKIs . However , simultaneous variation of CDK2 and CKIs produces a dramatic reduction of damage cells passing the G1/S with CDK2&p27 combination causing senescence in almost all damaged cells . This combined effect of CDK2&CKIs on senescence is a novel contribution in this study . A review of the crucial protein complexes revealed that the concentration of active CycE/CDK2-p that controls cell cycle arrest provides support for the above findings with CycE/CDK2-p undergoing the largest reduction ( over 100% ) under the combined CDK2&CKI conditions leading to the arrest of most of the damaged cells . Our study thus provides quantitative assessments for the previously published qualitative findings on senescence and highlights new avenues for bringing forward senescence bar .", "label": [0, 0, 0, 1, 1, 1, 0, 0, 0, 0], "id": "23254306"}
{"sentence": "An accidental exposure of six workers to ethylene oxide ( EO ) provided the rationale for a biomonitoring and follow-up study , whose aim was to analyse protein adduct kinetics and examine the differentiation between accidental and environmental exposure , e.g. , from tobacco smoke . For this purpose , the decrease in the concentration of the haemoglobin adduct N-2-hydroxyethylvaline ( HEV ) was followed during a five-month period after the accident , together with N-2-cyanoethylvaline ( CEV ) and urinary cotinine , two well-established biomarkers for smoking . The follow-up study showed that EO adduct concentrations significantly increased after a short but presumably high exposure . Initial biomonitoring revealed HEV levels above 500 pmol g(-1) globin in all cases , with a maximum of about 2,400 pmol g(-1) globin . This compares to a German EKA value ( exposure equivalent for carcinogenic substances ) for a daily 8-h-exposure to 1 ppm EO of 90 \\u03bcg L(-1) blood ( pmol g(-1) globin ) . The adduct levels dropped in accordance with the expected zero-order kinetics for a single exposure . After the five-month observation interval , the HEV concentrations in blood reflected the individual background from tobacco smoking . The results of this study show that even a short exposure to ethylene oxide may result in a significant rise in haemoglobin adduct levels . Although protein adducts and their occupational-medical assessment values are considered for long-term exposure surveillance , they can also be used for monitoring accidental exposures . In these cases , the calculation of daily ' ppm-equivalents ' may provide a means for a comparison with the existing assessment values .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22728792"}
{"sentence": "We investigated the effectiveness of continuous hyperthermic peritoneal perfusion ( CHPP ) for the peritoneal dissemination of gastric cancer . A total 124 patients with advanced gastric cancer were enrolled in this study . Prophylactic CHPP ( P-CHPP ) was performed in 45 patients who had macroscopic serosal invasion without peritoneal dissemination , and 79 patients without CHPP were a control group . Therapeutic CHPP ( T-CHPP ) was performed in 21 patients with peritoneal dissemination , and 52 patients without CHPP were a control group . There was no significant difference in 5 year survival between patients treated and not treated with P-CHPP . Univariate analysis showed that location of tumor , tumor diameter , and lymph node metastasis influenced prognosis , but there was no prognostic factor in the Cox proportional regression hazard model . There was no significant difference in 5-year survival between patients treated and not treated with T-CHPP . Univariate analysis showed that degree of peritoneal dissemination and adjuvant chemotherapy influenced prognosis , and the Cox proportional regression hazard model showed that the macroscopic types and degree of peritoneal dissemination affected prognosis . In the patients with CHPP , the incidences of respiratory failure and renal failure were each statistically greater than in the patients undergoing CHPP .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12484029"}
{"sentence": "Filamin-A cross-links actin filaments into dynamic orthogonal networks , and interacts with an array of proteins of diverse cellular functions . Because several filamin-A interaction partners are implicated in signaling of cell mobility regulation , we tested the hypothesis that filamin-A plays a role in cancer metastasis . Using four pairs of filamin-A proficient and deficient isogenic cell lines , we found that filamin-A deficiency in cancer cells significantly reduces their migration and invasion . Using a xenograft tumor model with subcutaneous and intracardiac injections of tumor cells , we found that the filamin-A deficiency causes significant reduction of lung , splenic and systemic metastasis in nude mice . We evaluated the expression of filamin-A in breast cancer tissues by immunohistochemical staining , and found that low levels of filamin-A expression in cancer cells of the tumor tissues are associated with a better distant metastasis-free survival than those with normal levels of filamin-A . These data not only validate filamin-A as a prognostic marker for cancer metastasis , but also suggest that inhibition of filamin-A in cancer cells may reduce metastasis and that filamin-A can be used as a therapeutic target for filamin-A positive cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23289018"}
{"sentence": "Metformin , one of the most widely used antidiabetic drugs , has recently been associated with potential antitumorigenic effects . In this study , we evaluated the possible cytotoxic impact of combined low doses of metformin and ionizing radiation ( IR ) on 2human hepatoma cell lines . The cytotoxic effect of metformin combined with IR was subsequently determined by clonogenic survival and cell cycle assays , assessment of mitochondrial complexI and lactate dehydrogenase ( LDH ) activity , measurement of cellular adenosine triphosphate ( ATP ) levels , comet assay and analyses of the formation and disappearance of phosphorylated histone H2AX ( \u03b3-H2AX ) protein . The combination of metformin and IR caused a much stronger cytotoxicity than the treatment with metformin or IR alone , leading to an decrease in cell viability and increase in the accumulation of cells in the G2/M phase of the cell cycle in the 2hepatoma cell lines . In addition , a reduction in mitochondrial complexI activity ( and a significant increase in LDH activity , as well as lactate production were observed in the cells exposed to metformin . Interestingly , a severe depletion in ATP , increased olive tail moment and the delayed disappearance of \u03b3-H2AX expression were detected in the hepatoma cells treated by metformin plus IR . These findings show that the combination of a low concentration of metformin and IR results in the considerable enhancement of cytotoxic effects in human hepatoma cell lines , leading to decreased DNA repair by reducing ATP production . The data provided in this study may elucidate the remarkable efficiency of this combination treatment and suggest that metformin may be used as a potential adjunct to the radiotherapy of hepatocellular carcinoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22843031"}
{"sentence": "ABSTRACT : BACKGROUND : Chemokine receptor CXCR4 , together with its ligand CXCL12 , plays critical roles in cancer progression , including growth , metastasis and angiogenesis . Ewing sarcoma is a sarcoma with poor prognosis despite current therapies , particularly for patients with advanced-stage disease . Lungs and bone ( marrow ) , organs of predilection for ( primary/metastatic ) Ewing sarcoma , represent predominant CXCL12 sources . METHODS : To gain insight into the role of the CXCR4-CXCL12 axis in Ewing sarcoma , CXCR4 , CXCL12 and hypoxia-inducible factor-1alpha protein expression was studied in therapy-naive and metastatic tumors by immunohistochemistry . CXCR4 function was assessed in vitro , by flow cytometry and proliferation/ cell viability assays , in the presence of recombinant CXCL12 and/or CXCR4-antagonist AMD3100 or under hypoxic conditions . RESULTS : Whereas CXCR4 was predominantly expressed by tumor cells , CXCL12 was observed in both tumor and stromal areas . Survival analysis revealed an ( expression level-dependent ) negative impact of CXCR4 expression ( p < 0.04 ) . A role for the CXCR4-CXCL12 axis in Ewing sarcoma growth was suggested by our observations that i ) CXCR4 expression correlated positively with tumor volume at diagnosis ( p = 0.013 ) , ii ) CXCL12 was present within the microenvironment of virtually all cases , iii ) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines , which could be abrogated by AMD3100 . CXCR4 expression was not correlated with occurrence of metastatic disease . Also , therapy-naive tumors demonstrated higher CXCR4 expression as compared to metastases ( p = 0.027 ) . Evaluation of in vivo hypoxia-inducible factor-1alpha expression and culture of cells under hypoxic conditions revealed no role for hypoxia in CXCR4 expression . CONCLUSIONS : Together , our results imply a crucial role for the CXCR4-CXCL12 axis in auto- and/or paracrine growth stimulation . Integration of CXCR4-targeting strategies into first- and/or second-line treatment regimens may represent a promising treatment option for Ewing sarcoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23249693"}
{"sentence": "The development and progression of esophageal cancer is associated with multiple alterations in the genome , including loss of the tumor suppressor phosphatase and tensin homolog deleted from the chromosome 10 ( PTEN ) gene . The purpose of this study was to determine the effects of adenovirus-mediated MMAC/PTEN expression on the growth and survival of human esophageal cancer cells in vitro and in vivo . We found that compared to control cells , overexpression of PTEN significantly suppressed growth and induced apoptosis in esophageal cancer cell lines Eca-109 and TE-1 via downregulation of Bcl-2 expression and changes in cell-cycle progression . Adenovirus PTEN also inhibited the growth of subcutaneous tumor xenografts by significantly reducing tumor size in vivo . Thus our results confirm the proposed functional role of MMAC/PTEN as a regulator of esophageal cancer progression in vivo and in vitro . PTEN might be an important biological marker and potential therapeutic target in the treatment of human esophageal cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20378992"}
{"sentence": "Inflammation is a major risk factor for carcinogenesis in patients affected by chronic colitis , yet the molecular mechanisms underlying the progression from chronic inflammation to cancer are not completely understood . Activation of the Toll-like receptor 4 ( TLR4)-NF\u03baB signaling axis is associated with inflammation . Thus , we hypothesized that inhibition of TLR4-NF\u03baB signaling might help in limiting inflammatory responses and inflammation-induced oncogenesis . In this work , we studied the effects of a TLR4-interacting surfactant protein A-derived ( SPA4 ) peptide on lipopolysaccharide ( LPS)-induced TLR4-NF\u03baB signaling and cancer progression . We first characterized this peptide for its ability to bind the TLR4 ligand-LPS and for physico-chemical characteristics . Inflammation was induced by challenging the colon cancer SW480 cells with Escherichia coli LPS . Cells were then treated with varying amounts of the SPA4 peptide . Changes in the expression of TLR4 , interleukin ( IL)-1\u03b2 and IL-6 , in intracellular NF\u03baB-related signal transducers ( IKB\u03b1 , p65 , phosphorylated IKB\u03b1 , phosphorylated p65 , RelB , COX-2 ) as well as in the transcriptional activity of NF\u03baB were studied by immunocytochemistry , immunoblotting and NF\u03baB reporter assay , respectively . Simultaneously , the effects on LPS-induced cell migration and invasion were determined . We found that the SPA4 peptide does not bind to LPS . Rather , its binding to TLR4 inhibits the LPS-induced phosphorylation of p65 , production of IL-1\u03b2 and IL-6 , activity of NF\u03baB , migration and invasion of SW480 cells . In conclusion , our results suggest that the inhibition of TLR4-NF\u03baB signaling by a TLR4-binding peptide may help for the treatment of chronic inflammation and prevention of inflammation-induced cancer in patients with colitis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23264896"}
{"sentence": "Tumor cells exhibit enhanced glucose consumption and lactate production even when supplied with adequate oxygen ( a phenomenon known as the Warburg effect , or aerobic glycolysis ) . Pharmacological inhibition of aerobic glycolysis represents a potential tumor-selective approach that targets the metabolic differences between normal and malignant tissues . Human breast tumor MDA-MB-231 cells were used to develop an assay system to discover natural product-based glycolysis inhibitors . The assay employed was based on hypersensitivity to glycolytic inhibition in tumor cells treated with the mitochondrial electron transport inhibitor rotenone . Under such conditions , ATP supply , and hence cell viability , depends exclusively on glycolysis . This assay system was used to evaluate 10648 plant and marine organism extracts from the U.S. National Cancer Institute's Open Repository . Bioassay-guided isolation of an active Moronobea coccinea extract yielded the new bis-geranylacylphloroglucinol derivative moronone ( 1 ) . Compound 1 exhibited enhanced antiproliferative/cytotoxic activity in the presence of rotenone-imposed metabolic stress on tumor cells . Surprisingly , mechanistic studies revealed that 1 did not inhibit glycolysis , but rather functions as a protonophore that dissipates the mitochondrial proton gradient . In the presence of rotenone , tumor cells may be hypersensitive to protonophores due to increased ATP utilization by the ATP synthase .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23245650"}
{"sentence": "Chronic inflammation is a risk factor for the development of colon cancer , providing genotoxic insults , growth and pro-angiogenic factors that can promote tumorigenesis and tumor growth . Immunomodulatory agents can interfere with the inflammation that feeds cancer , but their impact on the transformed cell is poorly understood . The calcium/calcineurin signaling pathway , through activation of NFAT , is essential for effective immune responses , and its inhibitors cyclosporin A ( CsA ) and FK506 are used in the clinics to suppress immunity . Moreover , the kinases GSK3\u03b2 and mTOR , modulated by PI-3K/Akt , can inhibit NFAT activity , suggesting a cross-talk between the calcium and growth factor signaling pathways . Both NFAT and mTOR activity have been associated with tumorigenesis . We therefore investigated the impact of calcineurin and PI-3K/mTOR inhibition in growth of human colon carcinoma cells . We show that despite the efficient inhibition of NFAT1 activity , FK506 promotes tumor growth , whereas CsA inhibits it due to a delay in cell cycle progression and induction of necroptosis . We found NF\u03baB activation and mTORC1 activity not to be altered by CsA or FK506 . Similarly , changes to mitochondrial homeostasis were equivalent upon treatment with these drugs . We further show that , in our model , NFAT1 activation is not modulated by PI3K/mTOR . We conclude that CsA slows cell cycle progression and induces necroptosis of human carcinoma cell lines in a TGF\u03b2- , NFAT- , NF\u03baB- and PI3K/mTOR-independent fashion . Nevertheless , our data suggest that CsA , in addition to its anti-inflammatory capacity , may target transformed colon and esophagus carcinoma cells without affecting non-transformed cells , promoting beneficial tumoristatic effects .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "22992618"}
{"sentence": "Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth . Hypoxia in tumors represents a hostile environment that can encourage these transformations . We report that glycogen metabolism is upregulated in tumors invivo and in cancer cells invitro in response to hypoxia . Invitro , hypoxia induced an early accumulation of glycogen , followed bya gradual decline . Concordantly , glycogen synthase ( GYS1 ) showed a rapid induction , followed by a later increase of glycogen phosphorylase ( PYGL ) . PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species ( ROS ) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis invivo . Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway . Thus , glycogen metabolism is a key pathway induced by hypoxia , necessary for optimal glucose utilization , which represents a targetable mechanism of metabolic adaptation .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 1], "id": "23177934"}
{"sentence": "Aberrant expression and polymorphism of fibroblast growth factor receptor 4 ( FGFR4 ) has been linked to tumor progression and anticancer drug resistance . We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix metalloproteinase ( MT1-MMP , MMP-14 ) induction at the edge of tumors expressing the FGFR4-R388 risk variant . Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas , where they were partially coexpressed at the tumor/stroma border and tumor invasion front . The strongest overall coexpression was found in prostate carcinoma . Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant , which has previously been associated with poor cancer prognosis , increased MT1-MMP-dependent collagen invasion . In this experimental model , knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen . This was coupled with impaired phosphorylation of FGFR substrate 2 and Src , upregulation of E-cadherin , and suppression of cadherin-11 and N-cadherin . These in vitro results were substantiated by reduced MT1-MMP content and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing . In contrast , knockdown of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo and within three-dimensional collagen . These results will help to explain the reported association of the FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20876804"}
{"sentence": "Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy . We identified benzo[e]pyridoindoles ( BePI ) as powerful aurora kinase inhibitors . Their efficiency was demonstrated both in enzymatic inhibition studies and in cell culture assays . New BePI molecules were synthesized , and a structure-activity relationship study was conducted with the aim of improving the activity and solubility of the lead compound . Tetracyclic BePI derivatives are characterized by a particular curved shape , and the presence of an oxo group on the pyridine ring was found to be required for aurora kinase\u2005B inhibition . New hydrosoluble benzo[e]pyridoindolones were subsequently designed , and their efficacy was tested by a combination of cell-cycle analysis and time-lapse experiments in live cells . The most active BePI derivative , 13\u2009b , inhibited the cell cycle , drove cells to polyploidy , and eventually induced apoptosis . It exhibited high antiproliferative activity in HeLa cells with an IC(50) value of 63\u2005nM . Relative to compounds tested in clinical trials , this antiproliferative potency places 13\u2009b among the top 10 aurora kinase inhibitors . Our results justify further in\u2005vivo evaluation in preclinical animal models of cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23281044"}
{"sentence": "Transforming growth factor beta ( TGF-\u03b2 ) signaling has been implicated in driving tumor progression and metastasis by inducing stem cell-like features in some human cancer cell lines . In this study , we have utilized a novel murine cell line NMuMG-ST , which acquired cancer stem cell ( CSC ) phenotypes during spontaneous transformation of the untransformed murine mammary cell line NMuMG , to investigate the role of autocrine TGF-\u03b2 signaling in regulating their survival , metastatic ability , and the maintenance of cancer stem cell characteristics . We have retrovirally transduced a dominant-negative TGF-\u03b2 type II receptor ( DNRII ) into the NMuMG-ST cell to abrogate autocrine TGF-\u03b2 signaling . The expression of DNRII reduced TGF-\u03b2 sensitivity of the NMuMG-ST cells in various cell-based assays . The blockade of autocrine TGF-\u03b2 signaling reduced the ability of the cell to grow anchorage-independently and to resist serum deprivation-induced apoptosis . These phenotypes were associated with reduced levels of active and phosphorylated AKT and ERK , and Gli1 expression suggesting that these pathways contribute to the growth and survival of this model system . More interestingly , the abrogation of autocrine TGF-\u03b2 signaling also led to the attenuation of several features associated with mammary stem cells including epithelial-mesenchymal transition , mammosphere formation , and expression of stem cell markers . When xenografted in athymic nude mice , the DNRII cells were also found to undergo apoptosis and induced significantly lower lung metastasis burden than the control cells even though they formed similar size of xenograft tumors . Thus , our results indicate that autocrine TGF-\u03b2 signaling is involved in the maintenance and survival of stem-like cell population resulting in the enhanced metastatic ability of the murine breast cancer cells .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23482850"}
{"sentence": "Induced pluripotent stem ( iPS ) cells share some basic properties , such as self-renewal and pluripotency , with cancer cells , and they also appear to share several metabolic alterations that are commonly observed in human tumors . The cancer cells ' glycolytic phenotype , first reported by Otto Warburg , is necessary for the optimal routing of somatic cells to pluripotency . However , how iPS cells establish a Warburg-like metabolic phenotype and whether the metabolic pathways that support the bioenergetics of iPS cells are produced by the same mechanisms that are selected during the tumorigenic process remain largely unexplored . We recently investigated whether the reprogramming-competent metabotype of iPS cells involves changes in the activation/expression status of the H ( + ) -ATPase , which is a core component of mitochondrial oxidative phosphorylation that is repressed at both the activity and protein levels in human carcinomas , and of the lipogenic switch , which refers to a marked overexpression and hyperactivity of the acetyl-CoA carboxylase ( ACACA ) and fatty acid synthase ( FASN ) lipogenic enzymes that has been observed in nearly all examined cancer types . A comparison of a starting population of mouse embryonic fibroblasts and their iPS cell progeny revealed that somatic cell reprogramming involves a significant increase in the expression of ATPase inhibitor factor 1 ( IF1 ) , accompanied by extremely low expression levels of the catalytic \u03b2-F1-ATPase subunit . The pharmacological inhibition of ACACA and FASN activities markedly decreases reprogramming efficiency , and ACACA and FASN expression are notably upregulated in iPS cells . Importantly , iPS cells exhibited a significant intracellular accumulation of neutral lipid bodies ; however , these bodies may be a reflection of intense lysosomal/autophagocytic activity rather than bona fide lipid droplet formation in iPS cells , as they were largely unresponsive to pharmacological modulation of PPARgamma and FASN activities . The AMPK agonist metformin , which endows somatic cells with a bioenergetic infrastructure that is protected against reprogramming , was found to drastically elongate fibroblast mitochondria , fully reverse the high IF1/\u03b2-F1-ATPase ratio and downregulate the ACACA/FASN lipogenic enzymes in iPS cells . The mitochondrial H ( + ) -ATP synthase and the ACACA/FASN-driven lipogenic switch are newly characterized as instrumental metabolic events that , by coupling the Warburg effect to anabolic metabolism , enable de-differentiation during the reprogramming of somatic cells to iPS cells .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23287468"}
{"sentence": "Lung cancers express the cholinergic autocrine loop , which facilitates the progression of cancer cells . The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers ( SCLCs ) . In this study we intended to investigate the growth inhibitory effect of R2HBJJ , a novel muscarinic antagonist , on non-small cell lung cancer ( NSCLC ) cells and the possible mechanisms . The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs . R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea . R2HBJJ markedly suppressed the growth of NSCLC cells , such as H1299 , H460 and H157 . In H1299 cells , both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin . Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition . Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection , respectively . Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb . Therefore , the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells . R2HBJJ , as a novel mAChRs antagonist , can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth , which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23285263"}
{"sentence": "Contradictory results have been reported regarding the association between vascularity ( used as an index of angiogenesis ) and thrombospondin-1 ( TSP-1 ) in human tumours . In previous studies , the reported association was based on the estimated average TSP-1 value per tumour , with a sufficient number of specimens collectively analysed per tumour type . Given the extent of intra-tumour heterogeneity , we determined the association between TSP-1 and vascularity within individual specimens , based on the average values of TSP-1 and vascularity in 10-20 pre-selected areas per tumour . Cells expressing TSP-1 mRNA were visualised by in situ hybridisation and quantified by point counting . Vascularity was quantified by point counting and vessel density of von Willebrand Factor-positive vessels . In 10 ductal breast carcinomas , a direct correlation between TSP-1 and vascularity was found in 4 tumours , no correlation in 3 and an inverse correlation in 3 . The effect of TSP-1 on endothelial cell migration in vitro was assessed in the Boyden chamber assay . TSP-1 stimulated cell migration at low concentrations ( 0.1-10 microg/ml ) and was inhibitory at high concentrations ( 25-100 microg/ml ) . These results suggest that TSP-1 may elicit a concentration-dependent , bi-phasic , effect on angiogenesis .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12814189"}
{"sentence": "The NF-kB family of transcription factors regulates important biological functions including cell growth , survival and the immune response . We found that Human Papillomavirus type 16 ( HPV-16 ) E7 and E6/E7 proteins inhibited basal and TNF-alpha-inducible NF-kB activity in human epithelial cells cultured from the cervical transformation zone , the anatomic region where most cervical cancers develop . In contrast , HPV-16 E6 regulated NF-kB in a cell type- and cell growth-dependent manner . NF-kB influenced immortalization of cervical cells by HPV16 . Inhibition of NF-kB by an IkB alpha repressor mutant increased colony formation and immortalization by HPV-16 . In contrast , activation of NF-kB by constitutive expression of p65 inhibited proliferation and immortalization . Our results suggest that inhibition of NF-kB by HPV-16 E6/E7 contributes to immortalization of cells from the cervical transformation zone .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "22284893"}
{"sentence": "Olfactomedin 4 ( OLFM4 ) is highly expressed in gastrointestinal cancers and has an anti-apoptotic function . The roles of OLFM4 in tumor growth and metastasis and how it functions in these processes remain elusive . We investigated the function of OLFM4 in tumor growth and metastasis using B16F10 mouse melanoma cells as an experimental system . Our results showed that OLFM4 had no positive effect on cell viability or cell cycle progression in B16F10 cells . However , it significantly suppressed the tumorigenicity of B16F10 cells , i.e. , intradermal primary tumor growth and lung metastasis . OLFM4 also suppressed the migration and invasion of B16F10 cells in vitro . For further insight into the mechanisms underlying OLFM4-mediated suppression of tumor progression , we examined the effect of OLFM4 on the expression of integrin and matrix metalloproteinase ( MMP ) , both of which are involved in tumor progression . Overexpression of OLFM4 clearly reduced the expression levels of integrin \u03b11 , integrin \u03b14 , integrin \u03b15 , integrin \u03b16 , and MMP9 . Moreover , forced expression of MMP9 attenuated the inhibitory activity of OLFM4 on migration and invasiveness . Our findings provide the experimental evidence that OLFM4 may function as a tumor suppressor and an anti-metastatic gene during tumor progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23161172"}
{"sentence": "Contrary to the paradigm that cancer incidence increases indefinitely with age , significant data now suggest cancer incidence may markedly reduce beyond age 80 years for humans and beyond 800 days for mice , and is not inevitable . We show that increasing cellular senescence with age is a possible cause of this reduction , since senescent cells are removed from the pool of cells that retain proliferative ability necessary for cancer . We further show that animal interventions appearing to alter senescence , p53 mutation and melatonin dosing , support the prediction that increasing senescence rate reduces cancer while reducing lifespan , and vice versa . Studies of environmental agents associated with increased cancer might be re-examined to find if there is an association with longevity increases , which may markedly alter our view of such agents . We also show that if an agent functions by slowing both senescence and carcinogenesis , longevity is increased while reducing cancer . Dietary restriction is the only known intervention that accomplishes this , but there may be others .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "15119525"}
{"sentence": "Surgery is the most effective therapy for cancer in the United States , but disease still recurs in more than 40% of patients within 5 years after resection . Chemotherapy is given postoperatively to prevent relapses ; however , this approach has had marginal success . After surgery , recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen . Phosphatidylserine ( PS ) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues . Thus , PS is an attractive target for cancer therapy after surgery . Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 ( a novel mouse chimeric monoclonal antibody that targets PS ) , cisplatin ( cis ) , or combination after surgery . Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone ( P = .02 ) . Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals . Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells , particularly granulocytes . This strategy was independent of the adaptive immune system . Together , these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "22577350"}
{"sentence": "Oral squamous cell carcinoma ( OSCC ) is the most common malignant tumor in the oral and maxillofacial region . The mechanism of carcinogenesis of OSCC is still unclear . Based on the previous cell line , HIOEC-B(a)P-96 ( HB96 ) , which we obtained by HPV16 E6/E7-immortalized human oral epithelial cells ( HIOEC ) and benzo(a)pyrene inducement , we prepared a new HB-second generation cancer cell line ( HB-2 ) by continuous passage . Its characteristics such as morphology , proliferation activity , karyotype , and tumorigenesis were studied . The HB-2 cells displayed uncontrolled cell division and lost contact inhibition leading to cell overlap . Cells were polygonal and unevenly shaped , with an increased nucleus versus plasma ratio . Increased proliferative activity was confirmed by MTT assays . The tumorigenicity was confirmed by tumor growth experiments in nude mice . Therefore , the HB-2 and HB96 cell lines are useful tools to study the mechanism of carcinogenesis of OSCC in vitro for future genomic and proteomic analyses .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20464641"}
{"sentence": "INTRODUCTION Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor ( ER)-positive breast cancer . However , there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner . METHODS In this study we assessed gene expression changes at multiple time points ( days 1 , 2 , 4 , 7 , 14 ) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis , proliferation and angiogenesis within 2 days of therapy . RESULTS Hierarchical clustering identified six time-related gene expression patterns , which separated into three groups : two with early/transient responses , two with continuous/late responses and two with variable response patterns . The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation ( e.g . BUB1B , CCNA2 , CDKN3 , MKI67 , UBE2C ) , whereas the continuous/late changed genes represented the more classical estrogen response genes ( e.g . TFF1 , TFF3 , IGFBP5 ) . Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer . The profiles of genes that were most differentially expressed on days 2 , 4 and 7 following treatment were able to predict prognosis , whereas those most changed on days 1 and 14 were not , in four tamoxifen treated datasets representing a total of 404 patients . CONCLUSIONS Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner . Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20569502"}
{"sentence": "Malignant peripheral nerve sheath tumors ( MPNSTs ) are sarcomas able to grow under conditions of metabolic stress caused by insufficient nutrients or oxygen . Both pituitary adenylate cyclase-activating polypeptide ( PACAP ) and activity-dependent neuroprotective protein ( ADNP ) have glioprotective potential . However , whether PACAP/ADNP signaling is involved in the resistance to cell death in MPNST cells remains to be clarified . Here , we investigated the involvement of this signaling system in the survival response of MPNST cells against hydrogen peroxide ( H(2)O(2))-evoked death both in the presence of normal serum ( NS ) and in serum-starved ( SS ) cells . Results showed that ADNP levels increased time-dependently ( 6-48 h ) in SS cells . Treatment with PACAP38 ( 10(-9) to 10(-5) M ) dose-dependently increased ADNP levels in NS but not in SS cells . PAC(1)/VPAC receptor antagonists completely suppressed PACAP-stimulated ADNP increase and partially reduced ADNP expression in SS cells . NS-cultured cells exposed to H(2)O(2) showed significantly reduced cell viability ( % ) , increased p53 and caspase-3 , and DNA fragmentation , without affecting ADNP expression . Serum starvation significantly reduced H(2)O(2)-induced detrimental effects in MPNST cells , which were not further ameliorated by PACAP38 . Altogether , these finding provide evidence for the involvement of an endogenous PACAP-mediated ADNP signaling system that increases MPNST cell resistance to H(2)O(2)-induced death upon serum starvation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22454142"}
{"sentence": "PTEN , a phosphoinositide-3-phosphatase , serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism . Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimposed a vulnerability to other mediators of oxidative stress and inflammation , especially reactive carbonyl species , which are commonly occurring by-products of arachidonic acid peroxidation . Using MCF7 and HEK-293 cells , we report that several reactive aldehydes and ketones , e.g. electrophilic \u03b1,\u03b2-enals ( acrolein , 4-hydroxy-2-nonenal ) and \u03b1,\u03b2-enones ( prostaglandin A(2) , \u039412-prostaglandin J(2) and 15-deoxy-\u0394-12,14-prostaglandin J(2) ) covalently modify and inactivate cellular PTEN , with ensuing activation of PKB/Akt kinase ; phosphorylation of Akt substrates ; increased cell proliferation ; and increased nuclear \u03b2-catenin signaling . Alkylation of PTEN by \u03b1,\u03b2-enals/enones and interference with its restraint of cellular PKB/Akt signaling may accentuate hyperplastic and neoplastic disorders associated with chronic inflammation , oxidative stress , or aging .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20975834"}
{"sentence": "Previously , stereoselective hydroxylation of \\u03b1-ionone by Cytochrome P450 BM3 mutants M01 A82W and M11 L437N was observed . While both mutants hydroxylate \\u03b1-ionone in a regioselective manner at the C3 position , M01 A82W catalyzes formation of trans-3-OH-\\u03b1-ionone products whereas M11 L437N exhibits opposite stereoselectivity , producing trans-(3S,6S)-OH-\\u03b1-ionone and cis-(3S,6R)-OH-\\u03b1-ionone . Here , we explore the stereoselective C3 hydroxylation of \\u03b1-ionone by Cytochrome P450 BM3 mutants M01 A82W and M11 L437N using molecular dynamics-based free energy calculations to study the interaction between the enzyme and both the substrates and the products . The one-step perturbation approach is applied using an optimized reference state for substrates and products . While the free energy differences between the substrates free in solution amount to kJ mol(-1) , the differences in mutant M01 A82W agree with the experimentally obtained dissociation constants K(d) . Moreover , a correlation with experimentally observed trends in product formation is found in both mutants . The trans isomers show the most favorable relative binding free energy in the range of all four possible hydroxylated diastereomers for mutant M01 A82W , while the trans product from ( 6S)-\\u03b1-ionone and the cis product from ( 6R)-\\u03b1-ionone show highest affinity for mutant M11 L437N . Marcus theory is subsequently used to relate the thermodynamic stability to transition state energies and rates of formation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22765880"}
{"sentence": "Reciprocity of inflammation , oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing and remodelling to cancer progression . Whereas the mechanism of hypoxia-driven angiogenesis is well understood , the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure . Here we show that the end products of lipid oxidation , \u03c9-(2-carboxyethyl)pyrrole ( CEP ) and other related pyrroles , are generated during inflammation and wound healing and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in both murine and human melanoma . The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 ( TLR2 ) , but not TLR4 or scavenger receptors on endothelial cells , leading to an angiogenic response that is independent of vascular endothelial growth factor . CEP promoted angiogenesis in hindlimb ischaemia and wound healing models through MyD88-dependent TLR2 signalling . Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue revascularization and diminished tumour angiogenesis . Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration . Taken together , these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns , providing a key link connecting inflammation , oxidative stress , innate immunity and angiogenesis .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "20927103"}
{"sentence": "UNLABELLED BACKGROUND Cell lines are very useful for clinical and basic research . Thus far , only 11 reports have documented the characteristics of ovarian endometrioid adenocarcinoma cell lines in the literature . Due to the scarcity of information , the establishment of an ovarian malignant tumor cell line with distinctive characteristics is particularly important to study this disease . Thus , this study was undertaken to establish and characterize a new human endometrioid adenocarcinoma cell line of the ovary . METHODS The cell line NOMH-1 was established from an ovarian tumor of a 44-year-old woman . Features of the cell line studied included morphology , chromosome analysis , heterotransplantation , tumor markers , and chemosensitivity . RESULTS This cell line has been growing well for 232 months and subcultured more than 50 times . Monolayer cultured cells were polygonal in shape , showing a pavement-like arrangement and a tendency to stack without contact inhibition . They exhibited a human karyotype with a modal chromosomal number in the hypertriploid range . The cells could be transplanted into the subcutis of nude mice and produced tumors resembling the original tumor . NOMH-1 cells expressed both CEA and CA19-9 which were identified immunohistochemically in the original tumor and the heterotransplanted tumor . The cells were sensitive to paclitaxel , an agent commonly used in the treatment of gynecological cancers . CONCLUSIONS NOMH-1 is the first ovarian endometrioid adenocarcinoma cell line in which CEA and CA19-9 expression have been defined . This newly established cell line should be useful for investigating the characteristics of ovarian endometrioid adenocarcinoma .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23379414"}
{"sentence": "OBJECTIVE To study the effects of genistein on the proliferation , apoptosis induction and expression of related gene proteins of human colon cancer cells in vitro and in vivo , and its mechanisms of action . METHODS MTT colorimetric assay was used to detect the effects of genistein on the proliferation of human colon adenocarcinoma SW480 cells . Light and transmission electron microscopy were used to study the histological and ultrastructural changes . Flow cytometry was used to determine the effects of genistein on cell cycle and apoptosis . Flow cytometry and immunohistochemistry were used to determine the effects of genistein on apoptosis induction and expression of related gene proteins of colon cancer cells . RESULTS The MTT colorimetric assay showed that genistein inhibited the proliferation of SW480 cells in a dose-dependent and time-dependent manner , and the highest inhibition rate was 60.2% after 80 microg/ml genistein treatment for 72 h . The light microscopy revealed that many genistein-treated cancer cells were shrunken , disrupted , or showing cytoplasmic vacuolization . The electron microscopic examination showed cell shrinkage , nuclear fragmentation and pronounced chromatin condensation , sometimes formed crescent chromatin condensation attached to the nuclear membrane . The results of flow cytometry showed that : after SW480 cells were treated with 0 , 20 , 40 , 80 microg/ml genistein for 48 h , the FI values of PCNA were 1.49 +/- 0.02 , 1.28 +/- 0.04 , 1.14 +/- 0.03 , and 0.93 +/- 0.08 ; the FI values of VEGF were 1.75 +/- 0.02 , 1.34 +/- 0.06 , 1.32 +/- 0.04 , and 1.23 +/- 0.04 ; the fluorescence index ( FI ) values of p21 were 1.26 +/- 0.05 , 1.36 +/- 0.06 , 1.61 +/- 0.03 , and 1.73 +/- 0.03 , respectively . There were statistically significant differences between the control group and each treatment group ( P < 0.05 or P < 0.01 ) . The scores of immunohistochemical staining of PCNA and VEGF proteins were decreased , while p21 increased . There were statistically significant differences between the control group and each treatment group ( P < 0.05 or P < 0.01 ) . CONCLUSION Genistein can inhibit the growth of colon cancer cells via apoptosis induction and cell cycle arrest at G(2)/M phase . The anti-tumor mechanisms of genistein may be related with the down-regulation of expression of VEGF and PCNA , and up-regulation of the expression of p21 .", "label": [0, 0, 0, 0, 1, 0, 1, 1, 1, 0], "id": "20211058"}
{"sentence": "We have developed fluorescent probes for the detection of strand scission in the excision repair of oxidatively damaged bases . They were hairpin-shaped oligonucleotides , each containing an isomer of thymine glycol or 5,6-dihydrothymine as a damaged base in the center , with a fluorophore and a quencher at the 5'- and 3'-ends , respectively . Fluorescence was detected when the phosphodiester linkage at the damage site was cleaved by the enzyme , because the short fragment bearing the fluorophore could not remain in a duplex form hybridized to the rest of the molecule at the incubation temperature . The substrate specificities of Escherichia coli endonuclease III and its human homolog , NTH1 , determined by using these probes agreed with those determined previously by gel electrophoresis using ( 32)P-labeled substrates . Kinetic parameters have also been determined by this method . Since different fluorophores were attached to the oligonucleotides containing each lesion , reactions with two types of substrates were analyzed separately in a single tube , by changing the excitation and detection wavelengths . These probes were degraded during an incubation with a cell extract . Therefore , phosphorothioate linkages were incorporated to protect the probes from nonspecific nucleases , and the base excision repair activity was successfully detected in HeLa cells .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20110254"}
{"sentence": "Molecular mechanisms involved in progression of clear-cell renal-cell carcinomas ( ccRCCs ) are poorly understood . A common genetic mutation found in ccRCC is the loss of the von Hippel-Lindau ( VHL ) gene , which contributes to cancer progression and metastasis . We investigated VIP effects on metastatic and angiogenic factors in human VHL-null A498 ccRCC and HK2 renal cells . VIP increased adhesion but decreased expression of metalloproteinases , MMP2 and MMP9 , as well as cell migration and VEGF expression and secretion in A498 but not in HK2 cells . VIP enhanced ROS levels and decreased nuclear levels of \u03b2-catenin and NF\u03baB p50-subunit in A498 cells , suggesting neuropeptide involvement in the observed decrease of metastatic ability in clear-cell carcinoma . VIP effects in A498 cells were blocked by the VPAC(1/2)-receptor antagonist JV-1-53 . In conclusion , present data point to a role of VIP in preventing invasion and metastasis in ccRCCs and support its potential therapeutic usefulness in this disease .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23123564"}
{"sentence": "Lanthanide(III) complexes [ Ln(pyphen)(acac)(2)(NO(3)) ] ( 1 , 2 ) , [ Ln(pydppz)(acac)(2)(NO(3)) ] ( 3 , 4 ) and [ La(pydppz)(anacac)(2)(NO(3)) ] ( 5 ) , where Ln is La(III) ( in 1 , 3 , 5 ) and Gd(III) ( in 2 , 4 ) , pyphen is 6-(2-pyridyl)-1,10-phenanthroline , pydppz is 6-(2-pyridyl)-dipyrido[3,2-a:2',3'-c]phenazine , anacac is anthracenylacetylacetonate and acac is acetylacetonate , were prepared , characterized and their DNA photocleavage activity and photocytotoxicity studied . The crystal structure of complex 2 displays a GdO(6)N(3) coordination . The pydppz complexes 3-5 show an electronic spectral band at nm in DMF . The La(III) complexes are diamagnetic , while the Gd(III) complexes are paramagnetic with seven unpaired electrons . The molar conductivity data suggest 1 : 1 electrolytic nature of the complexes in aqueous DMF . They are avid binders to calf thymus DNA giving K(b) in the range of 5.4 \ufffd 10(4)-1.2 \ufffd 10(6) M(-1) . Complexes 3-5 efficiently cleave supercoiled DNA to its nicked circular form in UV-A light of 365 nm via formation of singlet oxygen ( (1)O(2) ) and hydroxyl radical ( HO\u02d9 ) species . Complexes 3-5 also exhibit significant photocytotoxic effect in HeLa cancer cells giving respective IC(50) value of 0.16(\ufffd0.01) , 0.15(\ufffd0.01) and 0.26\ufffd(0.02) \u03bcM in UV-A light of 365 nm , while they are less toxic in dark with an IC(50) value of >3 \u03bcM . The presence of an additional pyridyl group makes the pydppz complexes more photocytotoxic than their dppz analogues . FACS analysis of the HeLa cells treated with complex 4 shows apoptosis as the major pathway of cell death . Nuclear localization of complex 5 having an anthracenyl moiety as a fluorophore is evidenced from the confocal microscopic studies .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22086203"}
{"sentence": "In recent years , microfluidic systems have been used to study fundamental aspects of angiogenesis through the patterning of single-layered , linear or geometric vascular channels . In vivo , however , capillaries exist in complex , three-dimensional ( 3D ) networks , and angiogenic sprouting occurs with a degree of unpredictability in all x,y,z planes . The ability to generate capillary beds in vitro that can support thick , biological tissues remains a key challenge to the regeneration of vital organs . Here , we report the engineering of 3D capillary beds in an in vitro microfluidic platform that is comprised of a biocompatible collagen I gel supported by a mechanical framework of alginate beads . The engineered vessels have patent lumens , form robust mm capillary networks across the devices , and support the perfusion of 1 \ufffdm fluorescent beads through them . In addition , the alginate beads offer a modular method to encapsulate and co-culture cells that either promote angiogenesis or require perfusion for cell viability in engineered tissue constructs . This laboratory-constructed vascular supply may be clinically significant for the engineering of capillary beds and higher order biological tissues in a scalable and modular manner .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23226527"}
{"sentence": "Osteopetrosis , a disorder of skeletal bone , can cause death during childhood . We previously described a new spontaneous autosomal recessive osteopetrosis mouse mutant , \" new toothless \" ( ntl ) . In this study , we reported for the first time the identification , cloning and characterization of the coiled-coil domain-containing 154 ( CCDC154 ) , a novel gene whose deletion of kb sequence including exons 1-6 was completely linked to the ntl mutant . The CCDC154 was conserved between mouse and human and is wildly expressed in mouse tissues . The cellular localization of CCDC154 was in the early endosomes . Overexpression of CCDC154 inhibited cell proliferation of HEK293 cells by inducing G 2/M arrest . CCDC154 also inhibited tumor cell growth , and the soft agar assay revealed a significant decrease of the colony size of Hela cells upon transfection of CCDC154 . Our results indicate that CCDC154 is a novel osteopetrosis-related gene involved in cell cycle regulation and tumor suppression growth .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22895184"}
{"sentence": "Plant lectins , carbohydrate-binding proteins of non-immune origin , have recently been reported to induce programmed cell death ( including apoptosis and autophagy ) in many types of cancer cells . MicroRNAs ( miRNAs ) , small , non-coding endogenous RNAs , nucleotides ( nt ) in length , have been well characterized to play essential roles in regulation of the autophagy process in cancer ; however , how these miRNAs regulate autophagic pathways in plant lectin-induced cancer cells , still remains an enigma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22882626"}
{"sentence": "Natural killer ( NK ) and CD56(+) T cells are thought to play a central role in antitumour immunity . Their cytolytic activities are controlled by a variety of receptors including CD94 and killer immunoglobulin-like receptors ( KIR ) , which bind to major histocompatibility complex ( MHC ) class I molecules on target cells and mediate cell activation or inhibition . We have examined the numbers , phenotypes and antitumour cytotoxic functions of hepatic NK and CD56(+) T cells isolated from 22 patients with hepatic malignancy and 19 healthy donors . Flow cytometry revealed that NK cell numbers were increased among hepatic mononuclear cells in malignancy compared to histologically normal livers ( mean : 38% vs 27% ; P=0.03 ) , but CD56(+) T cell numbers were not ( 28% vs 27% ) . NK cells and CD56(+) T cells from tumour-bearing livers exhibited lymphokine-activated killing of K562 targets and T cell receptor-mediated lysis of P815 cells . The expression of CD94 and the KIR isotypes CD158a , CD158b and KIR3DL1 by CD56(+) T cells and NK cells was significantly and consistently reduced in tumour-bearing livers compared to healthy livers ( P<0.05 in all cases ) . Simultaneous ligation of CD158a , CD158b and KIR3DL1 caused an overall partial inhibition of CD56(+) T cell cytotoxic activity , suggesting that the observed reductions in KIR(+) cell numbers in malignancy are likely to lead to enhanced cytotoxicity . Our results suggest that , while hepatic CD56(+) T cells are not expanded in malignancy , downregulation of KIR and CD94 expression may be a mechanism by which the hepatic immune system can be activated to facilitate tumour rejection .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12536240"}
{"sentence": "The aim of this study was to determine whether isorhamnetin , an immediate 3'-O-methylated metabolite of quercetin , affects proliferation , cell death , and the cell cycle of human colon carcinoma ( HCT-116 ) cells . Isorhamnetin was found to be a potent antiproliferative agent in a dose- and time-dependent manner , with an IC50 of 72 \u03bcM after 48 h of incubation as estimated by MTT assay . Flow cytometry and fluorescence microscopy analysis showed that isorhamnetin exerted a stimulatory effect on apoptosis and necrosis . Isorhamnetin also increased the number of cells in G2/M phase . Serum deprivation appeared to potentiate the effects of isorhamnetin on cell death and facilitated cell cycle progression to G0/G1 phase . These results suggest that isorhamnetin might mediate inhibition of HCT-116 cell growth through the perturbation of cell cycle progression and are consistent with the notion that G2/M checkpoints could be a conserved target for flavonoids in human colon cancer cells , leading to apoptotic and necrotic death . These antiproliferative , apoptotic , necrotic , and cell cycle effects suggest that isorhamnetin may have clinically significant therapeutic and chemopreventive capabilities . To our knowledge , this is the first report of the effect of isorhamnetin on human colon cancer cells .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20923189"}
{"sentence": "Lentinula edodes mycelia ( L.E.M. ) is a dried powder extracted from shiitake mushrooms ( Lentinula edodes ) . We previously demonstrated that it has immunomodulatory effects . In this paper , the direct cytotoxic effects of the polysaccharide-rich fraction of L.E.M . ( L.E.M. ethanol precipitate ; LEP ) on HepG2 human hepatocellular carcinoma ( HCC ) cells were investigated . LEP directly killed the HepG2 cells efficaciously , but had only minor effects on normal rat hepatocytes and normal mouse dermal cells under the same conditions . Characteristic morphological changes associated with apoptosis such as shrinkage , rounding , and floating as well as chromatin condensation were confirmed ; terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling ( TUNEL ) staining was positive as determined by fluorescence microscopy analyses . The caspase-3 and -8 death receptor pathway was found largely responsible for the apoptotic death of HepG2 cells treated with LEP . In conclusion , LEP can directly induce apoptosis of HepG2 cells , and thus may have potential chemotherapeutic applications for the treatment of HCC .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22791146"}
{"sentence": "Photodynamic therapy ( PDT ) may trigger apoptosis or necrosis in cancer cells . Several steps in the induction and execution of apoptosis require high amounts of adenosine-5'-triphosphate ( ATP ) . Because the mitochondrial membrane potential ( delta psi ) decreases early in apoptosis , we raised the question about the mechanisms of maintaining a sufficiently high ATP level . We therefore monitored delta psi and the intracellular ATP level of apoptotic human epidermoid carcinoma cells ( A431 ) after photodynamic treatment with aluminum ( III ) phthalocyanine tetrasulfonate . A maximum of caspase-3-like activity and nuclear fragmentation was found at fluences of about 4 J cm(-2) . Under these conditions apoptotic cells reduced delta psi rapidly , while the ATP level remained high for 4-6 h after treatment for cells supplied with glucose . To analyze the contribution of glycolysis to the energy supply during apoptosis , experiments were carried out with cells deprived of glucose . These cells showed a rapid drop of ATP content and neither caspase activation nor nuclear fragmentation could be detected . We conclude that the use of glucose as a source of ATP is obligatory for the execution of PDT-induced apoptosis .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "12511053"}
{"sentence": "The type I insulin-like growth factor receptor ( IGF1R ) contributes to cancer cell biology . Disruption of IGF1R signaling alone or in combination with cytotoxic agents has emerged as a new therapeutic strategy . Our laboratory has shown that sequential treatment with doxorubicin ( DOX ) and anti-IGF1R antibodies significantly enhanced the response to chemotherapy . In this study , we examined whether inhibition of the tyrosine kinase activity of this receptor family would also enhance chemotherapy response . Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine ( PQIP ) inhibited IGF1R and insulin receptor ( InsR ) kinase activity and downstream activation of ERK1/2 and Akt in MCF-7 and LCC6 cancer cells . PQIP inhibited both monolayer growth and anchorage-independent growth in a dose-dependent manner . PQIP did not induce apoptosis , but rather , PQIP treatment was associated with an increase in autophagy . We examined whether sequential or combination therapy of PQIP with DOX could enhance growth inhibition . PQIP treatment together with DOX or DOX followed by PQIP significantly inhibited anchorage-independent growth in MCF-7 and LCC6 cells compared to single agent alone . In contrast , pre-treatment with PQIP followed by DOX did not enhance the cytotoxicity of DOX in vitro . Furthermore , OSI-906 , a PQIP derivative , inhibited IGF-I signaling in LCC6 xenograft tumors in vivo . When given once a week , simultaneous administration of OSI-906 and DOX significantly enhanced the anti-tumor effect of DOX . In summary , these results suggest that timing and duration of the IGF1R/InsR tyrosine kinase inhibitors with chemotherapeutic agents should be evaluated in clinical trials . Long-term disruption of IGF1R/InsR may not be necessary when combined with cytotoxic chemotherapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21850397"}
{"sentence": "FCE 23762 ( 3 ' desamino-3'[2(s)methoxyl-4-morpholinyl]doxorubicin ) is a new doxorubicin ( Dx ) derivative that has been selected for clinical testing for its favourable antitumor characteristics , which include efficacy on Dx-resistant tumors . Immunosuppression is an undesirable side-effect of anti-cancer chemotherapy and the therapeutic efficacy of Dx is probably also related to its low immunotoxicity . It was , thus , of interest to compare the effects of FCE 23762 and its parental drug on the immune responses . Both compounds were injected i.v. into healthy mice at equitoxic doses and according to different treatment schedules . Single doses of FCE 23762 and Dx , given concomitant or after the antigen , suppressed at the same degree and dose-dependently the primary anti-SRBC antibody response . Following a multiple treatment schedule after the antigen , FCE 23762 was less suppressive than Dx on both primary and secondary antibody production . Differently from Dx , that was completely inactive , FCE 23762 moderately inhibited DTH reaction to SRBC , only at the highest single dose tested or for repeated administrations given simultaneously or after priming . Both drugs were totally ineffective in delaying skin allograft rejection . Since spleen cellularity and ex vivo lymphocyte proliferation to Con A and LPS were similarly impaired by the two drugs , the differentiated immunodepressive activity of FCE 23762 and Dx cannot be merely associated to their cytotoxic and antiproliferative action . The hypothesis of a selective effect on different regulatory cell subsets and/or immune mechanisms is discussed .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1295379"}
{"sentence": "Members of the Orai family are highly selective calcium ion channels that play an important role in store-operated calcium entry . Among the three known Orai isoforms , Orai3 has gained increased attention , notably for its emerging role in cancer . We recently demonstrated that Orai3 channels are over-expressed in breast cancer ( BC ) biopsies , and involved specifically in proliferation , cell cycle progression and survival of MCF-7 BC cells . Here , we investigate the downstream signaling mechanisms affected by Orai3 silencing , leading to the subsequent functional impact specifically seen in MCF-7 cancer cells . We report a correlation between Orai3 and c-myc expression in tumor tissues and in the MCF-7 cancer cell line by demonstrating that Orai3 down-regulation reduces both expression and activity of the proto-oncogene c-myc . This is likely mediated through the MAP Kinase pathway , as we observed decreased pERK1/2 levels and cell-cycle arrest in G1 phase after Orai3 silencing . Our results provide strong evidence that the c-myc proto-oncogene is influenced by the store-operated calcium entry channel Orai3 through the MAP kinase pathway . This connection provides new clues in the downstream mechanism linking Orai3 channels and proliferation , cell cycle progression and survival of MCF-7 BC cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23266555"}
{"sentence": "It is commonly believed that neurons remain in G(0) phase of the cell cycle indefinitely . Cell-cycle re-entry , however , is known to contribute to neuronal apoptosis . Moreover , recent evidence demonstrates the expression of cell-cycle proteins in differentiated neurons under physiological conditions . The functional roles of such expression remain unclear . Since DNA repair is generally attenuated by differentiation in most cell types , the cell-cycle-associated events in postmitotic cells may reflect the need to re-enter the cell cycle to activate DNA repair . We show that cyclin-C-directed , pRb-dependent G(0) exit activates the non-homologous end joining pathway of DNA repair ( NHEJ ) in postmitotic neurons . Using RNA interference , we found that abrogation of cyclin-C-mediated exit from G(0) compromised DNA repair but did not initiate apoptosis . Forced G(1) entry combined with prevention of G(1) --> S progression triggered NHEJ activation even in the absence of DNA lesions , but did not induce apoptosis in contrast to unrestricted progression through G(1) --> S. We conclude that G(0) --> G(1) transition is functionally significant for NHEJ repair in postmitotic neurons . These findings reveal the importance of cell-cycle activation for controlling both DNA repair and apoptosis in postmitotic neurons , and underline the particular role of G(1) --> S progression in apoptotic signaling , providing new insights into the mechanisms of DNA damage response ( DDR ) in postmitotic neurons .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20111042"}
{"sentence": "Peptide 11 , CDPGYIGSR-NH2 , is a segment of laminin which blocks tumor cell invasion . A high affinity laminin receptor in tumor cells is thought to be blocked by the carboxyl-terminal YIGSR , and conformational energy calculations suggest that the glycine in YIGSR allows an important conformational bend . We replaced the YIGSR glycine residue in peptide 11 with either D-alanine or L-alanine to allow or disfavor the proposed glycine bend . We found the Gly7-->D-Ala7 analog to be equal to peptide 11 in inhibiting tumor cell invasion of basement membrane matrix . The Gly7-->L-Ala7 analog was much less capable of invasion inhibition . Two-dimensional 1H-1H NMR was used to study the solution conformations of the peptide 11 analogs . NOESY experiments revealed close NH-NH contacts in peptide 11 and the D-Ala7 analog , but not in the L-Ala7 analog . Molecular dynamics generated low energy structures with excellent NOE agreement for peptide 11 and its analogs . Both peptide 11 and the D-Ala7 analog , but not the less active L-Ala7 analog , were predicted to have similar bends around Gly7 or D-Ala7 . These results suggest that a bend in the YIGSR region of peptide 11 may be important for the binding of laminin to its metastasis-associated receptor .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1460013"}
{"sentence": "The mechanisms by which hematopoietic stem and progenitor cells ( HSC and HPC ) from myelodysplastic syndromes ( MDS ) undergo ineffective production of blood cells and disease transformation into acute myeloid leukemia remain to be investigated . It has been confirmed that increased production of reactive oxygen species ( ROS ) under various pathological conditions impairs HSC self-renewal and causes HSC premature exhaustion and BM suppression primarily via induction of HSC senescence , and oncogene induces accumulation of ROS and DNA damage and subsequently cellular senescence , which functions as an important barrier to prevent the growth of transformed cells to form a neoplasia . Here we investigated whether MDS CD34(+) cells enriched with HSC and HPC undergo senescence through accumulation of ROS and DNA damage and their action mechanisms . In this study , the percentages of SA-\u03b2-gal positive senescent CD34(+) cells increased in lower-risk MDS patients , but not in higher-risk MDS and AML patients , compared to that of healthy controls . The increases were associated with an elevated expression of p21 but not the activation of p38 . Further study found that there were increased ROS and DNA damage in CD34(+)CD38(-) cells enriched with HSC progression from lower-risk MDS , higher-risk MDS to AML . Therefore , these data suggest that CD34(+) cells from patients with lower-risk MDS present p21 dependent premature senescence , increased accumulation of ROS and DNA damage in CD34(+)CD38(-) cells could contribute to this process ; however , CD34(+) cells from patients with higher-risk MDS could develop some mechanisms to uncouple ROS and DNA damage induced senescence .", "label": [0, 1, 0, 1, 0, 1, 0, 0, 0, 1], "id": "23219618"}
{"sentence": "Even when patients with nonsmall cell lung cancer undergo surgical resection at an early stage , recurrent disease often impairs the clinical outcome . There are numerous causes potentially responsible for a relapse of the disease , one of them being extensive angiogenesis . The balance of at least two systems , VEGF VEGFR and Ang Tie , regulates vessel formation . The aim of this study was to determine the impact of surgery on the plasma levels of the main angiogenic factors during the first month after surgery in nonsmall cell lung cancer patients . The study group consisted of 37 patients with stage I nonsmall cell lung cancer . Plasma concentrations of Ang1 , Ang2 , sTie2 , VEGF , and sVEGF R1 were evaluated by ELISA three times : before surgical resection and on postoperative days 7 and 30 . The median of Ang2 and VEGF concentrations increased on postoperative day 7 and decreased on day 30 . On the other hand , the concentration of sTie2 decreased on the 7th day after resection and did not change statistically later on . The concentrations of Ang1 and sVEGF R1 did not change after the surgery . Lung cancer resection results in proangiogenic plasma protein changes that may stimulate tumor recurrences and metastases after early resection .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22550599"}
{"sentence": "Aurora A kinase has drawn considerable attention as a therapeutic target for cancer therapy . However , the underlying molecular and cellular mechanisms of the anticancer effects of Aurora A kinase inhibition are still not fully understood . Herein , we show that depletion of Aurora A kinase by RNA interference ( RNAi ) in hepatocellular carcinoma ( HCC ) cells upregulated FoxO1 in a p53-dependent manner , which induces cell cycle arrest . Introduction of an RNAi-resistant Aurora A kinase into Aurora A-knockdown cells resulted in downregulation of FoxO1 expression and rescued proliferation . In addition , silencing of FoxO1 in Aurora A-knockdown cells allowed the cells to exit cytostatic arrest , which , in turn , led to massive cell death . Our results suggest that FoxO1 is responsible for growth arrest at the G 2/M phase that is induced by Aurora A kinase inhibition .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23255113"}
{"sentence": "PURPOSE To characterize the clinical features of a Chinese Uygur pedigree with primary open-angle glaucoma ( POAG ) and to identify mutations in two candidate genes , trabecular meshwork inducible glucocorticoid response ( MYOC/TIGR ) and human dioxin-inducible cytochrome P450 ( CYP1B1 ) . METHODS Twenty one members from a Chinese Uygur family of four generations were included in the study . All participants underwent complete ophthalmologic examinations . Five were diagnosed as POAG , four as glaucoma suspects , and the rest were asymptomatic . Molecular genetic analysis was performed on all subjects included in the study . All exons of CYP1B1 and MYOC were amplified by polymerase chain reaction ( PCR ) , sequenced and compared with a reference database . The variations detected were evaluated in available family members as well as 102 normal controls . Possible changes in structure and function of the protein induced by amino acid variance were predicted by bioinformatics analysis . RESULTS Elevated intraocular pressure and late-stage glaucomatous cupping of the optic disc were found in five patients of this family . A novel heterozygous missense mutation c.1151 A>G in exon 3 of MYOC was found in all five patients diagnosed as POAG and four glaucoma suspects , but not in the rest of the family members and 102 normal controls . This mutation caused an amino acid substitution of aspartic acid to glycine at position 384 ( p . D384G ) of the MYOC protein . This substitution may cause structural and functional changes of the protein based on bioinformatics analysis . No mutations were found in CYP1B1 . CONCLUSIONS Our study suggests that the novel mutation D384G of MYOC is likely responsible for the pathogenesis of POAG in this pedigree .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22876119"}
{"sentence": "We have exploited properties of photosensitizers to study an aspect of the packing of chromatin in the cell nucleus . The fluorescent photosensitizers mesotetra(3-hydroxyphenyl) porphyrin and Photofrin II were both localized in the nuclear membrane and other membrane structures , but could not be found inside the nuclei . Light exposure of cells at 1 degrees C in the presence of the sensitizers induced DNA double-strand breaks . The length distributions of DNA fragments were determined by pulsed field gel electrophoresis . Because DNA damage is produced mainly via singlet oxygen diffusing less than 0.1 microns from the sensitizer , DNA double-strand breaks were supposedly produced within this distance of the nuclear membrane . Consistent with this , with prolonged illumination and with increasing concentrations of sensitizer the distribution of DNA fragment lengths reached a plateau level . In contrast , with the hydrophilic , intranuclear sensitizer meso-tetra(4-sulphonatophenyl)porphyrin , no such plateau level was found . The plateau distributions of DNA fragment lengths of different cell types had the same general shape with average fragment lengths ranging from 174 to 194 kilobasepairs . Particular genes , c-myc , fos and p53 , were found on broad distributions of photocleaved fragment lengths . The results indicate that on each side of the genes the locus of the chromatin fibre situated close to the nuclear membrane , varied randomly .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1480490"}
{"sentence": "We have investigated the possibility that photoexcited titanium dioxide ( TiO2 ) could inhibit the growth of malignant cells . We studied the anti-glioma effects of nano-TiO2 excited with ultraviolet A ( UVA ) irradiation both in vitro and in vivo . Transmission electron microscopy demonstrated that glioma cells take up TiO2 by phagocytosis , and vital staining revealed that TiO2 alone has no effect on glioma cell proliferation . However , if TiO2 was combined with UVA irradiation the proliferation rate was decreased significantly compared to controls ( P<0.05 ) . RT-PCR suggested that TiO2 induction of glioma cell apoptosis is associated with changes in the expression of genes encoding Bcl-2 family members . We then investigated the in vivo antitumor effects of combined TiO2 plus UVA treatment of established glioma tumors . TiO2 plus UVA led to pronounced areas of necrosis , elevated indices of apoptosis , delayed tumor growth , and increased survival compared with the TiO2-alone control group ( P<0.001 ) . Log-rank survival analysis showed that median survival duration was prolonged ( P<0.001 ) . These findings suggest that nano-TiO2 based photodynamic therapy has potential in the treatment of glioma .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20352345"}
{"sentence": "The secretin receptor ( SR ) , a G protein-coupled receptor , mediates the effects of the gastrointestinal hormone secretin on digestion and water homeostasis . Recently , high SR expression has been observed in pancreatic ductal adenocarcinomas , cholangiocellular carcinomas , gastrinomas , and bronchopulmonary carcinoid tumors . Receptor overexpression associates with enhanced secretin-mediated signaling , but whether this molecule plays an independent role in tumorigenesis is currently unknown . We recently discovered that pheochromocytomas developing in rats affected by the MENX ( multiple endocrine neoplasia-like ) syndrome express at very high-level Sctr , encoding SR . We here report that SR are also highly abundant on the membranes of rat adrenal and extraadrenal pheochromocytoma , starting from early stages of tumor development , and are functional . PC12 cells , the best characterized in vitro pheochromocytoma model , also express Sctr at high level . Thus , we used them as model to study the role of SR in neoplastic transformation . Small interfering RNA-mediated knockdown of Sctr decreases PC12 cells proliferation and increases p27 levels . The proproliferative effect of SR in PC12 cells is mediated , in part , by the phosphatidylinositol 3 kinase ( PI3K)/serine-threonine protein kinase ( AKT ) pathway . Transfection of Sctr in Y1 adrenocortical carcinoma cells , expressing low endogenous levels of Sctr , stimulates cell proliferation also , in part , via the PI3K/AKT signaling cascade . Because of the link between SR and PI3K/AKT signaling , tumor cells expressing high levels of the receptor ( MENX-associated primary pheochromocytoma and NCI-H727 human bronchopulmonary carcinoid cells ) respond well and in a SR-dependent manner to PI3K inhibitors , such as NVP-BEZ235 . The association between SR levels and response to PI3K inhibition might open new avenues for the treatment of tumors overexpressing this receptor .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "22692904"}
{"sentence": "Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells . Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines . Since new compounds with biological activity are needed , the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones , derived from 1-naphthaldehyde and 2-naphthaldehyde , on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells . Based on the results , the most cytotoxic compound ( A1 ) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line ( HT-29 ) . Chalcone A1 significantly reduced the cell viability of K562 , Jurkat , Kasumi , U937 , CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group ( IC(50) values between \u223c1.5\u03bcM and 40\u03bcM ) . It was also cytotoxic to HL-29 cells . To further examine its effect on normal cells , peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound . It has also been incubated with human fibroblasts cultured from bone marrow ( JMA ) . Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells . A1 caused significant cell cycle arrest in all phases according to the cell line , and increased the proportion of cells in the sub G0/G1 phase . To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway , cell morphology was examined using fluorescence microscopy . Cells treated with A1 at IC(50) demonstrated the morphological characteristic of apoptosis , such as chromatin condensation and formation of apoptotic bodies . Apoptosis was confirmed by externalization of phosphatidylserine , which was detected by the Annexin V-FITC method , and by DNA fragmentation . The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23257665"}
{"sentence": "DNA repair is an essential cellular process required to maintain genomic stability . Every cell is subjected to thousands of DNA lesions daily under normal physiological conditions . Ionizing radiation ( IR ) is a major DNA damaging agent that can be produced by both natural and man-made sources . A common source of radiation exposure is through its use in medical diagnostics or treatments such as for cancer radiotherapy where relatively high doses are received by patients . To understand the detailed DNA repair gene transcription response to high dose IR , gene expression exon array studies have been performed and the response to radiation in two divergent cell types , lymphoblastoid cell lines and primary fibroblasts , has been examined . These exon arrays detect expression levels across the entire gene , and have the advantage of high sensitivity and the ability to identify alternative transcripts . We found a selection of DNA repair genes , including some not previously reported , that are modulated in response to radiation . Detailed dose and time course kinetics of DNA repair transcription was conducted and results have been validated utilizing PCR methods . Alternative transcription products in response to IR were identified in several DNA repair genes including RRM2B and XPC where alternative initiation sites were found . These investigations have advanced the knowledge about the transcriptional response of DNA repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23285288"}
{"sentence": "A novel compound 2-arylidene-4,7-dimethyl indan-1-one synthesized was screened for anticancer effect against the human breast adenocarcinoma cell line , MCF-7 . An IC50 value of > or = 80 microM , nontoxic to the normal breast cell line HBL-100 , showed complete inhibition of the MCF-7 cells . Analysis of mechanisms showed nuclear fragmentation and DNA laddering in gel electrophoresis . GSH and GR levels were found to be reduced after the compound treatment . Cell cycle analysis using fluorescent cytometry revealed G2/M phase arrest , which indicates the compound deserves consideration for further studies against cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20681405"}
{"sentence": "Adipose tissue growth and development are thought to be associated with angiogenesis and extracellular matrix remodeling . Because ginseng has been shown to inhibit angiogenesis and matrix metalloproteinase ( MMP ) activity , we hypothesized that adipose tissue growth and obesity can be regulated by Korean ginseng ( Panax ginseng C.A. Meyer ) . Wild-type C57BL/6J mice were fed for 8 weeks with a low fat diet , a high fat diet ( HFD ) , or HFD supplemented with 0.5% or 5% Korean red ginseng extract . We measured body weight , adipose tissue mass , food intake , MMP activity , and the expression of genes involved in angiogenesis and MMPs . Administering ginseng to HFD-induced obese mice produced reductions in body weight and adipose tissue mass compared with untreated counterparts . Ginseng treatment decreased blood vessel density and MMP activity in adipose tissues . Ginseng also reduced mRNA levels of angiogenic factors ( e.g. , VEGF-A and FGF-2 ) and MMPs ( e.g. , MMP-2 and MMP-9 ) , whereas it increased mRNA levels of angiogenic inhibitors ( e.g. , TSP-1 , TIMP-1 , and TIMP-2 ) in adipose tissues . These results demonstrate that ginseng effectively reduces adipose tissue mass and prevents obesity in diet-induced obese mice and that this process may be mediated in part through the anti-angiogenic actions of ginseng .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23232078"}
{"sentence": "Levels of regulatory T cells ( Tregs ) are increased in different cancer types as well as in inflammatory diseases , such as rheumatoid arthritis . Treg accumulation may result from aberrant proliferation and trafficking as well as greater resilience to oxidative stress compared with conventional T cells . This enhanced antioxidative capacity of Tregs possibly serves as feedback inhibition during inflammation and prevents uncontrolled immune reactions by favoring survival of suppressor rather than effector cells . In this study , we demonstrate that human Tregs express and secrete higher levels of thioredoxin-1 , a major antioxidative molecule . Thioredoxin-1 has an essential role in maintaining their surface thiol density as the first line of antioxidative defense mechanisms and is sensitive to proinflammatory stimuli , mainly tumor necrosis factor-\u03b1 , in a nuclear factor-\u03baB-dependent fashion . The antiapoptotic and oncogenic potential of ( secreted ) Trx-1 suggests that it may exert effects in Tregs beyond redox regulation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21030559"}
{"sentence": "Lewis y ( LeY ) antigen is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface . Overexpression of LeY is frequently observed in epithelial-derived cancers and has been correlated to the pathological staging and prognosis . However , the effects of LeY on ovarian cancer are not yet clear . Previously , we transfected the ovarian cancer cell line RMG-I with the \u03b11,2-fucosyltransferase gene to obtain stable transfectants , RMG-I-H , that highly express LeY . In the present study , we examined the proliferation , tumorigenesis , adhesion and invasion of the cell lines with treatment of LeY monoclonal antibody ( mAb ) . Additionally , we examined the expression of TGF-\u03b21 , VEGF and b-FGF in xenograft tumors . The results showed that the proliferation and adhesion in vitro were significantly inhibited by treatment of RMG-I-H cells with LeY mAb . When subcutaneously inoculated in nude mice , RMG-I-H cells produced large tumors , while mock-transfected cells RMG-I-C and the parental cells RMG-I produced small tumors . Moreover , the tumor formation by RMG-I-H cells was inhibited by preincubating the cells with LeY mAb . Notably , the expression of TGF-\u03b21 , VEGF and b-FGF all increased in RMG-I-H cells . In conclusion , LeY plays an important role in promoting cell proliferation , tumorigenecity and adhesion , and these effects may be related to increased levels of growth factors . The LeY antibody shows potential application in the treatment of LeY-positive tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21152298"}
{"sentence": "Cyclin E2 , but not cyclin E1 , is included in several gene signatures that predict disease progression in either tamoxifen-resistant or metastatic breast cancer . We therefore examined the role of cyclin E2 in antiestrogen resistance in vitro and its potential for therapeutic targeting through cyclin-dependent kinase ( CDK ) inhibition . High expression of CCNE2 , but not CCNE1 , was characteristic of the luminal B and HER2 subtypes of breast cancer and was strongly predictive of shorter distant metastasis-free survival following endocrine therapy . After antiestrogen treatment of MCF-7 breast cancer cells , cyclin E2 mRNA and protein were downregulated and cyclin E2-CDK2 activity decreased . However , this regulation was lost in tamoxifen-resistant ( MCF-7 TAMR ) cells , which overexpressed cyclin E2 . Expression of either cyclin E1 or E2 in T-47D breast cancer cells conferred acute antiestrogen resistance , suggesting that cyclin E overexpression contributes to the antiestrogen resistance of tamoxifen-resistant cells . Ectopic expression of cyclin E1 or E2 also reduced sensitivity to CDK4 , but not CDK2 , inhibition . Proliferation of tamoxifen-resistant cells was inhibited by RNAi-mediated knockdown of cyclin E1 , cyclin E2 , or CDK2 . Furthermore , CDK2 inhibition of E-cyclin overexpressing cells and tamoxifen-resistant cells restored sensitivity to tamoxifen or CDK4 inhibition . Cyclin E2 overexpression is therefore a potential mechanism of resistance to both endocrine therapy and CDK4 inhibition . CDK2 inhibitors hold promise as a component of combination therapies in endocrine-resistant disease as they effectively inhibit cyclin E1 and E2 overexpressing cells and enhance the efficacy of other therapeutics .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22564725"}
{"sentence": "OBJECTIVES To evaluate the impact of the category of unclassified renal cell carcinoma ( URCC ) on survival following nephrectomy . METHODS Patients with clear cell RCC ( ccRCC , n = 3048 ) and URCC ( n = 38 ) were identified . Patients with URCC were matched 4:1 with ccRCC patients based on year of surgery , symptoms at presentation , tumor size , stage , regional lymph node involvement , metastases , grade , coagulative tumor necrosis , and sarcomatoid differentiation . Survival was estimated using the Kaplan-Meier method and compared between ccRCC and URCC patients using log-rank tests . RESULTS Patients with URCC were more likely to have regional lymph node involvement ( P <.001 ) , higher grade ( P <.001 ) , tumor necrosis ( P <.001 ) , and sarcomatoid differentiation ( P <.001 ) as compared to patients with ccRCC . Overall survival was not significantly different between URCC and ccRCC patients in either the unmatched ( P = .337 ) or matched ( P = .345 ) cohorts . Cancer-specific survival was significantly worse for URCC patients compared with unmatched ccRCC patients ( P = .020 ) . However , this difference was not statistically significant when the URCC patients were compared with the matched cohort ( P = .688 ) . Distant metastases-free survival was somewhat worse for M0 URCC patients compared with unmatched M0 ccRCC patients ( P = .063 ) , but not in the matched cohort ( P = .788 ) . CONCLUSIONS Although URCC is more likely to present with advanced clinicopathologic features compared with ccRCC , no statistically significant differences in outcome were noted after adjusting for these features in a matched analysis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20223503"}
{"sentence": "SCOPE Glyceollins are a novel class of soybean phytoalexins with potential cancer-preventive and antiestrogenic effects . The angiogenic cascade during tumor development consists of the release of angiogenic factors and binding of angiogenic factors to receptors on endothelial cells to activate downstream signaling pathways . However , the potential medicinal value of glyceollins , especially in antiangiogenesis , remains unexplored . METHODS AND RESULTS Here , we investigated the antiangiogenic activity of glyceollins and their underlying mechanisms . Glyceollins inhibited vascular endothelial growth factor ( VEGF ) or basic fibroblast growth factor ( bFGF ) induced in vitro angiogenic activity . Glyceollins inhibited VEGF receptor-2 or FGF receptor-1 activity and their downstream signaling pathways such as extracellular regulated kinase 1/2 , c-Jun N-terminal kinase , as well as p38 mitogen-activated protein kinase and focal adhesion kinase induced by VEGF or bFGF . Glyceollins significantly suppressed VEGF receptor-2 kinase activity assayed by the ELISA . Glyceollins significantly attenuated in vivo and ex vivo microvessel development in a dose-dependent manner and tumor growth by suppressing microvessel density in Lewis lung carcinoma ( LLC ) mouse xenograft . CONCLUSION Thus , glyceollins , elicited ingredients of soy source , target the signaling pathways mediated by VEGF or bFGF , providing new perspectives into potential therapeutics for preventing and treating hypervascularized diseases including cancer .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23229497"}
{"sentence": "We studied whether feeding pregnant female rats different high fat diets affects structural zones in the spleen and lymph nodes , involved in production of T and B cells , as well as cell kinetics and apoptosis in some offspring with mammary glands tumors . Rat mothers were fed either a 7% or 15% corn-oil or a 7% or 15% olive-oil diet . At four weeks of age , female offspring ( n=10-15 per group ) were transferred to 7% corn oil diet . Five-week old offspring were exposed twice to the carcinogen , dimethylbenz(a)antracene ( 10 mg/rat/week ) . Three months later , tumors were counted and sized , and samples from the spleen , axillary lymph nodes and tumors collected for immunohistochemical analyses . Feeding the mothers with both the 7% and 15% olive-oil diets significantly increased the number of tumor-free rats in offspring . Tumors were characterized with active mitosis , intensive lymphoid infiltration inside a knot and high rates of apoptosis , particularly in tumors obtained from rats whose mothers were fed the 15% olive-oil diet . In the spleen , the 15% olive-oil diet significantly increased the areas of the follicles and germinal centers but only in tumor-free rats . In tumor-bearing rats , areas of germinal centers increased compared to the 7% olive-oil diet . The 15% olive-oil diet increased all areas of the lymph nodes in tumor-free rats , while in tumor-bearing rats , this diet increased the areas of the cortex and mantle layer . We conclude that exposure to various diets in utero and during lactation affects the immune system . In addition , the promotion of apoptosis may play a key role in the mechanisms involved in the transplacental effects on mammary tumor development as seen using a 15% olive-oil diet , similar to the high fat diets of Mediterranean countries .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12430006"}
{"sentence": "Among several types of DNA lesions , the DNA double strand breaks ( DSBs ) are one of the most deleterious and harmful . Mammalian cells mount a coordinated response to DSBs with the aim of appropriately repair the DNA damage . Indeed , failure of the DNA damage response ( DDR ) can lead to the development of cancer-prone genetic diseases . The identification and development of drugs targeting proteins involved in the DDR is even more investigated , as it gives the possibility to specifically target cancer cells . Indeed , the administration of DNA repair inhibitors could be combined with chemo- and radiotherapy , thus improving the eradication of tumor cells . Here , we provide an overview about DSBs damage response , focusing on the role of the DSBs repair mechanisms , of chromatin modifications , and of the cancer susceptibility gene BRCA1 which plays a multifunctional role in controlling genome integrity . Moreover , the most investigated DSBs enzyme inhibitors tested as potential therapeutic agents for anti-cancer therapy are reported .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20423312"}
{"sentence": "Gene trapping is a method of inserting DNA into the genome at random , generating insertional mutations throughout the genome . The efficiency of retroviral gene trapping is not sufficient in part because of a strong preference for retroviral integration near transcription start sites . In contrast , lentiviral vectors strongly favor integration in the entire region of highly active genes , suggesting that lentiviral vectors would improve the efficiency of gene trapping . In this study , we constructed both lentiviral and retroviral gene-trap vectors and analyzed integration sites in mouse embryonic stem ( ES ) cells . The frequency of false-positive gene-trap events was about 12-fold higher for the retroviral vector compared to the lentiviral vector . Within intragenic regions , most of the retroviral vector integration sites were found in the 5 ' untranslated region , while the lentiviral vector integrated uniformly throughout transcriptional units . The trapping efficiency of unique genes was significantly higher for the lentiviral vector ( than for the retroviral vector ( Our data demonstrate that the lentiviral vector can trap the active genes more efficiently than the retroviral vector and will facilitate efficient generation of gene-trap libraries not only in ES cells but also in a wide variety of cell lines and primary cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22842569"}
{"sentence": "Myotonia congenita-inducing mutations in the muscle chloride channel CLC-1 normally result in reduced open probability ( P ( o) ) of this channel . One well-accepted mechanism of the dominant inheritance of this disease involves a dominant-negative effect of the mutation on the function of the common-gate of this homodimeric , double-barreled molecule . We report here a family with myotonia congenita characterized by muscle stiffness and clinical and electrophysiologic myotonic phenomena transmitted in an autosomal dominant pattern . DNA sequencing of DMPK and ZNF9 genes for myotonic muscular dystrophy types I and II was normal , whereas sequencing of CLC-1 encoding gene , CLCN1 , identified a single heterozygous missense mutation , G233S . Patch-clamp analyses of this mutant CLC-1 channel in Xenopus oocytes revealed an increased P ( o ) of the channel's fast-gate , from in the wild type to >0.9 in the mutant at -90 mV . In contrast , the mutant exhibits a minimal effect on the P ( o ) of the common-gate . These results are consistent with the structural prediction that the mutation site is adjacent to the fast-gate of the channel . Overall , the mutant could lead to a significantly reduced dynamic response of CLC-1 to membrane depolarization , from a fivefold increase in chloride conductance in the wild type to a twofold increase in the mutant-this might result in slower membrane repolarization during an action potential . Since expression levels of the mutant and wild-type subunits in artificial model cell systems were unable to explain the disease symptoms , the mechanism leading to dominant inheritance in this family remains to be determined .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22790975"}
{"sentence": "OBJECTIVE Hepatocellular carcinoma ( HCC ) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis . We assessed the safety , efficacy , and potential biomarkers of activity of bevacizumab in patients with advanced HCC . METHODS In this phase II trial , eligible patients received bevacizumab , 5 mg/kg or 10 mg/kg every 2 weeks . The disease-control rate at 16 weeks ( 16W-DCR ) was the primary endpoint . Circulating endothelial cells ( CECs ) and plasma cytokines and angiogenic factors ( CAFs ) were measured at baseline and throughout treatment . RESULTS The 16W-DCR was 42% ( 95% confidence interval , 27%-57% ) . Six of the 43 patients who received bevacizumab achieved a partial response ( objective response rate [ ORR ] , 14% ) . Grade 3-4 asthenia , hemorrhage , and aminotransferase elevation occurred in five ( 12% ) , three ( 7% ) , and three ( 7% ) patients , respectively . During treatment , placental growth factor markedly increased , whereas vascular endothelial growth factor ( VEGF)-A dramatically decreased ( p < .0001 ) ; soluble VEGF receptor-2 ( p < .0001 ) and CECs ( p = .03 ) transiently increased on day 3 . High and increased CEC counts at day 15 were associated with the ORR ( p = .04 ) and the 16W-DCR ( p = .02 ) , respectively . Lower interleukin ( IL)-8 levels at baseline ( p = .01 ) and throughout treatment ( p \u2264 .04 ) were associated with the 16W-DCR . High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times ( p \u2264 .04 ) . CONCLUSION Bevacizumab is active and well tolerated in patients with advanced HCC . The clinical value of CECs , IL-6 , and IL-8 warrants further investigation .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22707516"}
{"sentence": "Induced pluripotent stem cells ( iPSCs ) generated by epigenetic reprogramming of personal somatic cells have limited therapeutic capacity for patients suffering from genetic disorders . Here we demonstrate restoration of a genomic mutation heterozygous for Pkd1 ( polycystic kidney disease 1 ) deletion ( Pkd1(+/-) to Pkd1(+/R+) ) by spontaneous mitotic recombination . Notably , recombination between homologous chromosomes occurred at a frequency of 1 per 10,000 iPSCs . Southern blot hybridization and genomic PCR analyses demonstrated that the genotype of the mutation-restored iPSCs was indistinguishable from that of the wild-type cells . Importantly , the frequency of cyst generation in kidneys of adult chimeric mice containing Pkd1(+/R+) iPSCs was significantly lower than that of adult chimeric mice with parental Pkd1(+/-) iPSCs , and indistinguishable from that of wild-type mice . This repair step could be directly incorporated into iPSC development programmes prior to cell transplantation , offering an invaluable step forward for patients carrying a wide range of genetic disorders .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22347511"}
{"sentence": "An epidemiological survey was conducted in the Seine estuary and in two smaller and relatively preserved estuaries on the French Atlantic coast in order to estimate the occurrence of liver lesions in European flounder , Platichthys flesus , and also to seek putative risk factors for the recorded pathologies . Four hundred and seventy-eight fish of both sexes and of different size ranges were sampled in the three studied areas , 338 of which in the Seine estuary . All fish were examined for histopathological liver lesions , while DNA adducts and otoliths were analyzed on a subsample . Five categories of hepatic lesions were recorded with the following prevalence for the Seine estuary : 36.7 % inflammations , 8 % parasites ( mainly encysted nematodes ) , 6.5 % foci of cellular alteration ( FCA ) , 5.3 % foci of necrosis or regeneration ( FNR ) , and 1.5 % tumors . Inflammation occurrence increased according to age , contrary to parasitic infestations and FCA which were more prevalent in young fish , notably those of <1 year old ( group 0 ) . Tumors were only observed in females of more than two winters . Females exhibited a higher prevalence of tumors ( 3.0 % ) and FCA ( 6.5 % ) than males ( 0 and 2.6 % , respectively ) . Parasitic and infectious lesions and FNR were equally distributed in males and females . The prevalence of FNR was also shown to vary according to sampling season , with significantly more occurrences of liver necrosis in the fish collected in summer than in spring . Spatial differences were observed with a higher occurrence of encysted parasites in flounders from the upper Seine estuary , while inflammations predominated in flounders living downstream . Temporal trends were also noted , with an increased prevalence of parasitic infestations , inflammations , and FCA in the 2002-2003 period in comparison to the 1996-1997 one . The three flounder populations from the Seine estuary ( Normandy ) , Ster estuary ( Brittany ) , and Bay of Veys ( Normandy ) showed different spectra of hepatic lesions . Flounders from the Bay of Veys had relatively few liver lesions as compared to flounders from the two other estuaries . Flounders from the Ster estuary exhibited the highest prevalence of parasites ( 37.2 % ) and inflammations ( 51.1 % ) . Finally , FCA and liver tumors occurred at very similar levels in both flounder populations from the Seine and the Ster estuaries . Group 0 flounders inhabiting the upper Seine estuary were more prone to parasitic and pre-neoplastic hepatic lesions and had higher levels of liver DNA adducts than the older ones living downstream . It was postulated that group 0 European flounders may serve as valuable bioindicators for assessing the quality of estuarine waters and the health status of euryhaline fish populations .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23161498"}
{"sentence": "The most potent tumorigen identified among the polycyclic aromatic hydrocarbons ( PAH ) is the nonplanar fjord region dibenzo[a,l]pyrene ( DB[a,l]P ) . It is metabolically activated in vivo through the widely studied diol epoxide ( DE ) pathway to form covalent adducts with DNA bases , predominantly guanine and adenine . The ( +)-11S,12R,13R,14S DE enantiomer forms adducts via its C14 position with the exocyclic amino group of guanine . Here , we present the first nuclear magnetic resonance solution structure of a DB[a,l]P-derived adduct , the 14R-(+)-trans-anti-DB[a,l]P-N(2)-dG ( DB[a,l]P-dG ) lesion in double-stranded DNA . In contrast to the stereochemically identical benzo[a]pyrene-derived N(2)-dG adduct ( B[a]P-dG ) in which the B[a]P rings reside in the B-DNA minor groove on the 3'-side of the modifed deoxyguanosine , in the DB[a,l]P-derived adduct the DB[a,l]P rings intercalate into the duplex on the 3'-side of the modified base from the sterically crowded minor groove . Watson-Crick base pairing of the modified guanine with the partner cytosine is broken , but these bases retain some stacking with the bulky DB[a,l]P ring system . This new theme in PAH DE-DNA adduct conformation differs from ( 1 ) the classical intercalation motif in which Watson-Crick base pairing is intact at the lesion site and ( 2 ) the base-displaced intercalation motif in which the damaged base and its partner are extruded from the helix . The structural considerations that lead to the intercalated conformation of the DB[a,l]P-dG lesion in contrast to the minor groove alignment of the B[a]P-dG adduct , and the implications of the DB[a,l]P-dG conformational motif for the recognition of such DNA lesions by the human nucleotide excision repair apparatus , are discussed .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23121427"}
{"sentence": "Three normal human diploid cell strains were transfected with an activated Ha-ras oncogene ( EJ ras ) or SV40 T-antigen . Multiple clones were examined for morphological alterations , growth requirements , ability to grow under anchorage independent conditions , immortality and tumorigenicity in nude mice . Clones expressing SV40 T-antigen alone or in combination with ras protein p21 were significantly radioresistant as compared with their parent cells or clones transfected with the neo gene only . This radioresistant phenotype persisted in post-crisis , immortalized cell lines . Cells transfected with EJ ras alone showed no morphological alterations nor significant changes in radiosensitivity . Cell clones expressing ras and/or SV40 T-antigen showed a reduced requirement for serum supplements , an increase in aneuploidy and chromosomal aberrations , and enhanced growth in soft agar as an early cellular response to SV40 T-antigen expression . The sequential order of transfection with SV40 T-antigen and ras influenced radio-sensitivity but not the induction of morphological changes . These data suggest that expression of the SV40 T-antigen but not activated Ha-ras plays an important role in the radiosensitivity of human diploid cells . The radioresistant phenotype in SV40 T transfected cells was not related to the enhanced level of genetic instability seen in pre-crisis and newly immortalized cells , nor to the process of immortalization itself .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "1355514"}
{"sentence": "Genetic and molecular analyses mainly in Arabidopsis and in some other plants have demonstrated involvement of light signaling in cell cycle regulation . In this report , we show light-mediated activation of the promoter of AtPol\\u03bb gene , a homolog of mammalian DNA polymerase \\u03bb in Arabidopsis thaliana and an important component of DNA damage repair/recombination machinery in plants . Analyses of the light-mediated promoter activity using various deletion versions of AtPol\\u03bb promoter in transformed Arabidopsis and tobacco ( Nicotiana tabaccum ) plants indicate that a 130-bp promoter region between -536 and -408 of AtPol\\u03bb promoter is essential for light-induced regulation of AtPol\\u03bb expression . DNA-protein interaction studies reveal that an ATCT-motif and AE-box light-responsive elements in the light-regulated promoter region confer light responsiveness of AtPol\\u03bb promoter . DNA-binding analysis has identified a 63-kDa trans-acting protein factor which showed specific binding to ATCT-motif , while another trans-acting factor of kDa was found to bind specifically to both ATCT and AE-box sequences . The 52-kDa protein has been identified as B3-domain transcription factor by MALDI-TOF/MS analysis . Overall , our results provide novel information on the role of light signaling in regulation of expression of an important component of DNA repair machinery in plants .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21947619"}
{"sentence": "Dose-dense ( DD ) regimens of combination chemotherapy may produce superior clinical outcomes , but the basis for these effects are not completely clear . In this study , we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared with a maximum tolerated dose ( MTD ) regimen in treating platinum-resistant ovarian cancer as modeled in mice . Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed . The DD regimen was less toxic to the immune system , reduced immunosuppression by the tumor microenvironment , and triggered recruitment of macrophages and tumor-specific CD8(+) T-cell responses to tumors [ as determined by interleukin ( IL)-2 and IFN-\u03b3 secretion ] . In this model , we found that the DD regimen exerted greater therapeutic effects than the MTD regimen , justifying its further clinical investigation . Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin ( AUC2 ) and paclitaxel ( 60-80 mg/m(2) ) as the third- or fourth-line treatment . Serum was collected over the course of treatment , and serial IFN-\u03b3 and IL-2 levels were used to determine CD8(+) T-cell activation . Of the four patients with disease control , three had serum levels of IL-2 and IFN-\u03b3 associated with cytotoxic CD8(+) T-cell activity . The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity , especially the antitumor CD8(+) T-cell response . Because the DD regimen controlled drug-resistant disease through a novel immune mechanism , it may offer a fine strategy for salvage treatment . Cancer Res ; 73(1) ; 119-27. \ufffd2012 AACR .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23108141"}
{"sentence": "In this study , laboratory experiments were carried out in order to come to a better understanding of the fate of polycyclic aromatic hydrocarbons ( PAHs ) in the marine environment and especially on their bioaccumulation , biotransformation and genotoxic effects in fish . Juveniles of turbot ( Scophthalmus maximus ) were exposed to PAHs through different routes via ( 1 ) a mixture of dissolved PAHs , ( 2 ) a PAH-polluted sediment and ( 3 ) an oil fuel elutriate . Fish were exposed 4 days followed by a 6-day depuration period . In each experiment , PAH concentrations in the seawater of the tanks were analysed regularly by gas chromatography coupled with mass spectrometry . Muscle and liver samples were also analysed for parent PAH levels and PAH bioconcentration factors were calculated . Biotransformation was evaluated by measuring the levels of PAH metabolites in fish bile . Genotoxicity was assessed by the alkaline comet assay . Regardless of exposure route , the parent PAH concentrations in the liver and muscle showed a peak level 1 day after the beginning of the exposure , followed by a decrease up to the background level towards the end of the experiment , except for the exposure to dissolved PAHs for which levels were relatively low throughout the study . As a consequence , no bioaccumulation was observed in fish tissues at the end of the experiment . In contrast , regardless of exposure routes , a rapid production of biliary metabolites was observed throughout the whole exposure experiment . This was especially true for 1-hydroxypyrene , the major metabolite of pyrene . After 6 days of recovery in clean water , a significant decrease in the total metabolite concentrations occurred in bile . Fish exposed through either route displayed a significant increase in DNA strand breaks after 4 days of exposure , and significant correlations were observed between the level of biliary PAH metabolites and the level of DNA lesions in fish erythrocytes . Overall results indicate that exposure to either a mixture of dissolved PAHs , a PAH-contaminated sediment or a dispersed oil fuel elutriate leads to biotransformation and increase in DNA damage in fish . The quantification of PAH metabolites in bile and DNA damage in erythrocytes appear to be suitable for environmental monitoring of marine pollution either in the case of accidental oil spills or sediment contamination .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23247530"}
{"sentence": "Muir-Torre syndrome ( MTS ) , a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome , or Lynch syndrome , is an autosomal dominantly inherited condition that combines at least one cutaneous sebaceous neoplasm and at least one visceral malignancy . Most patients ( with MTS carry mutations in the MSH2 gene ; less than 10% of the cases are associated with a mutation MLH1 gene , and only 3 MTS patients with a pathogenic MSH6 mutation have been previously documented . We report a family affected with MTS in which 3 members ( father and 2 sons ) were found to harbor a missense mutation c.2633T>C ( p.V878A ) in exon 4 of the MSH6 gene .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22814321"}
{"sentence": "The immune system of vertebrates is able to detect bacterial DNA based on the presence of unmethylated CpG motifs . We examined the therapeutic potential of oligodeoxynucleotides with CpG motifs ( CpG ODN ) in a colon carcinoma model in BALB/c mice . Tumors were induced by s.c. injection of syngeneic C26 cells or Renca kidney cancer cells as a control . Injection of CpG ODN alone or in combination with irradiated tumor cells did not protect mice against subsequent tumor challenge . In contrast , weekly injections of CpG ODN into the margin of already established tumors resulted in regression of tumors and complete cure of mice . The injection site was critical , since injection of CpG ODN at distant sites was not effective . Mice with two bilateral C26 tumors rejected both tumors upon peritumoral injection of one tumor , indicating the development of a systemic immune response . The tumor specificity of the immune response was demonstrated in mice bearing a C26 tumor and a Renca tumor at the same time . Mice that rejected a tumor upon peritumoral CpG treatment remained tumor free and were protected against rechallenge with the same tumor cells , but not with the other tumor , demonstrating long term memory . Tumor-specific CD8 T cells as well as innate effector cells contributed to the antitumor activity of treatment . In conclusion , peritumoral CpG ODN monotherapy elicits a strong CD8 T cell response and innate effector mechanisms that seem to act in concert to overcome unresponsiveness of the immune system toward a growing tumor .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12244187"}
{"sentence": "Glioblastoma multiforme ( GBM ) and oxidative stress are closely linked . Oxidative stress affects many signaling pathways and may cause the induction of autophagy . The NF-E2-related factor 2 ( Nrf2)/Kelch-like ECH-associated protein 1 ( Keap1 ) signaling pathway is the main pathway responsible for cell defense against oxidative stress and Nrf2 is a critical transcription factor related with cancer multidrug resistance . However , the relation between Nrf2 and regulation of autophagy is not well understood . In this study , we used temozolomide ( TMZ ) , which inhibited the viability of GBM cells mainly by inducing autophagic cell death and explored the role of Nrf2 downregulation on autophagy induced by TMZ in GBM cells . In U251-Si-Nrf2 48h after transfection the protein levels of Nrf2 were significantly downregulated , while the protein levels of LC3B-II increased by western blot analysis . Knockdown of Nrf2 also led to a significant increase of autophagic vacuoles and acidic vesicular organelles ( AVOs ) , revealed by trans-mission electron microscopy ( TEM ) and acridine orange ( AO ) staining using flow cytometry . Collectively , these findings demonstrate that knockdown of Nrf2 can enhance the basal level of autophagy in the U251 glioma cell line . Furthermore , after the treatment with TMZ ( 100\u00b5M ) for 3 days , the U251-Si-Nrf2 transfected cells showed less viability rate by cell counting kit-8 ( CCK-8 ) assay and the levels of autophagy increased obviously through analysis of western blot and AO staining using flow cytometry . Taken together , our results suggest that knockdown of Nrf2 may enhance autophagy induced by TMZ in the U251 glioma cell line , which should be further evaluated for novel anticancer activity .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23128449"}
{"sentence": "Prostate cancer is the second most common cancer in elderly men worldwide and its incidence rate is rising continuously . Agents capable of inducing apoptosis in prostate cancer cells seem a promising approach to treat this malignancy . In this study we describe the synthesis of a number of novel N- and N,N'-substituted S-2,3,4,5,6-pentabromobenzylisothiouronium bromides and their activity against the human prostate adenocarcinoma PC3 cell line . All the compounds produced changes in mitochondrial transmembrane potential and cell cycle progression , showed a cytostatic effect and induced apoptosis in the tested cancer line in a concentration- and time-dependent manner . The most effective compounds ZKK-3 , ZKK-9 and ZKK-13 produced , at 20 microM concentration , apoptosis in 42 , 46 , and 66% of the cells , respectively , after 48 h incubation . Two selected S-2,3,4,5,6-pentabromobenzylisothiouronium bromides ( ZKK-3 , ZKK-9 ) showed also a synergic proapoptotic effect with the new casein kinase II inhibitor 2-(4-methylpiperazin-1-yl)-4,5,6,7-tetrabromo-1H-benzimidazole ( TBIPIP ) in the PC3 cell line .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23285698"}
{"sentence": "BACKGROUND/AIMS We investigated whether the anticancer drug Ukrain ( UK ) is able to modulate the expression of some of the key markers of tumor progression in pancreatic cell carcinoma , in order to assess its potential therapeutic effect . METHODS Three cell lines ( HPAF-II , PL45 , HPAC ) were treated with UK ( 5 , 10 and 20 \u03bcM ) for 48 h , or left untreated . Secreted protein acidic and rich in cysteine ( SPARC ) mRNA levels were assessed by real-time PCR . Matrix metalloproteinases ( MMP)-2 and -9 activity was analyzed by SDS zymography ; SPARC protein levels in cell lysates and supernatants were determined by Western blot . Cell cycle was determined by flow cytometric analysis , and invasion by matrigel invasion assay . RESULTS UK down-regulated MMP-2 and MMP-9 , suggesting that UK may decrease pancreatic cancer cell invasion , as confirmed by the matrigel invasion assay . SPARC protein down-regulation in supernatants points to an inhibition by UK of extracellular matrix remodeling in the tumor microenvironment . At the same time , SPARC mRNA and cellular protein level up-regulation suggests that UK can affect cell proliferation by cell cycle inhibition , showing a cell cycle G2/M arrest in UK-treated cells . CONCLUSION Our results suggest that UK modulates two major aspects involved in tumorigenesis of pancreatic cancer cells , such as extracellular matrix remodeling and cell proliferation .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20975318"}
{"sentence": "Purpose of this work was to synthesize several cis-/trans- isomer pairs of the platinum(II) complexes , and study the extent and the mode of their antiproliferative activity on HeLa cells . Six platinum(II) isomer pairs have a general formula cis-/trans-[PtA2X2] , where A is ligand : ammonia ( NH3 ) , pyridine ( Py ) ; and X is ligand : chloride ion ( Cl- ) , bromide ion ( Br- ) , iodide ion ( I- ) , thiocyanato ion ( SCN- ) ; four compounds have different structural formulas , and these are cis-/trans-[Pt(NH2OH)2(NH3)2]Cl2 , and cis-/trans-Pt(Gly)2 , where Gly is bidentate glycinato ligand . Results of the MTT assay , showed that six cis- and one trans-platinum(II) complexes exhibited cytotoxicity ( IC50 ) ranging between 5 and 33 microM . Most of the cis-platinum(II) isomers caused significant alteration of cell cycle phases progression , and induced apoptosis in degree that varied among different compounds , as evaluated using flowcytometry and morphological study . Spectrophotometric analysis ( AAS ) indicated that there is no correlation between intracellular platinum(II) accumulation and cytotoxicity of tested complexes .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12636098"}
{"sentence": "BACKGROUND/AIMS Endoscopic mucosal resection and laparoscopic wedge resection have become more common in the treatment of early gastric cancer . However , lymph node metastasis is a major poor prognostic factor influencing tumor recurrence and survival . To predict the risk of lymph node metastasis in early gastric cancer , the authors conducted a study to investigate the clinicopathologic characteristics of early gastric cancer with lymph node metastasis . METHODOLOGY From 1982 to 1998 , 181 patients of early gastric cancer underwent primary surgery and were included in the study . Patient data was postoperatively reviewed regarding age , gender , tumor size , depth of invasion , histologic differentiation , macroscopic classification and anatomic level of lymph node metastasis . The chi 2 test or Student's t test was used for statistical analysis . Logistic regression analysis was used to evaluate the independent risk factors for lymph node metastasis . RESULTS Lymph node metastasis was observed in 19 cases ( 11% ) . Early gastric cancer with size larger than 4 cm ( P < 0.05 ) , with submucosal invasion ( P < 0.01 ) , and with poor differentiation ( P < 0.05 ) was associated with higher risk of lymph node metastasis . The macroscopic classification had no predictive value . Multivariate analysis showed that submucosal invasion correlated best with lymph node spread ( OR 10.25 , 95% CI : 2.10-49.96 ) , followed by tumor size larger than 4 cm ( OR 4.99 , 95% CI : 1.46-17.05 ) , and poorly differentiated histological subtype ( OR 3.31 , 95% CI : 1.16-9.45 ) . CONCLUSIONS Poor differentiation , submucosal invasion and large tumor size were independent risk factors for lymph node metastasis in early gastric cancer . Macroscopic classification was not correlated with lymph node metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12239968"}
{"sentence": "Systemic oxidative stress is associated with a wide range of pathological conditions . Oxidative DNA damage is frequently measured in circulating lymphocytes . Mitochondrial DNA ( mtDNA ) is known to be more sensitive to oxidative damage than nuclear DNA but is rarely used for direct measurement of DNA damage in clinical studies . Based on the supercoiling-sensitive real-time PCR method , we propose a new approach for the noninvasive monitoring of systemic oxidative stress by quantifying the mtDNA structural damage and copy number change in isolated lymphocytes in a single test . We show that lymphocytes have significantly less mtDNA content and relatively lower baseline levels of damage than cancer cell lines . In an ex vivo challenge experiment , we demonstrate , for the first time , that exogenous H2O2 induces a significant increase in mtDNA damage in lymphocytes from healthy individuals , but no repair activity is observed after 1 h recovery . We further demonstrate that whole blood may serve as a convenient alternative to the isolated lymphocytes in mtDNA analysis . Thus , the blood analysis with the multiple mtDNA end-points proposed in the current study may provide a simple and sensitive test to interrogate the nature and extent of systemic oxidative stress for a broad spectrum of clinical investigations .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23484085"}
{"sentence": "Autophagy is one of the survival processes of cancer cells , especially in stressful conditions such as starvation , hypoxia and chemotherapeutic agents . However , its roles in tumor survival have not yet been fully elucidated . Here , we found for the first time that JAK2/STAT3 was activated in HeLa cells when they were starved or treated with rapamycin . STAT3 activation was associated with autophagic processes , because it was completely inhibited by 3-methyladenine , partially inhibited by knockdown of molecules associated with autophagic processes and blocked by antioxidants , DPI , a Nox inhibitor and knockdown of p22 phox , indicating that ROS generated by Nox that was activated during autophagic processes activated JAK2/STAT3 pathway . Activated STAT3 directly bound to IL6 promoter and increased IL6 mRNA and protein secretion . Finally , the conditioned media , which included IL6 , from starved HeLa cells promoted cancer cell survival in both normal and starved conditions , confirmed by clonogenic , proliferation and cell death assays . These data together indicate that the autophagic process in cancer cells can contribute to their survival by JAk2/STAT3 activation and subsequent secretion of growth factors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20930550"}
{"sentence": "Apoptosis , programmed cell death , was previously shown to be induced by the mAb anti-APO-1 ( IgG3 , kappa ) by binding to the APO-1 cell surface Ag , a new member of the nerve growth factor/TNF receptor superfamily . To investigate the role of the Ig H chain Fc regions we compared induction of apoptosis by the original mAb IgG3 anti-APO-1 with anti-APO-1 F(ab')2 fragments and different anti-APO-1 isotypes ( IgG1 , IgG2b , IgG2a , and IgA ) isolated by sequential sublining . We found that IgG3 was the most active isotype ; IgG1 , IgG2a , and IgA showed intermediate activity , and IgG2b and F(ab')2 were inactive . Cytotoxic activity of the inactive or less active antibody preparations was fully reconstituted by protein A , anti-mouse Ig , or anti-mouse Ig F(ab')2 , respectively . Thus , APO-1-mediated induction of apoptosis was dependent on efficient cross-linking of APO-1 cell surface Ag , indirectly augmented by anti-APO-1 Fc-Fc self-aggregation . Because of their different in vitro activity we selected IgG3- , IgG2b- , and IgA anti-APO-1 to test their antitumor activity against solid human B lymphoblastoid tumors in SCID mice . The isotypes showed a different serum half-life ( IgG3 : 9.2-10.4 days , IgG2b : 1.9-2.6 days , and IgA : 14.1-29.2 h ) and a different initial tumor localization 4 h after i.p. injection ( IgG3 around the blood vessels , IgG2b homogeneously , and IgA heterogeneously distributed in the tumor ) . All antibody preparations induced tumor regression by induction of apoptosis , even IgG2b anti-APO-1 inactive in vitro without cross-linking . The activity of IgA anti-APO-1 , which did not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity indicates that apoptosis may be used as the main if not the only mechanism of induction of tumor regression in vivo . As with in vitro , IgG3 anti-APO-1 was the most effective isotype also in vivo . This result suggests that cross-linking of APO-1 on the tumor cell surface may also be required for tumor regression by apoptosis in vivo . Taken together , our data show that selective targeting of apoptosis to tumors may be an efficient antitumor mechanism .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1431095"}
{"sentence": "A metaphase chromosome analysis method was used to evaluate the mutagenic activity of volatile petroleum fractions in chronically intoxicated rats . The findings indicate that chronic inhalation exposure of the rats to volatile petroleum fractions at different concentrations results in a significant ( 2.5-fold ) increase , compared to the spontaneous level , in the occurrence of chromosomal aberrations in the bone marrow cells in a number of generations . In addition to chromosomal structural abnormalities , there are genomic changes ( aneuploidy , polyploidy ) . There is a tendency towards an increased rate of petroleum-induced chromosomal aberrations in a number of generations ( P , F1 , and F2 ) in the rat bone marrow cells . The maximum mutagenic effect of volatile petroleum fractions was found when used at concentrations of 10 and 100 mg/l upon long-term chronic exposure during three generations ( P1 , F1 , and F2 ) . The findings are indicative of the mutagenic activity of volatile petroleum fractions , which is likely to pose a potential risk from environmental pollution to biota and population health in the area of intensive oil extraction and refining .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23082676"}
{"sentence": "Epithelial-mesenchymal transition ( EMT ) is a critical process providing tumor cells with the ability to migrate and escape from the primary tumor and metastasize to distant sites . Recently , EMT was shown to be associated with the cancer stem cell ( CSC ) phenotype in breast cancer . Snail is a transcription factor that mediates EMT in a number of tumor types , including colorectal cancer ( CRC ) . Our study was done to determine the role of Snail in mediating EMT and CSC function in CRC . Human CRC specimens were stained for Snail expression , and human CRC cell lines were transduced with a retroviral Snail construct or vector control . Cell proliferation and chemosensitivity to oxaliplatin of the infected cells were determined by the MTT ( colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ) assay . Migration and invasion were determined in vitro using modified Boyden chamber assays . EMT and putative CSC markers were analyzed using Western blotting . Intravenous injection of tumor cells was done to evaluate their metastatic potential in mice . Snail was overexpressed in human CRC surgical specimens . This overexpression induced EMT and a CSC-like phenotype in human CRC cells and enhanced cell migration and invasion ( P < 0.002 vs. control ) . Snail overexpression also led to an increase in metastasis formation in vivo ( P < 0.002 vs. control ) . Furthermore , the Snail-overexpressing CRC cells were more chemoresistant to oxaliplatin than control cells . Increased Snail expression induces EMT and the CSC-like phenotype in CRC cells , which enhance cancer cell invasion and chemoresistance . Thus , Snail is a potential therapeutic target in metastatic CRC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23342249"}
{"sentence": "Numerous scientific studies have examined the relationship between coffee consumption and an array of medical conditions , including cancer , and yet the direct effect of commercially brewed coffee on cancer cells has not been evaluated . The purpose of this study was to evaluate the antiproliferation effect of 4 different regular and decaffeinated coffee brews and 3 of coffee's bioactive ingredients-caffeine , chlorogenic acids , and caffeic acid-on 2 human ovarian cancer cell lines alone and in combination with cisplatin ( CDDP ) . Antiproliferation IC(50) for Brand A regular and decaffeinated coffee on A2780 cells was 1:70.79 \u00b1 5.66 and 1:55.68 \u00b1 2.00 dilution ( vol/vol ) in tissue culture medium ( mean \u00b1 standard error of the mean ; N = 12 ) , respectively , and slightly lower on A2780CP70 cells . Three other brands showed lower antiproliferation activity . Antiproliferation IC(50) concentrations of chlorogenic acids and caffeic acid are many folds lower than caffeine . In combination with CDDP , both Brand A coffee brews , and the 3 bioactive compounds , showed additive antiproliferation effect on both cancer cell lines . Flow cytometry analysis showed that coffee treatment induced apoptosis of A2780 and A2780CP70 cells . To our knowledge , this is the first report showing the antiproliferation activity and the additive effect with CDDP of commercially prepared coffee brews on human cancer cell lines .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21058192"}
{"sentence": "OBJECTIVE To investigate the mutations of epidermal growth factor receptor ( EGFR ) in tumor tissue and pleural effusion in advanced non-small cell lung cancer ( NSCLC ) patients , and to analyze the relationship between EGFR mutations and the clinicopathologic characteristics . METHODS Two-hundred and forty-one cases of formalin-fixed , paraffin-embedded tumor tissues and 14 paired pleural effusions from advanced NSCLC patients were collected . Twenty-nine different EGFR mutations in exons 18-21 were assessed by scorpions and amplification refractory mutation system ( scorpions ARMS ) using real time PCR . The relationship between the EGFR mutations and clinical parameters was analyzed using statistical methods . EGFR mutation of 37 cases were detected with direct sequencing , and assessed the sensitivity , the specificity and the accuracy of scorpions ARMS . RESULTS EGFR somatic mutations were detected in 114 of 234 advanced NSCLC patients , with the mutation rate of 48.7% , including deletions in exon 19 in 65 patients and point mutation of L858R in exon 21 in 39 patients ; both accounting for 91.2% ( 104/114 ) of all types of EGFR mutations . The test results of 14 paired pleural effusion specimens were entirely the same to the tissues . The concordance rate of 2 different detection methods was 94.6% . Mutation rate was higher in women ( 55.9% ) than in men ( 42.2% ) , and there was no difference in mutation rates between smokers and non-smokers ; patients in stage IIIB and stage IV ; adenocarcinoma and non-adenocarcinoma . CONCLUSIONS EGFR somatic mutations appear to occur frequently in Chinese . Scorpions ARMS technology is a sensitive method to detect EGFR mutations and is suitable for screening patients who would likely respond to EGFR inhibitors therapy .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23157744"}
{"sentence": "Bulky DNA adducts are considered a potential biomarker of cancer risk . In this study , the association between various lifestyle , environmental , and genetic factors and the levels of bulky DNA adducts in peripheral leukocytes was examined in a study group nested within a population-based prospective Danish cohort . At enrollment , blood samples were collected and information on lifestyle , including dietary and smoking habits , obtained . Previously , bulky DNA adducts were measured in 245 individuals who developed lung cancer and 255 control members of the cohort . Of these 500 individuals , data on 375 individuals were included in this study , excluding 125 cases , which developed lung cancer within the first 3 yr after blood sampling . Bulky DNA adduct levels were measured by 32P-postlabeling technique and polymorphisms in carcinogen metabolism and DNA repair genes were determined . Potential predictors of bulky DNA adduct levels were analyzed by univariate and multivariate regression analyses . Women tended to have higher adduct levels than men . Living in central Copenhagen and surface darkness of fried meat and fish were associated with quantitative higher adduct levels . No significant associations were found between dietary factors or smoking and DNA adduct levels . Further , the results showed no prominent associations between any of 12 genetic polymorphisms and adduct levels . Overall , our study showed only few associations between dietary , environmental , and genetic factors and levels of bulky DNA adducts measured in peripheral leukocytes in a general Danish population .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20391138"}
{"sentence": "BACKGROUND Apoptosis-stimulating protein of p53 ( ASPP ) family members can stimulate the apoptotic function of p53 but have no impact on its cell cycle arrest function . MATERIAL AND METHODS The expression pattern of the ASPP family consisting of ASPP1 , ASPP2 , and iASPP was examined by immunohistochemistry in 45 formalin-fixed and paraffin-embedded endometrial endometrioid adenocarcinoma ( EEA ) specimens and 26 normal endometrial tissue ( NET ) samples . RESULTS The expression rates of ASPP1 and ASPP2 in EEA were significantly lower than those in NET ( p < 0.05 ) . However , the iASPP expression rate in EEA was statistically higher in contrast to NET ( p < 0.05 ) . Expression of ASPP1 and iASPP in EEA had no correlation with any clinicopathological features ( p > 0.05). iASPP was associated with grade , invasion , and lymph node metastasis ( p < 0.05 ) . CONCLUSIONS It is a novel finding that the expression pattern of the ASPP family members has respective pathological and clinical implications in EEA , and iASPP might be a candidate target for EEA therapy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "20926896"}
{"sentence": "A cell line designated HUUCLEC was established from a human uterine cervical lymphoepithelial carcinoma obtained from a 61-year-old Japanese woman . The cell line has grown slowly without interruption and serial passages were successively carried out 60 times within 3 years . The cultured cells were spindle or round in shape , showing anaplastic and pleomorphic features , a pavement cell arrangement and multilayering without contact inhibition . The population doubling time of the HUUCLEC line was 72 hours while the chromosomal number varied widely and showed aneuploidy . The modal chromosomal number was stable at the triploid range and marker chromosomes were present ; the Ebstein-Barr virus was absent in the cultured cells .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "12227504"}
{"sentence": "Although the immunomodulatory effects of many herbs have been extensively studied , research related to possible immunomodulatory effects of various spices is relatively scarce . Here , the potential immunomodulatory effects of black pepper and cardamom are investigated . Our data show that black pepper and cardamom aqueous extracts significantly enhance splenocyte proliferation in a dose-dependent , synergistic fashion . Enzyme-linked immunosorbent assay experiments reveal that black pepper and cardamom significantly enhance and suppress , respectively , T helper ( Th)1 cytokine release by splenocytes . Conversely , Th2 cytokine release by splenocytes is significantly suppressed and enhanced by black pepper and cardamom , respectively . Experimental evidence suggests that black pepper and cardamom extracts exert pro-inflammatory and anti-inflammatory roles , respectively . Consistently , nitric oxide production by macrophages is significantly augmented and reduced by black pepper and cardamom , respectively . Remarkably , it is evident that black pepper and cardamom extracts significantly enhance the cytotoxic activity of natural killer cells , indicating their potential anti-cancer effects . Our findings strongly suggest that black pepper and cardamom exert immunomodulatory roles and antitumor activities , and hence they manifest themselves as natural agents that can promote the maintenance of a healthy immune system . We anticipate that black pepper and cardamom constituents can be used as potential therapeutic tools to regulate inflammatory responses and prevent/attenuate carcinogenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20210607"}
{"sentence": "High-grade gliomas ( HGG ) , are the most common aggressive brain tumours in adults . Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate . To accurately evaluate response to targeted therapies further in vitro studies are necessary . Growth factor pathway expression using epidermal growth factor receptor ( EGFR ) , mutant EGFR ( EGFRvIII ) , platelet derived growth factor receptor ( PDGFR ) , C-Kit and C-Abl together with phosphatase and tensin homolog ( PTEN ) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 ( P70S6K ) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors ( TKIs ) erlotinib , gefitinib and imatinib . Response to TKIs was assessed using 50% inhibitory concentrations ( IC(50) ) . Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis ( HCA ) and principal component analysis ( PCA ) . Erlotinib response was not strongly associated with high expression of the growth factor pathway components . PTEN expression did not correlate with response to any of the three TKIs . Increased EGFR expression was associated with gefitinib response ; increased PDGFR-\u03b1 expression was associated with imatinib response . The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22285130"}
{"sentence": "BACKGROUND : CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus . In addition , CD81 has been suggested to be involved in a broad range of other cellular functions . Its putative implication in tumorigenesis has so far , however , remained largely unexplored . To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development , we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines . METHODS : The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated . RESULTS : CD81 mRNA levels were found to be low in 16 of 40 ( 40% ) primary tumors and 9 of 14 ( 64.2% ) cell lines , and these low expression levels were found to correlate with the stage and grade of the tumors . Genomic alterations of CD81 were not encountered , whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment . Bisulfite DNA sequencing analysis of 10 CpG sites within the 5 ' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation . Subsequent restoration of CD81 expression induced a G(1) cell cycle arrest and apoptosis , whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli . Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation , respectively . CD81 was found to inhibit p38 ( but not ERK , JNK and AKT ) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation . CONCLUSION : From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells , at least partially through p38 signaling .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23264205"}
{"sentence": "Osteoblastic bone metastases are the most common metastases produced by human prostate cancers ( PCa ) . Deregulated activity of Wnt growth factors resulting from overexpression of the Wnt inhibitor Dickkopf-1 ( DKK-1 ) is known to contribute to formation of the osteoblastic component of PCa skeletal bone metastases . In this study , we report that DKK-1 knockdown in osteolytic human PCa cells unexpectedly delays the development of both soft tissue and osseous lesions . PCa cells deficient in DKK-1 expression did not increase canonical Wnt signaling in target osteoblast cell lines ; however , DKK-1 knockdown PCa cells exhibited increased expression of the CDK inhibitor p21(CIP1/WAF1) and a 32% increase in G(1) arrest compared with control cells . Ablating p21(CIP1/WAF1) in PCa cells deficient in DKK-1 was sufficient to rescue tumor growth . Collectively , our findings demonstrate that DKK-1 overexpression supports tumor growth in part by restricting expression of p21(CIP1/WAF1) through a mechanism independent of canonical Wnt signaling .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21098705"}
{"sentence": "Earlier studies indicated that density-arrested cancer cells released an unidentified growth inhibitor whose secretion was prevented by overexpression of the lysosomal protease cathepsin D ( cath D ) . In this study , this growth inhibitor was purified by affinity chromatography and identified as the heat shock cognate 70 protein ( hsc70 ) based on its peptide microsequencing and specific antibody recognition . Among intracellular proteins , including other heat shock proteins , only constitutive hsc70 was secreted in response to the high-cell density . Moreover , hsc70 secretion from cancer cells was generated by serum deprivation , whereas its cellular concentration did not change . Prevention of Hsc70 secretion by cath D overexpression was associated with the formation of multilayer cell cultures , thus indicating a loss of contact inhibition . In addition , we showed that supplementing the culture medium with purified hsc70 inhibited cell proliferation in the nanomolar range . Conversely , removal of this extracellular hsc70 from the medium by either retention on ADP-agarose or competition at the Hsc70 binding site restored cell proliferation . Hsc70 appears active in human breast cancer cells and hypersecreted by direct cath D inhibition . These results suggest a new role of this secreted hsc70 chaperone in cell proliferation that might account for the higher tumor growth of cancer cells overexpressing cath D .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "19802014"}
{"sentence": "Tumor cells trigger angiogenesis through overexpression of various angiogenic factors including vascular endothelial growth factor ( VEGF ) and angiopoietin 1 ( Ang1 ) . Therefore , inhibition of the expression of both VEGF and Ang1 , the initial step of tumor angiogenesis , is a promising strategy for cancer chemoprevention and therapy . Grape seed proanthocyanidins ( GSPs ) are widely consumed dietary supplements that have antitumor activity . Due to their polymeric structure , GSPs are poorly absorbed along the gastrointestinal tract and can reach the colon at high concentrations , allowing these chemicals to act as chemopreventive agents for colon cancer . In the present study , we found that GSPs inhibited colon tumor-induced angiogenesis and , thus , the growth of colon tumor xenografts on the chick chorioallantoic membranes . The mechanisms of their action were related to inhibiting the expression of both VEGF and Ang1 through scavenging reactive oxygen species . Previous studies have demonstrated that the chemopreventive effects of GSPs on colon cancer are associated with their growth inhibitory and apoptosis-inducing effects . Our results demonstrate another mechanism by which GSPs inhibit colon tumor growth , which will be helpful for developing GSPs as a pharmacologically safe angiopreventive agent against colorectal cancer .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 1], "id": "23026853"}
{"sentence": "Breast cancer consists in a chronic inflammatory disease with multiple biological and clinical behaviors . Based on high throughput technologies data , this disease is currently classified according to the molecular expression of estrogen ( ER ) , progesterone ( PR ) and human epidermal growth factor ( HER-2 ) receptors . In this study , we defined the inflammatory profile of the main molecular subtypes of breast cancer patients : luminal ( ER and PR positive , HER-2 negative ) , HER-2 enriched ( HER-2 positive ) and triple negative ( ER , PR and HER-2 negative ) . Cytokines panel was assessed by measurement of TNF-\u03b1 , TGF-\u03b2 , IL-1 , IL-10 and IL-12 plasmatic levels . Oxidative profile was assessed by determination of lipid peroxidation , total antioxidant capacity of plasma , malondialdehyde levels , carbonyl content and nitric oxide ( NO ) . Clinical data were correlated with inflammatory findings . Our findings demonstrated that patients bearing the luminal subtype displayed high TNF-\u03b1 , TGF-\u03b2 and enhanced oxidative stress levels associated with reduced IL-12 . HER-2-enriched group exhibited higher levels of TNF-\u03b1 , IL-12 and TGF-\u03b2 associated with enhanced oxidative stress . Triple-negative subtype exhibited the most aggressive profile of disease behavior , with reduction in both TNF-\u03b1 and TGF-\u03b2 , with high levels of lipid peroxidation and NO . The clinical importance of our findings lies in the fact that the inflammatory status varies in distinct ways due to molecular subtype of breast cancer , opening potential therapeutic targets to future therapies .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22618884"}
{"sentence": "The activity of DNA methyltransferase 1 ( DNMT1 ) is associated with diverse biological activities , including cell proliferation , senescence and cancer development . Here , we demonstrated that the HMG box-containing protein 1 ( HBP1 ) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence . The DNMT1 gene contains an HBP1-binding site at position -115 to -134bp from the transcriptional start site . HBP1 repressed the endogenous DNMT1 gene through sequence-specific binding , resulting in both gene-specific ( e.g. p16(INK4) ) and global DNA hypomethylation changes . The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence , the latter of which could be induced by Ras and HBP1 itself . A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions-both of which contribute to premature senescence . HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence . The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation . While intricate , the reciprocal partnership between HBP1 and DNMT1 has exceptional importance , since its abrogation compromises senescence and promotes tumorigenesis . Together , our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence with an impact on overall DNA methylation state .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23249948"}
{"sentence": "We report the formation , detection , quantitation and structural characterization of products resulting from the adduction of deoxynucleosides ( deoxyadenosine , deoxyguanosine , deoxycytidine and 5-methyldeoxycytidine ) to the catechol estrogens ( CE ) of estrone , estradiol-17beta and estradiol-17 alpha . The crude products are obtained in a one-pot synthesis through oxidation of catechols to quinones and subsequent Michael-type reaction with the deoxynucleosides in acidic medium . In all experiments , adducts are detected by electrospray ionization mass spectrometry analysis after HPLC separation ( LC/ESI/MS(n) ) . The two pyrimidines deoxycytidine and 5-methyldeoxycytidine yield only CE adducts to deoxynucleosides , which correspond to stable adducts on DNA . For purines , the results depend on the CE ( 2,3- or 3,4-catechols ) used , the function and configuration on carbon 17 ( ketone for estrone , alcohol for alpha and beta isomers of estradiol ) , and on the purine itself ( deoxyadenosine or deoxyguanosine ) . Both stable adducts and deglycosylated adducts are formed , and therefore formation of stable adducts on DNA as well as the loss of purines from the DNA strands could be possible . MS(2) and MS(3) experiments prove to be relevant for further structural determinations , enabling in some cases the elucidation of the regiochemistry of adduction on the A and B rings of the steroid moiety .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12441195"}
{"sentence": "PURPOSE Radiation therapy appears to kill cells mainly by inducing DNA double-strand breaks . We investigated whether the DNA repair gene expression status might influence the risk of locoregional recurrence ( LRR ) in breast cancer patients . METHODS AND MATERIALS We used a quantitative reverse transcriptase PCR-based approach to measure messenger RNA levels of 20 selected DNA repair genes in tumor samples from 97 breast cancer patients enrolled in a phase III trial ( Centre Ren\u00e9 Huguenin cohort ) . Normalized mRNA levels were tested for an association with LRR-free survival ( LRR-FS ) and overall survival ( OS ) . The findings were validated in comparison with those of an independent cohort ( Netherlands Cancer Institute ( NKI ) cohort ) . Multivariate analysis encompassing known prognostic factors was used to assess the association between DNA repair gene expression and patient outcome . RESULTS RAD51 was the only gene associated with LRR in both cohorts . With a median follow-up of 126 months in the CRH cohort , the 5-year LRR-FS and OS rates were 100% and 95% in the 61 patients with low RAD51 expression , compared with 70% and 69% in the 36 patients with high RAD51 expression , respectively ( p < 0.001 ) . RAD51 overexpression was associated with a higher risk of LRR ( hazard ratio [ HR ] , 12.83 ; 95% confidence interval [ CI ] , 3.6-45.6 ) and death ( HR , 4.10 ; 95% CI , 1.7-9.7 ) . RAD51 overexpression was also significantly associated with shorter LRR-FS and OS in the NKI cohort . CONCLUSIONS Overexpression of RAD51 , a key component of the homologous DNA repair pathway , is associated with poor breast cancer outcome . This finding warrants prospective studies of RAD51 as a prognosticator and therapeutic target .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20092964"}
{"sentence": "We recently isolated an exon-4-deleted epidermal growth factor receptor ( EGFR ) variant , termed de4 EGFR . Because the extracellular domain alteration of receptors often influences the antitumor effect of therapeutic antibodies , it is essential to test the sensitivity of de4 EGFR(+) tumors to anti-EGFR antibodies . Therefore , in this study , the antitumor activities of mAb CH12 , an anti-EGFRvIII antibody developed in our laboratory , as well as a U.S. Food and Drug Administration-approved anti-EGFR antibody , cetuximab ( C225 ) , were characterized on de4 EGFR(+) models . The results of FACS assays showed that CH12 bound to de4 EGFR with a higher avidity than did C225 . Interestingly , CH12 , but not C225 , significantly inhibited the metastasis and growth of U87MG-de4 EGFR xenografts , with a growth-inhibition ratio of 46.48% in vivo , and prolonged the survival of the tumor-bearing mice by 37.2% . Treatment with CH12 significantly suppressed tumor proliferation and angiogenesis with increased tumor apoptosis . Mechanistically , de4 EGFR protein expression was virtually undetectable in the U87MG-de4 EGFR xenografts treated with CH12 . This may account for the observed reduction of Akt and Erk phosphorylation , cyclin D1 , Bcl-2 , and Bcl-x(L) expression and the increase of p27 and E-cadherin expression . Intriguingly , LAMP-1 , a major component of the lysosome , was significantly up-regulated in the CH12-treated group but not in the C225-treated group , suggesting its contribution to the degradation of de4 EGFR . Taken together , our data demonstrated that mAb CH12 is a promising therapeutic agent for treating de4 EGFR(+) gliomas .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "21917986"}
{"sentence": "The purpose of this study was to evaluate the effects of composite wound dressing films made of silk fibroin ( SF ) containing hydroxyapatite ( HA ) or polarized HA ( pHA ) powders on endothelial cell ( EC ) behaviors that have important roles in the wound-healing process . XRD revealed the SF films to be semicrystalline , with a broad peak centered at about 20.7\ufffd which is characteristic of \u03b2-sheets embedded within an amorphous matrix . The SF composite films with 0.6 ( w/v)% in concentration of HA powder ( HA/SF ) or pHA powder ( pHA/SF ) contained HA crystals of amorphous and silk II crystalline structures . SEM observation showed that there were differences in SF morphology between HA/SF and pHA/SF . The pHA/SF exhibited a furry texture around the pHA crystals , most likely due to the stored charged and zeta potentials . The HA/SF and pHA/SF films enhanced EC migration compared with that on the SF film . The number of migrated cells on the HA/SF and pHA/SF was times larger than that on the SF . The quantitative analysis of the endothelial morphogenesis indicated that the pHA/SF film enhanced the formation of capillary-like structures compared with SF and HA/SF . Thus , pHA/SF may potentially stimulate and contribute to the enhancement of angiogenesis in the wound-healing process .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22275235"}
{"sentence": "Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis . Chemotherapeutic resistance hinders successful treatment . This resistance is often associated with mutations in codon 12 of the K-Ras gene ( K-Ras 12 ) , which is present in over 90% of all pancreatic adenocarcinomas . Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation . Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate ( BITC ) . BITC is a component of cruciferous vegetables and a cell cycle inhibitor . BxPC3 , MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance . Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20559452"}
{"sentence": "Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors , including cellular immunity . We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms . However , how metastasis susceptibility genes interact with the tumor stroma is incompletely understood . Here , we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis . We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth . Unexpectedly , Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion , but required the host's adaptive immune system to affect metastasis . The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell-mediated immunity , which was partially phenocopied by depleting CD8(+) T cells in immune-competent mice . Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms , and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23028344"}
{"sentence": "The \" high-risk \" human papillomavirus types 16 ( HPV-16 ) and 18 ( HPV-18 ) have been etiologically implicated in the majority of human cervical carcinomas . In these cancers , the viral DNAs are often integrated into the host genome so that expression of the E1 and the E2 genes is lost , suggesting that disruption of these regulatory genes plays an important role in carcinogenic progression . Previous studies defining the viral genes affecting HPV-16 transformation functions have used the \" prototype \" viral genome , which was cloned from a human cervical carcinoma and later discovered to harbor a mutation in the E1 gene . In this study , we have corrected this mutation and have evaluated the effect of mutations of either the E1 or the E2 gene on the efficiency of HPV-16 immortalization of human keratinocytes . Mutation of either the E1 gene or the E2 gene in the background of a \" wild-type \" HPV-16 genome markedly increased immortalization capacity . Mutations were also generated in the E2-binding sites located upstream of the P97 promoter , which directs synthesis of the viral E6 and E7 transforming genes . E2 negatively regulates the P97 promoter through binding at adjacent sites . Surprisingly , the mutation of these sites only partially relieved the negative effect of E2 on viral immortalization , implicating additional mechanisms in the E2 repression of viral immortalization functions . Our results provide genetic evidence that the E1 and E2 gene products each can repress HPV-16 immortalization and support the hypothesis that a selective growth advantage is provided by integration of the viral genome in a manner that causes the loss of expression of either E1 or E2 .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "1313584"}
{"sentence": "Approximately 10% of the U.S. population ingests <50% of the current recommended daily allowance for zinc . We investigate the effect of zinc deficiency on DNA damage , expression of DNA-repair enzymes , and downstream signaling events in a cell-culture model . Low zinc inhibited cell growth of rat glioma C6 cells and increased oxidative stress . Low intracellular zinc increased DNA single-strand breaks ( comet assay ) . Zinc-deficient C6 cells also exhibited an increase in the expression of the zinc-containing DNA-repair proteins p53 and apurinic endonuclease ( APE ) . Repletion with zinc restored cell growth and reversed DNA damage . APE is a multifunctional protein that not only repairs DNA but also controls DNA-binding activity of many transcription factors that may be involved in cancer progression . The ability of the transcription factors p53 , nuclear factor kappaB , and activator protein 1 ( AP1 ) to bind to consensus DNA sequences was decreased markedly with zinc deficiency , as assayed by electrophoretic mobility-shift assays . Thus , low intracellular zinc status causes oxidative DNA damage and induces DNA-repair protein expression , but binding of p53 and important downstream signals leading to proper DNA repair are lost without zinc .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12481036"}
{"sentence": "Hepatocellular carcinoma ( HCC ) is the most common primary malignant tumor that accounts for of all liver cancer cases worldwide . It is a multifactorial disease caused by a variety of risk factors and often develops in the background of underlying cirrhosis . A number of cellular phenomena , such as tumor microenvironment , inflammation , oxidative stress , and hypoxia act in concert with various molecular events to facilitate tumor initiation , progression , and metastasis . The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease . Intense research in this multitude of areas has led to significant progress in our understanding of cellular processes and molecular mechanisms that occur during multistage events that lead to hepatocarcinogenesis . In this review , we discuss the current knowledge of HCC , focusing mainly on advances that have occurred during the past 5years and on the development of novel therapeutics for liver cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23007558"}
{"sentence": "OBJECTIVES To investigate the expression of TLR-4 ( toll-like receptor ) on human cervical cancer and find the biological function of the TLR-4 signal system . METHODS The immunohistochemistry method was performed to study the protein expression and distribution of TLR-4 . The viability of HeLa cells was determined by cell viability assay . Cell proliferation was detected by FCM , ELISA and Western blot were used to observe the gene and protein expression of IL-6 and TGF-beta1 in Hela cell lines . RESULTS TLR-4 was over-expressed in cervix cancer , and its activation by LPS promotes proliferation and anti-apoptosis in Hela cells in vitro . Moreover the cell line proliferation increased in a dose- and time-dependent manner . The production of IL-6 and TGF-beta1 were promoted through the activation of the NF-kappaB signaling pathway .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22873102"}
{"sentence": "Eukaryotic High-Mobility Group B ( HMGB ) proteins alter DNA elasticity while facilitating transcription , replication and DNA repair . We developed a new single-molecule method to probe non-specific DNA interactions for two HMGB homologs : the human HMGB2 box A domain and yeast Nhp6Ap , along with chimeric mutants replacing neutral N-terminal residues of the HMGB2 protein with cationic sequences from Nhp6Ap . Surprisingly , HMGB proteins constrain DNA winding , and this torsional constraint is released over short timescales . These measurements reveal the microscopic dissociation rates of HMGB from DNA . Separate microscopic and macroscopic ( or local and non-local ) unbinding rates have been previously proposed , but never independently observed . Microscopic dissociation rates for the chimeric mutants ( s(-1) ) are higher than those observed for wild-type proteins ( s(-1) ) , reflecting their reduced ability to bend DNA through short-range interactions , despite their increased DNA-binding affinity . Therefore , transient local HMGB-DNA contacts dominate the DNA-bending mechanism used by these important architectural proteins to increase DNA flexibility .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23143110"}
{"sentence": "SET and MYND domain-containing protein 3 ( SMYD3 ) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis . It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes , including several oncogenes ( e.g. , N-myc , CrkL , Wnt10b , RIZ and hTERT ) and genes involved in the control of cell cycle ( e.g. , CyclinG1 and CDK2 ) and signal transduction ( e.g. , STAT1 , MAP3K11 and PIK3CB ) . To determine the effects of SMYD3 over-expression on cell proliferation , we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar . Besides , we show here that down-regulation of SMYD3 could induce G1-phase cell cycle arrest , indicating the potent induction of apoptosis by SMYD3 knockdown . These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "20957523"}
{"sentence": "BACKGROUND Knowledge of gene expression kinetics around neuronal cell birth is required to dissect mechanisms underlying progenitor fate . Here , we timed cell cycle and neuronal protein silencing/induction during cell birth in the developing murine retina . RESULTS The pan-cell cycle markers Pcna and Mcm6 were present in the post-mitotic ganglion cell layer . Although confined to the neuroblastic layer ( NBL ) , 6-7% of Ki67(+) cells lacked six progenitor/cell cycle markers , and expressed neuronal markers . To define protein extinction/induction timing , we defined G2/M length throughout retinogenesis , which was typically 1-2 h , but <10% cells took double this time . BrdU-chase analyses revealed that at E12.5 , Tubb3 ( Tuj1 ) appeared at M-phase , followed by Calb2 and Dcx at h , Elavl2/3/4 at h , and Map2 at h after cell birth , and these times extended with embryonic age . Strikingly , Ki67 was not extinguished until up to a day after cell cycle exit , coinciding with exit from the NBL and induction of late markers such as Map1b/Uchl1/Rbfox3 . CONCLUSIONS A minor population of progenitors transits slowly through G2/M and , most importantly , some cell cycle proteins are retained for an unexpectedly long period in post-mitotic neurons . The high-resolution map of cell birth kinetics reported here provides a framework to better define mechanisms that regulate neurogenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22837015"}
{"sentence": "BACKGROUND Phosphorylation of the H2AX histone is an early indicator of DNA double-strand breaks and of the resulting DNA damage response . In the present study , we assessed the expression and prognostic significance of \\u03b3-H2AX in a cohort of 96 patients with operable non-small cell lung carcinoma . METHODS Ninety-six paraffin-embedded specimens of non-small cell lung cancer patients were examined . All patients underwent radical thoracic surgery of primary tumor ( lobectomy or pneumonectomy ) and regional lymph node dissection. \\u03b3-H2AX expression was assessed by standard immunohistochemistry . Follow-up was available for all patients ; mean duration of follow-up was 27.50 \u00b1 14.07 months ( range 0.2-57 months , median 24 months ) . RESULTS Sixty-three patients ( 65.2% ) died during the follow-up period . The mean survival time was 32.2 \u00b1 1.9 months ( 95% confidence interval [ CI ] : 28.5-35.8 months ; median 30.0 months ) ; 1- , 2- and 3-year survival rates were 86.5% \u00b1 3.5% , 57.3% \u00b1 5.1% , and 37.1% \u00b1 5.4% , respectively . Low \\u03b3-H2AX expression was associated with a significantly better survival as compared with those having high \\u03b3-H2AX expression ( 35.3 months for low \\u03b3-H2AX expression versus 23.2 months for high \\u03b3-H2AX expression , P = 0.009 ; hazard ratio [ HR ] 1.95 , 95% CI : 1.15-3.30 ) . Further investigation with multivariate Cox proportional hazards regression analysis revealed that high expression of \\u03b3-H2AX remained an independent prognostic factor of shorter overall survival ( HR 2.15 , 95% CI : 1.22-3.79 , P = 0.026 ) . A combined p53/\\u03b3-H2AX analysis was performed , and we found that the p53 low/\\u03b3-H2AX low phenotype was associated with significantly better survival compared with all other phenotypes . CONCLUSION Our study is the first to demonstrate that expression of \\u03b3-H2AX detected by immunohistochemistry may represent an independent prognostic indicator of overall survival in patients with non-small cell lung cancer . Further studies are needed to confirm our results .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23180966"}
{"sentence": "Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells . This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell . Why cancer cells are defective in contact inhibition of locomotion is not understood . Here , we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts , and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited . The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2 , which we show activates Cdc42 and cell migration . Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells . Conversely , homotypic collisions between two cancer cells results in contact inhibition of locomotion , mediated by EphA-Rho-Rho kinase ( ROCK ) signalling . Thus , the migration of cancer cells can switch from restrained to invasive , depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21076414"}
{"sentence": "The Salvador/Warts/Hippo ( Hippo ) signaling pathway defines a novel signaling cascade regulating cell contact inhibition , organ size control , cell growth , proliferation , apoptosis and cancer development in mammals . The upstream regulation of this pathway has been less well defined than the core kinase cassette . KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP , but functional consequences of these biochemical changes have not been previously addressed . We show that in MCF10A cells , loss of KIBRA expression displays epithelial-to-mesenchymal transition ( EMT ) features , which are concomitant with decreased LATS and YAP phosphorylation , but not MST1/2 . In addition , ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA , Willin and Merlin differentially regulate genes controlled by YAP . Finally , reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype , an aggressive sub-group with EMT features and a poor prognosis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22614006"}
{"sentence": "The protein nanopore Mycobacteria smegmatis porin A ( MspA ) , can be used to sense individual nucleotides within DNA , potentially enabling a technique known as nanopore sequencing . In this technique , single-stranded DNA electrophoretically moves through the nanopore and results in an ionic current that is nucleotide-specific . However , with a high transport velocity of the DNA within the nanopore , the ionic current cannot be used to distinguish signals within noise . Through extensive ( \\u03bcs in total ) all-atom molecular dynamics simulations , we examine the effect of positively charged residues on DNA translocation rate and the ionic current blockades in MspA . Simulation of several arginine mutations show a fold reduction of DNA translocation speed without eliminating the nucleotide induced current blockages . Comparison of our results with similar engineering efforts on a different nanopore ( \\u03b1-hemolysin ) reveals a nontrivial effect of nanopore geometry on the ionic current blockades in mutant nanopores .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22747101"}
{"sentence": "MCF-7 human breast cancer cells propagated in vitro were treated with adenosine derivatives added to the culture medium . The effects on cell proliferation , glycolysis , and glutaminolysis were investigated . Of all adenosine derivatives tested , AMP was the most efficient inhibitor of cell proliferation . In AMP-treated cells , DNA synthesis decreased , whereas RNA and protein syntheses rose normally with time . In terms of carbohydrate metabolism , lactate production from glucose was drastically reduced ; therefore , most of lactate produced must have been derived from glutamine . Increases in the enzyme activities involved in glutamate degradation and in the malate-aspartate shuttle were observed . In contrast , actual glycolytic flux rates declined , whereas key glycolytic enzyme activities increased . Metabolites such as fructose 1,6-bisphosphate and pyruvate accumulated in AMP-arrested cells . Based on the lowered NAD level in the AMP-treated cells , lactate dehydrogenase , but not malate dehydrogenase , was impaired ; thereby the whole of glycolysis was inhibited . In compensation , glutamine catabolism was increased . NAD concentrations fell drastically because of the known inhibition of P-ribose-PP synthesis through heightened intracellular AMP levels . A hypothetical metabolic scheme to explain these results and to show how extracellular AMP may influence carbohydrate metabolism and cell proliferation is presented .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "1447315"}
{"sentence": "The cytotoxic activity of cyclosporin A ( CsA ) and the three non-immuno-suppressive CsA analogues B3-243 , WO-039 and B3-665 were studied in tumor cell lines representing both classical and atypical forms of multidrug resistance ( MDR ) : T-ALL GM3639 L100 cells selected for vincristine ( vcr ) resistance and displaying characteristics of classical MDR , including P-glycoprotein ( pgp ) expression and increased drug efflux which can be inhibited by pgp blockers ( e.g. verapamil ) , and U-1285/ADR , a small cell lung cancer ( SCLC ) cell line selected for doxorubicin resistance which lacks pgp , is insensitive to pgp-blockers and shows cross resistance to cis-platinum . At 1 micrograms/ml CsA was the most active agent in reversing Vcr resistance in L100 cells followed by B3-243 and WO-039 , with no effect of B3-665 . Parental LO cells were only marginally sensitized to Vcr by these agents . No reversing effect of any cyclosporin was observed in the U-1285/ADR or its parental cell line . Compared to LO cells , L100 cells showed a marked hypersensitivity to CsA > B3-243 > WO-039 with B3-665 being inactive . No collateral sensitivity was observed for cyclosporins in U-1285/ADR cells . Although of different magnitude , the pattern of cytotoxic activity for the different cyclosporins alone closely parallelled that of L100 cells for U-1285 , U1285/ADR and LO cells . The results indicate that not only the collateral sensitivity in classical MDR but also the cytotoxic actions of cyclosporins per se on tumor cells alone are independent of immunosuppressive activity . The results also suggest a structure-activity relationship for cyclosporin-induced cytotoxicity similar to , but independent of , MDR reversing activity .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1444225"}
{"sentence": "OBJECTIVES The aim of this study is to examine the expression of MCM-2 and conventional proliferation marker Ki-67 in breast carcinoma by stereologic technique and to compare it with various clinicopathologic parameters . METHODS The expression of MCM-2 and Ki-67 on paraffin-embedded tumor tissue sections of patients with invasive breast carcinoma was analyzed immunohistochemically . Stereologic method was used for evaluation of the percentage of positively stained tumor cells . RESULTS Significant positive correlation was found between the expression of MCM-2 and that of Ki-67 ( r = 0.74 , p < 0.001 ) . MCM-2 and Ki-67 expression was significantly associated with histologic grade ( p < 0.05 ) , and negative correlation was observed between MCM-2 or Ki-67 expression and estrogen status ( p < 0.05 ) . No significant association was observed between MCM-2 or Ki-67 expression and patient age , tumor size , lymph node status , clinical stage and menopausal status . CONCLUSION Our results suggest that MCM-2 expression is significantly associated with histologic grade of breast carcinoma and with cell proliferation capacity ( Ki-67 labelling index ) . Additional studies are required using the stereologic method to compare and understand the utility of Ki-67 and MCM-2 expression in invasive breast carcinoma ( Tab. 1 , Fig. 4 , Ref. 34 ) . Full Text ( Free , PDF ) www.bmj.sk .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20429312"}
{"sentence": "BACKGROUND Insulin-like growth factor I ( IGF-I ) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor . The major binding protein for IGF-I , insulin-like growth factor-binding protein 3 ( IGFBP-3 ) , modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor . In a prospective study of men in Shanghai , China , we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer . METHODS From 1986 to 1989 , serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer . We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects . RESULTS Among 230 case patients and 659 matched control subjects , increased IGF-I levels were not associated with increased risk of lung cancer . However , for subjects in the highest quartile relative to the lowest quartile of IGFBP-3 , the odds ratio ( OR ) for lung cancer , adjusted for smoking and IGF-I , was 0.50 ( 95% confidence interval [ CI ] = 0.25 to 1.02 ) . When the analysis was restricted to ever smokers ( 184 case patients and 344 matched control subjects ) , the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile , adjusted for smoking and IGF-I , was 0.41 ( 95% CI = 0.18 to 0.92 ) . CONCLUSIONS In this prospective study of Chinese men , higher serum levels of IGF-I did not increase the risk of lung cancer . However , subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer . This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12011225"}
{"sentence": "A6 is an eight amino acid peptide derived from the non-receptor binding region of urokinase plasminogen activator ( uPA ) , which interferes with the uPA/uPA receptor system . A6 has been synthesized as a potential anti-angiogenic , anti-cancer agent . The current study has investigated the potential therapeutic activity of A6 in the Lewis lung carcinoma ( 3LL ) model of pulmonary metastasis . A6 was found to have direct anti-tumor activity against established 3LL pulmonary metastases at a low tumor burden ( 10-20 colonies per lung ) and was therapeutic in combination with cyclophosphamide at high tumor burdens ( > 100 colonies per lung ) . Mechanistic studies have revealed that A6 directly inhibits the invasion of 3LL cells through a Matrigel model basement membrane by 40-45% . Moreover , treatment with either A6 or doxorubicin resulted in thicker tubes in endothelial tube formation studies . Our results suggest that A6 , by virtue of its anti-invasive and anti-angiogenic properties , might work additively or synergistically with chemotherapeutic agents and thereby contribute to enhanced therapy of established 3LL cancer metastases .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12494889"}
{"sentence": "We have previously reported the frequent occurrence of bile duct invasion by liver metastases from colorectal cancer . We found that patients with macroscopic intrabiliary cancer growth survive longer after hepatectomy than those without this feature . In the present study , we analyzed the clinicopathological features of primary colorectal cancer showing macroscopic intrabiliary extension of liver metastases . We reviewed 217 patients who underwent initial hepatic resection for colorectal liver metastasis between 1992 and 1998 , and analyzed the corresponding primary colorectal cancers clinicopathologically . Microscopic bile duct invasion was found in 89 of 217 cases ( 40.6% ) and , of these cases , 23 ( 10.6% ) had macroscopic intrabiliary extension . Histological sections of the corresponding primary colorectal cancer were available in eight ( group A ) of these 23 cases . These were compared with 20 cases , selected randomly , of colorectal cancer that did not show bile duct invasion and were diagnosed as liver metastases . These patients underwent hepatectomy during the same period as group A and were used as a control ( group B ) . The histology of the primary tumors revealed well-differentiated adenocarcinoma in 100% of group A and in 25% of group B. The average maximum diameter of the primary tumor was 5.32 cm in group A and 3.61 cm in group B. Venous invasion was detected in 25% of group A and in 90% of group B ( P < 0.01 ) , while the incidences of lymphatic vessel invasion and lymph node metastases were similar between the groups . These data suggest that macroscopic intrabiliary extension could be a good indicator of a unique subgroup of colorectal cancers showing less aggressive features even though they develop liver metastases . Careful histological evaluation is important even for metastatic tumors .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12366810"}
{"sentence": "Between 1965 and 1985 , 489 patients with advanced gastric cancer who were treated with gastric resection and in whom tumor cells remained after the operation were defined as cases of a \" noncurative resection. \" The clinicopathological features and prognosis of these patients were examined and two groups were prepared : locally advanced cancer and cancer with a distant metastasis . In locally advanced cancer cases , tumor cells remained in the neighboring organs , lymph nodes , and/or resected margins ; in those with distant metastasis , peritoneal dissemination and/or liver metastasis were present regardless of whether or not the metastasis was removed , with or without locally noncurative factors . Serosal invasion was prominent and high rates of lymph node metastasis and lymphatic involvement were evident in both groups . The survival rate for patients with locally advanced gastric cancer was better than that of patients with distant metastasis ( P < 0.01 ) . Survival time in patients with locally advanced cancer can be lengthened by resecting all of the primary tumor and as much of the metastatic lesions as possible , even if the surgical management is \" noncurative. \" Aggressive postoperative chemotherapy for patients with distant metastasis from a gastric cancer is to be recommended .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1434651"}
{"sentence": "The purpose of this study was to generate a selective radiosensitising effect by the intra-hepatic-arterial infusion of misonidazole ( MISO ) . MISO ( 10 mg ) was infused after transcatheter hepatic-arterial embolisation into the livers of rabbits bearing VX2 liver cancer . This procedure was followed by 15 Gy electron irradiation . Evaluation of tumour volume and histological examination was carried out on the 7th day after treatment . The greatest tumour response was obtained in the group which received MISO followed by radiation and was characterised by extensive fibrosis around the tumour and nearly complete tumour necrosis . Liver cell regeneration was also noted in adjacent liver tissue . The advantages of regional infusion of MISO following hepatic-arterial embolisation are : ( 1 ) Selectivity increased radiosensitivity of liver cancer alongside very low drug concentration in the plasma . ( 2 ) Reduced or absent deleterious side effects of MISO with higher tumour/normal tissue ratios of drug concentration . ( 3 ) Reduced cost due to the lower dosage of MISO required for regional infusion .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1457353"}
{"sentence": "Tricyclic antidepressants , such as amitriptyline ( Elavil ) , and the nontricyclic agent , fluoxetine ( Prozac ) , bind to growth-regulatory intracellular histamine receptors , associated with anti-estrogen binding sites in microsomes and nuclei . The prototype anti-estrogen binding site/intracellular histamine receptor ligand , N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl , inhibits normal cell proliferation in vitro but stimulates tumor growth in vivo . Because of their structural similarity to N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl , we carried out studies to determine whether amitriptyline and fluoxetine stimulate tumor growth and/or development in rodents at concentrations relevant to the treatment of human depression ( equivalent human dose range , approximately 100-150 mg/day for amitriptyline and approximately 20-80 mg/day for fluoxetine ) . All experiments were performed blinded . In studies of growth stimulation of transplantable syngeneic tumors , groups of mice were inoculated s.c. with C-3 fibrosarcoma cells or given i.v. or s.c. injections of B16f10 melanoma cells , followed 24 h later by daily i.p. injections of saline , amitriptyline , or fluoxetine . Tumor latency ( fibrosarcoma ) , aggregate tumor weight ( s.c. injected melanoma ) , or time to death from pulmonary metastasis ( i.v. injected melanoma ) was determined ; drug-induced stimulation of DNA synthesis in C-3 fibrosarcoma cells in vitro was correlated with tumor growth acceleration in vivo . In a mammary carcinogenesis model , the effects of chronic saline , amitriptyline , or fluoxetine administration on the rate and frequency of development of mammary tumors in rats fed dimethylbenzanthracene ( DMBA ) were compared . Eight of 20 amitriptyline- or fluoxetine-treated mice developed fibrosarcoma tumors by day 5 , as compared to none of 20 saline controls ( P less than 0.002 ) . Similarly , 20 of 21 DMBA-treated rats receiving the antidepressant drugs developed 33 mammary tumors by week 15 as compared to 5 tumors in 4 of 7 DMBA-treated rats receiving saline ( P less than 0.001 ) . For both models , tumor latency decreased 30-40% and , in the DMBA model , tumor frequency increased greater than 2-fold in the antidepressant-treated rats as compared to controls . Stimulation of fibrosarcoma growth in vivo correlated with a corresponding bell-shaped drug-induced increase in DNA synthesis in vitro . While the median time to death from pulmonary metastases did not differ among groups given i.v. injections of melanoma cells , a significant ( P less than 0.01 ) stimulation of growth of s.c. injected melanoma was observed in mice receiving the antidepressants.(ABSTRACT TRUNCATED AT 400 WORDS )", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1617649"}
{"sentence": "Fifty-six previously untreated stage-I ( according to Rai ) chronic lymphocytic leukemia ( CLL ) patients were examined for their clinical data , immunological characteristics , and hormonal values . Dysfunction of T and B lymphocytes was demonstrated by changed lymphocyte blastogenic response to stimulation with phytohemagglutinin ( PHA ) , concanavalin A ( ConA ) , pisum sativatum agglutinin ( PSA ) , wheat germ agglutinin ( WGA ) , recombinant interleukin 2 ( IL 2 ) , and dextran sulfate ( DxS ) ; also by decreased immunoglobulin levels ( IgG , IgA , IgE ) and increased beta 2-microglobulin ( beta 2-M ) values . Simultaneously , dysregulation of the hypothalamic-pituitary-adrenal axis , immune system integration , imbalance of sex hormones , and changes in thyroid hormones were observed in the same group of patients . Disturbed immunohormonal interactions in early-stage CLL may be responsible for the pathogenetic mechanisms in this lymphoproliferative malignancy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1457579"}
{"sentence": "BACKGROUND Multiple myeloma ( MM ) is a fatal plasma cell malignancy exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype ( i.e. , the Warburg effect ) . We have previously demonstrated that myeloma cells exhibit constitutive plasma membrane ( PM ) localization of GLUT4 , consistent with the dependence of MM cells on this transporter for maintenance of glucose consumption rates , proliferative capacity , and viability . The purpose of this study was to investigate the molecular basis of constitutive GLUT4 plasma membrane localization in MM cells . FINDINGS We have elucidated a novel mechanism through which myeloma cells achieve constitutive GLUT4 activation involving elevated expression of the Rab-GTPase activating protein AS160_v2 splice variant to promote the Warburg effect . AS160_v2-positive MM cell lines display constitutive Thr642 phosphorylation , known to be required for inactivation of AS160 Rab-GAP activity . Importantly , we show that enforced expression of AS160_v2 is required for GLUT4 PM translocation and activation in these select MM lines . Furthermore , we demonstrate that ectopic expression of a full-length , phospho-deficient AS160 mutant is sufficient to impair constitutive GLUT4 cell surface residence , which is characteristic of MM cells . CONCLUSIONS This is the first study to tie AS160 de-regulation to increased glucose consumption rates and the Warburg effect in cancer . Future studies investigating connections between the insulin/IGF-1/AS160_v2/GLUT4 axis and FDG-PET positivity in myeloma patients are warranted and could provide rationale for therapeutically targeting this pathway in MM patients with advanced disease .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24280290"}
{"sentence": "Immunosuppressive oligodeoxynucleotides ( SupODNs ) containing repetitive TTAGGG motifs reduce inflammation and , thus , may have an impact on inflammation\u2011related tumor growth . In this study , we found a significant antiproliferative effect of Sup ODNs on the A549 non\u2011small cell lung cancer ( NSCLC ) cell line compared to those treated with control ODNs ( p<0.05 ) . Sup-ODN-mediated G1 phase cell cycle arrest was achieved via inhibition of Akt and extracellular signal-regulated kinase 1/2 phosphorylation and the p15INK4b and p27KIP1/retinoblastoma protein pathway . In addition , Sup ODNs induced apoptosis and enhanced apoptosis when combined with vinorelbine . In a setting similar to clinical use of multidrug chemotherapy for advanced NSCLC , these effects were investigated by using Sup ODNs in combination with conventional anticancer drugs . Sup ODNs had a significant synergistic effect with 5-fluorouracil , vinorelbine , gemcitabine , paclitaxel and irinotecan , with a mean combination index of 0.43-0.78 ( <1.0 indicates synergism ) in the A549 NSCLC cell line . In conclusion , our results showed that Sup ODNs have an anticancer effect and increase the sensitivity of NSCLC cells to conventional anticancer drugs by modifying Akt and the extracellular signal-regulated kinase 1/2 pathway . Thus , Sup ODNs may serve as a novel therapeutic strategy for NSCLC patients .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23291718"}
{"sentence": "Nitric oxide ( NO ) shows tumoricidal activity . We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway , but upregulates the MEK/ERK pathway downstream of growth factor signaling . We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone . We determined the effects of S-nitrosoglutathione ( GSNO , NO-donor ) and U0126 ( MEK inhibitor ) on insulin-like growth factor-I ( IGF-I ) and epidermal growth factor ( EGF ) signaling , proliferation and invasion in cancer cell lines . GSNO inhibits phosphorylation of IGF-I receptor ( IGF-IR ) , EGF receptor ( EGFR ) and Akt , but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF . On the other hand , U0126 inhibits phosphorylation of ERK1/2 , but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells . The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR , EGFR , Akt and ERK1/2 after stimulation by IGF-I and EGF . GSNO as well as U0126 , inhibits the proliferation of MIAPaCa-2 , HCT-116 , Panc-1 , MCF-7 , HT-29 and AGS cells in a dose-dependent manner . GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells . These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22025280"}
{"sentence": "AIMS Cisplatin-induced nephrotoxicity is associated with increased oxidative stress and inflammatory cytokines in the kidney . Epigallocatechin-3-gallate ( EGCG ) has anti-oxidant , anti-inflammatory , and anti-tumorigenic properties . In this study , we investigated the effects of EGCG on cisplatin-induced nephrotoxicity and potential mechanisms by which it enhances antioxidant activities and resolves inflammation after EGCG treatment during cisplatin-induced nephrotoxicity . MAIN METHODS Twenty-eight rats were divided into four groups as control ( group 1 ; no treatment ; n=7 ) , EGCG ( group 2 ; n=7 ) , cisplatin ( group 3 ; n=7 ) or cisplatin and EGCG ( group 4 ; n=7 ) . After 2 days of EGCG treatment at a dose of l00 mg/kg BW , rats were treated with a single i.p. injection of cisplatin ( 7 mg/kg BW ) . On day 12 ( 10days after the cisplatin treatment ) , all rats were sacrificed by cervical dislocation . The level of protein was examined by Western blotting . KEY FINDINGS Cisplatin caused a significant decrease in the expression nuclear levels of NF-E2-related factor-2 ( Nrf2 ) , heme oxygenase-1(HO-1) , and an increase in the levels of nuclear factor-kappa B ( NF-kappaB p65 ) and 4-hydroxynonenal ( HNE ) an oxidative stress marker . EGCG supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing levels of Nrf-2 and HO-1 , and decreasing levels of NF-kappaB and HNE . Renal activities of antioxidant enzymes ( catalase , superoxide dismutase , glutathione peroxidase ) and glutathione were significantly lower in cisplatin-treated rats compared with control rats , and EGCG treatment significantly increased the activities of antioxidant enzymes and glutathione ( P<0.001 ) . SIGNIFICANCE The results suggest that Nrf2/HO-1 signaling pathway may be the primary target for prevention of cisplatin-induced nephrotoxicity by EGCG , and that reduces it inflammation by inhibiting NF-kappaB .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20619277"}
{"sentence": "Nucling is a stress-inducible protein associated with apoptosomes . The cytochrome c-triggered formation of apoptosomes represents a key-initiating event in apoptosis . We have recently reported that Nucling regulates the apoptotic pathway by controlling the activation of NF-kappaB as well . Here we show that hepatocellular carcinoma ( HCC ) arising spontaneously against a background of hepatitis occurred more frequently in Nucling-knockout ( KO ) mice than wild-type ( WT ) mice . Biochemical serum testing revealed potential liver dysfunction with hypercholesterolemia in Nucling-KO males . In the background of Nucling-KO mice , we observed the up-regulation of TNFalpha , spontaneous NF-kappaB-activation and the induction of galectin-3 expression in liver . In addition , we observed a decrease in the number of Kupffer cells ( KCs ) in the KO mice . KCs are important for the hepatic immune system , acting as phagocytes or antigen-presenting cells ( APCs ) . We found that KCs in Nucling-KO mice were apoptotic possibly through the up-regulation of TNFalpha . These observations indicate that Nucling is important for the regulation of NF-kappaB signals in liver . We propose that Nucling deficiency could be a powerful tool to reveal the NF-kappaB-related molecular networks leading to hepatitis and HCC development .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "19637241"}
{"sentence": "Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia . Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells , it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors . More than a metabolic waste , the lactate anion is known to participate to cancer aggressiveness , in part through activation of the hypoxia-inducible factor-1 ( HIF-1 ) pathway in tumor cells . Whether lactate may also directly favor HIF-1 activation in endothelial cells ( ECs ) thereby offering a new druggable option to block angiogenesis is however an unanswered question . In this study , we therefore focused on the role in ECs of monocarboxylate transporter 1 ( MCT1 ) that we previously identified to be the main facilitator of lactate uptake in cancer cells . We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis . Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 ( VEGFR2 ) and basic fibroblast growth factor ( bFGF ) expression . Furthermore , using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry , we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects . Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells , the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22428047"}
{"sentence": "UNLABELLED BACKGROUND We aimed to develop a mouse spontaneous liver metastasis model from an orthotopically implanted human colon cancer cell line stably expressing a human sodium/iodide symporter ( NIS ) reporter gene , which can be imaged with single-photon emission computed tomography ( SPECT ) using 99mTcO4- . METHODS A recombinant plasmid containing a constitutively driven NIS gene ( pcDNA3-NIS ) was transfected into the human colon cancer cell line HCT116 , and stable cell lines were established . The stable cells were subcutaneously injected into the nude mice . When the diameter reached 10\u2009mm , the xenografts were excised , cut into small fragments , and orthotopically implanted into the cecal walls of another nude mice. 99mTcO4- SPECT/CT imaging was initiated 8\u2009weeks later and repeated every 1 to 2\u2009weeks . RESULTS The production and function of NIS protein was confirmed in vitro by Western blotting and 99mTcO4- uptake assay . On SPECT/CT imaging , focal 99mTcO4- uptake was detected in the liver . Necropsy revealed local growth of the orthotopic colon xenografts with extensive invasion , microscopic serosal metastasis , and metastatic foci in the corresponding hepatic regions showing focal 99mTcO4- uptake . Immunohistochemistry revealed high levels of NIS expression in cells forming liver tumor , indicating that the liver tumor cells originated from the orthotopic colon xenografts . CONCLUSIONS The present proof-of-concept study provided a rationale for employing a radionuclide reporter gene for the specific visualization of spontaneous liver metastasis in living mice . This unique animal model of clinically relevant and externally detectable liver metastasis will be a powerful tool for investigating tumor biology and developing novel therapies for cancer metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22953701"}
{"sentence": "Annexin II is secreted into the extracellular environment , where , via interactions with specific proteases and extracellular matrix proteins , it participates in plasminogen activation , cell adhesion , and tumor metastasis and invasion . However , mechanisms regulating annexin II transport across the cellular membrane are unknown . In this study , we used coimmunoprecipitation to show that Annexin-II was bound to insulin and insulin-like growth factor-1 ( IGF-1 ) receptors in PC12 cells and NIH-3T3 cells overexpressing insulin ( NIH-3T3(IR) ) or IGF-1 receptor ( NIH-3T3(IGF-1R) ) . Stimulation of insulin and IGF-1 receptors by insulin caused a temporary dissociation of annexin II from these receptors , which was accompanied by an increased amount of extracellular annexin II detected in the media of PC12 , NIH-3T3(IR) , and NIH-3T3(IGF-1R) cells but not in that of untransfected NIH-3T3 cells . Activation of a different growth factor receptor , the platelet-derived growth factor receptor , did not produce such results . Tyrphostin AG1024 , a tyrosine kinase inhibitor of insulin and IGF-1 receptor , was shown to inhibit annexin II secretion along with reduced receptor phosphorylation . Inhibitors of a few downstream signaling enzymes including phosphatidylinositol 3-kinase , pp60c-Src , and protein kinase C had no effect on insulin-induced annexin II secretion , suggesting a possible direct link between receptor activation and annexin II secretion . Immunocytochemistry revealed that insulin also induced transport of the membrane-bound form of annexin II to the outside layer of the cell membrane and appeared to promote cell aggregation . These results suggest that the insulin receptor and its signaling pathways may participate in molecular mechanisms mediating annexin II secretion .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12431980"}
{"sentence": "It is well known that ErbB2 , a receptor tyrosine kinase , localizes to the plasma membrane . Here we describe a novel observation that ErbB2 also localizes in mitochondria of cancer cells and patient samples . We found that ErbB2 translocates into mitochondria through association with mtHSP70 . Additionally , mitochondrial ErbB2 ( mtErbB2 ) negatively regulates mitochondrial respiratory functions . Oxygen consumption and activities of complexes of the mitochondrial electron transport chain were decreased in mtErbB2-overexpressing cells . Mitochondrial membrane potential and cellular ATP levels were also decreased . In contrast , mtErbB2 enhanced cellular glycolysis . The translocation of ErbB2 and its impact on mitochondrial function are kinase dependent . Interestingly , cancer cells with higher levels of mtErbB2 were more resistant to the ErbB2-targeting antibody trastuzumab . Our study provides a novel perspective on the metabolic regulatory function of ErbB2 and reveals that mtErbB2 has an important role in the regulation of cellular metabolism and cancer cell resistance to therapeutics .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23232401"}
{"sentence": "Photodynamic Therapy ( PDT ) involves the administration of a tumor localizing photosensitizing agent , which upon activation with light of an appropriate wavelength leads to the destruction of the tumor cells . The aim of the present study was to determine the efficacy of erythrosine as a photosensitizer for the PDT of oral malignancies . The drug uptake kinetics of erythrosine in malignant ( H357 ) and pre-malignant ( DOK ) oral epithelial cells and their susceptibility to erythrosine-based PDT was studied along with the determination of the subcellular localization of erythrosine . This was followed by initial investigations into the mechanism of cell killing induced following PDT involving both high and low concentrations of erythrosine . The results showed that at 37 \u00b0C the uptake of erythrosine by both DOK and H357 cells increased in an erythrosine dose dependent manner . However , the percentage of cell killing observed following PDT differed between the 2 cell lines ; a maximum of of DOK cell killing was achieved as compared to killing for H357 cells . Both the DOK and H357 cell types exhibited predominantly mitochondrial accumulation of erythrosine , but the mitochondrial trans-membrane potential ( \u0394\u03a8(m) ) studies showed that the H357 cells were far more resistant to the changes in \u0394\u03a8(m) when compared to the DOK cells and this might be a factor in the apparent relative resistance of the H357 cells to PDT . Finally , cell death morphology and caspase activity analysis studies demonstrated the occurrence of extensive necrosis with high dose PDT in DOK cells , whereas apoptosis was observed at lower doses of PDT for both cell lines . For H357 cells , high dose PDT produced both apoptotic as well as necrotic responses . This is the first instance of erythrosine-based PDT's usage for cancer cell killing .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22485174"}
{"sentence": "OBJECTIVE To investigate a potential mechanism of invasion and metastasis of oral cancers , and the possibility of the adhesion molecules being markers for evaluating the prognosis of oral cancers . METHODS Randomly selecting achieved paraffin blocks , including 60 cases of squamous cell carcinoma(SCC) , 30 cases of verrucous carcinoma(VC) of oral mucosa and 30 cases of basal cell carcinoma ( BCC ) of epidermis . All cases were followed up . Using immunohistochemistry method ( Envision ) to detect the expression of E-cadherin antibody and observe under light microscope . RESULTS The studies demonstrated that 38.2% of SCC had recurrence and/or metastases after operation . However , only 0.0% and 0.04% , in VC and BCC , respectively , had recurrence and/or metastases . There was significant difference on prognoses between SCC and VC or BCC . The immunostaining showed significant difference of E-cad expression between SCC and VC ( P<0.01 ) , SCC and BCC ( P<0.05 ) . The former was weaker than VC and BCC . However , no difference was showed in E-cad expression between VC and BCC ( P>0.05 ) . CONCLUSION E-cad plays an important role in maintaining the phenotype of epithelial cell of SCC and normal oral mucosa . The degree of expression of E-cad was correlated with the ability of invasion and/or metastasis of SCC , VC and BCC . It indicates that E-cad may be as a helpful marker to evaluate the prognosis of oral cancers .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "14983378"}
{"sentence": "BACKGROUND The epidermal growth factor receptor ( EGFR ) is a validated therapeutic target in non-small cell lung cancer ( NSCLC ) . However , current single agent receptor targeting does not achieve a maximal therapeutic effect , and some mutations confer resistance to current available agents . In the current study we have examined , in different NSCLC cell lines , the combined effect of RNA interference targeting the EGFR mRNA , and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors ( TKIs ) or a monoclonal antibody cetuximab . METHODS NSCLC cells ( cell lines HCC827 , H292 , H358 , H1650 , and H1975 ) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib , erlotinib , and afatinib , and/or with the monoclonal antibody cetuximab . The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR . The down-regulation of EGFR protein expression was measured by western blot , and the proliferation , viability , caspase3/7 activity , and apoptotic morphology were monitored by spectrophotometry , fluorimetry , and fluorescence microscopy . The combined effect of EGFR siRNA and different drugs was evaluated using a combination index . RESULTS EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied , albeit with a different magnitude . The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs . The effects of siRNA probably correlate with the overall oncogenic significance of the receptor , which is only partly inhibited by the TKIs . The cells which showed weak response to TKIs , such as the H1975 cell line containing the T790M resistance mutation , were found to be responsive to siRNA knockdown of EGFR , as were cell lines with downstream TKI resistance mutations . The cell line HCC827 , harboring an exon 19 deletion mutation , was more than 10-fold more sensitive to TKI proliferation inhibition and apoptosis induction than any of the other cell lines . Cetuximab alone had no relevant in vitro activity at concentrations obtainable in the clinic . The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines , independent of the EGFR mutation status ( wild-type or sensitizing mutation or resistant mutation ) . The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA . CONCLUSIONS EGFR knockdown by siRNA further decreases the cell growth of lung cancer cells that are treated with TKIs or cetuximab alone , confirming that single agent drug targeting does not achieve a maximal biological effect . The siRNA inhibits EGFR oncogenic activity that bypasses downstream \" resistance \" mutations such as KRAS and PTEN . The combined treatment of siRNA and EGFR inhibitory agents is additive . The combination of a potent , irreversible kinase inhibitor such as afatinib , with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers , including those with downstream resistance mutations .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 1, 0], "id": "22436374"}
{"sentence": "Our study was to elucidate the mechanisms whereby BMS-345541 ( BMS , a specific I\\u03baB kinase \\u03b2 inhibitor ) inhibits the repair of DNA double-strand breaks ( DSBs ) and evaluate whether BMS can sensitize MCF-7 breast cancer cells ( MCF-7 cells ) to ionizing radiation ( IR ) in an apoptosis-independent manner . In this study , MCF-7 cells were exposed to IR in vitro and in vivo with or without pretreatment of BMS . The effects of BMS on the repair of IR-induced DSBs by homologous recombination ( HR ) and non-homologous end-joining ( NHEJ ) were analyzed by the DR-GFP and EJ5-GFP reporter assays and IR-induced \\u03b3-H2AX , 53BP1 , Brca1 and Rad51 foci assays . The mechanisms by which BMS inhibits HR were examined by microarray analysis and quantitative reverse transcription PCR . The effects of BMS on the sensitivity of MCF-7 cells to IR were determined by MTT and clonogenic assays in vitro and tumor growth inhibition in vivo in a xenograft mouse model . The results showed that BMS selectively inhibited HR repair of DSBs in MCF-7 cells , most likely by down-regulation of several genes that participate in HR . This resulted in a significant increase in the DNA damage response that sensitizes MCF-7 cells to IR-induced cell death in an apoptosis-independent manner . Furthermore , BMS treatment sensitized MCF-7 xenograft tumors to radiation therapy in vivo in an association with a significant delay in the repair of IR-induced DSBs . These data suggest that BMS is a novel HR inhibitor that has the potential to be used as a radiosensitizer to increase the responsiveness of cancer to radiotherapy .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23259762"}
{"sentence": "The DNA damage response ( DDR ) cascade and ROS ( reactive oxygen species ) signaling are both involved in the induction of cell death after DNA damage , but a mechanistic link between these two pathways has not been clearly elucidated . This study demonstrates that ROS induction after treatment of cells with neocarzinostatin ( NCS ) , an ionizing radiation mimetic , is at least partly mediated by increasing histone H2AX . Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine ( NAC ) , the NADP(H) oxidase ( Nox ) inhibitor DPI , expression of Rac1N17 , and knockdown of Nox1 , but not Nox4 , indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase . H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta . These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "22237206"}
{"sentence": "BACKGROUND Although basal cell carcinoma ( BCC ) is the most common type of skin cancer , the incidence of metastasis is exceedingly low . OBJECTIVE Case presentation of a basal cell carcinoma arising on the dorsum of the foot with inguinal and pelvic lymph node metastases . METHOD Case presentation with literature review . RESULT On the basis of our review of Japanese literature , the risk factors for BCC metastasis are occurrence on the genitalia , diameter of more than 3 cm , deep invasion of tumor cells into extradermal structures , and infiltrative/morpheic histological type . CONCLUSION Although metastasis from BCC is extremely rare , the prognosis of metastatic BCC is often poor . Careful follow-up is recommended in cases with high risk factors .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22909360"}
{"sentence": "Many reports have emphasized the role of gastrin as a growth factor for normal gastrointestinal mucosa and gastrointestinal cancers . Recent studies have pointed out that this peptide acts also as a growth factor for the pancreatic cancer cell line AR42J . This effect is mediated by gastrin [ cholecystokinin ( CCK)-B ] receptors . In the present study , we investigated gastrin ( CCK-B ) receptor expression in the azaserine-induced rat pancreatic carcinoma DSL-6 , comparing it to normal rat pancreas , and we also characterized CCK receptor subtypes in this tumor . The results showed that there is extensive gastrin binding to the DSL-6 pancreatic carcinoma . No evidence of specific gastrin binding to normal pancreas was found . Analysis of the ability of gastrin-17-I to inhibit 125I-gastrin-I binding demonstrated that gastrin bound to a single class of receptors with a Kd of 0.21 +/- 0.04 nM and a binding capacity of 184 +/- 29 fmol/mg protein. 125I-Gastrin-I binding was inhibited by the specific CCK-B receptor antagonist L365,260 approximately 40 times more effectively than by the specific CCK-A receptor antagonist L364,718 . Analysis of the ability of cholecystokinin octapeptide ( CCK-8 ) to inhibit 125I-Bolton-Hunter-CCK-8 binding revealed two CCK binding sites , i.e. , a high affinity site and a low affinity site . The observed binding affinities of CCK-8 were then introduced into the computer analysis of the dose-inhibition curve of the ability of gastrin-17-I to inhibit binding of 125I-Bolton-Hunter-CCK-8 , which was significantly better fit by a three-site model than by a two-site model . The three sites meet the criteria for CCK-B , high affinity CCK-A , and low affinity CCK-A receptors . The binding capacity of CCK-B receptors constitutes 34% of the total high affinity CCK binding sites . This study demonstrated that DSL-6 pancreatic carcinoma expresses three subtypes of CCK receptors . Gastrin ( CCK-B ) receptors , which were not detected in normal rat pancreas , constitute about one third of the total high affinity CCK receptors . We suggest that novel expression of gastrin ( CCK-B ) receptors may be generated by gene mutation or amplification during carcinogenesis and may play an important role in promoting tumor growth .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1458479"}
{"sentence": "MAP17 is a small 17 kDa non-glycosylated membrane protein previously identified as being overexpressed in carcinomas . Breast tumor cells that overexpress MAP17 show an increased tumoral phenotype with enhanced proliferative capabilities both in the presence or the absence of contact inhibition , decreased apoptotic sensitivity , and increased migration . MAP17-expressing clones also grow better in nude mice . The increased malignant cell behavior induced by MAP17 is associated with an increase in reactive oxygen species ( ROS ) production , and the treatment of MAP17-expressing cells with antioxidants results in a reduction in the tumorigenic properties of these cells . The MAP17-dependent increase in ROS and tumorigenesis relies on its PDZ-binding domain because disruption of this sequence by point mutations abolishes the ability of MAP17 to enhance ROS production and tumorigenesis . MAP17 is overexpressed in a great variety of human carcinomas , including breast tumors . Immunohistochemical analysis of MAP17 during cancer progression demonstrates that overexpression of the protein strongly correlates with tumoral progression . Generalized MAP17 overexpression in human carcinomas indicates that MAP17 can be a good marker for tumorigenesis and , especially , for malignant progression .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "22973555"}
{"sentence": "TNF , an inflammatory cytokine that is enriched in the tumor microenvironment , promotes tumor growth and subverts innate immune responses to cancer cells . We previously reported that tumors implanted in TNF receptor-deficient ( Tnfr-/- ) mice are spontaneously rejected ; however , the molecular mechanisms underlying this rejection are unclear . Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells ( MDSCs ) . MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell-mediated antitumor responses . Peripheral accumulation of MDSCs was drastically impaired in Tnfr-/- mice . Signaling of TNFR-2 , but not TNFR-1 , promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein ( c-FLIP ) and inhibition of caspase-8 activity . Loss of TNFRs impaired the induction of MDSCs from bone marrow cells , but this could be reversed by treatment with caspase inhibitors . These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23064360"}
{"sentence": "Invasion and metastasis are the major causes of cancer-related death . Pharmacological or therapeutic interventions such as chemoprevention of the progression stages of neoplastic development could result in substantial reduction in the incidence of cancer mortality . ( -)-Epigallocatechin-3-gallate ( EGCG ) , a promising chemopreventive agent , has attracted extensive interest for cancer therapy utilizing its antioxidant , anti- proliferative and inhibitory effects on angiogenesis and tumor cell invasion . In this study , we assessed the influence of EGCG on the proliferative potential of HeLa cells by cell viability assay and authenticated the results by nuclear morphological examination , DNA laddering assay and cell cycle analysis . Further we analyzed the anti-invasive properties of EGCG by wound migration assay and gene expression of MMP-9 and TIMP-1 in HeLa cells . Our results indicated that EGCG induced growth inhibition of HeLa cells in a dose- and time- dependent manner . It was observed that cell death mediated by EGCG was through apoptosis . Interestingly , EGCG effectively inhibited invasion and migration of HeLa cells and modulated the expression of related genes ( MMP-9 and TIMP-1 ) . These results indicate that EGCG may effectively suppress promotion and progression stages of cervical cancer development .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23167425"}
{"sentence": "The relationship between thyroid hormone ( triiodothyronine , T(3) ) and breast cancer is unclear . We studied the effect of the c-erbA/TR alpha proto-oncogene encoding a functional T(3) receptor ( TR alpha 1 ) , of its ligand T(3) , and of its retroviral , mutated counterpart , the v-erbA oncogene , on the proliferation capacity of nontumorigenic mammary epithelial cells ( EpH4 ) . We found that EpH4 cells expressing ectopically TR ( EpH4 + TR alpha 1 ) or v-erbA ( EpH4 + v-erbA ) proliferated faster than parental EpH4 cells that contained low levels of endogenous TR . T(3) inhibited DNA synthesis and proliferation in EpH4 + TR alpha 1 cells but not EpH4 or EpH4 + v-erbA cells . The study of cell-cycle genes showed that T(3) decreased cyclin D1 RNA and protein levels in EpH4 + TR alpha 1 cells . In addition , T(3) downregulated the expression of T1 , a gene that is overexpressed in human breast adenocarcinomas and is induced by mitogens , serum , and several oncogenes and cytokines . Inhibition of the T1 gene by T(3) required both de novo mRNA and protein synthesis . Furthermore , T(3) abolished the induction of T1 by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and inhibited the activity of an activation protein 1-dependent promoter ( -73-Col-CAT ) in EpH4 + TR alpha 1 cells , suggesting that interference with activation protein 1 transcription factor plays a part in the inhibition of the T1 gene . Our results showed that T(3) reduced the proliferation of mammary epithelial cells and inhibited the expression of cyclin D1 and T1 genes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12112320"}
{"sentence": "Some people consume chronically glutamine ( GLN ) in high quantities ( g/d ) , although a number of biochemical pathways and cellular functions may be negatively affected . The following side effects of GLN supplementation are discussed : ( 1 ) Alterations in amino acid transport-as GLN shares the transporters with other amino acids , enhanced GLN intake may impair amino acid distribution among tissues and their absorption in the gut and kidneys . ( 2 ) Alterations in GLN metabolism-GLN supplementation may impair synthesis of endogenous GLN and enhance glutamate and ammonia production . ( 3 ) Alterations in ammonia transport-GLN supplementation may impair ammonia detoxification and negatively affect the role of GLN as the carrier of ammonia among tissues . ( 4 ) Abnormalities in aminoacidemia-increased plasma levels of GLN , glutamate , citrulline , ornithine , arginine , and histidine and decreased levels of valine , leucine , isoleucine , glycine , threonine , serine , and proline are reported . ( 5 ) Alterations in immune system-as GLN has immunomodulating properties , the effect of chronic GLN consumption on the immune system needs to be assessed . ( 6 ) Effect on tumor growth-it should be elucidated whether chronic intake of GLN increases the risk of cancer . ( 7 ) Effect of the withdrawal of GLN supplementation-due to the adaptive response of the organism to enhanced GLN consumption , the withdrawal of GLN may enhance the risk of health problems resulting from GLN deficiency . It is concluded that enhanced intake of GLN has substantial side effects , and long-term studies should be performed to justify chronic consumption of a GLN-enriched diet .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22990615"}
{"sentence": "The aim of the present study was to evaluate immunomodulator ginsan , a polysaccharide extracted from Panax ginseng , on carbon tetrachloride ( CCl(4))-induced liver injury . BALB/c mice were injected i.p. with ginsan 24 h prior to CCl(4) administration . Serum liver enzyme levels , histology , expression of antioxidant enzymes , and several cytokines/chemokines were subsequently evaluated . Ginsan treatment markedly suppressed the serum alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) levels , and hepatic histological necrosis increased by CCl(4) treatment . Ginsan inhibited CCl(4) induced lipid peroxidation through the cytochrome P450 2E1 ( CYP2E1 ) downregulation . The hepatoprotective effect of ginsan was attributed to induction of anti-oxidant protein contents , such as superoxide dismutase ( SOD ) , catalase , and glutathione peroxidase ( GPX ) as well as restoration of the hepatic glutathione ( GSH ) concentration . The marked increase of proinflammatory cytokines ( IL-1beta , IFN-gamma ) and chemokines ( MCP-1 , MIP-2beta , KC ) in CCl(4) treated mice was additionally attenuated by ginsan , thereby preventing leukocyte infiltration and local inflammation . Our results suggest that ginsan effectively prevent liver injury , mainly through downregulation of oxidative stress and inflammatory response .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19913046"}
{"sentence": "Ghrelin was identified in the stomach as an endogenous ligand specific for the growth hormone secretagogue receptor ( GHS-R ) . GHS-R is found in various tissues , but its function is unknown . Here we show that GHS-R is found in hepatoma cells . Exposure of these cells to ghrelin caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor substrate-1 ( IRS-1 ) , association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1 , mitogen-activated protein kinase activity , and cell proliferation . Unlike insulin , ghrelin inhibited Akt kinase activity as well as up-regulated gluconeogenesis . These findings raise the possibility that ghrelin modulates insulin activities in humans .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "11724768"}
{"sentence": "Cytochrome P450 2A6 ( CYP2A6 ) is known to metabolize nicotine , the major constituent of tobacco , leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer . Recently , we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species ( ROS ) in U937 monocytes . However , the mechanism by which CYP2A6 is induced by ethanol is unknown . In this study , we have examined the role of the PKC/Nrf2 pathway ( protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus ) in ethanol-mediated CYP2A6 induction . Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein ( and increased ROS formation , and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor ( diallyl sulfide ) or an antioxidant ( vitamin C ) . The results suggest the role of oxidative stress in the regulation of CYP2A6 expression . Subsequently , we investigated the role of Nrf2 pathway in oxidative stress-mediated regulation of CYP2A6 expression in U937 monocytes . Our results showed that butylated hydroxyanisole , a stabilizer of nuclear Nrf2 , increased CYP2A6 levels >200% . Staurosporine , an inhibitor of PKC , completely abolished ethanol-induced CYP2A6 expression . Furthermore , our results showed that a specific inhibitor of mitogen-activated protein kinase kinase ( MEK ) ( U0126 ) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation . Overall , these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway , resulting in the induction of CYP2A6 in monocytes . An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism . Thus , this study has clinical relevance because of the high incidence of alcohol use among smokers , especially in HIV-infected individuals .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22530035"}
{"sentence": "BACKGROUND Sorafenib has recently been shown to reduce tumour growth in hepatoblastoma ( HB ) xenografts . The effect of a combined administration with cytostatic agents was now investigated . METHODS Cell viability after treatment with sorafenib and different cytostatic agents was evaluated in two HB cell lines ( HUH6 and HepT1 ) using MTT assay . ERK signalling was investigated by western blot , NOXA expression by rt-PCR , and formation of DNA adducts using immunocytology . NMRI mice bearing subcutaneous HUH6-derived tumours were treated with sorafenib alone or in combination with cisplatin . Tumour progression , viability , apoptosis , and vascularisation were monitored by tumour volume , AFP levels , TUNEL assay , and CD31 immunostaining , respectively . RESULTS The combination of sorafenib and cisplatin led to a remarkable decrease in cell viability . The cisplatin-induced enhanced ERK1/2 activation , but not NOXA expression and the formation of DNA adducts was partly abrogated by sorafenib . In HB xenografts , both , sorafenib and alternated application of sorafenib and cisplatin significantly reduced tumour growth ( P<0.05 ) . Levels of AFP were lower in both treated groups ( P=0.08 ) . Relative apoptotic areas were increased ( P=0.003 ) . Mean vascular density was the lowest in the sorafenib/CDDP group ( P=0.02 ) . CONCLUSION The combination of sorafenib with cisplatin might be a promising treatment option for high risk or recurrent HB .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23257893"}
{"sentence": "The transcription factor MycN is the prototypical neuroblastoma oncogene and a potential therapeutic target . However , its strong expression caused by gene amplification in about 30% of neuroblastoma patients is a considerable obstacle to the development of therapeutic approaches aiming at eliminating its tumourigenic activity . We have previously reported that B-Myb is essentially required for transcription of the MYCN amplicon and have also shown that B-MYB and MYCN are engaged in a feed forward loop promoting the survival/proliferation of neuroblastoma cells . We postulated that pharmacological strategies breaking the B-MYB/MYCN axis should result in clinically desirable effects . Thus , we implemented a high throughput chemical screen , using a curated library of compounds from the National Cancer Institute , whose endpoint was the identification of small molecules that inhibited B-Myb . At the end of the screening , we found that the compounds pinafide , ellipticine and camptothecin inhibited B-Myb transcriptional activity in luciferase assays . One of the compounds , the topoisomerase-1 inhibitor camptothecin , is of considerable clinical interest since its derivatives topotecan and irinotecan are currently used as first and second line treatment agents for various types of cancer , including neuroblastoma . We found that neuroblastoma cells with amplification of MYCN are more sensitive than MYCN negative cells to camptothecin and topotecan killing . Campothecin and topotecan caused selective down-regulation of B-Myb and MycN expression in neuroblastoma cells . Notably , forced overexpression of B-Myb could antagonize the killing effect of topotecan and camptothecin , demonstrating that the transcription factor is a key target of the drugs . These results suggest that camptothecin and its analogues should be more effective in patients whose tumours feature amplification of MYCN and/or overexpression of B-MYB .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22619121"}
{"sentence": "Capillary endothelial cells can be induced to form capillary-like structures in vitro by plating on fibronectin-coated dishes ( Ingber , D. E. , and Folkman , J . ( 1989 ) J. Cell Biol. 109 , 317-330 ) , thereby mimicking angiogenesis . To assess the role of glycoproteins bearing asparagine-linked oligosaccharides in this process , we tested the effect of oligosaccharide processing inhibitors on the formation of capillary tubes . Deoxymannojirimycin , a compound that prevents synthesis of hybrid and complex-type oligosaccharides , inhibited the formation of capillary tubes . In contrast , swainsonine , an inhibitor that blocks synthesis of complex- but not hybrid-type oligosaccharides , did not inhibit tube formation . Lectin affinity chromatography of 2-[3H] mannose-labeled glycopeptides from endothelial cells induced to form tubes did not reveal a striking difference in the spectrum of oligosaccharides compared to uninduced cells . Since endothelial cells formed tubes normally in the presence of swainsonine , we analyzed glycopeptides from swainsonine-treated induced and uninduced cells . Cells induced to form tubes were enriched in monosialylated hybrid-type oligosaccharides sensitive to alpha-fucosidase , beta-galactosidase , and beta-N-acetylhexosaminidase , suggestive of sialyl Lewis-X determinants . We used an enzyme-linked immunoassay to measure sialyl Lewis-X epitopes on capillary endothelial cells and found that both induced and uninduced cells expressed sialyl Lewis-X epitopes . Deoxymannojirimycin and , to a lesser extent , swainsonine reduced the level of sialyl Lewis-X epitopes in cells induced to form capillary tubes , but neither compound affected the level of epitopes in cell monolayers . We conclude that synthesis of at least hybrid-type oligosaccharides is required for capillary tube formation in vitro and that an increase in monosialylated , fucosylated glycans on asparagine-linked oligosaccharides occurs during this process .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "1464626"}
{"sentence": "Family with sequence similarity 189 , member B ( FAM189B ) , alias COTE1 , a putative oncogene selected by microarray , for the first time was here found to be significantly up-regulated in hepatocellular carcinoma ( HCC ) specimens and HCC cell lines. mRNA expression of COTE1 in HCC samples and cell lines was detected by reverse transcription-polymerase chain reaction ( RT-PCR ) and real-time PCR , while protein expression of COTE1 in HCC tissues was assessed by immunohistochemistry . In addition , invasion of HCC cells was observed after overexpressing or silencing COTE1 . In the total of 48 paired HCC specimens , compared with the adjacent non-cancer tissues , the expression of COTE1 was up-regulated in 31 ( p<0.01 ) . In HCC cell lines , COTE1 expression was significantly higher than in normal human adult liver ( p<0.01 ) . Overexpression of COTE1 enhanced HCC-derived LM6 and MHCC-L cellular invasion in vitro . In contrast , COTE1 knockdown via RNAi markedly suppressed these phenotypes , as documented in LM3 and MHCC-H HCC cells . Mechanistic analyses indicated that COTE1 could physically associate with WW domain oxidoreductase ( WWOX ) , a tumor suppressor . COTE1 may be closely correlated with invasion of hepatocellular carcinoma ( HCC ) cells and thus may serve as an effective target for gene therapy .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23317259"}
{"sentence": "Nur77 is an orphan receptor . Although Nur77 affects cell proliferation and apoptosis through its capability of binding to a variety of response elements and regulating their transactivation activities , the intrinsic function of Nur77 is not yet fully understood ; in particular , its regulation of apoptosis and proliferation has been characterized as cell type-dependent and agent context-dependent . In this study , Nur77 can be seen to regulate apoptosis via its expression and translocation , rather than its transactivation activity in gastric cancer cells . Nur77 was constitutively expressed in BGC-823 cells . The tetradecanoylphorbol-1,3-acetate ( TPA ) treatment not only resulted in up-regulation of the Nur77 mRNA level , but also led to translocation of Nur77 protein from the nucleus to the mitochondria , and caused the release of cytochrome c . This TPA-induced translocation of Nur77 was in association with the initiation of apoptosis in gastric cancer cells . Although all-trans retinoic acid ( ATRA ) could not induce apoptosis in BGC-823 cells due to failure of stimulating Nur77 translocation , expression of Nur77 in the nucleus was required for cell growth inhibition by ATRA . Transfection of antisense Nur77 receptor into BGC-823 cells resulted in resistance of cell growth against ATRA inhibition , and the cells were still arrested in the S phase . Furthermore , the action of Nur77 in TPA-induced apoptosis was mediated through a protein kinase C signaling pathway , while mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways were responsible for the regulation of Nur77 mRNA expression . Taken together , the data revealed the dual functioning mechanisms of Nur77 in gastric cancer cells in response to TPA and ATRA .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12376465"}
{"sentence": "The anti-tumor antibiotic salinomycin ( Sal ) was recently identified as a selective inhibitor of breast cancer stem cells ; however , the effect of Sal on hepatocellular carcinoma ( HCC ) is not clear . This study aimed to determine the anti-tumor efficacy and mechanism of Sal on HCC . HCC cell lines ( HepG2 , SMMC-7721 , and BEL-7402 ) were treated with Sal . Cell doubling time was determinated by drawing growth curve , cell viability was evaluated using the Cell Counting Kit 8 . The fraction of CD133(+) cell subpopulations was assessed by flow cytometry . We found that Sal inhibits proliferation and decreases PCNA levels as well as the proportion of HCC CD133(+)cell subpopulations in HCC cells . Cell cycle was analyzed using flow cytometry and showed that Sal caused cell cycle arrest of the various HCC cell lines in different phases . Cell apoptosis was evaluated using flow cytometry and Hoechst 33342 staining . Sal induced apoptosis as characterized by an increase in the Bax/Bcl-2 ratio . Several signaling pathways were selected for further mechanistic analyses using real time-PCR and Western blot assays . Compared to control , \u03b2-catenin expression is significantly down-regulated upon Sal addition . The Ca(2+) concentration in HCC cells was examined by flow cytometry and higher Ca(2+) concentrations were observed in Sal treatment groups . The anti-tumor effect of Sal was further verified in vivo using the hepatoma orthotopic tumor model and the data obtained showed that the size of liver tumors in Sal-treated groups decreased compared to controls . Immunohistochemistry and TUNEL staining also demonstrated that Sal inhibits proliferation and induces apoptosis in vivo . Finally , the role of Sal on in vivo Wnt/\u03b2-catenin signaling was evaluated by Western blot and immunohistochemistry . This study demonstrates Sal inhibits proliferation and induces apoptosis of HCC cells in vitro and in vivo and one potential mechanism is inhibition of Wnt/\u03b2-catenin signaling via increased intracellular Ca(2+) levels .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23284640"}
{"sentence": "Cancer-prone diseases ataxia-telangiectasia ( AT ) , Nijmegen breakage syndrome ( NBS ) and ataxia-telangiectasia-like disorder ( ATLD ) are defective in the repair of DNA double-stranded break ( DSB ) . On the other hand , arsenic ( As ) has been reported to cause DSB and to be involved in the occurrence of skin , lung and bladder cancers . To dissect the repair mechanism of As-induced DSB , wild type , AT and NBS cells were treated with sodium arsenite to study the complex formation and post-translational modification of Rad50/NBS1/Mre11 repair proteins . Our results showed that Mre11 went through cell cycle-dependent phosphorylation upon sodium arsenite treatment and this post-translational modification required NBS1 but not ATM . Defective As-induced Mre11 phosphorylation was rescued by reconstitution with full length NBS1 in NBS cells . Although As-induced Mre11 phosphorylation was not required for Rad50/NBS1/Mre11 complex formation , it might be required for the formation of Rad50/NBS1/Mre11 nuclear foci upon DNA damage .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "12509260"}
{"sentence": "The spatial chromatin organisation and molecular interactions within and between chromatin domains and chromosome territories ( CTs ) are essential for fundamental processes such as replication , transcription and DNA repair via homologous recombination . To analyse the distribution and interaction of whole CTs , centromeres , ( sub)telomeres and interstitial chromatin segments in endopolyploid nuclei , specific FISH probes from Arabidopsis thaliana were applied to 2-64C differentiated leaf nuclei . Whereas CTs occupy a distinct and defined volume of the nucleus and do not obviously intermingle with each other in 2-64C nuclei , sister chromatin segments within these CTs become more non-cohesive with increasing endopolyploidy . Centromeres , preferentially located at the nuclear periphery , may show ring- or half-moon like shapes in 2C and 4C nuclei . Sister centromeres tend to associate up to the 8C level . From 16C nuclei on , they become progressively separated . The higher the polyploidy level gets , the more separate chromatids are present . Due to sister chromatid separation in highly endopolyploid nuclei , the centromeric histone variant CENH3 , the 180-bp centromeric repeats and pericentromeric heterochromatin form distinct subdomains at adjacent but not intermingling positions . The ( sub)telomeres are frequently associated with each other and with the nucleolus and less often with centromeres . The extent of chromatid separation and of chromatin decondensation at subtelomeric chromatin segments varies between chromosome arms . A mainly random distribution and similar shapes of CTs even at higher ploidy levels indicate that in general no substantial CT reorganisation occurs during endopolyploidisation . Non-cohesive sister chromatid regions at chromosome arms and at the ( peri)centromere are accompanied by a less dense chromatin conformation in highly endopolyploid nuclei . We discuss the possible function of this conformation in comparison to transcriptionally active regions at insect polytene chromosomes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22476443"}
{"sentence": "Hypoxia is one of the inevitable circumstances of various tumors . It controls various levels of regulation in tumor progression and results in tumor resistance to radiotherapy and chemotherapy . Here we investigated a synthetic TPZ derivative , N-ethoxymethyl-3-amino-1,2,4-benzotriazine-1,4-dioxide ( XQ2 ) , a novel compound that induced anti-cancer effects both in normoxia and in hypoxia , cell proliferation assay found that XQ2 exhibited a potent inhibitory effect on the tested cancer cell lines both in normoxia and in hypoxia . Flow cytometry and western blot studies indicated that XQ2 induces G2/M arrest and a caspase-dependent apoptosis in A549 cells . Additionally , intracellular reactive oxygen species ( ROS ) appear to play a key role in the anticancer effect of XQ2 in hypoxia . Taken together , our data suggest that XQ2 exerted anticancer action by suppressing the ROS level and triggering cell-cycle arrest and the caspase-dependent pathway , which is associated with apoptosis .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20530905"}
{"sentence": "Bladder cancer is one of the most common tumors of the genitourinary tract ; however , the molecular events underlying growth and invasion of the tumor remain unclear . Here , role of the CXCR7 receptor in bladder cancer was further explored . CXCR7 protein expression was examined using high-density tissue microarrays . Expression of CXCR7 showed strong epithelial staining that correlated with bladder cancer progression . In vitro and in vivo studies in bladder cancer cell lines suggested that alterations in CXCR7 expression were associated with the activities of proliferation , apoptosis , migration , invasion , angiogenesis and tumor growth . Moreover , CXCR7 expression was able to regulate expression of the proangiogenic factors IL-8 or VEGF , which may involve in the regulation of tumor angiogenesis . Finally , we found that signaling by the CXCR7 in bladder cancer cells activates AKT , ERK and STAT3 pathways . The AKT and ERK pathways may reciprocally regulate , which are responsible for in vitro and in vivo epithelial to mesenchymal transition ( EMT ) process of bladder cancer . Simultaneously targeting the two pathways by using U0126 and LY294002 inhibitors or using CCX733 , a selective CXCR7 antagonist drastically reduced CXCR7-induced EMT process . Taken together , our data show for the first time that CXCR7 plays a role in the development of bladder cancer . Targeting CXCR7 or its downstream-activated AKT and ERK pathways may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for bladder cancer .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "22525723"}
{"sentence": "NKX3.1 is a homeodomain protein that functions as a dosage sensitive prostate-specific transcription factor . Diminished NKX3.1 expression is associated with prostate epithelial cell proliferation in vitro and with increasing Gleason grade in patient samples . Mouse Nkx3.1 also functions as a negative regulator of prostate cell growth in prostate cancer models . Identifying biological and environmental factors that modulate NKX3.1 accumulation is therefore central to efforts aimed at elucidating prostate growth control mechanisms . To determine the effect of inflammation on Nxk3.1 accumulation , bacterial prostatitis was induced by intraurethral inoculation of a uropathogenic E. coli strain in mice . Nkx3.1 expression was profoundly reduced in infected prostate lobes and correlated with increased expression of a proliferation marker . Androgen receptor levels were also reduced in concert with Nkx3.1 , and a marked increase in the basal cell marker p63 was observed . Analyses of the inflammatory infiltrate revealed a classic acute inflammatory response that attained characteristics of a chronic state within fourteen days postinoculation . Comparison of the four prostate lobes revealed clear differences in the extent of inflammation . These data demonstrate that acute inflammation in response to a bacterial agent in the prostate is associated with a significant diminution in the level of a key regulator of prostate cell proliferation . These observations provide a plausible mechanism whereby prostate inflammation may establish a local environment conducive to epithelial cell growth .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "20363913"}
{"sentence": "Covalent bonding interactions between the Lewis acid and Lewis base functionalities have been probed in a series of \" frustrated Lewis pairs \" ( FLPs ) ( mainly substituted vinylene linked intramolecular phosphane-borane adducts ) , using solid-state nuclear magnetic resonance techniques and accompanying DFT calculations . Both the ( 11)B NMR isotropic chemical shifts and nuclear electric quadrupolar coupling parameters turn out to be extremely sensitive experimental probes for such interactions , revealing linear correlations with boron-phosphorus internuclear distances . The principal component V(zz) of the ( 11)B electric field gradient tensor is tilted slightly away ( from the boron-phosphorus internuclear vector , leading to an improved understanding of the remarkable reactivity of the FLPs . Complementary ( 31)P{(1)H}-CPMAS experiments reveal significant ( 31)P-(11)B scalar spin-spin interactions ( (1)J \\u2248 50 Hz ) , evidencing covalent bonding interactions between the reaction centers . Finally , ( 11)B{(31)P} rotational echo double resonance ( REDOR ) experiments show systematic deviations from calculated curves based on the internuclear distances from X-ray crystallography . These deviations suggest non-zero contributions from anisotropic indirect spin-spin ( J anisotropy ) interactions , thereby offering additional evidence for covalent bonding .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22280301"}
{"sentence": "Proline- , glutamic acid- and leucine-rich protein-1/modulator of non-genomic activity of estrogen receptor ( ER ) ( PELP1/MNAR ) is a novel nuclear receptor ( NR ) co-activator that plays an essential role in the actions of ER . Emerging findings suggest that PELP1/MNAR is a novel proto-oncogene , whose expression is deregulated in several hormone-responsive cancers , including endometrial cancer . In this study , we demonstrate that PELP1/MNAR is widely expressed in endometrial carcinoma cell lines . To investigate its possible role in endometrial carcinoma progression , we adopted an RNA interference technology to downregulate PELP1/MNAR expression in Ishikawa endometrial carcinoma cells . PELP1/MNAR downregulation substantially reduced cell proliferation , and the cells in which PELP1/MNAR expression was knocked down also exhibited a decreased migration and invasion ability , as shown by Boyden chamber and invasion assays . The results showed that the expression of MMP-2 and MMP-9 was also decreased . These results suggest that PELP1/MNAR plays a role in endometrial cancer progression and metastasis , and that PELP1/MNAR may be a potential therapeutic target for endometrial cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22992812"}
{"sentence": "BACKGROUND Brain-metastatic breast cancer ( BMBC ) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown . Recent work has demonstrated that deregulation of epidermal growth factor receptor ( EGFR ) may correlate with BMBC progression . However , the exact contribution that EGFR makes to BMBC remains unclear . METHODS The role of EGFR in BMBC was explored by serial analyses in a brain-trophic clone of human MDA-MB-231 breast carcinoma cells ( 231-BR cells ) . EGFR expression was inhibited by stable short-hairpin RNA transfection or by the kinase inhibitor erlotinib , and it was activated by heparin-binding epidermal growth factor-like growth factor ( HB-EGF ) . Cell growth and invasion activities also were analyzed in vitro and in vivo . RESULTS EGFR inhibition or activation strongly affected 231-BR cell migration/invasion activities as assessed by an adhesion assay , a wound-healing assay , a Boyden chamber invasion assay , and cytoskeleton staining . Also , EGFR inhibition significantly decreased brain metastases of 231-BR cells in vivo . Surprisingly , changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ( MTT ) assay , an anchorage-independent growth assay , and cell cycle analysis . Immunoblot analysis suggested that EGFR drives cells ' invasiveness capability mainly through phosphoinositide 3-kinase/protein kinase B and phospholipase C \u03b3 downstream pathways . In addition , EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen-activated protein kinase pathway . CONCLUSIONS The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231-BR cells , providing new evidence of the potential value of EGFR inhibition in treating BMBC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22510844"}
{"sentence": "Clones of mortal chicken fibroblasts and erythroblasts transformed by temperature-sensitive v-src and v-erb B oncoproteins have been developed into immortal cell lines that retain the conditional transformed phenotype . The expressions of two tumor suppressor genes , the retinoblastoma ( Rb ) gene and the p53 gene , were investigated during senescence , crisis , and cell line establishment . In temperature-sensitive ( ts)-v-erb B erythroblasts and ts-v-src fibroblasts ( as well as in v-myc macrophages ) , loss of p53 mRNA or expression of a mutated p53 gene invariably occurred in the early phase of immortalization . In contrast , expression of the Rb gene was unchanged at all stages of immortalization . Inactivation of the original temperature-sensitive oncogene led to loss of the transformed phenotype in fibroblasts and to differentiation in erythroblasts , even in lines that were immortal and lacked p53 . The results demonstrate that the process of immortalization is distinct from cell transformation , probably requiring different mutational events .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "1577279"}
{"sentence": "The modifying effects of an immunosuppressive agent , 6-mercaptopurine ( 6-MP ) , on development of focal lesions in liver cirrhosis models induced by carbon tetrachloride ( CCl4 ) or furfural were studied in male F344 rats . Feeding of 6-MP at 50 p.p.m. for 20 weeks to animals with pre-existing liver cirrhosis caused immunosuppression , and significantly enhanced the induction of gamma-glutamyltranspeptidase ( GGT)-positive foci and nodules in the CCl4 but not furfural case . Glutathione S-transferase P ( GST-P)-positive preneoplastic lesions were not affected . Moreover , phenobarbital ( PB ) also enhanced the induction of GGT-positive hepatocellular lesions only in the CCl4-induced liver cirrhosis model , no promotion influence being exerted after treatment with the non-carcinogenic furfural . This study , therefore , suggests that 6-MP can enhance the induction of one type of preneoplastic foci and nodules and that essential differences exist between focal lesions arising in cirrhotic livers caused by CCl4 as opposed to furfural .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1354082"}
{"sentence": "DNA repair enzymes play an important role in the development of various kinds of cancer . We here analyzed associations of XPD Lys751Gln , APEX1 Asp148Glu , XRCC1 Arg399Gln , and XRCC3 Thr241Met gene polymorphisms in DNA repair pathways in relation to the risk of lung cancer using PCR-RFLP . The study involved 104 lung cancer patients and 120 non-cancer controls divided into non-smokers and smokers . We found a statistically significant interaction between APEX1 Asp148Glu and the risk for lung cancer ( adjusted OR 2.78 , 95% CI 1.58-4.90 , p=0.0004 ) , of both adenocarcinoma ( adjusted OR 2.24 , 95%CI 1.18-4.25 , p=0.014 ) and squamous cell carcinoma ( adjusted OR 4.75 , 95%CI 1.79-12.6 , p=0.002 ) types . XRCC1 Arg399Gln showed a borderline significant association with adenocarcinoma ( adjusted OR 1.89 , 95%CI 1.00-3.57 , p=0.051 ) . The combined effect of smoking and presence of the APEX1 Asp148Glu demonstrated a significant association with risk of lung cancer ( adjusted OR 3.61 , 95% CI 1.74-7.50 , p=0.001 ) . The XPD Lys751Gln and XRCC3 Thr241Met genotypes displayed no statistically significant risk . Our findings suggest that the APEX1 Asp148Glu is associated with increased risk for primary lung cancer in Japanese individuals partaking in smoking .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21198260"}
{"sentence": "UVB from solar radiation is both an initiating and promoting agent for skin cancer . We have found that primary human keratinocytes undergo an apoptotic response to UVB . To determine whether these responses are altered during the course of immortalization , we examined markers of apoptosis in primary human foreskin keratinocytes ( HFK ) transduced with either a retroviral vector expressing the E6 and E7 genes of HPV-16 or with empty vector alone ( LXSN-HFK ) . Whereas LXSN-HFK as well as early passage keratinocytes expressing HPV-16 E6 and E7 ( p7 E6/7-HFK ) were both moderately responsive to UVB irradiation , late passage-immortalized keratinocytes ( p27 E6/7-HFK ) were exquisitely sensitive to UVB-induced apoptosis . After exposure to UVB , enhanced annexin V-positivity and internucleosomal DNA fragmentation were observed in p27 E6/7-HFK compared with either LXSN- or p7 E6/7-HFK . Caspase-3 fluorometric activity assays as well as immunoblot analysis with antibodies to caspase-3 and poly(ADP-ribose) polymerase revealed elevated caspase-3 activity and processing at lower UVB doses in p27 E6/7-HFK compared with LXSN- or p7 E6/7-HFK . In addition , the caspase inhibitor DEVD-CHO reduced the apoptotic response and increased survival of all three HFK types . Immunoblot analysis revealed that caspase-8 was activated in all three cell types , but caspase-9 was only activated in p27 E6/7-HFK . Cell cycle analysis further showed that only p27 E6/7-HFK exhibit G(2)/M accumulation that is enhanced by UVB treatment . This accumulation was associated with a rapid down-regulation of Bcl-2 in these cells . The immortalization process subsequent to the expression of HPV E6 and E7 may therefore determine UVB sensitivity by switching the mode of apoptosis from a caspase-8 to a Bcl-2-caspase-9-mediated pathway of apoptosis .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "11976323"}
{"sentence": "The incidence of oral squamous cell carcinoma ( SCC ) is increasing but the long-term survival rate remains low . An animal model would therefore be helpful for evaluation of new treatment modalities for oral SCC . Hamster is small animal , therefore , the cancer of hamster cheek pouch is not optimal for tumor imaging . The VX2 cell line has been used in many carcinoma-related studies , including oral SCC research , but it is derived from cutaneous tissue and not mucosa . We chemically induced tongue squamous cell carcinoma in rabbits and subsequently established a rabbit squamous cell line . The cells grew in multiple layers without contact inhibition for 60 passages over 2 years and were positive for cytokeratin ( CK ) . Electron microscopy revealed that cells were polygonal with rich microvilli on the surface , and there were desmosomes between cells and bundles of tonofibril beside the cell membrane . The chromosome number ranged from 71 to 272 , with a modal value of 145 ( 12.4% ) . The cells were transplantable into nude mice subcutaneously or rabbit submucosally and produced carcinomas in all the animals . The cell line should be a useful tool for the study of the biological characteristics of oral SCC , especially tongue SCC .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21071263"}
{"sentence": "Anal canal cancer is a rare tumor without clear treatment evidence in the metastatic setting . In terms of the bad prognosis of patients with metastatic anal cancer , further therapeutic options are urgently needed . In this paper we present the case of a 64-year-old man suffering from undifferentiated squamous cell carcinoma with liver metastases . After progression on cisplatin and fluorouracil , tumor tissue was analyzed with respect to anti-EGFR therapy with cetuximab . There was no KRAS mutation and the EGFR expression level in the tumor tissue was 2+ ; ideal conditions for the immunotherapy . Encouraged by these results we started a therapy using FOLFIRI in combination with cetuximab . Fortunately the patient showed a partial response after 6 cycles . On patient's preference we did a therapy break of 6 weeks . Within this time period the disease was progressive indicating its aggressiveness . However , the same immunotherapy was able to stabilize the disease for a further 3 months . The patient died 21 months after diagnosis because of liver failure . Nevertheless , from our perspective the combination of FOLFIRI and cetuximab is quite a promising therapeutic option for patients with metastatic anal cancer . Potential predictive factors of the immunochemotherapy are discussed in this paper .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22949905"}
{"sentence": "BACKGROUND The pTalpha/preTCR regulates the beta-selection , a crucial T-cell developmental checkpoint , providing a most potent survival advantage to thymocytes mediated by the src-kinase p56(Lck) . METHODS To define the relevance of pTalpha in human T-cell lymphoblastic leukemia ( T-ALL ) , we analyzed in T-ALL cell lines ( n=14 ) pTalpha and p56(Lck) mRNA and protein expression as also the tyrosine-phosphorylation . The p56(Lck) specific src-protein-tyrosine kinase inhibitor ( PTK-I ) PP1 was used in growth inhibition assays . IC(50) value determination , cell cycle- and apoptosis analyses were performed in T-ALL- , non-T-ALL- and murine transgenic cell lines . RESULTS pTalpha expression patterns were markedly different in T-ALL cell lines as compared to those reported for normal lymphoid counterparts . PP1 induced in 6/11 T-ALL cell lines a survival disadvantage resulting from a cell cycle arrest in the G(1/0) phase in thymic lymphoblastic cells and apoptosis induction in the immature cell line HSB-2 , respectively . PP1 sensitive cell lines expressed the target protein p56(Lck) and showed a corresponding P-Tyr signal . CONCLUSION Sensitivity of thymic T-ALLs to PP1 clearly underlines the impact of pTalpha mediated proliferation in this leukemic sub-type . In addition , p56(Lck) represents also independently of pTalpha a promising therapeutical target for the src-kinase inhibitors in neoplastic lymphoid diseases .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20208138"}
{"sentence": "Glioblastoma multiforme , the most common form of malignant brain tumor,is resistant to all forms of therapy and causes death within 9-12 months of diagnosis . Glioblastomas are known to contain numerous genetic and physiological alterations affecting cell survival and proliferation ; one of the most common alterations being platelet-derived growth factor ( PDGF ) autocrine signaling characterized by coexpression of PDGF and its receptor . The PDGF family consists of four members , PDGF-A , -B , -C , and -D , that signal through the alpha and beta PDGF receptor ( PDGFR ) tyrosine kinases . Numerous studies have demonstrated expression of PDGF-A , PDGF-B , and the PDGFRs in gliomablastomas , but such studies have not been conducted for the newly identified PDGF-C and -D . Therefore , we examined the expression of all PDGF ligands and receptors in 11 glioma cell lines and 5 primary glioblastoma tumor tissues by quantitative reverse transcription-PCR . Expression of PDGF/PDGFR pairs that are known to functionally interact were identified in all of the samples . Interestingly , PDGF-C expression was ubiquitous in brain tumor cells and tissues but was very low or absent in normal adult and fetal brain . PDGF-D was expressed in 10 of 11 brain tumor cell lines and 3 of 5 primary brain tumor samples . As a strategy for blocking PDGFR signaling , CT52923 , a potent selective small molecule piperazinyl quinazoline kinase inhibitor of the PDGFR , was identified . In model systems using NIH/3T3 cells , CT52923 blocked PDGF autocrine-mediated phosphorylation of PDGFR , Akt , and mitogen-activated protein kinase ( MAPK ) , while having no effect on v-fms or V12-ras-mediated Akt or extracellular signal-regulated protein kinase ( Erk ) phosphorylation . More importantly , p.o. administration of CT52923 to nude mice caused a significant 61% reduction ( P < 0.006 ) in tumor growth of NIH/3T3 cells transformed by PDGF , whereas tumor formation by cells expressing v-fms was unaffected . We next characterized PDGF autocrine signaling in five glioblastoma cell lines . In all of the cases , PDGF autocrine signaling was evident because treatment with 1-10 microM CT52923 inhibited PDGFR autophosphorylation when present at a detectable level and blocked downstream Akt and/or Erk phosphorylation . The functional significance of PDGF autocrine signaling in these cells was demonstrated by the fact that the CT52923 inhibited soft agar colony formation , and , when given p.o. to nude mice , it effectively reduced tumor formation by 44% ( P < 0.0019 ) after s.c. injection of C6 glioblastoma cells . This study of glioblastoma cells and primary tissues is the first to implicate PDGF-C and -D in brain tumor formation and confirms the existence of autocrine signaling by PDGF-A and -B . More importantly , treatment with the PDGFR antagonist CT52923 inhibited survival and/or mitogenic pathways in all of the glioblastoma cell lines tested and prevented glioma formation in a nude mouse xenograft model . Together these findings demonstrate the potential therapeutic utility of this class of compounds for the treatment of glioblastoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12097282"}
{"sentence": "It is known that sperm samples from recurrent pregnancy loss ( RPL ) couples have an increase in their sperm DNA fragmentation ( SDF ) , but no studies have been performed in order to identify differences between single stranded SDF ( ssSDF ) and double stranded SDF ( dsSDF ) in these patients . This could be relevant because the type of DNA damage could have different effects . Semen samples were classified attending their clinical status : 25 fertile donors and 20 RPL patients with at least two unexplained first trimester miscarriages . SDF was analysed using alkaline and neutral Comet assay , SCD test and pulsed-field gel electrophoresis ( PFGE ) , and ROC analysis including data from 105 more infertile patients ( n\\u200a=\\u200a150 ) was performed to establish predictive threshold values . SDF for alkaline and neutral Comet , and the SCD test was analysed in these categories of individuals . Data revealed the presence of two subgroups within fertile donors . The values obtained were 21.10\u00b19.13 , 23.35\u00b110.45 and 12.31\u00b14.31 , respectively , for fertile donors with low values for both ssSDF and dsSDF ; 27.86\u00b112.64 , 80.69\u00b112.67 and 12.43\u00b15.22 , for fertile donors with low ssSDF and high dsSDF ; and 33.61\u00b115.50 , 84.64\u00b111.28 and 19.28\u00b16.05 , for unexplained RPL patients , also showing a low ssSDF and high dsSDF profile . This latter profile was seen in 85% of unexplained RPL and 33% of fertile donors , suggesting that it may be associated to a male risk factor for undergoing RPL . ROC analysis regarding recurrent miscarriage set the cut-off value at 77.50% of dsDNA SDF . PFGE for low ssSDF and high dsSDF profile samples and positive controls treated with DNase , to induce dsDNA breaks , showed a more intense band of about 48 kb , which fits the toroid model of DNA compaction in sperm , pointing out that some nuclease activity may be affecting their sperm DNA in RPL patients . This work identifies a very specific SDF profile related to the paternal risk of having RPL .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23028579"}
{"sentence": "Treatment of cells with the anti-cancer drug camptothecin ( CPT ) induces topoisomerase I ( Top1)-mediated DNA damage , which in turn affects cell proliferation and survival . In this report , we demonstrate that treatment of the wild-type HCT116 ( wt HCT116 ) human colon cancer cell line and the isogenic p53(-/-) HCT116 and p21(-/-) HCT116 cell lines with a high concentration ( 250 nm ) of CPT resulted in apoptosis , indicating that apoptosis occurred by a p53- and p21-independent mechanism . In contrast , treatment with a low concentration ( 20 nm ) of CPT induced cell cycle arrest and senescence of the wt HCT116 cells , but apoptosis of the p53(-/-) HCT116 and p21(-/-) HCT116 cells . Further investigations indicated that p53-dependent expression of p21 blocked apoptosis of wt HCT116 cells treated with 20 nm , but not 250 nm CPT . Interestingly , blocking of the apoptotic pathway , by Z-VAD-FMK , in p21(-/-) HCT116 cells following treatment with 20 nm CPT did not permit the cells to develop properties of senescence . These observations demonstrated that p21 was required for senescence development of HCT116 cells following treatment with low concentrations of CPT .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 1, 0], "id": "11877436"}
{"sentence": "BACKGROUND Growth Regulation by Estrogen in Breast cancer ( GREB1 ) was an estrogen receptor ( ER ) target gene , and GREB1 expression inversely correlated with HER2 status , possibly as a surrogate marker for ER status and a predictor for tamoxifen resistance in breast cancer patients . In the present study , we examine the function and regulation of GREB1 in breast cancer , with the goal to develop GREB1 as a biomarker in breast cancer with de novo and acquired tamoxifen resistance . METHODS We overexpressed GREB1 using adenovirus containing the full length GREB1 cDNA ( Ad-GREB1 ) in breast cancer cell lines . The soft agar assay was used as a measure of anchorage independent growth . The effects of GREB1 on cell proliferation in MCF-7 cells transduced with Ad-GREB1 were also measured by the me olic activity using AlamarBlue assay . We tested whether there was interaction between STAT3 and ER , which could repress GREB1 expression by immunoprecipitation assay . The effects of IL-6/JAK/STAT3 cascade activation on estrogen-induced GREB1 promoter activity were determined by luciferase assay and those on gene expression were measured by real time reverse transcription polymerase chain reaction ( qRT-PCR ) . RESULTS We found that the ability of breast cancer cells to grow in soft agar is enhanced following GREB1 transfection . In MCF-7 cells transduced with Ad-GREB1 or transfected with siRNA GREB1 , the metabolic activity was increased or completely abolished , suggesting that GREB1 may function as a growth promoter in breast cancer . E2 treatment increased GREB1 promoter luciferase activity . IL-6 inhibited E2-induced GREB1 transcription activity and GREB1 mRNA expression . Constitutively expressing active STAT3 construct ( STAT3-C ) dramatically decreased GREB1 transcription . CONCLUSIONS These data indicate that overexpression of GREB1 promotes cell proliferation and increases the clonogenic ability in breast cancer cells . Moreover , Il6/STAT3 modulates estrogen-induced GREB1 transcriptional activity in breast cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23056300"}
{"sentence": "Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers ; however , therapies targeting this gene have not proved to be as effective as was initially hoped . Transcriptional profiling meta-analyses have shown that there are approximately 150 genes co-overexpressed with ERBB2 , suggesting that these genes may represent alternative factors influencing ERBB2-positive tumors . Here we describe an RNA interference-based analysis of these genes that identifies transcriptional regulators of fat synthesis and storage as being critical for the survival of these cells . These transcription factors , nuclear receptor subfamily 1 , group D , member 1 ( NR1D1 ) and peroxisome proliferator activated receptor gamma binding protein ( PBP ) , both reside on ERBB2-containing 17q12-21 amplicons and are part of the ERBB2 expression signature . We show that NR1D1 and PBP act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network , which is highly active in ERBB2-positive breast cancer cells . Malate dehydrogenase 1 and malic enzyme 1 , enzymes that link glycolysis and fatty acid synthesis , are also regulated by NR1D1 . The resulting high-level fat production from increased expression of these genes likely contributes to an abnormal cellular energy metabolism based on aerobic glycolysis . Together , these results show that the cells of this aggressive form of breast cancer are genetically preprogrammed to depend on NR1D1 and PBP for the energy production necessary for survival .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20160030"}
{"sentence": "AIM The goal of this study was to characterize the AFP receptor , its possible signal transduction pathway and its proliferative functions in human hepatoma cell line Bel 7402 . METHODS Cell proliferation enhanced by AFP was detected by MTT assay , 3H-thymidine incorporation and S-stage percentage of cell cycle analysis . With radioactive labeled 125I-AFP for receptor binding assay ; cAMP accumulation , protein kinase A activity were detected by radioactive immunosorbent assay and the change of intracellular free calcium ( Ca2+i ) was monitored by scanning fluorescence intensity under TCS-NT confocal microscope . The expression of oncogenes N- ras , p 53 , and p21( ras ) in the cultured cells in vitro were detected by Northern blotting and Western blotting respectively . RESULTS It was demonstrated that AFP enhanced the proliferation of human hepatoma Bel 7402 cell in a dose dependent fashion as shown in MTT assay , ( 3)H-thymidine incorporation and S-phase percentage up to 2-fold . Two subtypes of AFP receptors were identified in the cells with Kds of 1.3 x 10(-9)mol.L(-1) and 9.9 x10(-8)mol . ( -1)L respectively . Pretreatment of cells with AFP resulted in a significant increase ( 625% ) in cAMP accumulation . The activity of protein kinase A activity were increased up to 37.5 , 122.6 , 73.7 and 61.2% at treatment time point 2 , 6 , 12 and 24 hours . The level of intracellular calcium were elevated after the treatment of alpha-fetoprotein and achieved to 204% at 4 min . The results also showed that AFP(20mg.L(-1)) could upregulate the expression of N- ras oncogenes and p 53 and p21( ras ) in Bel 7402 cells . In the later case,the alteration were 81.1%(12h) and 97.3%(12h) respectively compared with control . CONCLUSION These results demonstrate that AFP is a potential growth factor to promote the proliferation of human hepatoma Bel 7402 cells . Its growth-regulatory effects are mediated by its specific plasma membrane receptors coupled with its transmembrane signaling transduction through the pathway of cAMP-PKA and intracellular calcium to regulate the expression of oncogenes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12046072"}
{"sentence": "Several basic leucine zipper ( B-ZIP ) transcription factors have been implicated in cancer , substance abuse , and other pathological conditions . We previously identified arylstibonic acids that bind to B-ZIP proteins and inhibit their interaction with DNA . In this study , we used electrophoretic mobility shift assay to analyze 46 arylstibonic acids for their activity to disrupt the DNA binding of three B-ZIP [ CCAAT/enhancer-binding protein \\u03b1 , cyclic AMP-response element-binding protein ( CREB ) , and vitellogenin gene-binding protein ( VBP) ] and two basic helix-loop-helix leucine zipper ( B-HLH-ZIP ) [ USF ( upstream stimulating factor ) and Mitf ] proteins . Twenty-five arylstibonic acids showed activity at micromolar concentrations . The most active compound , P6981 [ 2-(3-stibonophenyl)malonic acid ] , had half-maximal inhibition at nM for CREB . Circular dichroism thermal denaturation studies indicated that P6981 binds both the B-ZIP domain and the leucine zipper . The crystal structure of an arylstibonic acid , NSC13778 , bound to the VBP leucine zipper identified electrostatic interactions between both the stibonic and carboxylic acid groups of NSC13778 [ (E)-3-(3-stibonophenyl)acrylic acid ] and arginine side chains of VBP , which is also involved in interhelical salt bridges in the leucine zipper . P6981 induced GFP-B-ZIP chimeric proteins to partially localize to the cytoplasm , demonstrating that it is active in cells . P6981 inhibited the growth of a patient-derived clear cell sarcoma cell line whose oncogenic potential is driven by a chimeric protein EWS-ATF1 ( Ewing's sarcoma protein-activating transcription factor 1 ) , which contains the DNA binding domain of ATF1 , a B-ZIP protein . NSC13778 inhibited the growth of xenografted clear cell sarcoma , and no toxicity was observed . These experiments suggest that antimony containing arylstibonic acids are promising leads for suppression of DNA binding activities of B-ZIP and B-HLH-ZIP transcription factors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22851716"}
{"sentence": "We present a new cell line , EJ established from an invasive endometrioid adenocarcinoma of the uterine corpus in a 56-year-old patient . The cells show rapid growth in culture with a doubling time of 16 h and high migration activity . Monolayer-cultured cells were polygonal in shape showing a tendency to pile up without contact inhibition . Subcutaneous transplantation of the EJ cells into nude mice formed solid tumors that were histologically diagnosed as adenocarcinoma , whereas no metastasis was observed . Cultured EJ cells produced tissue polypeptide antigen ( IPA ) . Genetic and molecular analyses revealed high telomerase activity but not estrogen receptor alpha expression . Using the DNA sequencing technique , we have screened EJ cells for p53 mutation in exon 5 to 8 but no mutation of p53 was observed . This cell line appears to represent the development of a more malignant clone with divergent receptor function and growth behavior , and provides us with an interesting new tool for the study of tumorigenesis in the human endometrium .", "label": [1, 0, 0, 0, 1, 1, 0, 0, 1, 0], "id": "12889855"}
{"sentence": "BACKGROUND O(6) -methylguanine-DNA methyltransferase ( MGMT ) is a DNA repair enzyme that can protect cells from carcinogenic effects of alkylating agents by removing adducts from the O(6) position of guanine . Evidences indicated that areca quid chewing may increase the risk of oral squamous cell carcinoma ( OSCC ) . This study was to investigate the role of MGMT expression in OSCCs and the normal oral tissues . METHODS Thirty-two OSCCs from areca quid chewers and ten normal oral tissue biopsy samples without areca quid chewing were analyzed by the immunohistochemistry for MGMT . Primary human oral keratinocytes ( HOKs ) were challenged with arecoline , the major alkaloid of areca nut , by Western blot . Nicotine , an important component of cigarette smoke , was added to find the possible regulatory mechanisms . RESULTS Significant association was observed between low MGMT expression and advanced clinical stage of OSCCs and lymph node metastasis ( P=0.03 ) . MGMT expression was significantly higher in patients only chewing areca quid than patients both chewing areca quid and smoking ( P=0.028 ) . Arecoline was found to elevate MGMT expression in a dose- and time-dependent manner . The addition of nicotine was found to enhance arecoline-induced MGMT expression . CONCLUSION Our results indicate that MGMT could be used clinically as a predictive marker for tumor processing , the potential for lymph node metastasis as well as advanced clinical stage . MGMT expression was significantly upregulated by arecoline in HOKs . Nicotine has a synergistic effect of arecoline-induced MGMT expression . The cigarette smoking may act synergistically in the pathogenesis of OSCC in areca quid chewers via the upregulation of MGMT .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23278137"}
{"sentence": "Reactive oxygen species ( ROS ) produced by phagocytic cells induce oxidative stress during chronic inflammation . ROS play a role in the pathogenesis of a broad range of diseases including autoimmune , cardiac and neoplastic abnormalities . We found that sera of patients with a variety of inflammatory dermatoses contain elevated levels of antibodies ( Ab ) binding to an oxidized DNA base derivative , 5-hydroxymethyl-2'deoxyuridine ( HMdU ) coupled to bovine serum albumin , as determined by the enzyme-linked immunosorbent assay . Patients with immune complex diseases and a history of neoplasm elaborated the highest titers of anti-HMdU Ab . Titers from sera of psoriatic subjects were lower than from the aforementioned groups but were still significantly elevated ( p < 0.001 ) above those of healthy controls . Treatment of inflammatory dermatoses with systemic antiinflammatory and cytotoxic drugs significantly lowered the titers [ p < 0.005 ( immune complex ) or p < 0.001 ( psoriasis and neoplastic ) diseases ] , suggesting that this assay may be of value in monitoring the response to therapy in these diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1365325"}
{"sentence": "INTRODUCTION Characterized by the development of hundreds to thousands of colonic adenomas , classic familial adenomatous polyposis ( FAP ) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer . Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However , there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 CASE PRESENTATION A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent , worsening , left lower quadrant abdominal pain . She had no family history of malignancy . Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon . Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa . Endoscopy revealed innumerable polyps . Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5 , resulting in a premature truncation of the APC protein at amino acid position 1312 . CONCLUSION Genetic information has only recently started being incorporated into clinical care . More research and randomized clinical trials need to be conducted to definitively characterize random mutations . Once these mutations are further understood , FAP patients may be able to be risk stratified and this may ultimately improve the screening , diagnosis , and treatment of this rare condition .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23115482"}
{"sentence": "OBJECTIVES To evaluate and compare the incidence , TNM staging and the current strate- gy for the surgical treatment of renal cell carcinoma ( RCC ) in two European urologic institutions , situated in Varna , Bulgaria and in Bari , Italy . Both clinics have sound experience of RCC surgery , and modern laparoscopic equipment . A retrospective chart review of all patients with RCC diagnosed and treated in the last year was conducted at the two sites . MATERIALS AND METHODS In total , 88 patients ( 66 males and 22 females , mean age 58 years , range 24-81 years ) were enrolled in the study . Comparisons were made between some clinical and pathologic parameters with an established prognostic and therapeutic impact . The type of surgery perormed at both sites was analyzed as well . All these comparative studies were performed in relation to the 2008 EAU guidelines on the current management of RCC . Commercially available statistical software was used for the purpose . RESULTS The results showed no difference between the two sites regarding the RCC incidence and the patients ' age and gender . Significant differences ( p value < 0.0001 ) emerged in terms of : the median size of the tumors at surgery ( 8.5 cm in Varna , SD + 4.04 vs. 4.4 cm in Bari , SD _ 2.02 ) ; T-stage of the tumor ( Varna T T2-30% , T3-22% , T4-15% vs. Bari T1-64% , T2-12% , T3-24% , T4-0% ) ; N-positive disese ( 24% vs. 2% ) ; distant metastases ( 20% vs. 2% ) and presence of necrosis in the renal masses ( 37% vs. 19% ) . Thus , 85% of Varna patients underwent open radical nephrectomy , 11% nephron-sparing surgery and 4% explorative laparotomy , due to inoperability of the renal mass . Only 29% of Bari patients were treated by open radical nephrectomy , 12% underwent laparoscopic nephrectomy , 57% open partial nephrectomy and 2% laparoscopic partial tumor resection . Conclusions : These numbers demonstrate more advantageous tumour features at the Italian clinic in terms of organ-sparing surgical options ( open and laparoscopic ) , whereas in the Bulgarian clinic the tumour features pose certain limitations to the application of modern surgical techniques . This difference is due to early diagnosis of RCC in Italy , allowing treatment of smaller volume tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20593709"}
{"sentence": "PURPOSE Tamoxifen , a selective oestrogen receptor modulator ( SERM ) , and brivanib alaninate , a vascular endothelial growth factor receptor 2 ( VEGFR-2 ) inhibitor , are two target specific agents that result in a substantial decrease in tumour growth when given alone . Tamoxifen activates SERM stimulated breast and endometrial tumour growth . Tamoxifen and brivanib alaninate have side-effects that can affect therapeutic outcomes . The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive , oestrogen stimulated tumour xenografts ( MCF-7 E2 tumours ) . Experiments were conducted to evaluate the response of SERM stimulated breast ( MCF-7 Tam , MCF-7 Ral ) and endometrial tumours ( EnCa 101 ) to demonstrate the activity of brivanib alaninate in SERM resistant models . EXPERIMENTAL DESIGN In the current study , tumour xenografts were minced and bi-transplanted into the mammary fat pads of athymic , ovariectomised mice . Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumour growth . Doses of 125 microg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated . An experiment was designed to evaluate the effect of the two agents together when started at the time of tumour implantation . An additional experiment was done in which tumours were already established and then treated , to obtain enough tumour tissue for molecular analysis . RESULTS Brivanib alaninate was effective at inhibiting tumour growth in SERM sensitive ( MCF-7 E2 ) and SERM stimulated ( EnCa 101 , MCF-7 Ral , MCF-7 Tam ) models . The effect of the low dose drug combination as an anti-tumour strategy for SERM sensitive ( MCF-7 E2 ) in early treatment was as effective as higher doses of either drug used alone . In established tumours , the combination is successful at decreasing tumour growth , while neither agent alone is effective . Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumours that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA . Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate . There was also increased necrosis in tumours treated with brivanib alaninate . CONCLUSION Historically , tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER . Tamoxifen and a low dose of an angiogenesis inhibitor , brivanib alaninate , can potentially be combined not only to maximise therapeutic efficacy but also to retard SERM resistant tumour growth .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "20303261"}
{"sentence": "BACKGROUND Ginkgolic acids ( GAs ) , extracted from the seed coat of Ginkgo biloba L. Our previous study has shown that GA monomer could inhibit the growth of Hep-2 significantly and induce the fragmentation of the chromosomal DNA . To further assess the antitumor potential and turn it into a candidate new antitumor drug , the antitumor mechanism of GA was investigated . METHOD The cytotoxicity and antitumor effect of GA monomer were assayed by MTT colorimetric assay with nontumorogenic MC-3T3-E1 as well as tumorogenic Hep-2 and Tac8113 cell lines . The effect of GA monomer on the proliferation of tumor cell lines was analyzed with MTT colorimetric and CFSE labeled assay . Cell cycle distribution and measurement of the percentage of apoptotic cells were performed by flow cytometry following stained with propidium iodide , annexin V-FITC . The expression of apoptotic proteins Bcl-2 , Bax and caspase-3 was analyzed with Western blot . RESULT GA only inhibited the growth of tumorogenic cell lines in a both dose- and time-dependent manner . Tumor cells were treated with GA for 72 h , 70.53 \u00b1 4.54% Hep-2 and 63.5 \u00b1 7.2% Tca8113 cells were retarded at GO/G1 phase , and the percentage of apoptosis was 40.4 \u00b1 1.58 and 38.4 \u00b1 1.7% , respectively . GA-treated activated caspase-3 downregulated the expression of anti-apoptotic Bcl-2 protein and upregulated the expression of pro-apoptotic Bax protein , eventually leading to a decrease in the Bcl-2/Bax ratio in tumor cells . CONCLUSIONS The antitumor action of GA was due to inhibiting the proliferation in a manner of inhibiting division , retarding the progress of cell cycle and inducing apoptosis , making GA a candidate as new antitumor drug .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "20948210"}
{"sentence": "Epidemiological studies have indicated that obesity is associated with colorectal cancer . The obesity hormone leptin is considered as a key mediator for cancer development and progression . The present study aims to investigate regulatory effects of leptin on colorectal carcinoma . The expression of leptin and its receptor Ob-R was examined by immunohistochemistry in 108 Chinese patients with colorectal carcinoma . The results showed that leptin/Ob-R expression was significantly associated with T stage , TNM stage , lymph node metastasis , distant metastasis , differentiation and expression of p-mTOR , p-70S6 kinase , and p-Akt . Furthermore , the effects of leptin on proliferation and apoptosis of HCT-116 colon carcinoma cells were determined . The results showed that leptin could stimulate the proliferation and inhibit the apoptosis of HCT-116 colon cells through the PI3K/Akt/mTOR pathway . Ly294002 ( a PI3K inhibitor ) and rapamycin ( an mTOR inhibitor ) could prevent the regulatory effects of leptin on the proliferation and apoptosis of HCT-116 cells via abrogating leptin-mediated PI3K/Akt/mTOR pathway . All these results indicated that leptin could regulate proliferation and apoptosis of colorectal carcinoma through the PI3K/Akt/ mTOR signalling pathway .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22357207"}
{"sentence": "The cellular mechanisms of anti-androgen-induced tumor regression have not been investigated in great detail . We have compared the induction of cell death in the androgen-dependent , non-invasive LNCaP prostate cancer cell line by Casodex and TNF-alpha . Both agents induce a dose and time-dependent decrease in cell viability in vitro . However , Casodex does not induce classical DNA fragmentation to oligonucleosomes typically induced by TNF-alpha , but rather induces cleavage to form intermediate 60 kb DNA fragments . RT-PCR based analysis demonstrates that in LNCaP cells Casodex coordinately alters the expression of steady-state level of mRNAs of several matrix metalloproteases and their cognate inhibitors ( most notably MMP2 and TIMP1 ) . Zymography and reverse zymography confirm that the ratio of metalloprotease(s) to inhibitor(s) is altered in favor of activation of the proteases . In a small percentage of the treated LNCaP cells , the activation of the extracellular matrix ( ECM)-proteases by Casodex also induces an invasive phenotype . The acquisition of an invasive phenotype is not seen when LNCaP cells are treated with TNF-alpha , and is not seen when the LNCaP cells are treated with both compounds simultaneously , suggesting that the phenomenon may be specific to particular classes of compounds . These observations have significant implications in the treatment of prostate cancer , since the appearance of a more aggressive phenotype following treatment is clearly undesirable .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12650706"}
{"sentence": "BACKGROUND Expression of epidermal growth factor receptor ( EGFR ) , a potent regulator of cellular homeostasis , is associated with aggressive tumor behavior . The mechanism by which EGFR inhibition functions is unclear , with controversial results demonstrating an effect on the tumor cells , endothelial cells , or pericytes . EGFR activation has been linked to the expression of vascular endothelial growth factor ( VEGF ) , a known mitogen of angiogenesis , but the relationship between these factors and their effect on tumor vessel development is vague . We hypothesized that using an EGFR inhibitor on a human Ewing's sarcoma model would inhibit tumor growth by suppressing vessel proliferation . METHODS A cell proliferation assay was performed on the Ewing's sarcoma ( SK-NEP-1 ) cell line . Tumor cells were implanted intrarenally in athymic mice . Animals received daily gavage with vehicle or gefitinib 1 wk following implantation . Mice ( n = 12/cohort ) were euthanized 6 wk following implantation . Remaining mice were maintained without treatment for 2 wk . Vascular changes were assessed by angiography and immunohistochemically . EGFR and vascular endothelial growth factor ( VEGF ) expression were quantified using quantitative polymerase chain reaction ( qPCR ) . RESULTS Gefitinib suppressed in vitro cell growth with an IC(50) = 1.36 \u03bcM . Minimal tumor growth suppression was noted at 6 wk ( 6.01 \ufffd 1.2 g in control versus 4.61 \ufffd 0.9 g treated , P = 0.36 ) . After cessation of gefitinib , tumor growth was increased in both groups ( 7.37 \ufffd 1.62 g versus 6.77 \ufffd 1.53 g , P = 0.79 ) . Microvessel density was unchanged despite EGFR inhibition ( 161,000 \ufffd 16,000 pixels versus 135,000 \ufffd 18,000 pixels , P = 0.31 ) . At 6 wk , the vascular maturity index was similar in both groups ( 3.63 \ufffd 1.12 versus 4.09 \ufffd 1.71 , P = 0.83 ) . A downward trend in EGFR expression ( 49% of control ) and an upward trend in VEGF levels ( 50% of control ) occurred in the treated group . CONCLUSIONS EGFR expression was suppressed in cultured cells and xenograft tumors . Despite a cytotoxic effect on cell lines , gefitinib had little effect on tumor growth . No effects on the tumor vasculature were noted in the setting of EGFR suppression , suggesting that angiogenesis induced by SK-NEP-1 cells is refractory to EGFR inhibition . Interestingly , the resulting increase in VEGF expression following EGFR blockade , provides an alternative pro-angiogenic pathway promoting tumor survival .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "21658718"}
{"sentence": "BACKGROUND Barrett's esophagus ( BE ) is caused by gastroesophageal reflux with consecutive mucosal inflammation , predisposing patients to the development of esophageal adenocarcinoma ( EAC ) . We investigated changes in T cell-related mucosal combinatorial molecular protein patterns in both diseases using the novel Multi-Epitope-Ligand-Cartography , a unique robotic whole-cell imaging technology that simultaneously visualizes dozens of proteins in structurally intact tissues and correlates cellular localization of proteins with function . RESULTS Biopsies were taken during endoscopy from BE , EAC , and normal control tissue , and proteomic microscopy was performed on 32 different epitopes . When the significance level was set to p < 0.0005 and the search depth to five antibody combinations , controls and BE can be differentiated by 63 , controls and EAC by 3222 , and BE from EAC by 1521 distinct protein combinations.For example , the number of activated apoptotic na\u00efve and memory T cells was significantly increased only in BE , whereas the number of activated apoptotic helper and regulatory T cells was significantly elevated in BE and EAC . In contrast , the number of activated apoptotic cytotoxic T cells was significantly elevated only in EAC . Confirming different pathways in BE and EAC , the number of T lymphocytes with p53 expression and downregulation of bcl2 expression ( CD3+p53+Bcl2-NfkB- ) was significantly increased in EAC compared to BE and controls . Interestingly , the number of precursor T cells ( CD7+ ) was significantly elevated only in EAC . These cells lack Bax and caspase-8 , suggesting impaired apoptosis in the early stages of T cell differentiation . CONCLUSION Proteomic analysis showed for the first time that proteins , which are critically involved in the mucosal immune system of the esophagus , are distinctly expressed in BE and EAC , whereas others are comparably altered in both diseases , suggesting that many pathogenic events might be shared by both diseases . Topological proteomic analysis , therefore , helps us to understand the different pathogenic events in the underlying disease pathways .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20604962"}
{"sentence": "The prediction of response or severe toxicity and therapy individualisation are extremely important in cancer chemotherapy . There are few tools to predict chemoresponse or toxicity in cancer patients . We investigated the correlation between the induction and repair of DNA double-strand breaks ( DSBs ) using constant-field gel electrophoresis ( CFGE ) and evaluating cell cycle progression and the sensitivity of four cancer cell lines to 5-fluorouracil ( 5FU ) . Using a sulphorhodamine-B assay , colon carcinoma cells ( HCT116 ) were found to be the most sensitive to 5FU , followed by liver carcinoma cells ( HepG2 ) and breast carcinoma cells ( MCF-7 ) . Cervical carcinoma cells ( HeLa ) were the most resistant . As measured by CFGE , DSB induction , but not residual DSBs , exhibited a significant correlation with the sensitivity of the cell lines to 5FU . Flow cytometric cell cycle analysis revealed that 14% of HCT116 or HepG2 cells and 2% of MCF-7 cells shifted to sub-G1 phase after a 96-h incubation with 5FU . Another 5FU-induced cell cycle change in HCT116 , HepG2 and MCF-7 cells was the mild arrest of cells in G1 and/or G2/M phases of the cell cycle . In addition , 5FU treatment resulted in the accumulation of HeLa cells in the S and G2/M phases . Determination of Fas ligand ( Fas-L ) and caspase 9 as representative markers for the extrinsic and intrinsic pathways of apoptosis , respectively , revealed that 5FU-induced apoptosis in HCT116 and HepG2 results from the expression of Fas-L ( extrinsic pathway ) . Therefore , the induction of DNA DSBs by 5FU , detected using CFGE , and the induction of apoptosis are candidate predictive markers that may distinguish cancer cells which are likely to benefit from 5FU treatment and the measurement of DSBs using CFGE may aid the prediction of clinical outcome .", "label": [0, 0, 0, 0, 1, 1, 0, 1, 1, 0], "id": "23255942"}
{"sentence": "Ultraviolet ( UV ) light induces DNA-damage checkpoints and mutagenesis , which are involved in cancer protection and tumorigenesis , respectively . How cells identify DNA lesions and convert them to checkpoint-activating structures is a major question . We show that during repair of UV lesions in noncycling cells , Exo1-mediated processing of nucleotide excision repair ( NER ) intermediates competes with repair DNA synthesis . Impediments of the refilling reaction allow Exo1 to generate extended ssDNA gaps , detectable by electron microscopy , which drive Mec1 kinase activation and will be refilled by long-patch repair synthesis , as shown by DNA combing . We provide evidence that this mechanism maybe stimulated by closely opposing UV lesions , represents a strategy to redirect problematic repair intermediates to alternative repair pathways , and may also be extended to physically different DNA damages . Our work has significant implications for understanding the coordination between repair of DNA lesions and checkpoint pathways to preserve genome stability .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20932474"}
{"sentence": "The Hippo signaling pathway inhibits cell growth and regulates organ size through a kinase cascade that leads to the phosphorylation and nuclear exclusion of the growth-promoting transcriptional coactivator Yes-associated protein ( YAP)/Yorkie . It mediates contact inhibition of cell growth downstream of cadherin adhesion molecules and other cell surface proteins . Contact inhibition is often antagonized by mitogenic growth factor signaling . We report an important mechanism for this antagonism , inhibition of Hippo pathway signaling by mitogenic growth factors . EGF treatment of immortalized mammary cells triggers the rapid translocation of YAP into the nucleus along with YAP dephosphorylation , both of which depend on Lats , the terminal kinase in the Hippo pathway . A small-molecule inhibitor screen of downstream effector pathways shows that EGF receptor inhibits the Hippo pathway through activation of PI3-kinase ( PI3K ) and phosphoinositide-dependent kinase ( PDK1 ) , but independent of AKT activity . The PI3K-PDK1 pathway also mediates YAP nuclear translocation downstream of lysophosphatidic acid and serum as a result of constitutive oncogenic activation of PI3K . PDK1 associates with the core Hippo pathway-kinase complex through the scaffold protein Salvador . The entire Hippo core complex dissociates in response to EGF signaling in a PI3K-PDK1-dependent manner , leading to inactivation of Lats , dephosphorylation of YAP , and YAP nuclear accumulation and transcriptional activation of its target gene , CTGF . These findings show that an important activity of mitogenic signaling pathways is to inactivate the growth-inhibitory Hippo pathway and provide a mechanism for antagonism between contact inhibition and growth factor action .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23359693"}
{"sentence": "Cancer therapy with rapamycin has been successfully implemented for kidney cancer , glioblastoma and prostate cancer . However , there are few studies concerning the effects of rapamycin on the treatment of human melanoma . In this study , we investigated whether rapamycin may be a promising strategy for the effective treatment of melanoma and explored the possible mechanism for this by culturing M14 cells in vitro and treating with rapamycin at three concentrations ( 10 , 50 or 100 nmol/l ) . MDC and LC3B staining , western blot analysis , flow cytometry and transmission electron microscopy were employed . We revealed that rapamycin induced autophagy and inhibited the proliferation of M14 cells in a concentration-dependent manner , Furthermore , western blot analysis revealed an upregulated expression of Bcl-2 and downregulated expression of Bax in M14 cells . In conclusion , rapamycin induced autophagy and inhibited the growth of M14 cells . The mechanism may involve regulation of the expression of Bcl-2 family proteins . Rapamycin appears to be a promising strategy for the effective treatment of melanoma .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23255914"}
{"sentence": "We have identified a rare small ( kb unique sequence ) recurrent deletion in a previously linked attention-deficit hyperactivity disorder ( ADHD ) locus at 2q21.1 in five unrelated families with developmental delay ( DD)/intellectual disability ( ID ) , ADHD , epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis . Additionally , a DECIPHER ( http://decipher.sanger.ac.uk ) patient 2311 was found to have the same deletion and presented with aggressive behavior . The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database . We have also identified reciprocal duplications in five unrelated families with autism , developmental delay ( DD ) , seizures and ADHD . This genomic region is flanked by large , complex low-copy repeats ( LCRs ) with directly oriented subunits of kb in size that have 97.7% DNA sequence identity . We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters , demonstrating non-allelic homologous recombination as a mechanism of formation . The rearranged segment harbors five genes : GPR148 , FAM123C , ARHGEF4 , FAM168B and PLEKHB2 . Expression of ARHGEF4 ( Rho guanine nucleotide exchange factor 4 ) is restricted to the brain and may regulate the actin cytoskeletal network , cell morphology and migration , and neuronal function . GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes . We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID , ADHD , epilepsy and other neurobehavioral abnormalities and , because of its small size , low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22543972"}
{"sentence": "In an attempt to find a strategy to modulate the proliferation of vascular endothelial cells , we examined whether constitutive activation of proto-oncogen protein p21 ( Ras ) induced the reentry of confluent human umbilical vascular endothelial cells ( HUVECs ) into the S phase . When an adenovirus construct expressing a constitutively active Ras mutant ( Ad/RasG12V ) was infected into HUVECs , their morphology changed strikingly and they appeared to be transformed . However , Ad/RasG12V-infected HUVECs did not enter the S phase , as determined by assessing 3H-thymidine incorporation . In accordance with the above results , the expression of cyclin A both at the transcript and protein levels did not increase in Ad/RasG12V-infected HUVECs relative to that in control cells , although the expression of cyclin D1 was induced in Ad/RasG12V-infected cells . Interestingly , the expression of the cyclin-dependent kinase ( CDK ) inhibitor p21cip1 was remarkably increased while that of p27kip1 did not decrease in Ad/RasG12V-infected HUVECs . Furthermore , CDK2 activity was not induced in Ad/RasG12V-infected HUVECs . These results suggested that the constitutive activation of Ras promoted the reentry of confluent HUVECs in the G0 phase into the G1 phase , but not into the S phase . The results also indicated that the constitutive activation of Ras might have induced the persistent expression of p21cip1 and p27kip1 , and that this induction of p21cip1 and p27kip1 expression possibly caused the cell cycle arrest at the G1 phase .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12452332"}
{"sentence": "Tumor cells are surrounded by infiltrating inflammatory cells , such as lymphocytes , neutrophils , macrophages , and mast cells . A body of evidence indicates that mast cells are associated with various types of tumors . Although role of mast cells can be directly related to their granule content , their function in angiogenesis and tumor progression remains obscure . This study aims to understand the role of mast cells in these processes . Tumors were chemically induced in BALB/c mice and tumor progression was divided into Phases I , II and III . Phase I tumors exhibited a large number of mast cells , which increased in phase II and remained unchanged in phase III . The expression of mouse mast cell protease ( mMCP)-4 , mMCP-5 , mMCP-6 , mMCP-7 , and carboxypeptidase A were analyzed at the 3 stages . Our results show that with the exception of mMCP-4 expression of these mast cell chymase ( mMCP-5 ) , tryptases ( mMCP-6 and 7 ) , and carboxypeptidase A ( mMC-CPA ) increased during tumor progression . Chymase and tryptase activity increased at all stages of tumor progression whereas the number of mast cells remained constant from phase II to III . The number of new blood vessels increased significantly in phase I , while in phases II and III an enlargement of existing blood vessels occurred . In vitro , mMCP-6 and 7 are able to induce vessel formation . The present study suggests that mast cells are involved in induction of angiogenesis in the early stages of tumor development and in modulating blood vessel growth in the later stages of tumor progression .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22815822"}
{"sentence": "Breast cancer is the malignant neoplasia with the highest incidence in women worldwide . Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression . Human studies have not considered the complexity of tumor biology during the stages of cancer advance , limiting their clinical application . The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early ( ED ; TNM I and II ) and advanced disease ( AD ; TNM III and IV ) of patients diagnosed with infiltrative ductal carcinoma breast cancer . Oxidative stress parameters were evaluated by plasmatic lipoperoxidation , carbonyl content , thiobarbituric reactive substances ( TBARS ) , nitric oxide levels ( NO ) , total radical antioxidant parameter ( TRAP ) , superoxide dismutase , and catalase activities and GSH levels . Immune evaluation was determined by TNF-\u03b1 , IL-1\u03b2 , IL-12 , and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence . Tissue damage analysis included heart ( total CK and CKMB ) , liver ( AST , ALT , GGT ) , and renal ( creatinine , urea , and uric acid ) plasmatic markers . C-reactive protein ( CRP ) and iron metabolism were also evaluated . Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages . ED was characterized by reduction in catalase , 8-isoprostanes , and GSH levels , with enhanced lipid peroxidation and TBARS levels . AD exhibited more pronounced oxidative status , with reduction in catalase activity and TRAP , intense lipid peroxidation and high levels of NO , TBARs , and carbonyl content . ED patients presented a Th2 immune pattern , while AD exhibited Th1 status . CRP levels and ferritin were increased in both stages of disease . Leukocytes burst impairment was observed in both the groups . Plasma iron levels were significantly elevated in AD . The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22048816"}
{"sentence": "Enhanced glycolysis represents a striking feature of cancers and can therefore serve to indicate a malignant transformation . We have developed a noninvasive , quantitative method to characterize tumor glycolysis by monitoring ( 13)C-labeled glucose and lactate with magnetic resonance spectroscopy . This method was applied in MCF7 human breast cancer implanted in the mammary gland of female CD1-NU mice and was further employed to assess tumor response to hormonal manipulation with the antiestrogen tamoxifen . Analysis of the kinetic data based on a unique physiological-metabolic model yielded the rate parameters of glycolysis , glucose perfusion , and lactate clearance in the tumor , as well as glucose pharmacokinetics in the plasma . Treatment with tamoxifen induced a twofold reduction in the rate of glycolysis and of lactate clearance but did not affect the other parameters . This metabolic monitoring can thus serve to evaluate the efficacy of new selective estrogen receptor modulators and may be further extended to improve diagnosis and prognosis of breast cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "12217878"}
{"sentence": "p53 plays an important role in regulating a wide variety of cellular processes , such as cell cycle arrest and/or apoptosis . Dysfunction of p53 is frequently associated with several pathologies , such as cancer and neurodegenerative diseases . In recent years substantial progress has been made in developing novel p53-activating molecules . Importantly , modulation of p53 interaction with its main inhibitor , Mdm2 , has been highlighted as a promising therapy target . In this regard , bimolecular fluorescence complementation ( BiFC ) analysis , by providing direct visualization of protein interactions in living cells , offers a straightforward method to identify potential modulators of protein interactions . In this study , we developed a simple and robust Venus-based BiFC system to screen for modulators of p53-p53 and p53-Mdm2 interactions in live mammalian cells . We used nutlin-3 , a well-known disruptor of p53-Mdm2 interaction , to validate the specificity of the assay . The reduction of BiFC signal mediated by nutlin-3 was correlated with an increase in Puma transactivation , PARP cleavage , and cell death . Finally , this novel BiFC approach was exploited to identify potential modulators of p53-Mdm2 complex formation among a commercially available chemical library of 33 protein phosphatase inhibitors . Our results constitute \" proof-of-concept \" that this model has strong potential as an alternative to traditional target-based drug discovery strategies . Identification of new modulators of p53-p53 and p53-Mdm2 interactions will be useful to achieve synergistic drug efficacy with currently used anti-tumor therapies .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23261524"}
{"sentence": "Hematopoietic stem cell transplantation is used for treatment of lymphoma . In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen , we investigated the cytotoxicity of the combination of busulfan ( B ) , melphalan ( M ) , and gemcitabine ( G ) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes . Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay , flow cytometry , and Western blotting . We used drug concentrations ( 57 \u03bcM B , 1 \u03bcM M and 0.02 \u03bcM G ) , which individually did not have major effects on cell proliferation . Their combination resulted in 50% inhibition of proliferation . Reduction to almost half concentration ( 20 \u03bcM B , 0.7 \u03bcM M and 0.01 \u03bcM G ) did not have significant effects , but addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid ( 0.6 \u03bcM ) to this combination resulted in a marked ( growth inhibition . The cytotoxicity of these combinations correlates with the activation of the ataxia telangiectasia mutated-CHK2 pathway , phosphorylation of KRAB-associated protein-1 , epigenetic changes such as methylation and acetylation of histone 3 , and activation of apoptosis . The relevance of epigenetic changes is further shown by the induction of DNA methyltransferases in tumor cells with low constitutive levels of DNMT3A and DNMT3B . The addition of 5-aza-2'-deoxycytidine to ( BMG+suberoylanilide hydroxamic acid ) further enhances cell killing . Overall , BMG combinations are synergistically cytotoxic to lymphoma cells . Epigenetic changes induced by suberoylanilide hydroxamic acid and 5-aza-2'-deoxycytidine further enhance the cytotoxicity . This study provides a rationale for an ongoing clinical trial in our institution using ( BMG+suberoylanilide hydroxamic acid ) as pre-hematopoietic stem cell transplantation conditioning for lymphoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22687754"}
{"sentence": "The anti-breast cancer drug tamoxifen has recently been shown to cause an increase in intracellular free-Ca(2+) concentrations ( [ Ca(2+)](i) ) in renal tubular cells , breast cells and bladder cells . Because tamoxifen is known to alter ovary function in human patients and in rats , the present study was aimed at exploring whether tamoxifen could alter Ca(2+) movement in Chinese hamster ovary ( CHO-K1 ) cells . Cytosolic free-Ca(2+) levels in populations of cells have been explored by using fura-2 as a fluorescent Ca(2+) indicator . Tamoxifen at concentrations above 1 micro M increased [ Ca(2+)](i) in a concentration-dependent manner with an EC(50) value of 8 micro M. The Ca(2+) signal was reduced by removing extracellular Ca(2+) , but was not affected by nifedipine , verapamil , diltiazem or ICI 182,780 ( an estrogen receptor antagonist ) . Pretreatment with 1 micro M thapsigargin ( an endoplasmic reticulum Ca(2+) pump inhibitor ) to deplete the endoplasmic reticulum Ca(2+) abolished 10 micro M tamoxifen-induced Ca(2+) release . Neither inhibition of phospholipase C with 2 micro M U73122 nor depletion of ryanodine-sensitive Ca(2+) stores with 50 micro M ryanodine affected tamoxifen-induced Ca(2+) release . Cell proliferation assays using ELISA revealed that overnight incubation with 5-10 micro M tamoxifen inhibited cell proliferation by 20% , and 20 micro M tamoxifen killed all cells . Together , the results suggest that , in CHO-K1 cells , tamoxifen induced a [ Ca(2+)](i) increase by causing store-Ca(2+) release from the endoplasmic reticulum in an phospholipase C-independent manner , and by inducing Ca(2+) influx . The action of tamoxifen appears to be dissociated from estrogen receptor activation . Longer incubation with tamoxifen ( >5 micro M ) was cytotoxic .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12632256"}
{"sentence": "Benzyl isothiocyanate ( BITC ) is a dietary chemopreventive agent that inhibits the growth of various human cancer cells by causing apoptotic cell death . In this study , we demonstrate that BITC not only induces apoptosis but also induces autophagy in human hormone-sensitive ( Rv1 ) and -refractory ( PC3 ) prostate cancer cells . In BITC-treated cells , the induction of autophagy was detected by monitoring the processing of an autophagy marker protein , microtubule-associated protein 1 light chain 3 ( LC3 ) , the aggregation of LC3 into granular structures and the formation of acidic organelles . Inhibition of autophagy using 3-methyladenine increased BITC-induced apoptosis , whereas the administration of caspase inhibitor suppressed BITC-induced cell death . Our data also showed that BITC inhibits mammalian target of rapamycin ( mTOR ) kinase activity in a dose-dependent manner . The expression of phospho-mTOR ( Ser2481 ) , an indicator of mTOR intrinsic catalytic activity , and phospho-UNC-51-like kinase 1 ( Ser757 ) , a direct substrate of mTOR , were decreased in BITC-treated cells . However , the increased expression of phospho-mTOR ( Ser2448 ) , phospho-AKT ( Ser473 ) and antiapoptotic Bcl-2 were detected only in PC3 cells at later stages of BITC treatment . Collectively , our results show that BITC induces a protective autophagy response in Rv1 and PC3 cells through inhibition of the mTOR signaling pathway . Activation of the AKT survival pathway was only observed in PC3 cells , representing a resistance mechanism of advanced prostate cancer upon BITC treatment . These findings could potentially contribute to the beneficial effect of BITC in prostate cancer treatments .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23172666"}
{"sentence": "Hepatocellular carcinoma ( HCC ) remains a common malignant cancer worldwide . There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches . Herein , we review the structure , function and biology of glypican-3 ( GPC3 ) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy . GPC3 is a cell-surface protein that is over-expressed in HCC . Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome ( SGBS ) , a rare X-linked overgrowth condition . GPC3 binds Wnt and Hedgehog ( Hh ) signalling proteins . GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains . GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC . An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC . There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21112773"}
{"sentence": "MYC oncogene family members are broadly implicated in human cancers , yet are considered \" undruggable \" as they encode transcription factors . MYC also carries out essential functions in proliferative tissues , suggesting that its inhibition could cause severe side effects . We elected to identify synthetic lethal interactions with c-MYC overexpression ( MYC-SL ) in a collection of druggable genes , using high-throughput siRNA screening . Of 49 genes selected for follow-up , 48 were confirmed by independent retesting and approximately one-third selectively induced accumulation of DNA damage , consistent with enrichment in DNA-repair genes by functional annotation . In addition , genes involved in histone acetylation and transcriptional elongation , such as TRRAP and BRD4 , were identified , indicating that the screen revealed known MYC-associated pathways . For in vivo validation we selected CSNK1e , a kinase whose expression correlated with MYCN amplification in neuroblastoma ( an established MYC-driven cancer ) . Using RNAi and available small-molecule inhibitors , we confirmed that inhibition of CSNK1e halted growth of MYCN-amplified neuroblastoma xenografts . CSNK1e had previously been implicated in the regulation of developmental pathways and circadian rhythms , whereas our data provide a previously unknown link with oncogenic MYC . Furthermore , expression of CSNK1e correlated with c-MYC and its transcriptional signature in other human cancers , indicating potential broad therapeutic implications of targeting CSNK1e function . In summary , through a functional genomics approach , pathways essential in the context of oncogenic MYC but not to normal cells were identified , thus revealing a rich therapeutic space linked to a previously \" undruggable \" oncogene .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22623531"}
{"sentence": "Hypoxia is known to play critical roles in cell survival , angiogenesis , tumor invasion , and metastasis . Hypoxia mediated over-expression of hypoxia-inducible factor ( HIF ) has been shown to be associated with therapeutic resistance , and contributes to poor prognosis of cancer patients . Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition ( EMT ) , maintenance of cancer stem cell ( CSC ) functions , and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance . However , the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood . Here , we show , for the first time , that hypoxia leads to increased expression of VEGF , IL-6 , and CSC signature genes Nanog , Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis , and the formation of pancreatospheres , concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer ( PC ) cells . The treatment of PC cells with CDF , a novel synthetic compound inhibited the production of VEGF and IL-6 , and down-regulated the expression of Nanog , Oct4 , EZH2 mRNAs , as well as miR-21 and miR-210 under hypoxia . CDF also led to decreased cell migration/invasion , angiogenesis , and formation of pancreatospheres under hypoxia . Moreover , CDF decreased gene expression of miR-21 , miR-210 , IL-6 , HIF-1\u03b1 , VEGF , and CSC signatures in vivo in a mouse orthotopic model of human PC . Collectively , these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways , and thus CDF could become a novel , and effective anti-tumor agent for PC therapy .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23272057"}
{"sentence": "One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype . Carbon monoxide ( CO ) , one of the products of the cytoprotective molecule heme oxygenase-1 ( HO-1 ) in cancer cells , has been implicated in carcinogenesis and therapeutic resistance . However , the functional contributions of CO and HO-1 to these processes are poorly defined . In human prostate cancers , we found that HO-1 was nuclear localized in malignant cells , with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes . Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy , with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe . CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption , free radical generation , and mitochondrial collapse . Collectively , our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics , ultimately resulting in metabolic exhaustion .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "24121491"}
{"sentence": "The triterpenoid fraction ( 100 and 200 mg/kg ) of the fruit bodies of Ganoderma lucidum inhibited primary solid-tumor growth in the spleen , liver metastasis and secondary metastatic tumor growth in the liver in intrasplenic Lewis lung carcinoma ( LLC)-implanted mice . In addition , the triterpenoid fraction ( 800 micrograms/mL ) inhibited angiogenesis induced by Matrigel ( a soluble basement membrane extract of the Engelbreth-Holm-Swam ( EHS ) tumor ) supplemented with vascular endothelial growth factor ( VEGF ) and heparin in an in vivo model . This suggested that the antitumor and antimetastatic activities of the triterpenoid fraction of G. lucidum might be due to the inhibition of tumor-induced angiogenesis . Next , we attempted to isolate the active substance(s) using the in vivo assay system of Matrigel-induced angiogenesis . The acidic fraction of the triterpenoid fraction inhibited the Matrigel-induced angiogenesis . Compound I was isolated from the acidic fraction as an active substance that inhibited the Martigel-induced angiogenesis . Compound I was identified as ganoderic acid F based on the data of IR , 1H- and 13C-NMR and MS analyses .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12530080"}
{"sentence": "Excessive exposure to solar UVA and UVB radiation is widely considered to cause skin cancers such as squamous cell carcinoma and basalioma . Direct UVB damage to skin cell DNA as well as UV-induced chronic skin inflammation , accelerated keratinocyte proliferation , inhibited apoptosis , and immunosuppression seem to underlie the UV-induced carcinogenesis . Also , UVB induces cytochrome P450 subfamilies ( CYP1A1 and CYP1B1 ) involved in metabolic activation of organic pro-carcinogens and their conversion to ultimate carcinogens . Here , the effects of several glycosylated and non-glycosylated plant polyphenols ( verbascoside , resveratrol , polydatin , rutin , and quercetin ) on the inflammatory , apoptotic , metabolic , and proliferative responses of cultured human epidermal keratinocytes ( HEK ) to non-cytotoxic doses of solar-simulated UVA+UVB and chemical mediators of UV signalling in HEK , 6-formylindolo[3,2-b]carbazole and squalene isolated from photo-oxidized skin surface lipids ( SSL ) , were evaluated . We showed that the stilbenes and quercetin being exposed to UV were photo-destroyed within a short period of time , while verbascoside and rutin were photo-stable . When SSL were exposed to UV , the stilbenes and quercetin remarkably accelerated photo-oxidation of alpha-tocopherol , squalene , and cholesterol fractions , whilst verbascoside protected them . Verbascoside invariably inhibited molecular pathways in HEK leading to inflammatory cytokine expression ( NFkappaB and EGFR/ERK phosphorylation ) , and cell proliferation ( EGFR nuclear translocation ) , and displayed a stimulus-specific effect on the metabolic axis aryl hydrocarbon receptor ( AhR)-CYP1A1/CYP1B1 . By contrast , the stilbenes inhibited UV-connected inflammatory cytokines excluding IL-8 , but they prevalently stimulated NFkappaB , EGFR nuclear translocation and the AhR-CYP pathway . We conclude that , among the PPs investigated , verbascoside does interfere with multiple UV-sensitive signalling in HEK in a way that it could have a major impact on skin cancer chemoprevention .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "23210792"}
{"sentence": "The Wnt/\u03b2-catenin pathway is constitutively activated in over 90% of human colorectal cancer . Activated \u03b2-catenin stimulates cell proliferation and survival , however , its anti-apoptotic mechanisms are not fully understood . We show here that activated \u03b2-catenin is required to suppress caspase-8 activation but only in colon cancer cells that are resistant to tumor necrosis factor-a ( TNF ) induced apoptosis . We found that lysosomal delivery of internalized TNF occurred at a faster pace in apoptosis-resistant than in apoptosis-sensitive colon cancer cells . Retardation of endosomal trafficking through V-ATPase inhibition enhanced caspase-8 activation in the apoptosis-resistant but not sensitive cells . Interestingly , knockdown of \u03b2-catenin also prolonged TNF association with the early endosome and enhanced caspase-8 activation in the apoptosis-resistant but not sensitive colon cancer cells . In a mouse model of inflammation-associated colon tumors , we found nuclear expression of \u03b2-catenin , resistance to TNF-induced apoptosis , and reactivation of apoptosis in vivo by cotreatment of TNF with a V-ATPase inhibitor . Together , these results suggest that activated \u03b2-catenin can facilitate endosomal trafficking of internalized TNF to suppress caspase-8 activation in colon cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23264463"}
{"sentence": "Current palliative chemotherapy ( CT ) regimens achieve clinical benefits in less than 50% of patients treated for metastatic gastric cancers , and long-term survivals are anecdotical . Genetic polymorphisms and differences at the level of transcription in genes involved in biological processes of drug metabolism , DNA repair and drug resistance can explain the observed individual differences in response to drugs , in survival and in different susceptibility to the toxic effects of CT . The possibility to classify patients on the basis of genetic signatures could help in choosing the CT regimen . We present herein an analysis of genetic and expression profiling of three patients affected by metastatic gastric cancer , treated with CT and alive , disease-free , at 66-82 months . Four patients with typical clinical outcome represented the control group . Expression profiling from paraffin-embedded tumor tissues was performed on an ad hoc set of genes involved in drug metabolism and resistance , DNA repair , cell cycle regulation and growth factors signalling . Genetic polymorphism analysis on DNA extracted from peripheral blood was done by pyrosequencing of genetic markers predictive of drug response . Expression analysis in long-term survivors revealed a significant upregulation of PTEN , TP63 , GADD45a and MAPK1 genes . We found also an upregulation of CYP1A1 , CYP3A4 and ERBB4 genes . EGF was found to be down-regulated in long-term survivors . ERCC1 C8092A polymorphism seems to be associated with survival in our set of patients . The present study shed light on a set of genes , which could have a predictive role in survival of patients with metastatic gastric tumors .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "20878069"}
{"sentence": "Vascular endothelial growth factor ( VEGF ) has emerged as one of the most important angiogenic growth factors from experimental in vitro and in vivo studies . In the present study , we investigated the relationship between VEGF expression and microvessel density ( MVD ) and defined their prognostic relevance on a series of 242 patients with node-negative breast cancer , using immunohistochemical methods . In parallel , estrogen and progesterone receptors were quantitatively assessed using the dextran-charcoal technique and cell proliferation was evaluated as S-phase cell fraction according to ( 3)H-thymidine-labeling index ( TLI ) . The percentage of VEGF-expressing cells varied from 0-95% in the different tumors and was unrelated to menopausal status , tumor size or steroid receptor status . Conversely , a significant inverse relation was observed with patient age or tumor cell proliferation , albeit with very poor correlation coefficients . A significant relation was observed between VEGF expression and MVD ( r(s) = 0.55 , p < 0.001 ) . Clinical outcome analyzed as a function of high and low VEGF expression showed slight differences in terms of both disease-free survival ( DFS ) and overall survival ( OS ) that never reached statistical significance . Moreover , the trend was paradoxically in favor of patients with highly VEGF-expressing tumors . Finally , DFS and OS curves , when analyzed as a function of VEGF expression or MVD , were superimposable . In conclusion , our study did not highlight a prognostic relevance of VEGF expression in patients with node-negative breast cancer , as already observed for MVD .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "11857413"}
{"sentence": "Growth of Caco-2 and many cancer cells is inhibited by 1,25(OH)(2)D(3) . Whereas TGF-beta 1 inhibits normal colonic epithelial cell growth , most human colon cancer-derived cells , including Caco-2 and SW480 cells , are resistant to it . The mechanisms underlying these antiproliferative actions and resistance to TGF-beta growth inhibition are largely unknown . We observed that 1,25-dihydroxyvitamin D(3) [ 1,25(OH)(2)D(3) ] sensitized Caco-2 and SW480 cells to TGF-beta 1 growth inhibitory effects . Versus 1,25(OH)(2)D(3) alone , the combination of 1,25(OH)(2)D(3) and TGF-beta 1 significantly reduced cell numbers . Also , the amount of active TGF-beta 1 was increased ( by this secosteroid in conditioned media from Caco-2 cells . The 1,25(OH)(2)D(3) increased the expression of IGF-II receptors ( IGF-IIR ) , which facilitated activation of latent TGF-beta 1 , and was found to activate TGF-beta signaling in Caco-2 cells . By using neutralizing antibodies to human TGF-beta 1 , we showed that this cytokine contributes to secosteroid-induced inhibition of Caco-2 cell growth . Also , 1,25(OH)(2)D(3) was found to enhance the type I TGF-beta receptor mRNA and protein abundance in Caco-2 cells . Whereas the 1,25(OH)(2)D(3)-induced sensitization of Caco-2 cells to TGF-beta 1 was IGF-IIR independent , the type I TGF-beta 1 receptor was required for this sensitization . Thus 1,25(OH)(2)D(3) treatment of Caco-2 cells results in activation of latent TGF-beta 1 , facilitated by the enhanced expression of IGF-IIR by this secosteroid . Also , 1,25(OH)(2)D(3) sensitized Caco-2 cells to growth inhibitory effects of TGF-beta 1 , contributing to the inhibition of Caco-2 cell growth by this secosteroid .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12223346"}
{"sentence": "The hedgehog signaling pathway is important in embryogenesis and post natal development . Constitutive activation of the pathway due to mutation of pathway components occurs in of medulloblastomas and also in basal cell carcinomas . In many other malignancies the therapeutic role for hedgehog inhibition though intriguing , based on preclinical data , is far from assured . Hedgehog inhibition is not an established part of the treatment paradigm of sarcoma but the scientific rationale for a possible benefit is compelling . In chondrosarcoma there is evidence of hedgehog pathway activation and an ontologic comparison between growth plate chondrocyte differentiation and different chondrosarcoma subtypes . Immunostaining epiphyseal growth plate for Indian hedgehog is particularly positive in the zone of pre-hypertrophic chondrocytes which correlates ontologically with conventional chondrosarcoma . In Ewing sarcoma/PNET tumors the Gli1 transcription factor is a direct target of the EWS-FLI1 oncoprotein present in 85% of cases . In many cases of rhabdomyosarcomas there is increased expression of Gli1 ( Ragazzini et al. , 2004 ) . Additionally , a third of embryonal rhabdomyosarcomas have loss of Chr.9q22 that encompasses the patched locus ( Bridge et al. , 2000 ) . The potential to treat osteosarcoma by inhibition of Gli2 and the role of the pathway in ovarian fibromas and other connective tissue tumors is also discussed ( Nagao et al. , 2011 ; Hirotsu et al. , 2010 ) . Emergence of acquired secondary resistance to targeted therapeutics is an important issue that is also relevant to hedgehog inhibition . In this context secondary resistance of medulloblastomas to treatment with a smoothened antagonist in two tumor mouse models is examined .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22906929"}
{"sentence": "In fission yeast cells cortical nodes containing the protein Blt1p and several kinases appear early in G2 , mature into cytokinetic nodes by adding anillin Mid1p , myosin-II , formin Cdc12p , and other proteins , and condense into a contractile ring by movements that depend on actin and myosin-II . Previous studies concluded that cells without Mid1p lack cytokinetic nodes and assemble rings unreliably from myosin-II strands but left open questions . Why do strands form outside the equatorial region ? Why is ring assembly unreliable without Mid1p ? We found in \\u0394mid1 cells that Cdc12p accumulates in cytokinetic nodes scattered in the cortex and produces actin filaments that associate with myosin-II , Rng2p , and Cdc15p to form strands located between the nodes . Strands incorporate nodes , and in of cells , strands slowly close into rings that constrict without the normal maturation period . Ring assembly is unreliable and slow without Mid1p because the scattered Cdc12p nodes generate strands spread widely beyond the equator , and growing strands depend on random encounters to merge with other strands into a ring . We conclude that orderly assembly of the contractile ring in wild-type cells depends on Mid1p to recruit myosin-II , Rng2p , and Cdc15p to nodes and to place cytokinetic nodes around the cell equator .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22918943"}
{"sentence": "Although interferon ( IFN ) has been often used as immunotherapy for bladder cancer , its efficacy is rather unsatisfactory , demanding further improvement . Combination therapy is one of viable options , and grape seed proanthocyanidin ( GSP ) could be such an agent to be used with IFN because it has been shown to have anticancer activity . We thus investigated whether combination of IFN and GSP might enhance the overall antiproliferative effect on bladder cancer cells in vitro . Human bladder cancer T24 cells were employed and treated with the varying concentrations of recombinant IFN-\u03b1(2b) ( 0-100,000 IU/ml ) , GSP ( 0-100 \u03bcg/ml ) , or their combinations . IFN-\u03b1(2b) alone led to a growth reduction at 20,000 ( 20K ) IU/ml , which further declined to at \u226550K IU/ml . Similarly , GSP alone induced a and growth reduction at 25 and \u226550 \u03bcg/ml , respectively . When IFN-\u03b1(2b) and GSP were then combined , combination of 50K IU/ml IFN-\u03b1(2b) and 25 \u03bcg/ml GSP resulted in a drastic >95% growth reduction . Cell cycle analysis indicated that such an enhanced growth inhibition was accompanied by a G(1) cell cycle arrest . This was further confirmed by Western blot analysis revealing that expressions of G(1)-specific cell cycle regulators ( CDK2 , CDK4 , cyclin E and p27/Kip1 ) were distinctly modulated with such IFN-\u03b1(2b)/GSP treatment . Therefore , these findings support the notion that combination of IFN-\u03b1(2b) and GSP is capable of additively enhancing antiproliferative effect on T24 cells with a G(1) cell cycle arrest , implying an adjuvant therapeutic modality for superficial bladder cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22393334"}
{"sentence": "Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus , a medicinal plant that possesses antitumorigenic properties . Our previous findings demonstrated that formononetin initiates growth-inhibitory and pro-apoptotic activities in human colon cancer cells . In the present study , we aimed to further examine the potential of formononetin in controlling angiogenesis and tumor cell invasiveness in human colon cancer cells and tumor xenografts . The results showed that formononetin downregulated the expression of the key pro-angiogenic factors , including vascular endothelial growth factor ( VEGF ) and matrix metalloproteinases . We also discovered that the invasiveness of metastatic colon cancer cells was alleviated following drug treatment . The potential anti-angiogenic effect of formononetin was examined in nude mouse xenografts . The tumor size and the number of proliferating cells were reduced in the tumor tissues obtained from the formononetin-treated group . The serum VEGF level was also reduced in the drug-treated animals when compared to the controls . These findings suggest that formononetin inhibits angiogenesis and tumor cell invasion , and thus support its use in the treatment of advanced and metastatic colon cancers .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23023137"}
{"sentence": "Low-dose cyclophosphamide ( CP ) therapy induces immunogenic tumor cell death and decreases regulatory T cell ( Treg ) numbers in mice with transplantable tumors . Using the ret transgenic murine melanoma model that resembles human melanoma , we detected no beneficial antitumor effects with such treatment , despite a decrease in Tregs . On the contrary , low-dose CP enhanced the production of chronic inflammatory mediators in melanoma lesions associated with increased accumulation of Gr1(+)CD11b(+) myeloid-derived suppressor cells ( MDSCs ) , which exhibit elevated suppressive activity and nitric oxide ( NO ) production as well as inhibition of T-cell proliferation . Moreover , the frequencies of CD8(+) T cells in the tumors and their ability to produce perforin were decreased . To study whether the observed CP-induced MDSC expansion and activation also occurs under chronic inflammatory tumor-free conditions , mice exhibiting chronic inflammation were treated with CP . Similar to tumor-bearing mice , CP-treated inflamed mice displayed elevated levels of MDSCs with enhanced production of NO , reactive oxygen species , and a suppressed in vivo natural killer ( NK ) cell cytotoxic activity indicating CP effects on the host immune system independent of the tumor . We suggest that melanoma therapy with low-dose CP could be efficient only when combined with the neutralization of MDSC immunosuppressive function and chronic inflammatory microenvironment.Journal of Investigative Dermatology advance online publication , 6 December 2012 ; doi:10.1038/jid.2012.444 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23223128"}
{"sentence": "Our previous study demonstrated that 5-aminolevulinic acid ( ALA ) administered to mice stimulates oxidative phosphorylation by upregulation of the mitochondrial respiratory chain complex IV enzyme cytochrome c oxidase ( COX ) . The present study investigated whether ALA disrupts the Warburg effect , which represents a shift in ATP generation from oxidative phosphorylation to glycolysis , protecting tumor cells against oxidative stress-mediated apoptosis . The human lung carcinoma cell line A549 exposed to ALA exhibited enhanced oxidative phosphorylation , which was indicated by an increase in COX protein expression and oxygen consumption . Furthermore , ALA suppressed glycolysis-mediated acidosis . This normalization of the ATP metabolic pathways significantly increased the generation of superoxide anion radical ( O2\\u2022- ) and the functional expression of active caspase-3 , leading to caspase-dependent apoptosis . These data demonstrate that ALA inhibits the Warburg effect and induces cancer cell death . Use of this endogenous compound might constitute a novel approach to cancer therapy .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "24366173"}
{"sentence": "Pseudolaric acid B ( PLAB ) is one of the major bioactive components of Pseudolarix kaempferi . It has been reported to exhibit inhibitory effect on cell proliferation in several types of cancer cells . However , there is no report elucidating its effect on glioma cells and organ toxicity in vivo . In the present study , we found that PLAB inhibited growth of U87 glioblastoma cells in a dose-dependent manner with IC(50) Flow cytometry analysis showed that apoptotic cell death mediated by PLAB was accompanied with cell cycle arrest at G2/M phase . Using Western blot , we found that PLAB induced G2/M phase arrest by inhibiting tubulin polymerization in U87 cells . Apoptotic cell death was only partially inhibited by pancaspase inhibitor , z-VAD-fmk , which suggested that PLAB-induced apoptosis in U87 cells is partially caspase-independent . Further mechanistic study demonstrated that PLAB induced caspase-dependent apoptosis via upregulation of p53 , increased level of proapoptotic protein Bax , decreased level of antiapoptotic protein Bcl-2 , release of cytochrome c from mitochondria , activation of caspase-3 and proteolytic cleavage of poly ( ADP-ribose ) polymerase ( PARP ) and caspase-independent apoptosis through apoptosis inducing factor ( AIF ) . Furthermore , in vivo toxicity study demonstrated that PLAB did not induce significant structural and biochemical changes in mouse liver and kidneys at a dose of 25\u2009mg/kg . Therefore , PLAB may become a potential lead compound for future development of antiglioma therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22778780"}
{"sentence": "Tumour cells primarily utilize aerobic glycolysis for energy production , a phenomenon known as the Warburg effect . Its mechanism is not well understood . The tumour suppressor gene p53 is frequently mutated in tumours . Many tumour-associated mutant p53 ( mutp53 ) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53 , defined as mutp53 gain of function ( GOF ) . Here we show that tumour-associated mutp53 stimulates the Warburg effect in cultured cells and mutp53 knockin mice as a new mutp53 GOF . Mutp53 stimulates the Warburg effect through promoting GLUT1 translocation to the plasma membrane , which is mediated by activated RhoA and its downstream effector ROCK . Inhibition of RhoA/ROCK/GLUT1 signalling largely abolishes mutp53 GOF in stimulating the Warburg effect . Furthermore , inhibition of glycolysis in tumour cells greatly compromises mutp53 GOF in promoting tumorigenesis . Thus , our results reveal a new mutp53 GOF and a mechanism for controlling the Warburg effect .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24343302"}
{"sentence": "Adhesion to the extracellular matrix ( ECM ) is critical for epithelial tissue homeostasis and function . ECM detachment induces metabolic stress and programmed cell death via anoikis . ECM-detached mammary epithelial cells are able to rapidly activate autophagy allowing for survival and an opportunity for re-attachment . However , the mechanisms controlling detachment-induced autophagy remain unclear . Here we uncover that the kinase PERK rapidly promotes autophagy in ECM-detached cells by activating AMP-activated protein kinase ( AMPK ) , resulting in downstream inhibition of mTORC1-p70(S6K) signaling . LKB1 and TSC2 , but not TSC1 , are required for PERK-mediated inhibition of mammalian target of rapamycinin MCF10A cells and mouse embryo fibroblast cells . Importantly , this pathway shows fast kinetics , is transcription-independent and is exclusively activated during ECM detachment , but not by canonical endoplasmic reticulum stressors . Moreover , enforced PERK or AMPK activation upregulates autophagy and causes luminal filling during acinar morphogenesis by perpetuating a population of surviving autophagic luminal cells that resist anoikis . Hence , we identify a novel pathway in which suspension-activated PERK promotes the activation of LKB1 , AMPK and TSC2 , leading to the rapid induction of detachment-induced autophagy . We propose that increased autophagy , secondary to persistent PERK and LKB1-AMPK signaling , can robustly protect cells from anoikis and promote luminal filling during early carcinoma progression.Oncogene advance online publication , 19 November 2012 ; doi:10.1038/onc.2012.512 .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23160380"}
{"sentence": "Arsenic trioxide ( ATO ) is a novel agent to treat acute promyelocytic leukemia ( APL ) . ATO can degrade chimeric PML-RAR proteins and induce apoptosis in various cancer cells . However , its effects on primary hematopoietic CD34+ have not been examined . In this study , we compared the effects of ATO on HL60 leukemic cells and primary umbilical cord blood ( UCB ) CD34+ cells . HL60 cells and UCB CD34+ cells were cultured with different concentrations of ATO for up to three weeks and examined for changes of cell cycle . We found that ATO ( < or = 5 microM ) caused prolongation of G1/S and G2/M phase in a dose-dependent manner . The percentage of cells in G2/M increased significantly ( from 8.6 to 53.8% ) . High-dose ATO ( > or = 25 microM ) caused non-specific cell death in HL60 cells without any changes in cell cycle . In contrast to HL60 cells , UCB CD34+ cells were more resistant to high-dose ATO and most ATO-resistant CD34+ cells remained in G0/G1 phase . Primary cells that were resistant to ATO were rich in CD34+ cells . We further show that the ATO resistance was not related to the expression of P-glycoprotein ( MDR-1 ) . Our results suggest that the resistance to ATO in primitive UCB CD34+ cells is most likely related to its cell-cycle status . These results could be useful to design treatments for non-APL malignancies and to enrich hematopoietic stem cells in clinically applicable settings .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12533046"}
{"sentence": "Necrotic cells are known to activate the innate immune system and trigger inflammation by releasing damage associated molecular patterns ( DAMPs ) . However , how necrotic cells influence the induction of antigen-specific CD8(+) T cell-mediated adaptive immune responses under sterile conditions , in the absence of pathogen associated molecular patterns ( PAMPs ) , remains poorly understood . Here , we examined antigen-specific CD8(+) T-cell responses to primary sterile necrotic tumor cells both in vitro and in vivo . We found that primary necrotic cells alone fail to generate CD8(+) T cell-dependent immune responses toward cell-associated antigens . We show that necrotic cells trigger CD8(+) T-cell immunity only in the presence of PAMPs or analogs , such as p(dI-dC) and/or unmethylated CpG DNA . The electroporation of tumor cells with these PAMPs prior to necrosis induction triggered antigen-specific CD8(+) T-cell responses through a TLR9/MyD88-dependent pathway . In addition , we found that necrotic cells contain factors that can block the cross-priming of CD8(+) T cells even under non-sterile conditions and can serve as a possible mechanism of immunosuppression . These results suggest that antigen-specific CD8(+) T-cell responses to primary necrotic tumor cells can be induced in the presence of PAMPs and thus have a substantial impact on the development of antitumor vaccination strategies .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23170250"}
{"sentence": "Chromosomal DNA must be in single-strand form for important transactions such as replication , transcription , and recombination to occur . The single-strand DNA ( ssDNA ) is more prone to damage than double-strand DNA ( dsDNA ) , due to greater exposure of chemically reactive moieties in the nitrogenous bases . Thus , there can be agents that damage regions of ssDNA in vivo while being inert toward dsDNA . To assess the potential hazard posed by such agents , we devised an ssDNA-specific mutagenesis reporter system in budding yeast . The reporter strains bear the cdc13-1 temperature-sensitive mutation , such that shifting to 37\u00b0C results in telomere uncapping and ensuing 5 ' to 3 ' enzymatic resection . This exposes the reporter region , containing three closely-spaced reporter genes , as a long 3 ' ssDNA overhang . We validated the ability of the system to detect mutagenic damage within ssDNA by expressing a modified human single-strand specific cytosine deaminase , APOBEC3G . APOBEC3G induced a high density of substitutions at cytosines in the ssDNA overhang strand , resulting in frequent , simultaneous inactivation of two reporter genes . We then examined the mutagenicity of sulfites , a class of reactive sulfur oxides to which humans are exposed frequently via respiration and food intake . Sulfites , at a concentration similar to that found in some foods , induced a high density of mutations , almost always as substitutions at cytosines in the ssDNA overhang strand , resulting in simultaneous inactivation of at least two reporter genes . Furthermore , sulfites formed a long-lived adducted 2'-deoxyuracil intermediate in DNA that was resistant to excision by uracil-DNA N-glycosylase . This intermediate was bypassed by error-prone translesion DNA synthesis , frequently involving Pol \\u03b6 , during repair synthesis . Our results suggest that sulfite-induced lesions in DNA can be particularly deleterious , since cells might not possess the means to repair or bypass such lesions accurately .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23271983"}
{"sentence": "Genetic and epigenetic changes in the von Hippel-Lindau ( VHL ) tumour suppressor gene are common in sporadic conventional ( clear cell ) renal cell carcinoma ( ccRCC ) . The effects on VHL expression are unknown but increased understanding may be relevant clinically , either in terms of prognosis or in therapy selection . We have examined the expression of VHL mutant RNA in 84 ccRCC tumours previously screened for mutations in genomic DNA , 56 of which contained 52 unique mutations or polymorphisms . Based on the predicted change to the primary amino acid sequence , 24 of the mutations were missense , 11 resulted in frameshifts with premature truncation , 9 resulted in immediate truncation at the site of the mutation and 2 were frameshifts which extended the reading frame beyond the normal stop codon . Nine tumours had intronic variants , including substitution of invariant residues at splice sites , deletion of nucleotides spanning the exon-intron junction , an intronic variant of unknown function and the polymorphism c.463+43A>G . Four variants were identified which were present in genomic DNA but not in mRNA . Three of these , all encoding apparent missense changes to the primary amino acid sequence , were located close to the ends of exons , reduced the strength of the splice site and function as null rather than missense variants . One nonsense variant was not detectable in mRNA but all other mutations resulting in premature truncation codons ( PTCs ) were , suggesting truncating VHL mutations may potentially generate truncated VHL protein . An intronic variant , c.341\\u201111T>A , previously regarded as of unknown function , is associated with an increased level of skipping of exon 2 and may , therefore , reduce production of pVHL . Our data show that the biological consequences of VHL mutations are not necessarily predictable from the sequence change of the mutation and that for the majority of VHL mutations , the potential for the generation of mutant protein exists .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22825683"}
{"sentence": "Arsenic trioxide ( As(2)O(3) ) has shown remarkable efficacy for the treatment of multiple myeloma ( MM ) . Histone deacetylases ( HDAC ) play an important role in the control of gene expression , and their dysregulation has been linked to myeloma . Especially , HDAC6 , a unique cytoplasmic member of class II , which mainly functions as \u03b1-tubulin deacetylase and Hsp90 deacetylase , has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation . However , the mechanisms of action for As(2)O(3) have not yet been defined . In this study , we investigated the effect of As(2)O(3) on proliferation and apoptosis in human myeloma cell line and primary myeloma cells , and then we studied that As(2)O(3) exerts antimyeloma effects by inhibiting activity in the \u03b1-tubulin and Hsp90 through western blot analysis and immunoprecipitation . We found that As(2)O(3) acts directly on MM cells at relatively low concentrations of 0.5 \ufffdM , which effects survival and apoptosis of MM cells . However , As(2)O(3) inhibited HDAC activity at the relatively high concentration and dose-dependent manner ( great than 4 \ufffdM ) . Subsequently , we found that As(2)O(3) treatment in a dose- and time-dependent fashion markedly increased the level of acetylated \u03b1-tubulin and acetylated Hsp90 , and inhibited the chaperone association with IKK\u03b1 activities and increased degradation of IKK\u03b1 . Importantly , the loss of IKK\u03b1-associated Hsp90 occurred prior to any detectable loss in the levels of IKK\u03b1 , indicating a novel pathway by which As(2)O(3) down-regulates HDAC6 to destabilize IKK\u03b1 protein via Hsp90 chaperone function . Furthermore , we observed the effect of As(2)O(3) on TNF-\u03b1-induced NF-\u03baB signaling pathway was to significantly reduced phosphorylation of Ser-536 on NF-\u03baB p65 . Therefore , our studies provide an important insight into the molecular mechanism of anti-myeloma activity of As(2)O(3) in HDAC6-Hsp90-IKK\u03b1-NF\u03baB signaling axis and the rationale for As(2)O(3) can be extended readily using all the HDAC associated diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22384180"}
{"sentence": "The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the DNA lesions 1-methyladenine and 3-methylcytosine , which are generated in single-stranded stretches of DNA . AlkB is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde . Here , we identify two human AlkB homologs , ABH2 and ABH3 , by sequence and fold similarity , functional assays , and complementation of the E. coli alkB mutant phenotype . The levels of their mRNAs do not appear to correlate with cell proliferation but tissue distributions are different . Both enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an alpha-ketoglutarate-dependent reaction , and act by direct damage reversal with the regeneration of the unsubstituted bases . AlkB , ABH2 , and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12486230"}
{"sentence": "A comparative study was undertaken between cancer of the uterine cervix ( n = 50 ) and female breast cancer ( n = 50 ) with reference to the expression of c-erbB-2 oncoprotein ( HER-2/neu ) and that of epidermal growth factor receptor ( EGF-R ) , both being highly homologous structurally . Expressions of EGF-R and c-erbB-2 oncoprotein were viewed in breast and cervical cancer tissues by immunochemical staining . Cervical cancer cases showed much higher expression of EGF-R which also revealed significant association with the expression of c-erbB-2 oncoprotein and tumour grading . Among breast cancer cases , over-expression of EGF-R correlated significantly with metastasis of lymph node ; and expression of c-erbB-2 oncoprotein showed a significant relationship with histological grading of the tumour . Moreover , an association was noticed between the tumour grade and the concomitant immuno positive expression of EGF-R and c-erbB-2 . Our study revealed an existence of a conflicting pattern in the expression of EGF-R and c-erbB-2 oncoprotein between carcinomas of the breast and uterine cervix .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12683217"}
{"sentence": "Polyphenol-enriched fractions from natural sources have been proposed to interfere with angiogenesis in pathological conditions . We recently reported that red propolis polyphenols ( RPP ) exert antiangiogenic activity . However , molecular mechanisms of this activity remain unclear . Here , we aimed at characterizing molecular mechanisms to explain the impact of RPP on endothelial cells ' ( EC ) physiology . We used in vitro and ex and in vivo models to test the hypothesis that RPP inhibit angiogenesis by affecting hypoxia-inducible factor-1\u03b1 ( HIF1\u03b1 ) stabilization in EC . RPP ( 10 mg/L ) affected angiogenesis by reducing migration and sprouting of EC , attenuated the formation of new blood vessels , and decreased the differentiation of embryonic stem cells into CD31-positive cells . Moreover , RPP ( 10 mg/L ) inhibited hypoxia- or dimethyloxallylglycine-induced mRNA and protein expression of the crucial angiogenesis promoter vascular endothelial growth factor ( VEGF ) in a time-dependent manner . Under hypoxic conditions , RPP at 10 mg/L , supplied for 1-4 h , decreased HIF1\u03b1 protein accumulation , which in turn attenuated VEGF gene expression . In addition , RPP reduced the HIF1\u03b1 protein half-life from min to 38 min under hypoxic conditions . The reduced HIF1\u03b1 protein half-life was associated with an increase in the von Hippel-Lindau ( pVHL)-dependent proteasomal degradation of HIF1\u03b1 . RPP ( 10 mg/L , 4 h ) downregulated Cdc42 protein expression . This caused a corresponding increase in pVHL protein levels and a subsequent degradation of HIF1\u03b1 . In summary , we have elucidated the underlying mechanism for the antiangiogenic action of RPP , which attenuates HIF1\u03b1 protein accumulation and signaling .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22279137"}
{"sentence": "INTRODUCTION The homeobox-containing transcription factor muscle segment homeobox 2 ( Msx2 ) plays an important role in mammary gland development . However , the clinical implications of Msx2 expression in breast cancer are unclear . The aims of this study were to investigate the potential clinical value of Msx2 as a breast cancer biomarker and to clarify its functional role in vitro . METHODS Msx2 gene expression was first examined in a well-validated breast cancer transcriptomic dataset of 295 patients . Msx2 protein expression was then evaluated by immunohistochemistry in a tissue microarray ( TMA ) containing 281 invasive breast tumours . Finally , to assess the functional role of Msx2 in vitro , Msx2 was ectopically expressed in a highly invasive breast tumour cell line ( MDA-MB-231 ) and an immortalised breast cell line ( MCF10a ) , and these cell lines were examined for changes in growth rate , cell death and cell signalling . RESULTS Examination of Msx2 mRNA expression in a breast cancer transcriptomic dataset demonstrated that increased levels of Msx2 were associated with good prognosis ( P = 0.011 ) . Evaluation of Msx2 protein expression on a TMA revealed that Msx2 was detectable in both tumour cell nuclei and cytoplasm . Cytoplasmic Msx2 expression was associated with low grade tumours ( P = 0.012 ) and Ki67 negativity ( P = 0.018 ) . Nuclear Msx2 correlated with low-grade tumours ( P = 0.015 ) , estrogen receptor positivity ( P = 0.038 ) , low Ki67 ( P = 0.005 ) and high cyclin D1 expression ( P = 0.037 ) . Increased cytoplasmic Msx2 expression was associated with a prolonged breast cancer-specific survival ( P = 0.049 ) , recurrence-free survival ( P = 0.029 ) and overall survival ( P = 0.019 ) . Ectopic expression of Msx2 in breast cell lines resulted in radically decreased cell viability mediated by induction of cell death via apoptosis . Further analysis of Msx2-expressing cells revealed increased levels of p21 and phosphorylated extracellular signal-regulated kinase ( ERK ) and decreased levels of Survivin and the ' split ends ' ( SPEN ) protein family member RBM15 . CONCLUSIONS We conclude that increased Msx2 expression results in improved outcome for breast cancer patients , possibly by increasing the likelihood of tumour cell death by apoptosis .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20682066"}
{"sentence": "Purpose . The purpose of this paper is to evaluate a new PET tracer ( 64)Cu-NODAGA-c(RGDyK ) for imaging of tumor angiogenesis using gene expression of angiogenesis markers as reference and to estimate radiation dosimetry for humans . Procedures . Nude mice with human neuroendocrine tumor xenografts ( H727 ) were administered ( 64)Cu-NODAGA-c(RGDyK ) i.v. for study of biodistribution as well as for dynamic PET . Gene expression of angiogenesis markers integrin \u03b1(V) , integrin \u03b2(3) , and VEGF-A were analyzed using QPCR and correlated to the tracer uptake in the tumors ( %ID/g ) . From biodistribution data human radiation-absorbed doses were estimated using OLINDA/EXM . Results . Tumor uptake was 1.2%ID/g with strong correlations between gene expression and tracer uptake , for integrin \u03b1(V)\u2009R = 0.76 , integrin \u03b2(3)\u2009R = 0.75 and VEGF-A R = 0.81 ( all P < 0.05 ) . The whole body effective dose for humans was estimated to be 0.038 and 0.029\u2009mSv/MBq for females and males , respectively , with highest absorbed dose in bladder wall . Conclusion . ( 64)Cu-NODAGA-c(RGDyK ) is a promising new angiogenesis PET tracer with potential for human use .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23091717"}
{"sentence": "5-Thyminyl-5,6-dihydrothymine ( also called spore photoproduct or SP ) is the exclusive DNA photodamage product in bacterial endospores . It is repaired by a radical SAM ( S-adenosylmethionine ) enzyme , the spore photoproduct lyase ( SPL ) , at the bacterial early germination phase . Our previous studies proved that SPL utilizes the 5'-dA\\u2022 generated by the SAM cleavage reaction to abstract the H(6proR) atom to initiate the SP repair process . The resulting thymine allylic radical was suggested to take an H atom from an unknown protein source , most likely cysteine 141 . Here we show that C141 can be readily alkylated in the native SPL by an iodoacetamide treatment , suggesting that it is accessible to the TpT radical . SP repair by the SPL C141A mutant yields TpTSO(2)(-) and TpT simultaneously from the very beginning of the reaction ; no lag phase is observed for TpTSO(2)(-) formation . Should any other protein residue serve as the H donor , its presence would result in TpT being the major product at least for the first enzyme turnover . These observations provide strong evidence to support C141 as the direct H atom donor . Moreover , because of the lack of this intrinsic H donor , the C141A mutant produces TpT via an unprecedented thymine cation radical reduction ( proton-coupled electron transfer ) process , contrasting to the H atom transfer mechanism in the wild-type ( WT ) SPL reaction . The C141A mutant repairs SP at a rate that is slower than that of the WT enzyme . Formation of TpTSO(2)(-) and TpT exhibits a V(max) deuterium kinetic isotope effect ( KIE ) of 1.7 \u00b1 0.2 , which is smaller than the ( D)V(max ) KIE of 2.8 \u00b1 0.3 determined for the WT SPL reaction . These findings suggest that removing the intrinsic H atom donor disturbs the rate-limiting process during enzyme catalysis . As expected , the prereduced C141A mutant supports only turnover , which is in sharp contrast to the >5 turnovers exhibited by the WT SPL reaction , suggesting that the enzyme catalytic cycle ( SAM regeneration ) is disrupted by this single mutation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22906093"}
{"sentence": "Recent surveys indicate that Pi intake has increased steadily as Pi-containing foods have increased . Our previous study demonstrated that high dietary Pi strongly stimulated lung tumorigeneis . In order to answer the issue whether low Pi may be chemopreventive , we examined the effects of low Pi on lung cancer . Eighteen 5-wk-old male K-ras(LA1) lung cancer model mice were randomly allocated to 2 groups . One group was fed a normal diet ( 0.5% Pi ) and other group was fed low Pi ( 0.1% Pi ) diet for 4 wk . Lung cancer development was evaluated by histopathological examination , Western blot , kinase assay , and immunohistochemistry . Low Pi increased the expression of sodium-dependent phosphate co-transporter 2b , and activated Akt signal with decreased PTEN expression in the lungs of K-ras(LA1) mice . Low Pi increased the Akt/mTOR-mediated protein translation through upregulating the phosphorylation of p70S6K and 4E-BP1 . In addition , low Pi stimulated cell cycling as evidenced by altered cell cycle regulators such as cyclin D1 and D3 . Finally , low Pi increased lung tumorigenesis in K-ras(LA1) mice compared to the normal diet group . Our results clearly demonstrated that low Pi also promoted lung tumorigenesis , thus suggesting that an appropriate intake of dietary Pi may be critical for lung cancer prevention as well as treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20432174"}
{"sentence": "This study was set up to investigate the relationships between the formation and removal of DNA damage in form of 8-oxodeoxyguanosine ( 8-oxodG ) in neonatal ( day 16 of gestation ) as compared to adult rats . The hypothesis addressed was whether the rapidly dividing foetal tissue has an enhanced requirement of DNA repair providing protection against potentially mutagenic DNA damages such as 8-oxodG . The activity of the primary 8-oxodG-repair protein OGG1 was measured by a DNA incision assay and the expression of OGG1 mRNA was measured by Real-Time PCR normalised to 18S rRNA . The tissue level of 8-oxodG was measured by HPLC-ECD . We found a 2-3-fold increased incision activity in the foetal control tissue , together with a 3-15-fold increase in mRNA of OGG1 as compared to liver tissue from adult rats . The levels of 8-oxodG in the foetal tissue were unaltered as compared to the adult groups . To increase the levels of 8-oxodG , the rats received an injection ( i.p. ) of the hepatotoxin 2-nitropropane . The compound induced significant levels of 8-oxodG in male rat livers 5h after the injection and in the foetuses 24h after the injection , while the female rats showed no increase in 8-oxodG . The incision activity was slightly depressed in both male and female liver tissue and in the foetal tissue 5h after the injection , but significantly increased from 5 to 24h after the injection . However , it did not reach levels significantly above the control levels . In conclusion , this study confirms that foetal tissue has increased levels of OGG1 mRNA and correspondingly an enhanced incision activity on an 8-oxodG substrate in a crude tissue extract .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12509275"}
{"sentence": "The goal of the present study was to examine hepatic differential gene expression patterns in Fisher-344 rats in response to dietary 2-aminoanthracene ( 2AA ) ingestion for 14 and 28 days . Twenty four post-weaning 3-4 week old F-344 male rats were exposed to 0 mgkg(-1)-diet ( control ) , 50 mgkg(-1)-diet ( low dose ) , 75 mgkg(-1)-diet ( medium dose ) and 100 mgkg(-1)-diet ( high dose ) 2AA for 14 and 28 days . This was followed by analysis of the liver for global gene expression changes . In both time points , the numbers of genes affected seem to correlate with the dose of 2AA . Sixteen mRNAs were differentially expressed in all treatment groups for the short-term exposure group . Similarly , 51 genes were commonly expressed in all 28-day exposure group . Almost all the genes seem to have higher expression relative to the controls . In contrast , cytochrome P450 family 4 , subfamily a , polypeptide 8 ( Cyp4a8 ) , and monocyte to macrophage differentiation-associated ( Mmd2 ) were down-regulated relative to controls . Differentially expressed mRNAs were further analyzed for associations via DAVID . GO categories show the effect of 2AA to be linked with genes responsible for carbohydrate utilization and transport , lipid metabolic processes , stress responses such as inflammation and apoptosis processes , immune system response , DNA damage response , cancer processes and circadian rhythm . The data from the current study identified altered hepatic gene expression profiles that may be associated with carcinoma , autoimmune response , and/or type 2 diabetes . Possible biomarkers due to 2AA toxicity in the liver for future study include Abcb1a , Nhej1 , Adam8 , Cdkn1a , Mgmt , and Nrcam .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 1], "id": "23038007"}
{"sentence": "Hypoxia and other adverse conditions are commonly encountered by rapidly growing cells . The RNA-binding protein RBM3 ( RNA-binding motif protein 3 ) , which is transcriptionally induced by low temperature and hypoxia , has recently been implicated in survival of colon cancer cells by mechanisms involving cyclooxygenase-2 ( COX-2 ) signaling . Immunohistochemically , we found strong RBM3 expression in a variety of malignant and proliferating tissues but low expression in resting and terminally differentiated cells . RBM3 expression in fibroblasts and human embryonal kidney ( HEK293 ) cells subjected to serum deprivation or contact inhibition closely paralleled proliferation rates , assessed by real-time RT-PCR and immunoblotting. siRNA-mediated RBM3 knockdown reduced cell viability and finally led to cell death , which did not involve caspase-3-mediated apoptosis , cell cycle arrest , or COX-2 regulation . In contrast , RBM3 over-expression rescued cells from death under serum starvation . This was associated with increased translation rates , as measured by C serine and H phenylalanine incorporation . Together , RBM3 is a critical factor providing cellular survival advantages in an adverse microenvironment presumably by restoring translation efficacy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "19770690"}
{"sentence": "p24 proteins comprise a family of type-I transmembrane proteins of that are present in yeast and plants as well as metazoans ranging from Drosophila to humans . These proteins are most commonly localized to the endoplasmic reticulum ( ER)-Golgi interface and are incorporated in anterograde and retrograde transport vesicles . Little is known about how disruption of p24 signaling affects individual tissue function or whole animals . Drosophila melanogaster express nine p24 genes , grouped into four subfamilies . Based upon our mRNA and protein expression data , Drosophila p24 family members are expressed in a variety of tissues . To identify functions for particular Drosophila p24 proteins , we used RNA interference ( RNAi ) to reduce p24 expression . Ubiquitous reduction of most p24 genes resulted in complete or partial lethality during development . We found that reducing p24 levels in adults caused defects in female fecundity ( egg laying ) and also reduced male fertility . We attributed reduced female fecundity to decreased neural p24 expression . These results provide the first genetic analysis of all p24 family members in a multicellular animal and indicate vital roles for Drosophila p24s in development and reproduction , implicating neural expression of p24s in the regulation of female behavior .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22554671"}
{"sentence": "BACKGROUND Hepatocellular carcinoma ( HCC ) is a leading cause of death worldwide . Frequent cytogenetic abnormalities that occur in HCC suggest that tumor-modifying genes ( oncogenes or tumor suppressors ) may be driving selection for amplification or deletion of these particular genetic regions . In many cases , however , the gene(s) that drive the selection are unknown . Although techniques such as comparative genomic hybridization ( CGH ) have traditionally been used to identify cytogenetic aberrations , it might also be possible to identify them indirectly from gene-expression studies . A technique we have called comparative genomic microarray analysis ( CGMA ) predicts regions of cytogenetic change by searching for regional gene-expression biases . CGMA was applied to HCC gene-expression profiles to identify regions of frequent cytogenetic change and to identify genes whose expression is misregulated within these regions . RESULTS Using CGMA , 104 HCC gene-expression microarray profiles were analyzed . CGMA identified 13 regions of frequent cytogenetic change in the HCC samples . Ten of these regions have been detected in previous CGH studies ( +lq , -4q , +6p , -8p , +8q , -13q , -16q , -17p , +17q , +20q ) . CGMA identified three additional regions that have not been previously identified by CGH ( +5q , +12q , +19p ) . Genes located in regions of frequent cytogenetic change were examined for changed expression in the HCC samples . CONCLUSIONS Our results suggest that CGMA predictions using gene-expression microarray datasets are a practical alternative to CGH profiling . In addition , CGMA might be useful for identifying candidate genes within cytogenetically abnormal regions .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12537564"}
{"sentence": "Gliomas display anoikis resistance , enhanced invasion in to the adjacent brain parenchyma and eventually recur despite using the standard therapies . Our studies on increased anoikis sensitization in matrix metalloproteinase-2 ( MMP-2)-knockdown 4910 and 5310 human glioma xenograft cells were interestingly correlated with p21-activated kinase 4 ( PAK4 ) inhibition , prompting us to further investigate the role of PAK4 in glioma . Here , we report the PAK4 upregulation in positive correlation with increasing glioma pathological grades . The siRNA-mediated PAK4 knockdown elevated anoikis , and inhibited invasion and migration by downregulating MMP-2 , \u03b1v\u03b23-integrin and phospho-epidermal growth factor receptor ( phospho-EGFR ) . The cDNA-PCR arrays revealed a transcriptional suppression of essential proteins involved in cell proliferation and adhesion in PAK4-knockdown cells . Most importantly , glutathione S-transferase pull-down assays demonstrated the MMP-2 as a new PAK4-interacting protein which binds to PAK4 kinase domain . Individual EGFR/ErbB2 inhibitor and \u03b1v\u03b23 antibody treatments in PAK4si-treated cells indicated the regulation of \u03b1v\u03b23/EGFR survival signaling by PAK4 . Overexpression of PAK4 significantly reversed the MMP2si-induced cell death in both cell lines . Codepletion of PAK4 and MMP-2 resulted in robust anoikis-mediated cell death , and severely inhibited invasive and migratory properties in these cells . PAK4si inhibited in vivo tumor growth in nude mice by inhibiting MMP-2 , \u03b23-integrin and phospho-EGFR levels in tumors . Our findings indicate a physical association between PAK4 and MMP-2 , and suggest the future therapeutic potential of PAK4/MMP-2 dual targeting in glioma treatment .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23254288"}
{"sentence": "Chronic myelogenous leukemia ( CML ) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein . Clinically , CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis . A CML-specific immune response is thought to contribute to the control of disease . Whether the immune system can also promote disease progression is not known . In the present study , we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells ( LSCs ) and mediates effects of the immune system on CML . In a mouse model of CML , BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27 . Binding of CD27 by its ligand , CD70 , increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active \u03b2-catenin and TRAF2- and NCK-interacting kinase ( TNIK ) . This resulted in increased proliferation and differentiation of LSCs . Blocking CD27 signaling in LSCs delayed disease progression and prolonged survival . Furthermore , CD27 was expressed on CML stem/progenitor cells in the bone marrow of CML patients , and CD27 signaling promoted growth of BCR/ABL+ human leukemia cells by activating the Wnt pathway . Since expression of CD70 is limited to activated lymphocytes and dendritic cells , our results reveal a mechanism by which adaptive immunity contributes to leukemia progression . In addition , targeting CD27 on LSCs may represent an attractive therapeutic approach to blocking the Wnt/\u03b2-catenin pathway in CML .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22232214"}
{"sentence": "Psoralen photoreaction with DNA produces interstrand crosslinks , which require the activity of excision and recombinational pathways for repair . Yeast replicating plasmids , carrying the HIS3 , TRP1 , and URA3 genes , were photoreacted with psoralen in vitro and transfected into Saccharomyces cerevisiae cells . Repair was assayed as the relative transformation efficiency . A recombination-deficient rad52 strain was the least efficient in the repair of psoralen-damaged plasmids ; excision repair-deficient rad1 and rad3 strains had repair efficiencies intermediate between those of rad52 and RAD cells . The level of repair also depended on the conditions of transformant selection ; repair was more efficient in medium lacking tryptophan than in medium from which either histidine or uracil was omitted . The plasmid repair differential between these selective media was greatest in rad1 cells , and depended on RAD52 . Plasmid-chromosome recombination was stimulated by psoralen damage , and required RAD52 function . Chromosome to plasmid gene conversion was seen most frequently at the HIS3 locus . In RAD and rad3 cells , the majority of the conversions were associated with plasmid integration , while in rad1 cells most were non-crossover events . Plasmid to chromosome gene conversion was observed most frequently at the TRP1 locus , and was accompanied by plasmid loss .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1494354"}
{"sentence": "When the prostate cancer cells become unresponsive to androgen therapy , resistance to chemotherapy becomes imminent , resulting in high mortality . To combat this situation , lycopodine , a pharmacologically important bioactive component derived from Lycopodium clavatum spores , was tested against hormone sensitive ( LnCaP ) and refractory ( PC3 ) prostate cancer cells in vitro . This study aims to check if lycopodine has demonstrable anti-cancer effects and if it has , to find out the possible mechanism of its action . The MTT assay was performed to evaluate the cytotoxic effect . Depolarization of mitochondrial membrane potential , cell cycle , EGF receptor activity and apoptosis were recorded by FACS ; profiles of different anti- and pro-apoptotic genes and their products were studied by semi-quantitative RT-PCR , indirect-ELISA , western blotting . Drug-DNA interaction was determined by CD spectroscopy . Administration of lycopodine down-regulated the expression of 5-lipoxygenase and the 5-oxo-ETE receptor ( OXE receptor1 ) and EGF receptor , and caused up-regulation of cytochrome c with depolarization of mitochondrial inner membrane potential , without palpable change in p53 activity , resulting in apoptosis , cell arrest at G0/G1 stage and ultimately reduced proliferation of cancer cells ; concomitantly , there was externalization of phosphotidyl serine residues . CD spectroscopic analysis revealed intercalating property of lycopodine with DNA molecule , implicating its ability to block cellular DNA synthesis . The overall results suggest that lycopodine is a promising candidate suitable for therapeutic use as an anti-cancer drug .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23142370"}
{"sentence": "INTRODUCTION The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug . Several studies have shown that nelfinavir induces cell cycle arrest , endoplasmic reticulum stress , autophagy , and apoptosis in cancer cells . In the present article , the effect of nelfinavir on human breast cancer cells is examined and potential combination treatments are investigated . METHODS The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7 , T47 D , MDA-MB-453 , and MDA-MB-435 were tested by analysing their influence on cell viability ( via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay ) , apoptosis ( annexin binding , poly(ADP-ribose) polymerase cleavage ) , autophagy ( autophagy marker light chain 3B expression ) , endoplasmic reticulum stress ( binding protein and activating transcription factor 3 expression ) , and the occurrence of oxidative stress ( intracellular glutathione level ) . RESULTS Nelfinavir induced apoptosis in all four breast cancer cell lines tested , although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines . The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 \u03bcg/ml to 6 \u03bcg/ml when combined with tamoxifen . At a concentration of 6 \u03bcg/ml , tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with binding protein ( BiP ) upregulation ( MCF7 , T47D ) , and enhanced autophagy in cell lines that responded to nelfinavir treatment with autophagy marker light chain 3B upregulation ( MDA-MB-453 ) . Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study ( 6 \u03bcg/ml ) , we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione level of breast cancer cells within hours of application by up to 32% , suggesting the induction of oxidative stress was an early event and an additional cause of the apoptosis induced by nelfinavir . CONCLUSIONS The results demonstrate that nelfinavir may be an effective drug against breast cancer and could be combined with tamoxifen to enhance its efficacy against breast cancer cells . Moreover , the cytotoxic effect of a tamoxifen and nelfinavir combination was independent of the oestrogen receptor status of the analysed breast cancer cells , suggesting a potential benefit of a combination of these two drugs even in patients with no hormone-responsive tumours . We therefore recommend that clinical studies on nelfinavir with breast cancer patients should include this drug combination to analyse the therapeutic efficacy as well as the safety and tolerability of this potential treatment option .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20594311"}
{"sentence": "An aqueous extract of Kefir , fermented milk originally produced in the Caucasus mountains , suppressed morphological changes of human melanoma HMV-1 and SK-MEL cells and human normal fibroblastTIG-1 cells caused by UVC-irradiation , suggesting that UV damage can be suppressed by the Kefir extract . The addition of the Kefir extract after UVC-irradiation of HVM-1 cells resulted in a remarkable decrease in intracellular reactive oxygen species ( ROS ) which had been increased by UVC irradiation . The Kefir extract also stimulated unscheduled DNA synthesis and suppressed UVC-induced apoptosis of HMV-1 cells . A colony formation assay revealed that the Kefir extract rescued HMV-1 cells from cell death caused by UVC irradiation . The Kefir extract , as well as methyl methanethiosulfonate which is known to enhance the nucleotide excision repair ( NER ) activity , exhibited strong thymine dimer repair-enhancing activity . Epigalocatechin exhibited a weak NER activity but vitamins A , C , and E and catechin showed no NER activity . The thymine dimer repair-enhancing factors in the Kefir extract were heat-stable and assumed to be molecules with a molecular weight of less than 5000 . The treatment of HMV-1 cells with the Kefir extract during or before UVC- irradiation also prevented the generation of ROS and thymine dimmer , and suppressed the apoptosis of HMV-1 cells , suggesting that application of Kefir can prevent UV damage .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 1], "id": "19003113"}
{"sentence": "Breast cancers amplified for the tyrosine kinase receptor Her-2/neu constitute of advanced breast cancer cases , and are characterized by hormone independence and aggressive growth , implicating this pathway in breast oncogenesis . The induction of Her-2/neu leads to tumor development in 60% of transgenic mice . We have previously examined the effects of estrogen in the MMTV-Her-2/neu background by generating the MMTV-Her-2/neu x aromatase double transgenic mouse strain . MMTV-Her-2/neu x aromatase mice developed fewer mammary tumors than the Her-2/neu parental strain . Our present data show the induction of several estrogen-related genes , including the tumor suppressors BRCA1 and p53 , and a decrease in several angiogenic factors . The phosphorylated forms of MAPK p42/44 and AKT were lower in the MMTV-Her-2/neu x aromatase double transgenic mice compared to the MMTV-Her-2/neu parental strain ; conversely , phospho-p38 levels were higher in the double transgenic strain . The ER\u03b2-selective antagonist THC reversed these changes . The regulation of these factors by ER\u03b2 was confirmed in clones of MCF7 breast cancer cells overexpressing Her-2/neu in combination with ER\u03b2 , suggesting that ER\u03b2 may play a direct role in regulating MAPK and AKT pathways . In summary , the data suggest that ER\u03b2 may play a major role in decreasing tumorigenesis and that it may affect breast cancer cell proliferation and survival by altering MAPK and AKT activation as well as modulation of tumor suppressor and angiogenesis factors . Treatment with selective ER\u03b2 agonist may provide therapeutic advantages for the treatment and prevention of breast cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22006184"}
{"sentence": "Both the deregulation of microRNAs and epidermal growth factor receptor ( EGFR ) are emerging as important factors in non-small-cell lung cancer ( NSCLC ) . Here , miR-133b was found to be associated with tumor stage , the extent of regional lymph node involvement , stage , visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC . Bioinformatic analysis and luciferase reporter assay revealed that miR-133b can interact specifically with the 3'-UTR of EGFR mRNA . Functionally , miR-133b transfection showed regulatory activity in translationally repressing EGFR mRNA . Moreover , miR-133b transfection may modulate apoptosis , invasion and sensitivity to EGFR-TKI through the EGFR signaling pathways , especially in EGFR-addicted NSCLC cells . Taken together , our findings show that miR-133b can inhibit cell growth of NSCLC through targeting EGFR and regulating its downstream signaling pathway . This finding has important implications for the development of targeted therapeutics for a number of EGFR-addicted cancers .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22883469"}
{"sentence": "Escherichia coli molecular hydrogen ( H(2) ) production was studied during mixed carbon ( glucose and glycerol ) fermentation at pH 6.5 . Wild type cells in the assays supplemented with glucose produced H(2) at fold lower level than cells grown on glucose only . When compared to the wild type , H(2) production in the assays added with glucose was decreased by fold in fhlA , hyfG and double fhlA hyfG mutants and by fold in hyaB , hybC , and double hyaB hybC mutants . However , in the assays with glycerol , no measurable H(2) production was detected . Taken together , these results suggest that during mixed carbon fermentation , H(2) could be produced with low efficiency via Hyd-3 and Hyd-4 . This is a novel finding for Hyd-4 activity at pH 6.5 . The insignificant decrease of H(2) production in the strains with defects in Hyd-1 and Hyd-2 was probably due to an interaction between the Hyd enzymes and their organization in the bacterial membrane . In the glucose assays , H(2) production in the wild type cells was inhibited fold by 0.3mM N,N'-dicyclohexylcarbodiimide ( DCCD ) , an inhibitor of the F(0)F(1)-ATPase . This inhibition was the same for fhlA and hyfG fhlA mutants but not hyaB , hybC , hyfG or hyaB hybC mutants . The results indicate that the FhlA protein coded by the fhlA gene might interact with the F(0)F(1)-ATPase . We propose that this interaction is mediated by mixed carbon fermentation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22771922"}
{"sentence": "Ceramide is a sphingolipid metabolite that induces cancer cell death . When C6-ceramide is encapsulated in a nanoliposome bilayer formulation , cell death is selectively induced in tumor models . However , the mechanism underlying this selectivity is unknown . As most tumors exhibit a preferential switch to glycolysis , as described in the \" Warburg effect \" , we hypothesize that ceramide nanoliposomes selectively target this glycolytic pathway in cancer . We utilize chronic lymphocytic leukemia ( CLL ) as a cancer model , which has an increased dependency on glycolysis . In CLL cells , we demonstrate that C6-ceramide nanoliposomes , but not control nanoliposomes , induce caspase 3/7-independent necrotic cell death . Nanoliposomal ceramide inhibits both the RNA and protein expression of GAPDH , an enzyme in the glycolytic pathway , which is overexpressed in CLL . To confirm that ceramide targets GAPDH , we demonstrate that downregulation of GAPDH potentiates the decrease in ATP after ceramide treatment and exogenous pyruvate treatment as well as GAPDH overexpression partially rescues ceramide-induced necrosis . Finally , an in vivo murine model of CLL shows that nanoliposomal C6-ceramide treatment elicits tumor regression , concomitant with GAPDH downregulation . We conclude that selective inhibition of the glycolytic pathway in CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for leukemia by targeting the Warburg effect .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "24367685"}
{"sentence": "We identified REDD1 as a novel transcriptional target of p53 induced following DNA damage . During embryogenesis , REDD1 expression mirrors the tissue-specific pattern of the p53 family member p63 , and TP63 null embryos show virtually no expression of REDD1 , which is restored in mouse embryo fibroblasts following p63 expression . In differentiating primary keratinocytes , TP63 and REDD1 expression are coordinately downregulated , and ectopic expression of either gene inhibits in vitro differentiation . REDD1 appears to function in the regulation of reactive oxygen species ( ROS ) ; we show that TP63 null fibroblasts have decreased ROS levels and reduced sensitivity to oxidative stress , which are both increased following ectopic expression of either TP63 or REDD1 . Thus , REDD1 encodes a shared transcriptional target that implicates ROS in the p53-dependent DNA damage response and in p63-mediated regulation of epithelial differentiation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12453409"}
{"sentence": "p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence . Consistent with this role , p21 is a downstream target of several tumour suppressors and oncogenes , and it is downregulated in the majority of tumours , including breast cancer . Here , we report that protein arginine methyltransferase 6 ( PRMT6 ) , a type I PRMT known to act as a transcriptional cofactor , directly represses the p21 promoter . PRMT6 knock-down ( KD ) results in a p21 derepression in breast cancer cells , which is p53-independent , and leads to cell cycle arrest , cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency ( SCID ) mice for all the cancer lines examined . We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence , and it restores their ability to grow on soft agar . We conclude that PRMT6 acts as an oncogene in breast cancer cells , promoting growth and preventing senescence , making it an attractive target for cancer therapy .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "22987071"}
{"sentence": "OBJECTIVE The goal of this study was to investigate the relationship between plasma levels of insulin-like growth factors-1 ( IGF-1 ) and IGF-binding protein-3 ( IGFBP-3 ) and the risk for cervical intraepithelial neoplasia ( CIN ) and cervical cancer . METHODS Plasma levels of IGF-1 and IGFBP-3 of 44 cervical cancer patients , 82 CIN patients and 40 neoplasm-free patients were investigated . Then the associations of the plasma levels of IGF-1 and IGFBP-3 with cervical neoplasm or its clinicopathologic parameters were analyzed . RESULTS The mean IGF-1 concentrations were significantly different among the control , CIN , and cervical cancer groups ; the levels were higher in the CIN group compared to the controls . According to the quartile category , the plasma IGF-1 level was significantly higher ( p=0.0015 ) in the CIN group than in the controls . The IGFBP-3 level showed no association between the controls and CIN groups ( p=0.842 ) . Although the mean IGF-1/IGFBP-3 molar ratio had borderline significance ( p=0.08 ) among the study population , the quartile comparison showed a significantly higher IGF-1/IGFBP-3 molar ratio in the CIN group compared to the control group ( p=0.041 ) . CONCLUSION Plasma levels of IGF-1 and the IGF-1/IGFBP-3 molar ratio might be useful for the development early detection of cervical lesions and used as an adjuvant diagnostic tool for cervical neoplasia after more larger scale research .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20922140"}
{"sentence": "Furan , a potent rodent liver carcinogen , is found in many cooked food items and thus represents a human cancer risk . Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays , combined with analysis of histopathological and gene expression changes . In addition , formamidopyrimidine DNA glycosylase ( Fpg ) and endonuclease III ( EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage . Rats were treated by gavage on four consecutive days with 2 , 4 , and 8mg/kg bw furan , doses that were tumorigenic in 2-year cancer bioassays , and with two higher doses , 12 and 16mg/kg . Rats were killed 3h after the last dose , a time established as producing maximum levels of DNA damage in livers of furan-treated rats . Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion , with statistically significant increases detected at cancer bioassay doses . No DNA damage was detected in bone marrow , a non-target tissue for cancer , and peripheral blood micronucleus assays were negative . Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation , single-cell necrosis , apoptosis , and cell proliferation . In addition , genes related to apoptosis , cell-cycle checkpoints , and DNA-repair were expressed at a slightly lower level in the furan-treated livers . Although a mixed mode of action involving direct DNA binding cannot be ruled out , the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress , accompanied by inflammation , cell proliferation , and toxicity .", "label": [0, 0, 0, 0, 1, 1, 0, 1, 0, 1], "id": "22507866"}
{"sentence": "Epidemiologic studies have examined the association between fruit and vegetable ( F&V ) consumption and the risk of cancer . Several cancer-preventive mechanisms have been proposed , such as antioxidant properties and modulation of biotransformation enzyme activities ; both may be associated with reducing DNA damage and hence the mutation rate . We investigated , in a randomized , controlled , crossover feeding trial , the effect of 10 servings/day of botanically defined F&V for 2 wk on endogenous DNA damage ; resistance to gamma -irradiation damage ; and DNA repair capacity in lymphocytes , measured by the Comet assay . We also explored the association between the UGT1A1*28 polymorphism and serum bilirubin concentrations and DNA damage and repair measures . Healthy men ( n = 11 ) and women ( n = 17 ) , age 20 to 40 yr , provided blood samples at the end of each feeding period . Overall , F&V did not affect DNA damage and repair measures in lymphocytes . The number of UGT1A1*28 alleles was inversely associated with sensitivity to gamma -irradiation exposure and DNA repair capacity , but a biological mechanism to explain this association is unclear . A larger sample size is needed to investigate the association between bilirubin concentrations and endogenous DNA damage . With inconsistent findings in the literature , additional dietary intervention studies on the effect of F&V on DNA damage and repair are needed .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20358470"}
{"sentence": "Telomerase is a ribonucleoprotein enzyme that functions to maintain telomeres , the terminal DNA that protects chromosomal integrity , regulating cellular replicative life span . Telomerase is not expressed in most normal human somatic cells but is active in stabilizing telomeres of certain self-renewing cell populations and most malignant cells , making the enzyme an appealing target for anticancer therapy . We describe here a novel cross-species approach to telomerase inhibition . Ectopic expression of the human telomerase catalytic reverse transcriptase component in murine cells inhibited endogenous murine telomerase activity . Using this approach , telomerase inhibition in immortal murine fibroblasts resulted in critical telomere shortening , leading to slowed proliferation , abnormal morphology , altered cell cycle , and telomere dysfunction with cytogenetic instability , followed by apoptotic cell death . Subpopulations of two telomerase-inhibited clones escaped widespread apoptosis , showing proliferative recovery in culture despite persistently inhibited telomerase activity with progressive telomere shortening and dysfunction . This study , by targeting immortal murine cells for telomerase inhibition , demonstrates the importance of telomerase to murine cell immortalization and telomere maintenance . Moreover , the murine model used here should prove useful in further evaluating telomerase inhibition as an anticancer therapy .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "11929832"}
{"sentence": "AIMS Angiogenesis from thyroid cancer cell plays the important roles in post-surgical persistent , recurrent , and metastatic papillary thyroid cancer ( PTC ) . This study is to investigate the expression of angiopoietin-1 ( Ang-1 ) , angiopoietin-2 ( Ang-2 ) , Tek/Tie-2 receptor , and vascular endothelial growth factors ( VEGF ) in normal , benign thyroid tissues and different stage of PTC . We expect angiogenetic factors are important in the presentation of local-regional neck or distant metastases in PTC . MATERIALS AND RESULTS A total of 101 tissues from the subjects underwent thyroidectomy were enrolled in the study . There were 22 control and 79 thyroid cancer patients in different TNM stagings were collected . Ang-1 illustrated highest mean immunostaining score in metastatic group . Comparing with normal and benign thyroid tissues , thyroid cancer tissues illustrated significantly high expression of three angiogenetic factors and Tie-2 receptor . Of the PTC , significantly high expression of three angiogenetic factors and Tie-2 receptor were illustrated in recurrent cases . VEGF showed statistical difference in disease-free cancer mortality , and recurrent groups . CONCLUSIONS Immunochemical staining illustrated VEGF , Ang-1 , Ang-2 expression in PTC tissues related to clinical staging ; however , we need more information concerning these factors with long-term follow-up results .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "21400522"}
{"sentence": "Properly regulated keratinocyte cell death is fundamentally important to maintain structural integrity and homeostatic function of epidermis . Moreover , from an oncological perspective , therapeutic approaches selectively targeting apoptosis of malignant cell types while sparing normal keratinocytes in surrounding skin is desirable . Apo2Ligand/tumor necrosis factor-related apoptosis-inducing ligand ( Apo2L/TRAIL ) has been observed to preferentially induce cytopathic effects on transformed/malignant cell types compared with their non-neoplastic counterparts . In this report , two different biologically active preparations of Apo2L/TRAIL , a non-tagged version , NT-Apo2L/TRAIL , and a leucine zipper fusion protein , LZ-Apo2L/TRAIL , were examined for their ability to trigger apoptosis in normal human keratinocytes , and in an immortalized cell line ( HaCaT cells ) . Differences between these preparations were observed , including : NT-Apo2L/TRAIL induced less keratinocyte apoptosis compared with LZ-Apo2L/TRAIL ; NT-Apo2L/TRAIL also induced less apoptosis of HaCaT cells compared with LZ-Apo2L/TRAIL ; LZ-Apo2L/TRAIL but not NT-Apo2L/TRAIL induced cytotoxic effects when keratinocytes became growth arrested due to undergoing spontaneous replicative senescence--a biological state previously observed to be resistant to UV-light-induced apoptosis . Similarities between preparations included : an enhanced ability for both Apo2L/TRAIL preparations to kill a greater relative percentage of HaCaT cells compared with keratinocytes ; enhanced cytotoxicity towards keratinocytes that had their NF-B activity inhibited ; a dependence of both Apo2L/TRAIL preparations on FADD and caspase activation ; triggering of the same caspase cascades including caspase 8 and 3 ; and an ability to induce apoptosis even when HaCaT cells and keratinocytes were transduced to overexpress either Bcl-2 or Bcl-x(L) ( survival factors that reduce susceptibility to UV-light-induced apoptosis ) . These results indicate that while both preparations of Apo2L/TRAIL possess biological activity , there are important differences as regards their ability to induce apoptosis in normal and immortalized keratinocytes . Moreover , the death receptor pathway triggered by LZ-Apo2L/TRAIL can overcome the apoptotic resistance normally observed in response to UV-light mediated by Bcl-2/Bcl-x(L) , as well as by the state of cellular senescence . Unraveling the molecular basis for these differential biological effects may reveal a new strategic role for these death receptor/ligands linked to apoptosis in maintaining the dynamic balance of keratinocyte proliferation , differentiation , and cell death necessary to achieve a homeostatic thickness and function of normal skin . In addition , it may be possible to utilize these Apo2L/TRAIL preparations for the treatment of various sun-induced skin cancers as they can differentially trigger apoptosis of transformed keratinocytes , or keratinocytes with abnormal NF-kappaB signaling , while sparing adjacent normal keratinocytes .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "12473065"}
{"sentence": "Resveratrol , a phytoalexin found in grapes and wine , has been shown to exhibit a wide range of pharmacological properties and is believed to play a role in the chemoprevention of human cancer . Resveratrol has also been shown to induce antiproliferation and apoptosis of several leukemia cell lines . In the present study , we investigated the effect of resveratrol in adult T cell leukemia . Our present observations showed that resveratrol induced growth inhibition in all five human T cell lymphotrophic virus-1-infected cell lines examined , with 50% effective dose of 10.4-85.6 mM . In the resveratrol-treated cells , induction of apoptosis was confirmed by annexin V-based analyses and morphological changes . The most surprising observation was that resveratrol treatment resulted in a gradual decrease in the expression of survivin , an antiapoptotic protein , during cell apoptosis . These findings indicate that resveratrol inhibits the growth of human T cell lymphotrophic virus-1-infected cell lines , at least in part , by inducing apoptosis mediated by downregulation in survivin expression . In view of the accumulating evidence that survivin may be an important determinant of a clinical response in adult T cell leukemia , our present findings have led to the suggestion that resveratrol , a common constituent of the human diet , merits further investigation as a potential therapeutic agent for this incurable disease .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12734068"}
{"sentence": "We have previously demonstrated the antiproliferative effect of two flavonoids-2,2'-dihydroxychalcone ( DHC ) , a novel synthetic flavonoid , and fisetin , a naturally occurring flavonol-in prostate cancer cells . In this study , we further examine the mechanisms of these compounds on survival and proliferation pathways . DHC and fisetin ( 1-50 microM ) caused a dose-dependent reduction in viability , a concomitant increase in apoptosis in PC3 cells at 72 h , and a decrease in clonogenic survival at 24 h treatment . DHC was considerably more potent than fisetin in these cytotoxicity assays . The mechanism of accelerated cellular senescence was not activated by either compound in PC3 or lymph node carcinoma of the prostate ( LNCaP ) cells . Gene expression alterations in PC3 and LNCaP cells treated with 15 muM DHC and 25 microM fisetin for 6 to 24 h were determined by oligonucleotide array . Amongst the most highly represented functional categories of genes altered by both compounds was the cell cycle category . In total , 100 cell cycle genes were altered by DHC and fisetin including 27 genes with key functions in G2/M phase that were downregulated by both compounds . Other functional categories altered included chromosome organization , apoptosis , and stress response . These results demonstrate the multiple mechanisms of antitumor activity of DHC and fisetin in prostate cancer cells in vitro .", "label": [0, 0, 0, 1, 1, 0, 0, 0, 1, 0], "id": "20574928"}
{"sentence": "We had demonstrated that plasminogen kringle 5 ( K5 ) , a potent angiogenic inhibitor , inhibited retinal neovascularization and hepatocellular carcinoma growth by anti-angiogenesis . The current study investigated the effects and the underlying mechanisms of K5 on both tumor growth and spontaneous pulmonary metastasis in Lewis lung carcinoma ( LLC ) implanted mouse model . Similarly , K5 could decrease expression of VEGF in LLC cells and grafted tissues and suppress tumor angiogenesis and growth . K5 had no direct effect on proliferation and apoptosis of LLC . However , K5 could significantly inhibit SDF-1\u03b1-induced chemotaxis movement of LLC cells and resulted in a great reduction of surface metastatic nodules and micrometastases in the lungs of LLC tumor-bearing mice . K5 also decreased expression of chemokine ( C-X-C motif ) receptor 4 ( CXCR4 ) in LLC cells and grafted tissues . Furthermore , K5 down-regulated SDF-1\u03b1 expression in metastatic lung tissues of LLC-bearing mice . Therefore , K5 may suppress tumor pulmonary metastasis through inhibiting SDF-1\u03b1-CXCR4 chemotaxis movement and down-regulation of VEGF . Moreover , the role of hypoxia inducible factor-1\u03b1 ( HIF-1\u03b1 ) , a crucial transcriptional factor for both VEGF and CXCR4 expression , was evaluated . The siRNA of HIF-1\u03b1 attenuated expression of VEGF and CXCR4 and inhibited LLC migration . K5 decreased HIF-1\u03b1 protein level and impaired nuclear HIF-1\u03b1 accumulation . These results showed for the first time that K5 inhibits LLC growth and metastasis via the dual effects of anti-angiogenesis and suppression of tumor cell motility by targeting the pivotal molecule , HIF-1\u03b1 .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "23300882"}
{"sentence": "The atmospheric polychlorinated dibenzo-p-dioxins ( PCDDs ) partition appreciably in the gas phase , where they undergo rapid oxidation . The atmospheric oxidation mechanisms of a few PCDDs , initiated by OH radical , are studied using density functional theory calculations . The oxidations start with OH-addition to the aromatic rings , dominantly at \\u03b3-sites , followed by the non-chlorinated \\u03b2-sites ; while additions to the \\u03b1-sites or chlorinated sites are negligible . For PCDDs with all \\u03b2-sites being chlorinated , formation of PCDD-\\u03b3-OH adducts become virtually the only reaction path . Under the atmospheric conditions , the PCDD-\\u03b2/\\u03b3-OH adducts combine with O(2) slowly at rates <1s(-1) . Instead , the PCDD-\\u03b2-OH adducts will react with O(2) through hydrogen abstraction at rates <50s(-1) , forming PCDD-\\u03b2-ol , and the PCDD-\\u03b3-OH adducts will decompose to the substituted phenoxy radicals by fused-ring C-O bond cleavage at rates of 10(3) s(-1) . The reaction mechanisms of PCDDs are drastically different from the peroxy mechanism for the atmospheric oxidations of benzene and dibenzofuran .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22835868"}
{"sentence": "Unlike the growth factor dependence of normal cells , cancer cells can maintain growth factor-independent glycolysis and survival through expression of oncogenic kinases , such as BCR-Abl . Although targeted kinase inhibition can promote cancer cell death , therapeutic resistance develops frequently , and further mechanistic understanding is needed . Cell metabolism may be central to this cell death pathway , as we have shown that growth factor deprivation leads to decreased glycolysis that promotes apoptosis via p53 activation and induction of the proapoptotic protein Puma . Here , we extend these findings to show that elevated glucose metabolism , characteristic of cancer cells , can suppress protein kinase C\u03b4 ( PKC\u03b4)-dependent p53 activation to maintain cell survival after growth factor withdrawal . In contrast , DNA damage-induced p53 activation was PKC\u03b4 independent and was not metabolically sensitive . Both stresses required p53 Ser(18) phosphorylation for maximal activity but led to unique patterns of p53 target gene expression , showing distinct activation and response pathways for p53 that were differentially regulated by metabolism . Consistent with oncogenic kinases acting to replace growth factors , treatment of BCR-Abl-expressing cells with the kinase inhibitor imatinib led to reduced metabolism and p53- and Puma-dependent cell death . Accordingly , maintenance of glucose uptake inhibited p53 activation and promoted imatinib resistance . Furthermore , inhibition of glycolysis enhanced imatinib sensitivity in BCR-Abl-expressing cells with wild-type p53 but had little effect on p53-null cells . These data show that distinct pathways regulate p53 after DNA damage and metabolic stress and that inhibiting glucose metabolism may enhance the efficacy of and overcome resistance to targeted molecular cancer therapies .", "label": [0, 0, 1, 0, 0, 1, 0, 0, 1, 0], "id": "20876800"}
{"sentence": "BACKGROUND Matrix metalloproteinases comprise a family of enzyme degrade components of extra cellular matrix . There are single nucleotide polymorphisms in the promoter regions of several genes with ability to influence cancer susceptibility . The aim of this study was to analyze association between MMP3 promoter polymorphisms and colorectal cancer occurrence and progression . MATERIALS AND METHODS In this case-control study 120 colorectal cancer patients and 100 controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism ( PCR-RFLP ) on the genomic deoxyribonucleic acid ( DNA ) . The patients group was divided into different subgroups : a subgroup without metastatic activity ( M(-) ) and a subgroup that had developed metastasis ( M(+) ) . RESULTS There was a significant difference in frequency of the MMP-3 genotype between cases and controls ( \\u03c7\\u0382 = 16.17 ; P = 0.0003 ) . The 5A homozygote in patients and controls was significantly different . The frequency of the 5A allele among affected patients ( 67.91% ) was significantly higher than among the healthy controls ( 49% ; \\u03c7(2) = 16.17 , P = 0.00005 ) . At the time of diagnosis , individual who was carrying the 5A allele was more represented in the M(+) subgroup than in M(-) subgroup ( \u03c7\u00b2 = 7.49 ; P = 0.006 , OR = 3.86 ; 95% CI , 1.43-10.33 ) . The difference between M(-) and controls did not observe statistically significant ( \u03c7\u00b2 = 0.009 ; P = 0.92 ) . CONCLUSIONS Our results suggest that the presence of 5A polymorphism at the MMP-3 promoter region may favor the growth and the metastasis process in colorectal cancer patients and could be looked at as a risk factor for a worse prognosis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23825998"}
{"sentence": "BACKGROUND Inorganic arsenic is a ubiquitous environmental carcinogen affecting millions of people worldwide . Evolving theory predicts that normal stem cells ( NSCs ) are transformed into cancer stem cells ( CSCs ) that then drive oncogenesis . In humans , arsenic is carcinogenic in the urogenital system ( UGS ) , including the bladder and potentially the prostate , whereas in mice arsenic induces multi-organ UGS cancers , indicating that UGS NSCs may represent targets for carcino-genic initiation . However , proof of emergence of CSCs induced by arsenic in a stem cell population is not available . METHODS We continuously exposed the human prostate epithelial stem/progenitor cell line WPE-stem to an environmentally relevant level of arsenic ( 5 microM ) in vitro and determined the acquired cancer phenotype . RESULTS WPE-stem cells rapidly acquired a malignant CSC-like phenotype by 18 weeks of exposure , becoming highly invasive , losing contact inhibition , and hyper-secreting matrix metalloproteinase-9 . When hetero-transplanted , these cells ( designated As-CSC ) formed highly pleomorphic , aggressive tumors with immature epithelial- and mesenchymal-like cells , suggesting a highly pluripotent cell of origin . Consistent with tumor-derived CSCs , As-CSCs formed abundant free-floating spheres enriched in CSC-like cells , as confirmed by molecular analysis and the fact that only these floating cells formed xeno-graft tumors . An early loss of NSC self-renewal gene expression ( p63 , ABCG2 , BMI-1 , SHH , OCT-4 , NOTCH-1 ) during arsenite exposure was sub-sequently reversed as the tumor suppressor gene PTEN was progressively suppressed and the CSC-like phenotype acquired . CONCLUSIONS Arsenite transforms prostate epithelial stem/progenitor cells into CSC-like cells , indicating that it can produce CSCs from a model NSC population .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20056578"}
{"sentence": "Blockage of the metastasis process remains a significant clinical challenge , requiring innovative therapeutic approaches . For this purpose , molecules that inhibit matrix metalloproteinases activity or induce the expression of their natural inhibitor , the tissue inhibitor of metalloproteinases ( TIMPs ) , are potentially interesting . In a previous study , we have shown that synthetic ligands binding to cell surface nucleolin/nucleophosmin and known as HB 19 for the lead compound and NucAnt 6L ( N6L ) for the most potent analog , inhibit both tumor growth and angiogenesis . Furthermore , they prevent metastasis in a RET transgenic mice model which develops melanoma . Here , we investigated the effect of N6L on the invasion capacity of MDA-MB-435 melanoma cells . Our results show that the multivalent pseudopeptide N6L inhibited Matrigel invasion of MDA-MB-435 cells in a modified Boyden chamber model . This was associated with an increase in TIMP-3 in the cell culture medium without a change in TIMP-3 mRNA expression suggesting its release from cell surface and/or extracellular matrix . This may be explained by our demonstrated N6L interaction with sulfated glycosaminoglycans and consequently the controlled bioavailability of glycosaminoglycan-bound TIMP-3 . The implication of TIMP-3 in N6L-induced inhibition of cell invasion was evidenced by siRNA silencing experiments showing that the loss of TIMP-3 expression abrogated the effect of N6L . The inhibition of tumor cell invasion by N6L demonstrated in this study , in addition to its previously established inhibitory effect on tumor growth and angiogenesis , suggests that N6L represents a promising anticancer drug candidate warranting further investigation .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23109338"}
{"sentence": "Clinically approved chemotherapeutic nanoparticles may provide advantages over free drugs by achieving slower clearance and preferential accumulation in tumors . However , the lack of leaky vasculatures can create barriers to the permeation of nm-sized nanoparticles in solid tumors . We hypothesized that nanoparticles designed to target both tumor and tumor stroma would penetrate deeper into the tumors . To construct such comprehensive drug carriers , we utilized cross-linked amphiphilic polymer nanoparticles and functionalized them to target ICAM-1 , a biomarker prevalent in various tumors and inflamed tumor stroma . The targeting moiety was derived from the modular domain present in \u03b1(L) integrin , which was engineered for high affinity and cross-reactivity with human and murine ICAM-1 . ICAM-1-selective delivery of paclitaxel produced potent tumor suppression of not only ICAM-1-positive cervical cancer cells but also ICAM-1-negative tumors , presumably by causing cytotoxicity in tumor-associated endothelium ( CD31(+) ) and macrophages ( CD68(+) ) over-expressing ICAM-1 . Contrary to the strategies of targeting only the tumor or specific tumor stromal constituents , we present a strategy in delivering therapeutics to the major cellular components of solid tumors . Drug carriers against inflammation-biomarkers may be effective against many different types of tumors , while being less susceptible to the highly mutable nature of tumor markers .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23099063"}
{"sentence": "BACKGROUND Investigations concerned the mechanism of HT-29 cells radiosensitization by cis-9,trans-11-conjugated linoleic acid ( c9,t11-CLA ) , a natural component of human diet with proven antitumor activity . METHODS The cells were incubated for 24h with 70\\u03bcM c9,t11-CLA and then X-irradiated . The following methods were used : gas chromatography ( incorporation of the CLA isomer ) , flow cytometry ( cell cycle ) , cloning ( survival ) , Western blotting ( protein distribution in membrane fractions ) , and pulse-field gel electrophoresis ( rejoining of DNA double-strand breaks ) . In parallel , DNA-PK activity , \\u03b3-H2AX foci numbers and chromatid fragmentation were estimated . Gene expression was analysed by RT-PCR and chromosomal aberrations by the mFISH method . Nuclear accumulation of the EGF receptor ( EGFR ) was monitored by ELISA . RESULTS AND CONCLUSIONS C9,t11-CLA sensitized HT-29 cells to X-radiation . This effect was not due to changes in cell cycle progression or DNA-repair-related gene expression . Post-irradiation DSB rejoining was delayed , corresponding with the insufficient DNA-PK activation , although chromosomal aberration frequencies did not increase . Distributions of cholesterol and caveolin-1 in cellular membrane fractions changed . The nuclear EGFR translocation , necessary to increase the DNA-PK activity in response to oxidative stress , was blocked . We suppose that c9,t11-CLA modified the membrane structure , thus disturbing the intracellular EGFR transport and the EGFR-dependent pro-survival signalling , both functionally associated with lipid raft properties . GENERAL SIGNIFICANCE The results point to the importance of the cell membrane interactions with the nucleus after injury inflicted by X -rays . Compounds like c9,t11-CLA , that specifically alter membrane properties , could be used to develop new anticancer strategies .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 1], "id": "23116821"}
{"sentence": "BACKGROUND Death receptors ( DR ) of the TNF family function as anti-tumor immune effector molecules . Tumor cells , however , often exhibit DR-signaling resistance . Previous studies indicate that radiation can modify gene expression within tumor cells and increase tumor cell sensitivity to immune attack . The aim of this study is to investigate the synergistic effect of sub-lethal doses of ionizing radiation in sensitizing colorectal carcinoma cells to death receptor-mediated apoptosis . METHODOLOGY/PRINCIPAL FINDINGS The ability of radiation to modulate the expression of multiple death receptors ( Fas/CD95 , TRAILR1/DR4 , TRAILR2/DR5 , TNF-R1 and LT\u03b2R ) was examined in colorectal tumor cells . The functional significance of sub-lethal doses of radiation in enhancing tumor cell susceptibility to DR-induced apoptosis was determined by in vitro functional sensitivity assays . The longevity of these changes and the underlying molecular mechanism of irradiation in sensitizing diverse colorectal carcinoma cells to death receptor-mediated apoptosis were also examined . We found that radiation increased surface expression of Fas , DR4 and DR5 but not LT\u03b2R or TNF-R1 in these cells . Increased expression of DRs was observed 2 days post-irradiation and remained elevated 7-days post irradiation . Sub-lethal tumor cell irradiation alone exhibited minimal cell death , but effectively sensitized three of three colorectal carcinoma cells to both TRAIL and Fas-induced apoptosis , but not LT\u03b2R-induced death . Furthermore , radiation-enhanced Fas and TRAIL-induced cell death lasted as long as 5-days post-irradiation . Specific analysis of intracellular sensitizers to apoptosis indicated that while radiation did reduce Bcl-X(L) and c-FLIP protein expression , this reduction did not correlate with the radiation-enhanced sensitivity to Fas and/or TRAIL mediated apoptosis among the three cell types . CONCLUSIONS/SIGNIFICANCE Irradiation of tumor cells can overcome Fas and TRAIL resistance that is long lasting . Overall , results of these investigations suggest that non-lethal doses of radiation can be used to make human tumors more amenable to attack by anti-tumor effector molecules and cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22389673"}
{"sentence": "Several members of the phosphatidylinositol 3-kinase family play key roles in recognising and responding to damage in DNA , induced by a variety of chemicals and other agents . One of these , ATM , the product of the gene mutated in the human genetic disorder ataxia-telangiectasia ( A-T ) , recognises double strand breaks in DNA caused by ionizing radiation and radiomimetic chemicals . In order to study DNA damage recognition and the abnormalities of genome instability and cancer predisposition that occur in A-T patients , we generated a mouse model expressing a mutant form of Atm corresponding to a common human mutation . In this model , a 9 nucleotide in-frame deletion was introduced into the Atm gene and has been designated Atm-Delta SRI . These animals had a longer lifespan than Atm gene disrupted mice ( Atm(-/-) ) and they developed less thymic lymphomas . A characteristic of the lymphomas appearing in Atm-Delta SRI mice was an increased rate of apoptosis compared to the corresponding tumours in Atm(-/-) mice . Increased expression of FasL in these tumours may account for the higher levels of apoptosis . These results demonstrate that expression of mutant Atm in mice gives rise to phenotypic differences compared to Atm(-/-) mice and has implications for heterogeneity described in the human syndrome .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "12505357"}
{"sentence": "Interleukin-23 ( IL-23 ) plays an essential role in the mucosal immune system . It has been suggested that IL-23 is able to induce carcinogenesis as well as inflammation and a recent study revealed that IL-23R is expressed in colorectal carcinoma cells . However , neither the differences in the IL-23R expression among the patients nor the concrete functions of IL-23 in colorectal carcinoma cells have been revealed . The aim of the present study was to examine the characteristics of IL-23R expression in colorectal carcinoma and the direct effects of IL-23 on colorectal cancer cells . We examined the IL-23R expression in human colorectal cancer tissue samples by immunohistochemistry . Cell proliferation and invasion assays under IL-23 stimulation were performed using cultured cells derived from colorectal cancer . ELISA and real-time PCR were used to evaluate the transforming growth factor ( TGF)-\u03b2 production due to IL-23 stimulation . All of the TNM stage IV patients were positive for IL-23R . IL-23R expression in the carcinoma tissue was also relatively high at the deepest point of invasion in certain cases . The proliferative and invasive activities and/or TGF-\u03b2 production of DLD-1 cells increased by IL-23 stimulation , whereas no change was observed in the activities of MIP101 and KM12c cells . IL-23 directly enhanced the malignancy of the colon carcinoma cells . An autocrine mechanism via TGF-\u03b2 production may underlie these effects . IL-23 is therefore a potential target for cancer immunotherapy . However , the homogeneity in IL-23R expression and the effects of IL-23 on colorectal carcinoma cells should be considered .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22844353"}
{"sentence": "The aim of this study was to evaluate the effects and molecular mechanisms of everolimus on Panc-1 human pancreatic cancer cells . Panc-1 human pancreatic cancer cells were treated with everolimus ( 10 \u03bcg/ml ) at selected time points ( 6 , 12 and 24 h ) . Cell proliferation and apoptosis were evaluated by MTT and flow cytometric analyses . The glycolytic activity was determined by measuring the activity of the key enzyme lactate dehydrogenase ( LDH ) and lactate production . The activity of mammalian target of rapamycin ( mTOR ) signaling was measured by western blotting . The expression of genes , including hexokinase 2 ( HK2 ) and microRNA-143 ( miR-143 ) , was evaluated by real-time polymerase chain reaction ( PCR ) . The administration of everolimus time-dependently inhibited proliferation and glycolysis and induced apoptosis in the Panc-1 human pancreatic cancer cells . As the time of treatment with everolimus increased , the mTOR signaling activity decreased , indicated by lower phosphorylation levels of S6 kinase ; however , the phosphorylation levels of mTOR barely changed . Moreover , our data showed an everolimus-induced increase in miR-143 and decrease in HK2 in Panc-1 cells in a time-dependent manner . In conclusion , the current study indicates a novel role of everolimus in its antitumor effect as an inhibitor of glycolysis in Panc-1 human pancreatic cancer cells . Furthermore , our data highlights the significance of exploring the mechanisms of everolimus and miR-143 in malignant tumors .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "23251295"}
{"sentence": "Aberrant expression of mucins is likely associated with cancer biology as alterations in the expression and/or glycosylation patterns of various mucins have been noted . Expression of the mucin family in gastric cancers has been reported in numerous studies , but the results are conflicting . Therefore , we investigated the potential use of mucin ( MUC)1 and 4 as prognostic markers in gastric cancer according to histological subtype . Three-hundred and sixty-five gastric adenocarcinoma patients who underwent surgical resection were selected for this study . Among the 365 gastric cancer samples tested here , 34% consisted of early gastric cancer and 66% were advanced . In terms of location , 68.7% of the cohort had intestinal-type cancer and 30.7% had diffuse-type . We constructed tissue microarrays with formalin-fixed paraffin-embedded blocks of gastric cancer and these micro-arrays were evaluated for phenotypic expression of MUC1/4 using monoclonal antibodies . Two-hundred and ninety-two patients ( 92.7% ) were positive for MUC1 and 216 ( 60.5% ) were positive for MUC4 . MUC1 expression was not correlated with any other clinicopathological variables such as age , gender , depth of invasion , lymph node metastasis , Lauren classification or recurrence . However , loss of MUC4 expression was significantly correlated with recurrence ( p=0.033 ) . MUC4 expression was also significantly correlated with better disease-free survival ( p=0.049 ) and particularly in the intestinal-type ( p=0.018 ) . Our present findings demonstrated that loss of MUC4 expression can be used as a prognostic marker in gastric cancer . Loss of MUC4 expression is a prognostic indicator of increased recurrence and poor disease-free survival in patients with gastric cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23139719"}
{"sentence": "BACKGROUND Human T-cell leukemia virus type I ( HTLV-I ) has efficiently adapted to its host and establishes a persistent infection characterized by low levels of viral gene expression and slow proliferation of HTLV-I infected cells over decades . We have previously found that HTLV-I p30 is a negative regulator of virus expression . RESULTS In this study we show that p30 targets multiple cell cycle checkpoints resulting in a delayed entry into S phase . We found that p30 binds to cyclin E and CDK2 and prevents the formation of active cyclin E-CDK2 complexes . In turn , this decreases the phosphorylation levels of Rb and prevents the release of E2F and its transcriptional activation of genes required for G1/S transition . Our studies also show that HTLV-II p28 does not bind cyclin E and does not affect cell cycle progression . CONCLUSIONS In contrast to HTLV-I , the HTLV-II-related retrovirus is not oncogenic in humans . Here we report that the HTLV-I p30 delays cell cycle progression while its homologue , HTLV-II p28 , does not , providing evidence for important differences between these two related retrovirus proteins .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "21092281"}
{"sentence": "PURPOSE We recently reported that overexpression of epidermal growth factor receptor ( EGFR ) positively correlated with radioresistance of murine carcinomas . Because cyclin D1 is a downstream sensor of EGFR activation , the present study investigated whether a relationship exists between the extent of cyclin D1 expression and in vivo radiocurability of murine tumors . We further investigated the influence of radiation on cyclin D1 expression and the expression of p27 , an inhibitor of the cyclin D1 downstream pathway , as well as the relationship of these molecular determinants to cell proliferation and induced apoptosis in tumors exposed to radiation . METHODS AND MATERIALS Cyclin D1 expression was assayed in nine carcinomas syngeneic to C3Hf/Kam mice using Western blot analysis . These tumors greatly differed in their radioresponse as assessed by TCD(50) . The expression of cyclin D1 and p27 proteins was determined by Western blotting . Cell proliferative activity in tumors was determined by proliferating cell nuclear antigen ( PCNA ) immunochemistry . The effect of irradiation on the expression of cyclin D1 or p27 proteins and on PCNA positivity was determined in the radiosensitive OCa-I and in the radioresistant SCC-VII tumors . RESULTS Cyclin D1 expression varied among tumors by 40-fold , and its magnitude positively correlated with poorer tumor radioresponse ( higher TCD(50) values ) . The level of cyclin D1 expression paralleled that of EGFR . A 15-Gy dose reduced constitutive expression of cyclin D1 in the radiosensitive OCa-I tumors , but had no influence on expression of cyclin D1 in the radioresistant SCC-VII tumors . In contrast , 15 Gy increased the expression of p27 in radiosensitive tumors and reduced it in radioresistant tumors . Radiation induced no significant apoptosis or change in the percentage of PCNA-positive ( proliferating ) cells in SCC-VII tumors with high cyclin D1 levels , but it induced significant apoptosis and a decrease in the percentage of proliferating cells in OCa-I tumors with low cyclin D1 expression . CONCLUSION Our findings show a positive correlation between cyclin D1 expression and tumor radioresistance . The expression of cyclin D1 and p27 was modified by radiation and was associated with cellular response to radiation , but this depended on the pretreatment level of cyclin D1 expression . These findings may have important clinical implications : The pretreatment assessment of cyclin D1 expression could serve as a useful predictor of radiotherapy outcome and assist in selecting an effective treatment modality .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "11872299"}
{"sentence": "CONTEXT Papillary thyroid carcinoma ( PTC ) is the most frequent thyroid tumor and is responsible for the overall increase in thyroid cancer incidence . S100A11 ( calgizzarin ) , a member of the S100 Ca(2+)-binding protein family , is involved in several different biological processes . S100A11 has been found up-regulated in PTC , both at the mRNA and protein levels . OBJECTIVE Through a combination of expression analysis and functional in vitro and in vivo studies , we have attempted to gain insight into the relevance of S100A11 overexpression in PTC biology . DESIGN The expression of the S100A11 gene in PTC was investigated in several gene expression data sets . The effect of S100A11 silencing on the hallmarks of the malignant phenotype of several PTC-derived cell lines was investigated . In NIH3T3 cells , the cooperation of S100A11 with the different PTC-specific oncogenes was assessed . RESULTS We found that the S100A11 gene expression is frequently up-regulated in PTC , anaplastic thyroid carcinoma , but not in follicular thyroid carcinoma . S100A11 overexpression was also detected in PTC-derived cell lines , which were then used for functional studies . S100A11 silencing in PTC-derived cell lines did not affect cell proliferation , whereas it reduced the loss of contact inhibition , anchorage-independent growth , and resistance to anoikis . Cotransfection experiments in NIH3T3 cells showed that overexpression of the S100A11 gene was able to enhance the transforming capabilities of the different PTC-associated oncogenes by affecting the loss of contact inhibition , anchorage-independent growth , and in vivo tumor formation . CONCLUSION Our data indicate that S100A11 overexpression exerts a protumoral functional role in PTC pathogenesis .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23928665"}
{"sentence": "Cancer cells convert glucose preferentially to lactate even in the presence of oxygen ( aerobic glycolysis-Warburg effect ) . New concepts in cancer treatment aim at inhibition of aerobic glycolysis . Pyruvate dehydrogenase converts pyruvate to acetylCoA thus preventing lactate formation . Therefore , the aim of this study was to evaluate compounds that could activate pyruvate dehydrogenase in cancer cells . We investigated the effects of ( R)-(+)-\u03b1-lipoic acid ( LPA ) and dichloroacetate ( DCA ) , possible activators of pyruvate dehydrogenase , on suppression of aerobic glycolysis and induction of cell death . The neuroblastoma cell lines Kelly , SK-N-SH , Neuro-2a and the breast cancer cell line SkBr3 were incubated with different concentrations ( 0.1-30 mM ) of LPA and DCA . The effects of both compounds on cell viability/proliferation ( WST-1 assay ) , [ 18F]-FDG uptake , lactate production and induction of apoptosis ( flow cytometric detection of caspase-3 ) were evaluated . Furthermore , NMRI nu/nu mice that had been inoculated s.c. with SkBr3 cells were treated daily for four weeks with LPA ( i.p , 18.5 mg/kg ) starting at day 7 p.i. . Tumor development was measured with a sliding calliper and monitored via [ 18F]-FDG-PET . Residual tumors after therapy were examined histopathologically . These data suggests that LPA can reduce ( 1 ) cell viability/proliferation , ( 2 ) uptake of [ 18F]-FDG and ( 3 ) lactate production and increase apoptosis in all investigated cell lines . In contrast , DCA was almost ineffective . In the mouse xenograft model with s.c . SkBr3 cells , daily treatment with LPA retarded tumor progression . Therefore , LPA seems to be a promising compound for cancer treatment .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "22954700"}
{"sentence": "The complement system contributes to various immune and inflammatory diseases , including cancer . In this study , we investigated the capacity of lung cancer cells to activate complement and characterized the consequences of complement activation on tumor progression . We focused our study on the production and role of the anaphylatoxin C5a , a potent immune mediator generated after complement activation . We first measured the capacity of lung cancer cell lines to deposit C5 and release C5a . C5 deposition , after incubation with normal human serum , was higher in lung cancer cell lines than in nonmalignant bronchial epithelial cells . Notably , lung malignant cells produced complement C5a even in the absence of serum . We also found a significant increase of C5a in plasma from patients with non-small cell lung cancer , suggesting that the local production of C5a is followed by its systemic diffusion . The contribution of C5a to lung cancer growth in vivo was evaluated in the Lewis lung cancer model . Syngeneic tumors of 3LL cells grew slower in mice treated with an antagonist of the C5a receptor . C5a did not modify 3LL cell proliferation in vitro but induced endothelial cell chemotaxis and blood-vessels formation . C5a also contributed to the immunosuppressive microenvironment required for tumor growth . In particular , blockade of C5a receptor significantly reduced myeloid-derived suppressor cells and immunomodulators ARG1 , CTLA-4 , IL-6 , IL-10 , LAG3 , and PDL1 ( B7H1 ) . In conclusion , lung cancer cells have the capacity to generate C5a , a molecule that creates a favorable tumor microenvironment for lung cancer progression .", "label": [0, 1, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23028051"}
{"sentence": "Numerous studies have reported a correlation between production of 72-kDa ( MMP-2 ) and 92-kDa ( MMP-9 ) type-IV collagenases/gelatinases and the metastatic potential of cancer cells . An abrogating effect of tissue inhibitors of metalloproteinases ( TIMP-1 and TIMP-2 ) on metastases has also been noted . In this report we have used sensitive enzyme-linked immunoassays to measure MMP-2 , MMP-9 , TIMP-1 and TIMP-2 levels in eight human lung-cancer cell lines which were characterized for biological behavior in nude mice . We demonstrated that the Calu-6 and A549 cell lines with the highest metastatic , invasive and tumorigenic potential secreted the highest levels of MMP-2 . MMP-9 and TIMP-1 secretions were comparatively low in all cell lines . TIMP-2 secretion , which exceeded MMP-2 secretion for all cell lines , did not correlate with metastatic potential . To further explore these correlations , the metastatic Calu-6 cell line was transfected with a K-rev-1 cDNA expression construct . The K-rev revertant cell lines demonstrated a more differentiated phenotype and were less tumorigenic , invasive and metastatic in nude mice . Nonetheless , the Calu-6 revertant cell lines secreted higher levels of MMP-2 than the parent cell line . In conclusion , invasion and metastasis by lung-cancer cells requires not only enhanced MMP production , but also other less well-understood tumorigenic characteristics . The multiplicity of factors required by cancer cells for dissemination helps to explain the minute fraction of cancer cells from a primary tumor that ever develop into a metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1399111"}
{"sentence": "BACKGROUND Alcohol consumption promotes hepatocellular carcinoma ( HCC ) . The responsible mechanisms are not well understood . Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration . Because alcohol is hepatotoxic , habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration . The alcohol-preferring ( P ) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol . Previously , we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats , with over 80% of alcohol-consuming P rats developing HCCs after 18months of alcohol exposure , compared with only 5% of water-drinking controls . METHODS Herein , we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6 , 12 , or 18months of drinking . We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog ( HH ) , a regenerative signaling pathway that is overactivated in HCC . RESULTS Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes , but did not cause appreciable liver inflammation or fibrosis even after 18months of heavy drinking . HH signaling was also enhanced by alcohol exposure , as evidenced by increased levels of mRNAs encoding HH ligands , HH-regulated transcription factors , and HH target genes . Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells . HH-related regenerative responses were also induced in alcohol-exposed rats . Three of these processes ( i.e. , deregulated progenitor expansion , the reverse Warburg effect , and epithelial-to-mesenchymal transitions ) are known to promote cancer growth in other tissues . CONCLUSIONS Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "24164383"}
{"sentence": "BACKGROUND Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands . Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects . It has previously been shown that IGF-1 suppresses radiation-induced apoptosis and enhances G2/M arrest leading to preservation of salivary gland function . In an effort to recapitulate the effects of IGF-1 , as well as increase the likelihood of translating these findings to the clinic , the small molecule therapeutic Roscovitine , is being tested . Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues . METHODOLOGY/PRINCIPAL FINDINGS Treatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G(2)/M phase , as demonstrated by flow cytometry . In contrast , mice treated with radiation exhibit no differences in the percentage of cells in G(2)/M when compared to unirradiated controls . Similar to previous studies utilizing IGF-1 , pretreatment with Roscovitine leads to a significant up-regulation of p21 expression and a significant decrease in the number of PCNA positive cells . Radiation treatment leads to a significant increase in activated caspase-3 positive salivary acinar cells , which is suppressed by pretreatment with Roscovitine . Administration of Roscovitine prior to targeted head and neck irradiation preserves normal tissue function in mouse parotid salivary glands , both acutely and chronically , as measured by salivary output . CONCLUSIONS/SIGNIFICANCE These studies suggest that induction of transient G(2)/M cell cycle arrest by Roscovitine allows for suppression of apoptosis , thus preserving normal salivary function following targeted head and neck irradiation . This could have an important clinical impact by preventing the negative side effects of radiation therapy in surrounding normal tissues .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23236487"}
{"sentence": "Multiprotein complexes , called editosomes , catalyze the uridine insertion and deletion RNA editing that forms translatable mitochondrial mRNAs in kinetoplastid parasites . We have identified here two new U1-like zinc finger proteins that associate with editosomes and have shown that they are related to KREPB6 , KREPB7 , and KREPB8 , and thus we have named them Kinetoplastid RNA Editing Proteins , KREPB9 and KREPB10 . They are conserved and syntenic in trypanosomatids although KREPB10 is absent in Trypanosoma vivax and both are absent in Leishmania . Tandem affinity purification ( TAP)-tagged KREPB9 and KREPB10 incorporate into editosomes and/or subcomplexes thereof and preferentially associate with deletion subcomplexes , as do KREPB6 , KREPB7 , and KREPB8 . KREPB10 also associates with editosomes that are isolated via a chimeric endonuclease , KREN1 in KREPB8 RNA interference ( RNAi ) cells , or MEAT1 . The purified complexes have precleaved editing activities and endonuclease cleavage activity that appears to leave a 5 ' OH on the 3 ' product . RNAi knockdowns did not affect growth but resulted in relative reductions of both edited and unedited mitochondrial mRNAs . The similarity of KREPB9 and KREPB10 to KREPB6 , KREPB7 , and KREPB8 suggests they may be accessory factors that affect editing endonuclease activity and as a consequence may affect mitochondrial mRNA stability . KREPB9 and KREPB10 , along with KREPB6 , KREPB7 , and KREPB8 , may enable the endonucleases to discriminate among and accurately cleave hundreds of different editing sites and may be involved in the control of differential editing during the life cycle of T. brucei .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22562468"}
{"sentence": "Elevated serum levels of vasoactive intestinal peptide ( VIP ) are associated with some cases of neuroblastoma and correlate with a favorable prognosis . VIP has previously been shown in our laboratory to cause the in vitro growth inhibition and morphological differentiation of the human neuroblastoma cell line , LA-N-5 . It is now shown that LA-N-5 cells express immunoreactive VIP and bear specific VIP receptors . Antagonism of endogenous VIP , either by competitive inhibition or receptor blockade , increased cell proliferation , suggesting that VIP is operative in normal growth regulation . Intracellular and extracellular levels of VIP were also shown to increase significantly during the retinoic acid-induced differentiation of these cells . Furthermore , a concomitant marked increase in VIP receptor expression was demonstrated with cellular differentiation . These receptors remain functional as evidenced by a matching increase in the level of detectable cAMP generated in response to exogenous VIP . It is concluded that VIP is a normal autoregulator of neuroblastoma cell growth and differentiation , and that retinoic acid-mediated differentiation may be , in part , due to endogenous VIP .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1328588"}
{"sentence": "The anthracycline doxorubicin is a widely used effective anti-cancer drug . However , its application and dosage are severely limited due to its cardiotoxicity . The exact mechanisms of doxorubicin-induced cardiotoxic side effects remain poorly understood . Even less is known about the impact of doxorubicin treatment on vascular damage . We found that low doses of doxorubicin induced a senescent response in human primary vascular smooth muscle cells ( VSMC ) . We observed that expression of urokinase receptor ( uPAR ) was upregulated in response to doxorubicin . Furthermore , the level of uPAR expression played a decisive role in developing doxorubicin-induced senescence. uPAR silencing in human VSMC by means of RNA interference as well as uPAR knockout in mouse VSMC resulted in abrogation of doxorubicin-induced cellular senescence . On the contrary , uPAR overexpression promoted VSMC senescence . We further found that proteasomal degradation of telomeric repeat binding factor 2 ( TRF2 ) mediates doxorubicin-induced VSMC senescence . Our results demonstrate that uPAR controls the ubiquitin-proteasome system in VSMC and regulates doxorubicin-induced TRF2 ubiquitination and proteasomal degradation via this mechanism . Therefore , VSMC senescence induced by low doses of doxorubicin may contribute to vascular damage upon doxorubicin treatment. uPAR-mediated TRF2 ubiquitination and proteasomal degradation are further identified as a molecular mechanism underlying this process .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23172421"}
{"sentence": "Reprogramming of cellular metabolism is a key eventduring tumorigenesis . Despite being known for decades ( Warburg effect ) , the molecular mechanisms regulating this switch remained unexplored . Here , we identify SIRT6 as a tumor suppressor thatregulates aerobic glycolysis in cancer cells . Importantly , loss of SIRT6 leads to tumor formation without activation of known oncogenes , whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth , suggesting that SIRT6 plays a role in both establishment and maintenance of cancer . By using a conditional SIRT6 allele , we show that SIRT6 deletion invivo increases the number , size , and aggressiveness of tumors . SIRT6 also functions as a regulator of ribosome metabolismby corepressing MYC transcriptional activity . Lastly,Sirt6 is selectively downregulated in several human cancers , and expression levels of SIRT6 predict prognosis and tumor-free survival rates , highlighting SIRT6 as a critical modulator of cancermetabolism . Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism .", "label": [0, 0, 1, 0, 0, 1, 0, 0, 0, 0], "id": "23217706"}
{"sentence": "Chromosomal inversions are usually portrayed as simple two-breakpoint rearrangements changing gene order but not gene number or structure . However , increasing evidence suggests that inversion breakpoints may often have a complex structure and entail gene duplications with potential functional consequences . Here , we used a combination of different techniques to investigate the breakpoint structure and the functional consequences of a complex rearrangement fixed in Drosophila buzzatii and comprising two tandemly arranged inversions sharing the middle breakpoint : 2m and 2n . By comparing the sequence in the breakpoint regions between D. buzzatii ( inverted chromosome ) and D. mojavensis ( noninverted chromosome ) , we corroborate the breakpoint reuse at the molecular level and infer that inversion 2m was associated with a duplication of a kb segment and likely generated by staggered breaks plus repair by nonhomologous end joining . The duplicated segment contained the gene CG4673 , involved in nuclear transport , and its two nested genes CG5071 and CG5079 . Interestingly , we found that other than the inversion and the associated duplication , both breakpoints suffered additional rearrangements , that is , the proximal breakpoint experienced a microinversion event associated at both ends with a 121-bp long duplication that contains a promoter . As a consequence of all these different rearrangements , CG5079 has been lost from the genome , CG5071 is now a single copy nonnested gene , and CG4673 has a transcript kb shorter and seems to have acquired a more complex gene regulation . Our results illustrate the complex effects of chromosomal rearrangements and highlight the need of complementing genomic approaches with detailed sequence-level and functional analyses of breakpoint regions if we are to fully understand genome structure , function , and evolutionary dynamics .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22328714"}
{"sentence": "A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases . In contrast to the currently approved HER-2-targeted agent ( lapatinib , 1 ) , our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance . The selected compound ( 19a ) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types : lapatinib-sensitive cell lines ( SK-Br3 , MDA-MB-175 , and N87 ) and lapatinib-resistant cell lines ( MDA-MB-453 , H1781 , and H1975 ) . The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors , especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22372864"}
{"sentence": "Our purpose in this randomized , double blind , placebo controlled study was to find out the possible effect of a polyphenolic pine bark extract , Pycnogenol\u00ae ( Pyc ) on the level of 8-oxo-7,8-dihydroguanine ( 8-oxoG ) as representative of oxidative damage to DNA and on the DNA repair ability of elderly people . According to our results , three months of Pyc administration had no effect on the level of oxidative damage to DNA or on repair ability , but we found a relationship between the level of 8-oxoG and repair ability of DNA in this group . To conclude , even if the positive effect of Pyc was not confirmed in the case of elderly people it is important to highlight the necessity of further investigations about the mechanisms of Pyc acting on different age groups .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21189165"}
{"sentence": "The covalent modification of proteins with ubiquitin is required for accurate cell division in all eukaryotes . Ubiquitylation depends on an enzymatic cascade , in which E3 enzymes recruit specific substrates for modification . Among human E3s , the SCF ( Skp1-cullin1-F-box ) and the APC/C ( anaphase-promoting complex/cyclosome ) are known for driving the degradation of cell cycle regulators to accomplish irreversible cell cycle transitions . The cell cycle machinery reciprocally regulates the SCF and APC/C through various mechanisms , including the modification of these E3s or the binding of specific inhibitors . Recent studies have provided new insight into the intricate relationship between ubiquitylation and the cell division apparatus as they revealed roles for atypical ubiquitin chains , new mechanisms of substrate and E3 regulation , as well as extensive crosstalk between ubiquitylation enzymes . Here , we review these emerging regulatory mechanisms of ubiquitin-dependent cell cycle control and discuss how their manipulation might provide therapeutic benefits in the future .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22357967"}
{"sentence": "Ovarian steroids are one of the strongest risk factors for breast cancer . Sex hormone-binding globulin ( SHBG ) binds and transports sex steroids in the blood , regulating their bioavailable fraction and access to target cells . It can also inhibit the estradiol-induced proliferation of breast cancer cells through its membrane receptor . Three coding-region polymorphisms , which lead to an amino acid change , have been reported . We studied the influence of these three polymorphisms on breast cancer risk in three different populations : Polish familial breast cancer cases , 27% of them carrying a BRCA1/BRCA2 mutation , Nordic familial and sporadic breast cancer cases . The reported G to A polymorphism in exon 1 was not found in the 423 analyzed samples . Instead , we found a C to T transition causing an arg to cys amino acid change within the same codon in one Polish breast cancer patient and her daughter . Both of them were heterozygotes for the exon 8 G to A polymorphism as well . They were diagnosed for bilateral breast cancer and carried a BRCA1 mutation ( 5382insC ) . Analysis of the tumor samples showed that they had lost the wild-type allele both at exons 1 and 8 of the SHBG gene . Analysis of the other Polish samples showed no correlation of the exon 8 polymorphism to breast cancer , bilateral breast cancer , BRCA1/BRCA2 mutations or age at diagnosis . No association of the exon 8 polymorphism with breast cancer in the Nordic familial or sporadic cases was found . The C to T polymorphism located in exon 4 was rare in all the studied populations ( overall allele frequency 0.011 ) . However , in each of the study populations there was a trend for a lower variant allele frequency in cancer cases than in controls . Variant allele frequency in all the breast cancer cases was significantly lower than in all the controls ( chi(2) = 5.27 , P-value 0.02 ; odds ratio = 0.23 , 95% confidence interval 0.05-0.84 ) .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12151349"}
{"sentence": "Using standard culture conditions , primary human mammary epithelial cells ( HMECs ) undergo a premature , transient growth arrest termed M0 ( mortality stage 0 ) after 10-15 population doublings in vitro . It has been reported that emergence from this growth arrest by the abrogation of p16(INK4a) , a cyclin-dependent kinase inhibitor , and expression of the catalytic component of human telomerase ( hTERT ) are necessary for HMEC immortalization . Here we show that primary HMECs , grown on feeder layers , do not undergo this growth arrest and can be immortalized without abrogating p16 . These findings support the concept that the so-called M0 stage represents a cell culture stress-induced growth arrest and that hTERT is sufficient to immortalize HMECs when cultured under adequate conditions .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12420227"}
{"sentence": "Certain mutations in BRCA1 and BRCA2 genes are frequent in the Ashkenazi Jewish population . Several factors contribute to this increased frequency , including consanguineous marriages and an event known as a \" bottleneck \" , which occurred in the past and caused a drastic reduction in the genetic variability of this population . Several studies were performed over the years in an attempt to elucidate the role of BRCA1 and BRCA2 genes in susceptibility to breast cancer . The aim of this study was to estimate the carrier frequency of certain common mutations in the BRCA1 ( 185delAG and 5382insC ) and BRCA2 ( 6174delT ) genes in an Ashkenazi Jewish population from Porto Alegre , Brazil . Molecular analyses were done by PCR followed by RFLP ( ACRS ) . The carrier frequencies for BRCA1 185delAG and 5382insC were 0.78 and 0 respectively , and 0.4 for the BRCA2 6174deT mutation . These findings are similar to those of some prior studies but differ from others , possibly due to excluding individuals with a personal or family history of cancer . Our sample was drawn from the community group and included individuals with or without a family or personal history of cancer . Furthermore , increased dispersion among Ashkenazi subpopulations may be the result of strong genetic drift and/or admixture . It is therefore necessary to consider the effects of local admixture on the mismatch distributions of various Jewish populations .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23055798"}
{"sentence": "The green fluorescent protein ( GFP ) is the most commonly used reporter protein for monitoring gene expression and protein localization in a variety of living and fixed cells , including not only prokaryotes , but also eukaryotes , e.g. , yeasts , mammals , plants and fish . In general , it is thought that GFP is nontoxic to cells , although there are some reports on the side effect of GFP . Further , details of the molecular mechanism concerning the side effect of GFP remain unclear . Here we show that Ku80 , but not XRCC4 , plays an important role in the mechanism of the resistance to cytotoxicity induced by enhanced GFP ( EGFP ) . EGFP inhibited both cell proliferation and colony formation , and induced cell death in Ku80-deficient hamster cells , i.e. , xrs-6 cells . In addition , Ku80 attenuated EGFP-induced cytotoxicity in the xrs-6 cells . No EGFP-induced cytotoxicity was observed in the NHEJ core protein XRCC4-deficient hamster cells , i.e. , XR-1 cells . Furthermore , EGFP markedly enhanced X-ray-induced cytotoxicity in the xrs-6 cells . These results suggest that Ku80 plays a key role in the novel NHEJ-independent defense mechanism against EGFP-induced cytotoxicity . Caution should be taken in considering of the potential influence by the stress response mechanism , namely , the Ku80-dependent elimination mechanism of EGFP-induced cytotoxicity , being activated , even when using EGFP-expressing cells in which Ku80 functions normally .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23772373"}
{"sentence": "Adenovirus small e1a oncoprotein causes reduction in cellular levels of histone H3 lysine 18 acetylation ( H3K18ac ) . It is unclear , however , where this dramatic reduction occurs genome-wide . ChIP-sequencing revealed that by 24 h after expression , e1a erases 95% of H3K18ac peaks in normal , contact-inhibited fibroblasts and replaces them with one-third as many at new genomic locations . The H3K18ac peaks at promoters and intergenic regions of genes with fibroblast-related functions are eliminated after infection , and new H3K18ac peaks are established at promoters of highly induced genes that regulate cell cycling and at new putative enhancers . Strikingly , the regions bound by the retinoblastoma family of proteins in contact-inhibited fibroblasts gain new peaks of H3K18ac in the e1a-expressing cells , including 55% of RB1-bound loci . In contrast , over half of H3K9ac peaks are similarly distributed before and after infection , independently of RB1 . The strategic redistribution of H3K18ac by e1a highlights the importance of this modification for transcriptional activation and cellular transformation as well as functional differences between the RB-family member proteins .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22499665"}
{"sentence": "Metastatic cancer is extremely difficult to treat , and the presence of metastases greatly reduces a cancer patient's likelihood of long-term survival . The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs ( miRs ) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors . Given that each miR can target multiple genes with diverse functions , we posited that the prometastatic network controlled by ZEB1 extends beyond these processes . We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1 , human lung carcinoma cells , and human breast carcinoma cells . Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs , including miR-34a . Ectopic expression of miR-34a decreased tumor cell invasion and metastasis , inhibited the formation of promigratory cytoskeletal structures , suppressed activation of the RHO GTPase family , and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas . We identified several miR-34a target genes , including Arhgap1 , which encodes a RHO GTPase activating protein that was required for tumor cell invasion . These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22850877"}
{"sentence": "We have studied the mutagenic specificity of abasic sites using the yeast oligonucleotides transformation assay . We introduced oligonucleotide containing a natural abasic site and a tetrahydrofuran abasic site into Rev1 mutants , rev1AA , which contains mutations of Asp467 and Glu468 residues of Rev1p to Ala in order to inactivate dCMP transferase activity , and rev1 delta , which lacks its whole coding sequence . The transformation efficiencies of rev1AA with abasic-containing oligonucleotides were lower than those of B7528 , a strain proficient in REV1 gene , but much higher than rev1 delta mutant . Sequence analysis opposite the lesions showed that the mutation spectra were different among these three strains .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12903118"}
{"sentence": "Verbascum thapsus commonly known as ' mullein ' is part of a large family of Scrophulariaceae consisting of more than 360 species . From antiquity Verbascum thapsus has been used as a medicinal herb , it contains diverse polysaccharides , iroid glycosides , flavonoids , saponins , volatile oils and phenylentanoids . Inducible nitric oxide synthase ( iNOS ) represents one of the three isoforms that produce nitric oxide using L-arginine as a substrate in response to an increase in superoxide anion activated by NF-kB . It is implicated in different pathophysiological events and its expression increases greatly during an inflammatory process , due to oxidative stress and the activation of the enzymes of the antioxidant network such as SOD , CAT and GPx.In this study an inflammatory state was reproduced by treating THP-1 cells ( human myelomonocytic leukaemia ) with pro-inflammatory stimuli , such as LPS and IFN-gamma , obtaining an up-regulation both in the expression and in the activity of iNOS . The aim of the work was to investigate the antiinflammatory action of verbascoside using a concentration of 100 mum . The results show a significant decrease of the expression and activity of iNOS , extracellular O(2) ( - ) production , SOD , CAT and GPx activity when the cells were treated with verbascoside . Based on these results it is hypothesized that verbascoside has antiinflammatory properties since it reduces the production of superoxide radicals and consequently reduces the activity of iNOS .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20812283"}
{"sentence": "Bisphenol A is a monomer used in the production of polycarbonate plastics , epoxy resins , and flame retardants . It is an endocrine disruptor with a variety of other effects , including genotoxicity . Oxidative metabolism of bisphenol A yields electophilic bisphenol A-3,4-quinone ( BPAQ ) , which may cause genotoxicity . To determine the genotoxic potential of bisphenol A , the mechanism of the reaction between the BPAQ and deoxyadenosine ( dA ) was studied in detail . The most probable reaction pathway was determined using quantum chemical methods . Our results demonstrate that the rate limiting step is Michael addition between BPAQ and dA , the main product being the unstable N7-modified adduct that rapidly undergoes depurination . In addition , our calculations provide strong evidence for protonation of the adducts prior to depurination , which indicates pH dependence of the reaction . The calculated activation barrier for Michael addition is 28.7 kcal/mol , indicating that the reaction with dA is very slow . Comparison with the activation energy of 23.1 kcal/mol for the corresponding deoxyguanosine reaction indicates that most of the DNA damage by BPAQ will occur at the guanine site . The detoxification reactions with glutathione compete with reactions between BPAQ and DNA . The calculated free energy of activation for the reaction with glutathione is significantly lower than that for the corresponding reaction with dA . This indicates that BPAQ will preferably react with glutathione and will only react with DNA when the level of glutathione in the cell is low .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23198967"}
{"sentence": "Despite the deployment of multimodal therapies involving neurosurgical resection , radio- and polychemotherapy , the prognosis for glioblastoma patients remains poor . These tumors are pathologically characterized by their associated angiogenesis and diffuse brain invasion , processes that are probably closely linked to the unfavorable prognosis of this disease . Accordingly , pharmacological inhibition of glioblastoma invasion and approaches that impede angiogenesis are considered to be promising therapeutic strategies to combat these tumors . Nevertheless , the anti-angiogenic therapies for glioblastoma currently available are transient and palliative at best . Blocking the effects of fibroblast growth factor ( FGF ) may represent a novel mean of inhibiting the angiogenesis associated with glioblastoma , as it mediates the angiogenesis induced by other factors and it is an angiogenic factor by itself . In addition , the survival of glioma cells and their resistance to chemotherapeutic agents are highly FGF-dependent . We show here that a recently described inhibitor of FGF , 2,5-dihydroxyphenyl-sulfonate ( 2,5DHPS , dobesilate ) , stimulates the apoptosis of tumor cells , inhibits glioblastoma invasion and suppresses its associated angiogenesis . Moreover , this agent augments the efficiency of chemotherapeutic agents in a rat model of orthotopic brain tumor . These results suggest that 2,5DHPS treatment may represent a promising therapy for malignant glioma .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "21193016"}
{"sentence": "High glycolysis , well known as \" Warburg effect, \" is frequently observed in a variety of cancers . Whether the deregulation of miRNAs contributes to the Warburg effect remains largely unknown . Because miRNA regulates gene expression at both mRNA and protein levels , we constructed a gene functional association network , which allows us to detect the gene activity instead of gene expression , to integratively analyze the microarray data for gene expression and miRNA expression profiling and identify glycolysis-related gene-miRNA pairs deregulated in cancer . Hexokinase 2 ( HK2 ) , coding for the first rate-limiting enzyme of glycolysis , is among the top list of genes predicted and potentially regulated by multiple miRNAs including miR-143 . Interestingly , miR-143 expression was inversely associated with HK2 protein level but not mRNA level in human lung cancer samples. miR-143 , down-regulated by mammalian target of rapamycin activation , reduces glucose metabolism and inhibits cancer cell proliferation and tumor formation through targeting HK2 . Collectively , we have not only established a novel methodology for gene-miRNA pair prediction but also identified miR-143 as an essential regulator of cancer glycolysis via targeting HK2 .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22593586"}
{"sentence": "PURPOSE The roles of terminal sialyl and fucosyl residues in cell surface glycans in the metastatic potential of H7721 cells , a human hepatocarcinoma cell line , were studied . METHODS Neuraminidase and alpha-L-fucosidase were used to remove the sialyl and fucosyl residues , respectively . Cell adhesion to fibronectin ( Fn ) , laminin ( Ln ) , and human umbilical vein epithelial cell ( HUVEC ) , as well as chemotactic cell migration and invasion , were selected as the parameters of metastatic potential ex vivo . RESULTS Sialyl residue is not essential for cell adhesion to Fn , but is important in cell adhesion to Ln and invasion , and is crucial in cell adhesion to HUVEC and migration . In contrast , fucosyl residue contributes more than sialyl residue to cell adhesion to Fn and Ln , but less to adhesion to HUVEC , and is not essential in chemotactic cell migration and invasion . Cell adhesion to HUVEC , migration , and invasion were inhibited by the monoclonal antibody of sialyl Lewis X , but not by the antibody of non-sialyl Lewis X. CONCLUSION Terminal sialyl residues on cell surface glycans are more important than fucosyl residues in mediating cell adhesion to HUVEC and cell migration/invasion , but the reverse is true in cell adhesion to Fn and Ln .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12458342"}
{"sentence": "Cantharidin is an active constituent of mylabris , a traditional Chinese medicine . It is a potent and selective inhibitor of protein phosphatase 2A ( PP2A ) that plays an important role in control of cell cycle , apoptosis , and cell-fate determination . Owing to its antitumor activity , cantharidin has been frequently used in clinical practice . In the present study , we investigated the therapeutic potential of cantharidin in pancreatic cancer . Cantharidin efficiently inhibited the growth of pancreatic cancer cells , but presented a much lighter toxicity effect against normal pancreatic duct cells . It caused G2/M cell-cycle arrest that was accompanied by the down-regulation of cyclin-dependent kinase 1 ( CDK1 ) and up-regulation of p21 expression . It induced apoptosis and elevated the expressions of pro-apoptotic factors tumor necrosis factor-alpha ( TNF-alpha ) , TNF-related apoptosis inducing receptor 1 ( TRAILR1 ) , TRAILR2 , Bad , Bak , and Bid , and decreased the expression of anti-apoptotic Bcl-2 . Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis . Interestingly , unlike previous studies on other cancer cells , we found that the inhibitory role of cantharidin is independent of oxidative stress in pancreatic cancer cells . Mitogen-activated protein kinases ( MAPKs ) , including ERK , JNK , and p38 , were activated after treatment with cantharidin . Inhibition of JNK , but not ERK or p38 , alleviated the cytotoxity effect of cantharidin , suggesting cantharidin exerted its anticancer effect through the JNK-dependent way . Hence , in addition to being an attractive candidate compound with therapeutic potential , cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20331621"}
{"sentence": "Regulation of adaptive immunity by innate immune cells is widely accepted . Conversely , adaptive immune cells can also regulate cells of the innate immune system . Here , we report for the first time the essential role of B cells in regulating macrophage ( M\u03c6 ) phenotype . In vitro B cell/M\u03c6 co-culture experiments together with experiments in transgenic mice models for B-cell deficiency or overexpression showed B1 cells to polarize M\u03c6 to a distinct phenotype . This was characterized by downregulated TNF-\u03b1 , IL-1\u03b2 and CCL3 , but upregulated IL-10 upon LPS stimulation ; constitutive expression of M2 M\u03c6 markers ( e.g . Ym1 , Fizz1 ) and overexpression of TRIF-dependent cytokines ( IFN-\u03b2 , CCL5 ) . Mechanistically , this phenotype was linked to a defective NF-\u03baB activation , but a functional TRIF/STAT1 pathway . B1-cell-derived IL-10 was found to be instrumental in the polarization of these M\u03c6 . Finally , in vivo relevance of B1-cell-induced M\u03c6 polarization was confirmed using the B16 melanoma tumor model where adoptive transfer of B1 cells induced an M2 polarization of tumor-associated M\u03c6 . Collectively , our results define a new mechanism of M\u03c6 polarization wherein B1 cells play a key role in driving M\u03c6 to a unique , but M2-biased phenotype . Future studies along these lines may lead to targeting of B1 cells to regulate M\u03c6 response in inflammation and cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20468007"}
{"sentence": "Acrolein ( Acr ) is a ubiquitous environmental pollutant found in cigarette smoke and automobile exhaust . It can also be produced endogenously by oxidation of polyunsaturated fatty acids . The Acr-derived 1,N(2)-propanodeoxyguanosine ( Acr-dG ) adducts in DNA are mutagenic lesions that are potentially involved in human cancers . In this study , monoclonal antibodies were raised against Acr-dG adducts and characterized using ELISA . They showed strong reactivity and specificity toward Acr-dG , weaker reactivity toward crotonaldehyde- and trans-4-hydroxy-2-nonenal-derived 1,N(2)-propanodeoxyguanosines , and weak or no reactivity toward 1,N(6)-ethenodeoxyadenosine and 8-oxo-deoxyguanosine . Using these antibodies , we developed assays to detect Acr-dG in vivo : first , a simple and quick FACS-based assay for detecting these adducts directly in cells ; second , a highly sensitive direct ELISA assay for measuring Acr-dG in cells and tissues using only 1 \\u03bcg of DNA without DNA digestion and sample enrichment ; and third , a competitive ELISA for better quantitative measurement of Acr-dG levels in DNA samples . The assays were validated using Acr-treated HT29 cell DNA samples or calf thymus DNA , and the results were confirmed by LC-MS/MS-MRM . An immunohistochemical assay was also developed to detect and visualize Acr-dG in HT29 cells as well as in human oral cells . These antibody-based methods provide useful tools for the studies of Acr-dG as a cancer biomarker and of the molecular mechanisms by which cells respond to Acr-dG as a ubiquitous DNA lesion .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23126278"}
{"sentence": "Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness . Together with anaerobic glycolysis , the Warburg effect , formally corresponding to uncoupling glycolysis from oxidative phosphorylation , directly participates in cancer aggressiveness , supporting both tumor progression and dissemination . The transcription factor hypoxia-inducible factor-1 ( HIF-1 ) is a key contributor to glycolysis . It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis . In this study , we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells . We report that lactate , the end-product of glycolysis , inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1\\u03b1 . These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype . Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo , an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 ( MCT1 ) expressed in tumor cells . Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells , MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways .", "label": [0, 0, 1, 0, 0, 0, 1, 0, 0, 0], "id": "23082126"}
{"sentence": "The polycomb group family protein BMI-1 is overexpressed by and functions as an oncogene in many different human cancers . We have previously shown that BMI-1 promotes the tumorigenicity of Ewing sarcoma family tumors ( ESFTs ) and that this is mediated independently of CDKN2A repression . In this study , we have discovered that high levels of BMI-1 confer resistance to contact inhibition in ESFT cells . Using stable retroviral transduction , we evaluated the consequences of BMI-1 knockdown on the growth of CDKN2A wild-type and mutant ESFT cells in subconfluent and confluent conditions . Although knockdown of BMI-1 had no effect on proliferation in low-density cultures , at high cell densities it resulted in cell cycle arrest and death . The normal cell contact inhibition response is mediated , in large part , by the recently described Hippo pathway which functions to inhibit cell proliferation and promote cell death by inactivating the Yes-Associated Protein ( YAP ) . Significantly , we found that YAP levels , activity and expression did not diminish in confluent ESFT cells that expressed high levels of BMI-1 . In contrast , YAP expression and nuclear localization were reduced in confluent BMI-1 knockdown cells suggesting that silencing of BMI-1 restored contact inhibition by restoring normal activation of the Hippo-YAP growth-suppressor pathway . Importantly , knockdown of YAP in ESFT cells resulted in profound inhibition of cell proliferation and anchorage-independent colony formation suggesting that stabilization and continued expression of YAP is critical for ESFT growth and tumorigenicity . Together , these studies reveal a previously unrecognized link between BMI-1 , contact inhibition and the Hippo-YAP pathway and suggest that resistance to contact inhibition in BMI-1 overexpressing cancer cells may be in part a result of Hippo inhibition and aberrant stabilization of YAP .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21170084"}
{"sentence": "DNA damage checkpoints in the cell cycle may be important barriers against cancer progression in human cells . Fanconi anemia ( FA ) is an inherited DNA instability disorder that is associated with bone marrow failure and a strong predisposition to cancer . Although FA cells experience constitutive chromosomal breaks , cell cycle arrest at the G2 DNA damage checkpoint , and an excess of cell death , some patients do become clinically stable , and the mechanisms underlying this , other than spontaneous reversion of the disease-causing mutation , are not well understood . Here we have defined a clonal phenotype , termed attenuation , in which FA patients acquire an abrogation of the G2 checkpoint arrest . Attenuated cells expressed lower levels of CHK1 ( also known as CHEK1 ) and p53 . The attenuation could be recapitulated by modulating the ATR/CHK1 pathway , and CHK1 inhibition protected FA cells from cell death . FA patients who expressed the attenuated phenotype had mild bone marrow deficiency and reached adulthood , but several of them eventually developed myelodysplasia or leukemia . Better understanding of attenuation might help predict a patient's clinical course and guide choice of treatment . Our results also highlight the importance of evaluating the cellular DNA damage checkpoint and repair pathways in cancer therapies in general .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "21183791"}
{"sentence": "BACKGROUND The cis-acting promoter element responsible for epigenetic silencing of retinoic acid receptor responder 1 ( RARRES1 ) by methylation is unclear . Likewise , how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown . METHODOLOGY/PRINCIPAL FINDINGS We first compared methylation occurring at the sequences ( -664 flanking the RARRES1 promoter in primary breast carcinomas to that in adjacent benign tissues . Surprisingly , tumor cores displayed significantly elevated methylation occurring solely at the upstream region ( -664 while the downstream element ( -85 proximal to the transcriptional start site ( +1 ) remained largely unchanged . Yet , hypermethylation at the former did not result in appreciable silencing effect . In contrast , the proximal sequence displayed full promoter activity and methylation of which remarkably silenced RARRES1 transcription . This phenomenon was recapitulated in breast cancer cell lines , in which methylation at the proximal region strikingly coincided with downregulation . We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings . Furthermore , knocking-down CTCF expression hampered RARRES1 expression , suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state . Moreover , RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents , denoting its tumor suppressive effect . Its role of attenuating invasion agreed with data generated from clinical specimens revealing that RARRES1 was generally downregulated in metastatic lymph nodes compared to the tumor cores . CONCLUSION/SIGNIFICANCE This report delineated silencing of RARRES1 by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF , an activator for RARRES1 expression . We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22615834"}
{"sentence": "Oxaliplatin is included in a number of effective combination regimens used as first and subsequent lines of therapy for metastatic colorectal cancer . Accumulating evidence indicates that autophagy plays a significant role in response to cancer therapy . However , the role of autophagy in oxaliplatin-induced cell death remains to be clarified . In this study , we showed that oxaliplatin induced cell death and autophagy in Caco-2 colorectal cancer cells . The suppression of autophagy using either pharmacologic inhibitors ( 3-methyladenine , bafilomycin A1 ) or RNA interference in essential autophagy genes ( ATG5 or Beclin1 ) enhanced the cell death and reactive oxygen species ( ROS ) production induced by oxaliplatin in Caco-2 cells . Blocking oxaliplatin-induced ROS production by using ROS scavengers ( NAC or Tiron ) decreased autophagy . Furthermore , numerous dilated endoplasmic reticula ( ER ) were present in oxaliplatin-treated Caco-2 cells , and blocking ER stress by RNA interference against candidate of metastasis-1 ( P8 ) and C/EBP-homologous protein ( CHOP ) decreased autophagy and ROS production . Taken together , these data indicate that oxaliplatin activates autophagy as a cytoprotective response via ER stress and ROS in human colorectal cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23226467"}
{"sentence": "Head and neck squamous cell carcinoma ( HNSCC ) is a major cause of morbidity and mortality underscoring the need for safe and effective chemopreventive strategies . Targeting epidermal growth factor receptor ( EGFR ) is attractive in that it is an early critical event in HNSCC pathogenesis . However , current agents lack efficacy or have unacceptable toxicity . Several groups have demonstrated that the over-the-counter medication , polyethylene glycol ( PEG ) has remarkable chemopreventive efficacy against colon carcinogenesis . Importantly , we reported that this effect is mediated through EGFR internalization/degradation . In the current study , we investigated the chemopreventive efficacy of this agent against HNSCC , using both the well validated animal model 4-NQO ( 4-nitroquinoline 1-oxide ) rat model and cell culture with the human HNSCC cell line SCC-25 . We demonstrated that daily topical application of 10% PEG-8000 in the oral cavity ( tongue and cavity wall ) post 4NQO initiation resulted in a significant reduction in tumor burden ( both , tumor size and tumors/tumor bearing rat ) without any evidence of toxicity . Immunohistochemical studies depicted decreased proliferation ( number of Ki67-positive cells ) and reduced expression of EGFR and its downstream effectors cyclin D1 in the tongue mucosa of 4NQO-rats treated with PEG . We showed that EGFR was also markedly downregulated in SCC-25 cells by PEG-8000 with a concomitant induction of G1-S phase cell-cycle arrest , which was potentially mediated through upregulated p21(cip1/waf1) . In conclusion , we demonstrate , for the first time , that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "22675506"}
{"sentence": "Overexpression/amplification of human epidermal growth factor receptor ( HER)2/neu ( erbB-2 ) oncogene plays a causal role in carcinogenesis and correlates with a poor clinical prognosis . However , little is known about HER2 in gastric cancer . In this study , we explored the pharmacological activities of natural triterpenoid corosolic acid ( CRA ) in HER2 signaling and its role in gastric cancer development and progression . In this study , CRA dramatically inhibited HER2 expression in a dose- and time-dependent manner , effectively inhibited cell proliferation , and induced G(0)/G(1) arrest through the induction of p27(kip1) and cyclin D(1) down-regulation . CRA exposure enhanced apoptotic cell death , as confirmed by caspase-3 and poly ( ADP-ribose ) polymerase cleavage activities . CRA inhibited signaling pathways downstream of HER2 , including phospho-proteins such as Akt and Erk . In addition , CRA combined with adriamycin and 5-fluorouracil enhanced this growth inhibition , but not with docetaxel and paclitaxel . These findings demonstrate that CRA suppresses HER2 expression , which in turn promotes cell cycle arrest and apoptotic cell death of gastric cancer cells , providing a rationale for future clinical trials of CRA in the treatment of HER2-positive gastric cancers .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20522955"}
{"sentence": "Cisplatin-based chemotherapy frequently resulted in acquired resistance of cancer cells . The underlying mechanism of such resistance is not fully understood especially the involvement of autophagy and autophagic cell death . This study thus investigated whether an alteration in autophagy could be responsible for cisplatin resistance in the long-term exposure lung carcinoma cells . The cisplatin resistant clone ( H460/cis ) of H460 cells was established by exposing the cells with gradually increasing concentrations of cisplatin until chemoresistance acquisition was elucidated by MTT , Hoechst 33342 staining and comet assays . Degree of autophagosome formation and level of LC3 marker were evaluated by acridine orange and western blot analysis , respectively . H460/cis cells exhibited irregular shape with resistant to cisplatin-induced apoptosis compared with H460 cells . Proteins analysis for LC3 indicated that the levels of LC3 in resistant cells were significantly lower than those in H460 cells . Moreover , autophagosome formation detected by acridine orange staining was dramatically reduced in the resistant cells , suggesting the role of autophagy in attenuating of cisplatin-induced cell death . Further , co-treatment of cisplatin with autophagy inducer , trifluorperazine , could resensitize H460/cis cells to cisplatin-induced cell death . Our findings reveal the novel mechanisms causing cisplatin resistance in lung carcinoma cells after long-term drug exposure regarding autophagy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22278384"}
{"sentence": "OBJECTIVES The aim of this study was to immunohistochemically evaluate the expression of matrix metalloproteinase ( MMP)-1 , MMP- 2 , tissue inhibitor of metalloproteinase ( TIMP)-1 , TIMP-2 , and podoplanin in oral squamous cell carcinoma ( OSCC ) . Immunohistochemical staining of podoplanin-positive lymphatic vessel density ( LVD ) was also assessed . STUDY DESIGN Forty cases of OSCC were analyzed by immunohistochemistry . RESULTS MMP-2 , MMP-10 , TIMP-1 , TIMP-2 , and podoplanin were detected in each of the 40 OSCC cases . The expression of MMP-2 was significantly correlated with histologic grade . The expression of podoplanin was positively correlated with gender and negatively correlated with tumor size . A significant positive correlation was also detected between LVD and the presence of lymph node metastases , gender , age , and diameter of the lymph node ( if involved ) , as well as histologic grade . CONCLUSIONS The results are suggestive of important roles that MMP-2 , MMP-10 , TIMP-2 , and podoplanin play in pathologic processes of OSCC , including invasion . Our findings also suggest that LVD may play a role in lymphatic metastasis and tumor progression .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22769410"}
{"sentence": "To protect the genome , cells have evolved a diverse set of pathways designed to sense , signal , and repair multiple types of DNA damage . To assess the degree of coordination and crosstalk among these pathways , we systematically mapped changes in the cell's genetic network across a panel of different DNA-damaging agents , resulting in differential measurements . Each agent was associated with a distinct interaction pattern , which , unlike single-mutant phenotypes or gene expression data , has high statistical power to pinpoint the specific repair mechanisms at work . The agent-specific networks revealed roles for the histone acetyltranferase Rtt109 in the mutagenic bypass of DNA lesions and the neddylation machinery in cell-cycle regulation and genome stability , while the network induced by multiple agents implicates Irc21 , an uncharacterized protein , in checkpoint control and DNA repair . Our multiconditional genetic interaction map provides a unique resource that identifies agent-specific and general DNA damage response pathways .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23273983"}
{"sentence": "In cancer cells , the aberrant conversion of pyruvate into lactate instead of acetyl-CoA in the presence of oxygen is known as the Warburg effect . The consequences and mechanisms of this metabolic peculiarity are incompletely understood . Here we report that p53 status is a key determinant of the Warburg effect . Wild-type p53 expression decreased levels of pyruvate dehydrogenase kinase-2 ( Pdk2 ) and the product of its activity , the inactive form of the pyruvate dehydrogenase complex ( P-Pdc ) , both of which are key regulators of pyruvate metabolism . Decreased levels of Pdk2 and P-Pdc in turn promoted conversion of pyruvate into acetyl-CoA instead of lactate . Thus , wild-type p53 limited lactate production in cancer cells unless Pdk2 could be elevated . Together , our results established that wild-type p53 prevents manifestation of the Warburg effect by controlling Pdk2 . These findings elucidate a new mechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "22123926"}
{"sentence": "We have isolated rabbit kidney proximal tubular epithelial cell lines . The selection was based on their ability to form confluent monolayers on porous supports and to maintain receptor-mediated signal transduction and ion transport , characteristic of the proximal tubule . The isolation method consisted of several steps : ( 1 ) superficial cortical proximal tubule segments were microdissected and cultured on a matrix-coated porous support until cells formed a confluent monolayer ; ( 2 ) primary cultures showing hormone-regulated ion transport typical for the proximal tubule were selected and co-cultured with irradiated fibroblasts ; and ( 3 ) the epithelial cells surviving after several passages were expanded and passaged on porous substrates . Most of the cell lines developed in this manner were obtained by co-culture with irradiated fibroblasts producing a recombinant retrovirus encoding SV40 large T antigen and G418 resistance . However , SV40 T antigen expression was not essential for immortalization , since neither T antigen nor G418 resistance was detected in the isolated cell lines and co-culture with non-producing 3T3 cells gave similar results . One cell line ( vEPT ) has been characterized in some detail with respect to morphological , biochemical , and ion transport properties . This line forms confluent monolayers with apical microvilli , tight junctions , and convolutions of the basolateral plasma membrane . Once confluent , monolayers maintain conductances of 25 to 32 mS/cm2 for several weeks in culture and possess phlorizin-sensitive short-circuit current ( Isc ) in glucose containing media , indicative of apical Na(+)-glucose co-transport. vEPT cells also retain receptor and signaling mechanisms for angiotensin II ( Ang II ) . Apical and basal Ang II and 5,6-epoxy-eicosatrienoic acid ( 5,6-EET ) modulate the Isc in a manner similar to primary cultures . The cell lines share with primary cultures expression of the cytokeratins K8 , K10/K11 , and K19 ( \"nomenclature \" [ 21] ) . They also retain several receptor and signal transduction mechanisms . For example , Ang II , arachidonate , bradykinin , 5,6-EET , parathyroid hormone ( residues 1 through 34 ) , and purine nucleotides increase cytosolic Ca2+ , PTH elevates cAMP levels , and Ang II enhances proximal tubule-specific arachidonic acid metabolism .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1280703"}
{"sentence": "Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance . Here we report the novel finding that Tph-1 ( tryptophan hydroxylase-1 ) , a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan , is a potent regulator of immunity . In models of skin allograft tolerance , tumor growth , and experimental autoimmune encephalomyelitis , Tph-1 deficiency breaks allograft tolerance , induces tumor remission , and intensifies neuroinflammation , respectively . All of these effects of Tph-1 deficiency are independent of its downstream product serotonin . Because mast cells ( MCs ) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect , these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23008335"}
{"sentence": "Heparin-binding epidermal growth factor-like growth factor ( HB-EGF ) is a member of the epidermal growth factor family and has a variety of physiological and pathological functions . Modulation of HB-EGF activity might have a therapeutic potential in the oncology area . We explored the therapeutic possibilities by characterizing the in vitro biological activity of anti-HB-EGF monoclonal antibody Y-142 . EGF receptor ( EGFR ) ligand and species specificities of Y-142 were tested . Neutralizing activities of Y-142 against HB-EGF were evaluated in EGFR and ERBB4 signaling . Biological activities of Y-142 were assessed in cancer cell proliferation and angiogenesis assays and compared with the anti-EGFR antibody cetuximab , the HB-EGF inhibitor CRM197 , and the anti-vascular endothelial growth factor ( VEGF ) antibody bevacizumab . The binding epitope was determined with alanine scanning . Y-142 recognized HB-EGF as well as the EGFR ligand amphiregulin , and bound specifically to human HB-EGF , but not to rodent HB-EGF . In addition , Y-142 neutralized HB-EGF-induced phosphorylation of EGFR and ERBB4 , and blocked their downstream ERK1/2 and AKT signaling . We also found that Y-142 inhibited HB-EGF-induced cancer cell proliferation , endothelial cell proliferation , tube formation , and VEGF production more effectively than cetuximab and CRM197 and that Y-142 was superior to bevacizumab in the inhibition of HB-EGF-induced tube formation . Six amino acids in the EGF-like domain were identified as the Y-142 binding epitope . Among the six amino acids , the combination of F115 and Y123 determined the amphiregulin cross-reactivity and that F115 accounted for the species selectivity . Furthermore , it was suggested that the potent neutralizing activity of Y-142 was derived from its recognition of R142 and Y123 and its high affinity to HB-EGF . Y-142 has a potent HB-EGF neutralizing activity that modulates multiple biological activities of HB-EGF including cancer cell proliferation and angiogenic activities . Y-142 may have a potential to be developed into a therapeutic agent for the treatment of HB-EGF-dependent cancers .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23251664"}
{"sentence": "The breast cancer resistance protein ( BCRP ) , an ATP binding cassette ( ABC ) efflux transporter , plays a role in multiple drug resistance ( MDR ) . Previous studies of the subcellular location of the ABC transporter P-glycoprotein indicated that this protein is expressed in nuclear membranes . This study examines the nuclear distribution of BCRP in seven human-derived glioblastoma ( GBM ) and astrocytoma cell lines . BCRP expression was observed in the nuclear extracts of 6/7 cell lines . Using the GBM LN229 cell line as a model , nuclear BCRP protein was detected by immunoblotting and confocal laser microscopy . Importantly , nuclear BCRP staining was found in a subpopulation of tumour cells in a human brain GBM biopsy . Mitoxantrone cytotoxicity in the LN229 cell line was determined with and without the BCRP inhibitor fumitremorgin C ( FTC ) and after downregulation of BCRP with small interfering RNA ( siRNA ) . FTC inhibition of BCRP increased mitoxantrone cytotoxicity with a reduction in the IC\u2085\u2080 and this effect was further potentiated in the siRNA-treated cells . In conclusion , BCRP is expressed in the nuclear extracts of select GBM and astrocytoma cell lines and in a human GBM tumour biopsy . Its presence in the nucleus of cancer cells suggests new role for BCRP in MDR .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22401348"}
{"sentence": "Senescence limits the proliferative capacity of primary cells in culture . We describe here a genetic screen to identify genes that allow bypass of this checkpoint . Using retroviral cDNA expression libraries , we identify BCL6 as a potent inhibitor of senescence . BCL6 is frequently activated in non-Hodgkin's lymphoma , but its mechanism of action has remained unclear . BCL6 efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation . BCL6 overrides the senescence response downstream of p53 through a process that requires induction of cyclin D1 expression , as cyclin D1 knockout fibroblasts are specifically resistant to BCL6 immortalization . We show that BCL6 expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces cyclin D1 expression , indicating that BCL6 has a similar activity in lymphoid cells . Our results suggest that BCL6 contributes to oncogenesis by rendering cells unresponsive to antiproliferative signals from the p19(ARF)-p53 pathway .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "11914273"}
{"sentence": "Cigarette smoke ( CS ) is a rich source of radicals , predisposing the cell to oxidative stress resulting in inflammation . Chronic inflammation is a recognized risk factor for carcinogenesis . Cyclooxygenase-2 ( COX-2 ) is a mediator of inflammatory pathway and may , therefore , contribute to carcinogenesis . There are several reports that suggest the association between CS and COX-2 associated risk to cancer . In the present study , we examined the role of celecoxib ( a selective COX-2 inhibitor ) in modulating the oxidative stress caused by CS inhalation in mice . CS exposure for a period of 10 weeks caused oxidative stress in the pulmonary and hepatic tissues , as evident from the increase in lipid peroxidation levels ( LPO ) and decrease in reduced glutathione ( GSH ) levels . Celecoxib ( 125 mg/kg body weight for 8 weeks ) administration to CS inhaling mice reduced the oxidative stress by decreasing the LPO levels and enhancing the GSH levels in comparison to the CS-exposed group . CS exposure repressed the enzymatic antioxidant defense system , as evident from the decrease in catalase ( CAT ) and superoxide dismutase ( SOD ) activities . Co-adminstration of celecoxib considerably reversed the changes in the enzymatic antioxidant defense system . Histopathological studies of lungs showed that CS exposure induced alveolar wall destruction and air space enlargement . In co-treated group , the alveolar septa were thicker than normal with apparent infiltration of inflammatory cells . In CS-exposed group , hepatic tissue exhibited vacuolization and macrophage infiltration . Co-treatment with celecoxib restored the normal histoarchitechture in hepatic tissues of CS inhaling mice . Thus , the present study demonstrated that celecoxib adminstration reduced the oxidative stress-mediated risk to carcinogenesis , due to its ability to boost the antioxidant defense system .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21280565"}
{"sentence": "Malaria parasites export ' a secretome ' of hundreds of proteins , including major virulence determinants , from their endoplasmic reticulum ( ER ) , past the parasite plasma and vacuolar membranes to the host erythrocyte . The export mechanism is high affinity ( nanomolar ) binding of a host ( cell ) targeting ( HT ) motif RxLxE/D/Q to the lipid phosphatidylinositol 3-phosphate ( PI(3)P ) in the ER . Cleavage of the HT motif releases the secretory protein from the ER membrane . The HT motif is thought to be the only export signal resident in an N-terminal vacuolar translocation sequence ( VTS ) that quantitatively targets green fluorescent protein to the erythrocyte . We have previously shown that the R to A mutation in the HT motif , abrogates VTS binding to PI(3)P ( K(d)>5 \\u03bcM ) . We now show that remarkably , the R to A mutant is exported to the host erythrocyte , for both membrane and soluble reporters , although the efficiency of export is reduced to of that seen with a complete VTS . Mass spectrometry indicates that the R to A mutant is cleaved at sites upstream of the HT motif . Antibodies to upstream sequences confirm that aberrantly cleaved R to A protein mutant is exported to the erythrocyte . These data suggest that export mechanisms , independent of PI(3)P as well as those dependent on PI(3)P , function together in a VTS to target parasite proteins to the host erythrocyte .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22828070"}
{"sentence": "Heart failure and arrhythmias occur at 3 to 5 times higher rates among individuals with diabetes mellitus , compared with age-matched , healthy individuals . Studies attribute these defects in part to alterations in the function of cardiac type 2 ryanodine receptors ( RyR2s ) , the principal Ca(2+)-release channels on the internal sarcoplasmic reticulum ( SR ) . To date , mechanisms underlying RyR2 dysregulation in diabetes remain poorly defined . A rat model of type 1 diabetes , in combination with echocardiography , in vivo and ex vivo hemodynamic studies , confocal microscopy , Western blotting , mass spectrometry , site-directed mutagenesis , and [ (3)H]ryanodine binding , lipid bilayer , and transfection assays , was used to determine whether post-translational modification by reactive carbonyl species ( RCS ) represented a contributing cause . After 8 weeks of diabetes , spontaneous Ca(2+) release in ventricular myocytes increased Evoked Ca(2+) release from the SR was nonuniform ( dyssynchronous ) . Total RyR2 protein levels remained unchanged , but the ability to bind the Ca(2+)-dependent ligand [ (3)H]ryanodine was significantly reduced . Western blotting and mass spectrometry revealed RCS adducts on select basic residues . Mutation of residues to delineate the physiochemical impact of carbonylation yielded channels with enhanced or reduced cytoplasmic Ca(2+) responsiveness . The prototype RCS methylglyoxal increased and then decreased the RyR2 open probability . Methylglyoxal also increased spontaneous Ca(2+) release and induced Ca(2+) waves in healthy myocytes . Treatment of diabetic rats with RCS scavengers normalized spontaneous and evoked Ca(2+) release from the SR , reduced carbonylation of RyR2s , and increased binding of [ (3)H]ryanodine to RyR2s . From these data , we conclude that post-translational modification by RCS contributes to the heterogeneity in RyR2 activity that is seen in experimental diabetes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22648972"}
{"sentence": "DNA double-strand breaks ( DSBs ) trigger ATM ( ataxia telangiectasia mutated ) signalling and elicit genomic rearrangements and chromosomal fragmentation if misrepaired or unrepaired . Although most DSB repair is ATM-independent , approximately 15% of ionizing radiation ( IR)-induced breaks persist in the absence of ATM-signalling. 53BP1 ( p53-binding protein 1 ) facilitates ATM-dependent DSB repair but is largely dispensable for ATM activation or checkpoint arrest . ATM promotes DSB repair within heterochromatin by phosphorylating KAP-1 ( KRAB-associated protein 1 , also known as TIF1beta , TRIM28 or KRIP-1 ; ref. 2 ) . Here , we show that the ATM signalling mediator proteins MDC1 , RNF8 , RNF168 and 53BP1 are also required for heterochromatic DSB repair . Although KAP-1 phosphorylation is critical for 53BP1-mediated repair , overall phosphorylated KAP-1 ( pKAP-1 ) levels are only modestly affected by 53BP1 loss. pKAP-1 is transiently pan-nuclear but also forms foci overlapping with gammaH2AX in heterochromatin . Cells that do not form 53BP1 foci , including human RIDDLE ( radiosensitivity , immunodeficiency , dysmorphic features and learning difficulties ) syndrome cells , fail to form pKAP-1 foci. 53BP1 amplifies Mre11-NBS1 accumulation at late-repairing DSBs , concentrating active ATM and leading to robust , localized pKAP-1 . We propose that ionizing-radiation induced foci ( IRIF ) spatially concentrate ATM activity to promote localized alterations in regions of chromatin otherwise inhibitory to repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20081839"}
{"sentence": "AIMS To screen the genes and possible signal transduction pathways with which nucleostemin ( NS ) interacts and explore the mechanism of NS in prostate cancer . METHODS NS-specific short-hairpin RNA expression plasmid was used to downregulate the NS level in PC-3 cells and the changes of cell cycle were studied . After that , oligonucleotide DNA microarray was used to screen the genome changes in PC-3 cells and quantitative real-time PCR was used to further confirm the differentially expressed genes . RESULTS Detection of cell cycle showed a decrease of S stage and an increase of G1 stage after downregulation of NS. 219 differentially expressed genes were found and these genes were involved in cell cycle , cell proliferation , signal transduction , cell apoptosis and cell differentiation , and so on . Genes related to cell cycle were discussed emphatically . INK4 family genes ( P15 , P16 , P18 ) were upregulated while cyclin D1 HDAC1 were downregulated . These genes were tightly related to CDK4/6-cyclin D and pRb-E2F1 complexes . CONCLUSION NS is an important G1/S checkpoint regulator and it could regulate cell cycles via a p53-independent pathway in prostate cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20664182"}
{"sentence": "Nitric oxide ( NO)-releasing non-steroidal anti-inflammatory drugs ( NO-NSAIDs ) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs , possess anti-proliferative , pro-apoptotic and anti-cancer activities . Here , we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice . Topical application of NO-sulindac reduced tumor incidence , number ( p<0.05 ) and volume ( p<0.005 ) as compared to UVB ( alone)-irradiated vehicle-treated mice . An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio . The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced . However , proliferation was identified as the major target of NO-sulindac in this study . A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed . The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway . UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2 , p38 and JNK1/2 . In this regard , NO-sulindac also inhibited NF\u03baB by enhancing I\u03baB\u03b1 as evidenced by the reduced expression of iNOS and COX-2 , the direct NF\u03baB transcription target proteins . NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial-mesenchymal transition . A marked decrease in the expression of mesenchymal markers such as Fibronectin , N-cadherin , SNAI , Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors . Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 1], "id": "23274568"}
{"sentence": "Tumor endothelial marker ( TEM ) 5 is an adhesion G-protein-coupled receptor upregulated in endothelial cells during tumor and physiologic angiogenesis . So far , the mechanisms leading to upregulation of TEM5 and its function during angiogenesis have not been identified . Here , we report that TEM5 expression in endothelial cells is induced during capillary-like network formation on Matrigel , during capillary morphogenesis in a three-dimensional collagen I matrix , and upon confluence on a two-dimensional matrix . TEM5 expression was not induced by a variety of soluble angiogenic factors , including VEGF and bFGF , in subconfluent endothelial cells . TEM5 upregulation was blocked by toxin B from Clostridium difficile , an inhibitor of the small GTPases Rho , Rac , and Cdc42 . The Rho inhibitor C3 transferase from Clostridium botulinum did not affect TEM5 expression , whereas the Rac inhibitor NSC23766 suppressed TEM5 upregulation . An excess of the soluble TEM5 extracellular domain or an inhibitory monoclonal TEM5 antibody blocked contact inhibition of endothelial cell proliferation resulting in multilayered islands within the endothelial monolayer and increased vessel density during capillary formation . Based on our results we conclude that TEM5 expression during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of proliferation in endothelial cells .", "label": [0, 0, 0, 0, 1, 0, 1, 0, 0, 0], "id": "19853600"}
{"sentence": "Elevated phosphorylation of estrogen receptor \u03b1 ( ER\u03b1 ) at serines 118 ( S118 ) and 167 ( S167 ) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ER\u03b1 signaling pathway in breast cancer . It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ER\u03b1 signaling , resulting in aggressive ER\u03b1-independent breast cancer cells . To this end , MCF-7 breast cancer cells were stably transfected with an ER\u03b1-specific short hairpin RNA that reduced endogenous ER\u03b1 . The resulting cell line was stably transfected with wild-type ER\u03b1 ( ER-AB cells ) , or ER\u03b1 containing serine to alanine mutation at S118 or S167 ( S118A cells and S167A cells , respectively ) . These stable cell lines expressed approximately equivalent ER\u03b1 compared with parental MCF-7 cells and were evaluated for growth , morphology , migration/invasion , and ER\u03b1-regulated gene expression . S118A cells and S167A cells exhibited increased growth and migration/invasion in vitro . Forward- and side-scatter flow cytometry revealed that S167A cells were smaller in size , and both S118A and S167A cells exhibited less cellular complexity . S118A and S167A cells expressed pancytokeratin and membrane localization of \u03b2-catenin and did not express vimentin , indicating retention of epithelial lineage markers . Expression of ER\u03b1-target genes and other genes regulated by ER\u03b1 signaling or involved in breast cancer were markedly altered in both S118A and S167A cells . In summary , attenuated phosphorylation of ER\u03b1 at S118 and S167 significantly affected cellular physiology and behavior in MCF-7 breast cancer cells , resulting in increased growth , migration/invasion , compromised expression of ER\u03b1 target genes , and markedly altered gene expression patterns .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22733972"}
{"sentence": "Vitamin D deficiency is associated with the high risk of colon cancer and a variety of other diseases . The active vitamin D metabolite 1\u03b1,25-dihydroxyvitamin D(3) ( 1,25(OH)(2)D(3) ) regulates gene transcription via its nuclear receptor ( VDR ) , and posttranscriptional regulatory mechanisms of gene expression have also been proposed . We have identified microRNA-22 ( miR-22 ) and several other miRNA species as 1,25(OH)(2)D(3) targets in human colon cancer cells . Remarkably , miR-22 is induced by 1,25(OH)(2)D(3) in a time- , dose- and VDR-dependent manner . In SW480-ADH and HCT116 cells , miR-22 loss-of-function by transfection of a miR-22 inhibitor suppresses the antiproliferative effect of 1,25(OH)(2)D(3) . Additionally , miR-22 inhibition increases cell migration per se and decreases the antimigratory effect of 1,25(OH)(2)D(3) in both cell types . In silico analysis shows a significant overlap between genes suppressed by 1,25(OH)(2)D(3) and miR-22 putative target genes . Consistently , miR-22 inhibition abrogates the 1,25(OH)(2)D(3)-mediated suppression of NELL2 , OGN , HNRPH1 , RERE and NFAT5 genes . In 39 out of 50 ( 78% ) human colon cancer patients , miR-22 expression was found lower in the tumour than in the matched normal tissue and correlated directly with that of VDR . Our results indicate that miR-22 is induced by 1,25(OH)(2)D(3) in human colon cancer cells and it may contribute to its antitumour action against this neoplasia .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22328083"}
{"sentence": "The effect of polychlorinated biphenyls ( PCBs ) on Vero cell proliferation was investigated , with the attempts to assess the possible hormetic dose-response and to compare their structure-dependent toxicity . Both PCB congeners revealed low doses stimulation in our experiment . However , significant cytotoxicity was only observed in PCB 52 concentrations larger than 0.1 microg ml(-1) , while there was no significant inhibition in PCB 77-treated cells at concentrations selected . Furthermore , the time-dependent cytotoxic trends were different . The comparison between PCB 52 and PCB 77 indicated that the cytotoxic mechanisms involved in coplanar or non-coplanar PCB congener exposure were different , and this difference might be associated with individual genotoxicity and the release of contact inhibition , respectively .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "20471162"}
{"sentence": "Retinoblastoma ( Rb ) is the most common intraocular tumor of childhood . In this study we examined primary Rb specimens and Rb cell lines for the expression of immunoglobulin superfamily ( IgSF ) antigens : MHC class I and II ( MHC-I and MHC-II ) , neural cell adhesion molecule ( NCAM ) , intercellular adhesion molecule-1 ( ICAM-1 ) , and Thy-1 , which play an important role in immune system and tumor cell interactions . MHC-I and-II , ICAM-1 ( CD54 ) , NCAM ( CD56 ) , and Thy-1 ( CDw90 ) immunoreactivity was studied in eight primary Rb biopsy specimens using immunohistochemistry , three using immunoelectron microscopy , and six Rb cell lines using flow cytometry ( FCM ) . Parenchymal and vascular-associated cells , phenotypically similar to retinal microglia , strongly expressed MHC-II immunoreactivity and were distributed throughout primary Rb specimens . However , MHC-II expression on Rb cell lines was similar to nonspecific control levels . Tumor cells in primary Rb specimens displayed high NCAM , moderate Thy-1 , and low MHC-I and ICAM-1 immunolabeling . Tumor vasculature expressed low to moderate MHC-I and ICAM-1 immunoreactivity and moderate Thy-1 immunoreactivity . NCAM was not detected on the vasculature of primary Rb specimens . Rb cell lines displayed variable expression of Thy-1 , ICAM-1 , and MHC-I . NCAM was highly expressed on five of six Rb cell lines . The high levels of constitutive NCAM immunoreactivity on Rb tumor cells confirm the neuroectodermal origins of this tumor . Additionally , the variable expression of Thy-1 may suggest separate neural lineages or differences in the maturational status ofsome Rb tumors . The presence of a population of infiltrating MHC-II-positive cells in primary Rb tumors has implications for immunomodulation of Rb growth .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12392158"}
{"sentence": "The aim of the present work was to study the expression of the proinflammatory cytokine , interleukin-6 ( IL-6 ) , mediated by bFGF signaling and its possible crosstalk with prostate-specific membrane antigen ( PSMA ) in LNCaP and PC3-PSMA prostate cancer cell lines . PC3 cells stably transfected with PSMA gene were used for restoring PSMA expression . LNCaP and PC3-PSMA cells were exposed to 10ng/mL of basic fibroblast growth factor ( bFGF ) . IL-6 production was measured by ELISA assay , and levels of PSMA expression were assessed by flow cytometry . AKT , ERK1/2 , and p38 phosphorylation were detected by Western blot. bFGF enhances IL-6 production in LNCaP and PC3-PSMA prostate cancer cells . The effect of bFGF on stimulating IL-6 secretion was greater in LNCaP than in PC3-PSMA cells . In the presence of bFGF , PSMA expression was activated after 4days of treatment in LNCaP and PC3-PSMA cells . This activation was not maintained after long term of treatment in both metastatic cell lines . Solely MAPKs pathways ( ERK1/2 and p38 ) were activated after bFGF stimulation in both metastatic cell lines , whereas AKT did not show any activation . The interference of the proinflammatory cytokine , IL-6 , with bFGF signaling and PSMA , should be of high clinical relevance in the treatment of metastatic prostate cancer . In developing novel therapeutic modalities targeting IL-6 , significant attention should be given to PSMA and its inactivation to fight against prostate cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23250823"}
{"sentence": "Alterations of the epidermal growth factor receptor ( EGFR ) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7 . We have previously shown that this mutant receptor , called DeltaEGFR , confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo . To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation , we examined the gene products that control cell cycle progression . We found that levels of the cyclin-dependent kinase ( CDK ) inhibitor , p27 , were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors . Consequently , CDK2-cyclin A activity was also elevated , concomitant with the RB protein hyperphosphorylation . In addition , activated phosphatidylinositol 3-kinase ( PI3-K ) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors . U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB . Treatment of U87MG.DeltaEGFR cells with LY294002 , a PI3-K inhibitor , caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27 . Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo . These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway . This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12438278"}
{"sentence": "Domestic dog breeds have undergone intense selection for a variety of morphologic features , including size . Among small-dog breeds , defined as those averaging less than in. at the withers , there remains still considerable variation in body size . Yet essentially all such dogs are fixed for the same allele at the insulin-like growth factor 1 gene , which we and others previously found to be a size locus of large effect . In this study we sought to identify additional genes that contribute to tiny size in dogs using an association scan with the single nucleotide polymorphism ( SNP ) dataset CanMap , in which 915 purebred dogs were genotyped at 60,968 SNP markers . Our strongest association for tiny size ( defined as breed-average height not more than 10 in. at the withers ) was on canine chromosome 3 ( p = 1.9 \u00d7 10(-70) ) . Fine mapping revealed a nonsynonymous SNP at chr3:44,706,389 that changes a highly conserved arginine at amino acid 204 to histidine in the insulin-like growth factor 1 receptor ( IGF1R ) . This mutation is predicted to prevent formation of several hydrogen bonds within the cysteine-rich domain of the receptor's ligand-binding extracellular subunit . Nine of 13 tiny dog breeds carry the mutation and many dogs are homozygous for it . This work underscores the central importance of the IGF1 pathway in controlling the tremendous size diversity of dogs .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22903739"}
{"sentence": "Mast cells ( MC ) are key effector cells in allergic reactions but also involved in host defence , tissue remodeling , angiogenesis , and fibrogenesis . Here , we show that human intestinal fibroblasts ( FB ) suppress apoptosis in human intestinal MC dependent on IL-6 . Intestinal FB produced IL-6 upon direct stimulation by intestinal MC in co-culture or by MC mediators such as TNF-\u03b1 , IL-1\u03b2 , tryptase or histamine . MC incubated with IL-6 survived for up to 3 weeks similar to MC co-cultured with FB and MC survival could be blocked by neutralizing anti-IL-6 Abs . Moreover , FB stimulated by MC mediators upregulated their expression of matrix metalloproteinase-1 ( MMP-1 ) , a key fibrolytic enzyme . Noteworthy , FB co-cultured with MC or treated with MMP-1 lost confluence and showed increased numbers of apoptotic cells . Our data indicate an intimate cross talk between mucosal MC and FB resulting in MC survival and induction of a fibrolytic rather than a profibrotic state in FB .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22356938"}
{"sentence": "Prognosis of patients with non small cell lung cancer ( NSCLC ) remains difficult to assess , even after adjustment for pathological stage . Prognostic value of numerous biological markers has been evaluated , with conflicting results . Data of 86 patients with NSCLC treated by surgery were collected with clinical characteristics , histopathological data including tumor differentiation and status of blood and lymphatic vessel invasion and evaluation by immunohistochemistry of Rb , Bcl-2 and Ki-67 expression . Prognostic values for overall survival ( OS ) and event-free survival ( EFS ) were analyzed by the log tank test and the multivariable Cox model . Using univariable analyses , pT , pN , poor differentiation or large cell subtype were associated with a poor OS , while lymphatic and/or blood vessel invasion were associated with a short EFS . None of the molecular markers had a significant prognostic value for either outcome . In multivariable analyses , only stage remained of prognostic value for OS . Interestingly , the presence of blood vascular invasion in the tumor was significantly predictive for subsequent metastatic occurrence in stages I and II . This feature might , therefore , be relevant for administration of adjuvant therapy in completely resected NSCLC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12399129"}
{"sentence": "Dichlorvos , an organophosphate ( OP ) , is known to cause oxidative stress in the central nervous system ( CNS ) . Previously we have shown that dichlorvos treatment promoted the levels of proinflammatory molecules and ultimately induced apoptotic cell death in primary microglial cells . Here we studied the effect of dichlorvos on crucial cell cycle regulatory proteins and the DNA damage sensor ataxia-telangiectasia mutated ( ATM ) . We found a significant increase in p53 and its downstream target , p21 , levels in dichlorvos-treated microglial cells compared with control cells . Moreover , dichlorvos exposure promoted the levels of different cell cycle regulatory proteins . These results along with flow cytometry results suggested that primary microglial cells were arrested at G1 and G2/M phase after dichlorvos exposure . We have shown in a previous study that dichlorvos can induce DNA damage in microglia ; here we found that microglial cells also tried to repair this damage by inducing a DNA repair enzyme , i.e. , ATM . We observed a significant increase in the levels of ATM after dichlorvos treatment compared with control .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23280485"}
{"sentence": "Often the use of cytotoxic drugs in cancer therapy results in stable disease rather than regression of the tumor , and this is typically seen as a failure of treatment . We now show that DNA damage is able to induce senescence in tumor cells expressing wild-type p53 . We also show that cytotoxics are capable of inducing senescence in tumor tissue in vivo . Our results suggest that p53 and p21 play a central role in the onset of senescence , whereas p16(INK4a) function may be involved in maintaining senescence . Thus , like apoptosis , senescence appears to be a p53-induced cellular response to DNA damage and an important factor in determining treatment outcome .", "label": [0, 0, 0, 1, 0, 1, 0, 1, 0, 0], "id": "11912168"}
{"sentence": "Senescence is a cellular response preventing tumorigenesis . The Ras oncogene is frequently activated or mutated in human cancers , but Ras activation is insufficient to transform primary cells . Ina search for cooperating oncogenes , we identify the lysine demethylase JMJD2A/KDM4A . We show that JMJD2A functions as a negative regulator of Ras-induced senescence and collaborates with oncogenic Ras to promote cellular transformation by negatively regulating the p53 pathway . We find CHD5 , a known tumor suppressor regulating p53 activity , as a target of JMJD2A . The expression of JMJD2A inhibits Ras-mediated CHD5 induction leading to a reduced activity of the p53 pathway . In addition , we show that JMJD2A is overexpressed inmouse and human lung cancers . Depletion of JMJD2A in the human lung cancer cell line A549 bearing an activated K-Ras allele triggers senescence . We propose that JMJD2A is an oncogene that represents a target for Ras-expressing tumors .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23168260"}
{"sentence": "Nectin-like molucule-5 ( Necl-5 ) is an immunoglobulin-like molecule that was originally identified as a poliovirus receptor and is often upregulated in cancer cells . It has been said that Necl-5 plays a role in not only cell-cell adhesion , but also cell migration , proliferation , and metastasis . In this study , we used a bronchioloalveolar carcinoma ( BAC ) cell line and fibroblasts to assess the expression of Necl-5 in the development of cancer-stroma communication by using an easy-to-prepare double-layered collagen gel hemisphere ( DL- CGH ) system that enables visualization of cell migration during invasion . The expression of Necl-5 was higher in BAC cells than in fibroblasts . This tendency didn't change even when the BAC cells were mixed with fibroblasts . To assess the role of Necl-5 in the invasive activity of the BAC cells , we knocked down its expression using RNA interference ( RNAi ) . The invasion assay with DL-CGH revealed that inhibitation of Necl-5 expression in the BAC cells was associated with suppressed invasiveness . In addition , Necl-5 knockdown inhibited the movement and proliferation of the BAC cells . Necl-5 expression in lung cancer cells is crucial for their invasiveness in the cancer-stromal interaction , suggesting that Necl-5 could be a favorable molecular target for the suppression of invasiveness in lung adenocarcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23276719"}
{"sentence": "BACKGROUND Adenoid cystic carcinoma ( ACC ) of the Breast is a rare tumour ( less than 1 % of all breast carcinomas ) . The aim of this study was to determine the clinical , histological and immunohistochemical characteristics of these tumours . METHODS From the database of the Bergoni\u00e9 Institute of Bordeaux , 30 cases of ACC were identified . The clinical and histological features of these carcinomas were characterized . An immunohistochemical study was performed with the following antibodies : ER , PR , HER-2-neu , Vimentin , EGFR , P63 , SMA , CK5/6 , CK8/18 , CK14 , cKIT , MIB1 , CD44 and CD24 . RESULTS Thirty patients were included ( median age 60.7 years ) . The 10 axillary lymph node dissections and two sentinel lymph procedures were negative . The architecture was frequently of a mixed type ( 26/30 ) and less often solid ( 4/30 ) . Among the 23 patients for whom follow up was available ( median follow-up : 84 months [ 2-288] ) , there were three local recurrences and three metastatic events . The tumors with recurrence and metastasis showed more necrosis , a mitotic count greater than 4/10hpf , and in one case perineural infiltration . All the tumours were ER , PR and Her-2-neu negative . Morphological and immunophenotypical analysis disclosed in each tumor , a basaloid and a luminal cell population with divergent immunophenotypical patterns . CONCLUSIONS The mammary ACC is made of two cell types and is of good prognosis despite its triple negative phenotype , similar to the basal-like infiltrating carcinoma NOS . Axillary lymph node dissection is not recommended . Good local control by at least large lumpectomy with long-term follow-up is necessary .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20223349"}
{"sentence": "p32/gC1qR/C1QBP/HABP1 is a mitochondrial/cell surface protein overexpressed in certain cancer cells . Here we show that knocking down p32 expression in human cancer cells strongly shifts their metabolism from oxidative phosphorylation ( OXPHOS ) to glycolysis . The p32 knockdown cells exhibited reduced synthesis of the mitochondrial-DNA-encoded OXPHOS polypeptides and were less tumorigenic in vivo . Expression of exogenous p32 in the knockdown cells restored the wild-type cellular phenotype and tumorigenicity . Increased glucose consumption and lactate production , known as the Warburg effect , are almost universal hallmarks of solid tumors and are thought to favor tumor growth . However , here we show that a protein regularly overexpressed in some cancers is capable of promoting OXPHOS . Our results indicate that high levels of glycolysis , in the absence of adequate OXPHOS , may not be as beneficial for tumor growth as generally thought and suggest that tumor cells use p32 to regulate the balance between OXPHOS and glycolysis .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20100866"}
{"sentence": "Melanocyte stimulating hormone ( alpha-MSH , alpha-melanotropin),Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Ly-Pro-Va l-NH2 , regulates melanogenesis within epidermal melanocytes of many animals . An MSH analogue ( [ Nle4,D-Phe7]alpha-MSH ) that exhibits superpotency and prolonged biological activity has been synthesized , biologically characterized , and is presently in clinical trials to determine its possible clinical use in tanning of the skin . It also has potential for the diagnosis , localization , and chemotherapy of melanoma . The effects of this analogue on the growth , metastatic behavior , and invasive potential of a melanotic variant of Cloudman S-91 murine melanoma are reported here . In an intracutaneous murine model of melanoma cell tumor growth , the analogue did not increase primary tumor growth ( size ) after the period of administration of the peptide hormone analogue and did not affect spontaneous lung metastases . Survival times for the control and melanotropin-treated groups were similar , suggesting that overall tumor burden was not affected by treatment with the hormone analogue . Last , melanoma cell invasion through a human amniotic basement membrane in vitro was not enhanced compared to untreated cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1337602"}
{"sentence": "We have investigated the cellular requirements for IL-2 production by autocrine proliferating tumor cells from four patients with adult T cell leukemia ( ATL ) . Cultures of these ATL cells both produced endogenous IL-2 protein in the absence of added mitogen and proliferated at higher levels when exogenous recombinant IL-2 was added . Depletion of macrophages in the tumor cell cultures resulted in a sharp decline in tumor cell IL-2 production , while re-addition of macrophages reconstituted this response . Macrophage-derived factors including IL-6 and IL-1 also reconstituted IL-2 production in these macrophage depleted cultures . These results raise the possibility that macrophages may play a central role in HTLV-I mediated immortalization of T cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1288288"}
{"sentence": "Cell adhesion molecule 1 ( CADM1 ) , expressed by human lung mast cells ( HLMCs ) , mediates their adhesion to airway smooth muscle ( ASM ) , and contributes to ASM-dependent HLMC proliferation and survival . CADM1 is expressed in alternatively spliced isoforms , but those present in HLMCs and their function are not known . We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2 , respectively , from HLMCs and human MC lines ( HMC-1 and LAD2 ) . Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 ( of clones ) , as well as SP1 ( exons 7/8/9/11 ) and a novel SP6 ( exons 7/8/9/10/11 ) . In contrast , immature HMC-1 cells expressed only functional SP4 . SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions . In contrast , CADM1 downregulation abolished homotypic adhesion , indicating that CADM1 is the sole receptor mediating mast cell aggregation . CADM1-mediated adhesion was enhanced by the presence of cell survival factors . SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control . CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1(L) , but not Blc-2 or Bcl-X(L) , and increased caspase-3/7 activity in both HMC-1 cells and HLMCs . This coincided with decreased basal Kit levels in HLMCs . In summary , human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion . The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis , and augment the pathophysiology of allergic diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22438059"}
{"sentence": "Indoleamine 2,3-dioxygenase ( IDO ) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis . Recently , we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis . Here , we report that IDO loss did not exacerbate classical inflammatory responses . Rather , IDO induction could be elicited by environmental signals and tumor promoters as an integral component of the inflammatory tissue microenvironment even in the absence of cancer . IDO loss had limited impact on tumor outgrowth in carcinogenesis models that lacked an explicit inflammatory tumor promoter . In the context of inflammatory carcinogenesis where IDO was critical to tumor development , the most important source of IDO was radiation-resistant non-hematopoietic cells , consistent with evidence that loss of the IDO regulatory tumor suppressor gene Bin1 in transformed skin cells facilitates IDO-mediated immune escape by a cell autonomous mechanism . Taken together , our results identify IDO as an integral component of ' cancer-associated ' inflammation that tilts the immune system toward tumor support . More generally , they promote the concept that mediators of immune escape and cancer-associated inflammation may be genetically synonymous .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20640572"}
{"sentence": "Previous studies have shown that 6-methoxy-8-hydroxylaminoquinoline ( MAQ-NOH ) , an N-hydroxy metabolite of the antimalarial drug , primaquine , is a direct-acting hemolytic agent in rats . To investigate the mechanism underlying this hemolytic activity , the effects of hemotoxic concentrations of MAQ-NOH on rat erythrocyte sulfhydryl status , membrane lipids , skeletal proteins , and morphology have been examined . Treatment of rat erythrocytes with a TC(50) concentration of MAQ-NOH ( 350 microM ) caused only a modest and transient depletion of reduced glutathione ( GSH ) ( which was matched by modest increases in the levels of glutathione disulfide and glutathione-protein mixed disulfides . Lipid peroxidation , as measured by thiobarbituric acid-reactive substances and F(2)-isoprostane formation , was induced in a concentration-dependent manner by MAQ-NOH . However , the formation of disulfide-linked hemoglobin adducts on membrane skeletal proteins and changes in erythrocyte morphology were not observed . These data suggest that hemolytic activity results from peroxidative damage to the lipid of the red cell membrane and is not dependent on skeletal protein thiol oxidation . However , when red cell GSH was depleted ( >90% ) by titration with diethyl maleate , hemolytic activity of MAQ-NOH was markedly enhanced . Of interest , exacerbation of hemotoxicity was not matched by increases in lipid peroxidation , but by the appearance of hemoglobin-skeletal protein adducts . Collectively , the data are consistent with the concept that MAQ-NOH may operate by more than one mechanism ; one that involves lipid peroxidation in the presence of normal amounts of erythrocytic GSH , and one that involves protein oxidation in red cells with low levels of GSH , such as are seen in individuals with glucose-6-phosphate dehydrogenase deficiency .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12235244"}
{"sentence": "Chromosomal instability and the subsequent genetic mutations are considered to be critical factors in the development of the majority of solid tumors , but the mechanisms by which a stable diploid cell loses the ability to maintain genomic integrity are not well characterized . We have approached this critical issue through the use of high-throughput screens in untransformed diploid epithelial cells . In a screen of a cDNA library , we identified 13 kinases whose overexpression leads to increased ploidy . In a series of shRNA screens , we identified 16 kinases whose loss leads to increased ploidy . In both cDNA and shRNA screens , the majority of hits have not been linked previously to genomic stability . We further show that sustained loss of the shRNA screening hits leads to multipolar spindles and heterogeneous chromosome content , two characteristics of chromosomal instability . Loss of several of the kinases leads to loss of contact inhibition and to anchorage-independent growth , vital traits acquired during tumor development . We anticipate that this work will serve as a template for the comprehensive identification of pathways whose dysregulation can drive tumorigenesis through impaired karyotypic maintenance .", "label": [0, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "20713694"}
{"sentence": "Recent studies have shown that the antiestrogen tamoxifen ( TAM ) can be used in the treatment of malignant neoplasms other than breast cancer . In the present study , we investigated the expression of estrogen receptor ( ER ) in six malignant rhabdoid tumor ( MRT ) cell lines . Alterations in MRT cell growth in response to estrogen or antiestrogens ( 4-hydroxytamoxifen ( 4-OHT ) , TAM , and ICI 182 780 ) were also investigated . RT-PCR and western blotting showed that ER-alpha was expressed in three of the six MRT cell lines . While 17-beta-estradiol ( E2 ) did not significantly alter MRT cell line proliferation , the hydroxylated tamoxifen metabolite 4-OHT significantly inhibited the growth of all 6 MRT cell lines . However , the steroidal antiestrogen ICI 182 780 did not alter the proliferation of any of the MRT cell lines. 4-OHT induced apoptosis in both ER-alpha-negative and ER-alpha-positive MRT cell lines , as assessed by nuclear morphology and DNA fragmentation . Neither growth inhibition nor induction of apoptosis due to 4-OHT was blocked by the addition of excess E2 . Our data suggested that 4-OHT induced cytotoxic effects against MRT cells , and that these effects were independent of ER expression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12495475"}
{"sentence": "Mast cells ( MC ) are critical for a number of pathological conditions , including acute and chronic inflammation and tumor angiogenesis . We have previously demonstrated that in B-cell non-Hodgkin's lymphoma ( B-NHL ) angiogenesis is correlated with total methachromatic and tryptase-positive MC and that both counts increase in step with the increase in malignancy , whereas the role of MC in malignant lymph nodes is not fully clear . An extensive ultrastructural study has been made of representative samples of 30 B-NHL and 10 benign lymphadenopathies . A heterogeneous population of MC characterized by the presence of granules with a semilunar aspect and containing scrolls was observed . The former are the expression of a slow but progressive release of angiogenic factors due to chronic , progressive stimulation of MC degranulation , while the latter contain tryptase , an angiogenic factor . These two ultrastructural data confirm the important role played by MC in the angiogenesis associated with progression in B-NHL .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12533047"}
{"sentence": "More than 50% of adults and of children with pre-B acute lymphoblastic leukemia ( ALL ) relapse following treatment . Dismal outcomes for patients with relapsed or refractory disease mandate novel approaches to therapy . We have previously shown that the combination of the mTOR inhibitor RAD001 ( everolimus ) and the chemotherapeutic agent vincristine increases the survival of non-obese diabetic/severe combined immuno-deficient ( NOD/SCID ) mice bearing human ALL xenografts . We have also shown that 16 \\u03bcM RAD001 synergized with agents that cause DNA damage or microtubule disruption in pre-B ALL cells in vitro . Here , we demonstrate that RAD001 has dose-dependent effects on the cell cycle in ALL cells , with 1.5 \\u03bcM RAD001 inhibiting pRb , Ki67 and PCNA expression and increasing G0/1 cell cycle arrest , whereas 16 \\u03bcM RAD001 increases pRb , cyclin D1 , Ki67 and PCNA , with no evidence of an accumulation of cells in G0/1 . Transition from G2 into mitosis was promoted by 16 \\u03bcM RAD001 with reduced phosphorylation of cdc2 in cells with 4 N DNA content . However , 16 \\u03bcM RAD001 preferentially induced cell death in cells undergoing mitosis . When combined with vincristine , 16 \\u03bcM RAD001 reduced the vincristine-induced accumulation of cells in mitosis , probably as a result of increased death in this population . Although 16 \\u03bcM RAD001 weakly activated Chk1 and Chk2 , it suppressed strong vincristine-induced activation of these cell cycle checkpoint regulators . We conclude that RAD001 enhances chemosensitivity at least in part through suppression of cell cycle checkpoint regulation in response to vincristine and increased progression from G2 into mitosis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23128395"}
{"sentence": "Sarcomatoid renal cell carcinomas of the kidney are rare neoplasms constituting about 1-5% of all renal malignant neoplasms . These are aggressive tumors and are commonly associated with conventional ( clear cell ) renal cell carcinomas , but cases associated with chromophobe renal cell carcinomas are sparse . Cytological features of such lesions have rarely been reported . Here , we report a unique case of a 48-year-old male patient who presented with right flank lump and pain . A fine needle aspiration was performed from the lesion under ultrasound guidance and a cytological diagnosis of pleomorphic sarcoma was made . A right-sided radical nephrectomy was carried out and subsequent histopathology revealed a sarcomatoid renal cell carcinoma with wide areas of necrosis coexisting with chromophobe renal cell carcinoma with calcification . Differentiation of pleomorphic sarcoma from a sarcomatoid renal cell carcinoma is , thus , challenging from cytopathology smears and the differential diagnoses should always be borne in mind while giving a cytopathological opinion .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21042532"}
{"sentence": "EBV latent antigen EBNA3C is indispensible for in vitro B-cell immortalization resulting in continuously proliferating lymphoblastoid cell lines ( LCLs ) . EBNA3C was previously shown to target pRb for ubiquitin-proteasome mediated degradation , which facilitates G1 to S transition controlled by the major transcriptional activator E2F1 . E2F1 also plays a pivotal role in regulating DNA damage induced apoptosis through both p53-dependent and -independent pathways . In this study , we demonstrate that in response to DNA damage LCLs knocked down for EBNA3C undergo a drastic induction of apoptosis , as a possible consequence of both p53- and E2F1-mediated activities . Importantly , EBNA3C was previously shown to suppress p53-induced apoptosis . Now , we also show that EBNA3C efficiently blocks E2F1-mediated apoptosis , as well as its anti-proliferative effects in a p53-independent manner , in response to DNA damage . The N- and C-terminal domains of EBNA3C form a stable pRb independent complex with the N-terminal DNA-binding region of E2F1 responsible for inducing apoptosis . Mechanistically , we show that EBNA3C represses E2F1 transcriptional activity via blocking its DNA-binding activity at the responsive promoters of p73 and Apaf-1 apoptosis induced genes , and also facilitates E2F1 degradation in an ubiquitin-proteasome dependent fashion . Moreover , in response to DNA damage , E2F1 knockdown LCLs exhibited a significant reduction in apoptosis with higher cell-viability . In the presence of normal mitogenic stimuli the growth rate of LCLs knockdown for E2F1 was markedly impaired ; indicating that E2F1 plays a dual role in EBV positive cells and that active engagement of the EBNA3C-E2F1 complex is crucial for inhibition of DNA damage induced E2F1-mediated apoptosis . This study offers novel insights into our current understanding of EBV biology and enhances the potential for development of effective therapies against EBV associated B-cell lymphomas .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "22438805"}
{"sentence": "p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance , in part , by disabling apoptosis . We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a) . Hence , tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo . Moreover , tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53 , p16(INK4a) , and senescence markers , and typically acquire p53 or INK4a mutations upon progression to a terminal stage . Finally , mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects . Therefore , cellular senescence contributes to treatment outcome in vivo .", "label": [0, 0, 0, 1, 0, 1, 0, 1, 0, 0], "id": "12015983"}
{"sentence": "n-3 Polyunsaturated fatty acids ( PUFA ) have a chemopreventive effect while n-6 PUFA promote carcinogenesis . The effect of these essential fatty acids may be related to oxidative stress . Therefore , the study was designed to evaluate the effect of different ratios of fish oil ( FO ) and corn oil ( CO ) in the prevention of colon cancer . Male Wistar rats were divided into control , dimethylhydrazine dihydrochloride ( DMH ) treated , FO + CO ( 1:1 ) and FO + CO ( 2.5:1 ) . All the groups , except the control received a weekly injection of DMH for 4 weeks . The animals were sacrificed either 48 h later ( initiation phase ) or kept for 16 weeks ( post initiation phase ) . DMH treatment in the initiation phase animals showed mild to moderate inflammation , decreased ROS and TrxR activity , increased antioxidants , apoptosis and ACF multiplicity . The post initiation study showed severe inflammation with hyperplasia , increased ACF multiplicity and ROS levels , a decrease in antioxidants and apoptosis . The FO + CO ( 1:1 ) treated animals showed severe inflammation , a decrease in ROS , an increase in antioxidants and apoptosis in the initiation phase . FO + CO ( 1:1 ) in the post initiation phase and FO + CO ( 2.5:1 ) in the initiation showed mild inflammation , increased ROS , apoptosis and decreased antioxidants . There was a decrease in ACF multiplicity and ROS levels , increased antioxidants and apoptosis in the post initiation phase study . The present study suggests that FO has a dose- and time-dependent chemopreventive effect in colon cancer mediated through oxidative stress and apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "20737228"}
{"sentence": "Hexachlorobenzene ( HCB ) is an organochlorine pesticide that acts as an endocrine disruptor in humans and rodents . The development of breast cancer strongly depends on endocrine conditions modulated by environmental factors . We have demonstrated that HCB is a tumor co-carcinogen in rats and an inducer of proliferation in MCF-7 cells , in an estrogen receptor \u03b1 ( ER\u03b1)-dependent manner , and of migration in MDA-MB-231 breast cancer cell line . In the present study , we examined HCB effect on c-Src/human epidermal growth factor receptor ( HER1 ) and ER\u03b1 signaling pathways in mammary glands and in N-nitroso-N-methylurea ( NMU)-induced mammary tumors in rats . Furthermore , we evaluated histopathological changes and serum hormone levels . Rats were separated into four groups : control , HCB ( 100 mg/kg b.w. ) , NMU ( 50 mg/kg b.w. ) and NMU-HCB . Our data show that HCB increases c-Src and HER1 activation , c-Src/HER1 association , and Y699-STAT5b and ERK1/2 phosphorylation in mammary glands . HCB also enhances Y537-ER\u03b1 phosphorylation and ER\u03b1/c-Src physical interaction . In tumors , HCB also induces c-Src and HER1 activation , c-Src/HER1 association , as well as T308-Akt and Y699-STAT5b phosphorylation . In addition , the pesticide increases ER\u03b1 protein content and decreases p-Y537-ER\u03b1 levels and ER\u03b1/c-Src association in tumors . HCB increases serum 17-beta estradiol and prolactin contents and decreases progesterone , FSH and LH levels in rats without tumors , while the opposite effect was observed in rats with tumors . Taken together , our results indicate that HCB induces an estrogenic effect in mammary gland , increasing c-Src/HER1 and ER\u03b1 signaling pathways . HCB stimulates c-Src/HER1 pathway , but decreases ER\u03b1 activity in tumors , appearing to shift them towards a higher malignancy phenotype .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22245120"}
{"sentence": "Contact inhibition is a crucial mechanism regulating proliferation in vitro and in vivo . Although it is generally accepted that contact inhibition plays a pivotal role in maintaining tissue homeostasis , the molecular mechanisms of contact inhibition are still not fully understood . FoxM1 is known as a proliferation-associated transcription factor and is upregulated in many cancer types . Vice versa , anti-proliferative signals , such as TGF-\\u03b2 and differentiation signals decrease FoxM1 expression . Here we investigated the role of FoxM1 in contact inhibition in fibroblasts . We show that protein expression of FoxM1 is severely and rapidly downregulated upon contact inhibition , probably by inhibition of ERK activity , which then leads to decreased expression of cyclin A and polo-like kinase 1 . Vice versa , ectopic expression of FoxM1 prevents the decrease in cyclin A and polo-like kinase 1 and causes a two-fold increase in saturation density indicating loss of contact inhibition . Hence , we show that downregulation of FoxM1 is required for contact inhibition by regulating expression of cyclin A and polo-like kinase 1 .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "22982677"}
{"sentence": "Background : Several polymorphisms in the DNA repair gene have been extensively studied in the association with various human cancers such as breast cancer . Material and methods : We investigated the association of polymorphisms in the DNA repair genes XRCC1-Arg399Gln , XRCC2-Arg188His and RAD51-135G/C with the breast cancer risk . Genotypes were determined by PCR-RFLP assays in 220 patients with breast cancer and 220 age-matched healthy controls . Results : Our results demonstrated a significant positive association between the XRCC1 399Gln/Gln homozygous genotype and breast carcinoma , with an adjusted odds ratio ( OR ) of 2.08 [ 1.08-3.98 ] . The 399Gln allele variant was also associated with type I breast cancer ( OR = 1.41 [ 0.98-2.01 ] , p = 0.034 ) . The distributions of genotypes and alleles of the genes XRCC2 and RAD51 polymorphism were not significantly associated with the different stages of breast carcinoma ( p > 0.05 ) . Conclusion : These results suggest that 399Gln allele of XRCC1 Arg399Gln may be a risk factor for breast cancer in the Polish population .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21290343"}
{"sentence": "Polo-like kinase 3 ( Plk3 , alternatively termed Prk ) is involved in the regulation of DNA damage checkpoint as well as in M-phase function . Plk3 physically interacts with p53 and phosphorylates this tumor suppressor protein on serine-20 , suggesting that the role of Plk3 in cell cycle progression is mediated , at least in part , through direct regulation of p53 . Here we show that Plk3 is rapidly activated by reactive oxygen species in normal diploid fibroblast cells ( WI-38 ) , correlating with a subsequent increase in p53 protein level . Plk3 physically interacts with Chk2 and the interaction is enhanced upon DNA damage . In addition , Chk2 immunoprecipitated from cell lysates of Daudi ( which expressed little Plk3 ) is capable of stimulating the kinase activity of purified recombinant Plk3 in vitro , and this stimulation is more pronounced when Plk3 is supplemented with Chk2 immunoprecipitated from Daudi after DNA damage . Furthermore , ectopic expression Chk2 activates cellular Plk3 . Together , our studies suggest Chk2 may mediate direct activation of Plk3 in response to genotoxic stresses .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12548019"}
{"sentence": "Acute endothelial cell apoptosis and microvascular compromise couple gastrointestinal tract irradiation to reproductive death of intestinal crypt stem cell clonogens ( SCCs ) following high-dose radiation . Genetic or pharmacologic inhibition of endothelial apoptosis prevents intestinal damage , but as the radiation dose is escalated , SCCs become directly susceptible to an alternate cell death mechanism , mediated via ceramide synthase ( CS)-stimulated de novo synthesis of the proapoptotic sphingolipid ceramide , and p53-independent apoptosis of crypt SCCs . We previously reported that ataxia-telangiectasia mutated deficiency resets the primary radiation lethal pathway , allowing CS-mediated apoptosis at the low-dose range of radiation . The mechanism for this event , termed target reordering , remains unknown . Here , we show that inactivation of DNA damage repair pathways signals CS-mediated apoptosis in crypt SCCs , presumably via persistent unrepaired DNA double-strand breaks ( DSBs ) . Genetic loss of function of sensors and transducers of DNA DSB repair confers the CS-mediated lethal pathway in intestines of sv129/B6Mre11(ATLD1/ATLD1) and C57BL/6(Prkdc/SCID) ( severe combined immunodeficient ) mice exposed to low-dose radiation . In contrast , CS-mediated SCC lethality was mitigated in irradiated gain-of-function Rad50(s/s) mice , and epistasis studies order Rad50 upstream of Mre11 . These studies suggest unrepaired DNA DSBs as causative in target reordering in intestinal SCCs . As such , we provide an in vivo model of DNA damage repair that is standardized , can be exploited to understand allele-specific regulation in intact tissue , and is pharmacologically tractable .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20086180"}
{"sentence": "Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence . Using a well characterized model system for breast cancer , we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells . Cells acutely exposed to adriamycin exhibited an increase in p53 activity , a decline in telomerase activity , and a dramatic increase in beta-galactosidase , a marker of senescence . Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis , demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents . Stable introduction of hTERT , the catalytic protein component of telomerase , into MCF-7 cells caused an increase in telomerase activity and telomere length . Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening , indicating that the senescence after treatment is telomere length-independent . However , we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres , showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype . To our knowledge , these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening .", "label": [0, 0, 0, 1, 0, 1, 0, 1, 0, 0], "id": "12101184"}
{"sentence": "The protein toxins ricin , abrin , Shiga toxin , and diphtheria toxin were found to induce lysis of several cell lines in a manner characteristic for programmed cell death or apoptosis . The toxins induced DNA degradation , and light and electron microscopical studies revealed that lysis was preceded by reorganization of intracellular vacuoles , cell blebbing , and chromatin condensation both in Vero and in MDCK cells . Cell lysis was efficiently inhibited by cycloheximide and 3-methyladenine ( 3MA ) , a specific inhibitor of autophagy . Cycloheximide , which like 3MA inhibits autophagy , protected even when added at a time when the protein synthesis had been blocked by ricin , suggesting that the effect of cycloheximide on cell lysis is independent of its ability to inhibit protein synthesis . Also theophylline and dibutyryl-cGMP had some protective effect , whereas a number of compounds reported to protect against apoptosis in other systems were without protective effects . The data suggest that autophagy is important for the toxin-induced cell lysis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1572394"}
{"sentence": "Cellular senescence is a permanent out-of-cycle state regulated by molecular circuits acting during the G1 phase of the cell cycle . Cdt1 is a central regulator of DNA replication licensing acting during the G1 phase and it is negatively controlled by Geminin . Here , we characterize the cell cycle expression pattern of Cdt1 and Geminin during successive passages of primary fibroblasts and compare it to tumour-derived cell lines . Cdt1 and Geminin are strictly expressed in distinct subpopulations of young fibroblasts , similarly to cancer cells , with Geminin accumulating shortly after the onset of S phase . Cdt1 and Geminin are down-regulated when primary human and mouse fibroblasts undergo replicative or stress-induced senescence . RNAi-mediated Geminin knock-down in human cells enhances the appearance of phenotypic and molecular features of senescence . Mouse embryonic fibroblasts heterozygous for Geminin exhibit accelerated senescence compared to control fibroblasts . In contrast , ectopic expression of Geminin in mouse embryonic fibroblasts delays the appearance of the senescent phenotype . Taken together , our data suggest that changes in Geminin expression levels affect the establishment of senescence pathways .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23142824"}
{"sentence": "Mitochondrial biogenesis , which depends on nuclear as well as mitochondrial genes , occurs in response to increased cellular ATP demand . The nuclear transcriptional factors , estrogen-related receptor alpha ( ERRalpha ) and nuclear respiratory factors 1 and 2 , are associated with the coordination of the transcriptional machinery governing mitochondrial biogenesis , whereas coactivators of the peroxisome proliferator-activated receptor gamma coactivator-1 ( PGC-1 ) family serve as mediators between the environment and this machinery . In the context of proliferating cells , PGC-1-related coactivator ( PRC ) is a member of the PGC-1 family , which is known to act in partnership with nuclear respiratory factors , but no functional interference between PRC and ERRalpha has been described so far . We explored three thyroid cell lines , FTC-133 , XTC.UC1 and RO 82 W-1 , each characterized by a different mitochondrial content , and studied their behavior towards PRC and ERRalpha in terms of respiratory efficiency . Overexpression of PRC and ERRalpha led to increased respiratory chain capacity and mitochondrial mass . The inhibition of ERRalpha decreased cell growth and respiratory chain capacity in all three cell lines . However , the inhibition of PRC and ERRalpha produced a greater effect in the oxidative cell model , decreasing the mitochondrial mass and the phosphorylating respiration , whereas the nonphosphorylating respiration remained unchanged . We therefore hypothesize that the ERRalpha-PRC complex plays a role in arresting the cell cycle through the regulation of oxidative phosphorylation in oxidative cells , and through some other pathway in glycolytic cells .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20067526"}
{"sentence": "Cytokines are known to play an important role in host defense by regulating the function , growth , and differentiation of the cells of the immune system . We hypothesize that , in the tumor microenvironment , tumor cells and resident tissue cells ( e.g. , fibroblasts ) also produce cytokines that may regulate the local immune response to tumors . Initially , homogenates of eight head and neck squamous cell carcinomas ( HNSCC ) were assayed for the presence of interleukin-1 ( IL-1 ) , interleukin-4 ( IL-4 ) , interleukin-6 ( IL-6 ) , and granulocyte-macrophage colony-stimulating factor ( GM-CSF ) to establish the presence of these cytokines in the tumors in vivo . We detected IL-1 in all tumor homogenates and IL-4 , IL-6 , and GM-CSF in some homogenates . To assess the ability of HNSCC to produce these cytokines , supernatants of short-term primary cultures of HNSCC were assayed for the same cytokines . No IL-1 was detected , although baseline levels of IL-4 , IL-6 , and GM-CSF were present . However , the stimulation of primary tumor cultures with exogenous IL-1 induced or significantly enhanced production of IL-4 ( p < 0.01 ) , IL-6 ( p < 0.001 ) , and GM-CSF ( p < 0.02 ) . These results support our hypothesis that HNSCC secrete cytokines that may influence the response of local immune cells . Our data also suggest that IL-1 may have a central role in regulating the local immune response through the enhancement or induction of cytokine production by tumor and/or resident tissue cells .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1463101"}
{"sentence": "OBJECTIVES Lymph node metastasis is among the most important prognostic factors for patients with esophageal squamous cell carcinoma after curative esophagectomy ; however , the extent of lymphadenectomy is still controversial . The objective of the present study was to determine the frequency of lymphatic metastases and to study the pattern of lymph node metastasis in a large study population . METHODS The data from 1361 patients with thoracic esophageal squamous cell carcinoma who underwent curative R0 esophagectomy were retrospectively examined . Logistic regression analysis was used to identify the factors associated with lymph node metastasis . RESULTS Of the 1361 patients , 714 ( 52.5% ) were found to have lymph node metastasis . The frequency of lymph node metastasis increased as the tumor invasion increased . Paratracheal nodes were the most frequent metastasis nodes ( 15.9% ) . The frequency of lymph node metastasis was 9.8% in the neck , 18.0% in the upper mediastinum , 18.9% in the middle mediastinum , 11.8% in the lower mediastinum , and 28.4% in the abdomen . Of these 714 patients , 424 ( 31.2% ) presented with 1 field involvement , 255 ( 18.7% ) with 2 fields , and 35 ( 2.6% ) with 3 fields involvement . Logistic regression analysis revealed tumor length ( P<.001 ) , tumor invasion ( P<.001 ) , tumor differentiation ( P=.003 ) , and lymphovascular invasion ( P<.001 ) were risk factors for lymph node metastasis . Tumor location ( P<.001 ) , tumor invasion ( P=.003 ) , lymphovascular invasion ( P=.004 ) , and paratracheal lymph node involvement ( P=.002 ) were identified as risk factors for cervical lymph node metastasis . CONCLUSIONS Metastases were more frequent in the abdomen than in the neck . Total mediastinal and upper abdominal lymphadenectomy should be carefully conducted . Certain factors , such as tumor location , depth of tumor invasion , lymphovascular invasion , and paratracheal lymph node involvement , might be helpful in determining the need to perform cervical lymphadenectomy in individual patients .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22889480"}
{"sentence": "BACKGROUND & OBJECTIVE Altered cell adhesion has a critical role in the development of epithelial cancers . E-cadherin act on the maintenance of cell-cell adhesion and its function was thought to be regulated by associated cytoplasmic proteins , such as alpha-catenin and beta-catenin . This study was designed to examine the expression of beta-catenin in gastric carcinoma and to determine the relationship between tumor characteristics and survival . METHODS Immunohistochemical staining of beta-catenin and E-cadherin was performed in 148 patients with gastric carcinoma . RESULTS Abnormal expression of beta-catenin and E-cadherin was performed in 148 patients with gastric carcinoma . RESULTS Abnormal expression of beta-catenin and E-cadherin was demonstrated in 43.2% and 44.6% of tumors respectively . Up to 63% of tumors stained abnormally for one or two components of the cadherin-catenin complex ( beta-catenin , E-cadherin ) . Abnormal beta-catenin and E-cadherin staining occurred more frequently in poor differentiated tumor than in good differentiated tumors ( P < 0.005 , respectively ) . There was a significant correlation between abnormal beta-catenin expression and depth of invasion(P < 0.025 ) . Moreover , abnormal beta-catenin expression was more frequent in tumors with positive lymph node metastasis ( 45/84 , 53.6% ) and distance metastasis(21/31 , 67.7% ) than in tumors without lymph node metastasis ( 19/64 , 29.7% ) ( P < 0.005 ) and distance metastasis ( 43/117 , 36.8% ) ( P < 0.005 ) . A survival advantage was noted in tumors retaining normal membranous expression of beta-catenin , independent of type , grade , or stage ( P < 0.005 ) . CONCLUSIONS Abnormal expression of the E-cadherin-catenin complex occurs frequently in gastric carcinoma . The close correlation with poor survival suggests that abnormal beta-catenin may be a useful prognostic marker .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12452049"}
{"sentence": "Bigelovin is a sesquiterpene lactone isolated from the plant Inula helianthus-aquatica which was traditionally used in cancer treatment in Yunnan , China . The potent apoptotic activities of bigelovin in human leukemia U937 cells were shown in our previous study . The present study investigated the anti-angiogenic and immunomodulatory effects of bigelovin using transgenic zebrafish Tg(fli1a:EGFP)y1 with fluorescent blood vessels and human peripheral blood mononuclear cells ( PBMCs ) , respectively . Furthermore , the inhibitory activities of bigelovin on the human endothelial cell adhesion molecules ( CAMs ) were also examined . Our results showed that the growth of subintestinal vessels of the bigelovin-treated zebrafish embryos was significantly inhibited and the gene expressions in angiogenesis signaling pathways ( e.g . Ang2 and Tie2 ) of the zebrafish were down-regulated after bigelovin treatment . Besides , the proliferation and Th1 cytokines productions ( e.g . IFN-\u03b3 , IL-2 and IL-12 ) were suppressed in bigelovin-treated PBMCs . On the other hand , bigelovin was shown to significantly inhibit the human monocyte adhesion to human endothelial cells and the gene expressions of inflammation-related CAMs ( e.g . ICAM-1 , VCAM-1 and E-selectin ) were significantly down-regulated in bigelovin-treated human endothelial cells . In summary , our data provide the first evidence that bigelovin possesses anti-angiogenic and immunomodulatory activities , suggesting bigelovin may exert multi-target functions against cancer in animal models .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23231968"}
{"sentence": "Prostate apoptosis response 4 ( Par-4 ) is a ubiquitously expressed proapoptotic tumor suppressor protein . Here , we show for the first time , that Par-4 is a novel substrate of caspase-3 during apoptosis . We found that Par-4 is cleaved during cisplatin-induced apoptosis in human normal and cancer cell lines . Par-4 cleavage generates a C-terminal fragment of kDa , and the cleavage of Par-4 is completely inhibited by a caspase-3 inhibitor , suggesting that caspase-3 is directly involved in the cleavage of Par-4 . Caspase-3-deficient MCF-7 cells do not show Par-4 cleavage in response to cisplatin treatment , and restoration of caspase-3 in MCF-7 cells produces a decrease in Par-4 levels , with the appearance of a cleaved fragment . Additionally , knockdown of Par-4 reduces caspase-3 activation and apoptosis induction . Site-directed mutagenesis reveals that Par-4 cleavage by caspase-3 occurs at an unconventional site , EEPD(131)\u2193G . Interestingly , overexpression of wild-type Par-4 but not the Par-4 D131A mutant sensitizes cells to cisplatin-induced apoptosis . Upon caspase-3 cleavage , the cleaved fragment of Par-4 accumulates in the nucleus and displays increased apoptotic activity . Overexpression of the cleaved fragment of Par-4 inhibits I\u03baB\u03b1 phosphorylation and blocks NF-\u03baB nuclear translocation . We have identified a novel specific caspase-3 cleavage site in Par-4 , and the cleaved fragment of Par-4 retains proapoptotic activity .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22184067"}
{"sentence": "Pyruvate kinase M2 ( PKM2 ) is upregulated in multiple cancer types and contributes to the Warburg effect by unclear mechanisms . Here we demonstrate that EGFR-activated ERK2 binds directly to PKM2 Ile429/Leu431 through the ERK2 docking groove and phosphorylates PKM2 at Ser37 , but does not phosphorylate PKM1 . Phosphorylated PKM2 Ser37 recruits PIN1 for cis-trans isomerization of PKM2 , which promotes PKM2 binding to importin \\u03b15 and translocating to the nucleus . Nuclear PKM2 acts as a coactivator of \\u03b2-catenin to induce c-Myc expression , resulting in the upregulation of GLUT1 , LDHA and , in a positive feedback loop , PTB-dependent PKM2 expression . Replacement of wild-type PKM2 with a nuclear translocation-deficient mutant ( S37A ) blocks the EGFR-promoted Warburg effect and brain tumour development in mice . In addition , levels of PKM2 Ser37 phosphorylation correlate with EGFR and ERK1/2 activity in human glioblastoma specimens . Our findings highlight the importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 1, 0], "id": "23178880"}
{"sentence": "\\u03b1-Tropomyosin ( \\u03b1Tm ) is central to Ca(2+)-regulation of cardiac muscle contraction . The familial hypertrophic cardiomyopathy mutation \\u03b1Tm E180G enhances Ca(2+)-sensitivity in functional assays . To investigate the molecular basis , we imaged single molecules of human cardiac \\u03b1Tm E180G by direct probe atomic force microscopy . Analyses of tangent angles along molecular contours yielded persistence length corresponding to increase in flexibility compared to wild-type . Increased flexibility of the mutant was confirmed by fitting end-to-end length distributions to the worm-like chain model . This marked increase in flexibility can significantly impact systolic and possibly diastolic phases of cardiac contraction , ultimately leading to hypertrophy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22958892"}
{"sentence": "The \u03b22-adrenergic receptor ( \u03b22AR ) mediates the effects of chronic stress in several neoplasms , however , \u03b22AR signaling is impaired by hypoxia in various tissues . While hypoxia is a common feature significant in the progression of solid tumors , little is known about the effect of hypoxia on \u03b22AR signaling in the tumor microenvironment . Previously , it has been reported that the systemic administration of mesenchymal stem cells ( MSCs ) increased the engraftment and metastatic colonization of rat osteosarcoma ( OS ) cells . In the current study , the effect of MSCs on the hypoxia-induced desensitization of the \u03b22AR in OS cells was investigated . Epinephrine , norepinephrine and isoproterenol increased the cellular proliferation of the rat OS cell line COS1NR and rat MSCs in a dose-dependent and \u03b22AR antagonist-sensitive manner . While isoproterenol had significant proliferative effects on MSCs under normoxic and hypoxic conditions , COS1NR cells did not respond under hypoxic conditions . A sensitivity assay for the \u03b22AR revealed that hypoxia impaired the sensitivity of COS1NR cells , whereas hypoxia did not affect MSCs . An immunoassay revealed no significant change in the expression of hypoxia-inducible factor-1\u03b1 ( HIF1\u03b1 ) in COS1NR cells , whilst an immunoassay demonstrated a 15% increase in MSCs following isoproterenol stimulation . In COS1NR cells co-cultured with MSCs under hypoxic conditions , isoproterenol caused a significant increase in proliferation and this effect was inhibited by an anti-interleukin ( IL)-6 antibody . A tumor formation assay in syngeneic rats revealed that the systemic administration of MSCs enhances the growth of OS and the effect of MSCs was inhibited by IL-6 neutralization . In conclusion , MSCs are resistant to the hypoxia-induced desensitization to \u03b22AR . Hypoxia caused a siginificant desensitization of the \u03b22AR in COS1NR cells alone , whereas MSCs may support tumor progression through cellular interactions .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23205094"}
{"sentence": "We previously found that cancer metastasis is accelerated by immunosuppression during Snail-induced epithelial-to-mesenchymal transition ( EMT ) . However , the molecular mechanism still remained unclear . Here , we demonstrate that CCL2 is a critical determinant for both tumor metastasis and immunosuppression induced by Snail(+) tumor cells . CCL2 is significantly upregulated in various human tumor cells accompanied by Snail expression induced by snail transduction or TGF\u03b2 treatment . The Snail(+) tumor-derived CCL2 amplifies EMT events in other cells including Snail(-) tumor cells and epithelial cells within tumor microenvironment . CCL2 secondarily induces Lipocalin 2 ( LCN2 ) in the Snail(+) tumor cells in an autocrine manner . CCL2 and LCN2 cooperatively generate immunoregulatory dendritic cells ( DCreg ) having suppressive activity accompanied by lowered expression of costimulatory molecules such as HLA-DR but increased expression of immunosuppressive molecules such as PD-L1 in human PBMCs . The CCL2/LCN2-induced DCreg cells subsequently induce immunosuppressive CD4(+)FOXP3(+) Treg cells , and finally impair tumor-specific CTL induction . In murine established tumor model , however , CCL2 blockade utilizing the specific siRNA or neutralizing mAb significantly inhibits Snail(+) tumor growth and metastasis following systemic induction of anti-tumor immune responses in host . These results suggest that CCL2 is more than a chemoattractant factor that is the significant effector molecule responsible for immune evasion of Snail(+) tumor cells . CCL2 would be an attractive target for treatment to eliminate cancer cells via amelioration of tumor metastasis and immunosuppression .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23143679"}
{"sentence": "This study examined the possible role of p120ctn in the pathogenesis and development of pancreatic cancer . PANC-1 cells , a kind of human pancreatic carcinoma cell line , were cultured in this study. p120ctn was immunocytochemically detected in PANC-1 cells . The recombinant lentivirus vector was constructed to knock down the p120ctn expression of PANC-1 cells . Real-time quantitative PCR ( RQ-PCR ) and Western blotting were used to determine the expression of p120ctn and E-cadherin in PANC-1 cells after p120ctn knockdown . The adhesion , invasion and migration capacity of PANC-1 cells after p120ctn knockdown was detected by cell adhesion , invasion and migration assays . Cell growth was measured by the MTT method . Cell cycle and apoptosis were analyzed by fluorescence-activated cell sorting . The results showed that p120ctn knockdown led to significantly down-regulated E-cadherin and a reduced cell-to-cell adhesion ability in PANC-1 cells. shRNA-mediated knockdown of p120ctn reduced invasion and migration capacity of PANC-1 cells , inhibited cell growth , caused a significant decrease in the percentage of cells in G(1) , an increase in S , and promoted apoptosis of PANC-1 cells . It was concluded that p120ctn plays a pivotal role in the proliferation and metastasis of pancreatic carcinoma , suggesting that p120ctn is a novel target for pancreatic carcinoma treatment .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23073801"}
{"sentence": "Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 ( CYP2E1 ) , which is associated with hepatocarcinogenesis . We investigated whether treatment with chlormethiazole ( CMZ ) , a CYP2E1 inhibitor , protects against alcohol-associated hepatic carcinogenesis in rats . Rats were fed either an ethanol liquid diet or a non-ethanol liquid diet , with or without CMZ for one and ten months . A single intraperitoneal injection of diethylnitrosamine ( DEN , 20 mg/kg ) was given to initiate hepatic carcinogenesis . CYP2E1 expression , inflammatory proteins , cell proliferation , protein-bound 4-HNE , etheno-DNA adducts , 8-hydroxy-2'-deoxyguanosine ( 8-OHdG ) , retinoid concentrations , and hepatic carcinogenesis were examined . Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levels and increased nuclear accumulation of NF-\\u03baB protein and TNF-\\u03b1 expression , which were associated with increased cyclin D1 expression and p-GST positive altered hepatic foci . All of these changes induced by ethanol feeding were significantly inhibited by the one month CMZ treatment . At 10-months of treatment , hepatocellular adenomas were detected in ethanol-fed rats only , but neither in control rats nor in animals receiving ethanol and CMZ . The 8-OHdG formation was found to be significantly increased in ethanol fed animals and normalized with CMZ treatment . In addition , alcohol-reduced hepatic retinol and retinoic acid concentrations were restored by CMZ treatment to normal levels in the rats at 10 months of treatment . These data demonstrate that the inhibition of ethanol-induced CYP2E1 as a key pathogenic factor can counteract the tumor-promoting action of ethanol by decreasing TNF-\\u03b1 expression , NF-\\u03baB activation , and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23543859"}
{"sentence": "BACKGROUND Folate ( vitamin B9 ) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate ( dTMP ) and s-adenosylmethionine ( AdoMet ) . The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance , but still unclear . We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis , which is prominent in prostate cells . We , therefore , hypothesized that prostate cells might be highly susceptible to genetic , epigenetic and phenotypic changes consequent to folate restriction . RESULTS We studied the consequences of long-term , mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate ( TRAMP ) model , recapitulating different stages of prostate cancer ; benign , transformed and metastatic . High-performance liquid chromatography analysis demonstrated that mild folate depletion ( 100 nM ) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines . Random oligonucleotide-primed synthesis ( ROPS ) revealed a significant increase in uracil misincorporation and DNA single strand breaks , while spectral karyotype analysis ( SKY ) identified five novel chromosomal rearrangements in cells grown with mild folate depletion . Using global approaches , we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine , indicating a broad effect of folate depletion on epigenetic regulation . These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion . CONCLUSIONS This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological amounts of folate ( 2 microM ) routinely used in tissue culture . In addition , we elucidate for the first time the contribution of these aspects to consequent phenotype changes in epithelial cells . These results provide a strong rationale for studying the effects of folate manipulation on the prostate in vivo , where cells might be more sensitive to changes in folate status resulting from folate supplementation or antifolate therapeutic approaches .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20092614"}
{"sentence": "Neuroblastoma ( NB ) , a common pediatric neoplasm , consists of two main cell populations : neuroblastic/ganglionic cells and Schwann cells . NB tumors with abundant Schwannian stroma display a more benign clinical behavior than stroma-poor tumors . Recent studies suggest that Schwann cells influence NB tumor growth via secreted factors that induce differentiation , suppress proliferation , and inhibit angiogenesis . Two angiogenesis inhibitors , pigment epithelium-derived factor and tissue inhibitor of metalloproteinase-2 , have been detected in Schwann cell secretions . Here , we isolated another Schwann cell-derived secreted inhibitor of angiogenesis , a 43-kDa protein identified as SPARC ( secreted protein acidic and rich in cysteine ) , an extracellular matrix protein . We found SPARC to be critical for the antiangiogenic phenotype of cultured Schwann cells . We also show that purified SPARC potently inhibits angiogenesis and significantly impairs NB tumor growth in vivo . SPARC may be an effective candidate for the treatment of children with clinically aggressive , Schwannian stroma-poor NB tumors .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12499280"}
{"sentence": "BACKGROUND The effect of chronic high altitude hypoxia ( CHAH ) in the juxta-alveolar region near the air-blood interface is unknown because of the experimental inaccessibility of this region . OBJECTIVE To examine primary cultures of digested juxta-alveolar smooth muscle cells for hypoxia-induced changes . METHODS Smooth Muscle Cells ( SMCs ) obtained by dispase digestion of the extreme lung parenchyma were used to study the effect of CHAH in the juxta-alveolar region and foetal and maternal cells were compared . Pulmonary venous SMCs were also obtained from dissected 5th to 7th generation levels pulmonary veins ( <0.5 mm ) . Fluorescence tagged antibodies against alpha smooth muscle actin ( alpha SMA ) and calponin respectively were used as markers to identify cellular structural differences by routine immunohistochemistry . Comparison of the functional integrity of the cells was made using their growth profiles obtained by radiolabeled thymidine incorporation and liquid scintillation counting . RESULTS Marked differences were seen in juxta-alveolar SMCs obtained by digestion of extreme lung parenchyma of hypoxic sheep . Hypoxic adult sheep cells showed increased filamentation . Hypoxic foetal sheep cells showed internal restructuring and disorganization of both alpha-SMA and calponin filaments . The growth profiles of juxta-alveolar SMCs showed that the hypoxia-affected cells of both the foetus and adult sheep had a fast initial growth rate peaking at 48h while their normoxic equivalents had a steadier growth rate peaking at 72h . Hypoxia-affected cells showed contact inhibition at subconfluence and apoptosis by 48h . CONCLUSION Chronic high altitude hypoxia causes both phenotypical and functional changes in pulmonary smooth muscle cells near the air/blood interface .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21465446"}
{"sentence": "Prostate cancer ( PCA ) is the most common invasive malignancy and the second leading cause of cancer-related death in males . The present study investigated the effects of fangchinoline ( Fan ) , an important compound in Stephania Tetradra S. Moore ( Fenfangji ) with pain-relieving , blood pressure-depressing , and antibiotic activities , on human PCA . It was found that Fan inhibited human prostate cancer cell lines ( PC3 ) cell proliferation in a dose- and time-dependent manner . Studies of cell-cycle progression showed that the anti-proliferative effect of Fan was associated with an increase in the G1/S phase of PC3 cells . Western blot results indicated that Fan-induced G1/S phase arrest was mediated through inhibition of cyclin-regulated signaling pathways . Fan induced p27 expression and inhibited cyclin D and proliferating cell nuclear antigen ( PCNA ) expression in PC3 cells . Increased exposure time to Fan caused apoptosis of PC3 cells , which was associated with up-regulation of pro-apoptotic proteins Bax and caspase 3 , and down-regulation of anti-apoptotic protein Bcl-2 . Furthermore , Fan had anti-tumorigenic activity in vivo , including reduction of tumor volume and pro-apoptotic and anti-proliferative effects in a PC3 nude mouse xenograft . Taking all this together , it can be concluded that Fan is an effective anti-proliferative agent that modulates cell growth regulators in prostate cancer cells .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20208355"}
{"sentence": "The CD4+CD25+ regulatory T cell ( Treg ) is a special kind of T cell subset . Studies have showed that Treg cells are involved in a number of physiological processes and pathologic conditions such as autoimmune diseases , transplantation tolerance and cancer . Tregs with unique capacity for immune inhibition can impair anti-tumour immunity and help tumor cells to escape from immune surveillance . The aim of our study was to investigate whether Tregs are involved in hepatocellular carcinoma ( HCC ) . A BABL/C mouse with HCC in situ model was established to evaluate the Treg existence in carcinoma tissues and the changes of Tregs in spleen using flow cytometry and immunohistochemistry methods . Granzyme B expression in carcinoma tissues was analyzed by immunohistochemistry to investigate the tumor local immune status . The proportion of CD4+CD25+/CD4+ spleen lymphocytes of tumor bearing mice ( 18.8% \ufffd 1.26% ) was found to be significantly higher than that in normal mice ( 9.99% \ufffd 1.90% ) ( P<0.01 ) . Immunohistochemistry of spleen tissue also confirmed that there was an increase in Treg in tumor-bearing mice , while in carcinomas it showed Treg cells to be present in tumor infiltrating lymphocyte areas while Granzyme B was rarely observed . Anti-tumour immunity was suppressed , and this might be associated with the increase of Tregs . Our observations suggest that the CD4+CD25+Treg/ CD4+ proportion in spleen lymphocytes can be a sensitive index to evaluate the change of Tregs in hepatocellular carcinoma mice and the Treg may be a promising therapeutic target for cancer .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23098476"}
{"sentence": "NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas . Despite the substantial efforts done to develop potent NK1 receptor antagonists , none of these antagonists had shown good antitumor activity in clinical trials . Now , we have tested the effect of inhibition of the neuropeptide Substance P ( SP ) , a NK1 ligand , as a potential therapeutic approach in cancer . We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast , colon , and prostate cancer cell lines . These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway . Interestingly , in some cell lines SP abrogation decreased the steady state of Her2 and EGFR , suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors . In consequence , we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR . SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2 , suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies . Thus , we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors , based in the immuno-blockade of the neuropeptide SP .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21604273"}
{"sentence": "It is well established that angiogenesis is the process of formation of new capillaries from pre-existing blood vessels . It is a complex process , involving both pro- and anti-angiogenic factors , and plays a significant role in physiological and pathophysiological processes such as embryonic development , atherosclerosis , post-ischemic vascularization of the myocardium , tumor growth and metastasis , rheumatoid arthritis etc . This is the first report of zinc oxide ( ZnO ) nanoflowers that show significant pro-angiogenic properties ( formation of new capillaries from pre-existing blood vessels ) , observed by in vitro and in vivo angiogenesis assays . The egg yolk angiogenesis assay using ZnO nanoflowers indicates the presence of matured blood vessels formation . Additionally , it helps to promote endothelial cell ( EA.hy926 cells ) migration in wound healing assays . Formation of reactive oxygen species ( ROS ) , especially hydrogen peroxide ( H(2)O(2))-a redox signaling molecule , might be the plausible mechanism for nanoflower-based angiogenesis . Angiogenesis by nanoflowers may provide the basis for the future development of new alternative therapeutic treatment strategies for cardiovascular and ischemic diseases , where angiogenesis plays a significant role .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23152079"}
{"sentence": "Bcl-2/E1B 19-kDa interacting protein 3 ( BNIP3 ) is a proapoptotic protein whose expression level is often low in colorectal cancer ( CRC ) cells due to the BNIP3 gene promoter DNA methylation by DNA methyltransferase ( DNMT ) . It is known that chemotherapy and radiotherapy suppress CRC through inducing tumor apoptosis . However , the molecular mechanisms underlying chemotherapy and radiotherapy-induced apoptosis of CRC cells are not well defined . In this study , we observed that the expression level of BNIP3 in colon cancer cells was significantly increased by treatment with therapeutic agents and radiation in vitro . The BNIP3 protein level in CRC tissues from patients who received preoperative concurrent chemotherapy was significantly higher than in those who received surgery alone . Furthermore , treatment with chemotherapeutic agents and radiation significantly decreased the DNMT1 expression level and enzymatic activity . Both expression level and activity of DNMT1 were inversely correlated with the expression level of BNIP3 in colon carcinoma cells after treatment with chemotherapeutic agents and radiation . Consistent with increased BNIP3 expression , chemotherapeutic agents and radiation induced colon carcinoma cell apoptosis in a dose-dependent manner . Based on these observations , we conclude that chemotherapy and radiotherapy inhibit DNMT1 expression to upregulate BNIP3 expression to promote CRC cell apoptosis . And , BNIP3 may play a role in the caspase-dependent apoptosis pathways , mainly during treatment with chemotherapy and radiotherapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23364257"}
{"sentence": "The induction of apoptosis by glucocorticoids in isolated thymocytes has been studied extensively . However , it is not known whether or not the same changes occur after in vivo glucocorticoid treatment . In order to investigate this , we have studied the changes occurring in thymocytes isolated from rats , from 2-24 hr after a dose of dexamethasone ( 1 mg/kg ) , which caused 50% thymic atrophy . Thymocytes were separated into four fractions by isopycnic Percoll gradients . A loss of cells occurred within 2-8 hr , primarily in only one of the two major fractions of normal thymocytes . This loss of normal thymocytes coincided with the appearance of small dense cells with characteristic features of apoptosis including condensed chromatin , increased DNA fragmentation , internucleosomal DNA cleavage and a \" hypodiploid \" peak on flow cytometric analysis . Striking differences occurred in the cellular composition of the different Percoll fractions with time . Initially ( up to 4 hr ) , the pattern of changes occurring in vivo resembled those found in vitro . However , at later times , the complex fate of apoptotic cells in vivo , such as phagocytosis , are not observed in the in vitro studies .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1472078"}
{"sentence": "OBJECT The intracellular events transducing mitogenic signals from platelet-derived growth factor-beta ( PDGFbeta ) receptor tyrosine kinases are not precisely known . In this study the authors evaluated whether the phosphatidylinositol 3-kinase ( PI3-K)-Akt-p70S6K pathway is expressed in meningiomas , regulates their growth , and transduces mitogenic signals of PDGF-BB . METHODS Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated ( activated ) Akt and phosphorylated p70S6K . Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K . The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases . In addition , the effects of wortmannin , an inhibitor of P13-K , on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated . Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K . Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture . Wortmannin ( 500 and 1000 nM ) significantly decreased PDGF-BB stimulation of meningioma cells ( p < 0.001 ) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal-regulated kinase ( MAPK/ERK ) phosphorylation . CONCLUSIONS These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K-Akt-p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1-MEK-1-MAPK/ERK cascade .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12296652"}
{"sentence": "PURPOSE We did this retrospective study to explore the association between epidermal growth factor receptor ( EGFR ) mutation and clinical features in postoperative recurrent female non-small-cell lung cancer ( NSCLC ) . MATERIALS AND METHODS We reviewed clinical data on 86 female patients who had postoperative recurrent disease between December 1992 and July 2007 . The start of tyrosine kinase inhibitor therapy was treated as a censoring event . Corresponding surgical specimens of primary tumors were used to test for EGFR mutations . RESULTS Thirty patients presented with local recurrence and distant recurrence was identified in 56 . Thirty-four of the 86 patients ( 40% ) harbored EGFR mutations . Patients with distant recurrence were more likely to have EGFR mutations than patients with local recurrence ( 48% versus 23% ; P = 0.024 ) . On multivariate analysis , distant recurrence was associated with a high frequency of EGFR mutations ( OR , 3.3 ; P = 0.028 ) . Survival analysis showed poor survival of patients with mutated EGFR ( HR , 2.3 ; P = 0.017 ) or with non-adenocarcinoma histology ( HR , 3.3 ; P = 0.001 ) . CONCLUSION The association between recurrence pattern and EGFR mutation status was suggested in recurrent female NSCLC patients . In addition , our data indicate unfavorable disease process of EGFR mutated tumors . Further studies need to be conducted to validate these findings .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "23174717"}
{"sentence": "A 33-year-old man presented with pain and palsy of the leg in 2008 for treatment of hepatocellular carcinoma with huge distant metastases . The patient's tumors had slowly enlarged despite several treatments . Oral administration of sorafenib at 800 mg/day with careful observation was commenced in 2009 . Laboratory investigations on day 7 showed massive tumor lysis . An abdominal CT showed multiple low density areas and tumor markers decreased , indicating extended tumor necrosis . In conclusion , clinicians should bear in mind not only the published adverse effects , but also massive tumor lysis , when treating patients with large tumor burden by sorafenib .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20519814"}
{"sentence": "OBJECTIVE To analyze histological factors not routinely assessed as potential prognostic factors in renal cell carcinoma , such as tumor necrosis , microscopic vascular invasion , and sinus fat invasion . MATERIALS AND METHODS A retrospective , analytical study was conducted of surgical specimens from 139 patients with localized renal cell carcinoma who underwent nephrectomy from 1993 to 2005 . Tumor necrosis , microscopic vascular invasion , and sinus fat invasion were analyzed and compared to the classical factors : TNM classification , Fuhrman grade , and tumor size . For statistical analysis , variables analyzed were categorized as pT1 , 2 vs pT3 , 4 ; Fuhrman grade 1 , 2 vs 3 , 4 ; tumor size < 7 cm vs >or= 7cm ; tumor necrosis vs no tumor necrosis ; microvascular invasion of sinus fat vs no invasion . Cancer-specific survival probability and disease-free survival were calculated . A descriptive and analytical statistical analysis was performed using logistic regression for univariate and multivariate analyses . Dependent variables were used to analyze cancer-specific survival rates . Disease-free survival was estimated using a Cox regression model and Kaplan-Meier curves . RESULTS In the univariate analysis , all variables analyzed had a significant influence on death for renal cell carcinoma . In the multivariate analysis , the variable having the greatest influence was Fuhrman grade ( p = 0,032 ) . The variables significantly influencing disease-free survival , estimated by the Cox method , were the pT stage ( p = 0.038 ) and Fuhrman grade ( p = 0.048 ) . CONCLUSIONS In patients with clinically localized renal cell carcinoma undergoing nephrectomy , pT stage and Fuhrman grade are the most important prognostic factors for survival and disease-free survival . Tumor necrosis , microscopic vascular invasion , and sinus fat invasion are prognostic factors for death from renal carcinoma which are associated to TNM classification , Fuhrman grade , and tumor size .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20223135"}
{"sentence": "INTRODUCTION A subpopulation of cancer cells , tumor-initiating cells , is believed to be the driving force behind tumorigenesis and resistance to radiation and chemotherapy . The persistence of tumor-initiating cells may depend on altered regulation of DNA damage and checkpoint proteins , as well as a reduced propensity to undergo apoptosis or senescence . METHODS To test this hypothesis , we isolated CD24-/low/CD44+ tumor-initiating cells ( as mammospheres ) from MCF-7 breast cancer cells grown in adherent monolayer culture , and carried out a comprehensive comparison of cell death and DNA damage response pathways prior to and after exposure to ionizing radiation in mammospheres and monolayer MCF-7 cells . Single and double-strand break repair was measured by single-cell gel electrophoresis . The latter was also examined by phosphorylation of histone H2AX and formation of 53BP1 and Rad51 foci . Apoptosis was quantified by flow-cytometric analysis of annexin V-binding and senescence was analyzed on the basis of cellular beta-galactosidase activity . We employed the telomeric repeat amplification protocol to quantify telomerase activity . Expression of key DNA repair and cell cycle regulatory proteins was detected and quantified by western blot analysis . RESULTS Our data demonstrate that in comparison to the bulk population of MCF-7 cells ( predominantly CD24+/CD44+ ) , the MCF-7 mammosphere cells benefit from a multifaceted approach to cellular protection relative to that seen in monolayer cells , including a reduced level of reactive oxygen species , a more active DNA single-strand break repair ( SSBR ) pathway , possibly due to a higher level of expression of the key SSBR protein , human AP endonuclease 1 ( Ape1 ) , and a significantly reduced propensity to undergo senescence as a result of increased telomerase activity and a low level of p21 protein expression . No significant difference was seen in the rates of double-strand break repair ( DSBR ) between the two cell types , but DSBR in mammospheres appears to by-pass the need for H2AX phosphorylation . CONCLUSIONS Enhanced survival of MCF-7 tumor-initiating cells in response to ionizing radiation is primarily dependent on an inherent down-regulation of the senescence pathway . Since MCF-7 cells are representative of cancer cells that do not readily undergo apoptosis , consideration of senescence pathways may play a role in targeting stem cells from such tumors .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "20525204"}
{"sentence": "Tea ( Camellia sinensis ) is one of the most popular beverages , consumed worldwide . The health promoting properties of tea have been attributed to its antioxidative polyphenolic constituents and their oxidative products . The aim of the present study was to evaluate the chemopreventive efficacy of a black tea infusion on azoxymethane induced colonic preneoplastic lesions , the aberrant crypt foci in Sprague-Dawley rats . Rats were injected with azoxymethane ( 15mg/kg.b.w. ) and received oral administration of 1% and 2% ( w/v ) tea infusions from the 1(st)day of carcinogen application . The treatment was continued for 12 weeks . The colons were then assessed for aberrant crypt foci and compared with the untreated carcinogen control group . In situ cell proliferation and in situ apoptosis were also estimated using Brdu incorporation and the TUNEL method , respectively . Aberrant crypt foci were reduced significantly ( by 44% in the 1% tea-treated and by about 40% in 2% tea-treated group ) . Significant decrease in proliferation and increase in apoptosis suggest a possible interplay between the two processes resulting in inhibition of colon carcinogenesis by black tea .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12718607"}
{"sentence": "The metastasis-associated lung adenocarcinoma transcript 1 , MALAT1 , is a long non-coding RNA ( lncRNA ) that has been discovered as a marker for lung cancer metastasis . It is highly abundant , its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes , and it is associated with many RNA binding proteins and highly conserved throughout evolution . The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation , apoptosis , migration and invasion . Here , we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA . In human tumor cells , MALAT1 expression was abrogated using Zinc Finger Nucleases . Unexpectedly , the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells . Moreover , genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals . Thus , loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22858678"}
{"sentence": "Radiotherapy is a useful component of treatment strategies for esophageal cancer . The role of autophagy in response to ionizing radiation was investigated in human esophageal squamous carcinoma cells . Cell viability and clonogenic survival assay were used to evaluate the radiosensitivity of autophagy inhibitor ( 3-MA ) on esophageal squamous carcinoma cells . The percentage of apoptotic cells and cell cycle analysis were assessed by flow cytometry ; DAPI staining was used to detect apoptotic cells . The expression of beclin-1 and LC3 was measured using a Western blot . The ultrastructural analysis was under the electron microscope. 6\u2003Gy irradiation induced a massive accumulation of autophagosomes accompanied by strong upregulation of beclin-1 and LC3-II expression in TE-1 cells . Compared with radiation alone , 3-MA combined with radiation significantly decreased cell viability , as well as autophagic ratio , beclin-1 , and LC3-II protein level . Inhibition of autophagy increased radiation-induced apoptosis and the percentage of G2/M-phase cells . Blockade of autophagy with 3-MA enhanced cytotoxicity of radiotherapy in human esophageal squamous carcinoma cells . It suggests that inhibition of autophagy could be used as adjuvant therapy to treat esophageal squamous cell carcinoma .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21166739"}
{"sentence": "Recent research has shown that the Na(+)/K(+)-ATPase alpha1 subunit is a novel anti-cancer target , which plays pivotal roles in malignant cell ion transport , metabolism , migration and signal transduction . The purpose of the present study was to investigate the anti-cancer effects of ouabain and Na(+)/K(+)-ATPase alpha1 small interfering ribonucleic acid ( siRNA ) on HepG2 cell proliferation , apoptosis and cell cycle , and to explore the molecular mechanisms . The expression of Na(+)/K(+)-ATPase alpha1 subunit in human hepatocellular carcinoma ( HCC ) , normal liver tissues and human HCC line ( HepG2 , SMMC-7721 and Bel-7402 ) has been investigated . Using the ouabain and Na(+)/K(+)-ATPase alpha1 subunit siRNA , which target the Na(+)/K(+)-ATPase , we have evaluated the effects of inhibiting Na(+)/K(+)-ATPase alpha1 in human HepG2 cells with respect to cell proliferation , morphology , cell cycle , impact on intracellular Ca2++ , reactive oxygen species ( ROS ) concentration , and correlated gene expression level on messenger ribonucleic acid ( mRNA ) and protein . Our data showed that the expression Na(+)/K(+)-ATPase alpha1 subunit in HCC tissues is higher than that in normal liver tissues . Ouabain and Na(+)/K(+)-ATPase alpha1 siRNA could inhibit HepG2 cell proliferation . Ouabain could induce HepG2 cell apoptosis and generate S phase arrest , and siRNA could enhance the anti-cancer effect of ouabain that induced HepG2 cells apoptosis via an intracellular Ca(2+) and ROS increase-mediated , and generated cell cycle S phase arresting by decreasing the CyclinA1/cyclin-dependent kinase 2 ( CDK2)/proliferating cell nuclear antigen ( PCNA ) complex product and increasing the expression of cyclin-dependent kinase inhibitor 1A ( P21(CIP1) ) . We believe that targeting of the Na(+)/K(+)-ATPase alpha1 subunit in human HCC cells could provide new sight into the treatment of HCC .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20460749"}
{"sentence": "Multiple myeloma ( MM ) is a clonal disease of plasma cells that remains incurable despite the advent of several novel therapeutics . In this study , we aimed to delineate the impact of snake venom extracted from Walterinnesia aegyptia ( WEV ) alone or in combination with silica nanoparticles ( WEV+NP ) on primary MM cells isolated from patients diagnosed with MM as well as on two MM cell lines , U266 and RPMI 8226 . The IC(50) values of WEV and WEV+NP that significantly decreased MM cell viability without affecting the viability of normal peripheral mononuclear cells ( PBMCs ) were determined to be 25 ng/ml and 10 ng/ml , respectively . Although both WEV ( 25 ng/ml ) and WEV+NP ( 10 ng/ml ) decreased the CD54 surface expression without affecting the expression of CXCR4 ( CXCL12 receptor ) on MM cells , they significantly reduced the ability of CXC chemokine ligand 12 ( CXCL12 ) to induce actin cytoskeleton rearrangement and the subsequent reduction in chemotaxis . It has been established that the binding of CXCL12 to its receptor CXCR4 activates multiple intracellular signal transduction pathways that regulate MM cell chemotaxis , adhesion , and proliferation . We found that WEV and WEV+NP clearly decreased the CXCL12/CXCR4-mediated activation of AKT , ERK , NF\u03baB and Rho-A using western blot analysis ; abrogated the CXCL12-mediated proliferation of MM cells using the CFSE assay ; and induced apoptosis in MM cell as determined by PI/annexin V double staining followed by flow cytometry analysis . Monitoring the expression of B-cell CCL/Lymphoma 2 ( Bcl-2 ) family members and their role in apoptosis induction after treatment with WEV or WEV+NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2 , Bcl(XL) and Mcl-1 ; conversely increased the expression of the pro-apoptotic effectors Bak , Bax and Bim ; and altered the mitochondrial membrane potential in MM cells . Taken together , our data reveal the biological effects of WEV and WEV+NP and the underlying mechanisms against myeloma cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23251606"}
{"sentence": "The aim of this study was to determine whether caffeine enhanced radiosensitivity of normal liver tissue in a rat radiation-induced liver disease model . Buffalo rat McA-RH7777 hepatocellular cancer cells and BRL3A normal liver cells were irradiated , and cell cycle distribution and apoptosis rates were analyzed . A rat model of radiation-induced liver disease was established , rats were randomized into four groups : control ; caffeine alone ; irradiation ( IR ) alone ; and caffeine plus IR ( Caff + IR ) group . Apoptosis rates in normal rat liver tissue after IR were evaluated by TUNEL staining and caspase-3 Western blot . Transaminase activity was measured and histopathological examination was done after IR . Caffeine abrogated IR-induced G2 phase arrest ( Caff + IR vs. IR : 40.9 \u00b1 4.0 vs. 60.7 \u00b1 5.5% , at 12 h after IR ) and increased apoptosis rates ( Caff + IR vs. IR : 56.1 \u00b1 6.8 vs. 35.5 \u00b1 4.0% , at 72 h after IR ) in McA-RH7777 cells , but did not affect IR-induced G2 phase arrest and apoptosis rates at any time point after IR in BRL3A cells . Caffeine did not enhance apoptosis , transaminase activity , or histopathological injury of normal rat liver tissue at any time points after IR . This study suggests that caffeine might not enhance radiosensitivity of normal liver tissue in vivo . In an earlier study , we reported that caffeine enhanced radiosensitivity of human hepatocellular cancer in a nude mice model . Together , these results offer feasibility of clinical application .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "21116849"}
{"sentence": "Cell invasion is required for neoplastic metastasis . Matrix metalloproteinase-9 ( MMP-9 ) , which degrades the extracellular matrix , is a major component in the process of cancer cell invasion . Sulfuretin is one of the major flavonoids isolated from Rhus verniciflua . Sulfuretin has been used to reduce oxidative stress , platelet aggregation , the inflammatory response and mutagenesis . However , the effect of sulfuretin on breast cancer metastasis is unknown . In this study , we investigated the inhibitory effect of sulfuretin on 12-O-tetradecanoylphorbol-13-acetate ( TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells . Sulfuretin inhibited TPA-induced transcriptional activation of nuclear factor-\\u03baB ( NF-\\u03baB ) . We demonstrated that sulfuretin mediated the inhibition of TPA-induced MMP-9 expression and that cell invasion in MCF-7 cells involved suppression of the NF-\\u03baB pathway . Therefore , inhibiting MMP-9 expression by sulfuretin may have therapeutic potential for controlling breast cancer invasiveness .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23292685"}
{"sentence": "Human podoplanin is a type-1 transmembrane sialomucin-like glycoprotein that is involved in cell migration , tumor cell invasion and metastasis . Our recent study of oral squamous cell carcinoma ( OSCC ) demonstrated that the degree of immunohistochemical expression of podoplanin was correlated with the severity of epithelial dysplasia and significantly associated with a poor pathologic grade of differentiation . Furthermore , it has been reported that Src directly associates with the epidermal growth factor receptor ( EGFR ) in OSCC cells upon stimulation with EGF and phosphorylates Crk-associated substrate ( Cas ) , podoplanin acting downstream of Src and Cas to promote cell migration . However , the molecular function of podoplanin remains unclear . In this study we performed real-time RT-PCR , Western blotting and scratch assay using OSCC cell lines in order to clarify the molecular biological function of podoplanin expression associated with various growth factors including EGF and with the Src-Cas signaling pathway . Podoplanin was found to have a marked influence on cancer cell migration and the expression of matrix metalloprotease-9 ( MMP-9 ) in the oral cavity upon stimulation with EGF . Podoplanin promotes oral cancer cell migration , and the EGF-Src-Cas pathway is one of the possible mechanisms responsible for progression of cancer in the oral cavity .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23047035"}
{"sentence": "Hypoxia has long been linked to the Warburg effect , yet the underlying mechanism remains largely unclear . It is also not known if lncRNAs are involved in the contribution of hypoxia to the Warburg effect . Here we show that lincRNA-p21 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis . Hypoxia/HIF-1\\u03b1-induced lincRNA-p21 is able to bind HIF-1\\u03b1 and VHL and thus disrupts the VHL-HIF-1\\u03b1 interaction . This disassociation attenuates VHL-mediated HIF-1\\u03b1 ubiquitination and causes HIF-1\\u03b1 accumulation . These data indicate the existence of a positive feedback loop between HIF-1\\u03b1 and lincRNA-p21 that promotes glycolysis under hypoxia . The ability of lincRNA-p21 to promote tumor growth is validated in mouse xenograft models . Together , these findings suggest that lincRNA-p21 is an important player in the regulation of the Warburg effect and also implicate lincRNA-p21 as a valuable therapeutic target for cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24316222"}
{"sentence": "BRIT1 protein ( also known as MCPH1 ) contains 3 BRCT domains which are conserved in BRCA1 , BRCA2 , and other important molecules involved in DNA damage signaling , DNA repair , and tumor suppression . BRIT1 mutations or aberrant expression are found in primary microcephaly patients as well as in cancer patients . Recent in vitro studies suggest that BRIT1/MCPH1 functions as a novel key regulator in the DNA damage response pathways . To investigate its physiological role and dissect the underlying mechanisms , we generated BRIT1(-/-) mice and identified its essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability . Both BRIT1(-/-) mice and mouse embryonic fibroblasts ( MEFs ) were hypersensitive to gamma-irradiation . BRIT1(-/-) MEFs and T lymphocytes exhibited severe chromatid breaks and reduced RAD51 foci formation after irradiation . Notably , BRIT1(-/-) mice were infertile and meiotic homologous recombination was impaired . BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis , and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis . In mutant spermatocytes , DNA double-strand breaks ( DSBs ) were formed , but localization of RAD51 or BRCA2 to meiotic chromosomes was severely impaired . In addition , we found that BRIT1 could bind to RAD51/BRCA2 complexes and that , in the absence of BRIT1 , recruitment of RAD51 and BRCA2 to chromatin was reduced while their protein levels were not altered , indicating that BRIT1 is involved in mediating recruitment of RAD51/BRCA2 to the damage site . Collectively , our BRIT1-null mouse model demonstrates that BRIT1 is essential for maintaining genomic stability in vivo to protect the hosts from both programmed and irradiation-induced DNA damages , and its depletion causes a failure in both mitotic and meiotic recombination DNA repair via impairing RAD51/BRCA2's function and as a result leads to infertility and genomic instability in mice .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20107607"}
{"sentence": "Recent reports provide evidence that some growth factors behave as inhibitors of the apoptosis of the endothelial cells , bringing forward the concept of vascular survival as a post-angiogenesis process . At least two different vasculature development processes occur within a tumor : the angiogenic ( formation of new vessels ) and the vascular survival pathway , which is devoted to the preservation of the newly-formed vessels in layers that lose contact with the adjacent normal tissue . We developed a method to assess these processes in tissue samples . We noted that differences among tumors may exist not only in the tumor angiogenic activity ( TAA ) but also in the vascular survival ability ( VSA ) . One third of the highly angiogenic breast cancer cases examined had a poor ability to maintain high vessel density in inner tumor areas . Both parameters are independently related to prognosis , while VSA was directly related to tumor dimensions and node involvement . Patients with high TAA and VSA had a particularly poor prognosis . It is suggested that although cancer angiogenic activity is important for the local invasion and dissemination into vessels and lymphatics , the VSA may be important for the effective formation of viable tumor foci in lymph nodes or distant organs . Recognition and quantification of the vascular survival ability in human tumors may significantly improve the prognostic value of the assessment of tumor vasculature , and may help to stratify patients for clinical trials with novel anti-angiogenic or angiotoxic drugs . Elucidation of the pathways may provide additional targets for antiangiogenic therapy .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12553372"}
{"sentence": "Cancer cells upregulate glycolysis , increasing glucose uptake to meet energy needs . A small fraction of a cell's glucose enters the hexosamine biosynthetic pathway ( HBP ) , which regulates levels of O-linked beta-N-acetylglucosamine ( O-GlcNAc ) , a carbohydrate posttranslational modification of diverse nuclear and cytosolic proteins . We discovered that breast cancer cells upregulate the HBP , including increased O-GlcNAcation and elevated expression of O-GlcNAc transferase ( OGT ) , which is the enzyme catalyzing the addition of O-GlcNAc to proteins . Reduction of O-GlcNAcation through RNA interference of OGT in breast cancer cells leads to inhibition of tumor growth both in vitro and in vivo and is associated with decreased cell-cycle progression and increased expression of the cell-cycle inhibitor p27(Kip1) . Elevation of p27(Kip1) was associated with decreased expression and activity of the oncogenic transcription factor FoxM1 , a known regulator of p27(Kip1) stability through transcriptional control of Skp2 . Reducing O-GlcNAc levels in breast cancer cells decreased levels of FoxM1 protein and caused a decrease in multiple FoxM1-specific targets , including Skp2 . Moreover , reducing O-GlcNAcation decreased cancer cell invasion and was associated with the downregulation of matrix metalloproteinase-2 , a known FoxM1 target . Finally , pharmacological inhibition of OGT in breast cancer cells had similar anti-growth and anti-invasion effects . These findings identify O-GlcNAc as a novel mechanism through which alterations in glucose metabolism regulate cancer growth and invasion and suggest that OGT may represent novel therapeutic targets for breast cancer .", "label": [0, 0, 1, 0, 1, 0, 0, 0, 0, 0], "id": "20190804"}
{"sentence": "Limited options for the treatment of prostate cancer have spurred the search for new therapies . One innovative approach is the use of targeted alpha therapy ( TAT ) to inhibit cancer growth , using an alpha particle emitting radioisotope such as ( 213)Bi . Because of its short range and high linear energy transfer ( LET ) , alpha-particles may be particularly effective in the treatment of cancer , especially in inhibiting the development of metastatic tumors from micro-metastases . Prostate-specific membrane antigen ( PSMA ) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung , colon , breast and others , but not in normal vascular endothelium . The expression is further increased in higher-grade cancers , metastatic disease and hormone-refractory prostate cancer ( PCA ) . J591 is one of several monoclonal antibodies ( mabs ) to the extracellular domain of PSMA . Chelation of J591 mab with ( 213)Bi forms the alpha-radioimmunoconjugate ( AIC ) . The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice . The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model . Apoptosis was documented using terminal deoxynucleotidyl transferase [ TdT]-mediated deoxyuridinetriphosphate [ dUTP ] nick end-labeling ( TUNEL ) assay , while proliferative index was assessed using the Ki-67 marker . We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line ( LNCaP-LN3 ) and in tumor xenografts from nude mice . We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion , causing the cells to undergo apoptosis . Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth , whereas results for a non-specific AIC were similar to those for untreated mice . Further , after 1 and 3 weeks post-tumor appearance , a single ( 100 microCi/100 microl ) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts ( volume<100 mm(3) ) in nude mice . Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable , while in control mice treated with a non-specific AIC using the same dose , tumor volume increased from 42 to 590 mm(3) . There were no observed side effects of the treatment . Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo , the ( 213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "15195129"}
{"sentence": "Cancer development is associated with genetic instability . Identification of specific loci altered during carcinogenesis in a particular tissue gives scope for early detection and predicting the progressive nature of the tissue pathology . Instability at microsatellite loci is widely attributed to mismatch repair errors due to epigenetic alterations . Using three dinucleotide markers , D3S1313 , D9S171 , D17S250 and two mononucleotide markers BAT25 , BATRII , we evaluated MSI in 97 cases enrolled for endoscopy of upper GI tract with symptoms of dyspepsia , reflux or dysphagia . We aimed at evaluating markers that reflect instability in esophageal malignancies , examine the prevalence of MSI in cancers and other pathologies of the esophagus , and determine the methylation status of hMLH1 gene in relation to MSI. 42% ( 21/50 ) cancers and 15.4%(2/13) precancers exhibited MSI where 85.7% cancers and 50% precancers with MSI , showed a hypermethylated hMLH1 promoter . Increased number of cases with repair gene methylation were seen with increasing severity of the esophageal pathology suggesting epigenetic progression parallels histologic changes . BAT25 and D3S1313 markers exhibited instability frequently and cases with MSI using these markers showed an abnormal hMLH1 promoter . Thus these markers were useful in identifying the mismatch repair phenotype . These two markers may be useful to screen cases for early cancer related changes , after validation on a larger sample .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21045259"}
{"sentence": "Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer . This requires both the identification of angiogenic regulators and their efficient delivery to target organs . Here , we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 ( termed PEX ) delivered by lentiviral vectors in different angiogenesis models . Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro . Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes . PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model . Thus , our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12611083"}
{"sentence": "Programmed cell death 6 ( PDCD6 ) was originally found as a pro-apoptotic protein , but its molecular mechanism is not well understood . In this study , we have attempted to investigate the effects of PDCD6 on the inhibition of angiogenesis-mediated cell growth as a novel anti-angiogenic protein . Purified recombinant human PDCD6 inhibited cell migration in a concentration-time-dependent manner . We also found that overexpressed PDCD6 suppressed vascular endothelial growth factor ( VEGF)-induced proliferation , invasion , and capillary-like structure tube formation in vitro . PDCD6 suppressed phosphorylation of signaling regulators downstream from PI3K , including Akt , mammalian target of rapamycin ( mTOR ) , glycogen synthase kinase-3\u03b2(GSK-3\u03b2) , ribosomal protein S6 kinase ( p70S6K ) , and also decreased cyclin D1 expression . We found binding PDCD6 to VEGFR-2 , a key player in the PI3K/mTOR/P70S6K signaling pathway . Taken together , these data suggest that PDCD6 plays a significant role in modulating cellular angiogenesis .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "21893193"}
{"sentence": "Colon cancer is the third most common malignant neoplasm in the world and it remains an important cause of death , especially in western countries . The toxic environmental pollutant , 1 , 2-dimethylhydrazine ( DMH ) , is also a colon-specific carcinogen . Tannic acid ( TA ) is reported to be effective against various types of chemically induced toxicity and also carcinogenesis . In the present study , we evaluated the chemopreventive efficacy of TA against DMH induced colon toxicity in a rat model . Efficacy of TA against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities , lipid peroxidation , histopathological changes and expression of early molecular markers of inflammation and tumor promotion . DMH treatment induced oxidative stress enzymes ( p<0.001 ) and an early inflammatory and tumor promotion response in the colons of Wistar rats . TA treatment prevented deteriorative effects induced by DMH through a protective mechanism that involved reduction of oxidative stress as well as COX-2 , i-NOS , PCNA protein expression levels and TNF-\u03b1(p<0.001) release . It could be concluded from our results that TA markedly protects against chemically induced colon toxicity and acts plausibly by virtue of its antioxidant , anti-inflammatory and antiproliferative activities .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23167349"}
{"sentence": "Because PRL has growth factor activities in several tissues , we have asked whether it also has autocrine growth factor activity in pituitary GH3 cells . GH3 cells were grown at increasing densities in the presence or absence of antirat PRL ( polyclonal and monoclonal ) or nonspecific antibodies . Cell proliferation increased with increasing cell density , as did the concentration of PRL in the medium . Antirat PRL , but not control antibody , markedly inhibited but did not eliminate cell proliferation , and this effect was diminished with increasing PRL concentration in the medium . PRL receptors were demonstrated on 40-50% of the cells by indirect immunofluorescence using a specific antirat PRL receptor monoclonal antibody . Cell surface PRL was colocalized to the same 40-50% of the cells and copatched or cocapped along with the receptors . Absence or presence of PRL receptors did not correlate with stage of the cell cycle , as judged by ethidium bromide dual labeling . Cell surface PRL was found to be on PRL-containing cells . These data have fulfilled four criteria necessary for establishment of a substance as a secreted autocrine growth factor : 1 ) the factor must be secreted ; 2 ) in log growth phase , increased cell proliferation should occur at increased cell densities ; 3 ) the cells must display a receptor for the factor ; and 4 ) there must be a growth response to the factor . Thus we have established that PRL is an autocrine growth factor for at least 40-50% of the GH3 cell population . This , to our knowledge , is the first example of autocrine growth factor activity of a major hormone normotopically expressed .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1639009"}
{"sentence": "The vacuolar H+-ATPase ( V-ATPase ) , a multisubunit proton pump , has come into focus as an attractive target in cancer invasion . However little is known about the role of V-ATPase in cell death and especially the underlying mechanisms remain mostly unknown . We used the myxobacterial macrolide archazolid B , a potent inhibitor of the V-ATPase , as an experimental drug as well as a chemical tool to decipher V-ATPase related cell death signaling . We found that archazolid induced apoptosis in highly invasive tumor cells at nanomolar concentrations which was executed by the mitochondrial pathway . Prior to apoptosis induction archazolid lead to the activation of a cellular stress response including activation of the hypoxia-inducible factor-1 alpha ( HIF1alpha ) and autophagy . Autophagy was induced at low concentrations of archazolid that do not alter pH in lysosomes and was shown by degradation of p62 or fusion of autophagosomes with lysosomes . HIF1alpha was induced due to energy stress shown by a decline of the ATP level and followed by a shut down of energy consuming processes . As silencing HIF1alpha increases apoptosis , the cellular stress response was suggested to be a survival mechanism . We conclude that archazolid leads to energy stress which activates adaptive mechanisms like autophagy mediated by HIF1alpha and finally leads to apoptosis . We propose V-ATPase as a promising drugable target in cancer therapy caught up at the interplay of apoptosis , autophagy and cellular/metabolic stress .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23168408"}
{"sentence": "Active avoidance by tumor cells from attack and elimination by immune cells is an emerging cancer hallmark that is achieved primarily through decreasing the levels of major histocompatibility complex class I ( MHC-I ) at the cancer cells ' surface . Deficiencies in MHC-I antigen-restricted immunosurveillance may be intertwined with an altered , Warburg-like cancer cell-intrinsic metabolism , another emerging hallmark of cancer that involves a switch from mitochondrial respiration to glycolysis to efficiently support large-scale biosynthetic programs that are required for active cell proliferation . We recently envisioned that intervention strategies aimed at reversing the bioenergetic signature of cancer cells ( e.g. , the antidiabetic biguanide metformin ) should correct oncogene ( e.g. , HER2)-driven MHC-I defects , thus preventing immune escape of oncogene transformants . First , we explored how metformin treatment impacted mitochondrial biogenesis in cultured breast cancer cells overexpressing the membrane tyrosine kinase receptor HER2 , the best-characterized downregulator of MHC-I . Metformin exposure was found to dose-dependently increase the expression levels of cytochrome c oxidase I and mitochondrial succinate dehydrogenase , which are encoded by mitochondrial and nuclear DNA , respectively . Second , we explored whether metformin-enhanced mitochondrial biogenesis might significantly alter the MHC-I status in breast carcinoma cells . MHC-I expression , as assessed by flow cytometry using an anti-HLA-ABC monoclonal antibody , was fully restored ( up to upregulation ) in MHC-I-negative HER2 gene-amplified carcinoma cells . These findings may help delineate a previously unrecognized mechanism through which metformin ( and metformin-like drugs ) may enable a cancer patient's own immune system to mount an efficient anti-metastasis response that can prevent or delay disease recurrence . Restored antigenicity and immunogenicity of tumor cells may represent a previously unrecognized primary mode of action underlying the cancer-preventive effects of metformin .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22333588"}
{"sentence": "Construction industry workers are exposed to many known carcinogens in their complex occupational environment . Since there are no past studies on genotoxicity among this group in the Indian subcontinent , workers engaged in different construction sites at Coimbatore , Tamil Nadu , India , were assessed here . We enrolled 96 workers and 68 control subjects with similar mean age , smoking , tobacco chewing prevalence and alcohol consumption , for analysis of DNA damage in blood leucocytes by micronucleus ( MN ) and comet assays . DNA repair inhibition was also analyzed by assessing the XPD gene . Construction workers showed a significant increase in MN and comet tail length compared to controls with adjustment for smoking habits , tobacco chewing , alcohol consumption and years of exposure ( P<0.05 ) . The results indicated that chronic occupational exposure to cement during construction work could lead to increased levels of DNA damage and repair inhibition .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21133594"}
{"sentence": "OBJECTIVE To study the mechanism of interleukin 7/interleukin 7 receptor ( IL-7/IL-7R ) in promoting cell proliferation and inducing lymphangiogenesis of non-small cell lung cancer ( NSCLC ) in vivo and in vitro . METHODS Immunohistochemical study for IL-7 , IL-7R , cyclin D1 and vascular endothelial growth factor-D ( VEGF-D ) was carried out in NSCLC tissues from 95 patients . The relationship between IL-7/IL-7R expression and various parameters was analyzed . The mechanism of IL-7/IL-7R in promoting cell proliferation and inducing lymphangiogenesis was studied by methylthiazolyldiphenyl-tetrazolium bromide , fluorescence-activated cell sorting , reverse transcriptase-PCR , Western blot , co-immunoprecipitation , chromatin immunoprecipitation and nude mice experiments with xenograft tumors . RESULTS IL-7 ( 63.2% , 60/95 ) , IL-7R ( 61.1% , 58/95 ) , cyclin D1 ( 52.6% , 50/95 ) and VEGF-D ( 58.9% , 56/95 ) showed that high level of expression in NSCLC . IL-7/IL-7R over-expression correlated with cyclin D1 expression ( P < 0.01 , P < 0.01 ) , VEGF-D expression ( P < 0.01 , P < 0.01 ) , increased lymphovascular density ( P = 0.005 , P = 0.013 ) , advanced clinical stage ( P = 0.008 , P = 0.005 ) and presence of lymph node metastasis ( P < 0.01 , P < 0.01 ) . IL-7/IL-7R could promote proliferation of A549 cell , increase cyclin D1 and VEGF-D expression , and enhance c-Fos/c-Jun expression and phosphorylation , resulting in formation of heterodimer . Furthermore , IL-7/IL-7R could induce binding of c-Fos/c-Jun to cyclin D1/VEGF-D promoters and regulate their transcription . IL-7/IL-7R could also promote proliferation and lymphangiogenesis of lung cancer xenograft tumors . CONCLUSIONS IL-7/IL-7R promotes c-Fos/c-Jun expression and activity in NSCLC . This further facilitates cyclin D1 expression and accelerates proliferation of cells and VEGF-D-induced lymphovascular formation .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23157741"}
{"sentence": "Waxy mutants , in which endosperm starch contains amylopectin rather than the wild-type composition of amylopectin and amylose , occur in many domesticated cereals . The cultivation of waxy varieties is concentrated in east Asia , where there is a culinary preference for glutinous-textured foods that may have developed from ancient food processing traditions . The waxy phenotype results from mutations in the GBSSI gene , which catalyzes amylose synthesis . Broomcorn or proso millet ( Panicum miliaceum L. ) is one of the world's oldest cultivated cereals , which spread across Eurasia early in prehistory . Recent phylogeographic analysis has shown strong genetic structuring that likely reflects ancient expansion patterns . Broomcorn millet is highly unusual in being an allotetraploid cereal with fully waxy varieties . Previous work characterized two homeologous GBSSI loci , with multiple alleles at each , but could not determine whether both loci contributed to GBSSI function . We first tested the relative contribution of the two GBSSI loci to amylose synthesis and second tested the association between GBSSI alleles and phylogeographic structure inferred from simple sequence repeats ( SSRs ) . We evaluated the phenotype of all known GBSSI genotypes in broomcorn millet by assaying starch composition and protein function . The results showed that the GBSSI-S locus is the major locus controlling endosperm amylose content , and the GBSSI-L locus has strongly reduced synthesis capacity . We genotyped 178 individuals from landraces from across Eurasia for the 2 GBSSI and 16 SSR loci and analyzed phylogeographic structuring and the geographic and phylogenetic distribution of GBSSI alleles . We found that GBSSI alleles have distinct spatial distributions and strong associations with particular genetic clusters defined by SSRs . The combination of alleles that results in a partially waxy phenotype does not exist in landrace populations . Our data suggest that broomcorn millet is a system in the process of becoming diploidized for the GBSSI locus responsible for grain amylose . Mutant alleles show some exchange between genetic groups , which was favored by selection for the waxy phenotype in particular regions . Partially waxy phenotypes were probably selected against-this unexpected finding shows that better understanding is needed of the human biology of this phenomenon that distinguishes cereal use in eastern and western cultures .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22936718"}
{"sentence": "BACKGROUND Helicobacter pylori is the main risk factor for the development of non-cardia gastric cancer . Increased proliferation of the gastric mucosa is a feature of H. pylori infection . Mucosal interkeukin-1beta production is increased in H. pylori infection and IL-1beta genotypes associated with increased pro-inflammatory activity are risk factors for the development of gastric cancer . The effect of IL-1beta on gastric epithelial cell proliferation has been examined in this study . METHODS AGS cells were cultured with IL-1beta . DNA synthesis was assed by [ 3H]thymidine incorporation and total viable cell numbers by MTT assay . RESULTS IL-1beta dose dependently increased DNA synthesis and cell numbers . The enhanced proliferation was blocked by interleukin-1 receptor antagonist . Addition of neutralising antibody to GM-CSF reduced IL-1beta-stimulated proliferation by 31 +/- 4 % . GM-CSF alone significantly stimulated proliferation . Addition or neutralisation of IL-8 had no effect on basal or IL-1beta-stimulated proliferation . The tyrosine kinase inhibitor genistein completely blocked IL-1beta-stimulated proliferation and inhibition of the extracellular signal related kinase pathway with PD 98059 inhibited IL-1beta stimulated proliferation by 58 +/- 5 % . CONCLUSIONS IL-1beta stimulates proliferation in gastric epithelial cells . Autocrine stimulation by GM-CSF contributes to this proliferative response . Signalling via tyrosine kinase activity is essential to the mitogenic response to IL-1beta . The extracellular signal related kinase pathway is involved in , but not essential to downstream signalling . IL-1beta may contribute to the hyperproliferation seen in H. pylori- infected gastric mucosa , and be involved in the carcinogenic process .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "11936957"}
{"sentence": "It has been well known for ages that in living organisms the rhythmicity of biological processes is linked to the 24-hour light-dark cycle . However , the exact function of the circadian clock system has been explored only in the past decades . It came to light that the photosensitive primary \" master clock \" is situated in the suprachiasmatic photosensitive nuclei of the special hypothalamic region , and that it is working according to changes of light and darkness . The master clock sends its messages to the peripheral \" slave clocks \" . In many organs , like pancreatic \u03b2-cells , the slave clocks have autonomic functions as well . Two essential components of the clock system are proteins encoded by the CLOCK and BMAL1 genes . CLOCK genes are in interaction with endonuclear receptors such as peroxisoma-proliferator activated receptors and Rev-erb-\u03b1 , as well as with the hypothalamic-pituitary-adrenal axis , regulating the adaptation to stressors , energy supply , metabolic processes and cardiovascular system . Melatonin , the product of corpus pineale has a significant role in the functions of the clock system . The detailed discovery of the clock system has changed our previous knowledge about the development of many diseases . The most explored fields are hypertension , cardiovascular diseases , metabolic processes , mental disorders , cancers , sleep apnoe and joint disorders . CLOCK genes influence ageing as well . The recognition of the periodicity of biological processes makes the optimal dosing of certain drugs feasible . The more detailed discovery of the interaction of the clock system might further improve treatment and prevention of many disorders .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22935429"}
{"sentence": "Next-generation DNA sequencing promises to revolutionize clinical medicine and basic research . However , while this technology has the capacity to generate hundreds of billions of nucleotides of DNA sequence in a single experiment , the error rate of results in hundreds of millions of sequencing mistakes . These scattered errors can be tolerated in some applications but become extremely problematic when \" deep sequencing \" genetically heterogeneous mixtures , such as tumors or mixed microbial populations . To overcome limitations in sequencing accuracy , we have developed a method termed Duplex Sequencing . This approach greatly reduces errors by independently tagging and sequencing each of the two strands of a DNA duplex . As the two strands are complementary , true mutations are found at the same position in both strands . In contrast , PCR or sequencing errors result in mutations in only one strand and can thus be discounted as technical error . We determine that Duplex Sequencing has a theoretical background error rate of less than one artifactual mutation per billion nucleotides sequenced . In addition , we establish that detection of mutations present in only one of the two strands of duplex DNA can be used to identify sites of DNA damage . We apply the method to directly assess the frequency and pattern of random mutations in mitochondrial DNA from human cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22853953"}
{"sentence": "Cancer cells typically display altered glucose metabolism characterized by a preference of aerobic glycolysis , known as the Warburg effect , which facilitates cell proliferation . Hypoxia-inducible factor ( HIF ) and oncoprotein Myc are two prominent transcription factors that drive glycolysis . Previously , we reported that the estrogen-related receptors ( ERRs ) act as cofactors of HIF and enhance HIF-dependent transcription of glycolytic genes under hypoxia . ERRs are orphan nuclear receptors and key regulators of energy metabolism by orchestrating mitochondrial biogenesis , fatty acid oxidation ( FAO ) and oxidative phosphorylation . Here , we show that ERRs also stimulate glycolysis under normoxia . ERRs directly bind to and activate promoters of many genes encoding glycolytic enzymes , and the ERR-binding sites in such promoters are essential for ERR-mediated transcriptional activation . ERRs interact with Myc , and the two factors synergistically activate transcription of glycolytic genes . Furthermore , overexpression of ERRs increases glycolytic gene expression and lactate production . Conversely , depletion of ERRs in cancer cells reduces expression of glycolytic genes and glucose uptake , resulting in decreased aerobic glycolysis and cell growth . Taken together , these results suggest that ERRs are important transcriptional activators of the glycolytic pathway and contribute to the Warburg effect in cancer cells .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 1, 0], "id": "22665055"}
{"sentence": "Isolinderanolide B ( IOB ) , a butanolide extracted from the stems of Cinnamomum subavenium , was investigated for its antiproliferative activity in T24 human bladder cancer cells . To identity the anticancer mechanism of IOB , its effect on apoptosis , cell cycle distribution , and levels of p53 , p21 Waf1/Cip1 , Fas/APO-1 receptor , and Fas ligand was assayed . Enzyme-linked immunosorbent assay showed that the G0/G1 phase arrest is because of increase in the expression of p21 Waf1/Cip1 . An enhancement in Fas/APO-1 and membrane-bound Fas ligand ( mFasL ) might be responsible for the apoptotic effect induced by IOB . This study reports the novel finding that the induction of p21 Waf1/Cip1 and activity of the Fas/mFas ligand apoptotic system may participate in the antiproliferative activity of IOB in T24 cells .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "21196431"}
{"sentence": "Adenoid cystic carcinoma ( ACC ) of the salivary glands is a highly infiltrative malignant tumour with a tendency for lung metastasis . Gene therapy could be a potentially effective therapy for ACC and its metastasis . The aims of the study were : To transduce interleukin-2 ( IL-2 ) gene into an ACC cell line with predisposition for lung metastasis ( ACC-M ) ; to compare the bioactivity of the gene-transduced cells and the parent cell line in vitro and in vivo . The IL-2 gene was transduced via a bicistronic retroviral vector into the ACC-M cells . The growth rate and DNA cell cycles of the parent ACC-M , the control viral vector AmGCEN , and the gene transduced AmIL-2 cell cultures were compared quantitatively and by flow cytometry , respectively . The tumourigenic ability of the three cell lines was verified by inoculation in athymic nude mice . The tumours developed were extracted and compared quantitatively and histologically . There was no difference in the growth rate and the DNA count between the ACC-M , AmGCEN , and AmIL-2 cell cultures . In the animal experiment , both the ACC-M and AmGCEN cells stimulated lung metastasis in all the mice , whereas there was no tumour found in the 1 x 10(6) AmIL-2 cells inoculation . On 3 x 10(6) AmIL-2 cells stimulation , three out of six mice developed tumours but the mass and volume of the tumours were smaller than the other two groups . Under light microscopy , the ACC-M tumours were mainly poorly differentiated with minimal cellular matrix , whereas the AmIL-2 tumours were well differentiated with ample matrix . The transduction of IL-2 gene can reduce the tumourigenicity of ACC-M cells and induces tumour cell differentiation in mice . The IL-2 gene can be a potential effective gene for the treatment of adenoid cystic carcinoma of salivary glands and its lung metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12521324"}
{"sentence": "UNLABELLED Hepatocellular carcinoma ( HCC ) is a major liver malignancy . We previously demonstrated that deregulation of epigenetic regulators is a common event in human HCC . Suppressor of variegation 3-9 homolog 1 ( SUV39H1 ) , the prototype of histone methyltransferase , is the major enzyme responsible for histone H3 lysine 9 trimethylation , which , essentially , is involved in heterochromatin formation , chromosome segregation , and mitotic progression . However , the implication of SUV39H1 in hepatocarcinogenesis remains elusive . In this study , we found that SUV39H1 was frequently up-regulated in human HCCs and was significantly associated with increased Ki67 expression ( P < 0.001 ) and the presence of venous invasion ( P = 0.017 ) . To investigate the role of SUV39H1 in HCC development , both gain- and loss-of-function models were established . SUV39H1 overexpression remarkably enhanced HCC cell clonogenicity , whereas knockdown of SUV39H1 substantially suppressed HCC cell proliferation and induced cell senescence . In addition , ectopic expression of SUV39H1 increased the migratory ability of HCC cells , whereas a reduced migration rate was observed in SUV39H1 knockdown cells . The significance of SUV39H1 in HCC was further demonstrated in a nude mice model ; SUV39H1 knockdown drastically inhibited in vivo tumorigenicity and abolished pulmonary metastasis of HCC cells . We also identified microRNA-125b ( miR-125b ) as a post-transcriptional regulator of SUV39H1 . Ectopic expression of miR-125b inhibited SUV39H1 3'-untranslated-region-coupled luciferase activity and suppressed endogenous SUV39H1 expression at both messenger RNA and protein levels . We have previously reported frequent down-regulation of miR-125b in HCC . Interestingly , miR-125b level was found to be inversely correlated with SUV39H1 expression ( P = 0.001 ) in clinical specimens . Our observations suggested that miR-125b down-regulation may account for the aberrant SUV39H1 level in HCC . CONCLUSION Our study demonstrated that SUV39H1 up-regulation contributed to HCC development and metastasis . The tumor-suppressive miR-125b served as a negative regulator of SUV39H1 .", "label": [1, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "22991213"}
{"sentence": "Cells dissociated from spontaneous and transplanted tumours of C3HJax mammary gland have been cultured on polylysine and gelatin substrates . The isolated cells proliferated to form monolayers with high degree of organoid structure as indicated by formation of alveolar cavities . Differences were observed in the cell attachment , growth pattern , number and size of alveolar cavities , cells which lined the cavity and cell morphology on polylysine and gelatin substrates as compared to conventional cell culture plastic surface . On polylysine more than 90% cells attached rapidly , within 15-45 min after plating , with or without serum and formed confluent monolayers marked by presence of large and small alveolar cavities . Multiple interacting cell types took part in organization of the cavity . Cells lining the cavity constantly proliferated and rearranged to expand it . On gelatin , 60-70% cells attached over a period of 6-24 hr in presence of serum and formed confluent monolayers dominated by small alveolar cavities . Cells forming the cavities were epithelial in nature and cavities once formed did not increase in size . Upon subculture , the cell morphology on these substrates was strikingly different . On polylysine , the predominant cell type had numerous irregular microvilli whereas on gelatin , cells had smoother boundaries with a few stunted cytoplasmic extensions . The cell attachment on conventional surface was low , 40-50% . When seeded at high cell density , formation of alveolar cavities was suppressed and at low cell density , cultures were marked by contact inhibition of cells and failure to attain confluence . These results suggest differential behaviour and interaction of mammary tumour epithelium with the substrates used .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "1478710"}
{"sentence": "Pathological features of amyotrophic lateral sclerosis ( ALS ) include , in addition to selective motor neuron ( MN ) degeneration , the occurrence of protein aggregates , mitochondrial dysfunction and astrogliosis . SOD1 mutations cause rare familial forms of ALS and have provided the most widely studied animal models . Relatively recent studies implicating another protein , TDP-43 , in familial and sporadic forms of ALS have led to the development of new animal models . More recently , mutations in the valosin-containing protein ( VCP ) gene linked to the human genetic disease , Inclusion Body Myopathy associated with Paget's disease of bone and frontotemporal dementia ( IBMPFD ) , were found also to be associated with ALS in some patients . A heterozygous knock-in VCP mouse model of IBMPFD ( VCP(R155H/+) ) exhibited muscle , bone and brain pathology characteristic of the human disease . We have undertaken studies of spinal cord pathology in VCP(R155H/+) mice and find age-dependent degeneration of ventral horn MNs , TDP-43-positive cytosolic inclusions , mitochondrial aggregation and progressive astrogliosis . Aged animals ( months ) show electromyography evidence of denervation consistent with the observed MN loss . Although these animals do not develop rapidly progressive fatal ALS-like disease during their lifespans , they recapitulate key pathological features of both human disease and other animal models of ALS , and may provide a valuable new model for studying events preceding onset of catastrophic disease .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22898872"}
{"sentence": "The xeroderma pigmentosum group C ( XPC ) protein specifically involved in genome-wide damage recognition for nucleotide excision repair ( NER ) was purified as a tight complex with HR23B , one of the two mammalian homologs of RAD23 in budding yeast . This XPC-HR23B complex exhibits strong binding affinity for single-stranded DNA , as well as preferential binding to various types of damaged DNA . To examine the structure-function relationship of XPC , a series of truncated mutant proteins were generated and assayed for various binding activities . The two domains participating in binding to HR23B and damaged DNA , respectively , were mapped within the carboxy-terminal half of XPC , which also contains an evolutionary conserved amino acid sequence homologous to the yeast RAD4 protein . We established that the carboxy-terminal 125 amino acids are dispensable for both HR23B and damaged DNA binding , while interactions with transcription factor IIH ( TFIIH ) are significantly impaired by truncation of this domain . Furthermore , deletion of the extreme carboxy-terminal domain totally abolished XPC activity in the cell-free NER reaction . These results suggest that following initial damage recognition , the carboxy terminus of XPC may be essential for the recruitment of TFIIH , and that most truncation mutations identified in XP-C patients result in non-functional proteins .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12509233"}
{"sentence": "BACKGROUND/AIMS by reducing the number of ATP molecules produced via aerobic glycolysis , the inhibition of lactic dehydrogenase ( LDH ) should hinder the growth of neoplastic cells without damaging the normal cells which do not rely on this metabolic pathway for their energetic needs . Here , we studied the effect of oxamic and tartronic acids , 2 inhibitors of LDH , on aerobic glycolysis and cell replication of HepG2 and PLC/PRF/5 cells , 2 lines from human hepatocellular carcinomas . METHODS aerobic glycolysis was measured by calculating the amounts of lactic acid formed . The effect on replication was assessed by culturing the cells in both standard conditions and glucose-deprived medium , which was used to shut down aerobic glycolysis . RESULTS the oxamic and tartronic acids inhibited aerobic glycolysis , impaired the growth of both cell lines and also induced an increased expression of p53-upregulated modulator of apoptosis , a signal of cell death . A strong impairment of cell replication by oxamic acid was only found when the cells were cultured in the presence of glucose , indicating that it was for the most part owing to inhibition of aerobic glycolysis . CONCLUSIONS inhibition of aerobic glycolysis achieved by blocking LDH could be useful in the treatment of human hepatocellular carcinomas . Without interfering with glucose metabolism in normal cells , it could hinder cell growth by itself and could also enhance the chemotherapeutic index of associated anticancer agents by decreasing the levels of ATP selectively in neoplastic cells .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20699632"}
{"sentence": "c-myc , c-erbB-2 , and Ki-67 expression was examined by immunohistochemistry in 11 normal breast tissues and 42 invasive and 14 noninvasive breast carcinomas . The c-myc product was detected in all breast carcinoma specimens and in 7 of 11 normal breast tissues . Invasive tumors stained more frequently with the anti-myc monoclonal antibody than did noninvasive tumors , while the level of expression in normal breast tissue was much less than that in breast cancer . Membrane staining of the c-erbB-2 protein was demonstrated in 29% ( 4 of 14 ) of noninvasive ductal carcinomas and in 45% ( 19 of 42 ) of invasive breast carcinomas . None of the 11 normal breast tissue samples was positive . The mean value of Ki-67-positive cells was 0.91 +/- 0.31% for normal breast tissue , 4.57 +/- 1.36% for noninvasive ductal carcinoma , and 12.76 +/- 2.18% for invasive breast cancer . In 42 invasive breast carcinomas , the expression of c-myc , c-erbB-2 , and Ki-67 proliferation marker were compared with lymph node status , estrogen receptor status , progesterone receptor status , and age of patients at diagnosis. c-erbB-2 overexpression and Ki-67 overexpression were identified as the only factors associated with lymph node status . We concluded that they might be additional prognostic factors for breast carcinoma .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1348967"}
{"sentence": "In order to increase the permeability of cell membranes for low doses of cytostatic drugs , two bioelectrochemical methods have been compared : ( a ) electric pore formation in the plasma membranes by single electric impulses ( electroporation ) , and ( b ) reordering of membrane structure by alternating currents ( capacitively coupled ) . These treatments were applied to human leukemic K-562 cells and human lymphoma U-937 cells , yielding apoptotic and necrotic effects , determined by flow cytometry . Additional cell death occurs after exposure to light irradiation at wavelengths lambda > 600 nm , of cells which were electroporated and had incorporated actinomycin-C or daunomycin ( daunorubicin ) . It is observed that drug uptake after an exponentially decaying electroporation pulse of the initial field strength Eo=1.4 kV/cm and pulse time constants in the time range 0.5-3 ms is faster than during PEMF-treatment , i.e. , application of an alternating current of 16 kHz , voltage U<100 V , I=55 mA , and exposure time 20 min . However , at the low a.c. voltage of this treatment , more apoptotic and necrotic cells are produced as compared to the electroporation treatment with one exponentially decaying voltage pulse . Thus , additional photodynamic action appears to be more effective than solely drugs and electroporation as applied in clinical electrochemotherapy , and more effective than the noninvasive pulsed electromagnetic fields ( PEMFs ) , for cancer cells in general and animals bearing tumors in particular .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20494629"}
{"sentence": "SCOPE In this study , we evaluated the efficacy of lycopene against the growth of prostate cancer in vivo . METHODS AND RESULTS Athymic nude mice were implanted subcutaneously with human androgen-independent prostate carcinoma PC-3 cells . They were supplemented with a low or a high dose of lycopene ( 4 and 16\u2009mg/kg ) and a single dose of \u03b2-carotene ( 16\u2009mg/kg ) twice a week for 7 wk . At the end of the experiment , both lycopene and \u03b2-carotene strongly inhibited the tumor growth , as evidenced by the decrease in tumor volume and tumor weight . High-dosage lycopene and \u03b2-carotene significantly decreased the expression of proliferating cell nuclear antigen in tumor tissues and increased the levels of insulin-like growth factor-binding protein-3 in plasma . In addition , high-dosage lycopene supplementation significantly decreased the vascular endothelial growth factor ( VEGF ) levels in plasma . In contrast , \u03b2-carotene supplementation significantly increased the VEGF levels , as compared with tumor control group . CONCLUSION Lycopene and \u03b2-carotene supplementation suppressed the growth of prostate tumor cells , and the effects are likely associated with reduction of proliferation ( attenuation of proliferating cell nuclear antigen expression ) and with interference of the insulin-like growth factor 1 signaling ( increased plasma insulin-like growth factor-binding protein-3 levels ) . Furthermore , the inhibition of VEGF by lycopene suggests that the antitumor mechanisms of lycopene also involve anti-angiogenesis .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "21462328"}
{"sentence": "Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 ( hSOD1 ) , models of familial amyotrophic lateral sclerosis . This denervation is especially marked in fast limb muscles , and precedes death of motor neuron somata . This study used mice that expressed yellow fluorescent protein ( YFP ) in neurons to investigate changes in the morphology and function of axons and motor terminals innervating a fast forelimb muscle ( epitrochleoanconeus , ETA ) in presymptomatic and symptomatic hSOD1-G85R mice , compared to those in mice that express wild-type ( wt ) hSOD1 . The percentage of endplates ( identified using fluorescently-labeled \\u03b1-bungarotoxin ) innervated by motor terminals remained high in presymptomatic SOD1-G85R mice , but fell to in symptomatic mice . The number of large diameter ( \\u22654 \\u03bcm ) axons in the ETA nerve also decreased as mice became symptomatic , and endplate innervation correlated best with the number of large diameter axons . Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials ; different components of the pH-dependent YFP signals reflect stimulation-induced Ca2+ entry and vesicular exo/endocytosis . Most visible motor terminals ( >90% ) remained capable of responding to nerve stimulation in both pre- and symptomatic hSOD1-G85R mice , but with functional alterations . Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release , whereas symptomatic terminals exhibited increased acidification and reduced vesicular release . The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22813866"}
{"sentence": "Prevention of environmentally related cancer will be enhanced by the availability of sensitive early warning systems and by improvements in quantitative assessment of human risks . Accordingly , we have carried out a series of molecular epidemiologic studies aimed at validating a panel of biologic markers , including carcinogen-DNA and -protein adducts , sister chromatid exchange , micronucleus formation , DNA strand breaks , and DNA repair capacity . Results from three such studies illustrate the usefulness of these biomarkers in elucidating low-dose-response relationships , correlations between biomarkers , and the range of variation in biomarkers between individuals exposed to similar concentrations of carcinogens . Low-level workplace or ambient exposures to styrene , ethylene oxide , and polycyclic aromatic hydrocarbons ( PAH ) were associated with significant increases in both molecular dose of carcinogens ( adducts ) and various markers of preclinical effects . Correlations between biomarkers varied by exposure . For example , in the styrene study , sister chromatid exchange frequency was not correlated with any of the markers , in contrast to the studies of ethylene oxide and PAH . Significant molecular effects were observed not only in occupationally exposed people but also in residents of an area in Poland characterized by high levels of air pollution . For example , the mean PAH-DNA level in exposed residents ( winter sample ) was 30.4 adducts per 10(8) nucleotides . This level was significantly higher than that of adducts seen in summer samples from the same area ( 4.2/10(8) , or in winter samples from residents of a rural area ( 11.01/10(8) . Significant seasonal variation in PAH-DNA adduct formation in this group was consistent with recorded fluctuations in air pollution levels . Striking interindividual variation was observed in all three exposed populations .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1486841"}
{"sentence": "BACKGROUND CDC4/FBXW7 , encoding a ubiquitin ligase , maps to 4q32 and has been implicated as a tumor suppressor gene and therapeutic target in many tumor types . Mutations in colonic adenomas , and the frequent losses on 4q described in gastric cancer prompt speculation about the role of CDC4/FBXW7 in gastric carcinogenesis . METHODS We assessed the role of CDC4/FBXW7 in gastric cancer , through loss of heterozygosity ( LOH ) and multiplex ligation-dependent probe amplification ( MLPA ) on 47 flow-sorted gastric carcinomas including early-onset gastric cancers ( EOGC ) and xenografted conventional gastric carcinomas . Ploidy analysis was carried out on 39 EOGCs and immunohistochemistry of CDC4/FBXW7 and its substrates c-myc , c-jun , Notch and cyclin E was performed on 204 gastric carcinomas using tissue microarrays ( TMAs ) . Sequence analysis of CDC4/FBXW7 was carried out on gastric carcinoma cell lines and xenografts . RESULTS Loss of heterozygosity of CDC4/FBXW7 occurred in 32% of EOGCs , and correlated with loss of expression in 26% . Loss of expression was frequent in both EOGC and conventional gastric cancers . No CDC4/FBXW7 mutations were found and loss of CDC4/FBXW7 did not correlate with ploidy status . There was a significant correlation between loss of CDC4/FBXW7 expression and upregulation of c-myc . CONCLUSION Loss of CDC4/FBXW7 appears to play a role in both EOGC and conventional gastric carcinogenesis , and c-myc overexpression is likely to be an important oncogenic consequence of CDC4/FBXW7 loss .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20448329"}
{"sentence": "We recently showed that Nox4 NADPH oxidase is highly expressed in pancreatic ductal adenocarcinoma and that it is activated by growth factors and plays a pro-survival , anti-apoptotic role . Here we investigate the mechanisms through which insulin-like growth factor I and serum ( FBS ) activate NADPH oxidase in pancreatic cancer ( PaCa ) cells . We show that in PaCa cells , NADPH oxidase is composed of Nox4 and p22(phox) catalytic subunits , which are both required for NADPH oxidase activity . Insulin-like growth factor I and FBS activate NADPH oxidase through transcriptional up-regulation of p22(phox) . This involves activation of the transcription factor NF-\u03baB mediated by Akt kinase . Up-regulation of p22(phox) by the growth factors results in increased Nox4-p22(phox) complex formation and activation of NADPH oxidase . This mechanism is different from that for receptor-induced activation of phagocytic NADPH oxidase , which is mediated by phosphorylation of its regulatory subunits . Up-regulation of p22(phox) represents a novel pro-survival mechanism through which growth factors and Akt inhibit apoptosis in PaCa cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21118808"}
{"sentence": "Hormone-independent tumor growth and metastasis are associated with increased mortality in human prostate cancer . In this study , we evaluate a potential role for ligand-mediated activation of HER2 receptor tyrosine kinase in androgen-independent prostate cancers . HER2 , HER3 , and epidermal growth factor receptor were detected in the androgen-independent cell line 22Rv1 . Heregulin stimulation results in receptor phosphorylation and cell proliferation that is inhibited by increasing concentrations of anti-HER2 recombinant humanized monoclonal antibody ( rhuMAb ) 2C4 . Furthermore , inhibition of tumor growth was observed in xenografts derived from 22Rv1 cells when treated with rhuMAb 2C4 in a dose-dependent manner . These studies provide a framework , both in vitro and in vivo , to examine the molecular mechanisms of ligand-driven HER2 activation in androgen-independent tumorigenesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12359757"}
{"sentence": "The Wnt/\u03b2-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells ( HNSCC ) . Increased \u03b2-catenin predisposes HNSCC patients to poor prognosis and survival . This study was conducted to determine the mechanism by which \u03b2-catenin regulates the viability of HNSCC . AMC-HN-3 , -HN-8 , UM-SCC-38 , and -SCC-47 cells , which were established from human head and neck cancer specimens , underwent cell death following \u03b2-catenin silencing. \u03b2-Catenin silencing significantly induced G1 arrest and increased the expression of Bax and active caspase-3 , which demonstrates the sequential activation of apoptotic cascades following treatment of HNSCC with targeted siRNA . Intriguingly , \u03b2-catenin silencing also induced autophagy . Here , we confirm that the number of autophagic vacuoles and the expression of type II light chain 3 were increased in cells that were treated with \u03b2-catenin siRNA . These cell death modes are most likely due to the activation of LKB1-dependent AMPK following \u03b2-catenin silencing . The activated LKB1/AMPK pathway in AMC-HN-3 cells caused G1 arrest by phosphorylating p53 and suppressing mTOR signaling . In addition , treating AMC-HN-3 cells with LKB1 siRNA preserved cell viability against \u03b2-catenin silencing-induced cytotoxicity . Taken together , these results imply that following \u03b2-catenin silencing , HNSCC undergo both apoptotic and autophagic cell death that are under the control of LKB1/AMPK . To the best of our knowledge , these results suggest for the first time that novel crosstalk between \u03b2-catenin and the LKB1/AMPK pathway regulates the viability of HNSCC . This study thus presents new insights into our understanding of the cellular and molecular mechanisms involved in \u03b2-catenin silencing-induced cell death .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23280187"}
{"sentence": "By using the rat azoxymethane ( AOM)-induced colon carcinogenesis model , which mirrors many clinical features of human colorectal cancer , we examined whether genetic changes occurring early in colonic mucosa are predictive of treatment efficacy . In the present study the administration of the chemopreventive agent lupulone over the course of 7 weeks postinitiation reduced the number of preneoplastic lesions in the colonic mucosa by 50% . At the molecular level we observed the downregulation of genes involved in the inflammatory response , including IL-1\u03b2 and TNF-\u03b1 , and of matrix metalloproteinase-7 gene and protein expression . We also observed a substantial upregulation of components of the innate immune system , \u03b1-defensin-5 and lipocalin 2 . Lupulone induced the expression of apoptosis-related genes and caused a reversal of the B-cell lymphoma/leukemia 2 ( Bcl-2 ; antiapoptotic ) to Bcl-2 associated X protein ( Bax ; proapoptotic ) transcript and protein ratios ( Bcl-2/Bax > 1 in AOM controls and Bcl-2/Bax < 1 in lupulone-treated AOM rats ) . Here , we identify several target genes that could be considered early biomarkers of colon carcinogenesis and indicative of drug efficacy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "21255184"}
{"sentence": "Mechanosensitive channels sense elevated membrane tension that arises from rapid water influx occurring when cells move from high to low osmolarity environments ( hypoosmotic shock ) . These non-specific channels in the cytoplasmic membrane release osmotically-active solutes and ions . The two major mechanosensitive channels in Escherichia coli are MscL and MscS . Deletion of both proteins severely compromises survival of hypoosmotic shock . However , like many bacteria , E. coli cells possess other MscS-type genes ( kefA , ybdG , ybiO , yjeP and ynaI ) . Two homologs , MscK ( kefA ) and YbdG , have been characterized as mechanosensitive channels that play minor roles in maintaining cell integrity . Additional channel openings are occasionally observed in patches derived from mutants lacking MscS , MscK and MscL . Due to their rare occurrence , little is known about these extra pressure-induced currents or their genetic origins . Here we complete the identification of the remaining E. coli mechanosensitive channels YnaI , YbiO and YjeP . The latter is the major component of the previously described MscM activity ( pS ) , while YnaI ( pS ) and YbiO ( pS ) were previously unknown . Expression of native YbiO is NaCl-specific and RpoS-dependent . A \\u03947 strain was created with all seven E. coli mechanosensitive channel genes deleted . High level expression of YnaI , YbiO or YjeP proteins from a multicopy plasmid in the \\u03947 strain ( MJFGH ) leads to substantial protection against hypoosmotic shock . Purified homologs exhibit high molecular masses that are consistent with heptameric assemblies . This work reveals novel mechanosensitive channels and discusses the regulation of their expression in the context of possible additional functions .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22874652"}
{"sentence": "Merkel cell polyomavirus ( MCV ) , discovered in 2008 , is clonally integrated in Merkel cell carcinoma ( MCC ) . MCV is a common skin flora and initiates cancer in susceptible hosts only after it acquires a precise set of mutations that render it replication incompetent . Both MCV large and small T proteins promote cancer cell survival and proliferation . Large T targets pocket proteins regulating cell cycle transit while small T activates cap-dependent translation critical for cancer cell growth . These findings already have led to new diagnostics and clinical trials to target MCV-induced survivin and to promote antitumor immunity . In four years , the cause , diagnosis and therapy for an intractable cancer has been changed due to the molecular discovery of MCV .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22710026"}
{"sentence": "The purpose of this investigation was to study the variation of p73 gene expression in the apoptotic process of acute myeloid leukemia ( AML ) cell line U937 induced by methotrexate ( MTX ) . Morphological changes of apoptotic cells were observed with microscopy and Wright's + Giemsa staining . DNA ladder and cell cycle were examined by agarose gel electrophoresis and flow cytometry respectively . Using semi-quantitive reverse transcription-polymerase chain reaction ( RT-PCR ) , the expression of p73 mRNA was examined . Results showed that MTX could induce U937 cell apoptosis effectively . Condensed nuclei , fragmentation of chromosome and DNA ladder were seen after 6 hour following treatment of MTX 5 micro mol/L . Sub-G(1) peak and S + G(2)/M arrest were also determined by FCM , but the quantity of p73 expression was generally constant . In conclusion , U937 cell apoptosis induced by MTX did not change p73 mRNA level .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12513808"}
{"sentence": "In the present study we examined the effects of menadione , a redox cycling agent , on structural changes of human osteosarcoma line 143B cells . It has been previously reported that menadione can cause necrotic or apoptotic cell death in a concentration- depending manner . In our experimental model , cells were treated with 100 microM menadione for 24 hours . Using electron microscopy technique cells carrying three kinds of morphological changes were detected : necrotic cells , apoptotic cells and those demonstrating a co-existence of apoptotic and necrotic features in one single cell .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12725487"}
{"sentence": "PURPOSE Recently , a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits ( SDHB/C/D ) of the Krebs cycle enzyme , succinate dehydrogenase . We report our experience with the diagnosis , evaluation and treatment of this novel form of hereditary kidney cancer . MATERIALS AND METHODS Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer . Individuals from families with germline SDHB , SDHC and SDHD mutations , and kidney cancer underwent comprehensive clinical and genetic evaluation . RESULTS A total of 14 patients from 12 SDHB mutation families were evaluated . Patients presented with renal cell cancer at an early age ( 33 years , range 15 to 62 ) , metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors . An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age ( 47 years , range 40 to 53 ) was identified with a germline SDHC mutation ( R133X ) Metastatic disease developed in 2 of these family members . A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation . CONCLUSIONS SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer , especially in younger individuals . Although detection and management of early tumors is most often associated with a good outcome , based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma , we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23083876"}
{"sentence": "In our study we investigated the level of apoptosis in PBMCs and the serological level of sFas ( CD95/APO-1 ) in 22 patients with malignant melanoma ( 12 patients with unique cutaneous primary tumour and 10 patients with unique brain metastasis ) . The first determination was performed before tumour excision and the second at 6-7 months after excision . Results in patients with primary tumour in the first determination : 6 patients with over normal values in PBMCs apoptosis and 5 patients with increased values of sFas . In the second determination : apoptosis was increased in 5 patients and sFas level was increased in 4 cases . In patients with metastases in the first determination apoptosis of PBMC was increased in 7 cases and sFas in 5 cases . In the second determination apoptosis was increased in 4 cases and sFas was increased in 4 cases . Our results show that half of the investigated patients presented elevated values of PBMCs apoptosis and Fas receptor both before and 6-7 months after tumour excision . Apoptosis values for PBMCs and sFas values were with 1/4 higher than normals . There was no difference in clinical evolution of the patients with normal or increased values for studied parameters . Clinical evolution was performed for 1 year . The presence of increased values for PBMCs and sFas after tumour excision , primary or metastasis is surprising and hard to explain . It is possible that tumoral evolution induces a disregulation at PBMCs level or other cells level that persists unexpectedly , after tumour excision or apoptotic processes , in a certain level to be independent and anterior to tumour development .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "15055260"}
{"sentence": "BACKGROUND Human Barrett's cancer cell lines have numerous , poorly-characterized genetic abnormalities and , consequently , those lines have limited utility as models for studying the early molecular events in carcinogenesis . Cell lines with well-defined genetic lesions that recapitulate various stages of neoplastic progression in Barrett's esophagus would be most useful for such studies . METHODOLOGY/PRINCIPAL FINDINGS To develop such model cell lines , we started with telomerase-immortalized , non-neoplastic Barrett's epithelial ( BAR-T ) cells , which are spontaneously deficient in p16 , and proceeded to knock down p53 using RNAi , to activate Ras by introducing oncogenic H-Ras(G12V) , or both . BAR-T cells infected with either p53 RNAi or oncogenic H-Ras(G12V) alone maintained cell-to-cell contact inhibition and did not exhibit anchorage-independent growth in soft agar . In contrast , the combination of p53 RNAi knockdown with expression of oncogenic H-Ras(G12V) transformed the p16-deficient BAR-T cells , as evidenced by their loss of contact inhibition , by their formation of colonies in soft agar , and by their generation of tumors in immunodeficient mice . CONCLUSIONS/SIGNIFICANCE Through these experiments , we have generated a number of transformed and non-transformed cell lines with well-characterized genetic abnormalities recapitulating various stages of carcinogenesis in Barrett's esophagus . These lines should be useful models for the study of carcinogenesis in Barrett's esophagus , and for testing the efficacy of chemopreventive and chemotherapeutic agents .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20927195"}
{"sentence": "Cellular senescence is a mechanism to inhibit the growth of mammalian cells after oncogenic activation , or in response to damage or stress . We describe here the identification of a novel gene , SENEX , that regulates stress induced premature senescence pathways in endothelial cells ( ECs ) involving p16(INK4a) and retinoblastoma protein activation . Endogenous levels of SENEX remain unchanged during replicative senescence but are regulated by H(2)O(2)-mediated stress . In contrast to that previously described for senescence in other cell types , the SENEX induced senescent ECs are profoundly anti-inflammatory . The cells are resistant to tumor necrosis factor ( TNF)\u03b1-induced apoptosis , adhesion of neutrophils and mononuclear cells , and the surface ( but not cytoplasmic ) expression of endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 . Furthermore they are resistant to thrombin induced vascular leak . Senescent ECs such as those lining atherosclerotic lesions may therefore function to limit the inflammatory response . SENEX is also essential for EC survival since depletion either ectopically by siRNA or by high- dose H(2)O(2) treatment causes apoptosis . Together , these findings expand our understanding of the role of senescence in the vasculature and identify SENEX as a fulcrum for driving the resultant phenotype of the endothelium after activation .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 1], "id": "20664062"}
{"sentence": "Pancreatic ductal adenocarcinoma ( PDAC ) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate . Immunosuppressive cell populations , e.g. regulatory T cells ( Treg ) , appear to be important in PDAC , contributing to patient's poor prognosis . Therefore , we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance . We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg . Remarkably , these cells exhibited the effector/memory phenotype , suggesting their enhanced suppressive activity and higher proliferation capacity . Although we observed a steady increase in transforming growth factor-\u03b2 ( TGF-\u03b2 ) levels in the tumors , treatment with a specific inhibitor of TGF-\u03b2 receptor I kinase failed to abrogate Treg accumulation . A CCR4 antagonist did not affect Treg percentage in the tumor either . However , intense Treg cell division in the tumor microenvironment was demonstrated , suggesting local proliferation as a major mechanism of Treg accumulation in PDAC . Notably , this accumulation was reduced by low-dose gemcitabine administration , resulting in a modestly increased survival of PDAC mice . Our results provide an insight into mechanisms of immunosuppression in PDAC , suggesting an important role for proliferative expansion of effector/memory Treg . Low-dose gemcitabine therapy selectively depletes Treg , providing a basis for new modalities of PDAC therapy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23233419"}
{"sentence": "Retrovirally induced immunosuppression may elevate the incidence of chemically induced cancers . A proposed hypothesis to explain this relationship is the increased free radical activity observed during retroviral infection and carcinogen activation . We previously found that vitamin E retarded growth of esophageal tumors accompanied by reductions of free radical products . This study investigated the contribution that retroviral immunosuppression has on esophageal cancer induced by the carcinogen N-nitrosomethylbenzylamine ( NMBzA ) , and the response that increased levels of dietary vitamin E has on this induced carcinogenesis . Female C57BL/6 mice received NMBzA or vehicle ( corn oil ) i.p. weekly for 3 weeks . Then some of the mice were infected with LP-BM5 murine retrovirus and fed diets containing 30 IU vitamin E or 172 IU vitamin E/kg of diet . As an assessment of free radical activity , exhaled ethane was measured prior to killing the animals at 26 weeks . Esophagi from the various mice groups were assessed for size and frequency of tumors . Livers homogenates were analyzed for vitamins A and E , lipid fluorescence , conjugated dienes and malondialdehyde . Hepatic levels of vitamin A and E were decreased ( P < 0.05 ) and indices of lipid peroxidation were greater ( P < 0.05 ) in NMBzA-treated mice relative to controls . Lipid peroxidation and serum transaminases ( ALT and AST ) were greatest in mice given NMBzA and infected with the retroviruses . Incidence of esophageal tumors were also greatest in the NMBzA-treated , immunocompromised animals . Mice fed vitamin E-supplemented diets showed increased ( P < 0.05 ) hepatic concentrations of vitamin E and vitamin A , decreased activities of serum transaminases , decreased indices of lipid peroxidation , and decreased size and frequency of esophageal tumors in both the immunocompromised and non-immunocompromised mice . These results suggest that vitamin E plays an antioxidant function that retards the incidence of esophageal cancers in immunocompromised and non-immunocompromised animals .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1330343"}
{"sentence": "Recent epidemiological and experimental investigations suggest a close relationship between cyclooxygenase ( COX ) and pathogenesis of colorectal cancer . There are two isoforms , COX-1 and COX-2 , which differ in physiological functions and distribution . This study is to investigate the possible roles of both isoforms in the proliferation of colon carcinoma cells . A human colon carcinoma cell line , COLO 320DM , was transfected with an eukaryotic expression vector ( pEF-BOS ) carrying cDNA of either COX-1 or COX-2 . Both COX-1 and COX-2-expressing cells exhibited a similar enzyme activity , 8-10 nmol/10 min/mg of protein . Growth rates of both COX-expressing cells were increased by about 2 fold as compared with mock-transfected cells . The stimulated growth of the COX-expressing cells was confirmed by the increased DNA synthesis as assessed by [ 3H]thymidine incorporation . Furthermore , expression of epidermal growth factor receptor ( EGFR ) was markedly increased in the COX-expressing cells as examined by reverse transcriptase-polymerase chain reaction ( RT-PCR ) . A COX inhibitor , indomethacin , suppressed the stimulated growth , increased DNA synthesis and induction of epidermal growth factor receptor in the COX-1 and COX-2-transfected cells . These results suggest that not only COX-2 but COX-1 is involved in the proliferation of human colon carcinoma cells through the induction of EGFR .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12664617"}
{"sentence": "Inflammation which is an indispensable participant in tumor progression is intricately linked with redox modulation . The pro-inflammatory cytokine Tumor Necrosis Factor ( TNFalpha ) elevates reactive oxygen species ( ROS ) in glioblastoma multiforme ( GBM ) . As both TNFalpha and oxidative stress independently play role in regulating cytoskeletal organization and cell survival pathways we investigated whether TNFalpha mediated oxidative stress regulates responses that offer survival advantages to glioblastoma cells . Treatment with TNFalpha elevated Akt phosphorylation in glioma cells . Increased in Akt phosphorylation was concurrent with the decrease in ROS scavenger SOD-1 levels . TNFalpha mediated increase in Akt phosphorylation was dependent on oxidative stress as Akt phosphorylation was abrogated in the presence of ROS inhibitor and elevated in cells transfected with SOD-1 siRNA . TNFalpha altered actin cytoskeletal organization and increased Cdc42 levels . This increase in Cdc42 was concomitant with its increased interaction with scaffold protein IQGAP-1 . Also , we report for the first time a ROS dependent interaction between pAkt and IQGAP-1 in TNFalpha treated cells . Importantly , Akt inhibition not only reversed TNFalpha mediated changes in actin cytoskeletal organization but also abrogated anchorage independent growth . Together , these results suggest that TNFalpha induced oxidative stress affects Akt activation to regulate actin organization and growth of glioma cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19836430"}
{"sentence": "Tumor metastasis represents a complex multistep process that requires migration , invasion , and angiogenesis . In this study , we examined the impact of molecular blockade of the epidermal growth factor receptor on the invasive and metastatic capacity of human squamous cell carcinoma ( SCC ) of the head and neck using in vitro and in vivo model systems . Treatment with the anti-epidermal growth factor receptor antibody C225 attenuated the migration of SCC-1 tumor cells through a chemotaxis chamber in a dose-dependent manner . Incubation of SCC cells with 10-100 nM C225 for 4 h resulted in 40-60% inhibition of cell migration . Furthermore , in the presence of C225 , the capacity of SCC-1 to invade across a layer of extracellular matrix ( Matrigel ) was significantly inhibited . Using an in vivo orthotopic floor-of-mouth xenograft model , locoregional tumor invasion of SCC-1 into muscle , vessel , bone , and perineural tissues was inhibited in C225-treated mice . This inhibition was additionally characterized by down-regulation in the expression of matrix metalloproteinase-9 . These data suggest that inhibition of metastatic potential by C225 may be mediated via decreased migration and invasion of SCC cells . Regarding angiogenesis in vitro , we first studied human umbilical vascular endothelial cells , which established a capillary-like network structure ( tube formation ) in the presence of reconstituted Matrigel . Treatment with C225 reduced cell-to-cell interaction of human umbilical vascular endothelial cells , resulting in disruption of tube formation . The effect of C225 was additionally examined using an in vivo tumor xenograft neovascularization model of angiogenesis . Systemic treatment with C225 not only reduced tumor growth and the number of blood capillaries but also hindered the growth of established vessels toward the tumor . Taken together , these results provide evidence that C225 can suppress tumor-induced neovascularization and metastasis in SCC of the head and neck .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12479268"}
{"sentence": "OBJECTIVES Human neutrophil proteins-1 , -2 , and -3 ( HNPs -1 , -2 , and -3 ) are expressed in several tumor types . However , the role of HNPs 1-3 in human bladder cancer has not yet been determined . We investigated the association between the plasma levels of HNPs 1-3 and clinicopathological parameters in bladder cancer patients . DESIGN AND METHODS The plasma levels of HNPs 1-3 were measured in 60 patients with bladder cancer and in 58 healthy controls . The plasma levels of HNPs 1-3 were determined by a solid-phase enzyme-linked immunosorbent assay ( ELISA ) . Plasma samples were obtained before surgery . Plasma samples were permitted to clot and were then stored at -80 \ufffdC until use . RESULTS The levels of the HNPs increased from grade 1 to 4 tumors and this difference was statistically significant ( p < 0.001 ) . Additionally , plasma HNP levels were significantly higher in patients with metastatic bladder cancer and in patients with lymphovascular involvement , metastasis of the lymph nodes , and increased tumor burden ( p < 0.001 ) . CONCLUSIONS The preoperative plasma levels of HNPs 1-3 paralleled the progression and pathological stages of the malignancies . This study suggests that HNPs 1-3 promote tumor invasion and are potential indicators of disease progression in patients with bladder cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23011762"}
{"sentence": "Clinical data and biological samples were prospectively collected in 42 children with lymphoproliferative disease ( LPD ) secondary to organ/bone marrow transplant-related immunosuppression ( 30 : 11 liver , 10 heart/lung , 8 kidney and 1 bone marrow ) , other drug-induced immunosuppression ( 2 ) , congenital immunodeficiency ( 8 ) or human immunodeficiency virus ( HIV)-related immune dysfunction ( 2 ) . Ages ranged from 10 months to 17 years and there were 15 girls . Pathology was centrally reviewed and showed polymorphic features in 5 cases , monomorphic in 23 , mixed pattern in 5 patients and 9 other types . Using the Revised European-American Classification of Lymphoid Neoplasms , 5 were B lymphoblastoid , 24 were high-grade B and 14 were other subtypes . Using the Pittsburgh classification , 9 were lymphadenopathic , 10 were systemic , 25 were lymphomatous and , with the Murphy grouping for non-Hodgkin's lymphoma ( NHL ) , 10 were localized and 32 non-localized . Twenty-four out of 38 evaluable cases were Epstein-Barr virus positive . Thirty-five patients were evaluable for clonality ; 24 were monoclonal and 11 were polyclonal . Reduced immunosuppression in solid organ transplant patients resulted in resolution of disease in 14/24 , which was sustained in 11 . Nineteen patients received chemotherapy , 14/18 evaluable responded , which was sustained in 8 cases . Seven out of 29 solid organ transplant and 10/13 other immune-deficient patients died . In the largest group of patients , solid organ transplants , no significant clinical or biological characteristics that predicted outcome were identified . In the transplant group close monitoring of response during reduction in immunosuppression is essential and the early use of B NHL chemotherapy may be effective .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12139732"}
{"sentence": "Our recent studies have mechanistically demonstrated that cancer-associated fibroblasts ( CAFs ) produce energy-rich metabolites that functionally support the growth of cancer cells . Also , several authors have demonstrated that DNA instability in the tumor stroma greatly contributes to carcinogenesis . To further test this hypothesis , we stably knocked-down BRCA1 expression in human hTERT-immortalized fibroblasts ( shBRCA1 ) using an shRNA lentiviral approach . As expected , shBRCA1 fibroblasts displayed an elevated growth rate . Using immunofluorescence and immunoblot analysis , shBRCA1 fibroblasts demonstrated an increase in markers of autophagy and mitophagy . Most notably , shBRCA1 fibroblasts also displayed an elevation of HIF-1\u03b1 expression . In accordance with these findings , shBRCA1 fibroblasts showed a 5.5-fold increase in ketone body production ; ketone bodies function as high-energy mitochondrial fuels . This is consistent with the onset of mitochondrial dysfunction in BRCA1-deficient fibroblasts . Conversely , after 48 h of co-culturing shBRCA1 fibroblasts with a human breast cancer cell line ( MDA-MB-231 cell ) , mitochondrial activity was enhanced in these epithelial cancer cells . Interestingly , our preclinical studies using xenografts demonstrated that shBRCA1 fibroblasts induced an increase in tumor growth when co-injected with MDA-MB-231 cells into nude mice . We conclude that a BRCA1 deficiency in the tumor stroma metabolically promotes cancer progression , via ketone production .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23047605"}
{"sentence": "BACKGROUND Hesperidin , a flavanone present in citrus fruits , has been identified as a potent anticancer agent because of its proapoptotic and antiproliferative characteristics in some tumor cells . However , the precise mechanisms of action are not entirely understood . AIM The main purpose of this study is to investigate the involvement of peroxisome proliferator-activated receptor-gamma ( PPAR\u03b3 ) in hesperidin's anticancer actions in human pre-B NALM-6 cells , which expresses wild-type p53 . METHODS The effects of hesperidin on cell-cycle distribution , proliferation , and caspase-mediated apoptosis were examined in NALM-6 cells in the presence or absence of GW9662 . The expression of peroxisome proliferator-activated receptor-gamma ( PPAR\u03b3 ) , p53 , phospho-I\u03baB , Bcl-2 , Bax , and XIAP proteins were focused on using the immunoblotting assay . The transcriptional activities of PPAR\u03b3 and nuclear factor-kappaB ( NF-\u03baB ) were analyzed by the transcription factor assay kits . The expression of PPAR\u03b3 and p53 was analyzed using the RT-PCR method . RESULTS Hesperidin induced the expression and transcriptional activity of PPAR\u03b3 and promoted p53 accumulation and downregulated constitutive NF-\u03baB activity in a PPAR\u03b3-dependent and PPAR\u03b3-independent manner . The growth-inhibitory effect of hesperidin was partially reduced when the cells preincubated with PPAR\u03b3 antagonist prior to the exposure to hesperidin . CONCLUSIONS The findings of this study clearly demonstrate that hesperidin-mediated proapoptotic and antiproliferative actions are regulated via both PPAR\u03b3-dependent and PPAR\u03b3-independent pathways in NALM-6 cells . These data provide the first evidence that hesperidin could be developed as an agent against hematopoietic malignancies .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21445621"}
{"sentence": "Stress-induced phosphoprotein 1 ( STIP1 ) , a cochaperone that organizes other chaperones , heat shock proteins ( HSPs ) , was recently shown to be secreted by human ovarian cancer cells . In neuronal tissues , binding to prion protein was required for STIP1 to activate the ERK ( extracellular-regulated MAP kinase ) signaling pathways . However , we report that STIP1 binding to a bone morphogenetic protein ( BMP ) receptor , ALK2 ( activin A receptor , type II-like kinase 2 ) , was necessary and sufficient to stimulate proliferation of ovarian cancer cells . The binding of STIP1 to ALK2 activated the SMAD signaling pathway , leading to transcriptional activation of ID3 ( inhibitor of DNA binding 3 ) , promoting cell proliferation . In conclusion , ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways . Although animal studies are needed to confirm these mechanisms in vivo , our results may pave the way for developing novel therapeutic strategies for ovarian cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22884369"}
{"sentence": "Compound C , a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase ( AMPK ) , has been reported to cause apoptotic cell death in myeloma , breast cancer cells and glioma cells . In this study , we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells . Compound C can induce upregulation , phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma ( BCC ) cells . The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species ( ROS ) generation and associated with activated ataxia-telangiectasia mutated ( ATM ) protein . Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines , we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy . The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression . Overall , our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status .", "label": [0, 0, 0, 0, 1, 1, 0, 1, 1, 1], "id": "23274516"}
{"sentence": "When cells were incubated in the presence of both interferon-gamma ( IFN-gamma ) and all-trans retinoic acid ( ATRA ) , the concentration of IFN-gamma required to induce apoptosis of B-cell lymphoma cells was much lower than that required for myeloid or erythroid cell lines . The concentration of IFN-gamma that effectively inhibited the proliferation of BALM-3 cells was 1/40 of that required for BALM-1 cells . STAT-1 phosphorylation , IRF-1 mRNA and protein expression and RAR-beta expression were enhanced to a greater degree in BALM-3 cells treated with IFN-gamma and ATRA than in BALM-1 cells treated with IFN-gamma and ATRA , suggesting that these IFN-gamma related genes were involved in the induction of apoptosis of BALM-3 cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12191570"}
{"sentence": "BACKGROUND In this report , we explored the role of PKCalpha and PKCe as mediators of phorbol 12-myristate13-acetate ( PMA)-induced proliferation in pituitary tumor GH3B6 cells , and determined if the ERK1/2 and Akt pathways were activated . METHODS The GH3B6 cell proliferation was estimated by BrdU incorporation and the cell cycle progression by flow cytometric cell cycle analysis . We determined the expression of PKCalpha and PKCe in membrane and cytosolic fractions by western blotting . The subcellular redistribution of both PKC isozymes was analyzed by confocal microscopy . RESULTS Incubation with PMA for 15 min stimulated PKCalpha and PKCe activation , which was correlated with the phosphorylation of ERK1/2 but not Akt . The activation of both these PKC isozymes was closely associated with the stimulation of proliferation and the cell cycle progression induced by PMA in GH3B6 cells , an effect that was blocked by the inhibitors of PKCalpha ( G\u00f66976 ) and PKCe ( eV1-2 ) . In addition , the pretreatment with the inhibitor of ERK1/2 ( PD98059 ) prevented the mitogenic activity induced by treatment with PMA for 15 min . CONCLUSION We demonstrated that the activation of PKCalpha and PKCe by phorbol ester in tumor pituitary GH3B6 cells led to cell proliferation and cell cycle progression , effects that involved ERK1/2 activation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20798497"}
{"sentence": "In eukaryotic cells , multiple DNA repair mechanisms respond to a wide variety of DNA lesions . Homologous recombination-dependent repair provides a pathway for dealing with DNA double-strand breaks and replication fork demise . A key step in this process is the resolution of recombination intermediates such as Holliday junctions ( HJs ) . Recently , nucleases from yeast ( Yen1 ) and human cells ( GEN1 ) were identified that can resolve HJ intermediates , in a manner analogous to the E. coli HJ resolvase RuvC . Here , we have analyzed the role of Yen1 in DNA repair in S. cerevisiae , and show that while yen1Delta mutants are repair-proficient , yen1Delta mus81Delta double mutants are exquisitely sensitive to a variety of DNA-damaging agents that disturb replication fork progression . This phenotype is dependent upon RAD52 , indicating that toxic recombination intermediates accumulate in the absence of Yen1 and Mus81 . After MMS treatment , yen1Delta mus81Delta double mutants arrest with a G2 DNA content and unsegregated chromosomes . These findings indicate that Yen1 can act upon recombination/repair intermediates that arise in MUS81-defective cells following replication fork damage .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20106725"}
{"sentence": "The human asparaginase-like protein 1 ( hASRGL1 ) catalyzes the hydrolysis of l-asparagine and isoaspartyl-dipeptides . As an N-terminal nucleophile ( Ntn ) hydrolase superfamily member , the active form of hASRGL1 is generated by an intramolecular cleavage step with Thr168 as the catalytic residue . However , in vitro , autoprocessing is incomplete ( fettering the biophysical characterization of hASRGL1 . We circumvented this obstacle by constructing a circularly permuted hASRGL1 that uncoupled the autoprocessing reaction , allowing us to kinetically and structurally characterize this enzyme and the precursor-like hASRGL1-Thr168Ala variant . Crystallographic and biochemical evidence suggest an activation mechanism where a torsional restraint on the Thr168 side chain helps drive the intramolecular processing reaction . Cleavage and formation of the active site releases the torsional restriction on Thr168 , which is facilitated by a small conserved Gly-rich loop near the active site that allows the conformational changes necessary for activation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22891768"}
{"sentence": "Therapy-induced senescence ( TIS ) , a cytostatic stress response in cancer cells , is induced inefficiently by current anticancer agents and radiation . The mechanisms that mediate TIS in cancer cells are not well defined . Herein , we characterize a robust senescence response both in vitro and in vivo to the quinone diaziquone ( AZQ ) , previously identified in a high-throughput senescence-induction small-molecule screen . Using AZQ and several other agents that induce senescence , we screened a series of cyclin-dependent kinase inhibitors and found that p27(Kip1) was induced in all investigated prostate cancer cell lines . The ubiquitin-ligase Skp2 negatively regulates p27(Kip1) and , during TIS , is translocated to the cytoplasm before its expression is decreased in senescent cells . Overexpression of Skp2 blocks the effects of AZQ on senescence and p27(Kip1) induction . We also find that stable long-term short hairpin RNA knockdown of Skp2 decreases proliferation but does not generate the complete senescence phenotype . We conclude that Skp2 participates in regulating TIS but , alone , is insufficient to induce senescence in cancer cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "22937180"}
{"sentence": "In the present study , post-treatment effects of dietary turmeric on markers related to apoptosis , cell proliferation , and inflammation in 7,12-dimethylbenz(a)anthracene ( DMBA)-induced hamster buccal pouch ( HBP ) tumors were investigated . Tumors were induced by applying 0.5% DMBA topically to the HBP three times per week for 12 weeks . After tumor development , half of the animals continued on the control diet and the other half were shifted to a 1% turmeric diet for 4 weeks . To rule out DMBA discontinuation as a cause of inhibition in tumor growth , DMBA treatment was continued during dietary exposure of turmeric in another set of animals until the end of the experiment . The turmeric diet inhibited tumor growth in animals with or without DMBA carcinogen treatment compared to the animals on the control diet . When compared to hamsters bearing tumors that remained on the control diet , the buccal pouches of hamsters bearing tumors receiving turmeric showed the following results : ( 1 ) decreased cell proliferation ( diminished PCNA , cyclin D1 , and Bcl-2 ) and PCNA labelling index , ( 2 ) enhanced apoptosis ( increased Bax , caspase-3 , caspase-9 , and cytochrome c , and decreased survivin ) and apoptotic index , ( 3 ) decreased inflammation ( decreased Cox-2 ) , and ( 4 ) decreased MAPK activation ( p-ERK and p-p38 ) . These data indicate that tumor growth decreased due to the modulation of cellular pathways associated with cell proliferation and apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 1], "id": "23394443"}
{"sentence": "Pam3CSK4 , a synthetic TLR2 ligand , has been shown to expand CD4+ regulatory T cells ( Treg cells ) . Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy ( IT ) . This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population . PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times : before IT and 6 mo and 1 y after the maximum-tolerated dose . This study was performed without a placebo-controlled group . D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production . Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition . TUNEL revealed that CD8+CD25+ Treg cells , but not CD4+CD25+ Treg cells , directly induced CD4+CD45ROhi+ apoptosis . Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells ; therefore , it may be a good adjuvant for the treatment of mite allergies .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "20483759"}
{"sentence": "The aryl hydrocarbon receptor ( AhR ) contributes to the control of cell-to-cell communication , cell adhesion , migration or proliferation . In the present study , we investigated the regulation of connexin43 ( Cx43 ) and Cx43-mediated gap junctional intercellular communication ( GJIC ) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells . The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells , which is frequently abolished in cancer cells ; however , the mechanisms contributing to its disruption are still only partially understood . Disruption of contact inhibition , which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD ) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells , reduced Cx43 protein levels , possibly via enhanced proteasomal degradation , significantly decreased the amount of gap junction plaques and downregulated GJIC , in an AhR-dependent manner . Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD , siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells . Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition , which occurs at the post-transcriptional level . This process runs in parallel with alterations of other forms of cell-to-cell communication , thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC , two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23085979"}
{"sentence": "Obesity and related metabolic abnormalities are risk factors for colorectal cancer . A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis . Statins , which are commonly used for the treatment of hyperlipidemia , are known to possess anti-inflammatory effects . Statins also exert chemopreventive properties against various cancers . The present study examined the effects of pitavastatin , a recently developed lipophilic statin , on the development of azoxymethane ( AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db ( db/db ) obese mice . Male db/db mice were administrated weekly subcutaneous injections of AOM ( 15 mg/kg body weight ) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks . Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions , beta-catenin accumulated crypts , by inhibiting proliferation and the surrounding inflammation . Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol , tumor necrosis factor-alpha ( TNF-alpha ) , interleukin ( IL)-6 , IL-18 , and leptin . Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase ( AMPK ) protein on the colonic mucosa of AOM-treated mice . In addition , the expression levels of TNF-alpha , IL-6 , IL-18 , and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent . These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines , both of which are caused by the presence of excess adipose tissues , thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model . Therefore , some types of statins , including pitavastatin , may be a useful chemoprevention modality for colon cancer in obese individuals .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20398056"}
{"sentence": "We present a novel gain-of-function mutation of TGF-\u03b2 receptor II ( T\u03b2RII ) found in human oral squamous cell carcinoma ( OSCC ) . Expression of E221V/N238I mutant T\u03b2RII enhanced TGF-\u03b2 signaling . Mutation of T\u03b2RII conferred cells higher migratory and invasive capabilities and MMP-2 activity . In mouse tumor model , mutant tumors exhibited poor differentiation and E-cadherin relocalization to the cytosol . Lipid-raft-dependent endocytosis of T\u03b2RII was attenuated in mutant T\u03b2RII , suggesting that enhancement of TGF-\u03b2 signaling by this mutation is due to delayed T\u03b2RII internalization . Taken together , our results show a novel gain-of-function T\u03b2RII mutation , which enhances TGF-\u03b2 signaling leading to more invasive phenotypic changes in human OSCC .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "22093616"}
{"sentence": "Recent advances allow multiplexed genome engineering in E. coli , employing easily designed oligonucleotides to edit multiple loci simultaneously . A similar technology in human cells would greatly expedite functional genomics , both by enhancing our ability to test how individual variants such as single nucleotide polymorphisms ( SNPs ) are related to specific phenotypes , and potentially allowing simultaneous mutation of multiple loci . However , oligo-mediated targeting of human cells is currently limited by low targeting efficiencies and low survival of modified cells . Using a HeLa-based EGFP-rescue reporter system we show that use of modified base analogs can increase targeting efficiency , in part by avoiding the mismatch repair machinery . We investigate the effects of oligonucleotide toxicity and find a strong correlation between the number of phosphorothioate bonds and toxicity . Stably EGFP-corrected cells were generated at a frequency of with an optimized oligonucleotide design combining modified bases and reduced number of phosphorothioate bonds . We provide evidence from comparative RNA-seq analysis suggesting cellular immunity induced by the oligonucleotides might contribute to the low viability of oligo-corrected cells . Further optimization of this method should allow rapid and scalable genome engineering in human cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22615794"}
{"sentence": "Patients on hemodialysis ( HD ) who undergo lung resection represent a high risk group requiring a careful perioperative management . To access a cardiac risk of HD patients a complete cardiac examination must be conducted preoperatively . The patients should undergo sufficient courses of HD to ameliorate electrolyte imbalance and volume disturbance before surgery . An elective operation should be scheduled on the day after HD . During operation , gentle operative maneuver and complete hemostatic technique are required to reduce a risk of postoperative bleeding . An adequate amount of antibiotics should be administrated to avoid a surgical site infection . Pulmonary edema due to volume overload and hyperkalemia are the most dangerous postoperative complications . Infusion should be conducted with potassium-free solution at 20 ml/h until the restart of HD . HD could be safely performed with nafamostat mesilate on the day after operation in most patients . If hyperkalemia and pulmonary edema are resistant to conservative managements , an emergency HD is required . Prognosis after lung resection for lung cancer patients on HD is not satisfactory . Many patients die of non cancer related causes such as heart failure and infection . Long term management of the underlying renal condition is necessary to improve their postoperative survival .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22868436"}
{"sentence": "NIH-3T3 cells are non-tumorigenic when injected into athymic mice . If these cells are mixed with an extract of basement-membrane proteins ( matrigel ) and injected s.c. , they form locally invasive and highly vascularized tumors . Cells cultured from the NIH-3T3-matrigel-induced tumors showed a transformed phenotype and lacked contact inhibition . When cultured in a gel of matrigel , they proliferated and formed branched and invasive colonies . In contrast , the parental NIH-3T3 cells cultured on matrigel remained as cell aggregates and were not invasive . I.V. injections of the tumor-derived NIH-3T3 cells produced many colonies on the surface of the lungs , whereas the parental NIH-3T3 cells were not metastatic . Zymographic analysis of the conditioned media obtained from both the tumor-derived and parental NIH-3T3 cells demonstrated higher amounts of the 72-kDa gelatinase ( type-IV collagenase ) enzyme in the tumor-derived cells . Also , tumor-derived NIH-3T3 cells , but not parental NIH-3T3 cells , secreted the 92-kDa type-IV collagenase . These studies suggest that the interaction of pre-malignant NIH-3T3 cells with extracellular matrix components may contribute to the process of tumor progression .", "label": [1, 0, 0, 0, 1, 0, 1, 0, 0, 0], "id": "1319408"}
{"sentence": "Cancer vaccines based on human tumor-associated antigens ( TAA ) have been tested in patients with advanced or recurrent cancer , in combination with or following standard therapy . Their immunogenicity and therapeutic efficacy has been difficult to properly evaluate in that setting characterized by multiple highly suppressive effects of the tumor and the standard therapy on the patient's immune system . In animal models of human cancer , vaccines administered in the prophylactic setting are most immunogenic and effectively prevent cancer development and progression . We report results of a clinical study that show that in patients without cancer but with a history of premalignant lesions ( advanced colonic adenomas , precursors to colon cancer ) , a vaccine based on the TAA MUC1 was highly immunogenic in 17 of 39 ( 43.6% ) of vaccinated individuals , eliciting high levels of anti-MUC1 immunoglobulin G ( IgG ) and long-lasting immune memory . Lack of response in 22 of 39 individuals was correlated with high levels of circulating myeloid-derived suppressor cells ( MDSC ) prevaccination . Vaccine-elicited MUC1-specific immune response and immune memory were not associated with significant toxicity . Our study shows that vaccines based on human TAAs are immunogenic and safe and capable of eliciting long-term memory that is important for cancer prevention . We also show that in the premalignant setting , immunosuppressive environment ( e.g. , high levels of MDSC ) might already exist in some individuals , suggesting an even earlier premalignant stage or preselection of nonimmunosuppressed patients for prophylactic vaccination . Cancer Prev Res ; 6(1) ; 18-26. \ufffd2012 AACR .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23248097"}
{"sentence": "Histone deacetylase inhibitors induce cell cycle arrest and apoptosis in tumor cells and are , therefore , promising anti-cancer drugs . The cyclin-dependent kinase inhibitor p21 is activated in histone deacetylase ( HDAC ) inhibitor-treated tumor cells , and its growth-inhibitory function contributes to the anti-tumorigenic effect of HDAC inhibitors . We show here that induction of p21 by trichostatin A involves MAP kinase signaling . Activation of the MAP kinase signaling pathway by growth factors or stress signals results in histone H3 serine 10 phosphorylation at the p21 promoter and is crucial for acetylation of the neighboring lysine 14 and recruitment of activated RNA polymerase II in response to trichostatin A treatment . In non-induced cells , the protein phosphatase PP2A is associated with the p21 gene and counteracts its activation . Induction of p21 is linked to simultaneous acetylation and phosphorylation of histone H3 . The dual modification mark H3S10phK14ac at the activated p21 promoter is recognized by the phospho-binding protein 14-3-3\u03b6 , which protects the phosphoacetylation mark from being processed by PP2A . Taken together we have revealed a cross-talk of reversible phosphorylation and acetylation signals that controls the activation of p21 by HDAC inhibitors and identify the phosphatase PP2A as chromatin-associated transcriptional repressor in mammalian cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20952396"}
{"sentence": "In previous work , three suppressors of defective group I introns ( 7151 , 71N1 , 7120 ) were isolated from a mutant of Chlamydomonas reinhardtii that had a splicing-deficient chloroplast large subunit ( LSU ) rRNA intron . Genetic analysis indicated that the 7151 and 71N1 suppressor mutations each involved single nuclear loci , and that the 7151 mutation was dominant . Here we present genetic evidence that the 7120 suppressor also involves a single nuclear locus and that the mutation is dominant in vegetative diploids . Moreover , we have employed crosses with the S1D2 strain and molecular markers to map the 7120 and 71N1 suppressors . Based on an analysis of 800 progeny from 7120 \u00d7 S1D2 , the 7120 suppressor is located in a region of kb on chromosome III that is devoid of recombination . The region contains at least 72 genes , about one-third of which ( i.e. , 22 ) are predicted to be organelle targeted . Similar analysis of 71N1 \u00d7 S1D2 using 400 progeny also pointed to the recombination-deficient region of chromosome III , raising the possibility that these mutations could affect the same gene . These efforts lay the foundation for identifying the css ( chloroplast splicing suppressor ) gene(s) , which promotes splicing of multiple chloroplast group I introns .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22708527"}
{"sentence": "P53 activity plays a key role in mammalian cells when they undergo replicative senescence at their Hayflick limit . To determine whether p63 proteins , members of the family of p53-related genes , are also involved in this process , we examined their expression in serially passaged rat embryo fibroblasts . Upon senescence , two truncated DeltaNp63 proteins decreased in abundance whereas two TAp63 isoforms accumulated. 2-D gel analysis showed that the DeltaNp63 proteins underwent post-translational modifications in both proliferating and senescent cells . Direct binding of DeltaNp63 proteins to a p53 consensus motif was greater in proliferating cells than senescent cells . In contrast p63alpha isoforms bound to DNA in a p53 dependent manner and this was higher in senescent cells than proliferating cells . An interaction of p63alpha proteins with SV40 large tumour antigen was also detected and ectopic expression of DeltaNp63alpha can extend the lifespan of rat embryo fibroblasts . Taken together the results indicate that p63 proteins may play a role in replicative senescence either by competition for p53 DNA binding sites or by direct interaction with p53 protein bound to DNA .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "11850815"}
{"sentence": "BACKGROUND The presence of distant metastases from colorectal cancer ( CRC ) does not preclude curative treatment . Early detection of pulmonary metastases at a potentially curable stage could improve survival . The aim of the present study was to assess the prognostic significance of commonly reported clinicopathologic features to identify high-risk patients who would likely benefit from more intensive chest surveillance for pulmonary metastases . MATERIAL AND METHOD A total of 351 consecutive patients , with surgical stages I-III colorectal cancer , who underwent curative resection at Phramongkutklao hospital from 1999 to 2005 , were followed regularly according to the established guidelines with routine physical examination , serum carcinoembryonic antigen ( CEA ) and colonoscopic surveillance . Imaging studies for detecting metastases were computed tomography ( CT ) , plain film radiography , and ultrasonograpy . Clinical and pathologic features were analyzed for their association with pulmonary metastasis . RESULTS There were 145 patients who had been operated for longer than five years after curative intent surgery . Of these , nineteen patients were lost to follow-up or died from other causes that were unrelated to colorectal cancer . Pulmonary metastases were detected in 26 patients by either CXR or CT scan . Median time to pulmonary metastasis was 19 months ( 95 percent CI , 12-35 ) . According to an univariate analysis , with log-rank test , identified four factors associated with pulmonary metastasis : Tumor stage T4 , Nodal stage N2 , elevation of serum CEA > 3.4 ng/ml and presence of lymphovascular invasion(LVI) . According to a multivariate analysis , with Cox regression , found an elevation of serum CEA > 3.4 ng/ml which was an independent factor that was significantly associated with pulmonary metastasis ( Hazard ratio ( HR ) , 8.9 ; 95 percent CI , 3.6-22 ; p < 0.01 ) . The present study revealed that 50 percent of patients who had more than one of these risk factors would eventually develop pulmonary metastases . CONCLUSION An elevation of serum CEA > or = 3.4 ng/ml was found as an independent factor that was significantly associated with pulmonary metastasis whereas tumor stage T4 , nodal stage N2 and presence of lymphovascular invasion ( LVI ) were not independent clinicopathologic features associated with subsequent pulmonary metastases . Chest CT scan has greater sensitivity than chest radiography in detection of pulmonary metastasis and should be considered as an imaging study of choice for intensive chest surveillance for patients who had more than one of these risk factors .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22934451"}
{"sentence": "Proliferating cell nuclear antigen ( PCNA ) , a potential anticancer target , forms a homotrimer and is required for DNA replication and numerous other cellular processes . The purpose of this study was to identify novel small molecules that modulate PCNA activity to affect tumor cell proliferation . An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners . Nine compounds , termed PCNA inhibitors ( PCNA-Is ) , were selected for further characterization . PCNA-I1 selectively bound to PCNA trimers with a dissociation constant ( K(d) ) of to 0.4 \u03bcM . PCNA-Is promoted the formation of SDS-refractory PCNA trimers . PCNA-I1 dose- and time-dependently reduced the chromatin-associated PCNA in cells . Consistent with its effects on PCNA trimer stabilization , PCNA-I1 inhibited the growth of tumor cells of various tissue types with an IC(50) of \u03bcM , whereas it affected the growth of nontransformed cells at significantly higher concentrations ( IC(50) , \u03bcM ) . Moreover , uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1 . Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA , inducing cancer cell arrest at both the S and G(2)/M phases . Thus , we have identified a class of compounds that can directly bind to PCNA , stabilize PCNA trimers , reduce PCNA association with chromatin , and inhibit tumor cell growth by inducing a cell cycle arrest . They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22399488"}
{"sentence": "BACKGROUND \u0393-Ionizing radiation ( IR ) therapy is one of major therapeutic tools in cancer treatment . Nevertheless , \u03b3-IR therapy failed due to occurrence of metastasis , which constitutes a significant obstacle in cancer treatment . The main aim of this investigation was to construct animal model which present metastasis during radiotherapy in a mouse system in vivo and establishes the molecular mechanisms involved . MATERIALS AND METHODS The C6L transfectant cell line expressing firefly luciferase ( fLuc ) was treated with \u03b3-IR , followed by immunoblotting , zymography and invasion assay in vitro . We additionally employed the C6L transfectant cell line to construct xenografts in nude mice , which were irradiated with \u03b3-IR . Irradiated xenograft-containing mice were analyzed via survival curves , measurement of tumor size , and bioluminescence imaging in vivo and ex vivo . Metastatic lesions in organs of mice were further assessed using RT-PCR , H & E staining and immunohistochemistry . RESULTS \u03b3-IR treatment of C6L cells induced epithelial-mesenchymal transition ( EMT ) and increased cell invasion . In irradiated xenograft-containing mice , tumor sizes were decreased dramatically and survival rates extended . Almost all non-irradiated xenograft-containing control mice had died within 4 weeks . However , we also observed luminescence signals in about 22.5% of \u03b3-IR-treated mice . Intestines or lungs of mice displaying luminescence signals contained several lesions , which expressed the fLuc gene and presented histological features of cancer tissues as well as expression of EMT markers . CONCLUSIONS These findings collectively indicate that occurrences of metastases during \u03b3-IR treatment accompanied induction of EMT markers , including increased MMP activity . Establishment of a murine metastasis model during \u03b3-IR treatment should aid in drug development against cancer metastasis and increase our understanding of the mechanisms underlying the metastatic process .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22963683"}
{"sentence": "PTEN loss of function enhances proliferation , but effects on cellular energy metabolism are less well characterized . We used an inducible PTEN expression vector in a PTEN-null glioma cell line to examine this issue . While proliferation of PTEN-positive cells was insensitive to increases in glucose concentration beyond 2.5mM , PTEN-null cells significantly increased proliferation with increasing glucose concentration across the normal physiologic range to approximately 10mM , coinciding with a shift to glycolysis and \" glucose addiction \" . This demonstrates that the impact of loss of function of PTEN is modified by glucose concentration , and may be relevant to epidemiologic results linking hyperglycemia to cancer risk and cancer mortality .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "19744772"}
{"sentence": "The capacity to repair DNA damage is an important factor that affects the therapeutic outcome in cancer treatment . To clarify the cellular repair response , we investigated the kinetics of DNA excision repair initiated by 1,3-bis(2-chloroethyl)-1-nitrosourea ( BCNU ) in human leukemia CCRF-CEM cells at an exponential growth phase in vitro . Using the alkaline single-cell gel electrophoresis ( comet ) assay , we quantitated the repair kinetics as the amount of DNA single-strand breaks that were generated from the incision and were diminished by the rejoining in the repair process . CEM cells could initiate DNA excision repair in response to BCNU by starting an incision reaction . However , the incision capacity came to a plateau at a concentration of 80 to 100 microM or after an incubation time of 90 to 120 minutes . When the cells were pulsed with 40 microM BCNU , the maximal incision occurred at the end of the incubation period , and the repair process was completed within 4 hours When cells were treated with 100 microM BCNU , the incised DNA was not rejoined at 4 hours , suggesting that the repair was not completed . Higher concentrations might surpass the cellular capacity for repair and would be associated with increased cell death . Evaluation of the repair process may provide a clue for therapeutic strategies to improve clinical efficacy if accelerated DNA repair is responsible for the drug resistance .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "12463595"}
{"sentence": "Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers . As chronic inflammations are associated with malignancies , it is important to prevent inflammation-mediated neoplastic formation , promotion and/or progression . One possible intervention will be using cancer chemopreventive agents such as curcumin ( CUR ) , a potent anti-inflammatory and anti-oxidative stress compound . Polyunsaturated fatty acids ( PUFA ) such as docosahexaenoic acid ( DHA ) or eicosapentaenoic acid ( EPA ) are potent anti-inflammatory agents by decreasing the production of inflammatory eicosanoids , cytokines , and reactive oxygen species ( ROS ) . The present study aims at examining whether CUR with DHA or EPA would have synergistic anti-inflammatory effects in RAW 264.7 cells . Non-toxic concentrations of single and combination of the compounds were investigated at 6 , 12 and 24h . The nitric oxide ( NO ) suppression effects were most prominent at 24h . All the combinations of CUR and DHA or EPA with lower concentrations of CUR 5 microM and 25 microM of DHA or EPA were found to have synergistic effects in suppressing LPS-stimulated NO and endogenous NO levels . Importantly , very low doses of CUR 2.5 microM and DHA or EPA of 0.78 microM could synergistically suppress the LPS-induced prostaglandin E(2) ( PGE(2) ) . The combinations were also found to suppress iNOS , COX-2 , 5-lipoxygenase ( 5-LOX ) and cPLA(2) but induce HO-1 . Taken together , the present study clearly shows the synergistic anti-inflammatory as well as anti-oxidative stress effects of CUR and PUFA .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19744468"}
{"sentence": "BACKGROUND Elevated levels of air pollution are associated with increased risk of lung cancer . Particulate matter ( PM ) contains transition metals that may potentiate neoplastic development through the induction of oxidative stress and inflammation , a lung cancer risk factor . Vanadium pentoxide ( V2O5 ) is a component of PM derived from fuel combustion as well as a source of occupational exposure in humans . In the current investigation we examined the influence of genetic background on susceptibility to V2O5-induced inflammation and evaluated whether V2O5 functions as a tumor promoter using a 2-stage ( initiation-promotion ) model of pulmonary neoplasia in mice . RESULTS A/J , BALB/cJ ( BALB ) , and C57BL/6J ( B6 ) mice were treated either with the initiator 3-methylcholanthrene ( MCA ; 10 microg/g ; i.p. ) or corn oil followed by 5 weekly aspirations of V2O5 or PBS and pulmonary tumors were enumerated 20 weeks following MCA treatment . Susceptibility to V2O5-induced pulmonary inflammation was assessed in bronchoalveolar lavage fluid ( BALF ) , and chemokines , transcription factor activity , and MAPK signaling were quantified in lung homogenates . We found that treatment of animals with MCA followed by V2O5 promoted lung tumors in both A/J ( 10.3 +/- 0.9 tumors/mouse ) and BALB ( 2.2 +/- 0.36 ) mice significantly above that observed with MCA/PBS or V2O5 alone ( P < 0.05 ) . No tumors were observed in the B6 mice in any of the experimental groups . Mice sensitive to tumor promotion by V2O5 were also found to be more susceptible to V2O5-induced pulmonary inflammation and hyperpermeability ( A/J>BALB>B6 ) . Differential strain responses in inflammation were positively associated with elevated levels of the chemokines KC and MCP-1 , higher NFkappaB and c-Fos binding activity , as well as sustained ERK1/2 activation in lung tissue . CONCLUSIONS In this study we demonstrate that V2O5 , an occupational and environmentally relevant metal oxide , functions as an in vivo lung tumor promoter among different inbred strains of mice . Further , we identified a positive relationship between tumor promotion and susceptibility to V2O5-induced pulmonary inflammation . These findings suggest that repeated exposures to V2O5 containing particles may augment lung carcinogenesis in susceptible individuals through oxidative stress mediated pathways .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20385015"}
{"sentence": "4-Hydroxy-2-nonenal ( HNE ) , a major racemic product of lipid peroxidation , reacts with histidine to form a stable HNE-histidine Michael addition-type adduct possessing three chiral centers in the cyclic hemiacetal structure . In the present study , we characterized configurational isomers of a HNE-N(alpha)-acetylhistidine adduct by NMR spectroscopy and by molecular orbital calculations . In addition , we raised monoclonal antibodies against ( R)-HNE-histidine and ( S)-HNE-histidine adducts , characterized their specificities , and examined in vivo localizations of each adduct under oxidative stress . To facilitate structural characterization of the configurational isomers of an HNE-histidine adduct , we prepared the ( R)-HNE-histidine and ( S)-HNE-histidine adducts by incubating N(alpha)-acetylhistidine with each HNE enantiomer , both of which provided two peaks ( Ra and Rb from ( R)-HNE-histidine and Sa and Sb from ( S)-HNE-histidine adducts ) in reversed-phase high-performance liquid chromatography . The NMR analysis showed that each peak was a mixture of two diastereomers . In addition , the analysis of the nuclear Overhauser effect enabled the determination of configurations of the eight isomers . The relative amounts of these isomers in the NMR analysis correlated with the relative energies calculated by molecular orbital methods . On the other hand , using ( R)-HNE-modified and ( S)-HNE-modified keyhole limpet hemocyanins as the antigens , we raised the monoclonal antibodies , mAbR310 and mAbS412 , which enantioselectively recognized the ( R)-HNE-histidine and ( S)-HNE-histidine adducts , respectively . Among the mixtures ( Ra , Rb , Sa , and Sb ) of diastereomers , mAbR310 showed the highest immunoreactivity to Rb ( the mixture of 2R,4S,5R and 2S,4S,5R isomers ) , whereas mAbS412 preferentially recognized Sa ( the mixture of 2R,4S,5S and 2S,4S,5S isomers ) . The presence of ( R)-HNE and ( S)-HNE epitopes in vivo was immunohistochemically examined in the kidney of rats exposed to the renal carcinogen , ferric nitrilotriacetate , by which nuclear and cytosolic stainings with mAbR310 and mAbS412 , respectively , were detected .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12473681"}
{"sentence": "The role of T cells in eradicating leukemic cells has been well demonstrated for chronic myeloid leukemia ( CML ) . Type 1 ( T1 ) T-cell cytokines play a major role in this antileukemic immune effect . Studies in cancer patients have demonstrated a decreased T1 cytokine production , measured by enzyme-linked immunosorbent assay ( ELISA ) , in cultures of peripheral blood mononuclear cells . This observation of malignancy-related suppressed T1 cytokines also occurs in untreated chronic-phase ( CP ) CML , raising the question of the influence of different CML treatment regimens on this immunosuppression . Intracellular flow cytometry ( ICF ) has facilitated the evaluation of cytokines on a single-cell level . This study analyzed T1 ( interferon-gamma ) cytokine production in purified peripheral blood T cells by ICF , comparing different therapy approaches for CML . Twenty-one newly diagnosed CP CML patients were compared with 24 patients treated with interferon-alpha ( IFN-alpha ) and to 30 allogeneic bone marrow transplant ( BMT ) recipients ( BCR-ABL negative by reverse-transcriptase polymerase chain reaction , and free of , or having only limited graft-versus-host disease at the time of study ) . Thirty-seven healthy controls were included . Our results showed a significantly decreased T-cell IFN-gamma synthesis in CP CML patients in relation to healthy controls ( P = 0.0007 ) . Treatment with IFN-alpha resulted in a shift from immunosuppression--documented for the group of untreated patients--to immunopotentiation , with an increase of T-cell IFN-gamma production ( P = 0.0266 ) . Notably , BMT enhanced IFN-gamma production of T cells to a level not only exceeding untreated patients ( P < 0.0001 ) but also healthy volunteers ( P < 0.0001 ) . The observation of T1 cytokine up-regulation with IFN-alpha therapy indicates that enhanced T-cell function may be achievable in patients with CML , even in the absence of an allo-response .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12607798"}
{"sentence": "Estrogen receptor \u03b1 ( ER\u03b1 ) expression in breast cancer is predictive of response to endocrine therapy ; however , resistance is common in ER\u03b1-positive tumors that overexpress the growth factor receptor ERBB2 . Even in the absence of estrogen , ER\u03b1 can be activated by growth factors , including the epidermal growth factor ( EGF ) . EGF induces a transcriptional program distinct from estrogen ; however , the mechanism of the stimulus-specific response is unknown . Here we show that the EGF-induced ER\u03b1 genomic targets , its cistromes , are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1 . The EGF-induced ER\u03b1 cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers . This provides a potential molecular explanation for the endocrine therapy resistance seen in ER\u03b1-positive breast cancers that overexpress ERBB2 . These results suggest a central role for ER\u03b1 in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ER\u03b1 , as opposed to blocking its estrogen responsiveness alone .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20889718"}
{"sentence": "Reversine is a small synthetic molecule that inhibits multiple mitotic kinases , including MPS1 as well as Aurora kinase A and B ( AURKA and AURKB ) . Here , we investigated the effects of reversine on p53-deficient vs p53-proficient cancer cells . We found that low doses ( \ufffdM ) of reversine , which selectively inhibit MPS1 and hence impair the spindle assembly checkpoint , kill human TP53 ( -/- ) colon carcinoma cells less efficiently than their wild-type counterparts . In sharp contrast , high doses ( \ufffdM ) of reversine induced hyperploidization and apoptosis to a much larger extent in TP53 ( -/- ) than in TP53 ( +/+ ) cells . Such a selective cytotoxicity could not be reproduced by the knockdown of MPS1 , AURKA and AURKB , neither alone nor in combination , suggesting that it involves multiple ( rather than a few ) molecular targets of reversine . Videomicroscopy-based cell fate profiling revealed that , in response to high-dose reversine , TP53 ( -/- ) ( but not TP53 ( +/+ ) ) cells undergo several consecutive rounds of abortive mitosis , resulting in the generation of hyperpolyploid cells that are prone to succumb to apoptosis upon the activation of mitotic catastrophe . In line with this notion , the depletion of anti-apoptotic proteins of the BCL-2 family sensitized TP53 ( -/- ) cells to the toxic effects of high-dose reversine . Moreover , the knockdown of BAX or APAF-1 , as well as the chemical inhibition of caspases , limited the death of TP53 ( -/- ) cells in response to high-dose reversine . Altogether , these results suggest that p53-deficient cells are particularly sensitive to the simultaneous inhibition of multiple kinases , including MPS1 , as it occurs in response to high-dose reversine .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22592527"}
{"sentence": "BACKGROUND Chemokines are involved in multiple aspects of pathogenesis and cellular trafficking in tumorigenesis . In this study , we report that the latest member of the C-X-C-type chemokines , CXCL17 ( DMC/VCC-1 ) , recruits immature myeloid-derived cells and enhances early tumor progression . METHODOLOGY/PRINCIPAL FINDINGS CXCL17 was preferentially expressed in some aggressive types of gastrointestinal , breast , and lung cancer cells . CXCL17 expression did not impart NIH3T3 cells with oncogenic potential in vitro , but CXCL17-expressing NIH3T3 cells could form vasculature-rich tumors in immunodeficient mice . Our data showed that CXCL17-expressing tumor cells increased immature CD11b(+)Gr1(+) myeloid-derived cells at tumor sites in mice and promoted CD31(+) tumor angiogenesis . Extensive chemotactic assays proved that CXCL17-responding cells were CD11b(+)Gr1(high)F4/80(-) cells ( \u2248 90% ) with a neutrophil-like morphology in vitro . Although CXCL17 expression could not increase the number of CD11b(+)Gr1(+) cells in tumor-burdened SCID mice or promote metastases of low metastatic colon cancer cells , the existence of CXCL17-responding myeloid-derived cells caused a striking enhancement of xenograft tumor formation . CONCLUSIONS/SIGNIFICANCE These results suggest that aberrant expression of CXCL17 in tumor cells recruits immature myeloid-derived cells and promotes tumor progression through angiogenesis .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22952881"}
{"sentence": "WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Previous studies have indicated that the levels of DNA damage induced in peripheral blood mononuclear cells by the alkylating drugs melphalan , cisplatin and carboplatin can serve as useful biomarkers predictive of the therapeutic response of cancer patients to these drugs . WHAT THIS STUDY ADDS In the present study we developed a quantitative PCR-based assay , for the measurement of DNA damage . The advantages of this methodology are based on : its far greater sensitivity ( about 250 times ) than the traditional Southern blot-based method ( the detection limit is lesions/10(6) nucleotides from the equivalent DNA of cells ) ; its simplicity and speed ( results obtained within its excellent reproducibility , with a coefficient of variance of 10-15% for different DNA preparations from similarly treated cells ; its requirement for only minute amounts of material , and ; the avoidance of radioisotope labeling . Moreover , emphasis was given to translate basic research findings into clinical practice through the validation of this assay for prediction of clinical outcome in multiple myeloma patients . AIM In order to develop and validate a simple , sensitive and rapid method for the quantitation of alkylating drug-induced DNA damage . METHODS HepG2 cells and blood samples were treated with alkylating drugs ( melphalan , cisplatin , carboplatin ) . Gene-specific damage was examined using Southern blot and a multiplex long quantitative PCR ( QPCR ) carried out in a 7\\u2003kb fragment ( part of the p53 gene ) and a 0.5\\u2003kb fragment ( part of the IFN-\\u03b21 sequence ; internal standard ) . RESULTS The extent of PCR amplification of a p53 fragment was inversely proportional to the treatment concentrations of all anticancer drugs examined , indicating a dose-related inhibition by the DNA adducts formed . Parallel analysis of the same samples using both Southern blot and QPCR showed that the DNA adducts measured by QPCR corresponded to the interstrand cross-links in the case of melphalan , and to total drug-induced lesions in the case of the platinum drugs . The detection limit was lesions/10(6) nucleotides using DNA from cells . The method is about 250 times more sensitive than the Southern blot-based method and the reproducibility is excellent , with an intraday coefficient of variance ( CV ) of 5-9% and an interday CV of 4-12% . Application of the QPCR assay to ex vivo melphalan-treated peripheral blood mononuclear cells from multiple myeloma patients , showed that the positive predictive value of this assay for clinical response to melphalan therapy was 92.9% . CONCLUSION The PCR-based assay developed in this study can be used for the selection of cancer patients more likely to benefit from therapeutic treatment with alkylating drugs .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22432918"}
{"sentence": "OBJECTIVE To study the effect of Zilongjin ( ZLJ , a composite Chinese drug ) on proliferation and apoptosis of human breast carcinoma cell line MCF-7 . METHODS MCF-7 cells were randomly divided into four groups depending on the culture solution used , the control group , cultured with 1640 medium not contained ZLJ ; and the three ZJL groups cultured with medium contained low ( 1.5 mg/mL ) , moderate ( 3 mg/mL ) and high ( 6 mg/mL ) dosage of ZLJ crude drug respectively . The changes of cell proliferation were assessed by cell growth curve assay and methyl thiazolyl tetrazolium ( MTT ) assay . And the cell apoptosis was analyzed by flow cytometry , Hoechst 33342 staining and DNA ladder assay . RESULTS Compared with that in the normal control , the counts of cells in the three ZLJ groups were decreased significantly ( P<0.05 ) at such time point as 24 , 48 , 72 , 96 , 120 , and 144 h . Furthermore , apart from the comparison of the growth inhibition rate between the low and moderate dosage group at 24 and 72 h which were found to be no significant difference ( P>0.05 ) , the comparison f that among the three ZLJ groups appeared to be significant difference ( P<0.05 ) . The inhibitory effect of ZLJ on cell proliferation of MCF-7 was time- and dose-dependent ; it could retard cells in G0/G1 cell phase ; apoptosis of MCF-7 cell was induced by moderate and high dosage of ZLJ with revealing of apoptotic body and DNA ladder formation . CONCLUSION ZLJ shows cell proliferation inhibitory and apoptosis inducing effects on human breast cancer cell line MCF-7 , and thus to realize its anti-tumor action .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20353033"}
{"sentence": "Glycolysis is the initial step of glucose catabolism and is up-regulated in cancer cells ( the Warburg Effect ) . Such shifts toward a glycolytic phenotype have not been explored widely in other biological systems , and the molecular mechanisms underlying the shifts remain unknown . With proteomics , we observed increased glycolysis in disused human diaphragm muscle . In disused muscle , lung cancer , and H(2)O(2)-treated myotubes , we show up-regulation of the rate-limiting glycolytic enzyme muscle-type phosphofructokinase ( PFKm , >2 fold , P<0.05 ) and accumulation of lactate ( >150% , P<0.05 ) . Using microRNA profiling , we identify miR-320a as a regulator of PFKm expression . Reduced miR-320a levels ( to \\u223c50% of control , P<0.05 ) are associated with the increased PFKm in each of these diverse systems . Manipulation of miR-320a levels both in vitro and in vivo alters PFKm and lactate levels in the expected directions . Further , miR-320a appears to regulate oxidative stress-induced PFKm expression , and reduced miR-320a allows greater induction of glycolysis in response to H(2)O(2) treatment . We show that this microRNA-mediated regulation occurs through PFKm's 3 ' untranslated region and that Ets proteins are involved in the regulation of PFKm via miR-320a . These findings suggest that oxidative stress-responsive microRNA-320a may regulate glycolysis broadly within nature .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "22767230"}
{"sentence": "To evaluate a radioprotective effect of sodium n-propyl thiosulfate ( NPTS ) and sodium 2-propenyl thiosulfate ( 2PTS ) derived from onions and garlic , respectively , rat hepatoma H4IIE cells and mouse lymphoma L5178Y cells were preincubated with each of these compounds for 48 hours at 37\u00b0C before receiving 10 Gy of X-ray irradiation . Cell damage caused by the irradiation was quantified as comet tail moment , which represents the degree of DNA damage . X-ray-induced DNA damage was significantly decreased in both H4IIE and L5178Y cells by micromolar concentrations of NPTS and 2PTS compared with the control without the compounds . The protective effect was more potent with 2PTS than NPTS . Onions and garlic have antiradiation potential .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22919357"}
{"sentence": "The association between acute myeloid leukaemia ( AML ) and the aberrant expression of Hoxa9 is evidenced by ( 1 ) proviral activation of Hoxa9 and Meis1 in BXH-2 murine AML , ( 2 ) formation of the chimeric Nup98-HoxA9 transactivator protein as a consequence of the t(7;11) translocation in human AML , and ( 3 ) the strong expression of HoxA9 and Meis1 in human AML . In mouse models , enforced retroviral expression of Hoxa9 alone in marrow is not sufficient to cause rapid AML , while co-expression of Meis1 and Hoxa9 induces rapid AML . In contrast , retroviral expression of Nup98-HoxA9 is sufficient to cause rapid AML in the absence of enforced Meis1 expression . Previously , we demonstrated that Hoxa9 could block the differentiation of murine marrow progenitors cultured in granulocyte-macrophage colony-simulating factor ( GM-CSF ) . These progenitors lacked Meis1 expression , could not proliferate in stem cell factor ( SCF ) , but could differentiate into neutrophils when switched into granulocyte colony-simulating factor ( G-CSF ) . Ectopic expression of Meis1 in these Hoxa9 cells suppressed their G-CSF-induced differentiation , permitted proliferation in SCF , and therein offered a potential explanation of cooperative function . Because Meis1 binds N-terminal Hoxa9 sequences that are replaced by Nup98 , we hypothesized that Nup98-HoxA9 might consolidate the biochemical functions of both Hoxa9 and Meis1 on target gene promoters and might evoke their same lymphokine-responsive profile in immortalized progenitors . Here we report that Nup98-HoxA9 , indeed mimicks Hoxa9 plus Meis1 coexpression - it immortalizes myeloid progenitors , prevents differentiation in response to GM-CSF , IL-3 , G-CSF , and permits proliferation in SCF . Unexpectedly , however , Nup98-Hoxa9 also enforced strong transcription of the cellular Hoxa9 , Hoxa7 and Meis1 genes at levels similar to those found in mouse AML's generated by proviral activation of Hoxa9 and Meis1 . Using Hoxa9(-/-) marrow , we demonstrate that expression of Hoxa9 is not required for myeloid immortalization by Nup98-HoxA9 . Rapid leukaemogenesis by Nup98-HoxA9 may therefore result from both the intrinsic functions of Nup98-HoxA9 , as well as of those of coexpressed HOX and MEIS1 genes .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12082612"}
{"sentence": "To characterize the impact of increased production of TGF-beta in a xenograft model of human breast cancer , TGF-beta-responsive MDA-231 cells were genetically modified by stable transfection so as to increase their production of active TGF-beta1 . Compared with control cells , cells that produced increased amounts of TGF-beta proliferated in vitro more slowly . In vivo , however , tumors derived from these cells exhibited increased proliferation and grew at an accelerated pace . To evaluate the role of autocrine TGF-beta signaling , cells were also transfected with a dominant-negative truncated type II TGF-beta receptor ( TbetaRII ) . Disruption of autocrine TGF-beta signaling in the TGF-beta-overexpressing cells reduced their in vivo growth rate . Co-inoculation of Matrigel with the TGF-beta-overexpressing cells expressing the truncated TbetaRII compensated for their diminished in vivo growth capacity , compared with the TGF-beta-overexpressing cells with an intact autocrine loop . Tissue invasion by the tumor was a distinctive feature of the TGF-beta-overexpressing cells , whether or not the autocrine loop was intact . Furthermore , tumors derived from TGF-beta-overexpressing cells , irrespective of the status of the autocrine TGF-beta-signaling pathway , had a higher incidence of lung metastasis . Consistent with the suggestion that TGF-beta's enhancement of invasion and metastasis is paracrine-based , we observed no significant differences among the cell clones in an in vitro invasion assay . Thus , in this experimental model system in vitro assays of cell proliferation and invasion do not accurately reflect in vivo observations , perhaps due to autocrine and paracrine effects of TGF-beta that influence the important in vivo-based phenomena of tumor growth , invasion , and metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "11791181"}
{"sentence": "Partial or whole-brain irradiation is often required to treat both primary and metastatic brain cancer . Radiation-induced normal tissue injury , including progressive cognitive impairment , however , can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year in the United States . Although the exact mechanisms underlying radiation-induced late effects remain unclear , oxidative stress and inflammation are thought to play a critical role . Microglia are key mediators of neuroinflammation . Peroxisomal proliferator-activated receptor ( PPAR ) \u03b4 has been shown to be a potent regulator of anti-inflammatory responses . Thus , we hypothesized that PPAR\u03b4 activation would modulate the radiation-induced inflammatory response in microglia . Incubating BV-2 murine microglial cells with the PPAR\u03b4 agonist L-165041 prevented the radiation-induced increase in : ( i ) intracellular reactive oxygen species generation , ( ii ) Cox-2 and MCP-1 expression , and ( iii ) IL-1\u03b2 and TNF-\u03b1 message levels . This occurred , in part , through PPAR\u03b4-mediated modulation of stress-activated kinases and proinflammatory transcription factors . PPAR\u03b4 inhibited NF-\u03baB via transrepression by physically interacting with the p65 subunit and prevented activation of the PKC\u03b1/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular reactive oxygen species generation . These data support the hypothesis that PPAR\u03b4 activation can modulate radiation-induced oxidative stress and inflammatory responses in microglia .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "22387176"}
{"sentence": "Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis , but targeting specific components of the pathway may provide more effective strategies . Here we show that the expression of Jagged1 , a ligand for canonical Notch signaling , was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine , respectively . In contrast , increased expression characterized half of human colon tumors , although not all tumors with elevated Wnt signaling displayed elevated Jagged1 . Increased Jagged1 was also present in intestinal tumors of Apc(1638N/+) and Apc(Min/+) mice , but to a higher level and more frequently in the former , and in 90% of mouse tumors Notch signaling was elevated when Jagged1 was elevated . In the human HT29Cl16E colonic carcinoma cell line , induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation , with signaling through Notch1 and Notch2 acting redundantly . Therefore , targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors , but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "19935714"}
{"sentence": "X-ray crystallography has been a useful tool in the development of site-directed spin labeling by resolving rotamers of the nitroxide spin-label side chain in a variety of \\u03b1-helical environments . In this work , the crystal structure of a doubly spin-labeled N8C/K28C mutant of the B1 immunoglobulin-binding domain of protein G ( GB1 ) was solved . The double mutant formed a domain-swapped dimer under crystallization conditions . Two rotameric states of the spin-label were resolved at the solvent-exposed \\u03b1-helical site , at residue 28 ; these are in good agreement with rotamers previously reported for helical structures . The second site , at residue 8 on an interior \\u03b2-strand , shows the presence of three distinct solvent-exposed side-chain rotamers . One of these rotamers is rarely observed within crystal structures of R1 sites and suggests that the H(\\u03b1) and S(\\u03b4) hydrogen bond that is common to \\u03b1-helical sites is absent at this interior \\u03b2-strand residue . Variable temperature continuous wave ( CW ) experiments of the \\u03b2-strand site showed two distinct components that were correlated to the rotameric states observed in crystallography . Interestingly , the CW data at room temperature could be fit without the use of an order parameter , which is consistent with the lack of the H(\\u03b1) and S(\\u03b4) interaction . Additionally , double electron electron resonance ( DEER ) spectroscopy was performed on the GB1 double mutant in its monomeric form and yielded a most probable interspin distance of 25 \u00b1 1 \u00c5 . In order to evaluate the accuracy of the measured DEER distance , the rotamers observed in the crystal structure of the domain-swapped GB1 dimer were modeled into a high-resolution structure of the wild type monomeric GB1 . The distances generated in the resulting GB1 structural models match the most probable DEER distance within \u00c5 . The results are interesting as they indicate by direct experimental measurement that the rotameric states of R1 found in this crystal provide a very close match to the most probable distance measured by DEER .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22809334"}
{"sentence": "Malignant gliomas are the most common primary brain tumors in humans . However , poor response to conventional therapeutic approaches , including chemotherapy , leads invariably to disease recurrence and progression . The organo-tin derivative triethyltin(IV)lupinylsulfide hydrochloride ( IST-FS 29 ) was identified and developed as potential antiproliferative agent in human cancer cell lines . However , for its peculiar chemical structure and good lipophilicity , this compound also appeared an eligible candidate for the treatment of gliobastoma cells . The present experiments were designed to explore the in vitro effects of IST-FS 29 on four human glioblastoma cell lines : A-172 , DBTRG.05MG , U-87MG and CAS-1 . The average IC50 values were obtained by MTT assay and ranged between 3 and 10 microM . Time-course assays with cell recovery after drug withdrawal , demonstrated marked cytotoxicity following exposure to IST-FS 29 for 8 , 24 and 72 h . Cultures treated for 8 h were able to partially re-grow by 144 h ; on the contrary , longer times of exposure did not allow surviving cells to recover from the damage and actively proliferate . Cell morphology of cultures exposed to IST-FS 29 was assessed by inverted light microscopy after 24 and 72 h and was more consistent with cell death by necrosis which included cell size reduction , vacuolation of cytoplasm , round dying cells . The present results and our previous data , in vitro and in vivo , indicate the relevant cytotoxic activity of this organo-tin compound and suggest that IST-FS 29 might be a promising novel agent to be developed for the treatment of malignant brain neoplasms .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12635657"}
{"sentence": "Sirtuin proteins regulate diverse cellular pathways that influence genomic stability , metabolism and ageing . SIRT7 is a mammalian sirtuin whose biochemical activity , molecular targets and physiological functions have been unclear . Here we show that SIRT7 is an NAD(+)-dependent H3K18Ac ( acetylated lysine 18 of histone H3 ) deacetylase that stabilizes the transformed state of cancer cells . Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets , where it deacetylates H3K18Ac and promotes transcriptional repression . The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific ( ETS ) transcription factor ELK4 , and comprises numerous genes with links to tumour suppression . Notably , selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation , and in patients is associated with aggressive tumour phenotypes and poor prognosis . We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells , including anchorage-independent growth and escape from contact inhibition . Moreover , SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A . Finally , SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice . Together , our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation , cellular transformation programs and tumour formation in vivo .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "22722849"}
{"sentence": "During the period of 1996-1998 ninety-four gastrectomy specimens with gastric carcinoma referred to Erciyes University , Medical Faculty , Department of Pathology , were examined histopathologically , histochemically and immunohistochemically . General characteristics of gastric carcinomas and prognostic factors were studied . According the Lauren classification , of the 94 cases of gastric carcinomas , 56 were intestinal type , 21 were diffuse type and 17 were mixed type carcinoma . The association rates of Helicobacter pylori , chronic atrophic gastritis and intestinal metaplasia with gastric carcinomas were high . There was strong immunorectivity with HSP70 in 62,5% of the intestinal type carcinomas . This ratios were lower in diffuse and mixed type carcinomas ( p<0.05 ) . The more tumor size and invasion depth increased , the more HSP70 immunoreactivity was obtained ( p<0.05 ) . HSP70 immunorectivity was considerably higher in the patients having lymph node metastasis and vascular invasion ( p<0.05 ) . It was found that the NK cell number was low in the tumor but higher around the tumor in early gastric carcinomas , compared with advanced carcinomas ( p>0.05 ) . In the tumors larger than 10 cm with vascular invasion , NK cell number was lower around the tumor ( p>0.05 ) . Defining prognostic factors of gastric carcinomas is of importance to clinicians . It is thought that HSP70 immunoreactivity , besides invasion depth , lymph node metastasis , vascular invasion , tumor size and inflammatory reaction against the tumor , is important in prognosis and associated with advanced stage .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "12579213"}
{"sentence": "Polycyclic aromatic hydrocarbons ( PAH ) such as dibenzo[a,l]pyrene ( DBP ) are wide-spread environmental pollutants most probably mutagenic and carcinogenic to humans . Detailed data on the cytogenetic effects of anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene ( DBPDE ) in mammalian cells are not available in the literature . The aim of this study is to elucidate the mechanisms involved in the induction of chromosomal aberrations and sister chromatid exchanges ( SCEs ) by DBPDE in mammalian cells . In order to achieve this a parental ( AA8 ) and different DNA repair-deficient Chinese hamster ovary cell lines such as UV4 , UV5 , UV61 ( nucleotide excision repair , NER ) , EM9 ( base excision repair , BER ) , irs1SF ( homologous recombination repair , HRR ) and V3-3 ( non-homologous end joining , NHEJ ) were used . The most sensitive cell lines for DBPDE-induced chromosome aberrations were EM9 and irs1SF , while EM9 and V3-3 cell lines were the most sensitive in terms of SCEs induction . It can be suggested that the BER pathway plays an important role in the repair of lesions induced by DBPDE , affecting both chromosomal aberrations and SCEs induction . Moreover , the HRR pathway seems to play a role in cellular resistance to DBPDE mainly in terms of chromosomal aberration induction while the NHEJ pathway takes part affecting only the induction of SCEs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20389043"}
{"sentence": "ABSTRACT : PurposeAutophagy has attracted attentions as a novel mechanism for tumor development . In this study Human ovarian carcinoma cell line SKOV3 and multidrug-resistant phenotype SKVCR cells were used and the roles of autophagy in radiation-induced cell death were analyzed.Methods and materialsCell viability was examined by colony formation and cell counting kit-8 ( CCK-8 ) assay , 3MA and ZVAD were used to block autophagy and apoptosis , respectively . Quantitative real-time PCR was used to detect mRNA level and Western blot was used to detect protein expression , monodansylcadaverine ( MDC ) staining and flow cytometery were used for autophagy , apoptosis and cell cycle dynamics , respectively . RESULTS : ( 1 ) The radiosensitivity exhibited differently in SKOV3 and SKVCR cells ( SKOV3 : D0=3.37 , SKVCR : D0= 4.18 ) ; compared with SKOV3 the constitutive expression of MAPLC3 in SKVCR was higher , but no change of Caspase-3 and cleaved Caspase-3 . ( 2 ) The ionizing radiation ( IR)- induced apoptosis and autophagy were significant in both cells ( P<0.05 ) ; inhibition of apoptosis with ZVAD showed no impact on survival of SKOV3 and SKVCR cells after radiation , while inhibition of autophagy significantly decreased viability in SKVCR cells , for SKVO3 cells only low level of radiation ( 2 Gy and 4 Gy ) could decrease the viability(P<0.05) . ( 3 ) ZVAD inhibited apoptosis and autophagy in both cells , 3MA inhibit apoptosis in SKOV3 , and promote apoptosis in SKVCR , together with inhibition of autophagy . ( 4 ) G2/M arrest was induced by radiation in both cells ; the accumulation of G2/M was more significant in SKOV3 , 3MA attenuated the radiation-induced S phase delay in SKVCR . CONCLUSION : IR-induced autophagy provides a self-protective mechanism against radiotherapy in SKVCR cells , the use of autophagy inhibitor , 3MA , increases the killing effects of radiation by inhibiting autophagy and radiation- induced S phase delay , also by the increase of apoptosis , which suggests a better therapeutic strategy in drug- resistant SKVCR ovarian cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23244773"}
{"sentence": "A tumor growth-dependent elevation in the hepatic levels of Zn and metallothionein ( MT ) , without a change in the level of Cu , was found in mice and rats bearing solid tumors in the inguinal region . The levels of Zn and MT thus elevated gave a significant correlation ( r = 0.95 ) between them . Nevertheless , when tumor-bearing mice and rats were fed a Zn-deficient diet , the hepatic levels of Zn and MT did not increase . In mice in which inflammation was induced at the same region , on the other hand , hepatic levels of Zn and MT increased transiently after the injection of turpentine or carrageenan even when they were fed the Zn-deficient diet . These results suggest that the elevation of MT and Zn levels can be a helpful marker for detecting malignancy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1472035"}
{"sentence": "The purpose of this study was to evaluate the usefulness of high-resolution MRI ( HR-MRI ) and proton MR spectroscopy ( (1)H-MRS ) for monitoring the early therapeutic response to radiotherapy . Twenty rabbits with VX2 carcinoma were divided into control ( n = 8 ) and irradiation ( n = 12 ) groups . The irradiation group underwent HR-MRI and ( 1)H-MRS using a microscopy coil at 1 , 3 , 7 or 14 days after irradiation . Rabbits in the control group were subjected to HR-MRI and ( 1)H-MRS at the same time intervals . All rabbits were killed after imaging and subjected to histopathologic examinations . The diameter of necrosis by HR-MRI was then compared to that on the gross specimens . The ratios of choline/creatine ( Cho/Cr ) and lactate/creatine ( Lac/Cr ) on the tumor and necrotic area detected by in vivo ( 1)H-MRS were compared between the control and irradiation groups , respectively . In addition , the ratios of Cho/Cr and Lac/Cr were compared between the tumor and necrotic area in each irradiation group . A significant correlation was found between the diameter of necrosis in each sequence of HR-MRI and that in the gross specimens ( r = 0.84-0.91 , p = 0.03- < 0.003 ) . The ratios of Lac/Cr in the tumors of the irradiation groups were significantly higher than those in the control groups after 1 day and 3 days of irradiation ( p = 0.04 , and p = 0.02 ) . Histological analysis showed necrosis and swelling of the endothelia of capillaries and arterioles at 1 day and 3 days after irradiation . It was suggested that HR-MRI and ( 1)H-MRS are useful methods for monitoring the early therapeutic response to radiotherapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21030797"}
{"sentence": "The HT29 adenocarcinoma is a common model of epithelial cell differentiation and colorectal cancer and its death is an oft-analyzed response to TNF family receptor signaling . The death event itself remains poorly characterized and here we have examined the involvement of caspases using pan-caspase inhibitors. zVAD-fmk did not block death of HT29 cells in response to activation of the Fas , TRAIL , TNF , TWEAK and LTbeta receptors . The secondary induction of TNF or the other known bona fide death inducing ligands did not account for death following LTbeta receptor activation indicating that TNF family receptors can trigger a caspase-independent death pathway regardless of the presence of canonical death domains in the receptor . To provide a frame of reference , the phenotype of HT29 death was compared to four other TNF family receptor triggered death events ; Fas induced Jurkat cell apoptosis , TNF/zVAD induced L929 fibroblast necrosis , TNF induced death of WEHI 164 fibroblastoid cells and TNF/zVAD induced U937 death . The death of HT29 and U937 cells under these conditions is an intermediate form with both necrotic and apoptotic features . The efficient coupling of TNF receptors to a caspase-independent death event in an epithelial cell suggests an alternative approach to cancer therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12478469"}
{"sentence": "Previously we have found deregulation of collagen metabolism in human pancreatitis and pancreatic cancer tissues . Insulin-like growth factor-I ( IGF-I ) is known to stimulate collagen biosynthesis through interaction with IGF-I receptor . IGF-I binding proteins ( BPs ) regulate the activity of IGF-I . We investigated whether serum and tissue IGF-I and IGF-BPs as well as tissue IGF-I receptor expression may reflect disturbances of collagen metabolism in patients with pancreatitis and pancreatic cancer . In pancreatitis tissue , a significant increase in IGF-I and IGFBP-3 content was accompanied by a distinct increase in IGF-I receptor expression , compared to control pancreas tissue . In contrast , serum from patients with pancreatitis did not show significant increases in IGF-I and IGFBP-3 levels , however , significant increases in IGFBP-1 level ( 2.5 fold ) . Moreover , a distinct decrease in radioactive IGF-binding to the BPs , compared to control serum , was found . Pancreatic cancer tissue and serum of patients with pancreatic cancer showed significant increases in IGF-I , IGFBP-3 and IGFBP-1 content , accompanied by dramatic increases in IGF-I tissue receptor expression , compared to controls . In serum of patients with pancreatic cancer distinct increases in radioactive IGF-binding to 46 kDa BP , compared to control serum , were observed . The data suggest that disturbances in tissue collagen metabolism during pancreatic diseases may result from deregulation of IGF-I homeostasis and that elevated serum levels of IGF-I , IGFBP-3 and IGFBP-1 may serve as markers of pancreatic cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12641820"}
{"sentence": "The deregulation of Met/hepatocyte growth factor ( HGF ) receptor tyrosine kinase signaling constitutes a common event in colorectal cancers . However , the physiopathological functions of such a deregulation remain poorly understood . In the present study , we investigated the role of the deregulation of Met receptor in the neoplastic transformation of intestinal epithelial cells . To do so , the normal , well-established and characterized rat intestinal epithelial IEC-6 cells were transduced with a retrovirus carrying the oncogenic constitutive active form of Met receptor , Tpr-Met . Herein , we show that compared with control IEC-6 cells , Tpr-Met-IEC-6 cells exhibit enhanced proliferation , loss of growth-contact inhibition , cell morphological alterations , actin cytoskeletal reorganization , loss of E-cadherin expression and anchorage-independent growth . Moreover , Tpr-Met-IEC-6 cells are conferred the capacity to produce the proangiogenic factor VEGF and to reduce the potent antiangiogenic factor thrombospondin-1 . Of significance , Tpr-Met-IEC-6 cells are endowed with the ability to elicit angiogenic responses and to form tumors and metastases in vivo . Hence , our study demonstrates for the first time that the sole oncogenic engagement of Met receptor in normal intestinal epithelial cells is sufficient to induce a wide array of cancerous biological processes that are fundamental to the initiation and malignant progression of colorectal cancers .", "label": [0, 0, 0, 0, 1, 0, 1, 0, 0, 0], "id": "20539003"}
{"sentence": "We have previously reported that stressed apoptotic tumor cells are more immunogenic in vivo than nonstressed ones . Using confocal microscopy we have confirmed our previous observation that heat-stressed apoptotic 12B1-D1 leukemia cells ( BCR-ABL(+) ) express HSP60 and HSP72 on their surface . To explore how the immune system distinguishes stressed from nonstressed apoptotic tumor cells , we analyzed the responses of dendritic cells to these 2 types of apoptotic cells . We found that nonstressed and heat-stressed apoptotic 12B1-D1 cells were taken up by dendritic cells in a comparable fashion . However , when stressed apoptotic 12B1-D1 cells were coincubated with immature dendritic cells for 24 hours , this resulted in greater up-regulation of costimulatory molecules ( CD40 , CD80 , and CD86 ) on the surface of dendritic cells . Moreover , stressed apoptotic 12B1-D1 cells were more effective in stimulating dendritic cells to secrete interleukin-12 ( IL-12 ) and in enhancing their immunostimulatory functions in mixed leukocyte reactions . Furthermore , we demonstrated that immunization of mice with stressed apoptotic 12B1-D1 cells induced the secretion of T helper-1 ( T(H)1 ) profile of cytokines by spleen cells . Splenocytes from mice immunized with stressed apoptotic cells , but not nonstressed ones , were capable of lysing 12B1-D1 and the parental 12B1 line , but not a B-cell leukemia line , A20 . Our data indicate that stressed apoptotic tumor cells are capable of providing the necessary danger signals , likely through increased surface expression of heat shock proteins ( HSPs ) , resulting in activation/maturation of dendritic cells and , ultimately , the generation of potent antitumor T-cell responses .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12393401"}
{"sentence": "Bimolecular reactions in Earth's atmosphere are generally assumed to proceed between reactants whose internal quantum states are fully thermally relaxed . Here , we highlight a dramatic role for vibrationally excited bimolecular reactants in the oxidation of acetylene . The reaction proceeds by preliminary adduct formation between the alkyne and OH radical , with subsequent O(2) addition . Using a detailed theoretical model , we show that the product-branching ratio is determined by the excited vibrational quantum-state distribution of the adduct at the moment it reacts with O(2) . Experimentally , we found that under the simulated atmospheric conditions O(2) intercepts of the excited adducts before their vibrational quantum states have fully relaxed . Analogous interception of excited-state radicals by O(2) is likely common to a range of atmospheric reactions that proceed through peroxy complexes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22936771"}
{"sentence": "Identification of the proteins that are associated with estrogen receptor ( ER ) status is a first step towards better understanding of the hormone-dependent nature of breast carcinogenesis . Although a number of gene expression analyses have been conducted , protein complement has not been systematically investigated to date . Because proteins are primary targets of therapeutic drugs , in this study , we have attempted to identify proteomic signatures that demarcate ER-positive and -negative breast cancers . Using highly enriched breast tumor cells , replicate analyses from 3 ER\u03b1+ and 3 ER\u03b1- human breast tumors resulted in the identification of 2,995 unique proteins with \u22652 peptides . Among these , a number of receptor tyrosine kinases and intracellular kinases that are abundantly expressed in ER\u03b1+ and ER\u03b1- breast cancer tissues were identified . Further , label-free quantitative proteome analysis revealed that 236 proteins were differentially expressed in ER\u03b1+ and ER\u03b1- breast tumors . Among these , 141 proteins were selectively up-regulated in ER\u03b1+ , and 95 proteins were selectively up-regulated in ER\u03b1- breast tumors . Comparison of differentially expressed proteins with a breast cancer database revealed 98 among these have been previously reported to be involved in breast cancer . By Gene Ontology molecular function , dehydrogenase , reductase , cytoskeletal proteins , extracellular matrix , hydrolase , and lyase categories were significantly enriched in ER\u03b1+ , whereas selected calcium-binding protein , membrane traffic protein , and cytoskeletal protein were enriched in ER\u03b1- breast tumors . Biological process and pathway analysis revealed that up-regulated proteins of ER\u03b1+ were overrepresented by proteins involved in amino acid metabolism , proteasome , and fatty acid metabolism , while up-regulated proteins of ER\u03b1- were overrepresented by proteins involved in glycolysis pathway . The presence and relative abundance of 4 selected differentially abundant proteins ( liprin-\u03b11 , fascin , DAP5 , and \u03b2-arrestin-1 ) were quantified and validated by immunohistochemistry . In conclusion , unlike in vitro cell culture models , the in vivo signaling proteins and pathways that we have identified directly from human breast cancer tissues may serve as relevant therapeutic targets for the pharmacological intervention of breast cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "21779449"}
{"sentence": "Contact-inhibition ubiquitously exists in non-transformed cells and explains the poor regenerative capacity of in vivo human retinal pigment epithelial cells ( RPE ) during aging , injury and diseases . RPE injury or degeneration may unlock mitotic block mediated by contact inhibition but may also promote epithelial-mesenchymal transition ( EMT ) contributing to retinal blindness . Herein , we confirmed that EMT ensued in post-confluent ARPE-19 cells when contact inhibition was disrupted with EGTA followed by addition of EGF and FGF-2 because of activation of canonical Wnt and Smad/ZEB signaling . In contrast , knockdown of p120-catenin ( p120 ) unlocked such mitotic block by activating p120/Kaiso , but not activating canonical Wnt and Smad/ZEB signaling , thus avoiding EMT . Nuclear BrdU labeling was correlated with nuclear release of Kaiso through p120 nuclear translocation , which was associated with activation of RhoA-ROCK signaling , destabilization of microtubules . Prolonged p120 siRNA knockdown followed by withdrawal further expanded RPE into more compact monolayers with a normal phenotype and a higher density . This new strategy based on selective activation of p120/Kaiso but not Wnt/\\u03b2-catenin signaling obviates the need of using single cells and the risk of EMT , and may be deployed to engineer surgical grafts containing RPE and other tissues .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "22590627"}
{"sentence": "OBJECTIVE To study the effect of anandamide ( AEA ) on necrosis in HepG2 cells and to explore the role of AEA in progression of liver cancer . METHODS Localization of the fatty acid hydrolytic enzyme ( FAAH ) , cannabinoid receptors 1(CB1) and cannabinoid receptors 2 ( CB2 ) proteins was detected in L02 and HepG2 cells using immunofluorescence . L02 and HepG2 cells were treated with different concentrations of AEA and methyl-beta-cyclodextrin , and the rates of cells necrosis were examined by PI stain . Meanwhile , the expression levels of FAAH , CB1 and CB2 receptor proteins , as well as P38 mitogen-activated protein kinase ( p-P38 MAPK ) and c-Jun-NH2-terminal kinase ( p-JNK ) proteins , were analyzed by Western blot . RESULTS The FAAH , CB1 and CB2 receptor proteins were observed both in cytoplasm and on membrane in L02 and HepG2 cells . The expression level of FAAH protein was higher in HepG2 than in L02 cells . The expression level of CB1 receptor protein was very low in both L02 and HepG2 cells . The expression level of CB2 receptor protein was high in both L02 and HepG2 cells . AEA treatment induced necrosis in HepG2 cells but not in L02 cells . Methyl-beta-cyclodextrin treatment prevented necrosis in HepG2 cells ( t = 3.702 ; 5.274 ; 3.503 , P less than 0.05 ) . The expression patterns of FAAH , CB1 and CB2 receptor protein in L02 and HepG2 cells were confirmed by western blot , which were consistent with the immunofluorescence results . AEA treatment increased the levels of p-P38MAPK and p-JNK proteins in a dose-dependent manner in HepG2 cells ( F = 11.908 ; 26.054 , P less than 0.05 ) and the increase can be partially by prevented by MCD ( t = 2.801 ; t = 12.829 , P less than 0.05 ) . CONCLUSION AEA treatment induces necrosis in HepG2 cells via CB1 and CB2 receptors and lipid rafts .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20380798"}
{"sentence": "Magnetite iron nanoparticles have been widely used as contrast agents and in thermal therapy for cancer . However , their adverse effects on human health have not been fully investigated . In this study , iron oxide nanoparticles were prepared using inorganic iron chloride ( size : 5.3+/-3.6 nm in phosphate buffered saline , surface charge : 23.14 mV ) , and their inflammatory responses were investigated . When mice were treated with iron oxide nanoparticles ( 250 microg/kg , 500 microg/kg , and 1mg/kg ) by a single intratracheal instillation , the level of intracellular reduced glutathione ( GSH ) was decreased in the cells of bronchoalveolar lavage ( BAL ) fluid . The arrest of cell cycles in G1 phase was observed , but S-phase was significantly decreased . The concentrations of pro-inflammatory cytokines ( IL-1 , TNF-alpha , and IL-6 ) were dose-dependently increased at day 1 after instillation in the BAL fluid and in the blood . During the experimental period of 28 days , pro-inflammatory cytokines ( IL-1 , TNF-alpha , and IL-6 ) , Th0 cytokine ( IL-2 ) , Th1 type cytokine ( IL-12 ) , Th2 type cytokines ( IL-4 and IL-5 ) , TGF-beta , and IgE were also elevated . Expressions of many genes related with inflammation or tissue damage such as heat shock protein , matrix metalloproteinase , tissue inhibitors of metalloproteinases , and serum amyloid A were significantly induced . Formation of microgranuloma , which is one of the indicators for chronic inflammatory response , was observed in the alveolar space . In addition , distribution of B cell and CD8+ T cell in blood lymphocytes was increased at day 28 . Based on the result , iron oxide nanoparticles may subchronic induce inflammatory responses via oxidative stress in mice by a single intratracheal instillation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "20540983"}
{"sentence": "Liquid chromatography coupled to tandem mass spectrometry has been used for the detection and the structural characterization of T-rich model oligonucleotides covalently modified by estradiol-2,3-quinone . After separation by gradient elution , adducts were analyzed by negative electrospray mass spectrometry , enabling to evidence and localize the modifications in the oligonucleotide sequence . Modifications by one molecule of estrogen were evidenced on purines ( A , G ) whereas no reaction was observed on pyrimidic bases ( T ) . Isomeric adducts were differentiated using tandem mass spectrometry , and energy resolved mass spectrometry allowed to underline differences in the behavior of the adducts towards collisional excitation into an ion trap device .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12462603"}
{"sentence": "Spindle cell oncocytoma ( SCO ) of the pituitary gland is a relatively recently established , very rare subtype of adenohypophysis tumours that was introduced as a distinct clinicopathological entity in the fourth edition of WHO classification of the central nervous system tumours ( 2007 ) . It is non-endocrine neoplasm of the anterior pituitary that occurs in adults and usually follows a benign clinical course , corresponding to WHO grade I. Up to now , pituitary SCO have been reported occasionally and only 14 cases of SCO have been documented in the literature . Because of their rarity , the pathogenesis and natural history of these tumours have not been fully characterized . We report two additional cases of SCO occurring in females aged 63 years ( Case 1 ) and 65 years ( Case 2 ) , who presented with pan-hypopituitarism , headache and visual field defect . In both cases , the magnetic resonance imaging showed solid sellar mass of moderate size with suprasellar extension . The clinical and radiological features suggested non-functioning pituitary macroadenomas without evidence of invasive growth . One patient presented with tumour recurrence 3 years after undergoing the previous surgical removal of tumour , which was initially misdiagnosed as schwannoma . The first tumour was removed by transsphenoidal surgery and the second one by frontal craniotomy . Histologically and immunohistochemically , both tumours displayed the features typical for SCO of the pituitary . They were composed of interwoven fascicles of spindle cells exhibiting abundant eosinophilic cytoplasm of oncocytic or granular appearance . Mitoses were rarely observed and necrosis was absent . In one case , the advanced lymphocytic infliltration was observed within neoplastic tissue . The tumour cells exhibited immunoreactivity for S-100 protein , galectin-3 , vimentin and epithelial membrane antigen but they were negative for GFAP , anterior pituitary neuroendocrine markers ( prolactin , growth hormone , TSH , ACTH , FSH , LH ) , chromogranin , synaptophysin , cytokeratin CK ( AE1/AE3 ) , smooth muscle actin , desmin , CD34 and CD68 . MIB1 labeling index did not exceed 10% . Ultrastructurally , the tumour cells were rich in mitochondria with lamellar cristae . Moreover , in Case 2 some tumour cells showed a number of giant mitochondria with severely destructed internal matrix . Spindle cell oncocytoma of the anterior pituitary is often misdiagnosed entity of uncertain histogenesis . It should be considered in the differential diagnosis of various sellar-region lesions of oncocytic morphology .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20925001"}
{"sentence": "Multiple myeloma is characterized by the clonal expansion of malignant plasma cells ( multiple myeloma cells [ MMCs] ) , in the bone marrow . Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation . MMCs are found closely associated with sites of increased bone resorption . Osteoclasts strongly support MMC survival in vitro . To further elucidate the mechanisms involved in osteoclast/MMC interaction , we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations . Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors . An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC , and CCR2 chemokines are also MMC growth factors , promoting mitogen-activated protein kinase activation in MMC . An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival . Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival . These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions . This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21097672"}
{"sentence": "Endoplasmic reticulum ( ER ) stress induces both autophagy and apoptosis yet the molecular mechanisms and pathways underlying the regulation of these two cellular processes in cells undergoing ER stress remain less clear . We report here that eukaryotic elongation factor-2 kinase ( EEF2K ) is a critical controller of the ER stress-induced autophagy and apoptosis in tumor cells . DDIT4 , a stress-induced protein , was required for transducing the signal for activation of EEF2K under ER stress . We further showed that phosphorylation of EEF2K at Ser398 was essential for induction of autophagy , while phosphorylation of the kinase at Ser366 and Ser78 exerted an inhibitory effect on autophagy . Suppression of the ER stress-activated autophagy via silencing of EEF2K aggravated ER stress and promoted apoptotic cell death in tumor cells . Moreover , inhibiting EEF2K by either RNAi or NH125 , a small molecule inhibitor of the enzyme , rendered tumor cells more sensitive to curcumin and velcade , two anticancer agents that possess ER stress-inducing action . Our study indicated that the DDIT4-EEF2K pathway was essential for inducing autophagy and for determining the fate of tumor cells under ER stress , and suggested that inhibiting the EEF2K-mediated autophagy can deteriorate ER stress and lead to a greater apoptotic response , thereby potentiating the efficacy of the ER stress-inducing agents against cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23182879"}
{"sentence": "BACKGROUND Androgens and the androgen receptor ( AR ) play important roles in the development of male urogenital organs . We previously found that mice with total AR knockout ( ARKO ) and epithelial ARKO failed to develop normal prostate with loss of differentiation . We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate . However , AR roles of stromal fibroblasts in prostate development remain unclear . METHODS To further probe the stromal fibroblast AR roles in prostate development , we generated tissue-selective knockout mice with the AR gene deleted in stromal fibroblasts ( FSP-ARKO ) . We also used primary culture stromal cells to confirm the in vivo data and investigate mechanisms related to prostate development . RESULTS The results showed cellular alterations in the FSP-ARKO mouse prostate with decreased epithelial proliferation , increased apoptosis , and decreased collagen composition . Further mechanistic studies demonstrated that FSP-ARKO mice have defects in the expression of prostate stromal growth factors . To further confirm these in vivo findings , we prepared primary cultured mouse prostate stromal cells and found knocking down the stromal AR could result in growth retardation of prostate stromal cells and co-cultured prostate epithelial cells , as well as decrease of some stromal growth factors . CONCLUSIONS Our FSP-ARKO mice not only provide the first in vivo evidence in Cre-loxP knockout system for the requirement of stromal fibroblast AR to maintain the normal development of the prostate , but may also suggest the selective knockdown of stromal AR might become a potential therapeutic approach to battle prostate hyperplasia and cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21739465"}
{"sentence": "Gliomas are the most common tumors in the central nervous system , the average survival time of patients with glioblastoma multiforme being about 1 year from diagnosis , in spite of harsh therapy . Aiming to study the transcriptional profiles displayed by glioma cells undergoing cisplatin treatment , gene expression analysis was performed by the cDNA microarray method . Cell survival and apoptosis induction following treatment were also evaluated . Drug concentrations of 12.5 to 300 \u03bcM caused a pronounced reduction in cell survival rates five days after treatment , whereas concentrations higher than 25 \u03bcM were effective in reducing the survival rates to However , the maximum apoptosis frequency was 20.4% for 25 \u03bcM cisplatin in cells analyzed at 72 h , indicating that apoptosis is not the only kind of cell death induced by cisplatin . An analysis of gene expression revealed 67 significantly ( FDR < 0.05 ) modulated genes : 29 of which down- and 38 up-regulated . These genes belong to several classes ( metabolism , protein localization , cell proliferation , apoptosis , adhesion , stress response , cell cycle and DNA repair ) that may represent several affected cell processes under the influence of cisplatin treatment . The expression pattern of three genes ( RHOA , LIMK2 and TIMP2 ) was confirmed by the real time PCR method .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21637621"}
{"sentence": "Curcumin , a well-known chemopreventive agent from turmeric , inhibits the expression of several oncogenes and cell proliferation genes in tumor cells . This study aims to understand the precise molecular mechanism by which curcumin exerts its effects on retinoblastoma cells , by performing whole genome microarray analysis to determine the gene expression profiles altered by curcumin treatment . Curcumin suppressed cell viability and altered the cell cycle of retinoblastoma cells . We identified 903 downregulated genes and 1,319 upregulated genes when compared with the control cells after treatment with 20 \u03bcM curcumin concentration for 48 h . These genes were grouped into respective functional categories according to their biological function . We found that curcumin regulated the expression of genes that are involved in the regulation of apoptosis , tumor suppressor , cell-cycle arrest , transcription factor , and angiogenesis . Quantitative real-time polymerase chain reaction ( qRT-PCR ) analysis was used to validate the results of genome array , and the results were consistent with the obtained data . In conclusion , treatment of curcumin affects the expression of genes involved in various cellular functions and plays an important role in tumor metastasis and apoptosis . Thus , curcumin might be an effective chemopreventive agent for retinoblastoma cancer .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "22489823"}
{"sentence": "To evaluate the effects of adenovirus ( Ad)-mediated transfer of p53 and p16 on human bladder cancer cells EJ , EJ were transfected with Ad-p53 and Ad-p16 . Cell growth , morphological change , cell cycle , apoptosis were measured using MTT assay , flow cytometry , cloning formation , immunocytochemical assays . Ad-p16 or Ad-p53 alone could inhibit the proliferating activity of EJ cells in vitro . Ad-p53 could induce apoptosis of partial EJ cells . G1 arrest was observed 72 h after infection with Ad-p16 , but apoptosis was not obvious . The transfer of Ad-p16 and Ad-p53 could significantly inhibit the growth of EJ cells , decrease the cloning formation rate and induce apoptosis of large number of EJ cells . The occurrence time of subcutaneous tumor was delayed and the tumor volume in 4 weeks was diminished by using Ad-p53 combined with Ad-p16 and the difference was significant compared with using Ad-p53 or Ad-p16 alone . It was suggested that the transfer of wild-type p53 and p16 could significantly inhibit the growth of human bladder cancer in vitro and in vivo .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "12674770"}
{"sentence": "Primary charge separation dynamics in the reaction center ( RC ) of purple bacterium Rhodobacter sphaeroides and its P870 heterodimer mutants have been studied using femtosecond time-resolved spectroscopy with 20 and 40fs excitation at 870nm at 293K . Absorbance increase in the 1060-1130nm region that is presumably attributed to P(A)(\\u03b4+) cation radical molecule as a part of mixed state with a charge transfer character P*(P(A)(\\u03b4+)P(B)(\\u03b4-)) was found . This state appears at 120-180fs time delay in the wild type RC and even faster in H(L173)L and H(M202)L heterodimer mutants and precedes electron transfer ( ET ) to B(A) bacteriochlorophyll with absorption band at 1020nm in WT . The formation of the P(A)(\\u03b4+)B(A)(\\u03b4-) state is a result of the electron transfer from P*(P(A)(\\u03b4+)P(B)(\\u03b4-)) to the primary electron acceptor B(A) ( still mixed with P* ) with the apparent time delay of Next step of ET is accompanied by the 3-ps appearance of bacteriopheophytin a(-) ( H(A)(-) ) band at 960nm . The study of the wave packet formation upon 20-fs illumination has shown that the vibration energy of the wave packet promotes reversible overcoming of an energy barrier between two potential energy surfaces P* and P*(P(A)(\\u03b4+)B(A)(\\u03b4-)) at For longer excitation pulses ( 40fs ) this promotion is absent and tunneling through an energy barrier takes about 3ps . This article is part of a Special Issue entitled : Photosynthesis Research for Sustainability : from Natural to Artificial .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22209778"}
{"sentence": "Cellular senescence is the genetically programmed cessation of cellular proliferation . We have recently mapped a putative senescence gene(s) on the X chromosome of Chinese hamster embryo ( CHE ) cells . In the present study , we have utilized microcell-mediated chromosome transfer ( microcell fusion ) to test whether : ( i ) the human X chromosome exhibits similar genetic potential to induce senescence and ( ii ) the deletion or inactivation of the X-linked senescence gene(s) in CHE cells is associated with nickel-induced immortalization . A normal CHE or human X chromosome was first introduced into mouse-cell hybrids , then transferred by microcell fusion into a nickel-transformed , immortal male CHE cell line ( Ni-2/TGR ) with an X deletion ( Xq1 ) . Microcell fusion of the normal CHE X chromosome into tumorigenic Ni-2/TGR cells yielded senescence of all X recipient clones . The normal human X chromosome induced dominant senescence of tumorigenic Ni-2/TGR cells in only 17% of the resulting microcell hybrids ( 14/81 ) . Karyotypic analyses of 13 non-senescing human X chromosome-derived microcell hybrid clones revealed that none of these clones retained the complete X. A normal CHE X chromosome induced senescence of 75% of hybrids obtained with another immortal and tumorigenic nickel-transformed male CHE cell line ( Ni-6/TGR ) , which exhibited no visible deletion of the X chromosome , while the normal human X chromosome , only induced senescence in 19% of these hybrids . Transfer of the normal CHE or human X chromosome into spontaneously transformed and tumorigenic cell lines , CHO/TGR or V79/TGR , had little or no effect on their growth . These data suggest that both human and CHE cells possess similar X-linked genetic activities that regulate the process of cellular senescence , and that in Chinese hamster cells nickel-induced immortalization but not that of CHO or V79 cells is associated with inactivation of an X-linked senescence gene .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1576706"}
{"sentence": "An efficent antitumor and antiviral cellular immune response requires optimal interferon-gamma ( IFN-gamma ) secretion and perforin expression in CD8(+) T cells . The aim of this study was to define whether CD4(+) and CD8(+) T cells from patients with undifferentiated carcinoma of nasopharyngeal type ( UCNT ) , a tumor regularly associated with the Epstein-Barr virus ( EBV ) , have abnormal phenotype profiles , cytokine production , perforin and CD3-zeta expressions . Our data showed that CD4 and CD8 subset distribution was not grossly altered in the peripheral blood of UCNT patients , while tumor biopsies contained an increased proportion of CD8(+) T cells . The analysis of the CD4(+) subset showed a defect in interleukin-2 ( IL-2 ) production and a moderate increase of IL-10 production , a situation consistent with a Th1/Th2 imbalance . We have also demonstrated that CD8(+) lymphocytes from UCNT patients had a marked impairment of IFN-gamma secretion and perforin expression . This impairment was not related to the presence of detectable EBV DNA in the plasma . In UCNT patients , the blockade of the perforin pathway and of IFN-gamma production may constitute important mechanisms for immune escape by the tumor and for impaired control of EBV replication .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12536237"}
{"sentence": "The effects of 17beta-estradiol ( E2 ) are mediated through activation of estrogen receptors ( ER ) : ERalpha and ERbeta . It is known that ERalpha/ERbeta ratio is higher in breast tumors than in normal tissue . Since antioxidant enzymes and uncoupling proteins ( UCPs ) are reactive oxygen species ( ROS ) production and mitochondrial biogenesis regulators , our aim was to study the E2-effect on oxidative stress , antioxidant enzyme expression , and UCPs in breast cancer cell lines with different ERalpha/ERbeta ratios . The lower ERalpha/ERbeta ratio T47D cell line showed low ROS production and high UCP5 levels . However , the higher ERalpha/ERbeta ratio MCF-7 cell line showed an up-regulation of antioxidant enzymes and UCPs , yet exhibited high oxidative stress . As a result , a decrease in antioxidant enzyme activities and UCP2 protein levels , coupled with an increase in oxidative damage was found . On the whole , these results show different E2-effects on oxidative stress regulation , modulating UCPs , and antioxidant enzymes , which were ERalpha/ERbeta ratio dependent in breast cancer cell lines .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 1], "id": "22615145"}
{"sentence": "Here , we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would \" fuel \" enhanced tumor growth . For this purpose , we generated MDA-MB-231 cells ( a triple-negative human breast cancer cell line ) overexpressing PGC-1\u03b1 and MitoNEET , which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation ( OXPHOS ) . Interestingly , both PGC-1\u03b1 and MitoNEET increased the abundance of OXPHOS protein complexes , conferred autophagy resistance under conditions of starvation and increased tumor growth by up to However , this increase in tumor growth was independent of neo-angiogenesis , as assessed by immunostaining and quantitation of vessel density using CD31 antibodies . Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1\u03b2 and POLRMT in MDA-MB-231 cells , which are also responsible for mediating increased mitochondrial biogenesis . Thus , we propose that increased mitochondrial \" power \" in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance . As such , PGC-1\u03b1 , PGC-1\u03b2 , mitoNEET and POLRMT should all be considered as tumor promoters or \" metabolic oncogenes. \" Our results are consistent with numerous previous clinical studies showing that metformin ( a weak mitochondrial \" poison\" ) prevents the onset of nearly all types of human cancers in diabetic patients . Therefore , metformin ( a complex I inhibitor ) and other mitochondrial inhibitors should be developed as novel anticancer therapies , targeting mitochondrial metabolism in cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23070475"}
{"sentence": "BACKGROUND Metastatic epithelioid hemangioendothelioma of the kidney is a rare malignant vascular tumor with a wide spectrum of behaviors . CASE REPORT We present the case of a 53-year-old male patient with tumor metastases which developed after radical nephrectomy . We describe the immunohistochemistry profile of the tumor and the successful long-term results of treatment with sunitinib , a multi-targeted tyrosine kinase inhibitor . Also , we discuss the rationale for using this type of medication based on immunohistochemistry results . CONCLUSION To the best of our knowledge , this is the first reported case of metastatic renal epithelioid hemangioendothelioma treated successfully with sunitinib .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22722460"}
{"sentence": "The metabolic detoxification capacity may critically regulate the susceptibility of human tissues to cancer development . We used standardized and quantitative , reverse transcription-polymerase chain reaction ( StaRT-PCR ) and microarray chip techniques to analyze transcript levels of multiple detoxification enzymes in cultured normal human oral keratinocytes ( NOK ) and the Siman virus 40 T antigen-immortalized oral keratinocyte line SVpgC2a , viewing the latter as a model of a benign tumor state . With good agreement between the 2 methodologies , NOK and SVpgC2a were found to express transcripts for cytochrome P450 enzymes ( CYPs ) , factors related to CYP induction and enzymes involved in conjugation reactions or detoxification of reactive oxygen . The cell types expressed similar levels of CYP 2B6/7 , CYP 2E1 , P450 oxidoreductase , the aryl hydrocarbon receptor nuclear translocator , sulfotransferase 1A1 , sulfotransferase 1A3 , epoxide hydrolase , glutathione S-transferase M3 , glutathione S-transferase pi and catalase , superoxide dismutase 1 , glutathione peroxidase 1 and glutathione peroxidase 3 . In contrast , SVpgC2a exhibited comparatively higher levels of CYP1A1 , 1B1 , aryl hydrocarbon receptor , glutathione S-transferase M1 , 2 , 4 , 5 , glutathione S-transferase theta 1 and superoxide dismutase 2 and comparatively lower levels of UDP glycosyltransferase 2 and microsomal glutathione S-transferase 1 . Some transcripts , e.g. , CYP 2A6/7 , were not detected by either standard , non quantitative RT-PCR or the above methods , whereas others were barely quantifiable by StaRT-PCR , i.e. , were present at 1-10 molecules/10(6) molecules of actin . Overall , the expression analysis demonstrated presence of mRNA for multiple enzymes involved in foreign compound metabolism and detoxification pathways , including several enzymes not previously reported for oral epithelium . Generally , the comparison of NOK from 2 individuals indicated relatively similar transcript levels of these enzymes . In contrast , differences between NOK and SVpgC2a , e.g. , for CYP1B1 , may reflect alteration caused by immortalization and aid identification of early stage tumor markers in oral epithelium .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12115477"}
{"sentence": "Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors . Consequently , the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types . In addition to host immune responses , intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance , metastatic dissemination and the induction of immune suppression . Cancer stem cells are far from a static cell population ; rather , their presence appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma . However , the impact immune responses have on tumor stem cell differentiation or expansion is not well understood . In this study , we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by inhibiting either the myeloid cell receptors CSF1R or CCR2 decreases the number of tumor-initiating cells in pancreatic tumors . Targeting CCR2 or CSF1R improves chemotherapeutic efficacy , inhibits metastasis and increases antitumor T-cell responses . Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3 , thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes . Together , our findings show how targeting tumor-infiltrating macrophages can effectively overcome therapeutic resistance mediated by tumor-initiating cells .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23221383"}
{"sentence": "BACKGROUND Apoptosis , a widely important mechanism that contributes to cell growth reduction , is reported to be induced by Crocus sativus in different cancer types . The present study was designed to elucidate apoptosis induction by crocin , a main component of Crocus sativus in a human pancreatic cancer cell line ( BxPC-3 ) . METHODS Cell viability was measured by MTT assay , Hoechest33258 staining was used to detect the chromatin condensation characteristic of apoptosis , and DNA fragmentation was assessed by gel electrophoresis and cell cycle analysis by flow cytometry . RESULTS Crocin induced apoptosis and G1-phase cell cycle arrest of BxPC-3 cells , while decreasing cell viability in a dose dependent and time dependent manner . Cells treated with 10\u03bcg/L crocin exhibited apoptotic morphology ( brightly blue-fluorescent condensed nuclei on Hoechst 33258 staining ) and reduction of volume . DNA analysis revealed typical ladders as early as 12 hours after treatment indicative of apoptosis . CONCLUSION Our preclinical study demonstrated a pancreatic cancer cell line to be highly sensitive to crocin-mediated growth inhibition and apoptotic cell death . Although the molecular mechanisms of crocin action are not yet clearly understood , it appears to have potential as a therapeutic agent .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "21039035"}
{"sentence": "The subtelomeric regions of organisms ranging from protists to fungi undergo a much higher rate of rearrangement than is observed in the rest of the genome . While characterizing these regions of the human fungal pathogen Cryptococcus neoformans , we have identified a recent gene amplification event near the right telomere of chromosome 3 that involves a gene encoding an arsenite efflux transporter ( ARR3 ) . The 3,177-bp amplicon exists in a tandem array of 2-15 copies and is present exclusively in strains with the C. neoformans var. grubii subclade VNI A5 MLST profile . Strains bearing the amplification display dramatically enhanced resistance to arsenite that correlates with the copy number of the repeat ; the origin of increased resistance was verified as transport-related by functional complementation of an arsenite transporter mutant of Saccharomyces cerevisiae . Subsequent experimental evolution in the presence of increasing concentrations of arsenite yielded highly resistant strains with the ARR3 amplicon further amplified to over 50 copies , accounting for up to of the whole genome and making the copy number of this repeat as high as that seen for the ribosomal DNA . The example described here therefore represents a rare evolutionary intermediate-an array that is currently in a state of dynamic flux , in dramatic contrast to relatively common , static relics of past tandem duplications that are unable to further amplify due to nucleotide divergence . Beyond identifying and engineering fungal isolates that are highly resistant to arsenite and describing the first reported instance of microevolution via massive gene amplification in C. neoformans , these results suggest that adaptation through gene amplification may be an important mechanism that C. neoformans employs in response to environmental stresses , perhaps including those encountered during infection . More importantly , the ARR3 array will serve as an ideal model for further molecular genetic analyses of how tandem gene duplications arise and expand .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22334577"}
{"sentence": "Klebsiella species are the most extensively studied among a number of 2,3-butanediol ( 2,3-BDO)-producing microorganisms . The ability to metabolize a wide variety of substrates together with the ease of cultivation made this microorganisms particularly promising for the application in industrial-scale production of 2,3-BDO . However , the pathogenic characteristics of encapsulated Klebsiella species are considered to be an obstacle hindering their industrial applications . Here , we removed the virulence factors from three 2,3-BDO-producing strains , Klebsiella pneumoniae KCTC 2242 , Klebsiella oxytoca KCTC1686 , and K. oxytoca ATCC 43863 through site-specific recombination technique . We generated deletion mutation in wabG gene encoding glucosyltransferase which plays a key role in the synthesis of outer core lipopolysaccharides ( LPS ) by attaching the first outer core residue D-GalAp to the O-3 position of the L,D-HeppII residue . The morphologies and adhesion properties against epithelial cells were investigated , and the results indicated that the wabG mutant strains were devoid of the outer core LPS and lost the ability to retain capsular structure . The time profile of growth and 2,3-BDO production from K. pneumoniae KCTC 2242 and K. pneumoniae KCTC 2242 \\u0394wabG were analyzed in batch culture with initial glucose concentration of 70g/l . The growth was not affected by disrupting wabG gene , but the production of 2,3-BDO decreased from 31.27 to 22.44g/l in mutant compared with that of parental strain . However , the productions of acetoin and lactate from wabG mutant strain were negligible , whereas that from parental strain reached to", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22832986"}
{"sentence": "Angiogenesis is essential for the growth , expansion and metastasis of human colorectal cancers ( CRCs ) . Histamine produced by mast cells is a potent proangiogenic factor . However , the significance of non-mast cell expressing histamine in the tumor microenvironment remains unknown . In this study , we evaluated the histamine positive microvessels with the specific marker for biosynthesis of histamine L-histidine decarboxylase ( HDC ) in the CRC tumor microenvironment . The relationship between HDC positive microvessel density ( HDC-MVD ) and clinical pathological parameters was assessed . The results revealed that HDC-MVD in the tumor microenvironment of CRCs was significantly increased as compared with the controls . CRC patients with lymph node invasion had a particularly higher density of HDC-MVD than those without . The density of HDC-MVD accounted for of CD34 positive MVD in CRCs and double IHC analysis demonstrated that these HDC positive microvessels were mostly CD34 positive microvessels and with a high proliferative activity . Our results suggest that histamine expressed in microvessels could be an additional cellular source and involved in the cancer invasion through promoting angiogenesis in human CRCs .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23239191"}
{"sentence": "Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells . In this study , we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma , documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes ( CTL). miR-210 was induced in hypoxic zones of human tumor tissues . Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis , independent of tumor cell recognition and CTL reactivity . A comprehensive approach using transcriptome analysis , argonaute protein immunoprecipitation , and luciferase reporter assay revealed that the genes PTPN1 , HOXA1 , and TP53I11 were miR-210 target genes regulated in hypoxic cells . In support of their primary importance in mediating the immunosuppressive effects of miR-210 , coordinate silencing of PTPN1 , HOXA1 , and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis . Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis , by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22962263"}
{"sentence": "Multiple myeloma ( MM ) is classically illustrated by a desynchronized cytokine system with rise in inflammatory cytokines . There are recent reports which emphasized the potential role of angiogenesis in the development of MM. Role of cyclooxygenase 2 ( COX-2 ) is well documented in the pathogenesis of solid tumors , but little is known about its occurrence and function in hematologic neoplasms . Involvement of neoangiogenesis is reported in the progression of MM , and angiopoietins probably contribute to this progression by enhancing neovascularization . Circulatory and mRNA levels of angiogenic factors and cyclooxygenase were determined in 125 subjects ( 75 MM patients and 50 healthy controls ) by using enzyme-linked immunosorbent assay and quantitative PCR . We observed significant increase for angiogenic factors ( Ang-1 , Ang-2 , hepatocyte growth factor , and vascular endothelial growth factor ) and cyclooxygenase at circulatory level , as well as at mRNA level , as compared to healthy controls except insignificant increase for Ang-1 at circulatory level . We have also observed the significant positive correlation of all angiogenic factors with cyclooxygenase . The strong association found between angiogenic factors and COX-2 in this study may lead to the development of combination therapeutic strategy to treat MM. Therefore , targeting COX-2 by using its effective inhibitors demonstrating antiangiogenic and antitumor effects could be used as a new therapeutic approach for treatment of MM .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "22971811"}
{"sentence": "PURPOSE Precise monitoring of active angiogenesis in neovascular eye diseases such as age-related macular degeneration ( AMD ) enables sensitive use of antiangiogenic drugs and reduces adverse side effects . So far , no in vivo imaging methods are available to specifically label active angiogenesis . Here , we report such a technique using fluorophore-labeled cationic liposomes ( CL ) detected with a standard clinical in vivo scanning laser ophthalmoscope ( SLO ) . METHODS C57Bl/6 mice underwent laser coagulations at day 0 ( d0 ) to induce choroidal neovascularization ( CNV ) . Liposomes labeled with Oregon green , rhodamine ( Rh ) , or indocyanine green ( ICG ) were injected into the tail vein at various time points after laser coagulation , and their fluorescence was observed in vivo 60 min later using an SLO , or afterwards in choroidal flatmounts or cryosections . RESULTS SLO detected accumulated fluorescence only in active CNV lesions with insignificant background noise . The best signal was obtained with CL-ICG . Choroidal flatmounts and cryosections of the eye confirmed the location of retained CL in CNV lesions . Neutral liposomes , in contrast , showed no accumulation . CONCLUSIONS These results establish fluorophore-labeled CL as high affinity markers to selectively stain active CNV . This novel , non-invasive SLO imaging technique could improve risk assessment and indication for current intraocular antiangiogenic drugs in neovascular eye diseases , as well as monitor therapeutic outcomes . Labeling of angiogenic vessels using CL can be of interest not only for functional imaging in ophthalmology but also for other conditions where localization of active angiogenesis is desirable .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22605917"}
{"sentence": "The tumor suppressor LKB1 is inactivated in 90% of Peutz-Jeghers cancer syndrome , 30-40% of non-small cell lung carcinoma , and a variety of other cancers , indicating the loss of LKB1 activity is a critical step in oncogenesis . However , current understanding of LKB1 function is largely limited to the results from cancer cells , and how LKB1 inactivation initiates malignant transformation in normal cells remains unclear . Here we ablated endogenous expression of LKB1 in two normal cell lines : human embryonic kidney 293T cells ( HEK-293T cells ) and human umbilical vein endothelial cells ( HUVECs ) by LKB1-specific short hairpin RNAs . Downregulation of endogenous LKB1 lead to a facilitated G(1)/S transition , accompanied by a concomitant increase in Rb phosphorylation ( Ser(807/811) ) . Furthermore , reduced expression of p53 and p16 was observed in LKB1 ablated cells , while no differences were detected for cyclin D1 and cyclin E. These results jointly suggest that endogenous LKB1 knockdown accelerates cell cycle progression through G(1)/S checkpoint in HEK-293T cells and HUVECs , which is at least in part , mediated by decline of p53 and p16 pathways . Our findings provided a plausible mechanism by which loss of LKB1 expression in normal cells contributes to the formation of malignancies .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20368693"}
{"sentence": "The vinorelbine sensitivity of eight recently established head and neck squamous cell carcinoma ( SCC ) cell lines was tested using the 96-well plate clonogenic assay . The chemosensitivity of these head and neck SCC cell lines to vinorelbine expressed as IC50 , corresponding to the drug concentration causing 50% inhibition in clonogenic survival , varied between 0.6 and 1.0 nM . The dose-dependent growth inhibition caused by vinorelbine was measured in three of these cell lines . A clear growth inhibition was observed at a concentration of 3 nM . The same cell lines were studied with flow cytometry . When exposed to 3 nM and 5 nM vinorelbine , an accumulation of the cells in the G2/M-phase was observed in all cultures after 12 hours . The morphological changes induced by 3 nM and 5 nM vinorelbine to the UT-SCC-33 cell line were analysed with time-lapse video microscopy . In the cultures treated with 5 nM vinorelbine , the cells stayed mitotically arrested for 2-32 hours and thereafter died morphologically by apoptosis . These results indicate that , in vitro , the head and neck SCC is consistently sensitive to vinorelbine , which blocks the cell cycle in G2/M , the most radiosensitive phase . These encouraging results suggest that vinorelbine may potentially be used in conjunction with radiotherapy in the treatment of head and neck SCC .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "12530056"}
{"sentence": "Pituitary carcinoma occurs in of resected pituitary tumours and carries a poor prognosis ( mean survival <4 years ) , with standard chemotherapy regimens showing limited efficacy . Recent evidence suggests that temozolomide ( TMZ ) , an orally-active alkylating agent used principally in the management of glioblastoma , may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas . A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase ( MGMT ) predicts TMZ responsiveness in glioblastomas , and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date . Here , we report a case of a silent pituitary corticotroph adenoma , which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases . The tumour exhibited low immunohistochemical MGMT expression in both primary ( pituitary ) and secondary ( hepatic ) lesions . Initial TMZ therapy ( 200 mg/m\u00b2 for 5 days every 28 days-seven cycles ) resulted in marked clinical , biochemical [ >50% fall in adrenocorticotrophic hormone ( ACTH) ] and radiological [ partial RECIST ( response evaluation criteria in solid tumors ) response ] improvements . The patient then underwent bilateral adrenalectomy . However , despite reintroduction of TMZ therapy ( further eight cycles ) ACTH levels plateaued and no further radiological regression was observed . We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours , and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma . Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22076588"}
{"sentence": "Piwi-interacting RNAs are a diverse class of small non-coding RNAs implicated in the silencing of transposable elements and the safeguarding of genome integrity . In mammals , male germ cells express two genetically and developmentally distinct populations of piRNAs at the pre-pachytene and pachytene stages of meiosis , respectively . Pre-pachytene piRNAs are mostly derived from retrotransposons and required for their silencing . In contrast , pachytene piRNAs originate from genomic clusters , and their biogenesis and function remain enigmatic . Here , we report that conditional inactivation of the putative RNA helicase MOV10L1 in mouse spermatocytes produces a specific loss of pachytene piRNAs , significant accumulation of pachytene piRNA precursor transcripts , and unusual polar conglomeration of Piwi proteins with mitochondria . Pachytene piRNA-deficient spermatocytes progress through meiosis without derepression of LINE1 retrotransposons , but become arrested at the post-meiotic round spermatid stage with massive DNA damage . Our results demonstrate that MOV10L1 acts upstream of Piwi proteins in the primary processing of pachytene piRNAs and suggest that , distinct from pre-pachytene piRNAs , pachytene piRNAs fulfill a unique function in maintaining post-meiotic genome integrity .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23166510"}
{"sentence": "The SR/CR mouse phenotype , first described in 1999 in BALB/c and later bred into C57BL/6 mice , is resistant to cancer formation following high doses of cancer cells administered intraperitoneally . The tumor cell targeting and destruction mechanisms have not been identified . By fluorescence-activated cell sorting analysis , the immune response of SR/CR mice after intraperitoneal injection of cancer cells was investigated and compared with parent strain mice . A massive influx of leukocytes into the peritoneal cavity was found . A large fraction of these leukocytes were polymorphonuclear granulocytes , macrophages and natural killer cells . A relative decrease in influx of B-cells compared with controls was demonstrated . Increased proportions of leukocytes belonging to the innate immune system were also demonstrated in splenocytes of SR/CR mice . Cytospins of peritoneal fluid from SR/CR mice after cancer cell injection showed formations of immune cells morphologically resembling polymorphonuclear granulocytes and macrophages adjoining the cancer cells . The results point to the potential involvement of innate immune cells in cancer immunology . Our data support migration of polymorphonuclear granulocytes , macrophages and NK cells into the peritoneum of the SR/CR mouse in response to intraperitoneal injection of S180 cancer cells . The cell composition of spleens of SR/CR mice reflected the differential regulation of the innate immune cells in peritoneal exudates . Both peritoneal exudates and the spleens of SR/CR mice contained decreased proportions of B-cells compared with BALB/c and C57BL/6 mice . We reproduce important aspects of previous published data and further extend them by showing differentially regulated populations of splenocytes including B-lymphocytes in SR/CR mice compared with parent strain controls . Importantly , this differentially regulated immune response of SR/CR mice could not be found in response to challenge with the lymphoma cell line EL-4 .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23030360"}
{"sentence": "The signal transducer and activator of transcription ( STAT)1 is a cytoplasmic-transcription factor that is phosphorylated by Janus kinases ( Jak ) in response to interferon gamma(IFN-gamma) . The phosphorylated STAT1 translocates to the nucleus , where it turns on specific sets of IFN-gamma-inducible genes , such as the interferon regulatory factor ( IRF)-1 . We show here that gamma irradiation reduces the IFN-gamma mRNA expression . The inhibition of the STAT1 phosphorylation and the IRF-1 expression by gamma irradiation was also observed . In contrast , the mRNA levels of IL-5 and transcription factor GATA-3 were slightly induced by gamma irradiation when compared to the non-irradiated sample . Furthermore , we detected the inhibition of cell-mediated immunity by gamma irradiation in the allogenic-mixed lymphocytes ' reaction ( MLR ) . These results postulate that gamma irradiation induces the polarized-Th2 response and interferes with STAT1 signals , thereby causing the immunosuppression of the Th1 response .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12470592"}
{"sentence": "The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity . Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms . Here , we show that SIRT1 , the human Sir2 homolog , is recruited to the promyelocytic leukemia protein ( PML ) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras ( Ha-rasV12 ) . SIRT1 binds and deacetylates p53 , a component of PML nuclear bodies , and it can repress p53-mediated transactivation . Moreover , we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation . When overexpressed in primary mouse embryo fibroblasts ( MEFs ) , SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence . Taken together , our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12006491"}
{"sentence": "Fus1 , encoded by a 3p21.3 tumour suppressor gene , is down-regulated , mutated or lost in the majority of inflammatory thoracic malignancies . The mitochondrial localization of Fus1 stimulated us to investigate how Fus1 modulates inflammatory response and mitochondrial function in a mouse model of asbestos-induced peritoneal inflammation . Asbestos treatment resulted in a decreased Fus1 expression in wild-type ( WT ) peritoneal immune cells , suggesting that asbestos exposure may compromise the Fus1-mediated inflammatory response . Untreated Fus1(-/-) mice had an higher proportion of peritoneal granulocytes than Fus1(+/+) mice , pointing at ongoing chronic inflammation . Fus1(-/-) mice exhibited a perturbed inflammatory response to asbestos , reflected in decreased immune organ weight and peritoneal fluid protein concentration , along with an increased proportion of peritoneal macrophages . Fus1(-/-) immune cells showed augmented asbestos-induced activation of key inflammatory , anti-oxidant and genotoxic stress response proteins ERK1/2 , NF\u03baB , SOD2 , \u03b3H2AX , etc . Moreover , Fus1(-/-) mice demonstrated altered dynamics of pro- and anti-inflammatory cytokine expression , such as IFN\u03b3 , TNF\u03b1 , IL-1A , IL-1B and IL-10 . ' Late ' response cytokine Ccl5 was persistently under-expressed in Fus1(-/-) immune cells at both basal and asbestos-activated states . We observed an asbestos-related difference in the size of CD3(+) CD4(-) CD8(-) DN T cell subset that was expanded four-fold in Fus1(-/-) mice . Finally , we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters ( ROS production , mitochondrial potential and UCP2 expression ) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells , thus supporting our hypothesis that Fus1 establishes its immune- and tumour-suppressive activities via regulation of mitochondrial homeostasis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22513871"}
{"sentence": "Recent evidences suggest that the activity of glycogen synthase kinase-3 ( GSK3 ) contributes to the tumorigenic potential of pancreatic cancer cells through modulation of cell proliferation and survival . However , further investigations are needed to identify GSK3-dependent mechanisms involved in the control of pancreatic cancer cell proliferation and survival . This study was undertaken to provide further support for a role of GSK3 in pancreatic cancer cell growth as well as to identify new cellular and molecular mechanisms involved . Herein , we demonstrate that prolonged inhibition of GSK3 triggers an apoptotic response only in human pancreatic cancer cells but not in human non-transformed pancreatic epithelial cells . We show that prolonged inhibition of GSK3 activity increases Bim messenger RNA and protein expressions . Moreover , we provide evidence that activation of the c-jun N-terminal kinase ( JNK ) pathway is necessary for the GSK3 inhibition-mediated increase in Bim expression and apoptotic response . Finally , we demonstrate that concomitant inhibition of GSK3 potentiates the death ligand-induced apoptotic response in pancreatic cancer cells but not in non-transformed pancreatic epithelial cells and that this effect also requires JNK activity . Considering that different approaches leading to stimulation of death receptor signaling are under clinical trials for treatment of unresectable or metastatic pancreatic cancer , inhibition of GSK3 could represent an attractive new avenue to improve their effectiveness .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22201186"}
{"sentence": "Complex interactions between effector T cells and Foxp3(+) regulatory T cells ( Treg ) contribute to clinical outcomes in cancer , and autoimmune and infectious diseases . Previous work showed that IL-12 reversed Treg-mediated suppression of CD4(+)Foxp3(-) T cell ( Tconv ) proliferation . We and others have also shown that Tregs express T-bet and IFN-\u03b3 at sites of Th1 inflammation and that IL-12 induces IFN-\u03b3 production by Tregs in vitro . To investigate whether loss of immunosuppression occurs when IFN-\u03b3 is expressed by Tregs we treated mouse lymphocyte cultures with IL-12 . IFN-\u03b3 expression did not decrease the ability of Tregs to suppress Tconv proliferation . Rather , IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs . We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells , diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells . Together , these IL-12 mediated changes favored the outgrowth of non-Tregs . Additionally , we showed that treatment with a second cytokine , IL-27 , decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation . Notably , IL-27 only slightly modified levels of IL-2R on non-Treg T cells . Together , these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-\u03b3 expression in IL-12-mediated reversal of Treg immunosuppression .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23029447"}
{"sentence": "The anti-apoptotic protein , BAX inhibitor-1 ( BI-1 ) , has a role in cancer/tumor progression . BI-1-overexpressing HT1080 and B16F10 cells produced higher lung weights and tumor volumes after injection into the tail veins of mice . Transfection of BI-1 siRNA into cells before injection blocked lung metastasis. in vitro , the overexpression of BI-1 increased cell mobility and invasiveness , with highly increased glucose consumption and cytosolic accumulation of lactate and pyruvate , but decreased mitochondrial O(2) consumption and ATP production . Glucose metabolism-associated extracellular pH also decreased as cells excreted more H(+) , and sodium hydrogen exchanger ( NHE ) activity increased , probably as a homeostatic mechanism for intracellular pH . These alterations activated MMP 2/9 and cell mobility and invasiveness , which were reversed by the NHE inhibitor , 5-(N-ethyl-N-isopropyl) amiloride ( EIPA ) , suggesting a role for NHE in cancer metastasis . In both in vitro and in vivo experiments , C-terminal deleted ( CDeltaBI-1 ) cells showed similar results to control cells , suggesting that the C-terminal motif is required for BI-1-associated alterations of glucose metabolism , NHE activation and cancer metastasis . These findings strongly suggest that BI-1 reduces extracellular pH and regulates metastasis by altering glucose metabolism and activating NHE , with the C-terminal tail having a pivotal role in these processes .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20118983"}
{"sentence": "OBJECTIVE The aims of this study were to analyse the results and long term outcome in a prospective non randomised trial of 74 patients treated by laparoscopic colo-rectal resection for cancer , and to determine wether survival and recurrence are or are not compromised by an initial laparoscopic approach . PATIENTS AND METHODS Seventy-four patients with colo-rectal carcinoma were included in a prospective trial and treated by laparoscopic resection . All patients were reviewed at 1 , 3 , and 6 months interval . A median of 5 years follow up was available . Forty-eight patients ( 65% ) had more than 3 years of follow up . RESULTS Six conversions ( 8.1% ) were necessary : 2 for tumor invasion of adjacent organs , 2 for limited margin resection in lower rectal tumors , 1 for small bowel injury and 1 for obesity . After surgery , passing flatus occurred at 34.3 +/- 16.7 h and oral intake could be reinstaured at 42.6 +/- 22 h . Mean postoperative stay was 8.2 +/- 3.4 days . No death occurred . The overall morbidity was about 13.5% . The rate of late complications was 5.4% . Two port site metastasis ( 2.6% ) were seen in locally advanced carcinoma . Recurrence rate at 5 years was 0% for Dukes A , 20% for Dukes B , 39.2% for Dukes C. Survival rate at 5 years was 100% for Dukes A , 80% for Dukes B , and 60.7% for Dukes C. These results are similar to those of conventional open surgery . CONCLUSION Laparoscopic colorectal resection for cancer can be performed safely , with a low morbidity and rare late complications . Long term follow up ( 5 years ) assessment shows similar outcome compared with conventional surgery .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12658828"}
{"sentence": "N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer . Activating mutations in N-Ras occur in a subset of colorectal cancers , but little in known about how the mutant protein contributes to onset and progression of the disease . Using genetically engineered mice , we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation . The pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function , which is mediated by activation of a non-canonical MAPK pathway that signals through Stat3 . As a result , inhibition of MEK selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-Ras . The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for colorectal cancer patients . These data demonstrate for the first time the important role that N-Ras plays in colorectal cancer .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23274911"}
{"sentence": "The ligand-gated ion channels in the Cys-loop receptor superfamily mediate the effects of neurotransmitters acetylcholine , serotonin , GABA , and glycine . Cys-loop receptor signaling is susceptible to modulation by ligands acting through numerous allosteric sites . Here we report the discovery of a novel class of negative allosteric modulators of the 5-HT(3) receptors ( 5-HT(3)Rs ) . PU02 ( 6-[(1-naphthylmethyl)thio]-9H-purine ) is a potent and selective antagonist displaying IC(50) values of \\u03bcM at 5-HT(3)Rs and substantially lower activities at other Cys-loop receptors . In an elaborate mutagenesis study of the 5-HT(3)A receptor guided by a homology model , PU02 is demonstrated to act through a transmembrane intersubunit site situated in the upper three helical turns of TM2 and TM3 in the ( +)-subunit and TM1 and TM2 in the ( -)-subunit . The Ser(248) , Leu(288) , Ile(290) , Thr(294) , and Gly(306) residues are identified as important molecular determinants of PU02 activity with minor contributions from Ser(292) and Val(310) , and we propose that the naphthalene group of PU02 docks into the hydrophobic cavity formed by these . Interestingly , specific mutations of Ser(248) , Thr(294) , and Gly(306) convert PU02 into a complex modulator , potentiating and inhibiting 5-HT-evoked signaling through these mutants at low and high concentrations , respectively . The PU02 binding site in the 5-HT(3)R corresponds to allosteric sites in anionic Cys-loop receptors , which emphasizes the uniform nature of the molecular events underlying signaling through the receptors . Moreover , the dramatic changes in the functional properties of PU02 induced by subtle changes in its binding site bear witness to the delicate structural discrimination between allosteric inhibition and potentiation of Cys-loop receptors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22589534"}
{"sentence": "Infection by Opisthorchis viverrini , a risk factor for cholangiocarcinoma ( CCA ) may act through chronic inflammation , oxidative stress and lipid peroxidation ( LPO)-related damage and growth stimuli. 1,N6-etheno-2'-deoxyadenosine ( epsilondA ) , and 3,N4-etheno-2'-deoxycytidine ( epsilondC ) , markers for LPO-derived DNA damage were highly increased in white blood cell and urine of O. viverrini-infected Thai patients . In order to investigate tissue specificity etheno adducts were measured in a cholangiocarcinogenesis model , in O. viverrini-infected hamsters that had received N-nitrosodimethylamine ( NDMA , 12.5 ppm in dw ) for 2 months. epsilondA- and epsilondC-levels were analyzed in paraffin-embedded liver sections by a novel immunohistochemical method , from 21 up to 180 days post-O. viverrini-infection . In inflamed areas of the liver , etheno adducts were localized in the nuclei of inflammatory cells and in the epithelial lining of the bile duct . Semi-quantitative image analysis showed higher adduct levels in the liver of O. viverrini-infected hamsters , treated with or w/o NDMA when compared with untreated controls . Levels were found highest in the liver of O. viverrini-infected plus NDMA-treated hamsters . Adducts increased in an age-dependent manner from O. viverrini-infection until CCA development . Increased adduct formation paralleled histopathological changes in plasma alkaline phosphatase ( ALP ) activity , bile duct hyperplasia , dysplasia , precancerous lesions , and CCA appearance . Also elevated expression of alkyladenine DNA glycosylase ( AAG ) , which excises 1,N6-ethenoadenine ( epsilonA ) was linked to higher adduct formation , suggesting imbalanced repair . Our results implicate accumulation of inflammation-related , promutagenic DNA damage in target tissue and possibly imbalanced repair in the onset of cholangiocarcinogenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20541562"}
{"sentence": "Sorafenib is a multi-targeted agent and has been reported to have potent antitumor effects against various types of tumors , including human non-small cell lung cancer ( NSCLC ) . In this study , we explored in vitro the antitumor effects of sorafenib alone and in combination with gemcitabine in epidermal growth factor receptor-tyrosine kinase inhibitor ( EGFR-TKI)-resistant human lung cancer cell lines and the related molecular mechanisms . The NSCLC cell lines A549 ( mutant KRAS ) , H1666 ( mutant BRAF ) and H1975 ( mutant EGFR-T790M ) were treated with sorafenib and gemcitabine alone and in combination . The cytotoxicity was assessed by MTT assay , cell cycle distribution was analyzed by flow cytometry , and alterations in signaling pathways were analyzed by western blotting . We found that sorafenib exhibited dose-dependent growth inhibition in all three EGFR-TKI-resistant NSCLC cell lines . When sorafenib was combined with gemcitabine , synergistic activity was observed in the A549 and H1666 cells and antagonistic activity was observed in the H1975 cells . Sorafenib arrested the cell cycle at the G1 phase , whereas gemcitabine arrested the cell cycle at the S phase . Sorafenib inhibited C-RAF and p-ERK in the A549 cells and B-RAF and p-ERK in the H1666 and H1975 cells . The molecular mechanism of this synergism is that RAF/MEK/ERK which are activated by gemcitabine are efficiently suppressed by simultaneously administered sorafenib . By contrast , the mechanism of antagonism may be due to mutual interference with the cell cycle in the H1975 cells . In conclusion , we found that sorafenib exhibits antiproliferative effects in EGFR-TKI-resistant NSCLC cell lines and when combined with gemcitabine demonstrates synergistic activity in A549 and H1666 cells but antagonistic activity in H1975 cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23255896"}
{"sentence": "17\u03b2-hydroxysteroid dehydrogenases ( 17\u03b2-HSDs ) catalyse the 17-position reduction / oxidation of steroids. 17\u03b2-HSD type 3 ( 17\u03b2-HSD3 ) catalyses the reduction of the weakly-androgenic androstenedione ( adione ) to testosterone , suggesting that specific inhibitors of 17\u03b2-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia . STX2171 is a novel selective non-steroidal 17\u03b2-HSD3 inhibitor with an IC50 of nM in a whole cell assay . It inhibits adione-stimulated proliferation of 17\u03b2-HSD3-expressing androgen receptor positive LNCaP[HSD3] prostate cancer cells in vitro . An androgen-stimulated LNCaP[HSD3] xenograft proof of concept model was developed to study the efficacies of STX2171 and a more established 17\u03b2-HSD3 inhibitor , STX1383 ( SCH-451659 , Schering-Plough ) , in vivo . Castrated male MF-1 mice were inoculated s.c. with 1 x 107 cells 24 hours after an initial daily dose of testosterone propionate ( TP ) or vehicle . After 4 weeks tumors had not developed in vehicle-dosed mice , but were present in 50% of those mice given TP . One week after switching the stimulus to adione , mice were dosed additionally with vehicle or inhibitor for a further 4 weeks . Both TP and adione efficiently stimulated tumor growth and increased plasma testosterone levels , but in the presence of either 17\u03b2-HSD3 inhibitor , adione-dependent tumor growth was significantly inhibited and plasma testosterone levels reduced . Mouse bodyweights were unaffected . Both inhibitors also significantly lowered plasma testosterone levels in intact mice . In conclusion , STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumor growth in vivo , indicating that 17\u03b2-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23132791"}
{"sentence": "Disruption of contact inhibition and serum afflux that occur after a tissue injury activate cell cycle , which then stops when confluence is reached again . Although the events involved in cell cycle entry have been widely documented , those managing cell cycle exit have remained so far ill defined . We have identified that the final stage of wound closure is preceded in keratinocytes by a strong accumulation of miR-483-3p , which acts as a mandatory signal triggering cell cycle arrest when confluence is reached . Blocking miR-483-3p accumulation strongly delays cell cycle exit , maintains cells into a proliferative state and retards their differentiation program . Using two models of cell cycle synchronization ( i.e. mechanical injury and serum addition ) , we show that an ectopic upregulation of miR-483-3p blocks cell cycle progression in early G1 phase . This arrest results from a direct targeting of the CDC25A phosphatase by miR-483-3p , which can be impeded using an anti-miRNA against miR-483-3p or a protector that blocks the complex formation between miR-483-3p and the 3'-untranslated region ( UTR ) of CDC25A transcript . We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which , in turn , abolishes CDK4/6 capacity to associate with D-type cyclins . This prevents CDK4/6 kinases ' activation , impairs downstream events such as cyclin E stimulation and sequesters cells in early G1 . We propose this new regulatory process of cyclin-CDK association as a general mechanism coupling miRNA-mediated CDC25A invalidation to CDK post-transcriptional modifications and cell cycle control .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23429262"}
{"sentence": "Chronic inflammation , increased reactivity to self-antigens and incidences of cancer are hallmarks of aging . However , the underlying mechanisms are not well understood . Age-associated alterations in the DNA either due to oxidative damage , defects in DNA repair or epigenetic modifications such as methylation that lead to mutations and changes in the expression of genes are thought to be partially responsible . Here we report that epigenetic modifications in aged DNA also increase its immunogenicity rendering it more reactive to innate immune system cells such as the dendritic cells . We observed increased upregulation of costimulatory molecules as well as enhanced secretion of IFN-alpha from dendritic cells in response to DNA from aged donors as compared to DNA from young donors when it was delivered intracellularly via Lipofectamine . Investigations into the mechanisms revealed that DNA from aged subjects is not degraded , neither is it more damaged compared to DNA from young subjects . However , there is significantly decreased global level of methylation suggesting that age-associated hypomethylation of the DNA may be the cause of its increased immunogenicity . Increased immunogenicity of self DNA may thus be another mechanism that may contribute to the increase in age-associated chronic inflammation , autoimmunity and cancer .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20354270"}
{"sentence": "We previously demonstrated that downregulation of protein kinase CKII induces cellular senescence in human colon cancer HCT116 cells . To investigate the role of microRNAs ( miRNAs ) in CKII downregulation during senescence , we employed computational algorithms . Four miRNAs ( miR-186 , miR-216b , miR-337-3p , and miR-760 ) were predicted to be miRNAs against CKII\u03b1 mRNA . Mimics of all four miRNAs jointly downregulated CKII\u03b1 expression in HCT116 cells . Reporter analysis and RT-PCR have suggested that these four miRNAs may stimulate degradation of CKII\u03b1 mRNA by targeting its 3 ' untranslated regions ( UTRs ) . The four miRNA mimics increased senescent-associated \u03b2-galactosidase ( SA-\u03b2-gal ) staining , p53 and p21(Cip1/WAF1) expression , and reactive oxygen species ( ROS ) production . In contrast , concomitant knockdown of the four miRNAs by antisense inhibitors increased the CKII\u03b1 protein level and suppressed CKII inhibition-mediated senescence . Finally , CKII\u03b1 overexpression antagonized senescence induced by the four miRNA mimics . Therefore , the present results show that miR-186 , miR-216b , miR-337-3p , and miR-760 cooperatively promote cellular senescence through the p53-p21(Cip1/WAF1) pathway by CKII downregulation-mediated ROS production in HCT116 cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 1], "id": "23137536"}
{"sentence": "beta-Defensins are small antimicrobial peptides of the innate immune system produced in response to microbial infection of mucosal tissue and skin . We demonstrate that murine beta-defensin 2 ( mDF2beta ) acts directly on immature dendritic cells as an endogenous ligand for Toll-like receptor 4 ( TLR-4 ) , inducing up-regulation of costimulatory molecules and dendritic cell maturation . These events , in turn , trigger robust , type 1 polarized adaptive immune responses in vivo , suggesting that mDF2beta may play an important role in immunosurveillance against pathogens and , possibly , self antigens or tumor antigens .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12411706"}
{"sentence": "Certain steroidal compounds have demonstrated an antiproliferative effect against several tumor cell lines ; however , their complete role on cancer cells is not currently established . Herein , we report the synthesis and evaluation of two new 26-hydroxy-22-oxocholestanic steroids on cervical cancer CaSki cells . The title compounds were prepared from diosgenin and hecogenin in excellent yields . We determined their effect on cell proliferation , cell cycle , and cell death . The cytotoxic effect of the title compounds on CaSki and human lymphocytes was also evaluated , indicating that the main cell death process is not necrosis ; the null effect on lymphocytes implies that they are not cytotoxic . The observation of apoptotic bodies as well as the increase in the expression of active caspase-3 along with the fragmentation of DNA confirmed that such new cholestanic frameworks induced apoptosis in tumor cells . Significantly , their antiproliferative activity on tumor cells did not affect the proliferative potential of normal fibroblasts from cervix and peripheral blood lymphocytes . The title compounds show selective antitumor activity and therefore serve as promising lead candidates for further optimization .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20303770"}
{"sentence": "AIM : To explore the inhibitory effect of sulfated polysaccharide from Masson pine ( Pinus massoniana ) pollen ( SPPM60 ) on G(2)/M phase of human liver cancer HepG2 cells and its mechanism . METHODS : The proliferation rate of HepG2 cells was evaluated by methyl thiazolyl tetrazolium ( MTT ) colorimetric assay . The cycles of HepG2 cells were measured by flow cytometry when 200\u03bcg/ml concentration of SPPM60 was adopted , the expression of the genes related to cell cycle was detected by real-time PCR . RESULTS : SPPM60 inhibited the proliferation of HepG2 cells and the inhibition rate was elevated with increase of SPPM60 concentration . After treatment with 200\u03bcg/ml of SPPM60 , the percentage of S phase cells was decreased , but that of G(2)/M phase was significantly increased ( 72h vs control : 32.96\ufffd0.33% vs 18.59\ufffd0.04% , 3.44\ufffd0.05% vs 18.30\ufffd0.08% , P<0.01 ) . The results of real-time PCR showed that SPPM60 could down-regulate the mRNA levels of CDK1 and CyclinB ( P<0.01 ) , and up-regulate the expression of p53 and p21 ( P<0.05 ) . CONCLUSION : SPPM60 causes arrest of HepG2 cells at G(2)/M phase , and the mechanism is related to the down-regulation of CDK1 and CyclinB and up-regulation of p53 and p21 expression .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23270833"}
{"sentence": "MOTIVATION The development of high-throughput sequencing technologies has enabled novel methods for detecting structural variants ( SVs ) . Current methods are typically based on depth of coverage or pair-end mapping clusters . However , most of these only report an approximate location for each SV , rather than exact breakpoints . RESULTS We have developed pair-read informed split mapping ( PRISM ) , a method that identifies SVs and their precise breakpoints from whole-genome resequencing data . PRISM uses a split-alignment approach informed by the mapping of paired-end reads , hence enabling breakpoint identification of multiple SV types , including arbitrary-sized inversions , deletions and tandem duplications . Comparisons to previous datasets and simulation experiments illustrate PRISM's high sensitivity , while PCR validations of PRISM results , including previously uncharacterized variants , indicate an overall precision of AVAILABILITY PRISM is freely available at http://compbio.cs.toronto.edu/prism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22851530"}
{"sentence": "AIM To develop a simple , fast and inexpensive approach as well as an instrument for detection of gene mutation . METHODS Pyrosequencing based on bioluminometry assay was employed to detect gene mutation . Pyrosequencing is a method of sequencing by synthesis step-by-step using four enzymes , DNA-polymerase , ATP sulfurylase , luciferase and apyrase . The signal was produced by detecting pyrophosphate released during a dNTP incorporation . For mutation detection , a DNA fragment was amplified by PCR at first , followed by a single-stranded DNA preparation . In the second step , a short primer was annealed to the position just before the mutation point . Finally , specific dNTPs were added in terms of the template sequence . The mutation species can be readily determined by the sequence . RESULTS A new instrument was developed for gene mutation detection by pyrosequencing . To iteratively inject small amount of each dNTP for the sequencing reaction , capillaries were used to connect dNTP reservoirs and the reaction chamber . Each dNTP was delivered by adding a gas pressure on the top of a corresponding dNTP reservoir , by which 0.2 microL of dNTP can be exactly added each time . It was theoretically proved that undesired liquid seep through the capillary did not affect the sequencing reactions in pyrosequencing . In addition , the three possible variants ( wildtype , mutant and heterozygote ) of a mutant point Cys275Ser in P53 gene exon 8 were determined by pyrosequencing using the instrument . A simple method was also described for rapidly distinguishing the type of a variant . CONCLUSION The developed method is very simple , and the corresponding instrument is inexpensive and easy to operate , which can be used to detect many types of mutation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12579898"}
{"sentence": "A hallmark of cancer cells is the ability to proliferate indefinitely . This acquisition of an immortal lifespan usually requires the activation of telomerase , the enzyme that elongates telomeres . Human telomerase is minimally composed of the reverse transcriptase subunit hTERT , and the RNA subunit hTR . While hTR is ubiquitously expressed in human cells , the hTERT subunit is generally transcriptionally repressed in most normal somatic cells , but is illegitimately activated to restore telomerase activity in cancer cells . Indeed , in the thousands of different human tumours assayed , 85% were scored positive for telomerase activity . However , the levels of telomerase activity detected in tumour samples can vary substantially and even some normal somatic cells have been found to have low levels of enzyme activity . As the functional significance of low levels of telomerase activity is unclear , we investigated whether there is a minimum level of telomerase activity required for tumourigenesis . Using mutants of hTERT that induce varying levels of telomerase activity , we show that there does indeed exist a threshold of activity required for the processes of immortalization , transformation and tumourigenesis . Thus , low levels of activity detected in certain somatic cells would not be expected to contribute to tumourigenesis , nor does the mere detection of telomerase in cancer cells necessarily signify an immortal lifespan .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12370834"}
{"sentence": "The study focuses on the effects of combined oral contraceptives ( COCs ) on the onset of cervical dysplasia among Zimbabwean women . Women who had used COCs for at least 2 years and were in continued use were compared to non-users of COCs ( control group ) . It was difficult to establish the average period of contraceptive use because in most instances there was no proper documentation on the exact dates as to when the subjects started using COCs . The number of subjects with each condition was noted from each of the following age groups ; <20 years , 20-29years , 30-39years , 40-49years and >50years . It was found that the percentage of the control group with benign conditions was higher than that of COC users in all age groups . Significant differences at 95 percent confidence level were noted for the 20-29 years age group ( z= -2.21 ) and 40-49 years age group ( z= -2.53).The number of subjects in the <20 years and >50 years age groups were too small for z-score computation . No significant differences were noted for mild to moderate cervical inflammation in all age groups . There was a higher percentage of COC users with severe cervical inflammation compared to the control group in all age groups . Significant differences were noted in the 30-39 years age group ( z=3.45 ) and 40-49 years age group ( z= 1.98 ) . A higher percentage of CIN I was noted among pooled COC users compared to the control group ( z= 2.00 ) although no significant differences were obtained within different age groups . In conclusion , severe cervical inflammation and CIN I are more frequent among Zimbabwean women who use COCs as compared to non-users of COCs . Frequencies of advanced CIN are low among women who undergo routine cytological screening because this enables early detection and subsequent treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "17298156"}
{"sentence": "The orphan receptor TR3 is an important regulator of cell proliferation and apoptosis . However , whether TR3 is involved in regulating the stem-like properties of cancer cells remains unknown . The present study shows that TR3 expression is increased in gastric tumorsphere cells and is positively correlated with cancer stem cell ( CSC ) characteristics . Knocking down TR3 leads to the suppression of its stem-like properties in both gastric cancer cells and tumorsphere cells . This process involves the decreased expression of the stemness-related genes Oct-4 and Nanog and the invasion-related gene MMP-9 . We further identify Nanog as a new target for the transcription factor TR3 . Together , these data demonstrate for the first time that TR3 is essential for the maintenance of stem-like properties in human gastric cancer cells and implicate TR3 as a new therapeutic target for gastric cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23043761"}
{"sentence": "Hypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature , which is recognized to play a role in the resistance of cancer cells to chemotherapy . Etoposide ( VP-16 ) , a drug commonly used in chemotherapy , leads to enhanced accumulation of cell populations in G2/M phase and increases levels of apoptosis as a topoisomerase II inhibitor . We evaluated the effects of hypoxia on the response of the neuroblastoma cell line CHP126 to VP-16 , in order to delineate the mechanisms responsible for the hypoxia-induced chemoresistance of this clinically conventional anti-cancer agent , with an insight to determining potential indications in neuroblastoma therapy . In this study , physiological hypoxia was shown to attenuate G2/M arrest and apoptosis induced in CHP126 cells by VP-16 . It suppressed drug-related Cdk1 activity with a less elevation of regulator proteins such as cyclin B1 , Cdk7 and reduced caspase activation and PARP cleavage compared to the efficiency observed in normoxic condition , which were significantly relative with hypoxia-driven inhibition of p53 and p-ERK1/2 activation . These results clearly demonstrated that hypoxia had a protective effect against VP-16-induced cytotoxicity , which is likely to provide a further therapeutic knowledge in neuroblastomas .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20187579"}
{"sentence": "OBJECTIVE The HER2 receptor is involved in pathways essential for cell proliferation , and is an important predictive and prognostic factor in breast cancer . HER2 probably plays a critical role in many types of cancer , including urothelial carcinoma of the bladder ( UCB ) . Stage T1 UCB exhibits heterogeneous clinical behaviour , and the frequency of HER2 expression in such disease has not been thoroughly examined . The aim of this study was to use an immunohistochemical technique to evaluate the frequency of HER2 expression in a defined population-based cohort of patients registered as having primary stage T1 UCB . MATERIAL AND METHODS The initial study population comprised 285 patients registered as having primary stage T1 UCB . The original histological specimens were re-evaluated with regard to T stage and World Health Organization grade . Hospital records provided information on tumour size , multiplicity , possible presence of histologically proven recurrence and progression . The patients were followed for at least 5 years or until death . In tumours still considered stage T1 after re-evaluation , HER2 was investigated by immunohistochemistry of paraffin-embedded material and scored according to the guidelines used in breast cancer . RESULTS After histopathological re-evaluation , 201 patients were still T1 UCB and could be investigated regarding HER2 expression . HER2 overexpression was observed in 25 of those patients ( 12.4% ) . HER2 status was not significantly associated with recurrence or progression . CONCLUSIONS HER2 was overexpressed in 12.4% of the present cohort of patients with primary stage T1 UCB . There was no significant association between tumour HER2 status and prognosis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22150625"}
{"sentence": "CrtJ from Rhodobacter capsulatus is a regulator of genes involved in the biosynthesis of haem , bacteriochlorophyll , carotenoids as well as structural proteins of the light harvesting-II complex . Fluorescence anisotropy-based DNA-binding analysis demonstrates that oxidized CrtJ exhibits increase in binding affinity over that of reduced CrtJ . Liquid chromatography electrospray tandem ionization mass spectrometric analysis using DAz-2 , a sulfenic acid ( -SOH)-specific probe , demonstrates that exposure of CrtJ to oxygen or to hydrogen peroxide leads to significant accumulation of a sulfenic acid derivative of Cys420 which is located in the helix-turn-helix ( HTH ) motif . In vivo labelling with 4-(3-azidopropyl)cyclohexane-1,3-dione ( DAz-2 ) shows that Cys420 also forms a sulfenic acid modification in vivo when cells are exposed to oxygen . Moreover , a Cys420 to Ala mutation leads to a reduction of DNA binding activity while a Cys to Ser substitution at position 420 that mimics a cysteine sulfenic acid results in a increase in DNA binding activity . These results provide the first example where sulfenic acid oxidation of a cysteine in a HTH-motif leads to differential effects on gene expression .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22715852"}
{"sentence": "DNA double-strand breaks ( DSBs ) representa serious threat for hematopoietic stem cells ( HSCs ) . How cytokines and environmental signals integrate the DNA damage response and contribute to HSC-intrinsic DNA repair processes remains unknown . Thrombopoietin ( TPO ) and its receptor , Mpl , are critical factors supporting HSC self-renewal and expansion . Here , we uncover an unknown function for TPO-Mpl in the regulation of DNA damage response . We show that DNA repair following \\u03b3-irradiation ( \\u03b3-IR ) or the action of topoisomerase-II inhibitors is defective in Mpl(-/-) and in wild-type mouse or human hematopoietic stem and progenitor cells treated in the absence of TPO . TPO stimulates DNA repair invitro and invivo by increasing DNA-PK-dependent nonhomologous end-joining efficiency . This ensures HSC chromosomal integrity and limits their long-term injury in response to IR.This shows that niche factors can modulate theHSC DSB repair machinery and opens new avenues for administration of TPO agonists for minimizing radiotherapy-induced HSC injury and mutagenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23246483"}
{"sentence": "A new cell line , CB109 , has been established from a human glioblastoma multiforme . The cytoskeleton was positive for glial fibrillary acidic protein , vimentin and fibronectin . Hyaluronan ( HA ) and the HA-binding protein hyaluronectin ( HN ) were expressed in the cell cytoplasm and in the extracellular matrix of spheroids and plated cells . Hyaluronidase did not prevent spheroid formation suggesting that HA was not involved in the cell-cell adhesion . HA precoating prevented cell adherence to the plates and favoured spheroid formation . HA was secreted in relatively large amounts into the culture medium . High performance liquid chromatography demonstrated that HA was in the high molecular weight form . The rate of HN secretion by cells was very low . Basic fibroblast growth factor significantly increased the proliferation in vitro and tumour growth after grafting into nude mice . The epidermal growth factor receptor was not expressed on cultivated CB109 cells . Cytogenetic analysis showed polysomy 7 , structural rearrangement of chromosome 10 short arm and a translocation 13q13-q14 without detectable alteration of the RB gene .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1378293"}
{"sentence": "Ninety-three patients with completely resected peripheral non-small cell lung cancer , clinically diagnosed 2 cm or less in diameter , were retrospectively reviewed . Their preoperative computed tomography ( CT ) and positron emission tomography ( PET ) findings , carcinoembryonic antigen ( CEA ) values , clinico-pathological features and postoperative outcomes were analysed . Ground-glass opacity ( GGO ) ratio( soft tissue density area of the tumor/maximum area of the tumor in diameter ) was measured . The overall survival rate at 3 years was 93.3% and the relapse-free survival rate at 3 years was 89.4% with a median follow-up period of 38.5 months . Patients with GGO ratio 0.25 or less had no lymph node ( LN ) involvement nor lymph vascular invasion . Only 2 of them ( 8% ) had vascular invasion . Fisher's exact probability test revealed CEA \u2265 5 ng/ ml as risk factor for LN involvement( p=0.0400 ) . Multiple logistic regression analysis showed that solid adenocarcinoma and squamous cell carcinoma recurred more frequently than adenocarcinoma with GGO ( p=0.0619 , odds ratio 4.969 , 95%CI 0.9242", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22314150"}
{"sentence": "Macrophages are the prominent components of solid tumors and have complex dual functions in their interaction with cancer cells . Strong evidence suggests that TAM is a part of inflammatory circuits that promote tumor progression . B7-homologue 3 ( B7-H3 ) , a recently identified homologue of B7.1/2 ( CD80/86 ) , has been described to exert co-stimulatory and immune regulatory functions . Here , we showed that a fraction of macrophages in tumor stroma expressed surface B7-H3 molecule . Normal macrophages , which did not express B7-H3 , would be induced expressing B7-H3 molecule when culturing with tumor cell . Although a lung cancer cell line constitutively expressed B7-H3 mRNA and protein in plasma , primary tumor cell isolated from the transplanted lung carcinoma model expressed B7-H3 on the surface . Interestingly , in transplanted lung carcinoma model , the expression of membrane-bound B7-H3 in tumor cells was increased as prolonging of tumor transformation . In support , IL-10 released from TAM could stimulate cancer cell expression of membrane bound B7-H3 . Furthermore , Lung cancer and TAM-related B7-H3 was identified as a strong inhibitor of T-cell effect and influenced the outcome of T cell immune response . In conclusion , TAM-tumor cell interaction-induced membrane-bound B7-H3 represents a novel immune escape mechanism which links the pro-inflammatory response to immune tolerance in the tumor milieu .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22999863"}
{"sentence": "Multiple endocrine neoplasia type 2 ( MEN2 ) is an autosomal , dominantly inherited disease characterized by medullary thyroid carcinoma , pheochromocytoma , and primary hyperparathyroidism and is divided into types 2A and 2B . Familial medullary thyroid carcinoma ( FMTC ) is characterized by the presence of medullary thyroid carcinoma alone in family members and is considered to be one of the subtypes of MEN2 . Clinical and genetic data on 505 Japanese patients from 275 MEN2 or FMTC families registered at 54 medical institutions were collected by the MEN Consortium of Japan . The diagnosis was MEN2A in 343 ( 67.9% ) patients , MEN2B in 29 ( 5.7% ) , FMTC in 103 ( 20.4% ) , and unclassified in 30 ( 5.9% ) . Medullary thyroid carcinoma was found in 91.2% of patients ( 437/479 ) , pheochromocytoma in 45.6% ( 212/465 ) , and primary hyperparathyroidism in 8.1% ( 37/457 ) . RET genetic testing was performed in 410 patients , and the germline RET mutation was found in 98.8% ( 397/402 ) .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22928441"}
{"sentence": "Cancer immunotherapies are designed to elicit T-cell responses that inhibit tumor growth . Previous studies have demonstrated that interleukin 21 ( IL-21 ) is a promising cytokine for cancer immunotherapy due to its ability to induce the immunity of T cells and natural killer cells , whereas blockade of the interaction of programmed death receptor-1 ( PD-1 ) with its ligand ( PD-L1 ) reduces peripheral tolerance . In the current study , we investigated IL-21 alone and in combination with soluble PD-1 ( sPD-1 ) for the treatment of experimental H22 murine hepatocarcinoma . The naked plasmids pmIL-21 and/or psPD-1 were used for local gene transfer by injection . In these assays , sPD-1 combined with IL-21 was found to significantly inhibit the growth of the tumors in mice . Combined treatment with IL-21 and sPD-1 enhanced the antitumor immune response compared with that induced by IL-21 alone . Combined treatment was found to increase CTL cytotoxicity , increase the number of CTLs and NK cells in splenocytes , upregulate the cytokines IFN-\u03b3 and IL-2 and downregulate IL-10 . Thus , immunotherapy with IL-21 in combination with sPD-1 was found to induce a more efficacious antitumor immune response , which may have potential clinical implications .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23255900"}
{"sentence": "This is a case report of a 69-year-old woman with sarcomatoid hepatocellular carcinoma ( HCC ) , which was diagnosed clinically as hemangioma . She was first admitted to our university hospital , complaining of general fatigue in December , 1988 , and cholelithiasis and liver cirrhosis with hepatic tumor in Segment 8 were diagnosed . The serum AFP level was within normal range , and the tumor was diagnosed as hemangioma radiologically . She underwent only cholecystectomy and was well without any therapy for the liver tumor up until March in 1991 when she was readmitted to our university hospital due to rapidly progressive liver dysfunction . The size of the liver tumor was unchanged . Despite intensive care , she died of hepatic failure due to cirrhosis in a decompensation state . At autopsy , a well defined yellowish white tumor of 3 cm in maximum diameter was seen in the cirrhotic liver . Although the largest part of the tumor revealed necrosis and hyalinization , a sarcomatoid part composed of spindle-shaped cells was noted in the peripheral portion . In addition , some necrotic ghost cells , probably hepatocellular carcinoma , were also noted . Low molecular cytokeratin , which is always found in HCCs , was seen in spindle-shaped sarcomatoid cells . The liver tumor was diagnosed as sarcomatoid HCC from these pathological findings . We report this histologically unusual HCC with an immunohistochemical study .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1470779"}
{"sentence": "Indolylmaleimides display a broad spectrum of biological activity and offer great opportunity to influence several aspects of cell fate , as proliferation and differentiation . In this study we describe the effect of PDA-66 , a newly synthesised indolylmaleimide , showing a strong dose dependent anti-proliferative effect on immortalised human progenitor and cancer cells . We demonstrated a highly depolymerizing effect on in vitro tubulin assembly and conclude that PDA-66 acts as microtubule destabilising agent . In addition we found that PDA-66 induces mitotic arrest of cells in the G(2)/M phase of the cell cycle . Subsequently cells undergo apoptosis , indicating the major mechanism of the anti-proliferative effect . To prove a potential anti-cancer activity of PDA-66 we examined the effect of PDA-66 on human SH-SY5Y neuroblastoma and A-459 lung cancer cells , showing a significant reduction in cancer cell proliferation in a dose dependent manner . Thus PDA-66 is a new anti-mitotic compound with an indole-core with the potential to be used for cancer therapy .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23274302"}
{"sentence": "Oxazaphosphorines are a class of DNA alkylating agents . The aim of the present study was to compare the possible influence of three new generation oxazaphosphorines , D-17272 ( mafosfamide cyclohexylamine salt ) , D-18864 ( 4-hydro-peroxy-cyclophosphamide ) , and D-19575 ( glufosfamide , beta-D-glucose-isophosphoramide mustard ) on DNA damage induction in the human histiocytic lymphoma U937 cells . The flow cytometry APO-BRDU assay , based on the TUNEL method , was used for the in situ detection of DNA strand breaks . After exposure of U937 cells to the oxazaphosphorines , the patterns of temporary changes in the frequency of TUNEL positive U937 cells , expressing DNA breakage , were determined . The effects of the oxazaphosphorines on U937 cells were dependent on the agent tested and its dose , and the time intervals after the drug application . The different potential of D-17272 , D-18864 and D-19575 to induce DNA strand breakage in the human histiocytic lymphoma U937 cells was shown .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20420190"}
{"sentence": "We have investigated the cytotoxic activity , the induction of apoptosis , and the interstrand cross-linking efficiency in the A2780cisR ovarian tumor cell line , after replacement of the two NH3 nonleaving groups in trans-[PtCl2(NH3)2] ( trans-DDP ) by dimethylamine and isopropylamine . The data show that trans-[PtCl2(NH(CH)2)(NHCH(CH3)2)] is able to circumvent resistance to cis-[PtCl2(NH3)2] ( cis-DDP , cisplatin ) in A2780cisR cells . In fact , trans-[PtCl2(NH(CH3)2)(NHCH(CH3)2)] shows a cytotoxic potency higher than that of cis-DDP and trans-DDP , with the mean IC50 values being 11 , 58 , and 300 microM , respectively . In addition , at equitoxic doses ( concentrations of the platinum drugs equal to their IC50 values ) and after 24 hours of drug treatment , the level of induction of apoptosis by trans-[PtCl2(NH(CH3)2)(NHCH(CH3)2)] is twice that produced by cis-DDP . Under the same experimental conditions , trans-DDP does not induce significant levels of apoptosis in A2780cisR cells . After 24 hours of incubation of A2780cisR cells at concentrations equal to the IC0o value of the platinum drugs , the level of DNA interstrand cross-links ( ICLs ) induced by trans-[PtCI2(NH(CH)2)(NHCH(CH3)] is two and three times higher , respectively , than those induced by cis-DDP and trans-DDP . We also found that trans-[PtCl2(NH(CH3)2)(NHCH(CH3)2)] formed DNA ICLs between guanine and complementary cytosine . We propose that , in A2780cisR cells , the induction of apoptosis by trans-[PtCl2(NH(CH3)2)(NHCH(CH3)2)] is related to its greater ability ( relative to cis-DDP and trans-DDP ) to form DNA ICLs .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "17590955"}
{"sentence": "Premature senescence , a key strategy used to suppress carcinogenesis , can be driven by p53/p21 proteins in response to various stresses . Here , we demonstrate that Wig1 plays a critical role in this process through regulation of p21 mRNA stability . Wig1 controls the association of Argonaute2 ( Ago2 ) , a central component of the RNA-induced silencing complex ( RISC ) , with target p21 mRNA via binding of the stem-loop structure near the microRNA ( miRNA ) target site . Depletion of Wig1 prohibited miRNA-mediated p21 mRNA decay and resulted in premature senescence . Wig1 plays an essential role in cell proliferation , as demonstrated in tumour xenografts in mice , and Wig1 and p21 mRNA levels are inversely correlated in human normal and cancer tissues . Together , our data indicate a novel role of Wig1 in RISC target accessibility , which is a key step in RNA-mediated gene silencing . In addition , these findings indicate that fine-tuning of p21 levels by Wig1 is essential for the prevention of cellular senescence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "23085987"}
{"sentence": "The published results on nanoparticles cytotoxicity and genotoxicity such as titanium dioxide nanoparticles ( TiO(2) NPs ) are inconsistent , and often conflicting and insufficient . Since different parameters may have impact on the toxicity results , there is need to lay stress on detailed characterization of NPs and the use of different testing conditions for assessment of NPs toxicity . In order to investigate whether dispersion procedures influence NP cytotoxicity and genotoxicity , we compared two protocols giving TiO(2) NP dispersions with different stability and agglomeration states . Detailed primary and secondary characteristics of both TiO(2) NP dispersions in culture media were carried out before toxicological testing ; TK6 human lymphoblast cells , EUE human embryonic epithelial cells and Cos-1 monkey kidney fibroblasts were used to assess cytotoxicity ( by trypan blue exclusion , proliferation activity and plating efficiency assays ) and genotoxicity ( by the comet assay ) . DNA strand breaks were detected by the alkaline comet assay . DNA oxidation lesions ( especially 8-oxo-7,8-dihydroguanine , 8-oxoG ) were measured with a modified comet assay including incubation with specific repair enzyme formamidopyrimidine DNA glycosylase ( FPG ) . The TiO(2) NPs dispersion with large agglomerates ( 3 min sonication and no serum in stock solution ) induced DNA damage in all three cell lines , while the TiO(2) NPs dispersed with agglomerates less than 200 nm ( foetal serum in stock solution and sonication 15 min ) had no effect on genotoxicity . An increased level of DNA oxidation lesions detected in Cos-1 and TK6 cells indicates that the leading mechanism by which TiO(2) NPs trigger genotoxicity is most likely oxidative stress . Our results show that the dispersion method used can influence the results of toxicity studies . Therefore at least two different dispersion procedures should be incorporated into assessment of cyto- and genotoxic effects of NPs . It is important , when assessing the hazard associated with NPs , to establish standard testing procedures and thorough strategies to consider the diverse conditions relevant to possible exposures .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "22277962"}
{"sentence": "OBJECTIVE The study was undertaken to document and highlight the shortcomings of histopathology reporting of breast carcinoma in Pakistan so that improvements can be recommended and a standardized protocol devised . METHODS This was a descriptive cross sectional study and was conducted at Histopathology Department , Armed Forces Institute of Pathology , Rawalpindi from 1st January 2008 to 31st October 2008 . Fifty consecutive breast carcinoma reports received for review from different laboratories were analyzed for documentation of patients age , sex , type of procedure/specimen , specimen size , tumour size , invasive tumour type , invasive tumour grade , comment on excision margins , extent of lymph node involvement , insitu component , lymphovascular invasion , necrosis , skin involvement and tabular format . Frequencies and percentages were calculated for presence of these above mentioned variables in different reports , keeping in mind the possible information that could be obtained from a particular sample . RESULTS It was found that the variable least mentioned in the reports was in situ component commented upon in only 23.2% of reports . Necrosis was mentioned in 35% of reports . Tabular format was found in 36% of reports only . CONCLUSION Marked deficiencies are seen in histopathology reports for breast carcinoma due to the lack of any standardized reporting system . Separate checklist formats for trucut biopsies , lumpectomies and mastectomies should be introduced to ensure uniform reporting .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20593952"}
{"sentence": "A glycolytic profile unifies a group of pheochromocytomas and paragangliomas ( PHEOs/PGLs ) with distinct underlying gene defects , including von Hippel-Lindau ( VHL ) and succinate dehydrogenase B ( SDHB ) mutations . Nevertheless , their tumor aggressiveness is distinct : PHEOs/PGLs metastasize rarely in VHL- , but frequently in SDHB-patients . To date , the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown . Recently , however , an excellent model to study aggressive PHEOs ( mouse tumor tissue ( MTT ) cells ) has been developed from mouse PHEO cells ( MPC ) . We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness , which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs . The increase of glucose transporter 1 in VHL , and of hexokinase 2 in VHL and SDHB , confirmed their glycolytic profile . In agreement with the cell model and in support of decoupling of glycolysis , the Krebs cycle and oxidative phosphorylation ( OXPHOS ) , SDHB tumors showed increased lactate dehydrogenase levels . In SDHB-PGLs OXPHOS complex activity was increased at complex III and , as expected , decreased at complex II . Moreover , protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors . Although there was no direct evidence for increased reactive oxygen species production , elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs . For the first time , we show that despite dysfunction in complex II and evidence for a glycolytic phenotype , the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS . In addition , we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs , proteins that have been proposed as promising therapeutic targets in other cancers . This study provides new insight into pathogenic mechanisms in aggressive human PHEOs/PGLs , which may lead to identifying new diagnostic and prognostic markers in the near future .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "22859959"}
{"sentence": "BACKGROUND Epithelial mesenchymal transition ( EMT ) is known to be associated with chemoresistance as well as increased invasion/metastasis . However , the relationship between EMT and resistance to an epidermal growth factor receptor ( EGFR ) -targeting drug in head and neck squamous cell carcinoma ( HNSCC ) remains unknown . In this study , we investigated the acquisition of EMT by gefitinib in HNSCC cell line ( UMSCC81B ) . METHODS We isolated fibroblastoid variant ( 81B-Fb ) from gefitinib-resistant UMSCC81B-GR3 cells obtained after increasing the doses of gefitinib treatment in vitro and examined EMT and its underlying mechanism . RESULT 81B-Fb cells exhibited fibroblast-like morphology , increased motility , loss of E-cadherin , acquisition of vimentin and snail expression . In 81B-Fb cells , downregulation of EGFR , which is mediated by increased ubiquitination , and activation of downstream protein kinase B ( Akt ) , glycogen synthase kinase-beta ( GSK-3\u03b2 ) signalling and upregulation of snail expression were observed compared with UMSCC81B cells . LY294002 , but not U0126 , suppressed foetal bovine serum or heregulin-\u03b21-induced phosphorylation of Akt/GSK-3\u03b2 and snail expression together with the inhibition of 81B-Fb cell motility . Furthermore , forced expression of EGFR resulted in partial restoration of gefitinib sensitivity and reversal of EMT . CONCLUSION These results suggest that EMT in the gefitinib-resistant cells is mediated by the downregulation of EGFR and compensatory activation of Akt/GSK-3\u03b2/snail pathway .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22315058"}
{"sentence": "Heterodimeric hCG is one of the key hormones determining early pregnancy success . We have previously identified rare missense mutations in hCG\\u03b2 genes with potential pathophysiological importance . The present study assessed the impact of these mutations on the structure and function of hCG by applying a combination of in silico ( sequence and structure analysis , molecular dynamics ) and in vitro ( co-immunoprecipitation , immuno- and bioassays ) approaches . The carrier status of each mutation was determined for 1086 North-Europeans [ 655 patients with recurrent miscarriage ( RM)/431 healthy controls from Estonia , Finland and Denmark ] using PCR-restriction fragment length polymorphism . The mutation CGB5 p.Val56Leu ( rs72556325 ) was identified in a single heterozygous RM patient and caused a structural hindrance in the formation of the hCG\\u03b1/\\u03b2 dimer . Although the amount of the mutant hCG\\u03b2 assembled into secreted intact hCG was only 10% compared with the wild-type , a stronger signaling response was triggered upon binding to its receptor , thus compensating the effect of poor dimerization . The mutation CGB8 p.Pro73Arg ( rs72556345 ) was found in five heterozygotes ( three RM cases and two control individuals ) and was inherited by two of seven studied live born children . The mutation caused of secreted \\u03b2-subunits to acquire an alternative conformation , but did not affect its biological activity . For the CGB8 p.Arg8Trp ( rs72556341 ) substitution , the applied in vitro methods revealed no alterations in the assembly of intact hCG as also supported by an in silico analysis . In summary , the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCG\\u03b2 genes CGB5 and CGB8 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22554618"}
{"sentence": "Onions ( Allium cepa L. ) are widely used in the food industry for its nutritional and aromatic properties . Our studies showed that ethyl acetate extract of onion ( EEO ) had potent inhibitory effects on animal fatty acid synthase ( FAS ) , and could induce apoptosis in FAS over-expressing human breast cancer MDA-MB-231 cells . Furthermore , this apoptosis was accompanied by reduction of intracellular FAS activity and could be rescued by 25 mM or 50 mM exogenous palmitic acids , the final product of FAS catalyzed synthesis . These results suggest that the apoptosis induced by EEO occurs via inhibition of FAS . We also found that EEO could suppress lipid accumulation during the differentiation of 3T3-L1 adipocytes , which was also related to its inhibition of intracellular FAS activity . Since obesity is closely related to breast cancer and obese patients are at elevated risk of developing various cancers , these findings suggested that onion might be useful for preventing obesity-related malignancy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23317220"}
{"sentence": "Oncogene-induced senescence is now recognized as being an important mechanism in protecting against cancer . The phenotypic consequences , i.e. , the inhibition of cell proliferation , are well described in model systems and specific events/key players defined . However , there is still the need to understand , at a more global level , the network of events involved both in terms of cause and consequence . This paper shows the power of systematic proteomic analyses , both targeted and global , in addressing such biological questions , highlighting the widespread nature of histone acetylation changes , and the opposite metabolic changes to those seen in the Warburg effect .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23922328"}
{"sentence": "p53 is a tumor suppressor gene that is mutated in many human malignancies , including gastric cancer . It remains unclear why patients with germ-line p53 mutations ( i.e. , Li-Fraumeni syndrome ) are not at increased risk for gastric adenocarcinoma , despite the fact that they show a high rate of many other tumors . Furthermore , the precise relationship between germ-line p53 mutations and the response to chronic bacterial infections ( such as Helicobacter spp. ) has not been investigated . To assess the role of germ-line p53 deletions in modulating the progression to gastric cancer , p53(+/-) and wild-type ( WT ) C57BL/6 mice were infected with H. felis . The gastric pathology and immune response in these two groups of mice were analyzed for up to 15 months postinfection . The gastric fundus and antrum were evaluated independently using a 0-4 scale to score inflammation , parietal and chief cell loss , mucus metaplasia , and helicobacter colonization . Nonparametric statistical analysis was performed to determine the effects of p53(+/-) , infection status , and postinoculation ( p.i. ) time on inflammation , preneoplastic changes , invasive lesions , and helicobacter colonization. mRNA expression for gammaIFN , interleukin ( IL)-1 , IL-10 , and IL-4 was quantified by PCR . Sera were also evaluated for H. felis antibody by ELISA . Antral inflammation increased significantly with time in infected mice . There was a significant , protective effect on the development of preneoplastic fundic lesions and invasive carcinoma attributable to the deletion of one p53 allele ( P < 0.05 ) . Submucosal invasive foci were observed in 9 of 11 WT-infected mice ranging from 13 to 15 months p.i. ; invasion of adjacent submucosal blood vessels by glandular epithelia also was present in 5 of these mice . None of these lesions were observed in 33 p53(+/-) mice , infected or not , at any time p.i. p53(+/-) mice had significantly higher helicobacter colonization consistent with a Th2 host response . In sera from WT mice , IgG2a , considered a proinflammatory Th1 response , continued to rise throughout the 15-month study ( P < 0.004 ) . In contrast , IgG2a levels of the p53(+/-) mice were 50-60% lower than those of the WT mice at each time point ( P range , <0.012 to 0.002 ) and did not progress in magnitude between 12 and 15 months of chronic H. felis infection ( P = 0.167). mRNA levels for gammaIFN and IL-1 were significantly up-regulated in WT mice infected with H. felis ( P < 0.05 ) but were slightly elevated or were at background levels in p53(+/-) mice . IL-10 and IL-4 mRNA expression was not significantly different from control samples . Our results support the hypothesis that germ-line deletion of one p53 allele results in a down-regulated Th1 response to gastric helicobacter infection , possibly because of T-cell senescence , which may indirectly protect against the development of gastric cancer and other epithelial-derived neoplasms associated with chronic inflammation .", "label": [1, 0, 0, 1, 0, 0, 0, 0, 0, 1], "id": "11830522"}
{"sentence": "The phosphoinositide 3-kinase ( PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers . In many cases , concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage . Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway , thereby decreasing the effectiveness of single-agent targeted therapies . In this study , we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers . We found that MEK inhibitor-induced activation of PI3K/AKT resulted from hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2 . Mutation of this amino acid led to increased ERBB receptor activation and upregulation of the ERBB3/PI3K/AKT signaling pathway , which was no longer responsive to MEK inhibition . Taken together , these results elucidate an important , dominant feedback network regulating central oncogenic pathways in human cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22552284"}
{"sentence": "Androgen receptor ( AR ) signals have been suggested to contribute to bladder tumorigenesis and cancer progression . Activation of epidermal growth factor receptor ( EGFR ) also leads to stimulation of bladder tumor growth . However , crosstalk between AR and EGFR pathways in bladder cancer remains uncharacterized . We have recently shown that androgens activate the EGFR pathway in bladder cancer cells . The purpose of this study was to investigate the effects of EGF on AR activity in bladder cancer . EGF increased AR transcriptional activity by 1.2- , 1.9- and 2.0-fold in UMUC3 , 5637-AR and J82-AR cell lines , respectively , over mock treatment and a specific EGFR inhibitor , PD168393 , antagonized the EGF effect . Combined treatment of EGF and dihydrotestosterone ( DHT ) further induced AR transactivation while an AR antagonist , hydroxyflutamide ( HF ) , abolished the effect of not only DHT but also EGF . In growth assays , EGF alone/DHT alone/EGF+DHT increased cell numbers by 16/12/19% , 6/14/18% and 30/12/38% in UMUC3-control-shRNA , 5637-AR and J82-AR , respectively , whereas the effects of EGF were marginal or less significant in UMUC3-AR-shRNA ( 8% ) or AR-negative 5637-V ( <1% ) and J82-V ( 17% ) cells . HF treatment at least partially counteracted the EGF effect on the growth of AR-positive cells . Western blotting demonstrated that EGF , especially in the presence of DHT , upregulated the expression of the p160 coactivator TIF2 and HF again blocked this stimulation . Co-immunoprecipitation revealed the association between AR and estrogen receptor ( ER)-\u03b2 or Src in UMUC3 cells and stronger associations with EGF treatment , implying the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and cell growth . Current results , thus , suggest that EGF promotes bladder cancer cell proliferation via modulation of AR signals . Taken together with our previous findings , crosstalk between EGFR and AR pathways can play an important role in the progression of bladder cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22922989"}
{"sentence": "The retinoic acid receptor beta2 ( RARbeta2 ) protein is a putative tumor suppressor that inhibits proliferation and can induce apoptosis when introduced into breast , cervical , lung , and pancreatic cancer cell lines . To determine if RARbeta2 suppresses proliferation of mammary-derived cancer cells in vivo , we transduced MDA-MB-435 breast cancer cells with the LXSN retroviral vector containing RARbeta2 and implanted LXSN vector- or RARbeta2-transduced cells into the mammary fat pads of nude and severe combined immune deficiency ( SCID ) mice . We analyzed the xenografts for several tumor parameters , including tumor size , inflammation , vascularity , mitoses , tumor recurrence at the primary site following resection , and metastases . We found that 19 of 52 mice inoculated with vector-transduced cells developed metastases in multiple organs while only one of 55 mice receiving RARbeta2-transduced cells displayed evidence of metastases ( p < 0.000001 , combined experiments , two-tailed Fisher's exact test ) . Moreover , RARbeta2-tumor cell recipient mice had a lower incidence of post-resection tumor recurrence ( 8/55 vs. 25/52 , p = 0.0004 ) , 34% less necrosis ( in three of four experiments , p = 0.001 ) , and 39% fewer mitoses in tumor tissue ( p < 0.000001 ) . Our findings suggest that RARbeta2 may play a role in inhibiting the metastatic cascade in a mouse mammary gland xenograft tumor model and is a potential candidate for therapeutic intervention in human breast cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12000222"}
{"sentence": "Widespread changes in gene expression drive tumorigenesis , yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood . Here , we demonstrate that metabolic transformation plays an important role . Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA , which was shown to be important not only for energetics but also for HAT activity . Due to the Warburg effect , cancerous colonocytes rely on glucose as their primary energy source , so butyrate accumulated and functioned as an HDAC inhibitor . Although both mechanisms increased histone acetylation , different target genes were upregulated . Consequently , butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring , whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect . These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23063526"}
{"sentence": "An epithelial cell line , referred to as A163 , was established from breast carcinoma derived from a patient with a strong family history of breast cancer but no known breast cancer susceptibility mutation . A163 was propagated in a serum-free culture medium including the epidermal growth factor . Immunophenotypic characterization demonstrated a mixed luminal and basal-like phenotype . When epidermal growth factor was excluded from the culture medium , A163 entered a quiescent period followed by a period of increased cell proliferation in a subpopulation of the cells . The epidermal growth factor-independent subpopulation retained the basal-like phenotype of the parental cell line . Karyotype and fluorescent in situ hybridization analysis showed an amplification of epidermal growth factor receptor on 7q in A163-S1 only , resulting in high expression of total and phosphorylated epidermal growth factor receptor . The A163-S1 sub-line piles up in culture , indicating a loss of contact inhibition . When grown on transwell filters , A163 shows basal expression of P63 and cytokeratin 14 , whereas A163-S1 expresses P63 ubiquitously , and has lost the basal specific expression of cytokeratin 14 , indicating a loss of polarity . Furthermore , when cultured in reconstituted basement membrane matrix , A163 form polarized normal like acini . In contrast , A163-S1 form large disorganized structures with lack of polarity . These cell lines may prove useful to understand molecular changes in breast cancer progression , in particular basal-like breast cancer subtype with bad prognosis and no current treatment options .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "21082277"}
{"sentence": "BACKGROUND Greying with age in horses is an autosomal dominant trait , associated with loss of hair pigmentation , melanoma and vitiligo-like depigmentation . We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype . The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation . RESULTS We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses . In contrast , clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines . A tendency of a higher copy number in aggressive tumours was also found . Massively parallel resequencing of the kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype , confirming the duplication as the true causative mutation . We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation . Thus , these three nucleotide substitutions must have occurred subsequent to the duplication , consistent with our interpretation that the Grey mutation arose more than 2,000 years before present . CONCLUSIONS These results suggest that the mutation acts as a melanoma-driving regulatory element . The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22857264"}
{"sentence": "Heat shock protein 27 ( Hsp27 ) is emerging as a promising therapeutic target for treatment of various cancers . Although the role of Hsp27 in protection from stress-induced intrinsic cell death has been relatively well studied , its role in Fas ( death domain containing member of the tumor necrosis factor receptor superfamily)-induced apoptosis and cell proliferation remains underappreciated . Here , we show that Hsp27 silencing induces dual coordinated effects , resulting in inhibition of cell proliferation and sensitization of cells to Fas-induced apoptosis through regulation of PEA-15 ( 15-kDa phospho-enriched protein in astrocytes ) . We demonstrate that Hsp27 silencing suppresses proliferation by causing PEA-15 to bind and sequester extracellular signal-regulated kinase ( ERK ) , resulting in reduced translocation of ERK to the nucleus . Concurrently , Hsp27 silencing promotes Fas-induced apoptosis by inducing PEA-15 to release Fas-associating protein with a novel death domain ( FADD ) , thus allowing FADD to participate in death receptor signaling . Conversely , Hsp27 overexpression promotes cell proliferation and suppresses Fas-induced apoptosis . Furthermore , we show that Hsp27 regulation of PEA-15 activity occurs in an Akt-dependent manner . Significantly , Hsp27 silencing in a panel of phosphatase and tensin homolog on chromosome 10 ( PTEN ) wild-type or null cell lines , and in LNCaP cells that inducibly express PTEN , resulted in selective growth inhibition of PTEN-deficient cancer cells . These data identify a dual coordinated role of Hsp27 in cell proliferation and Fas-induced apoptosis via Akt and PEA-15 , and indicate that improved clinical responses to Hsp27-targeted therapy may be achieved by stratifying patient populations based on tumor PTEN expression .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22179576"}
{"sentence": "MYH7 mutations are found in of hypertrophic cardiomyopathy ( HCM ) patients . Currently , mutational analysis is based on the sequencing of the coding exons and a few exon-flanking intronic nucleotides , resulting in omission of single-exon deletions and mutations in internal intronic , promoter , and 3 ' UTR regions . We amplified and sequenced large MYH7 fragments in 60 HCM patients without previously identified sarcomere mutations . Lack of aberrant PCR fragments excluded single-exon deletions in the patients . Instead , we identified several new rare intronic variants . An intron 26 single nucleotide insertion ( -5 insC ) was predicted to affect pre-mRNA splicing , but allele frequencies did not differ between patients and controls ( n = 150 ) . We found several rare promoter variants in the patients compared to controls , some of which were in binding sites for transcription factors and could thus affect gene expression . Only one rare 3 ' UTR variant ( c.*29T>C ) found in the patients was absent among the controls . This nucleotide change would not affect the binding of known microRNAs . Therefore , MYH7 mutations outside the coding exon sequences would be rarely found among HCM patients . However , changes in the promoter region could be linked to the risk of developing HCM . Further research to define the functional effect of these variants on gene expression is necessary to confirm the role of the MYH7 promoter in cardiac hypertrophy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22765922"}
{"sentence": "INTRODUCTION Clinical and experimental studies indicate oxygen free radicals and their reactive derivatives participation in formation of chronic inflammation states , which facilitate gastrointestinal tract tumors development . During malignant changes formation in epithelium of gastrointestinal tract increased oxygen radicals generation initiates lipid peroxidation and DNA and proteins oxidation processes . Final lipid peroxidation products ( saturated and unsaturated aldehydes ) are highly reactive and characterized by greatly longer half life time than reactive oxygen species and capability to diffuse from places of their formation to distant cell areas . In cells they react with important biological macromolecules such as DNA and proteins causing their structural and functional damages . The effects of changes in cell membranes structure are increase in their permeability , depolarization , decrease of hydrophobicity and inhibition of enzymes , membrane channels and transporters . These changes lead to the loss of cell integrity . STUDY AIM Determination of lipid peroxidation level in blood serum patients with gastrointestinal tract tumors . MATERIALS AND METHODS Materials for studies were obtained from 170 patients with gastrointestinal tract tumors : 10 with stomach cancer , 20 with pancreatic cancer , 30 with primary liver cancer , 60 with primary colorectal cancer and 50 with metachronic colorectal cancer liver metastases . Blood was taken from patients 1 day before and 6 days after surgery . Control blood was obtained from 53 healthy blood donors . Lipid peroxidation level was determined spectrophotometrically as a concentration of final lipid peroxidation products , which in reaction with tiobarbituric acid ( TBA ) form colour complex ( thiobarbituric acid-reactive substances , TBARS ) . RESULTS Higher lipid peroxidation level was observed in pre- and postoperative blood sera patients with gastrointestinal tumors in comparison to serum from healthy blood donors . CONCLUSIONS Increased lipid peroxidation level in peripheral blood of patients with gastrointestinal tract tumors is evidence of intensive oxidative stress and might indicate impairment of antioxidant defense mechanisms in organism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21125741"}
{"sentence": "Ataxia telangiectasia ( AT ) cells , with their defective double-strand break ( DSB ) repair processes , exhibit high sensitivity to low-LET radiation such as X-rays irradiation and gamma beams . Since heavy ion beam treatment for cancer is becoming increasingly common in Japan and elsewhere , it is important to also determine their sensitivity to high-LET radiation . For this purpose we irradiated AT and normal human cells immortalized with the human telomerase gene using high- ( 24-60 keV/microm carbon and 200 keV/microm iron ions ) or low-LET ( X-rays ) radiation in non-proliferative conditions . In normal cells the RBE ( relative biological effectiveness ) of carbon and iron ions increased from 1.19 to 1.81 in proportion to LET . In contrast , their RBE in AT cells increased from 1.32 at 24 keV/microm to 1.59 at 40 keV/microm , and exhibited a plateau at over 40 keV/microm . In normal cells most gamma-H2AX foci induced by both carbon- and iron-ion beams had disappeared at 40 h . In AT cells , however , a significant number of gamma-H2AX foci were still observed at 40 h . The RBEs found in the AT cells after heavy-ion irradiation were consistent with the effects predicted from the presence of non-homologous end joining defects . The DSBs remaining after heavy-ion irradiation suggested defects in the AT cells ' DSB repair ability .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20197645"}
{"sentence": "Palmitoylation is required for the activities of several cancer-associated proteins , making the palmitoyl acyltransferase ( PAT ) enzymes that catalyze these reactions potential targets for anticancer therapeutics . In this study , we sought to identify and characterize a human PAT with activity toward N-terminally myristoylated and palmitoylated proteins . NIH/3t3 cells were stably transfected with vectors containing no insert , wild type human DHHC20 , or a serine-substituted DHHS20 mutant . Compared with control cells , cells overexpressing wild-type DHHC20 displayed an increase in palmitoylation activity toward a peptide that mimics the N-terminus of myristoylated and palmitoylated proteins , but had no change in activity toward a peptide that mimics the C-terminus of farnesylated and palmitoylated proteins . Cells expressing DHHS20 had no significant change in activity toward either peptide . Overexpression of DHHC20 also caused phenotypic changes consistent with cellular transformation , including colony formation in soft agar , decreased contact inhibition of growth , and increased proliferation under low-serum conditions . Quantitative polymerase chain reaction analyses of human tissues demonstrated that DHHC20 is expressed in a tissue-specific manner , and is overexpressed in several types of human tumors , including ovarian , breast and prostate . Overall , these results demonstrate that DHHC20 is a human N-terminal-myristoyl-directed PAT involved in cellular transformation , that may play a role in cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20334580"}
{"sentence": "AIM To investigate whether luteolin , a highly prevalent flavonoid , reverses the effects of epithelial-mesenchymal transition ( EMT ) in vitro and in vivo and to determine the mechanisms underlying this reversal . METHODS Murine malignant melanoma B16F10 cells were exposed to 1% O(2) for 24 h . Cellular mobility and adhesion were assessed using Boyden chamber transwell assay and cell adhesion assay , respectively . EMT-related proteins , such as E-cadherin and N-cadherin , were examined using Western blotting . Female C57BL/6 mice ( 6 to 8 weeks old ) were injected with B16F10 cells ( 1\ufffd10(6) cells in 0.2 mL per mouse ) via the lateral tail vein . The mice were treated with luteolin ( 10 or 20 mg/kg , ip ) daily for 23 d . On the 23rd day after tumor injection , the mice were sacrificed , and the lungs were collected , and metastatic foci in the lung surfaces were photographed . Tissue sections were analyzed with immunohistochemistry and HE staining . RESULTS Hypoxia changed the morphology of B16F10 cells in vitro from the cobblestone-like to mesenchymal-like strips , which was accompanied by increased cellular adhesion and invasion . Luteolin ( 5-50 \u03bcmol/L ) suppressed the hypoxia-induced changes in the cells in a dose-dependent manner . Hypoxia significantly decreased the expression of E-cadherin while increased the expression of N-cadherin in the cells ( indicating the occurrence of EMT-like transformation ) , which was reversed by luteolin ( 5 \u03bcmol/L ) . In B16F10 cells , luteolin up-regulated E-cadherin at least partly via inhibiting the \u03b23 integrin/FAK signal pathway . In experimental metastasis model mice , treatment with luteolin ( 10 or 20 mg/kg ) reduced metastatic colonization in the lungs by 50% . Furthermore , the treatment increased the expression of E-cadherin while reduced the expression of vimentin and \u03b23 integrin in the tumor tissues . CONCLUSION Luteolin inhibits the hypoxia-induced EMT in malignant melanoma cells both in vitro and in vivo via the regulation of \u03b23 integrin , suggesting that luteolin may be applied as a potential anticancer chemopreventative and chemotherapeutic agent .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22983392"}
{"sentence": "Many breast cancers are estrogen independent , and even in patients who initially respond to estrogen suppression therapy , the regression is often temporary . We have recently shown that antagonists of bombesin and gastrin-releasing peptide , including RC-3095 , inhibit the growth of pancreatic , colonic , and prostatic cancers in experimental animals . This effect was associated with a substantial decrease in epidermal growth factor ( EGF ) receptor levels in pancreatic and colon cancers .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1460673"}
{"sentence": "The molecular mechanism mediating expression of senescent cell antigen-aggregated or cleaved band 3 and externalized phosphatidylserine ( PS ) on the surface of aged erythrocytes and their premature expression in certain anemias is not completely elucidated . The erythrocytes with these surface modifications undergo macrophage-mediated phagocytosis . In this study , the role of protein kinase C ( PKC ) isoforms in the expression of these surface modifications was investigated . Inhibition of PKC \u03b1 by 30\u2009\u03bcM rottlerin ( R30 ) and 2.3\u2009nM G\ufffd 6976 caused expression of both the senescent cell marker-externalized PS measured by FACS analysis and aggregated band 3 detected by western blotting . In contrast to this observation , but in keeping with literature , PKC activation by phorbol-12-myristate-13-acetate ( PMA ) also led to the expression of senescence markers . We explain this antithesis by demonstrating that PMA-treated cells show reduction in the activity of PKC \u03b1 , thereby simulating inhibition . The reduction in PKC \u03b1 activity may be attributed to the known downregulation of PMA-activated PKC \u03b1 , caused by its membrane translocation and proteolysis . We demonstrate membrane translocation of PKC \u03b1 in PMA-treated cells to substantiate this inference . Thus loss of PKC \u03b1 activity either by inhibition or downregulation can cause surface modifications which can trigger erythrophagocytosis .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "22988493"}
{"sentence": "Continuous exposure to high concentrations of hexavalent chromium [ Cr(VI) ] in drinking water results in intestinal tumors in mice but not rats . Concentration-dependent gene expression effects were evaluated in female F344 rat duodenal and jejunal epithelia following 7 and 90 days of exposure to 0.3-520 mg/L ( as sodium dichromate dihydrate , SDD ) in drinking water . Whole-genome microarrays identified 3269 and 1815 duodenal , and 4557 and 1534 jejunal differentially expressed genes at 8 and 91 days , respectively , with significant overlaps between the intestinal segments . Functional annotation identified gene expression changes associated with oxidative stress , cell cycle , cell death , and immune response that were consistent with reported changes in redox status and histopathology . Comparative analysis with B6C3F1 mouse data from a similarly designed study identified 2790 differentially expressed rat orthologs in the duodenum compared to 5013 mouse orthologs at day 8 , and only 1504 rat and 3484 mouse orthologs at day 91 . Automated dose-response modeling resulted in similar median EC\u2085\u2080s in the rodent duodenal and jejunal mucosae . Comparative examination of differentially expressed genes also identified divergently regulated orthologs . Comparable numbers of differentially expressed genes were observed at equivalent Cr concentrations ( \u03bcg Cr/g duodenum ) . However , mice accumulated higher Cr levels than rats at \u2265 170 mg/L SDD , resulting in a increase in the number of differentially expressed genes . These qualitative and quantitative differences in differential gene expression , which correlate with differences in tissue dose , likely contribute to the disparate intestinal tumor outcomes .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22561333"}
{"sentence": "PURPOSE Pyruvate kinase isoenzyme M2 ( PKM2 ) is a key enzyme in aerobic glycolysis ; inhibition of PKM2 leads to the tumor growth inhibition . In this study , the effects of combined treatment with cisplatin ( DDP ) and a plasmid that expresses a short hairpin RNA ( shRNA ) targeting PKM2 on the growth of human A549 xenograft lung cancer model were investigated . METHODS The expression of PKM2 in A549 cells was determined by immunofluorescence . PKM2 expression levels were evaluated by Western blot analysis . In a human A549 lung cancer xenograft model , the effects of treatment with shRNA , with or without cisplatin , on tumor volume were determined . Apoptosis and cell proliferation status were examined to determine the mechanisms of tumor growth inhibition . RESULTS Expression of shRNA targeting PKM2 resulted in inhibition of PKM2 expression in A549 cells . In the lung cancer xenograft model , average tumor volume in the group treated with both cisplatin and shRNA was statistically lower than those of other groups ( P < 0.05 ) . The levels of apoptotic cells were significantly higher in samples from animals in the combined treatment group than those from untreated animals ( P < 0.05 ) . The cell proliferation rate , as determined by counting cells labeled with an anti-phospho-histone H3 , a marker for mitosis , was lower in samples from animals treated with both cisplatin and shRNA than in samples from other groups ( P < 0.05 ) . CONCLUSIONS Use of RNA interfering ( RNAi ) targeting PKM2 significantly inhibited tumor growth when combined with cisplatin in a human A549 lung cancer xenograft model . The enhanced antitumor activity of the combined treatment compared to treatment with shRNA alone may result in part from increased induction of apoptosis and augmented inhibition of cancer cell proliferation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20336315"}
{"sentence": "p53 is a well-known transcription factor that controls cell cycle arrest and cell death in response to a wide range of stresses . Moreover , p53 regulates glucose metabolism and its mutation results in the metabolic switch to the Warburg effect found in cancer cells . Nucleotide biosynthesis is also critical for cell proliferation and the cell division cycle . Nonetheless , little is known about whether p53 regulates nucleotide biosynthesis . Here we demonstrated that p53-inducible microRNA-34a ( miR-34a ) repressed inosine 5'-monophosphate dehydrogenase ( IMPDH ) , a rate-limiting enzyme of de novo GTP biosynthesis . Treatment with anti-miR-34a inhibitor relieved the expression of IMPDH upon DNA damage . Ultimately , miR-34a-mediated inhibition of IMPDH resulted in repressed activation of the GTP-dependent Ras signaling pathway . In summary , we suggest that p53 has a novel function in regulating purine biosynthesis , aided by miR-34a-dependent IMPDH repression .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22301190"}
{"sentence": "Momordica charantia has been found to exhibit anticancer activity , in addition to its well-known therapeutic functions . We have demonstrated that the leaf extract of Momordica charantia ( MCME ) induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways . In this study , a different susceptibility to MCME was found in human lung adenocarcinoma CL1 cells with different metastatic ability , leading to the significant difference of cell viability and invasiveness between MCME-treated CL1-0 and CL1-5 cells . MCME was found to upregulate the expression of Wnt-2 and affect the migratory and invasive ability of CL1 cells through suppressed MMP-2 and MMP-9 enzymatic activities . We proposed that MCME mediates inhibition against migration of CL1 cells by reducing the expression and activation of Src and FAK to decrease the expression of downstream Akt , \u03b2-catenin , and MMPs .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23320038"}
{"sentence": "The apoptotic effects of interferon lambdas ( IFN\u03bbs ) have been described in several types of cancers . However , their effects on human lung cancer cells and the mechanisms are elusive . In addition , the interaction between IFN\u03bbs and other interferons remains unclear . The interplay between IFN\u03b1 and IFN\u03bb has been reported . However , although IFN\u03b3 is a well-known regulatory interferon , the mechanisms through which it regulates IFN\u03bbs in lung cancer cells are unknown . These issues are critical for the application of IFN\u03bbs in lung cancer therapy . In this study , we used A549 , a cell line derived from a human lung carcinoma , to characterize the antiproliferative and apoptotic effects of IFN\u03bbs on lung cancer , and the interplay between IFN\u03b3 and IFN\u03bb . Because overexpression of full-length ectopic IFN\u03bbR1 led to cell death , we generated A549 cells stably expressing a chimeric receptor ( 10R1/\u03bbR1 ) , which is composed of the extracellular domain of IL-10 receptor ( IL10R1 ) fused in tandem to the transmembrane and intracellular domains of the IFN\u03bb receptor ( IFN\u03bbR1 ) . By comparing with A549 cells stably expressing its cognate vector , we demonstrated that IL-10 stimulation triggered the intracellular IFN\u03bb signaling via 10R1/\u03bbR1 receptor . By using A549 cells expressing 10R1/\u03bbR1 , we report that the IFN\u03bbR1 chain of IFN\u03bb receptor possesses an intrinsic ability to trigger apoptosis in human lung cancer cells . Although it did not suppress cell proliferation , IFN\u03bb signaling via 10R1/\u03bbR1 receptor induced cell cycle arrest , externalization of phosphatidylserine , DNA fragmentation , activation of caspase-3 , caspase-8 and caspase-9 . However , the caspase inhibitor Z-VAD-FMK did not prevent apoptosis . In addition , the extent of induced apoptosis correlate with the expression levels of the IFN\u03bb receptor and the levels of STAT1 activation . Lastly , we demonstrated that IFN\u03b3 sensitized A549 cells to IFN\u03bb-induced apoptosis , via upregulation of IFN\u03bbR1 . These data indicate the potential of IFN\u03bb , alone or in combination with IFN\u03b3 , in the treatment of human lung carcinoma .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22766785"}
{"sentence": "Squamous cell carcinoma ( SCC ) is the most frequent cancer in organ transplant recipients ( OTRs ) . The immune system plays a major role in the fight against SCC , however , little is known about the local inflammatory response in SCC at all . We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmunosuppressed OTRs . RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis . SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4 , CD8 , TBET , GATA-3 , FOXP3 , RORC , IFN-gamma , IL-4 , TGF-beta , IL-10 , and IL-17A mRNA expression . Immunohistochemistry was carried out in SCC for CD3 , CD4 , CD8 , and FOXP3 expression . Considerable inflammation was seen in both patient groups . SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature . CD4(+) mRNA was diminished in immunosuppression . Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients . T-BET and IFN-gamma mRNA expression were decreased in the OTR group . Although Th17-weighted inflammation was unchanged , IL-17A mRNA level was markedly decreased with immunosuppression . Regulatory T cells , characterized by FOX-P3 and TGF-beta mRNA level , were decreased in OTRs . Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20463594"}
{"sentence": "To investigate the significance of sialylation and sulfation of lactosylceramide in transformed cells , we established ganglioside GM3- and lactosylsulfatide ( SM3)-reconstituted cells by transfecting cDNAs of GM3 synthase and cerebroside sulfotransferase into the J5 subclone of 3LL Lewis lung carcinoma cells . The J5 clone was selected for the transfection of these genes because it lacks GM3 and SM3 but accumulates lactosylceramide . The anchorage-dependent growth of both GM3- and SM3-reconstituted cells was similar . However , anchorage-independent growth ( as measured by colony-forming ability in soft agar ) of the SM3- reconstituted cells was almost completely lost , which supports our previous observation showing the suppression of tumorigenic potential in vivo and beta1 integrin gene expression induced by the introduction of cerebroside sulfotransferase gene ( Kabayama et al. [ 2001 ] J. Biol . Chem. , 276 , 26777-26783 ) . The GM3-reconstituted cells formed a significantly higher number of colonies in soft agar compared to mock-transfected cells and began to proliferate and become resistant to apoptosis when serum was depleted , indicating that endogenous GM3 is essential for maintaining these fundamental properties of malignant cells . We also found that serum-induced ERK1/2 activation was suppressed in the GM3-reconstituted cells , suggesting that anchorage-independent cell cycle initiation by endogenous GM3 is elicited through pathway(s) independent of ERK1/2 activation . The selective down-regulation of platelet-derived growth factor ( PDGF)-dependent ERK1/2 activation in the GM3-reconstituted cells was due to the substantial decreases of PDGF alpha receptor mRNA and protein , but in the SM3-reconstituted cells PDGF alpha receptor expression was similar to mock cells . Thus , endogenously produced GM3 and SM3 differentially and distinctly regulate tumor-progression ability , that is , GM3 leads the transformed phenotype of J5 cells to promotion and SM3 to abrogation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12626418"}
{"sentence": "Liver metastasis from colorectal cancer is a leading cause of cancer mortality . Myeloid cells play pivotal roles in the metastatic process , but their prometastatic functions in liver metastasis remain incompletely understood . To investigate their role , we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells . Among the heterogeneous myeloid infiltrate , we identified a distinct population of CD11b/Gr1(mid) cells different from other myeloid populations previously associated with liver metastasis . These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2 . Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets . Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1(mid) recruitment and decreased tumor burden . Depletion of the CD11b/Gr1(mid) subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation . There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1(mid) cells . Additionally , an analogous myeloid subset was found in liver metastases of some colorectal cancer patients . Conclusion : Collectively , our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1(mid) subset-in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy . ( HEPATOLOGY 2012 ) .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23081697"}
{"sentence": "Medicinal mushroom Ganoderma lucidum is one of the most esteemed natural products that have been used in the traditional Chinese medicine . In this article , we demonstrate that G. lucidum triterpene extract ( GLT ) suppresses proliferation of human colon cancer cells HT-29 and inhibits tumor growth in a xenograft model of colon cancer . These effects of GLT are associated with the cell cycle arrest at G0/G1 and the induction of the programmed cell death Type II-autophagy in colon cancer cells . Here , we show that GLT induces formation of autophagic vacuoles and upregulates expression of Beclin-1 ( 1.3-fold increase ) and LC-3 ( 7.3-fold increase ) proteins in colon cancer cells and in tumors in a xenograft model ( Beclin-1 , 3.9-fold increase ; LC-3 , 1.9-fold increase ) . Autophagy is mediated through the inhibition of p38 mitogen-activated protein kinase ( p38 MAPK ) because p38 MAPK inhibitor , SB202190 , induces autophagy and expression of Beclin-1 ( 1.2-fold increase ) and LC-3 ( 7.4-fold increase ) , and GLT suppresses phosphorylation of p38 MAPK ( approximately 60% inhibition ) in colon cancer cells . Taken together , our data demonstrate a novel mechanism responsible for the inhibition of colon cancer cells by G. lucidum and suggest GLT as natural product for the treatment of colon cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20574924"}
{"sentence": "Previous experiments have shown that emodin is highly active in suppressing the proliferation of several tumor cell lines . However , it is not clear that emodin can induce growth inhibition of hepatoma cells . We have found that emodin induces apoptotic responses in the human hepatocellular carcinoma cell lines ( HCC ) Mahlavu , PLC/PRF/5 and HepG2 . The addition of emodin to these three cell lines led to inhibition of growth in a time- and dose-dependent manner . Emodin generated reactive oxygen species ( ROS ) in these cells which brought about a reduction of the intracellular mitochondrial transmembrane potential ( DeltaPsim ) , followed by the activation of caspase-9 and caspase-3 , leading to DNA fragmentation and apoptosis . Our findings demonstrate that ROS and the resulting oxidative stress play a pivotal role in apoptosis . Preincubation of hepatoma cell lines with the hydrogen peroxide-scavenging enzyme , catalase ( CAT ) and cyclosporin A ( CsA ) , partially inhibited apoptosis . These results demonstrate that enhancement of generation of ROS , DeltaPsim disruption and caspase activation may be involved in the apoptotic pathway induced by emodin .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "12716464"}
{"sentence": "Bladder cancer ( BCa ) remained a major health problem . Med19 was related to tumor growth of BCa . Bone morphogenetic proteins ( BMPs ) were reported to be critical in bone metastasis of cancer . We therefore investigated the relations between Med19 and BMPs in BCa and their effect on bone metastasis of BCa . Bladder cancer cell lines were cultured and interfered with Med19 shRNA and control . Expressions of BMP-1 , BMP-2 , BMP-4 , BMP-5 , BMP-6 , BMP-7 , BMP-9 , and BMP-15 were studied between 2 groups . Fifty-two BCa samples were included for immunohistochemical staining of Med19 and BMP-2 . Expressions were scored and studied statistically . Invasiveness was studied with Transwell assay . Silencing or Med19 in BCa cells induced altered expressions of BMPs . Increased expressions of BMP-1 , BMP-4 , BMP-6 , BMP-7 , and BMP-15 and decreased expressions of BMP-2 , BMP-5 , and BMP-9 were noticed , but only BMP-2 reached statistical significance . Expressions of Med19 and BMP-2 were significantly higher in cases with bone metastasis and were positively correlated in cases with bone metastasis and muscle invasion . Med19 is a critical factor involved in the invasiveness and promotion of bone metastasis of BCa , possibly via BMP-2 .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23276457"}
{"sentence": "BACKGROUND The MYB superfamily constitutes one of the most abundant groups of transcription factors described in plants . Nevertheless , their functions appear to be highly diverse and remain rather unclear . To date , no genome-wide characterization of this gene family has been conducted in a legume species . Here we report the first genome-wide analysis of the whole MYB superfamily in a legume species , soybean ( Glycine max ) , including the gene structures , phylogeny , chromosome locations , conserved motifs , and expression patterns , as well as a comparative genomic analysis with Arabidopsis . RESULTS A total of 244 R2R3-MYB genes were identified and further classified into 48 subfamilies based on a phylogenetic comparative analysis with their putative orthologs , showed both gene loss and duplication events . The phylogenetic analysis showed that most characterized MYB genes with similar functions are clustered in the same subfamily , together with the identification of orthologs by synteny analysis , functional conservation among subgroups of MYB genes was strongly indicated . The phylogenetic relationships of each subgroup of MYB genes were well supported by the highly conserved intron/exon structures and motifs outside the MYB domain . Synonymous nucleotide substitution ( dN/dS ) analysis showed that the soybean MYB DNA-binding domain is under strong negative selection . The chromosome distribution pattern strongly indicated that genome-wide segmental and tandem duplication contribute to the expansion of soybean MYB genes . In addition , we found that\\u2009 of soybean R2R3-MYB genes had undergone alternative splicing events , producing a variety of transcripts from a single gene , which illustrated the extremely high complexity of transcriptome regulation . Comparative expression profile analysis of R2R3-MYB genes in soybean and Arabidopsis revealed that MYB genes play conserved and various roles in plants , which is indicative of a divergence in function . CONCLUSIONS In this study we identified the largest MYB gene family in plants known to date . Our findings indicate that members of this large gene family may be involved in different plant biological processes , some of which may be potentially involved in legume-specific nodulation . Our comparative genomics analysis provides a solid foundation for future functional dissection of this family gene .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22776508"}
{"sentence": "The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies . However , the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies . Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy , but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies . Here , we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses , but not high antivascular/antiangiogenic doses , of an anti-VEGF receptor 2 ( VEGFR2 ) antibody results in a more homogeneous distribution of functional tumor vessels . Furthermore , lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration . Based on this mechanism , scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models . These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies . Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients , our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies .", "label": [0, 1, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23045683"}
{"sentence": "BACKGROUND A retrospective study was performed to determine the indications for positron emission tomography ( PET ) using [ (18)F]fluorodeoxyglucose ( FDG ) in patients with esophageal cancer , including those with early cancer , and to investigate whether the tumor-to-normal ratio ( T/N ratio ) could be used as a substitute for the standardized uptake value ( SUV ) . METHODS Thirty-six patients were included in the study . Thirty-one patients who had 36 biopsy-proven lesions ( 35 squamous cell carcinomas and one small cell carcinoma ) underwent PET study prior to treatment . PET images were evaluated visually and the relationship between the depth of invasion and the PET findings were examined in 22 lesions of 19 patients from whom specimens were obtained from the primary tumor by surgery or endoscopic mucosal resection . PET results were also compared with computed tomography ( CT ) and endoscopic ultrasonography ( EUS ) for detection of regional lymph node metastases in 18 patients who underwent extended lymph node dissection . Five patients underwent PET studies for the detection of recurrence and the PET findings were compared with their CT findings . The T/N ratio and the SUV were calculated for 20 primary tumors . RESULTS Among the 15 tumors that were pT1b or greater , all 15 were positive on PET and all seven of the lesions confined to the mucosa ( Tis or T1a ) were negative . The sensitivity , specificity and accuracy of detecting nodal involvement were , respectively , 37.5 , 96.1 and 88.3% by CT , 30.8 , 88.5 and 81.0% by EUS and 41.7 , 100 and 92.2% by PET . More sites of recurrence were detected by PET than by CT . There was no statistically significant correlation between the SUV and the T/N ratio . CONCLUSIONS PET imaging can detect primary esophageal cancer with a depth of invasion of T1b or greater , but Tis and T1a tumors are undetectable . PET seems to be more accurate than CT or EUS for diagnosing lymph node metastasis . The T/N ratio cannot be used as a substitute for the SUV .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12417599"}
{"sentence": "Investigation has been conducted to delineate the action of some phenolic compounds of natural origin in four human tumor cell lines : acute myeloblastic leukemia ( HL-60 ) , chronic myelogenic leukemia ( K-562 ) , breast adenocarcinoma ( MCF-7 ) and cervical epithelial carcinoma ( HeLa ) . In cells grown in appropriate media the phenolics curcumin , yakuchinone B , resveratrol and capsaicin exhibited growth inhibition as assessed by trypan blue dye exclusion . It was evident from the results of the MTT reduction assay and [ (3)H]thymidine incorporation into nuclear DNA that the phenolics were cytotoxic and inhibited cell proliferation . Dose response studies indicated curcumin to be most cytotoxic towards HL-60 , K-562 and MCF-7 but did not show much activity in HeLa cells . On the other hand , yakuchinone B , although less active than curcumin , displayed cytotoxicity towards all four cell lines . Resveratrol was cytotoxic only in leukemic cells , while capsaicin was marginally cytotoxic . All these phenolics did not elicit any cytotoxic activity as judged by the above parameters towards lymphocytes purified from normal human blood . When cells treated with phenolics were stained with propidium iodide and examined under a fluorescent microscope , characteristic apoptotic features such as chromatin condensation and nuclear fragmentation were observed . Scoring of cells with apoptotic and non-apoptotic features showed positive correlation of apoptotic index with dose of phenolic , and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern . These phenolics which have human exposure are known cancer chemopreventive agents and their action as inducers of apoptosis in tumor cells suggest their potential use in a strategy for cancer control .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "12718610"}
{"sentence": "INTRODUCTION Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses . METHODS In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques . RESULTS Lovastatin inhibited proliferation of breast cancer cell lines . MDAMB231 cells were more sensitive to its effects , and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone . Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A ( RhoA ) leading to a decreased expression of its active , membrane-bound form . Its downstream targets cofilin , CDC42 and G3BP1 are members of the GTPase family affected by lovastatin . Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma ( Rb ) . This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 ( MCM7 ) and MutS homolog 2 ( MSH2 ) . Lovastatin also regulated the AKT-signaling pathway . Increased phosphatase and tensin homolog ( PTEN ) and decreased DJ-1 expression lead to a down-regulation of the active pAkt . Lovastatin's involvement in the AKT-signaling pathway was confirmed by an upregulation of its downstream target , tumor progressor NDRG1 . Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity , and lipid biosynthesis . CONCLUSIONS The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin . Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20205716"}
{"sentence": "CEACAM1 , CEA/CEACAM5 , and CEACAM6 are cell adhesion molecules ( CAMs ) of the carcinoembryonic antigen ( CEA ) family that have been shown to be deregulated in lung cancer and in up to 50% of all human cancers . However , little is known about the functional impact of these molecules on undifferentiated cell growth and tumor progression . Here we demonstrate that cell surface expression of CEACAM1 on confluent A549 human lung adenocarcinoma cells plays a critical role in differentiated , contact-inhibited cell growth . Interestingly , CEACAM1-L , but not CEACAM1-S , negatively regulates proliferation via its ITIM domain , while in proliferating cells no CEACAM expression is detectable . Furthermore , we show for the first time that CEACAM6 acts as an inducer of cellular proliferation in A549 cells , likely by interfering with the contact-inhibiting signal triggered by CEACAM1-4L , leading to undifferentiated anchorage-independent cell growth . We also found that A549 cells expressed significant amounts of non-membrane anchored variants of CEACAM5 and CEACAM6 , representing a putative source for the increased CEACAM5/6 serum levels frequently found in lung cancer patients . Taken together , our data suggest that post-confluent contact inhibition is established and maintained by CEACAM1-4L , but disturbances of CEACAM1 signalling by CEACAM1-4S and other CEACAMs lead to undifferentiated cell growth and malignant transformation .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20090913"}
{"sentence": "Genomic instability has long been recognized as the main feature of neoplasia and a factor modulating individual cancer susceptibility . There are attempts to find effective assays of both individual DNA repair capacity and genetic instability , and their relation to the cancer risk . Genetic predisposition plays an important role in the etiology and development of head and neck squamous cell carcinoma ( HNSCC ) . The aim of our study was to search for a correlation between chromosomal instability and DNA repair capacity in HNSCC patients and healthy controls . The chromosomal instability was measured by the number of bleomycin ( BLM)-induced chromosomal aberrations and diepoxybutane ( DEB)-induced sister chromatid exchanges . The DNA repair capacity was assessed using the DEB-induced adaptive response ( AR ) . The HNSCC patients in our study showed a significant increase in chromosomal instability after a preterminal exposure of their lymphocytes to either BLM for the last 5 h or DEB for the last 24 h of incubation . However , the AR was higher in HNSCC patients than in the control group , suggesting an increase in the DNA repair capacity in the cancer patients as compared to the control . There is no correlation between the DNA repair capacity estimated on the basis of preterminal exposures to BLM and DEB and the DNA repair capacity estimated on the basis of the adaptive response to DEB . The preterminal exposure and the adaptive response test may activate different DNA repair mechanisms .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12441637"}
{"sentence": "The DNA mismatch repair ( MMR ) pathway corrects specific types of DNA replication errors that affect microsatellites and thus is critical for maintaining genomic integrity . The genes of the MMR pathway are highly conserved across different organisms . Likewise , defective MMR function universally results in microsatellite instability ( MSI ) which is a hallmark of certain types of cancer associated with the Mendelian disorder hereditary nonpolyposis colorectal cancer . ( Lynch syndrome ) . To identify previously unrecognized deleted genes or loci that can lead to MSI , we developed a functional genomics screen utilizing a plasmid containing a microsatellite sequence that is a host spot for MSI mutations and the comprehensive homozygous diploid deletion mutant resource for Saccharomyces cerevisiae . This pool represents a collection of non-essential homozygous yeast diploid ( 2N ) mutants in which there are deletions for over four thousand yeast open reading frames ( ORFs ) . From our screen , we identified a deletion mutant strain of the PAU24 gene that leads to MSI . In a series of validation experiments , we determined that this PAU24 mutant strain had an increased MSI-specific mutation rate in comparison to the original background wildtype strain , other deletion mutants and comparable to a MMR mutant involving the MLH1 gene . Likewise , in yeast strains with a deletion of PAU24 , we identified specific de novo indel mutations that occurred within the targeted microsatellite used for this screen .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23667739"}
{"sentence": "Melanoma progression is associated with the expression of different growth factors , cytokines , and chemokines . Because TGF\u03b21 is a pleiotropic cytokine involved not only in physiologic processes but also in cancer development , we analyzed in A375 human melanoma cells , the effect of TGF\u03b21 on monocyte chemoattractant protein-1 ( MCP-1 ) and interleukin-10 ( IL-10 ) expression , two known factors responsible for melanoma progression . TGF\u03b21 increased the expression of MCP-1 and IL-10 in A375 cells , an effect mediated by the cross-talk between Smad , PI3K ( phosphoinositide 3-kinase)/AKT , and BRAF-MAPK ( mitogen activated protein kinase ) signaling pathways . Supernatants from TGF\u03b21-treated A375 cells enhanced MCP-1-dependent migration of monocytes , which , in turn , expressed high levels of TGF,\u03b21 , bFGF , and VEGF mRNA . Moreover , these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms . When using in vitro , the TGF\u03b21-blocking peptide P144 , TGF\u03b21-dependent Smad3 phosphorylation , and expression of MCP-1 and IL-10 were inhibited . In vivo , treatment of A375 tumor-bearing athymic mice with P144 significantly reduced tumor growth , associated with a lower macrophage infiltrate and decreased intratumor MCP-1 and VEGF levels , as well as angiogenesis . Finally , in C57BL/6 mice with B16-OVA melanoma tumors , when administered with immunotherapy , P144 decreased tumor growth and intratumor IL-10 levels , linked to enhanced activation of dendritic cells and natural killer cells , as well as anti-OVA T-cell responses . These results show new effects of TGF\u03b21 on melanoma cells , which promote tumor progression and immunosuppression , strongly reinforcing the relevance of this cytokine as a molecular target in melanoma .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "21159663"}
{"sentence": "Glioblastoma multiforme ( GBM ) is the most common primary brain tumour in adults , with a median survival of months post-diagnosis . GBM usually recurs within 12 months post-resection , with poor prognosis . Thus , novel therapeutic strategies to target and kill GBM cells are urgently needed . The marked difference of tumour cells with respect to normal brain cells renders glioblastoma a good candidate for selective targeted therapies . Recent experimental strategies focus on over expressed cell surface receptors . Targeted toxins represent a new class of selective molecules composed by a potent protein toxin and a carrier ligand . Targeted toxins approaches against glioblastoma were under investigation in phase I and II clinical trials with several immunotoxins ( IT)/ligand toxins such as IL4-Pseudomonas aeruginosa exotoxin A ( IL4-PE , NBI-3001 ) , tumour growth factor fused to PE38 , a shorter PE variant , ( TGF)alpha-TP-38 , IL13-PE38 , and a transferrin-C diphtheriae toxin mutant ( Tf-CRM107 ) . In this work , we studied the effects of the plant ribosome-inactivating saporin and of its chimera transferrin-saporin against two different GBM cell lines . The data obtained here indicate that cell proliferation is affected by the toxin treatments but that different mechanisms are used , directly linked to the presence of an active or inactive p53 . A model is proposed for these alternative intracellular pathways .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21503892"}
{"sentence": "OBJECTIVE Chemotherapy options for advanced endometrial cancer are limited and newer therapeutic agents are urgently needed . This study describes the therapeutic potential of 7 Methyl-indole ethyl isothiocyanate ( 7Me-IEITC ) in endometrial cancer cell lines . METHODS 7Me-IEITC was synthesized in our laboratory . The cell viability of 7Me-IEITC treated ECC-1 and KLE endometrial cancer cell was determined by MTS assay . Morphology and apoptosis were further confirmed by DAPI-staining and TUNEL assay . The measurement of reactive oxygen species ( ROS ) , mitochondrial transmembrane depolarization potential ( \\u0394\\u03a8m ) and cell cycle phase was determined by FACS analysis . Expression of proteins involved in apoptosis , survival and cell-cycle progression was analyzed by Western blotting . RESULTS 7Me-IEITC reduced the viability of the ECC-1 and KLE cancer cell-lines ( IC(50) \\u03bcM ) in a dose dependent fashion. 7Me-IEITC treatment caused mitochondrial transmembrane potential reduction , elevated the production of ROS , leading to activation of apoptosis in endometrial cancer KLE and ECC-1 cells. 7Me-IEITC treatment activated Bad , suppressed Bcl2 phosphorylation followed by PARP-1 deactivation and caspase 3 and 7 activation. 7Me-IEITC treatment arrested the progression of KLE cells in S-phase and caused CDC25 and cyclin-D1 downregulation . Pre-treatment with ascorbic acid abrogated 7Me-IEITC induced apoptosis in ECC-1 and KLE cells , suggesting that 7Me-IEITC mediated cytotoxicity is primarily through ROS production . CONCLUSION 7Me-IEITC demonstrated promising cytotoxic effects in endometrial cancer cell line model .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22561404"}
{"sentence": "The beneficial effect of yoghurt consumption on health and on the improvement of the mucosal immune system is well established , as is the diet-associated risk of colon cancer . In an experimental model in BALB/c mice we demonstrated that yoghurt added to the diet for 10 consecutive days , with the procedure repeated each 10 days for 6 months , inhibited the development of a colorectal carcinoma induced by 1,2 dimethylhydrazine ( DMH ) . The immunoregulatory mechanisms involved in the inhibition of tumour growth by yoghurt were also examined in these studies . We determined B lymphocytes IgA(+) and IgG(+) , as well as CD4(+) and CD8(+) T cells in the large intestine . We measured cellular apoptosis and the cytokines TNF-alpha , IFN-gamma and IL-10 . An increase in the number of IgA(+) ( P<0.01 ) was observed , but not in IgG(+) ( P<0.01 ) , or in the CD4(+) population ( P<0.01 ) in the mice treated with DMH and yoghurt . While in the group with the carcinogen there was an enhancement in the IgG(+) B cells ( P<0.01 ) and CD8(+) T cells ( P<0.01 ) . Yoghurt increased the number of apoptotic cells and induced IFN-gamma and TNF-alpha cytokine release , their production being regulated by an increase in IL-10 ( P<0.001 ) . We demonstrated that yoghurt may exert antitumour activity by a decrease in the inflammatory immune response mediated by IgA(+) increase , apoptosis induction and IL-10 release .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "12142967"}
{"sentence": "Senescence , an inherent tumor suppressive mechanism , is a critical determinant for chemotherapy . In the present study , we show that the monocarboxylate transporter 2 ( MCT2 ) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction , cell-cycle arrest , and senescence without additional cellular stress in colorectal cancer cell lines . Moreover , the reactive oxygen species ( ROS ) scavenger , N-acetylcysteine , blocked MCT2 knockdown-induced growth arrest and cellular senescence , indicating a pivotal role of ROS in this pathway . Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed , indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation . Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies , \u03b3H2AX foci , and SAHF . Conversely , overexpression of MCT2 prevented doxorubicin-induced ROS accumulation ( P = 0.0002 ) and cell growth inhibition ( P = 0.001 ) . MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo . In addition , MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect . These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 1, 1], "id": "22964484"}
{"sentence": "Aberrant glucose metabolism characterized by high levels of glycolysis , even in the presence of oxygen , is an important hallmark of cancer . This metabolic reprogramming referred to as the Warburg effect is essential to the survival of tumor cells and provides them with substrates required for biomass generation . Molecular mechanisms responsible for this shift in glucose metabolism remain elusive . As described herein , we found that aberrant expression of the proinflammatory protein transglutaminase 2 ( TG2 ) is an important regulator of the Warburg effect in mammary epithelial cells . Mechanistically , TG2 regulated metabolic reprogramming by constitutively activating nuclear factor ( NF)-\\u03baB , which binds to the hypoxia-inducible factor ( HIF)-1\\u03b1 promoter and induces its expression even under normoxic conditions . TG2/NF-\\u03baB-induced increase in HIF-1\\u03b1 expression was associated with increased glucose uptake , increased lactate production and decreased oxygen consumption by mitochondria . Experimental suppression of TG2 attenuated HIF-1\\u03b1 expression and reversed downstream events in mammary epithelial cells . Moreover , downregulation of p65/RelA or HIF-1\\u03b1 expression in these cells restored normal glucose uptake , lactate production , mitochondrial respiration and glycolytic protein expression . Our results suggest that aberrant expression of TG2 is a master regulator of metabolic reprogramming and facilitates metabolic alterations in epithelial cells even under normoxic conditions . A TG2-induced shift in glucose metabolism helps breast cancer cells to survive under stressful conditions and promotes their metastatic competence .", "label": [1, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "24477458"}
{"sentence": "Mice defective in the mismatch repair ( MMR ) gene Msh2 manifest an enhanced predisposition to skin cancer associated with exposure to UVB radiation . This predisposition is further heightened if the mice are additionally defective for the nucleotide excision repair gene Xpc . To test the hypothesis that the predisposition of Msh2 mutant mice to skin cancer reflects a mutator phenotype associated with increased proliferation of skin cells following exposure to UV radiation , Msh2 mutant mice were exposed to the tumor promoter TPA . Such mice showed a robust proliferative response in the skin , but did not manifest evidence of dysplasia or neoplasia . We conclude that the predisposition of Msh2 mice to UVB radiation-induced skin cancer reflects an interaction between the processes of mismatch repair and some other excision repair mode , the exact nature of which remains to be established .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12531020"}
{"sentence": "Mutations in the tumor suppressor tuberin ( TSC2 ) are a common factor in the development of lymphangioleiomyomatosis ( LAM ) . LAM is a cystic lung disease that is characterized by the infiltration of smooth muscle-like cells into the pulmonary parenchyma . The mechanism by which the loss of tuberin promotes the development of LAM has yet to be elucidated , although several lines of evidence suggest it is due to the metastasis of tuberin-deficient cells . Here we show that tuberin-null cells become nonadherent and invasive . These nonadherent cells express cleaved forms of \u03b2-catenin . In reporter assays , the \u03b2-catenin products are transcriptionally active and promote MMP7 expression . Invasion by the tuberin-null cells is mediated by MMP7 . Examination of LAM tissues shows the expression of cleaved \u03b2-catenin products and MMP7 consistent with a model that tuberin-deficient cells acquire invasive properties through a \u03b2-catenin-dependent mechanism , which may underlie the development of LAM .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "20042714"}
{"sentence": "Silver nanoparticles ( Ag-np ) have been used in medicine and commercially due to their anti-microbial properties . Therapeutic potentials of these nanoparticles are being explored extensively despite the lack of information on their mechanism of action at molecular and cellular level . Here , we have investigated the DNA damage response and repair following Ag-np treatment in mammalian cells . Studies have shown that Ag-np exerts genotoxicity through double-strand breaks ( DSBs ) . DNA-PKcs , the catalytic subunit of DNA dependent protein kinase , is an important caretaker of the genome which is known to be the main player mediating Non-homologous End-Joining ( NHEJ ) repair pathway . We hypothesize that DNA-PKcs is responsible for the repair of Ag-np induced DNA damage . In vitro studies have been carried out to investigate both cytotoxicity and genotoxicity induced by Ag-np in normal human cells , DNA-PKcs proficient , and deficient mammalian cells . Chemical inhibition of DNA-PKcs activity with NU7026 , an ATP-competitive inhibitor of DNA-PKcs , has been performed to further validate the role of DNA-PKcs in this model . Our results suggest that Ag-np induced more prominent dose-dependent decrease in cell viability in DNA-PKcs deficient or inhibited cells . The deficiency or inhibition of DNA-PKcs renders the cells with higher susceptibility to DNA damage and genome instability which in turn contributed to greater cell cycle arrest/cell death . These findings support the fact that DNA-PKcs is involved in the repair of Ag-np induced genotoxicity and NHEJ repair pathway and DNA-PKcs particularly is activated to safeguard the genome upon Ag-np exposure .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "22707954"}
{"sentence": "The high glucose consumption of tumor cells even in an oxygen-rich environment , referred to as the Warburg effect , has been noted as a nearly universal biochemical characteristic of cancer cells . Targeting the glycolysis pathway has been explored as an anti-cancer therapeutic strategy to eradicate cancer based on this fundamental biochemical property of cancer cells . Oncoproteins such as Akt and c-Myc regulate cell metabolism . Accumulating studies have uncovered various molecular mechanisms by which oncoproteins affect cellular metabolism , raising a concern as to whether targeting glycolysis will be equally effective in treating cancers arising from different oncogenic activities . Here , we established a dual-regulatable FL5.12 pre-B cell line in which myristoylated Akt is expressed under the control of doxycycline , and c-Myc , fused to the hormone-binding domain of the human estrogen receptor , is activated by 4-hydroxytamoxifen . Using this system , we directly compared the effect of these oncoproteins on cell metabolism in an isogenic background . Activation of either Akt or c-Myc leads to the Warburg effect as indicated by increased cellular glucose uptake , glycolysis , and lactate generation . When cells are treated with glycolysis inhibitors , Akt sensitizes cells to apoptosis , whereas c-Myc does not . In contrast , c-Myc but not Akt sensitizes cells to the inhibition of mitochondrial function . This is correlated with enhanced mitochondrial activities in c-Myc cells . Hence , although both Akt and c-Myc promote aerobic glycolysis , they differentially affect mitochondrial functions and render cells susceptible to the perturbation of cellular metabolic programs .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20018866"}
{"sentence": "BACKGROUND Thrombospondin-1 ( TSP-1 ) promotes breast cancer cell invasion of collagen by upregulating matrix metalloproteinase-9 ( MMP-9 ) production . Stromal TSP-1 may play a role in regulating tumor cell invasion . We hypothesize that fibroblasts promote breast cancer cell invasion by upregulating the production of MMP-9 through TSP-1 . METHODS MDA-MB-231 human breast carcinoma cells were grown alone or in coculture with human fibroblasts . Gelatin zymography and Western immunoblot analysis for MMP-9 were performed on the coculture cell media and the single cell media . Inhibition of fibroblast-mediated breast tumor cell invasion by an anti-TSP-1 or an anti-MMP-9 antibody was evaluated using a modified Boyden chamber . RESULTS Coculture experiments showed an increased production of MMP-9 when compared with breast cancer single cell culture or fibroblast single cell culture experiments as demonstrated by zymography and Western immunoblot analysis . Fibroblast-stimulated MMP-9 production was comparable with TSP-1-stimulated MMP-9 production . Anti-TSP-1 antibody and anti-MMP-9 antibody inhibited fibroblast-stimulated tumor cell invasion to 30% and 26% of controls , respectively ( P <.05 ) . CONCLUSIONS Fibroblasts may regulate breast cancer cell invasion by promoting tumor MMP-9 production through TSP-1 . Inhibition of stromal TSP-1 stimulation of MMP-9 synthesis may prevent matrix degradation necessary for tumor invasion and metastasis .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12219015"}
{"sentence": "BACKGROUND IL-6 is a pro-inflammatory cytokine that signals via binding to a soluble or membrane bound receptor , while nitric oxide ( NO ) , an oxidative stress molecule , diffuses through the cell membrane without a receptor . Both mediators signal through different mechanisms , yet they are dependent on NF\u03baB . We proposed that both mediators are co-induced and co-regulated in inflamed mammary epithelial cells . METHODS SCp2 mammary epithelial cells were treated with bacterial endotoxin ( ET ) for different time periods and analyzed for induction of IL-6 secretion and NO production by ELISA and Griess reaction , respectively . The expression of IL-6 and induced NO synthase ( iNOS ) was assayed by real time PCR and/or western immunoblots , and the activation of NF\u03baB was assayed by immunobinding assay . To investigate the role of mammary cell microenvironment ( cell-substratum or interaction of mammary epithelial cell types ; critical to mammary development , function , and disease ) in modulation of the inflammatory response , SCp2 cells were cultured with or without extracellular matrix ( EHS ) or in coculture with their myoepithelial counterpart ( SCg6 ) , and assayed for ET-induced IL-6 and NO . RESULTS Endotoxin induced NF\u03baB activation at 1 h after ET application . IL-6 secretion and NO production were induced , but with unexpected delay in expression of mRNA for iNOS compared to IL-6 . NF\u03baB/p65 activation was transient but NF\u03baB/p50 activation persisted longer . Selective inhibition of NF\u03baB activation by Wedelolactone reduced ET-induced expression of IL-6 mRNA and protein but not iNOS mRNA or NO production , suggesting differences in IL-6 and iNOS regulation via NF\u03baB . SCp2 cells in coculture with SCg6 but not in presence of EHS dramatically induced IL-6 secretion even in the absence of ET . ET-induced NO production was blunted in SCp2/SCg6 cocultures compared to that in SCp2 alone . CONCLUSIONS The differential regulation of IL-6 and iNOS together with the differential activation of different NF\u03baB dimers suggest that IL-6 and iNOS are regulated by different NF\u03baB dimers , and differentially regulated by the microenvironment of epithelial cells . The understanding of innate immune responses and inflammation in epithelia and linkage thereof is crucial for understanding the link between chronic inflammation and cancer in epithelial tissues such as the mammary gland .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21118556"}
{"sentence": "Regulator of Cullins-1 ( ROC1 ) or RING box protein-1 ( RBX1 ) is an essential RING component of Cullin-RING ligase ( CRL ) . Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL , leading to cell cycle arrest , cell senescence and/or apoptosis . However , it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL . Moreover , the role of ROC1 in liver cancer remains elusive . In this study , we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence . Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin ( mTOR ) activity due to accumulation of mTOR-inhibitory protein Deptor , a substrate of CRL . Consistently , Deptor knockdown significantly blocked autophagy response upon ROC1 silencing . Biologically , autophagy response upon ROC1 silencing was a survival signal , and blockage of autophagy pathway sensitized cancer cells to apoptosis . Finally , we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas , which is associated with poor prognosis of liver cancer patients . These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.Cell Death and Differentiation advance online publication , 31 August 2012 ; doi:10.1038/cdd.2012.113 .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 0, 0], "id": "22935614"}
{"sentence": "Although the p16(INK4a) and p21Waf1/Cip1 cyclin-dependent kinase ( CDK ) inhibitors are known to play key roles in cellular senescence in vitro , their roles in senescence remain rather poorly understood in vivo . This situation is partly due to the possibility of compensatory effect(s) between p16INK4a and p21Waf1/Cip1 or to the upregulation of functionally related CDK inhibitors . To directly address the cooperative roles of p16INK4a and p21Waf1/Cip1 in senescence in vivo , we generated a mouse line simply lacking both p16INK4a and p21Waf1/Cip1 genes [ double-knockout ( DKO) ] . Mouse embryonic fibroblasts ( MEF ) derived from DKO mice displayed no evidence of cellular senescence when cultured serially in vitro . Moreover , DKO MEFs readily escaped Ras-induced senescence and overrode contact inhibition in culture . This was not the case in MEFs lacking either p16INK4a or p21Waf1/Cip1 , indicating that p16(INK4a) and p21Waf1/Cip1 play cooperative roles in cellular senescence and contact inhibition in vitro . Notably , we found the DKO mice to be extremely susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis that involves oncogenic mutation of the H-ras gene . Mechanistic investigations suggested that the high incidence of cancer in DKO mice likely reflected a cooperative effect of increased benign skin tumor formation caused by p21Waf1/Cip1 loss , with increased malignant conversion of benign skin tumors caused by p16(INK4a) loss . Our findings establish an intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo .", "label": [0, 0, 0, 1, 1, 1, 0, 0, 0, 0], "id": "21062974"}
{"sentence": "Mucoepidermoid carcinoma ( MEC ) , the most common primary salivary malignancy , shows great variability in clinical behaviour , thus demanding investigation to identify of prognostic markers . Since Warburg's studies , unrestricted cell growth during tumorigenesis has been linked to altered metabolism , implying hypoxic stimulation of glycolysis and diminished contribution of mitochondrial oxidative phosphorylation to cellular ATP supply . Hypothesizing that the study of MEC metabolic status could lead to the discovery of prognostic markers , we investigated by immunohistochemistry the expression of glucose transporter 1 ( Glut-1 ) , mitochondrial antigen and peroxiredoxin I ( Prx I ) in samples of MEC from different histological grades . Our results showed that mitochondrial antigen and Prx I were expressed in the majority of the MEC cases independent of the histological grade . In contrast Glut-1 expression increased significantly as the tumours became more aggressive . These results suggested that oxidative phosphorylation may contribute to ATP supply in all stages of MEC progression , and that the relative contribution of glycolysis over mitochondria for cellular ATP supply increases during MEC progression , favouring growth under low oxygen concentration . In addition , the observed high Prx I protein levels could provide protection to tumour cells against reactive oxygen species generated as a consequence of mitochondrial function and hypoxia-reoxygenation cycling . Altogether our findings suggest that upregulation of Glut-1 and Prx I constitute successful adaptive strategies of MEC cells conferring a growth advantage over normal salivary gland cells in the unstable oxygenation tumour environment .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20113375"}
{"sentence": "Principal components analysis ( PCA ) combined to Fourier transform infrared ( FTIR ) microspectroscopic imaging was used to screen biochemical changes associated to C6 glioma tumor from 7 to 19 days growth . Normal brain and tumor obtained at 7 , 12 , 19 days after C6 cell injection were used to develop a diagnostic model of brain glioma based on PCA analysis . This classification model was validated using extra-measurements on normal and tumor at 9 and 15 days post-implantation . The spatial and biochemical information obtained from FTIR/PCA maps can be used to improve the discrimination between normal and grading human glioma . The first 4 PCs which account for more than 93.6% of total spectral variance were used to construct pseudo-color scores maps and compared each map to the corresponding hematoxylin and eosin ( H&E ) staining . Our results reported that by correlating pseudocolor map scores with H&E staining it was possible to screen histological changes associated with tissue transformation . In fact , PC1 and PC4 were associated to the tumor , surrounding tumor and necrosis . Indeed , at day 7 after tumor implantation , FTIR investigations displayed a very small abnormal zone associated with the proliferation of C6 cells in the caudate putamen ( CP ) . PC2 and PC3 described normal brain structures such as white matter ( corpus callosum ( CC ) and commissura anterior ( CA) ) and some cortex layers ( grey matter ) . After delipidation of the tissues , we were still able to differentiate between different tissue features based on nucleic acid and protein content . By comparing the patterns of the PC loads with the spectra of lipids extracted from white and gray matters , and DNA , we have identified some biochemical changes associated with tissue transformation . This work demonstrated that our classification model provides a successful histological classification of different brain structures .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20419261"}
{"sentence": "Overexpression of the melanoma differentiation associated gene-7 ( MDA-7)/IL-24 in vitro generally results in the growth suppression and induction of apoptosis of diverse human tumor cells . In this study , we investigated the effects of overexpression of the MDA-7/IL-24 gene in human hepatocellular carcinoma ( HCC ) cells in vitro and in vivo . Adenovirus-mediated overexpression of MDA-7 facilitated the MDA-7/IL-24-induced apoptosis and G2/M arrest in HCC cells , but not in the normal liver cell line L02 , and the effect was independent of the p53 status . Inhibition of metastasis and angiogenesis was correlated with decreasing expression of STAT3 , P-STAT3 , MMP-2 , VEGF , and TGF-beta genes , regulated by STAT3 in MHCCLM6 cells . We also showed that Ad.mda-7 combined with doxorubicin ( ADM ) had significantly enhanced antitumor and antimetastatic effects in vivo , accompanied by the downregulation of VEGF , MMP-2 , and TGF-beta genes and the upregulation of E-cadherin genes . These data suggested that MDA-7/IL-24 induces its selective antitumor properties in HCC cells by promoting apoptosis independent of p53 status , inhibiting subcutaneous tumor growth and metastasis , and increasing the effect of chemotherapeutic agents . MDA-7/IL-24 represents a new class of cancer suppressor genes that may be useful in the targeted therapy of HCC .", "label": [1, 0, 0, 0, 1, 0, 1, 1, 1, 0], "id": "20939432"}
{"sentence": "Vanadium pentoxide , commercially the most important compound of vanadium , presents a potential occupational hazard during the cleaning of oil-fired boilers and furnaces , the handling of catalysts , and during the refining , processing , or burning of vanadium-rich mineral ores or fossil fuels . Vanadium pentoxide was nominated for study by the National Cancer Institute as a representative of the metals class study . Male and female F344/N rats and B6C3F1 mice were exposed to vanadium pentoxide ( 99% pure ) by inhalation for 16 days , 14 weeks , or 2 years . Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood. 16-DAY STUDY IN RATS : Groups of five male and five female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0 , 2 , 4 , 8 , 16 , or 32 mg/m(3) by inhalation , 6 hours per day , 5 days per week for 16 days . Three males in the 32 mg/m(3) group died before the end of the study . Mean body weights of males and females exposed to 8 mg/m(3) or greater were less than those of the chamber controls . Clinical findings included rapid respiration and hypoactivity in rats exposed to 16 or 32 mg/m(3) . Relative lung weights of 4 mg/m(3) or greater males and 2 mg/m(3) or greater females were significantly greater than those of the chamber controls . Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 16-DAY STUDY IN MICE : Groups of five male and five female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0 , 2 , 4 , 8 , 16 , or 32 mg/m(3) by inhalation , 6 hours per day , 5 days per week for 16 days . All males exposed to 32 mg/m(3) and one 8 mg/m(3) male died or were killed moribund before the end of the study . Mean body weights of 16 mg/m(3) males and 8 mg/m(3) or greater females were significantly less than those of the chamber controls , and the 32 mg/m(3) females lost weight during the study . Absolute and relative lung weights of 4 mg/m(3) or greater males and all exposed groups of females and liver weights of 16 mg/m(3) males were significantly greater than those of the chamber controls . The mediastinal lymph nodes were enlarged in 4 , 8 , and 16 mg/m(3) males and females , and lymphoid hyperplasia was confirmed histologically . Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 3-MONTH STUDY IN RATS : Groups of 10 male and 10 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0 , 1 , 2 , 4 , 8 , or 16 mg/m(3) by inhalation , 6 hours per day , 5 days per week for 3 months . Seven males and three females exposed to 16 mg/m(3) died during the study . Mean body weights were significantly less in males exposed to 4 mg/m(3) or greater and in females exposed to 16 mg/m(3) . Abnormal breathing , thinness , lethargy , abnormal posture , and ruffled fur were observed in rats exposed to 16 mg/m(3) . Hematology results indicated that exposure of rats to vanadium pentoxide induced a microcytic erythrocytosis in males and females . Absolute and relative lung weights were significantly greater for 4 mg/m(3) or greater males and females than for the chamber controls as were the relative lung weights of 2 mg/m(3) males . The estrous cycle of females exposed to 8 mg/m(3) was significantly longer than that of the chamber control group , and the number of cycling females in the 16 mg/m(3) group was reduced . The incidences of several nonneoplastic lesions of the lung and nose were significantly increased in males and females exposed to 2 mg/m(3) or greater . Data from pulmonary function analyses indicated that a restrictive lung disease was present in male and female rats exposed to 4 mg/m(3) or greater , while an obstructive lung disease was present only in the 16 mg/m(3) groups. 3-MONTH STUDY IN MICE : Groups of 10 male and 10 female mice were exposed to par", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "12533744"}
{"sentence": "Bone marrow necrosis ( BMN ) is a rare finding in children with malignancy occurring most commonly in children with acute lymphoblastic leukemia . This article describes the first case of a girl who developed BMN during treatment for Hodgkin's disease . During the second cycle of chemotherapy , she experienced sudden profound bone pain in the lumbosacral region associated with elevated levels of lactate dehydrogenase ( LDH ) , fibrin degradation products ( D-Dimer ) , and alkaline phosphatase as well as pancytopenia and leukoerythroblastosis . MRI studies showed multiple confluent areas with low signal intensity and rim contrast enhancement in all vertebral bodies . Bone marrow biopsy revealed focal necrosis within hypocellular bone marrow . The patient responded quickly to symptomatic treatment with analgetics and heparin ; however , elevations of LDH and D-Dimer persisted for 1.5 and 8 months , respectively . Clinicians should be aware of this rare condition to establish the diagnosis and to continue oncologic treatment as early as possible .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22773298"}
{"sentence": "The early stages of head and neck cancer are presumed to require a senes of genetic alterations that are not represented by a distinct clinical phenotype . Therefore , genes with altered expression in the preneoplasia may be useful for the early detection of this highly recurrent cancer . In this study , we immortalized normal human oral keratinocytes ( NHOK ) by retroviral-mediated infection of HPV 16 transforming oncogenes , E6 and E7 ( HOK16E6E7 ) . Using the Affymetrix gene chip ( U95Av2 ) , we identified 177 known genes and EST that were overexpressed at least 3-fold or above in the immortalized cells , while 133 were down-regulated compared to NHOK . Northern blot analysis showed elevated levels of p55CDC in the immortalized cells , while NHOK showed high basal expression of small proline rich protein ( SPRR2 ) . The altered expression of these genes maybe associated with cellular proliferation or differentiation and the early stages of oral carcinogenesis .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12643451"}
{"sentence": "Radix of Asiasarum heterotropoides var. mandshuricum F. Maekawa ( A. radix ) has been prescribed for treating pain , allergies and inflammatory disorders in traditional oriental medicine . However , only limited information on the anticancer effects of A. radix is currently available . The aim of this study was to determine the anticancer effect of the ethanol extract of A. radix ( EEAR ) on HCT-116 human colon cancer cells and to investigate its underlying mechanisms of action . EEAR significantly induced G2/M cell cycle arrest and apoptosis in HCT-116 cells . EEAR-induced apoptosis was observed in parallel with activation of caspases and an increased ratio of Bax ( pro-apoptotic)/Bcl2 ( anti-apoptotic ) . Western blot analyses revealed that EEAR elevated the expression of p53 and p21(Waf/Cip1) and decreased the expression of the regulator proteins of G2/M phase progression , such as cdc2 and cyclin B. The upregulation of p53 by EEAR was due to the increased levels of p53 mRNA without a similar increase in proteasome-mediated p53 degradation . EEAR-induced apoptosis in HCT-116 cells was dependent on p53 expression , as determined by siRNA-mediated p53 knockdown . Taken together , these results suggest that EEAR inhibits the growth of the HCT-116 cells through induction of G2/M cell cycle arrest and apoptosis , which are mediated by p53 expression .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23255939"}
{"sentence": "Heat shock protein 90 ( Hsp90 ) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation . Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth , leading to the acceptance of Hsp90 as a potential therapeutic target for cancer . Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system , we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity . EC144 , a synthetic Hsp90 inhibitor , blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2 , MEK1/2 , JNK , and p38 MAPK but not NF-\u03baB . Ex vivo LPS-stimulated CD11b(+) peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2 , MEK1/2 , and ERK1/2 . Consequently , EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-\u03b1 release . Inhibiting Hsp90 also blocked in vitro CD4(+) T cell proliferation in mouse and human MLRs . In vivo , semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response . In a mouse collagen-induced arthritis model , EC144 also suppressed disease development , which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4(+) T cells . Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 1], "id": "21131419"}
{"sentence": "Clear cell renal cell carcinoma ( ccRCC ) is the most common pathological subtype of kidney cancer . Here , we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease . One of the most potent survival regulators , the monocarboxylate transporter MCT4 ( SLC16A3 ) , impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta-analysis of five ccRCC expression datasets . MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis . Silencing MCT4 resulted in intracellular acidosis , and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines . Intra-tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs . MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse-free survival , whereas modal intensity correlated with Fuhrman nuclear grade . Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression , MCT4 expression was greater at sites of metastatic disease . These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC .", "label": [1, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "22362593"}
{"sentence": "Id proteins are negative regulators of basic helix-loop-helix transcription factors , which are critical for expression of genes associated with cellular differentiation . Previous studies have shown that overexpression of Id-1 delays cellular senescence in several cell types , including fibroblasts , mammary epithelial cells , and keratinocytes . Although previous studies have demonstrated the expression of Id-1 in endothelium , the regulation of Id-1 has not been studied in these cells . In this report , a retroviral vector was used to overexpress Id-1 in human endothelial cells . Sustained expression of Id-1 resulted in a 2- to 3-fold increase in the total number of population doublings ( replicative capacity ) of the cells compared with vector-treated controls , which correlated with low levels of p16 , p21 , and p27 expression . The cells , however , were not immortalized and did eventually undergo senescence despite elevated Id-1 levels . Senescence was characterized by a dramatic increase in p16 , but not p21 and p27 . Under these experimental conditions , telomerase activity was not detected and the telomeres became progressively shorter with time . These results demonstrate the importance of Id-1 in endothelial cell proliferation and indicate that Id-1 represses p16 expression , resulting in delayed senescence . These findings may have implications in the development of endothelial cell-derived tumors .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12177246"}
{"sentence": "BACKGROUND To identify potential tumor suppressor genes , genome-wide data from exome and transcriptome sequencing were combined to search for genes with loss of heterozygosity and allele-specific expression . The analysis was conducted on the breast cancer cell line HCC1954 , and a lymphoblast cell line from the same individual , HCC1954BL . RESULTS By comparing exome sequences from the two cell lines , we identified loss of heterozygosity events at 403 genes in HCC1954 and at one gene in HCC1954BL . The combination of exome and transcriptome sequence data also revealed 86 and 50 genes with allele specific expression events in HCC1954 and HCC1954BL , which comprise 5.4% and 2.6% of genes surveyed , respectively . Many of these genes identified by loss of heterozygosity and allele-specific expression are known or putative tumor suppressor genes , such as BRCA1 , MSH3 and SETX , which participate in DNA repair pathways . CONCLUSIONS Our results demonstrate that the combined application of high throughput sequencing to exome and allele-specific transcriptome analysis can reveal genes with known tumor suppressor characteristics , and a shortlist of novel candidates for the study of tumor suppressor activities .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21108794"}
{"sentence": "Overexpression of growth factors and/or their receptors is a common event in malignancy and provides the underlying mechanisms for one of the hallmarks of cancer , uncontrolled proliferation . Mounting evidence suggests that IGF-1 is involved in the pathogenesis and progression of different types of human cancer such as colon , breast , prostate and lung . However , only a few studies have investigated the association between IGF-1 levels and childhood cancer risk . We aimed to compare the IGF-1 serum level in children with de novo malignancies to healthy children , and to assess its relationship with cancer type , stage , metastasis and different disease characteristics . The study was carried out on 100 children ; 50 children with de novo malignancies and 50 healthy children of matched age and gender as a control group . The patients were subjected to a routine work-up for their cancers according to our local standards . Estimation of the serum level of IGF-1 was carried out in the two groups using ELISA . Our results showed that children with cancer had significantly higher levels of IGF-1 than healthy controls of the same age and gender . No association was found between IGF-1 and tumor type , stage , metastasis and other disease characteristics . In conclusion , the IGF-1 serum level is an important indicator of risk for the most prevalent forms of childhood cancer . It may be used to identify children at the highest risk for these cancers and aid in determing who may benefit most from preventive strategies . Given the small number of children in our study , studies with larger populations are required to confirm these results .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22870112"}
{"sentence": "We have already shown that IL-10 plays an important role in immunosuppression and metastatic dissemination in the rat B-cell lymphoma L-TACB model . It was suggested that the up-regulation of IL-10 production and IL-10 receptor ( IL-10R ) expression would be part of the transition from primary tumor to metastatic phenotype and that IL-10 , besides its immunosuppressive activity , may act as a growth factor for metastatic L-TACB cells . The treatment of L-TACB-bearing rats with a single low-dose cyclophosphamide decreased IL-10 production , reverted immunosuppression and induced the immunologic rejection of tumor metastasis without any effect on primary tumor growth . Our current aim was to investigate the effects of cyclophosphamide on the expression of IL-10 and IL-10R on primary and metastatic L-TACB cells . Considering that cyclophosphamide is a prodrug , we used mafosfamide , a compound that yields in vitro the same active metabolites as cyclophosphamide does in vivo . Mafosfamide induced down-regulation of IL-10 production and IL-10R expression on metastatic cells and , concomitantly , inhibited metastatic cell proliferation . We suggest that mafosfamide would inhibit the regulatory loop mediated by the IL-10/IL-10R system and , as a consequence , metastatic cell proliferation . These results may have a considerable impact on the design of new therapies for metastatic lymphomas .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23185784"}
{"sentence": "The lengths of human telomeres , which protect chromosome ends from degradation and end fusions , are crucial determinants of cell lifespan . During embryogenesis and in cancer , the telomerase enzyme counteracts telomeric DNA shortening . As shown in cancer cells , human telomerase binds the shelterin component TPP1 at telomeres during the S phase of the cell cycle , and adds nucleotides in a single round of extension , after which telomerase is turned off by unknown mechanisms . Here we show that the human CST ( CTC1 , STN1 and TEN1 ) complex , previously implicated in telomere protection and DNA metabolism , inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 ( POT1)\u2013TPP1 telomerase processivity factor . CST competes with POT1\u2013TPP1 for telomeric DNA , and CST\u2013telomeric-DNA binding increases during late S/G2 phase only on telomerase action , coinciding with telomerase shut-off . Depletion of CST allows excessive telomerase activity , promoting telomere elongation . We propose that through binding of the telomerase-extended telomere , CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle . Our findings define the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22763445"}
{"sentence": "In response to genotoxic stress , a transient arrest in cell-cycle progression enforced by the DNA-damage checkpoint ( DDC ) signalling pathway positively contributes to genome maintenance . Because hyperactivated DDC signalling can lead to a persistent and detrimental cell-cycle arrest , cells must tightly regulate the activity of the kinases involved in this pathway . Despite their importance , the mechanisms for monitoring and modulating DDC signalling are not fully understood . Here we show that the DNA-repair scaffolding proteins Slx4 and Rtt107 prevent the aberrant hyperactivation of DDC signalling by lesions that are generated during DNA replication in Saccharomyces cerevisiae . On replication stress , cells lacking Slx4 or Rtt107 show hyperactivation of the downstream DDC kinase Rad53 , whereas activation of the upstream DDC kinase Mec1 remains normal . An Slx4-Rtt107 complex counteracts the checkpoint adaptor Rad9 by physically interacting with Dpb11 and phosphorylated histone H2A , two positive regulators of Rad9-dependent Rad53 activation . A decrease in DDC signalling results from hypomorphic mutations in RAD53 and H2A and rescues the hypersensitivity to replication stress of cells lacking Slx4 or Rtt107 . We propose that the Slx4-Rtt107 complex modulates Rad53 activation by a competition-based mechanism that balances the engagement of Rad9 at replication-induced lesions . Our findings show that DDC signalling is monitored and modulated through the direct action of DNA-repair factors .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23160493"}
{"sentence": "OBJECTIVE To analyze the profiles of interleukin-2 ( IL-2 ) , IL-6 , IL-8 , IL-10 , tumor necrosis factor-alpha ( TNF-alpha ) , transforming growth factor-beta1 ( TGF-beta1 ) and interferon-gamma ( IFN-gamma ) in serum and the tumor microenvironment ( cyst fluid , ascites ) in women with ovarian cancer or benign ovarian tumors to find the differences in their immunological status . We also estimated serum cytokines as biomarkers to distinguish preoperatively between malignant or benign character of tumors . DESIGN Prospective study . SETTING Tertiary referral hospital . POPULATION 51 women with epithelial ovarian cancer , 26 with benign ovarian tumors of epithelial origin and 21 healthy controls . METHODS The levels of cytokines were measured using ELISA sets . RESULTS We did not found differences in the levels of IFN-gamma , TNF-alpha and IL-2 in all fluids isolated from patients with malignant or benign tumors . Women with advanced cancer had significantly higher serum IL-6 , IL-10 and TGF-beta1 levels than women with early stages or benign tumors . Moreover , women with very advanced cancer in whom the optimal cytoreduction was disabled had the highest serum levels of IL-10 , TGF-beta1 and IL-8 . The concentrations of IL-6 and IL-8 were higher in ascites of cancer patients than in ascites of women with benign tumors . The areas under curves constructed for the selected cutoff serum cytokines levels ( AUC-ROC ) showed good predictive values for IL-6 ( 0.87 ) , IL-10 ( 0.836 ) and IL-8 ( 0.797 ) . CONCLUSIONS Our results indicate on intensified inflammatory process in women with ovarian cancer ( accompanied by their immunosuppression ) . Preoperative analysis of serum IL-6 , IL-10 and IL-8 may improve the differential diagnosis of ovarian tumors .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20588232"}
{"sentence": "Chemoprevention is one feasible approach to decreasing morbidity and mortality of non-small cell lung cancer ( NSCLC ) . The present study aimed to explore the mechanisms of chemoprevention of NSCLC by Prunella vulgaris L . ( PV ) using a PV extract of 60% ethanol ( P-60 ) . In an A/J mouse model benzo[a]pyrene induction of lung tumors was significantly reduced difference by P-60 group . In addition , P-60 was found to have the ability to regulate cell cycle and induce apoptosis in SPC-A-1 cells . Therefore , we propose that P-60 has potential as a lung cancer chemopreventive agent .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21198292"}
{"sentence": "K-Ras dependent non-small cell lung cancer ( NSCLC ) cells are ' addicted ' to basal autophagy that reprograms cellular metabolism in a lysosomal-sensitive manner . Here we demonstrate that the xenophagy-associated kinase TBK1 drives basal autophagy , consistent with its known requirement in K-Ras-dependent NSCLC proliferation . Furthermore , basal autophagy in this context is characterised by sequestration of the xenophagy cargo receptor Ndp52 and its paralogue Tax1bp1 , which we demonstrate here to be a bona fide cargo receptor . Autophagy of these cargo receptors promotes non-canonical NF-\u03baB signalling . We propose that this TBK1-dependent mechanism for NF-\u03baB signalling contributes to autophagy addiction in K-Ras driven NSCLC .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23209807"}
{"sentence": "The expression of the angiogenic phenotype is regulated by a balance of pro-angiogenic and anti-angiogenic factors released into the tumor microenvironment . Nuclear protein 7 ( NOL7 ) , a novel tumor suppressor , acts as a master regulator of angiogenesis by downregulating pro-angiogenic factors and upregulating anti-angiogenic factors . Using cervical cancer as a model of investigation , we have previously shown that loss of NOL7 mRNA and protein expression is observed as early as the premalignant phase . Analysis of the gene failed to identify tumor-specific promoter methylation or coding region mutations , suggesting that NOL7 loss may be mediated by aberrant expression of its upstream regulators . In this study , we show that the RB tumor suppressor gene ( RB ) positively regulates NOL7 at the transcriptional level by recruiting transcription factors and transcription machinery proteins to its promoter region . Conversely , the loss of RB represses NOL7 transcription by inhibiting assembly of these proteins . This loss of NOL7 expression is also observed in RB-deficient human malignancies . Together , this work further characterizes the transcriptional activator function of RB and defines a potential role for RB in regulating angiogenesis through activation of NOL7 . Current anti-angiogenic therapies lack long-term efficacy , as they are unable to target the diverse angiogenic signals generated by tumors . Our data provide evidence to support the hypothesis that reactivation of pRB can potentially modulate the expression of the angiogenic phenotype through regulation of NOL7 . Therefore , this knowledge may be employed to design more comprehensive and effective therapies .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23308053"}
{"sentence": "Non-small cell lung cancer ( NSCLC ) , accounting for 80% of lung cancers , is the leading cause of all cancer deaths . Previously , we demonstrated that delta-tocotrienol inhibits NSCLC cell proliferation , invasion and induces apoptosis by down-regulation of the Notch-1 signaling pathway . The objective of this study was to investigate whether delta-tocotrienol , could enhance the anticancer effects of cisplatin . Treatment with a combination of delta-tocotrienol and cisplatin resulted in a dose-dependent , significant inhibition of cell growth , migration , invasiveness , and induction of apoptosis in NSCLC cells , as compared to the single agents . This was associated with a decrease in NF-\u03baB DNA binding activity , decrease in Notch-1 , Hes-1 , Bcl-2 and increase in cleaved Caspase-3 and PARP expressions . These results suggest that down-regulation of Notch-1 , via inhibition of NF-\u03baB signaling pathways by delta-tocotrienol and cisplatin , in combination , could provide a potential novel approach for tumor arrest in NSCLC , while lowering the effective dose of cisplatin .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22753722"}
{"sentence": "A key requirement for the development of cancer immunotherapy is the identification of tumour-associated antigens that are differentially or exclusively expressed on the tumour and recognized by the host immune system . However , immune responses to such antigens are often muted or lacking due to the antigens being recognized as \" self \" , and further complicated by the tumour environment and regulation of immune cells within . In an effort to circumvent the lack of immune responses to tumour antigens , we have devised a strategy to develop potential synthetic immunogens . The strategy , termed mirror image phage display , is based on the concept of molecular mimicry as demonstrated by the idiotype/anti-idiotype paradigm in the immune system . Here as ' proof of principle ' we have selected molecular mimics of the well-characterised tumour associated antigen , the human mucin1 protein ( MUC1 ) from two different peptide phage display libraries . The putative mimics were compared in structure and function to that of the native antigen . Our results demonstrate that several of the mimic peptides display T-cell stimulation activity in vitro when presented by matured dendritic cells . The mimic peptides and the native MUC1 antigenic epitopes can cross-stimulate T-cells . The data also indicate that sequence homology and/or chemical properties to the original epitope are not the sole determining factors for the observed immunostimulatory activity of the mimic peptides .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23166757"}
{"sentence": "Cellular senescence , initially observed during subculturing of normal diploid fibroblasts , can also be induced by chronic exposure to cellular stress , such as UV light , oxidative stress , or DNA damaging agents . Here we demonstrate that stable expression of an activated form of MKK6 ( MKK6EE ) , a direct activator of the stress-induced p38(HOG) mitogen-activated protein kinase pathway , is sufficient for inducing features of senescence including a flattened , vacuolated , and irregular morphology , staining for acidic beta-galactosidase , and accumulation of age-associated pigments . Consistent with the senescent phenotype , p38(HOG) activation induces a G(1) cell cycle arrest , which is permanent and irreversible after 4 days . MKK6EE also induces biochemical features of senescence in a p38-dependent manner , including enhanced expression of p21(CIP) , a cyclin-dependent kinase inhibitor . Microarray analysis of MKK6EE cells showed a pattern of gene expression noted previously in Werner Syndrome and senescent fibroblasts . These results define p38(HOG) as an intracellular pathway that activates a senescence checkpoint in tumor cells and may play a role in Ras- or stress-induced senescence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "12208764"}
{"sentence": "Retinoic acid ( RA ) has been believed to be an anticancer drug for a long history . However , the molecular mechanisms of RA actions on cancer cells remain diverse . In this study , the dose-dependent inhibition of RA on DU145 cell proliferation was identified . Interestingly , RA treatment triggered p35 cleavage ( p25 formation ) and Cdk5 overactivation , and all could be blocked by Calpain inhibitor , Calpeptin ( CP ) . Subsequently , RA-triggered DU145 apoptosis detected by sub-G1 phase accumulation and Annexin V staining could also be blocked by CP treatment . Furthermore , RA-triggered caspase 3 activation and following Cdk5 over-activation were destroyed by treatments of both CP and Cdk5 knockdown . In conclusion , we report a new mechanism in which RA could cause apoptosis of androgen-independent prostate cancer cells through p35 cleavage and Cdk5 over-activation . This finding may contribute to constructing a clearer image of RA function and bring RA as a valuable chemoprevention agent for prostate cancer patients .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23304206"}
{"sentence": "The EGF-stimulated ERK/MAPK pathway is a key conduit for cellular proliferation signals and a therapeutic target in many cancers . Here , we characterize two central quantitative aspects of this pathway : the mechanism by which signal strength is encoded and the response curve relating signal output to proliferation . Under steady-state conditions , we find that ERK is activated in discrete , asynchronous pulses with frequency and duration determined by extracellular concentrations of EGF spanning the physiological range . In genetically identical sister cells , cell-to-cell variability in pulse dynamics influences the decision to enter S phase . While targeted inhibition of EGFR reduces the frequency of ERK activity pulses , inhibition of MEK reduces their amplitude . Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23219535"}
{"sentence": "Several germline single nucleotide polymorphisms ( SNPs ) have been identified in the POLB gene , but little is known about their cellular and biochemical impact . DNA Polymerase \\u03b2 ( Pol \\u03b2 ) , encoded by the POLB gene , is the main gap-filling polymerase involved in base excision repair ( BER ) , a pathway that protects the genome from the consequences of oxidative DNA damage . In this study we tested the hypothesis that expression of the POLB germline coding SNP ( rs3136797 ) in mammalian cells could induce a cancerous phenotype . Expression of this SNP in both human and mouse cells induced double-strand breaks , chromosomal aberrations , and cellular transformation . Following treatment with an alkylating agent , cells expressing this coding SNP accumulated BER intermediate substrates , including single-strand and double-strand breaks . The rs3136797 SNP encodes the P242R variant Pol \\u03b2 protein and biochemical analysis showed that P242R protein had a slower catalytic rate than WT , although P242R binds DNA similarly to WT . Our results suggest that people who carry the rs3136797 germline SNP may be at an increased risk for cancer susceptibility .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23144635"}
{"sentence": "OBJECTIVES Epidermal growth factor ( EGF ) stimulates cell proliferation by binding to its receptor ( epidermal growth factor receptor ) , and the overexpression of this receptor is associated with poorer prognosis . The EGF gene presents a polymorphism at position 61 ( A/G ) , associated with higher EGF production . We examined the association between this polymorphism and cervical cancer through a case-control study . METHODS This study used the PCR-restriction fragment length polymorphism method on a sample of 384 women with cervical lesions and 500 controls of white ethnicity . RESULTS In cases of cervical cancer , we found an increased risk of progression to advanced disease ( The International Federation of Gynecology and Obstetrics stage IIb/IV ) ( odds ratios=2.05 ; 95% confidence intervals=1.11 to 3.79 ; P=0.021 ) , and this risk was particularly evident in G carriers for younger women ( odds ratios=2.96 ; 95% confidence intervals=1.41-6.20 , P=0.003 ) . CONCLUSIONS We hypothesize the onset of an advanced disease-driven selective pressure due to the effect of oncogenic human papillomavirus types in a favorable genetic background observed in G carrier women . These results suggest that EGF functional polymorphism may influence cervical cancer prognosis through an EGF/epidermal growth factor receptor pathway .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21358296"}
{"sentence": "In human epithelial cancers , the microRNA ( miRNA ) mir-30d is amplified with high frequency and serves as a critical oncomir by regulating metastasis , apoptosis , proliferation , and differentiation . Autophagy , a degradation pathway for long-lived protein and organelles , regulates the survival and death of many cell types . Increasing evidence suggests that autophagy plays an important function in epithelial tumor initiation and progression . Using a combined bioinformatics approach , gene set enrichment analysis and miRNA target prediction , we found that mir-30d might regulate multiple genes in the autophagy pathway including BECN1 , BNIP3L , ATG12 , ATG5 , ATG2 . Our further functional experiments demonstrated that the expression of these core proteins in the autophagy pathway was directly suppressed by mir-30d in cancer cells . Finally , we showed that mir-30d regulated the autophagy process by inhibiting autophagosome formation and LC3B-I conversion to LC3B-II . Taken together , our results provide evidence that the oncomir mir-30d impairs the autophagy process by targeting multiple genes in the autophagy pathway . This result will contribute to understanding the molecular mechanism of mir-30d in tumorigenesis and developing novel cancer therapy strategy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23274497"}
{"sentence": "INTRODUCTION Necrosis at the tumor center is a common feature of aggressive breast cancers and has been associated with poor prognosis . It is commonly identified by means of invasive histopathology , which often correlates with morbidity and potential tumor cell dissemination , and limits the reconstruction of the whole necrotic domain . In this study we hypothesized that non covalent association to serum albumin ( SA ) and covalent binding to ligands for tumor-abundant cell receptors should synergistically drive selective accumulation and prolonged retention of imaging and therapeutic agents in breast tumor necrotic domains enabling in vivo identification , imaging and possibly treatment of such tumors . METHODS Cyclo-Arg-Gly-Asp-D-Phe-Lys ( c(RGDfK) ) were conjugated to bacteriochlorophyll-derivatives ( Bchl-Ds ) , previously developed as photodynamic agents , fluorescent probes and metal chelators in our lab . The c(RGDfK) component drives ligation to alphaVbeta3 integrin receptors over-expressed by tumor cells and neo-vessels , and the Bchl-D component associates to SA in a non-covalent manner . STL-6014 , a c(RGDfK)-Bchl-D representative , was i.v. injected to CD-1 , nude female mice bearing necrotic and non-necrotic human MDA-MB-231-RFP breast cancer tumors . The fluorescence signals of the Bchl-Ds and RFP were monitored over days after treatment , by quantitative whole body imaging and excised tumor/tissue samples derived thereof . Complementary experiments included competitive inhibition of STL-6014 uptake by free c(RGDfK) , comparative pharmacokinetics of nonconjugated c(RGDfK) Bchl-D ( STL-7012 ) and of two human serum albumin ( HSA ) conjugates : HSA-STL-7012 and HSA-STL-6014 . RESULTS STL-6014 and STL-7012 formed complexes with HSA ( HSA/STL-6014 , HSA/STL-7012 ) . STL-6014 , HSA-STL-7012 and HSA-STL-6014 , selectively accumulated at similar rates , in tumor viable regions over the first 8 h post administration . They then migrated into the necrotic tumor domain and presented tumor half lifetimes ( T1/2 ) in the range of days where T1/2 for HSA-STL-6014 > STL-6014 > HSA-STL-7012 . No accumulation of STL-7012 was observed . Pre-injection of c(RGDfK) excess , prevented the uptake of STL-6014 in the small , but not in the large tumors . CONCLUSIONS Non-covalent association to SA and covalent binding to c(RGDfK) , synergistically enable the accumulation and prolonged retention of Bchl-Ds in the necrotic regions of tumors . These findings provide novel guidelines and strategy for imaging and treatment of necrotic tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20497549"}
{"sentence": "Tumors are infiltrated by macrophages , T and B-lymphocytes , which may favor tumor development by promoting angiogenesis , growth and invasion . The aim of this study was to investigate the clinical relevance of the relative amount of macrophages ( CD68\u207a ) , T-cells ( CD3\u207a and B-cells ( CD20\u207a ) at the invasive front of breast carcinomas , and the expression of matrix metalloproteases ( MMPs ) and their inhibitors ( TIMPs ) either at the invasive front or at the tumor center . We performed an immunohistochemical study counting CD3 , CD20 and CD68 positive cells at the invasive front , in 102 breast carcinomas . Also , tissue sections were stained with MMP-2 , -9 , -11 , -14 and TIMP-2 antibodies , and immunoreactivity location , percentage of reactive area and intensity were determined at the invasive front and at the tumor center . The results showed that an increased CD68 count and CD68/(CD3+CD20) ratio were directly associated with both MMP-11 and TIMP-2 expression by mononuclear inflammatory cells at the tumor center ( p\u200a=\u200a0.041 and p\u200a=\u200a0.025 for CD68 count and p\u200a=\u200a0.001 and p\u200a=\u200a0.045 for ratio , respectively for MMP-11 and TIMP-2 ) . In addition , a high CD68/(CD3+CD20) ratio ( >0.05 ) was directly associated with a higher probability of shortened relapse-free survival . Multivariate analysis revealed that CD68/(CD3+CD20) ratio was an independent factor associated with distant relapse-free survival ( RR : 2.54 , CI : ( 1.23-5.24 ) , p<0.01 ) . Therefore , CD68/(CD3+CD20) ratio at the invasive front could be used as an important prognostic marker .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23300781"}
{"sentence": "XRCC4 , in association with DNA ligase IV , is thought to play a critical role in the ligation of two DNA ends in DNA double-strand break ( DSB ) repair through non-homologous end-joining ( NHEJ ) pathway . In the present study , we captured radiation-induced chromatin-recruitment of XRCC4 by biochemical fractionation using detergent Nonidet P-40 . A subpopulation of XRCC4 changed into a form that is resistant to the extraction with 0.5% Nonidet P-40-containing buffer after irradiation . This form of XRCC4 was liberated by micrococcal nuclease treatment , indicating that it had been tethered to chromatin DNA . This chromatin-recruitment of XRCC4 could be seen immediately ( < 0.1 hr ) after irradiation and remained up to 4 hr after 20 Gy irradiation . It was seen even after irradiation of small doses , i.e. , 2 Gy , but the residence of XRCC4 on chromatin was very transient after 2 Gy irradiation , returning to near normal level in 0.2-0.5 hr after irradiation . The chromatin-bound XRCC4 represented only approximately 1% of total XRCC4 molecules even after 20 Gy irradiation and the quantitative analysis using purified protein as the reference suggested that only a few XRCC4-DNA ligase IV complexes were recruited to each DNA end . We further show that the chromatin-recruitment of XRCC4 was not attenuated by wortmannin , an inhibitor of DNA-PK , or siRNA-mediated knockdown of the DNA-PK catalytic subunit ( DNA-PKcs ) , indicating that this process does not require DNA-PKcs . These results would provide us with useful experimental tools and important insights to understand the DNA repair process through NHEJ pathway .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20448413"}
{"sentence": "OBJECT A considerable body of evidence indicates that inflammation and angiogenesis play a significant role in the development and progression of chronic subdural hematoma ( CSDH ) . While various experimental and clinical studies have implicated placental growth factor ( PlGF ) in the processes that underpin pathological angiogenesis , no study has thus far investigated its expression in CSDH . The actions of PlGF and its related proangiogenic vascular endothelial growth factor ( VEGF ) are antagonized by a high-affinity soluble receptor , namely soluble VEGF receptor-1 ( sVEGFR-1 ) , and thus the ratio between sVEGFR-1 and angiogenic factors provides an index of angiogenic capacity . METHODS In the present study , using an automated electrochemiluminescence assay , levels of PlGF and sVEGFR-1 were quantified in serum and hematoma fluid obtained in 16 patients with CSDH . RESULTS Levels of PlGF and sVEGFR-1 were significantly higher in hematoma fluid than in serum ( p < 0.0001 ) . In serum , levels of sVEGFR-1 were higher than those of PlGF ( p < 0.0001 ) , whereas in hematoma fluid this difference was not apparent . Furthermore , the ratio of sVEGFR-1 to PlGF was significantly lower in hematoma fluid than in serum ( p < 0.0001 ) . CONCLUSIONS Given previous evidence indicating a role for PlGF in promoting angiogenesis , inflammatory cell chemotaxis , and stimulation , as well as its ability to amplify VEGF-driven signaling under conditions favoring pathological angiogenesis , enhanced expression of PlGF in hematoma fluid suggests the involvement of this factor in the mechanisms of inflammation and angiogenesis in CSDH . Furthermore , a reduced ratio of sVEGFR-1 to PlGF in hematoma fluid is consistent with the proangiogenic capacity of CSDH . Future studies are warranted to clarify the precise role of PlGF and sVEGFR-1 in CSDH .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23140147"}
{"sentence": "Diffuse intrinsic pontine glioma ( DIPG ) is a fatal pediatric disease . Thus far no therapeutic agent has proven beneficial in the treatment of this malignancy . Hence , conventional DNA-damaging radiotherapy ( RT ) remains the standard treatment , providing transient neurological improvement without improving probability of overall survival . During RT , WEE1 kinase controls the G2 cell cycle checkpoint allowing for repair of irradiation ( IR)-induced DNA damage . Here we show that WEE1 kinase is one of the highest overexpressed kinases in primary DIPG tissues as compared to matching non-neoplastic brain tissues . Inhibition of WEE1 by MK-1775 treatment of DIPG cells inhibited the IR-induced WEE1-mediated phosphorylation of CDC2 , resulting in reduced G2/M arrest and decreased cell viability . Finally , we demonstrate that MK-1775 enhances the radiation response of E98-Fluc-mCherry DIPG mouse xenografts . Altogether , these results show that inhibition of WEE1 kinase in conjunction with RT holds potential as a therapeutic approach for the treatment of DIPG .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23270927"}
{"sentence": "A panel of primary human cells and virus-transformed derivatives were tested for events that coincide with immortalization . In all primary and precrisis cells , two proteins of 92 and 150 kDa that shared an epitope with p53 were found ; in most of their immortalized derivatives , however , they were absent . Expression of these proteins may be involved in senescence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1370093"}
{"sentence": "Phenotype-driven approaches to gene discovery using inbred mice have been instrumental in identifying genetic determinants of inherited blood dyscrasias . The recessive mutant scat ( severe combined anemia and thrombocytopenia ) alternates between crisis and remission episodes , indicating an aberrant regulatory feedback mechanism common to erythrocyte and platelet formation . Here , we identify a missense mutation ( G125V ) in the scat Rasa3 gene , encoding a Ras GTPase activating protein ( RasGAP ) , and elucidate the mechanism producing crisis episodes . The mutation causes mislocalization of RASA3 to the cytosol in scat red cells where it is inactive , leading to increased GTP-bound Ras . Erythropoiesis is severely blocked in scat crisis mice , and succumb during the second crisis ( d of age ) from catastrophic hematopoietic failure in the spleen and bone marrow . Megakaryopoiesis is also defective during crisis . Notably , the scat phenotype is recapitulated in zebrafish when rasa3 is silenced . These results highlight a critical , conserved , and nonredundant role for RASA3 in vertebrate hematopoiesis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22773809"}
{"sentence": "Inorganic arsenic in the drinking water is a multisite human carcinogen that potentially targets the kidney . Recent evidence also indicates that developmental arsenic exposure impacts renal carcinogenesis in humans and mice . Emerging theory indicates that cancer may be a disease of stem cells ( SCs ) and that there are abundant active SCs during early life . Therefore , we hypothesized that inorganic arsenic targets SCs , or partially differentiated progenitor cells ( PCs ) , for oncogenic transformation . Thus , a rat kidney SC/PC cell line , RIMM-18 , was chronically exposed to low-level arsenite ( 500 nM ) for up to 28 weeks . Multiple markers of acquired cancer phenotype were assessed biweekly during arsenic exposure , including secreted matrix metalloproteinase ( MMP ) activity , proliferation rate , colony formation in soft agar , and cellular invasiveness . Arsenic exposure by 10 weeks and after also induced marked and sustained increases in colony formation , indicative of the loss of contact inhibition , and increased invasiveness , both cancer cell characteristics . Compared to the passage-matched control , chronic arsenic exposure caused exposure-duration dependent increases in secreted MMP-2 and MMP-9 activity , Cox-2 expression , and more rapid proliferation ( all >2-fold ) , characteristics typical of cancer cells . Dysregulation of SC maintenance genes and signaling pathways are common during oncogenesis . During arsenite exposure , expression of several genes associated with normal kidney development and SC regulation and differentiation ( i.e. , Wt-1 , Wnt-4 , Bmp-7 , etc. ) were aberrantly altered . Arsenic-exposed renal SCs produced more nonadherent spheroid bodies that grew much more aggressively in Matrigel , typical of cancer SCs ( CSCs ) . The transformed cells also showed gene overexpression typical of renal SCs/CSCs ( CD24 , Osr1 , Ncam ) and arsenic adaptation such as overexpression of Mt-1 , Mt2 , Sod-1 , and Abcc2 . These data suggest that inorganic arsenic induced an acquired cancer phenotype in vitro in these rat kidney SCs potentially forming CSCs and , consistent with data in vivo , indicate that these multipotent SCs may be targets of arsenic during renal carcinogenesis .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 1, 1], "id": "23137061"}
{"sentence": "BACKGROUND The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases . Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis . Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases , we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress . METHODOLOGY/PRINCIPAL FINDINGS The severity of colitis , changes in expression of genes involved in DNA repair and inflammation , DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium ( DSS ) . The Mutyh(-/-) phenotype was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice . A single DSS cycle induced severe acute ulcerative colitis in wild-type mice , whereas lesions were modest in Mutyh(-/-) mice , and this was associated with moderate variations in the expression of several cytokines . Eight DSS cycles caused chronic colitis in both wild-type and Mutyh(-/-) mice . Lymphoid hyperplasia and a significant reduction in Foxp3(+) regulatory T cells were observed only in Mutyh(-/-) mice . CONCLUSIONS The findings indicate that , in this model of ulcerative colitis , Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20706593"}
{"sentence": "We investigated the mechanisms of DNA exit during single-cell gel electrophoresis ( the comet assay ) by measuring the kinetics of the comet tail formation . In the neutral comet assay , the rate of DNA exit was found to be dependent on the topological state of DNA , which was influenced by either ethidium bromide or a low radiation dose . The results clearly show that the comet tail is formed by extended DNA loops : the loop extension , being reversible when the DNA torsional constraint remains in the loops , is favored when the constraint is relaxed . The kinetics of the comet formation in the case of a high radiation dose points out that accumulation of the single-strand breaks causes DNA fragmentation . In contrast to the neutral comet assay , the alkaline comet assay is not related to the chromatin loops . Our results imply that the alkaline treatment induces detachment of the loops from the nuclear matrix , and the comet tail is formed by ssDNA fragments , the ends of which are pulled out from the comet head by electric force . We suggest that the kinetic approach can be considered as an important improvement of the comet assay .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20119958"}
{"sentence": "To explore the possibility of a new therapeutic strategy for leukemia by intervening in the DNA methylation to re-express p15 suppressor gene , methylation inhibitors , 5-Aza-2'-deoxycytidine ( 5-Aza-CdR ) and cell differentiation agent ( CDAII ) were used to treat myelogenous leukemia cell line KG1a in which p15 gene expression was suppressed due to DNA hypermethylation . The biological characteristics of KG1a cells untreated or treated with the agents were investigated and analyzed using morphology , methylation specific-PCR ( MSP ) , ( 3)H-labeled microassay technique , restriction endonuclease reaction , flow cytometry and immunofluorescence methods . The results indicated that both agents showed concentration-dependent and time-dependent inhibition of cell proliferation. 5-Aza-CdR and CDAII induced apoptosis and cell differentiation with G(2) and G(0)/G(1) arrest respectively . Furthermore , DNA methyltransferase activity and level of methylation in genomic DNA were decreased and p15 protein was re-expressed partially . It is concluded that it is possible to treat leukemia by intervening in the DNA methylation using methyltransferase inhibitors and it is worth to make a thorough study on mechanism of the new strategy .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "12513759"}
{"sentence": "PURPOSE : Prostate cancer ( PCa ) development is often associated with deletion or silencing of tumor suppressor PTEN , a negative regulator of the PI3K-Akt pathway , leading to resistance to various therapies . Therefore , the PI3K/Akt pathway plays a central role in various cellular processes leading to malignant phenotype , and , consequently is an attractive target . However , the efficacy of AKT inhibitors is limited by resistance mechanisms that result in minimal tumor cell death . Methods:Effects of Akt inhibitor AZD5363 were investigated on cell proliferation , apoptosis , Akt pathway and survival mechanisms . We then examined the impacts of inhibition of autophagy combined with AZD5363 on cell proliferation and apoptosis . Furthermore , the anti-cancer activity of combination treatment of the lysosomotropic inhibitor of autophagy ( chloroquine ) with Akt inhibitor AZD5363 was evaluated in PC-3 prostate cancer xenografts . RESULTS : we show that AZD5363 affected Akt downstream pathway by reducing p-mTOR , p-P70S6K and p-S6K . While AZD5363 monotherapy induced G2 growth arrest and autophagy , it failed to induce significant apoptosis in PC-3 and DU145 PCa cells . Blocking autophagy using pharmacological inhibitors or genetic inhibitors enhanced cell death induced by AZD5363 in these PCa cells . Importantly , the combination of AZD5363 with chloroquine significantly reduced tumor volume by 84.9% compared with the control group and by 77.5% compared with either drug alone in PC3 xenografts . CONCLUSIONS : These data demonstrate that Akt inhibitor AZD5363 , synergizes with the lysosomotropic inhibitor of autophagy , chloroquine , to induce apoptosis and delay tumor progression in PCa models that are resistant to monotherapy AZD5363 , providing a new therapeutic approach potentially translatable to patients .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23258740"}
{"sentence": "OBJECTIVES To investigate the immunoexpression of epidermal growth factor receptor ( EGFR ) in a sample of oral leukoplakias ( OL ) and to determine the receptor ' s association with dysplasia , tobacco consumption , lesion site , and proliferation rate . Although EGFR should be overexpressed in some oral leukoplakias , the factors that may interfere with this expression and the influence of this receptor on epithelial proliferation have yet to be investigated . STUDY DESIGN Samples of oral leukoplakias ( 48 ) and of normal oral epithelium ( 10 ) were immunohistologically examined for expression of EGFR . Immunohistochemistry for Ki-67 , and p27 were also performed in leukoplakias . EGFR expression was associated with clinical and pathological features . RESULTS EGFR was positive in 62.5% of the leukoplakias and 50% of normal oral epithelium . The number of EGFR positive OL located in high-risk sites was significantly higher than EGFR positive OL located in low-risk sites . Most of the p27 negative leukoplakias were EGFR positive , and the p27 index in the parabasal layer was diminished in the presence of dysplasia . Positivity for EGFR was not associated with dysplasia , tobacco exposure , or Ki-67 . CONCLUSION EGFR is expressed in leukoplakia regardless of dysplasia , but EGFR positivity should be more frequent in lesions sited in areas of high cancer risk . The association between EGFR and p27 may represent an important mechanism in the control of cellular proliferation and malignant progression of oral epithelium and therefore warrants further investigation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22322523"}
{"sentence": "We recently reported that chronic myeloid leukaemia ( CML ) patients harbour high levels of STAT5 when they progress to advanced phases of disease . Advanced disease is characterized by an increased incidence of BCR-ABL1 mutations . We now describe a highly significant correlation between STAT5 expression and the incidence of BCR-ABL1 mutations in primary CML . Forced expression of STAT5 in murine BCR-ABL1 transformed cells sufficed to enhance the production of reactive oxygen species ( ROS ) and to trigger DNA damage . STAT5-mediated ROS production is independent of JAK2 but requires concomitant BCR-ABL1 signalling as forced STAT5 expression in untransformed BCR-ABL1 negative cells has no impact on ROS levels . Only within the context of a BCR-ABL1 positive cell does STAT5 transcriptionally regulate a target gene or set of genes that causes the enhanced ROS production . Our study suggests the existence of a feed-forward loop accelerating disease progression , in which BCR-ABL1 enhances its own mutation rate in a STAT5-ROS dependent manner . This model explains the increased occurrence of inhibitor-resistant BCR-ABL1 mutations in advanced disease stages driven and characterized by high STAT5 expression .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23458731"}
{"sentence": "BACKGROUND AND AIM The importance of glycolysis in cancer cells is well documented . The effects of inhibiting glycolysis using metabolic inhibitors iodoacetate ( IAA ) , an inhibitor of GAPDHase , and 3-bromopyruvate ( 3BP ) , an inhibitor of hexokinase-II , on survival and signaling of pancreatic cancer cells ( Panc-1 ) were investigated . MATERIALS AND METHODS Cellular survival was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ( MTT ) assay . Lactate dehydrogenase ( LDH ) assay was used to analyze the induced necrosis and protein levels were evaluated using Western blot analysis . RESULTS The results show that the inhibitors lowered cellular survival and increased cellular necrosis . Mitogenic signaling pathways were affected by 3BP but not by IAA . CONCLUSION We conclude that there may be a cross-talk between signaling pathways and glycolysis in regulating pancreatic cancer cell survival and signaling . Thus , a combination of agents that inhibit both energy production and cell signaling may provide a novel and effective approach to target pancreatic cancer effectively .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "20392992"}
{"sentence": "BACKGROUND Non-alcoholic fatty liver disease ( NAFLD ) is associated with obesity , insulin resistance and hepatic steatosis . Non-alcoholic steatohepatitis ( NASH ) is a serious consequence of NAFLD where chronic tissue damage and inflammation result in fibrosis which may progress to cirrhosis . Transforming growth factor beta1 ( TGFbeta1 ) , proinflammatory cytokines and oxidative stress are thought to play crucial roles in the pathogenesis of these conditions . The contributions of individual liver cell types to fibrogenesis remain controversial and the influence of selenium status has not been investigated . METHODS In this study we have used a cell culture model of fat-loading using oleate-treated human hepatoblastoma ( C3A ) cells to investigate how fat-loading and selenium status might influence the production of collagen in response to TGFbeta1 . The secretion of inflammatory cytokines was also investigated , together with the epithelial character of the treated cells . RESULTS We found that in response to treatment with TGFbeta1 , C3A cells produced mRNA encoding the pro-alphaI chain of procollagen I , secreted procollagen I peptide , up-regulated production of the proinflammatory cytokine interleukin-8 ( IL-8 ) and the mesenchymal marker vimentin , and down-regulated albumin production . Most of these responses were considerably enhanced when cells were fat-loaded with oleate and were attenuated by selenium addition at a dose that optimised the expression of thioredoxin reductase and glutathione peroxidase . CONCLUSIONS Our data establish that both fat-loading and suboptimal selenium status enhance collagen and IL-8 production by C3A hepatocytes in response to TGFbeta1 , possibly as part of an epithelial to mesenchymal transition . GENERAL SIGNIFICANCE These findings suggest that the hepatocyte may be an important contributor to the pathogenesis of fibrosis associated with NAFLD .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20188144"}
{"sentence": "Maintenance of genomic integrity is essential for adult tissue homeostasis and defects in the DNA-damage response ( DDR ) machinery are linked to numerous pathologies including cancer . Here , we present evidence that the DDR exerts tumor suppressor activity in gliomas . We show that genes encoding components of the DDR pathway are frequently altered in human gliomas and that loss of elements of the ATM/Chk2/p53 cascade accelerates tumor formation in a glioma mouse model . We demonstrate that Chk2 is required for glioma response to ionizing radiation in vivo and is necessary for DNA-damage checkpoints in the neuronal stem cell compartment . Finally , we observed that the DDR is constitutively activated in a subset of human GBMs , and such activation correlates with regions of hypoxia .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21156285"}
{"sentence": "OBJECTIVE Increases in plasma angiotensinogen ( Ang-N ) due to genetic polymorphisms or pharmacological stimuli like estrogen have been associated with a blood pressure ( BP ) rise , increased salt sensitivity and cardiovascular risk . The relationship between Ang-N , the resetting of the renin-angiotensin system , and BP still remains unclear . Angiotensin ( Ang ) II-induced genetic hypertension should respond to lisinopril treatment . METHODS A new transgenic rat line ( TGR ) with hepatic overexpression of native ( rat ) Ang-N was established to study high plasma Ang-N . The transgene contained a mutation producing Val(5)-Ang-II , which was measured separately from nontransgenic Ile-Ang-II in plasma and renal tissue . RESULTS Male homozygous TGR had increased plasma Ang-N ( systolic BP ( \\u0394BP+26 mmHg ) , renin activity ( renin activity/concentration ( 5-fold ) , total Ang-II ( kidney 1.7-fold ) but decreased plasma renin concentrations ( -46% , kidney -85% ) and Ile(5)-Ang-I and II ( -93% , -94% ) vs. controls . Heterozygous TGR exhibited higher plasma Ang-N and 17 mmHg \\u0394BP . Lisinopril decreased their SBP ( -23 vs. -13 mmHg in controls ) , kidney Ang-II/I ( vs. and Ile(5)-Ang-II ( -70 vs. -40% ) , and increased kidney renin and Ile(5)-Ang-I ( >2.5-fold vs. <2.5-fold ) . Kidney Ang-II remained higher and renin lower in TGR compared with controls . CONCLUSION High plasma Ang-N increases plasma and kidney Ang-II levels , and amplifies the plasma and renal Ang-II response to a given change in renal renin secretion . This enzyme-kinetic amplification dominates over the Ang-II mediated feedback reduction of renin secretion . High Ang-N levels thus facilitate hypertension via small increases of Ang II and may influence the effectiveness of renin-angiotensin system inhibitors .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22728903"}
{"sentence": "Cancer cells preferentially metabolize glucose through aerobic glycolysis . This phenomenon , known as the Warburg effect , is an anomalous characteristic of glucose metabolism in cancer cells . Chronic inflammation is a key promoting factor of tumourigenesis . It remains , however , largely unexplored whether and how pro-tumourigenic inflammation regulates glucose metabolism in cancer cells . Here , we show that pro-inflammatory cytokines promote glycolysis in breast cancer cells , and that the inflammation-induced miR-155 functions as an important mediator in this process . We further show that miR-155 acts to upregulate hexokinase 2 ( hk2 ) , through two distinct mechanisms . First , miR-155 promotes hk2 transcription by activation of signal transducer and activator of transcription 3 ( STAT3 ) , a transcriptional activator for hk2 . Second , via targeting C/EBP\\u03b2 ( a transcriptional activator for mir-143 ) , miR-155 represses mir-143 , a negative regulator of hk2 , thus resulting in upregulation of hk2 expression at the post-transcriptional level . The miR-155-mediated hk2 upregulation also appears to operate in other types of cancer cells examined . We suggest that the miR-155/miR-143/HK2 axis may represent a common mechanism linking inflammation to the altered metabolism in cancer cells .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 1], "id": "22354042"}
{"sentence": "Metastases in the sellar region are rare and are frequently found incidentally or in necropsies . Only 7% are reported to be symptomatic . Diabetes insipidus , anterior pituitary dysfunction , visual field defects , headache/pain and ophthalmoplegia are the most commonly reported symptoms . We present the cases of two male patients with a small-cell lung carcinoma whose first clinical symptoms were due to pituitary metastasis . One case presented with symptoms of cavernous sinus invasion and panhypopituitarism and the other case with diabetes insipidus . Both patients had a rapid progression of their disease despite chemotherapy and died after a few months . Pituitary metastases occur most commonly with breast cancer in women and lung cancer in men . The presence of polyuria and polydipsia in an oncologic patient should alert the physician for diabetes insipidus and , if confirmed , an imaging procedure of the pituitary gland is mandatory . Treatment for these tumors is often multimodal and includes surgery , radiation therapy , chemotherapy and hormone replacement . Although surgical series have not shown any significant survival benefits given by tumor resection , the patient's quality of life may be improved .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23513490"}
{"sentence": "Food-derived heterocyclic aromatic amines ( HCAs ) have proved to be carcinogenic in both rodents and nonhuman primates . Two different metabolic pathways are suggested for the metabolic activation of HCA . The hepatic pathway proceeds via a two-step process involving N-hydroxylation by cytochrome P4501A2 and subsequent O-acetylation by N-acetyltransferase-2 . An alternative pathway may be of particular interest in extrahepatic tissues and proceeds via one-electron oxidation catalyzed by prostaglandin H synthase ( PHS ) , rendering free-radical metabolites . In this study , we investigated the metabolic activation of two HCAs , 2-amino-3-methylimidazo[4,5-f]quinoline ( IQ ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) , by two different enzyme systems in vitro , generating different primary and secondary reactive metabolites . Rat liver S9 mix and PHS were used as the activating system and represent the hepatic and extrahepatic pathways , respectively . Electron-spin resonance spectroscopy showed that both IQ and PhIP exerted inhibiting effects on PHS-mediated formation of hydroxyl radicals during the conversion of arachidonic acid to prostaglandins . Evidence for the formation of HCA free radicals was presented in an indirect way by the formation of glutathione-derived thiyl radicals , with purified PHS as the activating system . Activation by S9 mix did not result in the formation of detectable radical metabolites , showing that the two metabolic routes primarily led to the formation of different metabolites . In all electron-spin resonance experiments , IQ appeared to be more effective than PhIP . In contrasts , DNA adduct analysis by means of ( 32)P-postlabeling showed similar adduct patterns for S9 and PHS in single-stranded and double-stranded salmon testes DNA after incubation with PhIP , indicating the ultimate formation of a common reactive intermediate . For IQ , activation by PHS led to an additional adduct spot that was not present after S9 activation . Furthermore , activation of IQ resulted in higher adduct levels compared with PhIP for both activation pathways . Overall , adduct levels were higher in single-stranded DNA than double-stranded DNA . Our results showed that the hepatic and extrahepatic pathways resulted in different primary metabolites , while the ultimate formation of a similar reactive intermediate for PhIP , possibly an arylnitrenium ion , suggested that both pathways could play an important role in the onset of carcinogenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12489111"}
{"sentence": "One of the immunosuppressive effects of both ultraviolet ( UV ) light and chemical carcinogens is to deplete Langerhans cells ( LC ) from the epidermis , suggesting that these cells play an important role in inducing immune responses to developing tumors during the early phases of carcinogenesis . Retinoids such as all-trans-retinoic acid ( RA ) are natural or synthetic derivatives of vitamin A ; RA binds to nuclear receptors in the skin , effecting transcription of a wide range of genes . Topical application of RA prevents the tumor promotor 12-O-tetradecanoylphorbol-13-acetate ( TPA ) from depleting the density of LC in murine epidermis . In contrast , topical RA did not itself alter the normal LC density . RA also inhibited the development of TPA-induced immunosuppression to a locally applied contact sensitizer . Topical RA also prevented UV light from reducing the density of both LC and Thy-1+ dendritic epidermal cells ( Thy-1+ dEC ) . However , the RA treatment did not prevent local immunosuppression to the contact sensitizer from developing in response to UV irradiation . The reasons for this are unclear , however , it is possible that RA does not inhibit some other immunosuppressive effect of UV light . Temarotene , a recently developed synthetic retinoid also inhibited UV light from reducing the LC and Thy-1+ dEC density from murine epidermis . Thus part of the anti-carcinogenic activity of retinoids may be due to their ability to protect LC during the early stages of carcinogenesis .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1358983"}
{"sentence": "Primary fibroblasts respond to activated H-RAS(V12) by undergoing premature arrest , which resembles replicative senescence . This irreversible ' fail-safe mechanism ' requires p19(ARF) , p53 and the Retinoblastoma ( Rb ) family : upon their disruption , RAS(V12)-expressing cells fail to undergo senescence and continue to proliferate . Similarly , co-expression of oncogenes such as c-MYC or E1A rescues RAS(V12)-induced senescence . To identify novel genes that allow escape from RAS(V12)-induced senescence , we designed an unbiased , retroviral complementary DNA library screen . We report on the identification of DRIL1 , the human orthologue of the mouse Bright and Drosophila dead ringer transcriptional regulators . DRIL1 renders primary murine fibroblasts unresponsive to RAS(V12)-induced anti-proliferative signalling by p19(ARF)/p53/p21(CIP1) , as well as by p16(INK4a) . In this way , DRIL1 not only rescues RAS(V12)-induced senescence but also causes these fibroblasts to become highly oncogenic . Furthermore , DRIL1 immortalizes mouse fibroblasts , in the presence of high levels of p16(INK4a) . Immortalization by DRIL1 , whose product binds the pRB-controlled transcription factor E2F1 ( ref. 8 ) , is correlated with induction of E2F1 activity . Correspondingly , DRIL1 induces the E2F1 target Cyclin E1 , overexpression of which is sufficient to trigger escape from senescence . Thus , DRIL1 disrupts cellular protection against RAS(V12)-induced proliferation downstream of the p19(ARF)/p53 pathway .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "11812999"}
{"sentence": "Cancers are characterized by an increasing glycolytic activity , which is called the Warburg effect . Although this phenomenon is well known , the mechanism of the enhanced rate of glycolysis in cancer has not yet been clearly recognized . The present study investigated the glycolytic rate , regulatory enzymatic activities and the expression of phosphofructokinase-1 ( PFK-1 ) in human breast cancer and paracancer tissues . Human breast cancer tissues have an increased degree of glycolytic efficiency and regulatory enzymatic activities , which have been shown in previous studies . However , the present study identified a number of novel observations . The total PFK-1 levels were higher in human breast cancer tissues than in paracancer tissues , and further investigations revealed differential PFK-1 isoenzyme expression patterns between human breast cancer and paracancer tissues . The human breast cancer and paracancer tissues mainly expressed PFK-P and PFK-L isoforms , respectively . Linear-regression analysis showed that , depending on the pathological stage of breast cancer , the expression of PFK-P was significantly positively correlated with the activity of PFK-1 . Thus , during the development of human breast cancer , the enhancement of glycolytic activity depends primarily on the conversion of the PFK-1 , from PFK-L to PFK-P .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24260065"}
{"sentence": "Mutation rate varies between sites in the genome . Part of this variation can be explained by well-recognized short nucleotide contexts , but a large component of this variation remains cryptic . We used data on interspecies divergence and intraspecies polymorphism in Drosophila and Hominidae to analyze variation of the average rate of the 12 possible kinds of single-nucleotide mutations and in the transition/transversion ratio \\u03ba at single-nucleotide resolution . Both the average mutation rate and \\u03ba vary by a factor of between nucleotide sites . The characteristic scale of variation in \\u03ba is up to at least nucleotides in Drosophila and nucleotides in Hominidae . Genome segments with locally elevated mutation rates possess lower values of \\u03ba ; however , a substantial fraction of variation in \\u03ba cannot be directly explained by the local mutation rates .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22337862"}
{"sentence": "In human fibroblasts , the expression of SV40 large T antigen is known to cause a variety of chromosomal aberrations and especially dicentric chromosomes . In some cases , the later aberrations have been reported to be reversible telomeric associations . We report here aberration and chromosome number studies of twenty-nine T antigen positive lineages , studied from their initiation by transfection of T antigen sequences into human diploid fibroblasts , until crisis or immortalization occurred or , in some cases until the lines became tumorigenic in nude mice . The data show that T antigen consistently produced chromosomal instability of both number and structure by an active process that began before transformation indicators were positive and continued throughout neoplastic progression . The most frequently observed aberrations were dicentric chromosomes , which were shown to be true dicentrics by examination by in situ hybridization with telomeric sequences . These data are consistent with the hypothesis that T antigen causes human fibroblasts to become neoplastically transformed by successive rounds of chromosomal mutation and lineage evolution .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "1281278"}
{"sentence": "AIM The study was designed to explore the effects of antisense human telomerase RNA ( ahTR ) on the malignant phenotype of gastric carcinoma cell line SGC-7901 , and its potential role in gene therapy for tumors . METHODS An ahTR eukaryotic expression vector , including the sequence of template region of telomere repeats , was constructed by recombinant technology of molecules and then transfected into gastric carcinoma cell line SGC-7901 by liposome DOTAP . Subsequently , the expression of hTR RNA and ahTR RNA by reverse transcription-polymerase chain reaction , telomerase activity by telomeric repeat amplification protocol-ELISA ( TRAP-ELISA ) , telomere length by Southern blotting , cell morphology under light microscope , cellular proliferation capacity by 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay , cell-cycle distribution by flow cytometry , efficiency of clone formation in soft agar , and tumorigenecity in nude mice were examined and evaluated in ahTR-transfected cells , control plasmid pCI-neo transfected cells and their parental cells . RESULTS An ahTR eukaryotic expression vector was constructed and successfully transfected into SGC-7901 cells . The telomerase activity in ahTR-transfected SGC-7901 cells decreased from 100% to approximately 25% , and telomere length in the cells shortened to 3.35 from 4.08 Kb at 60 population doublings . Compared with the parental cells and pCI-neo transfected cells , ahTR-transfected cells displayed some morphological changes , such as decreased atypia , and recovery of contact inhibition and density inhibition under light microscope . Furthermore , ahTR-transfected cells displayed decreased invasive capacity in Borden's chamber invasive model , increased G0/G1 phase rate and apoptotic rate . Surprisingly , ahTR-transfected SGC-7901 cells lost their capacity for clone formation in soft agar and tumorigencity in nude mice . CONCLUSION Antisense-hTR transfection can inhibit the growth of SGC-7901 cells and partially reverse the malignant phenotypes . This study provides an exciting approach for cancer therapy by inhibiting telomerase activity using an antisense gene .", "label": [1, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "12453272"}
{"sentence": "BACKGROUND The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy . Unlike breast cancer , the prognostic role of the human epidermal growth factor receptor-2 ( HER-2 ) in ovarian carcinoma remains controversial . METHODS The aim of this preclinical study was to further characterise the biological , molecular and cellular effects of trastuzumab ( Herceptin ) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo . RESULTS In vitro assessments have shown that trastuzumab treatment inhibited total and phosphorylated HER-2 . This was associated with inhibition of the phosphorylated form of phosphatase and tensin homologue ( PTEN ) , mitogen-activated protein kinase and AKT , and the total level of p27(kip) . Inhibition of PTEN is associated with phosphorylated MEK1/2 upregulation , suggesting a specific inhibition of the protein phosphatase function of PTEN . Moreover , trastuzumab induced the upregulation of RhoB . These molecular modifications promote inhibition of cell migration and potentially restoration of tumour cell contact inhibition . RhoB induction in NIH-OVCAR-3 control cell lines mimics the molecular and cellular trastuzumab long-time exposition effects . RhoB inhibition in NIH-OVCAR-3 long-time exposed to trastuzumab cell line reverses the cellular and molecular effects observed in this model . In vivo examinations have shown that these changes are also associated with the restoration of structural , morphological and normal functions of the peritoneum of an ovarian carcinoma mouse model . CONCLUSION These results provide an indication of the mechanisms underlying the anti-tumour activity of trastuzumab that strongly implicate RhoB in an ovarian carcinoma model that does not show HER-2 amplification or overexpression . These findings highlight that trastuzumab effects involve a possible cross-talk between RhoB and PTEN in the early stages of tumour re-growth in a model of micrometastatic ovarian cancer .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "20588279"}
{"sentence": "The widespread use of synthetic musk fragrances and the resultant presence of these substances and their metabolites in the aquatic environment ( as well as their accumulation in human adipose tissue ) raises the question of whether musk fragrances display endocrine and in particular estrogenic activity . A variety of musk fragrances were tested using the E-screen assay . A statistically significant increase in proliferation rate of human MCF-7 breast cancer cells was detected for two nitro musks ( musk xylene , musk ketone ) , a major metabolite of musk xylene ( p-amino-musk xylene ) , and the polycyclic musk fragrance AHTN . This indicates that these substances do , in fact , demonstrate estrogenic activity . Coincubation with the antiestrogen tamoxifen showed that the increase in proliferation rate by the musk fragrances is estrogen receptor-mediated . It must be noted , however , that the effective estrogenic strength and estrogenic potency were low compared to 17 b-estradiol . The naturally occurring fragrance muscone from the group of macrocyclic musk fragrances , a group of substances that have not yet been well characterized in respect to their toxicological properties , has also been shown to be weakly estrogenically active in vitro . E-screen analysis showed that the nitro musk metabolites o-amino musk xylene and 2-amino-MK , the macrocyclic musk fragrances ethylene brassylate , ethylene dodecandioate , and cyclopentadecanolide , are not estrogenically active .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12202919"}
{"sentence": "OBJECTIVE Overexpression of epidermal growth factor receptor ( EGFR ) in glioblastoma multiforme ( GBM ) secondary to EGFR gene amplification is associated with a more aggressive tumor phenotype and a worse clinical outcome . The purpose of this study was to analyze whether blocking this receptor with the anti-EGFR chimeric monoclonal antibody C225 would decrease proliferation and increase apoptosis in GBM cells . METHODS EGFR expression and amplification were analyzed for seven human GBM cell lines . These lines were then exposed to different concentrations of C225 for 48 hours , 72 hours , and 7 days , after which time cytotoxicity , apoptosis , and vascular endothelial growth factor expression were assessed in vitro . Two EGFR-amplified human GBM were implanted in the flanks of nude mice , and the animals received C225 twice per week intraperitoneally for 5 weeks . Tumor volumes and survival times were compared with those of sham-treated mice . RESULTS EGFR gene amplification was demonstrated in three of the primary GBM lines . C225 treatment produced significant cytotoxicity in all three EGFR-amplified GBM lines , but not in unamplified lines . Flow cytometry demonstrated increased apoptosis in C225-treated , EGFR-amplified GBM lines , but not in unamplified lines . There was a decrease in vascular endothelial growth factor expression in all GBM lines with exposure to C225 . Tumor-bearing mice treated with C225 experienced significant inhibition of tumor growth as well as a 200% increase in median survival . CONCLUSION Blocking EGFR in GBM cells that overexpress this receptor significantly changes tumor cell biology by promoting apoptosis while decreasing proliferation and vascular endothelial growth factor expression . This approach holds great promise for the treatment of patients with GBMs .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "12234411"}
{"sentence": "Ovarian smooth muscle tumors are a very rare type of ovarian tumor . In this paper , we report the case of a 62-year-old woman who had a huge smooth muscle tumor of the right ovary . The values of all the serum tumor markers were within normal limit . The tumor measured 25 cm in diameter and weighed 6,200 g . Histological examination revealed that coagulative cellular atypia was moderate to severe , necrosis was not present and mitotic index was low . According to the criteria for the evaluation of the uterine smooth muscle tumors , this huge tumor was diagnosed as atypical leiomyoma . However , we finally made a diagnosis of this tumor as a smooth muscle tumor of uncertain malignant potential ( STUMP ) because of its huge size . Further information is required regarding the characteristics of ovarian smooth muscle tumor and the propriety to introduce uterine tumor histological criteria to ovarian tumors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20299756"}
{"sentence": "We previously reported that hepatic stellate cells ( HSCs ) activated by angiotensin II ( AngII ) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma ( ICC ) . AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition ( EMT ) in renal epithelial cells , alveolar epithelial cells and peritoneal mesothelial cells . However , in the past , the relationship between AngII and stromal cell-derived factor-1 ( SDF-1 ) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail . SDF-1 and its specific receptor , CXCR4 , are now receiving attention as a mechanism of cell progression and metastasis . In this study , we examined whether activated HSCs promote tumor fibrogenesis , tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor ( AT-1 ) and the SDF-1/CXCR4 axis . Two human ICC cell lines and a human HSC line , LI-90 , express CXCR4 . Significantly higher concentration of SDF-1\u03b1 was released into the supernatant of LI-90 cells to which AngII had been added . SDF-1\u03b1 increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor . Furthermore , addition of SDF-1\u03b1 and AngII enhanced the increase of the migratory capability and vimentin expression , reduced E-cadherin expression , and translocated the expression of \u03b2-catenin into the nucleus and cytoplasm in ICC cells . Co-culture with HSCs also enhanced the migratory capability of ICC cells . These findings suggest that SDF-1\u03b1 , released from activated HSCs and AngII , play important roles in cancer progression , tumor fibrogenesis , and migration in autocrine and paracrine fashion by mediating EMT . Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1\u03b1-initiated signaling pathway that regulates fibrogenesis in cancerous stroma , tumor progression and meta-stasis of tumor cells expressing AT-1 and CXCR4 .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22664794"}
{"sentence": "Angiogenesis is critical for cancer growth and metastasis . Steps of angiogenesis are energy consuming , while vascular endothelial cells are highly glycolytic . Glioblastoma multiforme ( GBM ) is a highly vascular tumor and this enhances its aggressiveness . D-amino acid oxidase ( DAO ) is a promising therapeutic protein that induces oxidative stress upon acting on its substrates . Oxidative stress-energy depletion ( OSED ) therapy was recently reported ( El Sayed et al. , Cancer Gene Ther , 19 , 1-18 , 2012 ) . OSED combines DAO-induced oxidative stress with energy depletion caused by glycolytic inhibitors such as 3-bromopyruvate ( 3BP ) , a hexokinase II inhibitor that depleted ATP in cancer cells and induced production of hydrogen peroxide. 3BP disturbs the Warburg effect and antagonizes effects of lactate and pyruvate ( El Sayed et al. , J Bioenerg Biomembr , 44 , 61-79 , 2012 ) . Citrate is a natural organic acid capable of inhibiting glycolysis by targeting phosphofructokinase . Here , we report that DAO , 3BP and citrate significantly inhibited angiogenesis , decreased the number of vascular branching points and shortened the length of vascular tubules . OSED delayed the growth of C6/DAO glioma cells. 3BP combined with citrate delayed the growth of C6 glioma cells and decreased significantly the number and size of C6 glioma colonies in soft agar . Human GBM cells ( U373MG ) were resistant to chemotherapy e.g. cisplatin and cytosine arabinoside , while 3BP was effective in decreasing the viability and disturbing the morphology of U373MG cells .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22802136"}
{"sentence": "Cytokeratin ( CK ) 19-positive hepatocellular carcinoma ( HCC ) has been reported to have a poor prognosis . The mechanism of the development of CK19-positive HCC remains to be studied . To clarify this , in vitro experiments were performed using human HCC cell lines ( PLC-5 , HepG2 ) , and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR , western blotting , and immunofluorescence staining . In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed . Among the growth factors tested , epidermal growth factor ( EGF ) had prominent effects on inducing CK19 expression in PLC-5 and HepG2 , which was accompanied by the reduced expression of \u03b1-fetoprotein in PLC-5 . The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase ( JNK)/stress-activated protein kinase , which was blocked by the addition of JNK inhibitors . EGF also increased proliferative abilities and invasive properties of the HCC cell lines . In vivo , 9 ( 12% ) of 78 HCC cases showed positive immunohistochemical staining of CK19 . The extent of positive immunohistochemical signals of EGF , EGF receptor ( EGFR ) , and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC . Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion , extrahepatic metastasis and an early relapse , which was associated with the worsened 2-year disease free survival . These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC , and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20856226"}
{"sentence": "Genotoxic stress induces cell cycle arrest and DNA repair which may enable tumor cells to survive radiation therapy . Here , we defined the role of Ca(2+) signaling in the cell cycle control and survival of chronic myeloid leukemia ( CML ) cells subjected to ionizing radiation ( IR ) . To this end , K562 erythroid leukemia cells were irradiated ( 0-10 Gy ) . Tumor survival was analyzed by clonogenic survival assay and cell cycle progression via flow cytometry . Plasma membrane cation conductance was assessed by patch-clamp whole-cell recording and the cytosolic free Ca(2+) concentration ( [ Ca(2+)](i) ) was measured by fura-2 Ca(2+) imaging . Nuclear activity of Ca(2+)/calmodulin-dependent kinase II ( CaMKII ) was defined by Western blotting . In addition , the effect of IR ( 5 Gy ) on the cation conductance of primary CML cells was determined . The results indicated that IR ( 10 Gy ) induced a G(2)/M cell cycle arrest of K562 cells within 24 h post-irradiation ( p.i. ) and decreased the clonogenic survival to 0.5 % of that of the control cells . In K562 cells , G(2)/M cell cycle arrest was preceded by activation of TRPV5/6-like nonselective cation channels in the plasma membrane 1-5 h p.i. , resulting in an elevated Ca(2+) entry as evident from fura-2 Ca(2+) imaging . Similarly , IR stimulated a Ca(2+)-permeable nonselective cation conductance in primary CML cells within 2-4 h p.i. . Ca(2+) entry , into K562 cells was paralleled by an IR-induced activation of nuclear CaMKII . The IR-stimulated accumulation in G(2) phase was delayed upon buffering [ Ca(2+)](i) with the Ca(2+) chelator BAPTA-AM or inhibiting CaMKII with KN93 ( 1 nM ) . In addition , KN93 decreased the clonogenic survival of irradiated cells but not of control cells . In conclusion , the data suggest that IR-stimulated cation channel activation , Ca(2+) entry and CaMKII activity participate in control of cell cycle progression and survival of irradiated CML cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "21063097"}
{"sentence": "Helicobacter hepaticus-infected Rag2(-/-) mice emulate many aspects of human inflammatory bowel disease , including the development of colitis and colon cancer . To elucidate mechanisms of inflammation-induced carcinogenesis , we undertook a comprehensive analysis of histopathology , molecular damage , and gene expression changes during disease progression in these mice . Infected mice developed severe colitis and hepatitis by 10wk post-infection , progressing into colon carcinoma by 20wk post-infection , with pronounced pathology in the cecum and proximal colon marked by infiltration of neutrophils and macrophages . Transcriptional profiling revealed decreased expression of DNA repair and oxidative stress response genes in colon , but not in liver . Mass spectrometric analysis revealed higher levels of DNA and RNA damage products in liver compared to colon and infection-induced increases in 5-chlorocytosine in DNA and RNA and hypoxanthine in DNA . Paradoxically , infection was associated with decreased levels of DNA etheno adducts . Levels of nucleic acid damage from the same chemical class were strongly correlated in both liver and colon . The results support a model of inflammation-mediated carcinogenesis involving infiltration of phagocytes and generation of reactive species that cause local molecular damage leading to cell dysfunction , mutation , and cell death . There are strong correlations among histopathology , phagocyte infiltration , and damage chemistry that suggest a major role for neutrophils in inflammation-associated cancer progression . Further , paradoxical changes in nucleic acid damage were observed in tissue- and chemistry-specific patterns . The results also reveal features of cell stress response that point to microbial pathophysiology and mechanisms of cell senescence as important mechanistic links to cancer .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 1], "id": "22689960"}
{"sentence": "Histone deacetylase inhibitors ( HDACi ) are promising epigenetic cancer chemotherapeutics rapidly approaching clinical use . In this study , we tested using in vitro and in vivo models the differential biological effects of a novel HDAC inhibitor [ belinostat ( PXD101) ] , in a wide panel of androgen-sensitive and androgen-independent tumor cells . Belinostat significantly increased acetylation of histones H3 and H4 . Belinostat potently inhibited the growth of prostate cancer cell lines ( IC50 range from 0.5 to 2.5 \ufffdM ) with cytotoxic activity preferentially against tumor cells . This agent induced G2/M arrest and increased significantly the percentage of apoptosis mainly in androgen-sensitive tumor cells confirming its growth-inhibitory effects . The cell death mechanisms were studied in three different prostate cancer cell lines with different androgen dependence and expression of androgen receptor ; LAPC-4 and 22rv1 ( androgen-dependent and expressing androgen receptor ) and PC3 ( androgen-independent not expressing androgen receptor ) . Belinostat induced the expression of p21 and p27 , acetylation of p53 and G2/M arrest associated with Bcl2 and Bcl-Xl downmodulation and significant reduction of survivin , IAPs and Akt/pAkt and increased caspase-8 and -9 expression/activity . Belinostat effectiveness was dependent on the androgen receptor ( AR ) , since the stable transfection of AR greatly increased the efficacy of this HDAC inhibitor . These observations were correlated using in vivo models . We demonstrated that belinostat preferentially resulted in antitumor effect in androgen-dependent tumor cells expressing AR . Our findings provide evidence that belinostat may be a promising anticancer drug for prostate cancer expressing AR , supporting its clinical role in prostate cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22134754"}
{"sentence": "\u039duclear factor-\u03baB ( NF-\u03baB ) and activator protein-1 ( AP-1 ) are major transcription factors that have been associated with breast cancer metastasis by inducing matrix metalloproteinase-9 ( MMP-9 ) expression . In this study , we investigated the inhibitory effects of guggulsterone isomers ( cis or trans ) on 12-O-tetradecanoylpho-bol-13-acetate ( TPA)-induced MMP-9 expression . Cis-guggulsterone inhibited TPA-induced MMP expression by blocking I\u03baB kinase ( IKK)/NF-\u03baB signaling , whereas trans-guggulsterone blocked mitogen-activated protein kinase ( MAPK)/AP-1 signaling . Cis-guggulsterone was more potent than trans-guggulsterone in the inhibition of TPA-induced MMP-9 expression and invasion of MCF-7 cells . Furthermore , we found that the combination of these isomers exerted an additive effect on the inhibition of MCF-7 cell invasion . These results suggest that guggulsterone isomers downregulate MMP-9 expression and tumor cell invasion through the isomer-specific suppression of IKK/NF-\u03baB and MAPK/AP-1 activation . In addition , the suppression of MMP-9 expression correlated well with the inhibition of cell invasion .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23242121"}
{"sentence": "Mesenchymal stem cells ( MSCs ) are generally used in tissue engineering , regenerative medicine and therapy for immune disorder disease . MSCs are also employed as drug carriers for tumor therapy due to their ability to migrate to tumor tissue . However , due to the immunosuppressive function of MSCs , the application of MSCs in prostate cancer therapy remains limited . In this study , we investigated the underlying mechanism by which MSCs enable prostate cancer cells to escape from immune surveillance in the inflammatory microenvironment . Firstly , we demonstrated that compared with the control groups , MSCs pretreated with IL-1\u03b1 effectively promoted the growth of the mouse prostate cancer cell line RM-1 invivo . Furthermore , when RM-1 prostate cancer cells were co-injected with MSCs pretreated with IL-1\u03b1 , tumor incidence significantly increased in allogeneic recipients . In addition , we investigated the mechanism through which MSCs promote the ability of RM-1 cells to escape from immune injury . The results revealed that IL-1\u03b1 led to the upregulation of TGF-\u03b2 in MSCs . The inflammatory cytokine-induced promotive effect of MSCs on RM-1 cells in vivo was inhibited by TGF-\u03b2 siRNA . The results of our study suggest that inflammatory cytokines induce the immunosuppressive function of MSCs which enables prostate cancer cells to escape from immune injury .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 1, 1], "id": "22895682"}
{"sentence": "Cancer cells undergo multi-step processes in obtaining the ability to metastasize , and are constantly exposed to signals that induce apoptosis . Acquisition of anti-apoptotic properties by cancer cells is important for metastasis , and recent studies suggest that transforming growth factor ( TGF)-\u03b2 promotes the survival of certain types of cancer cells . Here , we found that in highly metastatic breast cancer cells , JygMC(A) , JygMC(B) and 4T1 , TGF-\u03b2 ligands were produced in autocrine fashion . Pharmacological inhibition of endogenous TGF-\u03b2 signalling by a TGF-\u03b2 type I receptor kinase inhibitor in serum-free conditions increased the expression of BH3-only protein , Bim ( also known as Bcl2-like 11 ) in JygMC(A) and JygMC(B) cells , and caused apoptotic cell death . We also found that induction of Bim by TGF-\u03b2 was not observed in Foxc1 knocked-down cancer cells . These findings suggest that TGF-\u03b2 plays a crucial role in the regulation of survival of certain types of cancer cells through the TGF-\u03b2-Foxc1-Bim pathway , and that specific inhibitors of TGF-\u03b2 signalling might be useful as apoptosis inducers in breast cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20880961"}
{"sentence": "Prostate cancer is the most frequent and second most lethal cancer in men in the United States . Innate immunity and inflammation may increase the risk of prostate cancer . To determine the role of innate immunity and inflammation in advanced prostate cancer , we investigated the association of 320 single nucleotide polymorphisms , located in 46 genes involved in this pathway , with disease risk using 494 cases with advanced disease and 536 controls from Cleveland , Ohio . Taken together , the whole pathway was associated with advanced prostate cancer risk ( P\u200a=\u200a0.02 ) . Two sub-pathways ( intracellular antiviral molecules and extracellular pattern recognition ) and four genes in these sub-pathways ( TLR1 , TLR6 , OAS1 , and OAS2 ) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk . Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23272139"}
{"sentence": "Identifying prognostic factors for osteosarcoma ( OS ) aids in the selection of patients who require more aggressive management . CD133 has been found to be a prognostic factor of certain tumor types . However , the association between CD133 expression and the prognosis of OS remains unknown . In this study , we analyzed the association of CD133 expression in OS with clinical factors and overall survival , and further investigated its potential role in metastasis in vitro . We found CD133 expression in 65.7% ( 46/70 ) of OS samples using immunohistochemistry , and it was positively correlated with lung metastasis analyzed by Chi-square test ( P=0.002 ) and shorter overall survival time using the Kaplan-Meier method compared by log-rank test ( P=0.000 ) . Multivariate analysis showed that CD133 expression was an independent prognostic factor of patients with OS . To test for direct participation of CD133 , we separated CD133(+) and CD133(-) cells in the MG63 cell line using magnetic-activated cell sorting and found that CD133(+) cells were more active in migration by scratch wound-healing assay and invasion by Matrigel invasion assay compared with CD133(-) cells . Elevated mRNA expression of the stemness gene octamer-binding transcription factor 4 ( Oct-4 ) and NANOG , and the metastasis-related receptor C-X-C chemokine receptor type 4 ( CXCR4 ) were also found in CD133(+) cells by reverse transcription-polymerase chain reaction . Thus , expression of CD133 was correlated with lung metastasis and poor prognosis in OS patients . CD133(+) cells may be a type of cancer stem cell with high expression of self-renewal capacity and metastasis-related genes .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23181114"}
{"sentence": "Growth differentiation factor-15 ( GDF-15 ) and the CCN family member , connective tissue growth factor ( CCN2 ) , are associated with cardiac disease , inflammation and cancer . The precise role and signaling mechanism for these factors in normal and diseased tissues remains elusive . Here we demonstrate an interaction between GDF-15 and CCN2 using yeast two-hybrid assays and have mapped the domain of interaction to the von Willebrand factor type C domain of CCN2 . Biochemical pull down assays using secreted GDF-15 and His-tagged CCN2 produced in PC-3 prostate cancer cells confirmed a direct interaction between these proteins . To investigate the functional consequences of this interaction , in vitro angiogenesis assays were performed . We demonstrate that GDF-15 blocks CCN2-mediated tube formation in human umbilical vein endothelial ( HUVEC ) cells . To examine the molecular mechanism whereby GDF-15 inhibits CCN2-mediated angiogenesis , activation of \u03b1(V) \u03b2(3) integrins and focal adhesion kinase ( FAK ) was examined . CCN2-mediated FAK activation was inhibited by GDF-15 and was accompanied by a decrease in \u03b1(V) \u03b2(3) integrin clustering in HUVEC cells . These results demonstrate , for the first time , a novel signaling pathway for GDF-15 through interaction with the matricellular signaling molecule CCN2 . Furthermore , antagonism of CCN2 mediated angiogenesis by GDF-15 may provide insight into the functional role of GDF-15 in disease states . J. Cell . Biochem. \ufffd 2012 Wiley Periodicals , Inc .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23280549"}
{"sentence": "Epigenetic deregulation of gene expression has a role in the initiation and progression of prostate cancer ( PCa ) . The histone methyltransferase MMSET/WHSC1 ( Multiple Myeloma SET domain ) is overexpressed in a number of metastatic tumors , but its mechanism of action has not been defined . In this work , we found that PCa cell lines expressed significantly higher levels of MMSET compared with immortalized , non-transformed prostate cells . Knockdown experiments showed that , in metastatic PCa cell lines , dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 ( H3K36me2 and H3K27me3 , respectively ) depended on MMSET expression , whereas depletion of MMSET in benign prostatic cells did not affect chromatin modifications . Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation , colony formation in soft agar and strikingly diminished cell migration and invasion . Conversely , overexpression of MMSET in immortalized , non-transformed RWPE-1 cells promoted cell migration and invasion , accompanied by an epithelial-mesenchymal transition ( EMT ) . Among a panel of EMT-promoting genes analyzed , TWIST1 expression was strongly activated in response to MMSET . Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus and leads to an increase in H3K36me2 , suggesting a direct role of MMSET in the regulation of this gene . Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT , indicating that TWIST1 was a critical target of MMSET , responsible for the acquisition of an invasive phenotype . Collectively , these data suggest that MMSET has a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22797064"}
{"sentence": "The INK4a/ARF tumor suppressor locus is implicated in the senescence-like growth arrest provoked by oncogenic Ras in primary cells . INK4a and ARF are distinct proteins encoded by transcripts in which a shared exon is decoded in alternative reading frames . Here we analyze dermal fibroblasts ( designated Q34 ) from an individual carrying independent missense mutations in each copy of the common exon . Both mutations alter the amino acid sequence of INK4a and functionally impair the protein , although they do so to different degrees . Only one of the mutations affects the sequence of ARF , causing an apparently innocuous change near its carboxy terminus . Unlike normal human fibroblasts , Q34 cells are not permanently arrested by Ras or its downstream effectors Ets1 and Ets2 . Moreover , ectopic Ras enables the cells to grow as anchorage-independent colonies , and in relatively young Q34 cells anchorage independence can be achieved without addition of telomerase or perturbation of the p53 pathway . Whereas ARF plays the principal role in Ras-induced arrest of mouse fibroblasts , our data imply that INK4a assumes this role in human fibroblasts .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12417717"}
{"sentence": "BACKGROUND Yes Associated Protein ( YAP ) has been implicated in the control of organ size by regulating cell proliferation and survival . YAP is a transcriptional coactivator that controls cellular responses through interaction with TEAD transcription factors in the nucleus , while its transcriptional functions are inhibited by phosphorylation-dependent translocation to the cytosol . YAP overexpression has been associated with different types of cancer , such as lung , skin , prostate , ovary and liver cancer . Recently , YAP was linked to E-cadherin-dependent regulation of contact inhibition in breast cancer cells . RESULTS In this study we examined YAP protein expression and cellular localization in 237 cases of human invasive breast cancer by immunohistochemistry and related its expression to clinicopathological features and E-cadherin expression . We observed that invasive lobular carcinoma is characterized by higher expression levels of both nuclear and cytosolic YAP ( p\u2009<\u20090.001 ) . Nuclear YAP expression did not associate with other variables such as lymph node involvement , tumor grade , tumor size , mitotic activity or the molecular sub-types of invasive breast cancer . We observed that high nuclear and cytosolic YAP expression are associated with the E-cadherin deficient breast cancer subtype ILC ( p\u2009<\u20090.001 ) and cell lines derived from human breast cancers and conditional mouse models of human lobular breast cancer . CONCLUSIONS Since our data indicate that nuclear YAP localization is more common in breast cancers lacking functional adherens junctions , it suggests that YAP-mediated transcription may be involved in the development and progression of invasive lobular breast cancer .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23949920"}
{"sentence": "Previous studies have shown that the E7 gene of human papillomavirus ( HPV ) type 16 or 18 alone was sufficient for immortalization of human foreskin epithelial cells ( HFE ) and that the efficiency was increased in cooperation with the respective E6 gene , whereas the HPV6 E6 or E7 gene was not active in HFE . To detect weak immortalizing activities of the HPV6 genes , cells were infected with recombinant retroviruses containing HPV genes , alone and in homologous and heterologous combinations . The HPV6 genes , alone or together ( HPV6 E6 plus HPV6 E7 ) , were not able to immortalize cells . However the HPV6 E6 gene , in concert with HPV16 E7 , increased the frequency of immortalization threefold over that obtained with HPV16 E7 alone . Interestingly , 6 of 20 clones containing the HPV16 E6 gene and the HPV6 E7 gene were immortalized , whereas neither gene alone was sufficient . Thus , the HPV6 E6 and E7 genes have weak immortalizing activities which can be detected in cooperation with the more active transforming genes of HPV16 . Acute expression of the HPV6 and HPV16 E6 and E7 genes revealed that only HPV16 E7 was able to stimulate the proliferation of cells in organotypic culture , resulting in increased expression of the proliferative cell nuclear antigen and the formation of a disorganized epithelial layer . Additionally , combinations of genes that immortalized HFE cells ( HPV16 E6 plus HPV16 E7 , HPV16 E6 plus HPV6 E7 , and HPV6 E6 plus HPV16 E7 ) also stimulated proliferation .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "1312623"}
{"sentence": "The aryl hydrocarbon receptor ( AHR ) is a ligand-activated transcription factor that mediates the effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD ) . Recently , AHR has emerged as a potential therapeutic target for breast cancer by virtue of its ability to modulate estrogen receptor-\u03b1 ( ER\u03b1 ) signalling and/or its ability to block cell proliferation . Our previous studies identified cyclin G2 ( CCNG2 ) , an inhibitor of cell-cycle progression , as an AHR target gene ; however , the mechanism of this regulation is unknown . Chromatin immunoprecipitation assays in T-47D human breast cancer cells revealed a TCDD-dependent recruitment of AHR , nuclear co-activator 3 ( NCoA3 ) and the transcription factor forkhead box A1 ( FOXA1 ) , a key regulator of breast cancer cell signaling , to CCNG2 resulting in increases in CCNG2 mRNA and protein levels . Mutation of the AHR response element ( AHRE ) and forkhead-binding sites abolished TCDD-induced CCNG2-regulated reporter gene activity . RNA interference-mediated knockdown of FOXA1 prevented the TCDD-dependent recruitment of AHR and NCoA3 to CCNG2 and reduced CCNG2 mRNA levels . Interestingly , knockdown of FOXA1 also caused a marked decrease in ER\u03b1 , but not AHR protein levels . However , RNA interference-mediated knockdown of ER\u03b1 , a negative regulator of CCNG2 , had no effect on TCDD-dependent AHR or NCoA3 recruitment to or expression of CCNG2 . These findings show that FOXA1 , but not ER\u03b1 , is essential for AHR-dependent regulation of CCNG2 , assigning a role for FOXA1 in AHR action .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22596188"}
{"sentence": "BACKGROUND Current treatments have a modest impact on survival of pancreatic cancer patients and this study investigates the interaction between sorafenib and gemcitabine and the molecular pharmacodynamics of this combination . METHODS The pancreatic cancer cells were treated with sorafenib and gemcitabine , alone or in combination . The effects of treatments were evaluated on cell proliferation , cell cycle , apoptosis , phosphorylation of Akt , c-Kit , ERK and VEGFR2 , and expression of genes related to drug activity . RESULTS Gemcitabine and sorafenib synergistically interacted on the inhibition of cell proliferation , and assessment of apoptosis demonstrated that drug associations increased the apoptotic index . Sorafenib reduced c-Kit , ERK and VEGFR2 activation and on the other hand , gemcitabine inhibited Akt phosphorylation . Moreover , quantitative PCR showed that sorafenib modulated the expression of genes related to gemcitabine activity , while gemcitabine induced the expression of RKIP . CONCLUSION These data demonstrate that gemcitabine and sorafenib combination displays a synergistic effect in pancreatic cancer cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20714148"}
{"sentence": "ANXA2 , a member of the annexin family , is overexpressed and plays important roles in tumor development . However , the significance of ANXA2 expression in gastric carcinoma has not been clarified.To elucidate its roles in growth of gastric cancer , ANXA2 expression in SGC-7901 cells was inhibited with a designated siRNA , then cell proliferation , cell cycling , apoptosis and motility were determined by MTT assay , flow cytometry , Hoechst 33342 staining and wound healing assay , respectively . To further assess the behavior of ANXA2 deleted SGC- 7901 cells , changes of microstructures were observed under fluorescence microscopy , laser scanning confocal microscopy and electron microscopy . We found that inhibition of ANXA2 expression caused cell proliferation to decrease significantly with G1 arrest , motility to be reduced with changes in pseudopodia/filopodia structure and F-actin and \u03b2-tubulin expression , and apoptosis to be enhanced albeit without significance . At the same time , ANXA2 deletion resulted in fewer pseudopodia/filopodia , non-stained areas were increased , contact inhibition among cells reappeared , and expression of F-actin and \u03b2-tubulin was decreased , with induction of polymerized disassembled forms . Taken together , these data suggest that ANXA2 overexpression is important to maintain the malignancy of cancer cells , and this member of the annexin family has potential to be considered as a target for the gene therapy of gastric carcinoma .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "24289616"}
{"sentence": "Mutations of the thyroid hormone receptor-\u03b2 gene ( THRB ) cause resistance to thyroid hormone ( RTH ) . A mouse model of RTH harboring a homozygous thyroid hormone receptor ( TR)-\u03b2 mutation known as PV ( Thrb(PV/PV) mouse ) spontaneously develops follicular thyroid cancer ( FTC ) . Similar to RTH patients with mutations of two alleles of the THRB gene , the Thrb(PV/PV) mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH . However , the heterozygous Thrb(PV/+) mouse with mildly elevated TSH ( does not develop FTC . The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in Thrb(PV/+) mice under stimulation by high TSH . Thrb(PV/+) mice and wild-type siblings were treated with propylthiouracil ( PTU ) to elevate serum TSH . Thrb(PV/+)mice treated with PTU ( Thrb(PV/+)-PTU ) spontaneously developed FTC similar to human thyroid cancer , but wild-type siblings treated with PTU did not . Interestingly , approximately 33% of Thrb(PV/+)-PTU mice developed asymmetrical thyroid tumors , as is frequently observed in human thyroid cancer . Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of Thrb(PV/+)-PTU mice . Moreover , via extranuclear signaling , the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells . Therefore , mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis . The present study suggests that the Thrb(PV/+)-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22919057"}
{"sentence": "The influence of radiation-induced apoptosis on radiosensitivity was studied in a set of closely related human lymphoblastoid cell lines differing in TP53 status . The clonogenic survival of irradiated TK6 cells ( expressing wild-type TP53 ) , WTK1 cells ( overexpressing mutant TP53 ) , and TK6E6 cells ( negative for TP53 owing to transfection with HPV16 E6 ) was assessed in relation to the induction of apoptosis and its suppression by caspase inhibition or treatment with PMA as well as after treatment with caffeine . Measurements using the alkaline comet assay and pulsed-field electrophoresis of the induction and repair of DNA strand breaks showed similar kinetics of the processing of early DNA damage in these cell lines . The cytochalasin B micronucleus assay revealed identical levels of residual damage in the first postirradiation mitosis of these cells . Abrogation of TP53-dependent apoptosis in TK6E6 cells resulted in a distinct increase in radioresistance . Further suppression of apoptosis as observed in WTK1 cells overexpressing mutant TP53 apparently was not responsible for the high radioresistance of WTK1 cells , since other means of highly efficient suppression of apoptosis ( caspase inhibition or PMA treatment ) increased the clonogenic survival of irradiated TK6 cells only to levels similar to those of TK6E6 cells with abrogated TP53-dependent apoptosis . Considering the similar levels of residual chromosomal damage in TK6E6 cells and WTK1 cells , a hitherto unknown mechanism of tolerance needs to be inferred for these TP53 mutant cells . This residual damage tolerance , however , appears to require an intact G2/M-phase checkpoint function since the relative radioresistance of the WTK1 cells was completely lost upon caffeine treatment , which also resulted in a failure of the TK6 and TK6E6 cells to execute apoptosis . In this situation , the cellular response seems to be dominated entirely by TP53-independent mitotic failure .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "12452772"}
{"sentence": "Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies . Therefore , we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor ( ER)-negative breast epithelial cell line , MCF-10A . Cells were chronically exposed to a low-level arsenite ( 500nM ) for up to 24weeks . Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells ( SCs ) were examined . After 24weeks , chronic arsenic-exposed breast epithelial ( CABE ) cells showed increases in secreted MMP activity , colony formation , invasion , and proliferation rate , indicating an acquired cancer cell phenotype . These CABE cells presented with basal-like breast cancer characteristics , including ER-\u03b1 , HER-2 , and progesterone receptor negativity , and overexpression of K5 and p63 . Putative CD44(+)/CD24(-/low) breast SCs were increased to 80% over control in CABE cells . CABE cells also formed multilayer cell mounds , indicative of loss of contact inhibition . These mounds showed high levels of K5 and p63 , indicating the potential presence of cancer stem cells ( CSCs ) . Epithelial-to-mesenchymal transition occurred during arsenic exposure . Overexpression of aromatase , a key rate-limiting enzyme in estrogen synthesis , occurred with arsenic starting early on in exposure . Levels of 17\u03b2-estradiol increased in CABE cells and their conditioned medium . The aromatase inhibitor letrozole abolished arsenic-induced increases in 17\u03b2-estradiol production and reversed cancer cell phenotype . Thus , chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs . Arsenic appears to transform breast epithelia through overexpression of aromatase , thereby activating oncogenic processes independent of ER .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "24068038"}
{"sentence": "We analyzed several factors which could influence the immunogenicity of colon tumor cells , using a series of clones derived from a single chemically induced rat adenocarcinoma cell line . These clones display variable tumorigenic potential in syngeneic immunocompetent animals , and it has been established that in this model the tumorigenicity of the cells depends on their ability to escape immune surveillance . The results show an absence of relationship between tumorigenicity and expression of MHC-class-I antigens , cell adhesion to rat fibroblasts or fibroblast extracellular matrix . The secretion of latent and active TGF beta I appeared to be quite variable from one clone to the other , but was unrelated to tumorigenicity . Unexpectedly , some regressive clones produced elevated levels of this cytokine , suggesting that in this model , spontaneous secretion of TGF beta I is not sufficient to impair the immune system of the host . In contrast , the more tumorigenic clones were more resistant than less tumorigenic ones to cytotoxicity mediated by NK or LAK cells . They also showed arrest of cell proliferation after reaching confluence , something not observed in the less tumorigenic clones . Finally , the strongest relationship with tumorigenicity was found for expression of blood-group carbohydrate antigens . Increased expression of blood-group-H antigen and , conversely , decreased expression of beta-galactoside precursors of this antigen correlated with increased tumorigenicity .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1459734"}
{"sentence": "It has been shown that injecting a suspension of IFN-\u03b3-secreting tumor cells results in their rejection . This effect has been attributed to IFN-\u03b3 preventing tumor stroma formation but not to a direct effect on the cancer cells . However , it is not known , which influence IFN-\u03b3 has on tumors with an established stroma . To address this question , the plasmacytoma cell line J558L was transduced with a vector allowing doxycycline-inducible IFN-\u03b3 gene expression . After the injection of the tumor cells into mice , IFN-\u03b3 was induced at different time points . Tumors did not grow when inducing IFN-\u03b3 immediately after tumor cell inoculation , while approximately half of the tumors were rejected when IFN-\u03b3 was induced in early established tumors within 2 weeks . Induction of IFN-\u03b3 2-3 weeks after tumor cell inoculation was less efficient ( 0-17% rejection ) . IFN-\u03b3 induction in established tumors led to a reduction of CD146(+) endothelial cells and massive necrosis . Together , we show that vascularized tumors can be rejected by local IFN-\u03b3 expression , but that rejection of established tumors was less efficient over time . This suggests that transplanted tumors became less susceptible to local IFN-\u03b3 treatment the better they are established .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "20333679"}
{"sentence": "Multivitamin preparation ( MVP ) is part of total parenteral nutrition given to premature infants . Photoactivated MVP carries an important load in peroxides , but their cellular effects have not yet been determined . We hypothesized that these peroxides may elicit a DNA-damage response . We found that photoactivation of MVP and the resulting peroxide production were time-dependent and required the simultaneous presence of ascorbic acid and riboflavin . Cells treated with photoactivated MVP showed strongly stimulated poly(ADP-ribosyl)ation , an early DNA-damage response in mammals . Poly(ADP-ribosyl)ation stimulation was dependent on the presence of ascorbic acid and riboflavin in the photoactivated MVP . It did not occur in the presence of a specific PARP inhibitor nor in mouse fibroblasts deficient in PARP-1 . Photoactivated MVP was able to induce single- and double-strand breaks in DNA , with a predominance of single-stand breaks . The presence of double-strand breaks was further confirmed using a 53PB1 focus analysis . Finally , photoactivated MVP was shown to be toxic to human cells and induced caspase-independent cell death . These results suggest that photoactivated MVP carries an important toxic load able to damage DNA and induce cell death . This study also emphasizes the importance of protecting MVP solution from light before use in preterm infants .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "20100566"}
{"sentence": "PURPOSE To develop PEGylated multi-walled carbon nanotubes as a sustained release drug delivery system . METHODS Oxaliplatin was incorporated into inner cavity of PEGylated multi-walled carbon nanotubes ( MWCNT-PEG ) using nano-extraction . Oxaliplatin release rates from MWCNT-PEG-Oxaliplatin were investigated using dialysis tubing . Cytotoxicity of oxaliplatin , MWCNT-Oxaliplatin and MWCNT-PEG-Oxaliplatin were evaluated in HT29 cell by MTT assay , Pt-DNA adducts formation , \\u03b3-H2AX formation and cell apoptosis assay . RESULTS Loading of oxaliplatin into MWCNT-PEG was Sustained release occurred to MWCNT-PEG-Oxaliplatin , with only 34% of oxaliplatin released into medium within 6h . In MTT assay , MWCNT-PEG-Oxaliplatin showed slightly decreased cytotoxic effect when cell viability was assessed at 12 and 24h . A drastic increase of cytotoxicity was found when cell viability was assessed at 48 and 96h . Pt-DNA adducts formation , \\u03b3-H2AX formation and cell apoptosis assay results showed the same trend as the MTT assay , suggesting sustained-release for MWCNT-Oxaliplatin and MWCNT-PEG-Oxaliplatin formulations . CONCLUSIONS PEGylated multi-walled carbon nanotubes can be used as sustained release drug delivery system , thus remarkably improving cytotoxicity of oxaliplatin on HT-29 cells .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22992831"}
{"sentence": "Aims : RAS-induced tumorigenesis has been suggested to follow a three-stage model consisting of an initial RAS activation , senescence induction , and evasion of p53-dependent senescence checkpoints . While reactive oxygen species ( ROS ) act as second messengers in RAS-induced senescence , they are also involved in oncogenic transformation by inducing proliferation and promoting mutations . In the current work , we investigated the role of extracellular superoxide dismutase ( SOD3 ) in RAS-induced senescence and immortalization in vitro and in vivo . We used a mouse embryonic fibroblast ( MEF ) primary cell model together with immortalized and transformed human cell lines derived from papillary and anaplastic thyroid cancer . Results : Based on our data , sod3 RNA interference in H-RasV12-transduced cells markedly inhibited cell growth , while sod3 over-expression in MEFs initially caused a proliferative burst followed by the activation of DNA damage checkpoints , induction of p53-p21 signal transduction , and senescence . Subsequently , sod3-transduced MEF cells developed co-operative p21-p16 down-regulation and acquired transformed cell characteristics such as increased telomerase activity , loss of contact inhibition , growth in low-nutrient conditions , and in vivo tumorigenesis . Interestingly , as reported previously with RAS , we showed a dose-dependent response to SOD3 in vitro and in vivo involving transcriptional and non-transcriptional regulatory mechanisms . Innovation : SOD3 may mediate H-RasV12-induced initiation of primary cell immortalization . Conclusions : Our results indicate that SOD3 influences growth signaling in primary and cancer cells downstream of the ras oncogene and could serve as a therapy target at an early tumorigenesis phase .", "label": [0, 0, 0, 1, 1, 1, 0, 0, 1, 1], "id": "24328532"}
{"sentence": "A rare immunohistochemical study using 28 surgical sections of human chondrosarcoma revealed that 67.9% of tumour cells had weak ( 10-40% ) or strong ( >40% ) positive immunoreaction for peroxisome proliferator-activated receptor-gamma . The expression of peroxisome proliferator-activated receptor-gamma mRNA and protein in human chondrosarcoma cell line OUMS-27 was also determined by reverse transcription-polymerase chain reaction and immunocytochemistry , respectively . Furthermore , the effects of peroxisome proliferator-activated receptor-gamma ligands on cell proliferation and survival were investigated in OUMS-27 cells . Pioglitazone , a selective ligand for peroxisome proliferator-activated receptor-gamma , and 15-deoxy-Delta(12,14)-prostaglandin J(2) ( 15d-PGJ(2) ) , a putative endogenous ligand for peroxisome proliferator-activated receptor-gamma , inhibited the proliferation of OUMS-27 cells in a dose-dependent manner . The mechanism of cytotoxic effects of 15d-PGJ(2) was via apoptosis as shown by DNA fragmentation using TUNEL stain and DNA ladder formation , and by ultrastructural analysis using transmission electron microscopy . Flow-cytometric analysis using annexin-V-fluorescein and propidium iodide detected the early change of apoptosis , as well as necrosis of OUMS-27 cells at 4 h after co-incubation with 15d-PGJ(2) . These results suggest that peroxisome proliferator-activated receptor-gamma may play a significant role in the pathogenesis of chondrosarcoma , and peroxisome proliferator-activated receptor-gamma ligands , especially 15d-PGJ(2) , may be of therapeutic value in the treatment of human chondrosarcoma .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "11953889"}
{"sentence": "Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy . Therefore , there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response . Recently , several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer . In order to explore the predictive value of inflammation in breast cancer patients , we measured the inflammatory biomarkers serum ferritin and C-reactive protein ( CRP ) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival . The elevation in pre-treatment serum ferritin ( >250 ng/ml ) or CRP ( >7.25 mg/l ) was a significant predictor of reduced progression-free survival and shorter overall survival . When patients were stratified based on their serum ferritin and CRP levels , patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy . Therefore , the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy . Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23300545"}
{"sentence": "The present study investigates extracts of Neuolaena lobata , an anti-protozoan ethnomedicinal plant of the Maya , regarding its anti-neoplastic properties . Firstly , extracts of increasing polarity were tested in HL-60 cells analyzing inhibition of cell proliferation and apoptosis induction . Secondly , the most active extract was further tested in anaplastic large cell lymphoma ( ALCL ) cell lines of human and mouse origin . The dichloromethane extract inhibited proliferation of HL-60 , human and mouse ALCL cells with an IC50 of 3.7 and 2.4\u00b5g/ml , respectively and arrested cells in the G2/M phase . The extract induced the checkpoint kinases Chk1 and Chk2 and perturbed the orchestrated expression of the Cdc25 family of cell cycle phosphatases which was paralleled by the activation of p53 , p21 and downregulation of c-Myc . Importantly , the expression of NPM/ALK and its effector JunB were drastically decreased , which correlated with the activation of caspase 3 . Subsequently also platelet derived growth factor receptor \\u03b2 was downregulated , which was recently shown to be transcriptionally controlled by JunB synergizing with ALK in ALCL development . We show that a traditional healing plant extract downregulates various oncogenes , induces tumor suppressors , inhibits cell proliferation and triggers apoptosis of malignant cells . The discovery of the ' Active Principle(s) ' is warranted .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23135783"}
{"sentence": "The DNA repair protein Ku70 is a key player in chemoresistance to anticancer agents ( e.g. , etoposide ) or radioresistance . The responses of different organs to radiation vary widely and likely depend on the cell population in the organs . Previously , we established and characterized Ku70-deficient murine lung epithelial ( Ku70 -/- MLE ) cells and found that these cells are more sensitive than Ku70 +/- MLE cells ( control cells ) to X-irradiation , as determined by clonogenic survival assay ; however , the mechanism underlying this sensitivity remains unclear . In this study , we examined the mechanism by which X-irradiation triggers the death of Ku70 -/- MLE cells . Our results showed that Ku70 -/- MLE cells were more sensitive to radiation-induced apoptosis than control cells , although X-irradiation activated caspase-3 and caspase-7 , and cleaved PARP in both cell lines . We also examined the expression level of phosphorylated H2AX ( \\u03b3H2AX ) , which is a marker of DSB , and observed the phosphorylation of H2AX and the elimination of \\u03b3H2AX in both cell lines after X-irradiation . The elimination in Ku70 -/- MLE cells was slower than that in control cells , suggesting that DSB repair activity in the Ku70 -/- MLE cells is lower than that in control cells . These findings suggest that Ku70 might play a key role in the inhibition of apoptosis through the DSB repair pathway in lung epithelial cells . Our findings also suggest that these cell lines might be useful for the study of Ku70 functions and the Ku70-dependent DSB repair pathway in lung epithelial cells .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23149547"}
{"sentence": "Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage . Using mice with an intestinal epithelial cell ( IEC)-specific p53 deletion , we demonstrate that loss ofp53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis . Whereas p53 controls DNA damage and IEC survival during the initiation stage , loss of p53 during tumor progression is associated with increased intestinal permeability , causing formation of an NF-\u03baB-dependent inflammatory microenvironment and the induction of epithelial-mesenchymal transition . Thus , we propose a p53-controlled tumor-suppressive function that is independent of its well-established role in cell-cycle regulation , apoptosis , and senescence .", "label": [1, 0, 0, 1, 1, 0, 0, 1, 0, 1], "id": "23273920"}
{"sentence": "We used cDNA-based genomic microarrays to examine DNA copy number changes in a panel of prostate tumors and found a previously undescribed amplicon on chromosome 17 containing a novel overexpressed gene that we termed prostate cancer gene 17 ( PRC17 ) . When overexpressed in 3T3 mouse fibroblast cells , PRC17 induced growth in low serum , loss of contact inhibition , and tumor formation in nude mice . The PRC17 gene product contains a GTPase-activating protein ( GAP ) catalytic core motif found in various Rab/Ypt GAPs , including RN-Tre . Similar to RN-Tre , we found that PRC17 protein interacts directly with Rab5 and stimulates its GTP hydrolysis . Point mutations that alter conserved amino acid residues within the PRC17 GAP domain abolished its transforming abilities , suggesting that GAP activity is essential for its oncogenic function . Whereas PRC17 is amplified in 15% of prostate cancers , it is highly overexpressed in approximately one-half of metastatic prostate tumors . The potent oncogenic activity of PRC17 is likely to influence the tumorigenic phenotype of these prostate cancers .", "label": [1, 0, 0, 0, 1, 1, 0, 0, 0, 0], "id": "12359748"}
{"sentence": "Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies . Thus , we have recently synthesized multifunctional non-toxic , brain permeable iron chelating compounds , M30 and HLA20 , possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug , monoamine oxidase ( MAO)-B inhibitor , rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator , VK28 . Here , we examined the hepatic regulatory effects of these novel compounds using two experimental approaches : chelation activity and glucose metabolism parameters . The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells . In electron microscopy analysis , M30 was shown to reduce the electron-dense deposits of siderosomes by % , as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells . In vivo studies demonstrated that M30 administration ( 1 mg/kg , P.O. three times a week ) reduced hepatic ferritin levels ; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes , the ob/ob ( leptin(-/-) ) . The results clearly indicate that the novel multifunctional drugs , especially M30 , display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters . Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism , including neurological diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22446839"}
{"sentence": "Background:Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma ( HCC ) . The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance , but such correlation is unclear in sorafenib resistance of HCC.Methods:Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line ( Huh-7R ; derived from sorafenib-sensitive Huh-7 ) were used . The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin . Dichloroacetate ( DCA ) , a pyruvate dehydrogenase kinase ( PDK ) inhibitor , and siRNA of hexokinase 2 ( HK2 ) were used to target relevant pathways of cancer metabolism . Cell viability , mitochondrial membrane potential , and sub-G1 fraction were measured for in vitro efficacy . Reactive oxygen species ( ROS ) , adenosine triphosphate ( ATP ) and glucose uptake were also measured . A subcutaneous xenograft mouse model was used for in vivo efficacy.Results:The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity ( R(2)=0.9067 , among sorafenib-naive cell lines ; P=0.003 , compared between Huh-7 and Huh-7\u2009R ) . DCA reduced lactate production and increased ROS and ATP , indicating activation of oxidative phosphorylation ( OXPHOS ) . DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis ( sub-G1 ( combination vs sorafenib ) : Hep3B , 65.4\u00b18.4% vs 13\u00b12.9% ; Huh-7\u2009R , 25.3\u00b1 5.7% vs 4.3\u00b11.5% ; each P<0.0001 ) , whereas siRNA of HK2 did not . Sorafenib ( 10\u2009mg\u2009kg(-1) per day ) plus DCA ( 100\u2009mg\u2009kg(-1) per day ) also resulted in superior tumour regression than sorafenib alone in mice ( tumour size : -87% vs -36% , P<0.001).Conclusion:The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity , and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.British Journal of Cancer advance online publication , 20 December 2012 ; doi:10.1038/bjc.2012.559 www.bjcancer.com .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 1], "id": "23257894"}
{"sentence": "We investigated the priming effect and mechanism of granulocyte colony-stimulating factor ( G-CSF ) in chemotherapy with low-dose Ara-C and VP-16 for acute myeloid leukemia . We analyzed cell proliferation , apoptosis , and cell cycle in vitro using leukemia cell lines 32Dcl3 , U937 , HL-60 , and Ba/F3 . Cell proliferation assays were performed using the Trypan Blue dye exclusion method . For detection of apoptosis , the Annexin V-binding capacity of treated cells was examined by flow cytometry . To evaluate the cell cycle , we used an FITC BrdU Flow kit and conducted analysis by flow cytometry . The combination of Ara-C and VP-16 significantly enhanced the observed effects compared with those of Ara-C or VP-16 alone . Concurrent administration of G-CSF further reduced the cell number and viability of 32Dcl3 and U937 cells , but not of HL-60 and Ba/F3 cells . Apoptotic cells were significantly increased in number by the addition of G-CSF to 32Dcl3 and U937 cells , while G-CSF had no significant effect on HL-60 and Ba/F3 cell lines . The addition of G-CSF significantly decreased the percentage of G0/G1-phase cells and significantly increased that of S-phase cells among 32Dcl3 and U937 cells . No significant effect was observed for HL-60 and Ba/F3 cells . An enhancement was confirmed for the combination of Ara-C , VP-16 , and G-CSF for 32Dcl3 and U937 cells but not for HL-60 and Ba/F3 cells . It was thought that this difference was a result of different responses to G-CSF . G-CSF potentiates Ara-C- and VP-16-induced cytotoxicities through apoptosis induction by mobilizing resting G0-G1-phase cells into S phase .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "21123967"}
{"sentence": "The flavonoid naringin is a polyphenolic compound that naturally occurs in citrus . Patients with cancer generally present features of malnutrition and cachexia . Levels of the proinflammatory cytokines tumor necrosis factor \u03b1 ( TNF-\u03b1 ) and interleukin-6 ( IL-6 ) are raised in patients with cancer . This study was designed to analyze the in vivo effect of naringin in the therapeutic treatment of rats bearing Walker 256 carcinosarcoma ( W256 ) . Rats were treated intraperitoneally with different doses of naringin ( 10 , 25 and 35 mg/kg ) , for 50 days . At 25 mg/kg , naringin inhibited tumor growth by With this treatment , TNF-\u03b1 and IL-6 levels decreased ( p<0.05 ) in comparison with the control . In addition , two rats presented complete tumor regression . Inhibition of tumor growth , survival increase and the reduction of TNF-\u03b1 and IL-6 levels in rats bearing W256 treated with naringin strongly suggest that this compound has potential as an anticarcinogenic drug .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22213297"}
{"sentence": "This article describes the leading steps to develop an assay of DNA damage for the marine amphipod Gammarus locusta , using agarose gel electrophoresis ( AGE ) . To test the sensitivity and feasibility of the AGE technique , X-ray assays were performed with naked DNA and with live amphipods . These positive controls demonstrated the effectiveness of the AGE technique to not only discriminate distinct levels of DNA strand breakage in a dose-dependent manner , but also to identify and quantify the type of strand breakage induced . It was also shown that it is possible to detect DNA damage using whole-body DNA extracts from amphipods . To explore the potential of this technique for use in ecotoxicological studies with amphipods , a 96-h waterborne-copper toxicity test was performed . Copper-induced DNA strand breakage was first observed after 24 h of exposure , and was recorded again at 96 h , at a copper concentration of 20 microg l(-1) . The absence of strand breakage after 48 h of exposure is discussed in the light of the underlying mechanisms of copper toxicity and DNA repair . These studies demonstrated the feasibility of including DNA damage as a biomarker in ecotoxicological studies with amphipods . Information gained from the use of this biomarker would help with the interpretation of chronic toxicity tests and would contribute to our understanding of the impact of genotoxic insult in marine invertebrates , particularly crustaceans .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12581481"}
{"sentence": "Coronavirus envelope ( E ) proteins are short ( residues ) polypeptides that contain at least one transmembrane ( TM ) domain and a cluster of 2-3 juxtamembrane cysteines . These proteins are involved in viral morphogenesis and tropism , and their absence leads in some cases to aberrant virions , or to viral attenuation . In common to other viroporins , coronavirus envelope proteins increase membrane permeability to ions . Although an NMR-based model for the TM domain of the E protein in the severe acute respiratory syndrome virus ( SARS-CoV E ) has been reported , structural data and biophysical studies of full length E proteins are not available because efficient expression and purification methods for these proteins are lacking . Herein we have used a novel fusion protein consisting of a modified \\u03b2-barrel to purify both wild type and cysteine-less mutants of two representatives of coronavirus E proteins : the shortest ( 76 residues ) , from SARS-CoV E , and one of the longest ( 109 residues ) , from the infectious bronchitis virus ( IBV E ) . The fusion construct was subsequently cleaved with cyanogen bromide and all polypeptides were obtained with high purity . This is an approach that can be used in other difficult hydrophobic peptides .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22819936"}
{"sentence": "In human colorectal adenomas or polyps , cyclooxygenase-2 is expressed predominantly by stromal ( or interstitial ) macrophages . Therefore , we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions . We report that macrophages can promote tumorigenic progression of intestinal epithelial cells ( evidenced by decreased cell-cell contact inhibition , increased proliferation and apoptosis , gain of anchorage-independent growth capability , decreased membranous E-cadherin expression , up-regulation of cyclooxygenase-2 expression , down-regulation of transforming growth factor-beta type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-beta(1) ) in a paracrine , cyclooxygenase-2-dependent manner . Pharmacologically relevant concentrations ( 1-2 microM ) of a selective cyclooxygenase-2 inhibitor had no detectable , direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression . Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer ( and other gastro-intestinal epithelial malignancies , which arise on a background of chronic inflammation , such as gastric cancer ) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce anti-neoplastic effects in vitro and in vivo .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 1], "id": "12370807"}
{"sentence": "Cell division and apoptosis are two crucial components of tumor biology and the importance of increased cell proliferation and reduced cell death have made them valid therapeutic targets . The plant kingdom is a relatively underexploited cache of novel drugs , and crude extracts of plants are known for their synergistic activity . The present study assessed the anti-proliferative activity of the medicinal plant Centrosema pubescens Benth . Centrosema pubescens dichloromethane extract ( CPDE ) inhibited the proliferation of HL-60 ( promyelocytic acute leukaemia ) cells with an IC\u2085\u2080 value of 5 \u03bcg/ml . Further studies also showed that CPDE induces growth arrest at the G1 phase and specifically down-regulates the expressions of cyclin E and CDK2 and up-regulates p27(CKI) levels . These events apparently lead to the induction of apoptosis , which was demonstrated qualitatively by a DNA fragmentation assay and propidium iodide staining . Quantitative assessment of the effective arrest of the cell cycle and of apoptosis was confirmed by flow cytometry . CPDE exhibited negligible cytotoxicity even at the highest dose tested ( 100 \u03bcg/ml ) in both normal peripheral blood mononuclear cells and in an in vitro model ( HL-60 ) . Our results strongly suggest that CPDE arrests the cell cycle at the G1 phase and triggers apoptosis by caspase activation .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 0, 0], "id": "21061467"}
{"sentence": "Acidosis commonly observed in solid tumors like pancreatic cancer promotes genetic instability and selection of a more malignant phenotype of cancer cells . Overexpression or activation of integral membrane proteins mediating H+ efflux may contribute to extracellular acidification . Neurotensin ( NT ) induces intracellular alkalinization and stimulates interleukin-8 production in pancreatic cancer cells and , as demonstrated here , the stable NT analog Lys(8)-psi-Lys(9)NT(8-13) enhances the amiloride-sensitive , Na+-dependent transmembrane H+ flux by a factor of 2.05+/-0.28 and 2.69+/-0.07 in BxPC-3 and PANC-1 pancreatic cancer cells , respectively , by phosphorylation of the Na+/H+ exchanger 1 ( NHE1 ) . Human genome-wide gene expression analysis was performed to detect effects of Lys(8)-psi-Lys(9)NT(8-13) on BxPC-3 cells . Results indicated upregulation of genes involved in regulation of NHE1 , hypoxic response and glycolysis in response to Lys(8)-psi-Lys(9)NT(8-13) even under normoxic conditions . Therefore , our findings suggest that growth factors like NT may be implicated in the early progression of pancreatic cancer by localized acidification and induction of an aerobic glycolytic phenotype with higher metastatic potential in small cell aggregates .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20138826"}
{"sentence": "Mode of action ( MOA ) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment . Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models . An MOA analysis , consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment , was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium ( Cr(VI) ) in drinking water . Based on review of the literature , key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract , absorption of Cr(VI) into the intestinal epithelium , oxidative stress and inflammation , cell proliferation , direct and/or indirect DNA modification , and mutagenesis . Although available data generally support the plausibility of these key events , several unresolved questions and data gaps were identified , highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range . Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species . This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "20947717"}
{"sentence": "Bisphosphonates ( BPs ) are the current standard of care for bone lesions in patients with multiple myeloma ( MM ) but they are associated with a number of side effects such as osteonecrosis of the jaw . The exact mechanisms of osteonecrosis are not elucidated , and its physiopathology is based on several hypotheses such as a decrease in bone remodeling or an inhibitory effect on angiogenesis . The aim of our study was to investigate the mechanism involved in the pathogenesis of osteonecrosis . We examined the apoptosis of circulating endothelial progenitor cells in MM subjects before and after BP treatment and in osteonecrosis patients using a flow-cytometric analysis . Our data showed an increase in endothelial cell apoptosis in MM patients after BP administration and in osteonecrosis subjects . Our study seems in agreement with the hypothesis that BPs can inhibit angiogenesis interfering with endothelial cell proliferation and survival , leading to loss of blood vessels and avascular necrosis .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "20639624"}
{"sentence": "BACKGROUND Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health . We focus on the longest living rodent , the naked mole-rat . This mouse-sized mammal lives times longer than do mice and , despite high levels of oxidative damage evident at a young age , it is not only very resistant to spontaneous neoplasia but also shows minimal decline in age-associated physiological traits . OBJECTIVES We assess the current status of stress resistance and longevity , focusing in particular on the molecular and cellular responses to cytotoxins and other stressors between the short-lived laboratory mouse and the naked mole-rat . RESULTS Like other experimental animal models of lifespan extension , naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat , heavy metals , DNA-damaging agents and xenobiotics , showing LD(50) values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice . Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage . Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity , and this increases even further in response to toxins . CONCLUSION Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage , augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity . These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat . Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22572398"}
{"sentence": "The increasing evidence supported the role of Enhancer of Zeste Homolog 2 ( EZH2 ) in the cancer development and progression . However , its precise role in the tumorigenesis of Nasopharyngeal Carcinoma ( NPC ) remains to be elucidated . EZH2 was depleted by retroviral infection in the NPC cells ( HK-1 , CNE-2 , CNE-1 and C666-1 ) . The degree of EZH2 knockdown was then assessed by real-time quantitative PCR and Western Blot analysis . Cell proliferation was assessed using the soluble tetrazolium salt ( MTS ) cell proliferation assay , and cell cycle was measured by FACS test . The methylation status of p16(INK4a )was determined by bisulphate treatment of the DNA , followed by MSP . EZH2 was over-expressed in NPC cells , and the expression in undifferentiated-derived NPC cells ( CNE-1 , C666-1 ) was more significant than differentiated-derived NPC cells ( HK-1 , CNE-2 ) . EZH2 was successfully depleted after retroviral infection in C666-1 cells , and the EZH2 depletion could inhibit the proliferation and arrested G1/S phase of NPC cells . In addition , both mRNA and protein levels of p16(INK4a) increased significantly in presence of EZH2 depletion . The further Methylation-Specific Polymerase Chain Reaction ( MSP ) assay suggested that over-expressed EZH2 may contribute to the reduction of p16(INK4a) expression by hyper methylating its promoter . EZH2 is overexpressed in NPC and reduces expression of p16(INK4a) by influencing methylation , opening therapeutic options .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23289480"}
{"sentence": "OBJECTIVES Toxicity caused by pharmacological and chemical substances , including carbon tetrachloride ( CCl(4) ) , is a major pathological factor for liver injury . Therefore , strategies to prevent toxicity are needed for maintaining a healthy liver . This study was designed to determine whether recombinant bovine pancreatic trypsin inhibitor ( rBPTI ) , a non-specific serine protease inhibitor , prevents CCl(4)-induced liver injury in mice . METHODS Mice were treated with CCl(4) in the presence or absence of co-treatment with rBPTI . Liver sections were prepared for histopathological assessment . Liver function was evaluated by detecting serum levels of alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) and liver index . Liver oxidative stress and inflammation were examined by detecting the liver malondialdehyde level and glutathione and superoxide dismutase activity , and serum tumour necrosis factor-alpha level , respectively . KEY FINDINGS CCl(4) induced hepatocyte necrosis , inflammatory cell infiltration and fatty degeneration , which were ameliorated by co-treatment with rBPTI in a concentration-dependent manner . Furthermore , rBPTI prevented CCl(4)-induced disruption of liver function . Importantly , rBPTI reduced CCl(4)-induced liver oxidative stress response and pro-inflammatory cytokine production . CONCLUSIONS These results indicated that rBPTI exerted a protective effect on CCl(4)-induced liver injury in mice . Thus , rBPTI may have potential application for prevention of liver injury induced by metabolism of drugs and toxic substances .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "20487216"}
{"sentence": "Sonodynamic therapy ( SDT ) has shown great potential in target cancer therapy , but it induced cell death modes hasn't been fully investigated . This study was to examine autophagic and apoptotic responses to protoporphyrin IX ( PpIX ) mediated SDT in murine leukemia L1210 cells . After SDT , the occurrence of autophagy was identified by morphological observation and biochemical analysis . Meanwhile , the mitochondria dependent apoptosis pathway was examined to participate in SDT induced cell death . The relationship between autophagy and apoptosis was further investigated by applying pharmacological inhibition studies , which indicated that impairment of autophagy enhanced the anti-tumor effect of SDT through induction of apoptosis and necrosis , while caspase inhibition didn't affect autophagic vacuoles formation or protect SDT induced cytotoxicity . The findings supported that autophagic vacuoles formed upstream and independently from caspase-dependent cell death . Additionally , the possible mechanism of SDT-induced autophagy was evaluated by measurement of ROS ( reactive oxygen species ) formation . Result suggested ROS play important role in initiating autophagy , possibly through the sono-damaged mitochondria being enclosed by autophagic vacuoles . All together , these data indicate that autophagy may be cytoprotective in our experimental system , and point to an important insight into how autophagy inhibitors , in combination with SDT may contribute a regimen for cancer therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23280101"}
{"sentence": "BACKGROUND Adenosine receptors ( A1 , A2A , A2B , A3 ) play an important role in the regulation of growth , proliferation and death of cancer and normal cells . We recently showed the expression profile of A2A and A2B receptors in normal and tumor breast tissues . In the present study , we used semiquantitative RT-PCR to measure the A1 and A3 gene expression levels in normal and tumor breast tissues . METHODS Breast tumors ( n = 18 ) and non-neoplastic mammary tissues ( n = 10 ) were collected and histologically confirmed to be neoplastic or non-neoplastic , respectively . Total RNA was extracted and reverse transcribed into cDNA , and PCR was performed under optimized condition for each receptor subtype . Amplification of beta-actin mRNA served as control for RT-PCR . The PCR products were separated on 1.7% agarose gels . The intensity of the bands was quantitated with ImageJ software after normalization against beta-actin expression . RESULTS All breast tumor and normal tissue specimens expressed A1 and A3 adenosine receptor transcripts . However , we observed that the expression level of the A3 receptor in tumor tissues was 1.27-fold that of normal tissues , whereas there was no significant difference between the expression levels of A1 in normal and tumor tissues . CONCLUSIONS Interestingly , the results of the present study indicate that breast tumors exhibit a higher level of A3 transcripts ( than normal tissues ) and support the possible key role of A3 adenosine receptor in tumor development . However , further studies based on real-time quantitative RT-PCR are needed to identify the exact gene expression levels .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22495714"}
{"sentence": "The CO(2) laser has been used extensively in dermatological surgery over the past 30 years and is now recognised as the gold standard for soft tissue vaporization . Considering that the continuous wave CO(2) laser delivery system and the newer \" superpulsed \" and scanned CO(2) systems have progressively changed our practice and patient satisfaction , a long range documentation can be useful . Our experience has demonstrated that the use of CO(2) laser involves a reduced healing time , an infrequent need for anaesthesia , reduced thermal damage , less bleeding , less inflammation , the possibility of intra-operative histologic and/or cytologic examination , and easy access to anatomically difficult areas . Immediate side effects have been pain , erythema , edema , typically see with older methods , using higher power . The percentage of after-treatment keloids and hypertrophic scars observed was very low ( especially upon the usage of lower parameters . The recurrence of viral lesions ( condylomas and warts ) have been not more frequent than those due to other techniques . Tumor recurrence is minor compared with radiotherapy or surgery . This method is a valid alternative to surgery and/or diathermocoagulation for microsurgery of soft tissues . Our results are at times not consistent with those published in the literature , stressing the concept that multicentric studies that harmonization methodology and the patient selection are vital .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22593693"}
{"sentence": "The phosphorylated form of histone H2AX ( \\u03b3-H2AX ) forms immunohistochemically detectable foci at DNA double strand breaks . In peripheral blood mononuclear cells ( PBMCs ) derived from leukapheresis from patients enrolled in the Baltimore Longitudinal Study of Aging , \\u03b3-H2AX foci increased in a linear fashion with regards to age , peaking at years . The relationship between the frequency of \\u03b3-H2AX foci and age-related pathologies was assessed . We found a statistically significant ( p = 0.023 ) 50% increase in foci in PBMCs derived from patients with a known history of vitamin D deficiency . In addition , there were trends toward increased \\u03b3-H2AX foci in patients with cataracts ( 34% increase , p<0.10 ) and in sleep apnea patients ( 44% , p<0.10 ) . Among patients \\u226557 y/o , we found a significant ( p = 0.037 ) 36% increase in the number of \\u03b3-H2AX foci/cell for patients with hypertension compared to non-hypertensive patients . Our results support a role for increased DNA damage in the morbidity of age-related diseases. \\u03b3 -H2AX may be a biomarker for human morbidity in age-related diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23029205"}
{"sentence": "Human NEIL2 , one of five oxidized base-specific DNA glycosylases , is unique in preferentially repairing oxidative damage in transcribed genes . Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line . This prompted us to screen for NEIL2 variants in lung cancer patients ' genomic DNA . We identified several polymorphic variants , among which R103Q and R257L were frequently observed in lung cancer patients . We then characterized these variants biochemically , and observed a modest decrease in DNA glycosylase activity relative to the wild type ( WT ) only with the R257L mutant protein . However , in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair ( BER ) proteins ( PNKP , Pol\\u03b2 , Lig III\\u03b1 and XRCC1 ) or using NEIL2-FLAG immunocomplexes , an decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2 , apparently due to the R257L mutant's lower affinity for other repair proteins , particularly Pol\\u03b2 . Notably , increased endogenous DNA damage was observed in NEIL2 variant ( R257L)-expressing cells relative to WT cells . Taken together , our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22497777"}
{"sentence": "Background and Objective . The cell cycle is regulated by proteins at different checkpoints , and dysregulation of this cycle plays a role in carcinogenesis . Matrix metalloproteinases ( MMPs ) are enzymes that degrade collagen and promote tumour infiltration . The aim of this study was to evaluate the expression of various cell cycle regulators and MMPs and to correlate such expression with progression and recurrence in patients with stage T1 urothelial carcinoma of the bladder ( UCB ) . Patients and Methods . This population-based cohort study comprised 201 well-characterized patients with primary stage T1 urothelial carcinoma of the bladder . Immunohistochemistry was performed on formalin-fixed material to quantify expression of cell cycle regulators and two MMPs . Results . Normal expression of p53 and abnormal expression of MMP9 were associated with greater risk of tumour recurrence . Also , normal p16 expression was related to a lower risk of tumour progression . MMP2 , p21 , cyclin D1 , and pRb showed no significant results that could estimate progression or recurrence . Conclusions . Normal p16 expression is associated with a lower risk of tumour progression , but immunohistochemistry on cell cycle regulators and MMPs has little value in predicting the prognosis in stage T1 UCB .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23304558"}
{"sentence": "Autophagy , or autophagocytosis , is a selective intracellular degradative process involving the cell's own lysosomal apparatus . An essential component in cell development , homeostasis , repair and resistance to stress , autophagy may result in either cell death or survival . The targeted region of the cell is sequestered within a membrane structure , the autophagosome , for regulation of the catabolic process . A key factor in both autophagosome formation and autophagosome maturation is a protein encoded by the ultraviolet irradiation resistance-associated gene ( UVRAG ) . Conversely , the serine/threonine-specific protein kinase B ( PKB , also known as Akt ) , which regulates survival in various cancers , inhibits autophagy through mTOR activation . We found that Akt1 may also directly inhibit autophagy by down-regulating UVRAG both in a 293T transient transfection system and breast cancer cells stably expressing Akt1 . The UVRAG with mutations at putative Akt1-phosphorylation sites were still inhibited by Akt1 , and dominant-negative Akt1 also inhibited UVRAG expression , suggesting that Akt1 down-regulates UVRAG by a kinase activity-independent mechanism . We showed that Akt1 overexpression in MDA-MB-231 breast cancer cells down-regulated UVRAG transcription . Cells over-expressing Akt1 were more resistant than control cells to ultraviolet light-induced autophagy and exhibited the associated reduction in cell viability . Levels of the autophagosome indicator protein LC3B-II and mRFP-GFP-LC3 were reduced in cells that over-expressing Akt1 . Inhibiting Akt1 by siRNA or reintroducing UVRAG gene rescued the level of LC3B-II in UV-irradiation . Altogether , these data suggest that Akt1 may inhibit autophagy by decreasing UVRAG expression , which also sensitizes cancer cells to UV irradiation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23200933"}
{"sentence": "Transforming growth factor-Beta ( TGF-beta ) is a potent growth inhibitor for several cell types including epithelial cells and hematopoietic progenitor cells . Using a human promonocytic leukemia cell line , THP-1 , we have shown that TGF-beta inhibits their proliferation and promotes differentiation into cells exhibiting macrophage-like properties . Therefore , a key question is whether TGF-beta influences the expression of genes associated with proliferation and/or growth inhibition . TGF-beta treatment of THP-1 cells results in downregulation of expression of c-myc . We also observe that TGF-beta 1-treated cells express reduced levels of the cell cycle regulated histone , H2B , but express elevated levels of an RNA splicing variant of this histone that has been observed to be upregulated in growth inhibited and terminally differentiated cells . In addition , a nuclear protein associated with senescence and withdrawal of cells from the cell cycle , statin , is also expressed by THP-1 cells in response to TGF-beta 1 treatment . These results suggest that TGF-beta 1 is capable of inducing expression of specific nuclear proteins associated with differentiation and/or cessation of proliferation that may result in changes in nuclear organization and altered gene expression . Such changes in nuclear organization may be incompatible with continued proliferation of the cells .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "1469065"}
{"sentence": "UVB is a major cause of nonmelanoma skin cancer in humans . Photochemoprevention represents an important strategy in protecting the skin against the detrimental effects of ultraviolet B ( UVB ) . We investigated the activity of Calluna vulgaris ( Cv ) delivered via a hydrogel on 3 main pathways ( oxidative stress , inflammation , DNA damage ) on skin exposed to multiple doses of UVB in SKH-1 mice . Fifty female mice were divided randomly into 5 groups : control , vehicle , UVB irradiated , Cv + UVB irradiated , and Cv + vehicle + UVB irradiated . The extract was applied topically on the skin in a dose of 4 mg polyphenols/cm2 30 minutes before each UVB ( 240 mJ/cm2 ) exposure over 10 consecutive days . Malondialdehyde , reduced glutathione , tumor necrosis factor-\u03b1 , interleukin-6 , cyclobutane pyrimidine dimer ( CPD ) levels , sunburn cell formation and epidermal thickness , and the number of epidermal cell layers in skin were evaluated 24 hours after the last treatment . UVB increased cytokine levels ( P < 0.001 ) , formation of CPDs ( P < 0.001 ) and sunburn cells ( P < 0.001 ) , and the epidermal thickness and number of epidermal cell layers ( P < 0.001 ) compared with the control group . The topical application of Cv protected the skin against inflammation and DNA damage , as shown by a decreased number of CPDs ( P < 0.001 ) and sunburn cells ( P < 0.001 ) . The administration of Cv via hydrogel may be a viable method for chemoprevention. .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "23339698"}
{"sentence": "BACKGROUND The most deadly form of cancer is not lung or colon , breast or prostate ; it is any cancer that has become metastatic . Mortality due to metastatic melanoma , one of the most aggressive and deadly cancers , has increased steadily over the last several decades . Unfortunately , the arsenal of chemotherapeutic agents available today is most often unsuccessful at extending and improving the life expectancy of afflicted individuals . We sought to identify an effective and nontoxic agent against metastatic melanoma . METHODOLOGY/PRINCIPAL FINDINGS We chose to study Cloudman S-91 mouse melanoma cells ( sub-clone M3 , CCL53.1 ) because these cells are highly aggressive and metastatic , representing one of the deadliest types of cancer . Melanoma cells also had an experimental advantage because their morphology , which is easily monitored , relates to the physiology of metastatic cells and normal melanocytes . We chose to test methyl sulfone as a chemotherapeutic agent for two reasons . Because of its chemical structure , we speculated a potential anti-cancer activity by targeting microtubules . Equally important , methyl sulfone has a well-established safety profile in humans . Surprisingly , we found that malignant melanoma cells exposed to methyl sulfone demonstrated the loss of phenotypes characteristic of malignant cells , and the reemergence of phenotypes characteristic of healthy melanocytes . Briefly , over time methyl sulfone induced contact inhibition , loss of ability to migrate through an extracellular matrix , loss of anchorage-independent growth , proper wound healing followed by contact inhibition , irreversible senescence followed by arborization with melanosomes in arbors as seen in normal melanocytes . CONCLUSIONS/SIGNIFICANCE Methyl sulfone may have clinical potential as a non-toxic agent effective against metastatic melanoma . Additionally , methyl sulfone has promise as a tool to explore molecular mechanisms of metastatic transformation as well as fundamental processes such as cell migration , contact inhibition , wound healing and cellular senescence .", "label": [1, 0, 0, 1, 1, 0, 0, 0, 0, 0], "id": "20694196"}
{"sentence": "Immunosuppression of immunoglobulin synthesis seen in patients with multiple myeloma is in part due to immunosuppressive CD5 positive B cells . In a 13 year longitudinal study of an IgA-deficient blood donor who developed multiple myeloma , the presence of immunosuppressive CD5 positive B cells and T cells preceded the diagnosis of overt multiple myeloma and the appearance of immunosuppressive monocytes . These data argue that certain immune defects may be involved in the development of myeloma and are not simply a consequence of overt malignancy .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1373558"}
{"sentence": "Previous reports showed that treatment with non-steroidal anti-inflammatory agents ( NSAIA ) can alter the growth profile of a variety of tumours . In this study , the effect of NSAIA treatment on the growth of the primary tumour and the appearance of spontaneous pulmonary metastases , was investigated . A mammary adenocarcinoma of non-detected immunogenicity , C7HI , was grafted subcutaneously in the lateral flank of Balb/c mice . Oral treatment with approximately 1 mg kg-1 day-1 piroxicam delayed both tumour growth and the growth of pulmonary metastases . Survival of mice bearing the primary tumour was significantly lengthened by anti-inflammatory treatment . Similarly , in separate experiments , after surgical removal of the primary tumour by day 34 after grafting , the group of mice treated orally with piroxicam also exhibited a higher survival rate than the control group . Upon surgical removal of the primary tumour 34 days after grafting , piroxicam treatment significantly decreased both the number and size of pulmonary metastases . The results of this study lends support to the hypothesis that inhibition or modulation of inflammation may delay tumour organisation and growth . It is suggested that piroxicam treatment may be an appropriate adjunct therapy to delay the appearance of pulmonary metastases and to increase life-expectancy in a host whose primary tumour has to be surgically removed .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1419623"}
{"sentence": "OBJECTIVES To investigate the effects of serotonin and melatonin ( MLT ) on the regulation of malignant growth and the activity of serotonin receptors ( 5HTR1a/-1b ) in prostate cancer ( PCa ) cell lines . MATERIALS AND METHODS In four PCa cell lines ( LNCaP , 22RV1 , PC3 , DU145 ) and two reference cell lines 5HTR1a and -1b , relative mRNA expression levels were assessed . Different serotonin and MLT receptor agonists and antagonists were used in stimulation and inhibition experiments . RESULTS mRNA expression of 5HTR1b was higher than that of 5HTR1a in all PCa cell lines . Serotonin showed a significant growth stimulatory effect in all PCa lines . The 5HTR1a and -1b agonists/antagonists did not significantly affect viability . MLT inhibited viability only in PC3 cells . Similarly , the 5HTR1a antagonist induced apoptotic changes in PC3 cells only at 10(-4)M , while the 5HTR1b antagonist induced necrosis at 10(-4)M in all cell lines . Cell cycle alterations were seen in PC3 and DU145 cells under the influence of the 5HTR1a antagonist . CONCLUSIONS Serotonin receptor antagonists and agonists as well as MLT influence viability and apoptosis of PCa cell lines at supraphysiologic concentrations . In contrast to other reports , our results do not support a regulatory role of serotonin or MLT receptor activation or inhibition in PCa growth .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20234124"}
{"sentence": "Neural stem cells ( NSCs ) are considered to be the cell of origin of glioblastoma multiforme ( GBM ) . However , the genetic alterations that transform NSCs into glioma-initiating cells remain elusive . Using a unique transposon mutagenesis strategy that mutagenizes NSCs in culture , followed by additional rounds of mutagenesis to generate tumors in vivo , we have identified genes and signaling pathways that can transform NSCs into glioma-initiating cells . Mobilization of Sleeping Beauty transposons in NSCs induced the immortalization of astroglial-like cells , which were then able to generate tumors with characteristics of the mesenchymal subtype of GBM on transplantation , consistent with a potential astroglial origin for mesenchymal GBM . Sequence analysis of transposon insertion sites from tumors and immortalized cells identified more than 200 frequently mutated genes , including human GBM-associated genes , such as Met and Nf1 , and made it possible to discriminate between genes that function during astroglial immortalization vs. later stages of tumor development . We also functionally validated five GBM candidate genes using a previously undescribed high-throughput method . Finally , we show that even clonally related tumors derived from the same immortalized line have acquired distinct combinations of genetic alterations during tumor development , suggesting that tumor formation in this model system involves competition among genetically variant cells , which is similar to the Darwinian evolutionary processes now thought to generate many human cancers . This mutagenesis strategy is faster and simpler than conventional transposon screens and can potentially be applied to any tissue stem/progenitor cells that can be grown and differentiated in vitro .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "23045694"}
{"sentence": "Ultraviolet ( UV ) of sunlight is a complete carcinogen that can burn skin , enhance inflammation , and drive skin carcinogenesis . Previously , we have shown that sulforaphane ( SFN ) inhibited chemically induced skin carcinogenesis via nuclear factor ( erythroid-derived 2)-like 2 ( Nrf2 ) and others have shown that broccoli sprout extracts containing high SFN protected against UV-induced skin carcinogenesis in SKH-1 hairless mice . A recent study showed that there was no difference between Nrf2 knockout ( Nrf2 KO ) and Nrf2 wild-type ( WT ) BALB/C mice after exposing to high dose of UVB . Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses , it is relevant to assess the role of Nrf2 for photoprotection against UV . In this context , the role of Nrf2 in UVB-induced skin inflammation in Nrf2 WT and Nrf2 KO C57BL/6 mice was studied . A single dose of UVB ( 300\u2009mJ/cm(2) ) resulted in skin inflammation in both WT and Nrf2 KO ( -/- ) mice ( KO mice ) at 8\u2009h and 8\u2009d following UVB irradiation . In the WT mice inflammation returned to the basal level to a greater extent when compared to the KO mice . SFN treatment of Nrf2 WT but not Nrf2 KO mice restored the number of sunburn cells back to their basal level by 8\u2009d after UVB irradiation . Additionally , UVB-induced short-term inflammatory biomarkers ( interleukin-1\u03b2 and interleukin-6 ) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT . Taken together , our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation , sunburn reaction , and SFN-mediated photoprotective effects in the skin .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21557329"}
{"sentence": "Contact inhibition of locomotion ( CIL ) is the process by which cells stop the continual migration in the same direction after collision with another cell . Highly invasive malignant cells exhibit diminished CIL when they contact stromal cells , which allows invasion of the tissue by tumors . We show that Nm23-H1 is essential for the suppression of Rac1 through inactivation of Tiam1 at the sites of cell-cell contact , which plays a pivotal role in CIL . U87MG cells show CIL when they contact normal glia . In spheroid confrontation assays U87MG cells showed only limited invasion of the glial population , but reduction of Nm23-H1 expression in U87MG cells abrogated CIL resulting in invasion . In U87MG cells , Nm23-H1 is translocated to the sites of contact with glia through association with \\u03b1-catenin and N-cadherin . Mutants of Nm23-H1 , which lacked the binding ability with Tiam1 , or \\u03b1-catenin did not restore CIL . Moreover , the expression of ephrin-B1 in tumor cells disrupted CIL and promoted invasion . As one mechanism , ephrin-B1 inhibits the association of Nm23-H1 with Tiam1 , which contributes for activation of Rac1 . These results indicate a novel function of Nm23-H1 to control CIL , and its negative regulation by ephrin-B1 .", "label": [1, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "22718351"}
{"sentence": "Hepatocyte growth factor ( HGF ) , a mesenchymal-derived factor which regulates growth , motility , and morphogenesis of epithelial and endothelial cells , functions as a hepatotrophic and renotrophic factor for regeneration of the liver and kidney . We have now obtained evidence that transforming growth factor-beta 1 ( TGF-beta 1 ) and glucocorticoids are negative regulators for HGF gene expression . When TGF-beta 1 or dexamethasone was added to cultures of MRC-5 human embryonic lung fibroblasts and HL-60 human promyelocytic leukemic cells , the amount of HGF secreted into the culture medium was inhibited to 30-40% of that of control cultures by 10 ng/ml TGF-beta 1 and to 40-50% by 10(-6) M dexamethasone . The inhibitory effect of TGF-beta 1 and dexamethasone on HGF synthesis in MRC-5 cells was additive , thereby suggesting that TGF-beta 1 and dexamethasone exert effects through distinct mechanisms . Hydrocortisone also inhibited HGF synthesis with the same potency as dexamethasone ; however , testosterone , estriol , and beta-estradiol had no effect . The rate of HGF synthesis in MRC-5 cells , as measured by pulse labeling with [ 35S]methionine and subsequent immunoprecipitation , was suppressed to 30-40% of the control with 10 ng/ml TGF-beta 1 , and to 30-45% by 10(-6) M dexamethasone . HGF mRNA levels in MRC-5 cells and HL-60 cells were dose-dependently suppressed by TGF-beta 1 and dexamethasone ; 10 ng/ml TGF-beta 1 suppressed HGF mRNA levels to 32% and 35% of control culture , respectively , in MRC-5 cells and HL-60 cells , and 10(-6) M dexamethasone suppressed to 43% and 38% , respectively . Thus , TGF-beta 1 and glucocorticoids seem to inhibit HGF synthesis by suppressing the expression of the HGF gene . We propose that a negative regulation of HGF gene expression by TGF-beta 1 or glucocorticoids may be involved in physiological or pathological processes during tissue regeneration .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1459995"}
{"sentence": "Breast cancer constitutes a major health problem for women worldwide . However , its incidence varies between populations and geographical locations . These variations could be diet-related , since there are several carcinogenic compounds in the modern diet , while natural products contain various anti-cancer elements . Several lines of evidence indicate that , in addition to their clear preventive effect , these compounds could also be used as therapeutic agents . In the present report we have shown that oleuropein , a pharmacologically safe natural product of olive leaf , has potent anti-breast cancer properties . Indeed , oleuropein exhibits specific cytotoxicity against breast cancer cells , with higher effect on the basal-like MDA-MB-231 cells than on the luminal MCF-7 cells . This effect is mediated through the induction of apoptosis via the mitochondrial pathway . Moreover , oleuropein inhibits cell proliferation by delaying the cell cycle at S phase and up-regulated the cyclin-dependent inhibitor p21 . Furthermore , oleuropein inhibited the anti-apoptosis and pro-proliferation protein NF-\u03baB and its main oncogenic target cyclin D1 . This inhibition could explain the great effect of oleuropein on cell proliferation and cell death of breast cancer cells . Therefore , oleuropein warrants further investigations to prove its utility in preventing/treating breast cancer , especially the less-responsive basal-like type .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23261678"}
{"sentence": "This study shows the effect of pterostilbene on intracellular neutral lipid accumulation in MCF-7 breast cancer cells leading to growth arrest and autophagy . On exposing the breast cancer cells with 30 \u03bcM pterostilbene for 72 h there was almost 2-folds increase in neutral lipids and triglycerides . Also the phytochemical caused a 4-folds increase in the expression of adipogenic differentiation marker c/EBP\u03b1 . Further , pterostilbene inhibited 3\u03b2-hydroxylsterol-\u0394(7)-reductase , the enzyme which catalyzes the last step conversion of 7-dehydrocholesterol to cholesterol , and thereby causes the intracellular accumulation of the former sterol . These results were associated with over-expression of oxysterol binding protein homologue and liver X receptor ( LXR ) by Pterostilbene also caused a simultaneous increase in the expression autophagic marker proteins Beclin 1 and LC3 II ( microtubule-associated protein 1 light chain 3 ) by approximately 6-folds , which leads to an alternative pathway of autophagy . These effects were observed in association with the loss of mitotic and metastatic potential of MCF-7 cells which was abolished in the presence of catalase ( ROS scavenger ) or 3MA ( autophagic inhibitor ) . Thus the present data shows that the long term exposure to pterostilbene causes growth arrest in MCF-7 cells which may be due to differentiation of the mammary carcinoma cells into normal epithelial cell like morphology and activation of autophagy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22273805"}
{"sentence": "In vitro model systems for studying uterine leiomyomas are limited in that human-derived leiomyoma cells grow poorly in culture compared with normal myometrial cells and begin to senesce early , at approximately passage 10 in our studies . To our knowledge , a good in vitro human-derived cell culturing system for leiomyomas does not exist . In an attempt to fill this void , we have immortalized a uterine leiomyoma cell line by inducing telomerase activity , which allows cells to bypass their normal programmed senescence . Telomerase activity was induced by infecting the target ( uterine leiomyoma and normal myometrial ) cells with a retroviral vector containing hTERT , the gene for the catalytic subunit of telomerase . Subsequent analysis by RT-PCR and the telomeric repeat amplification protocol assay confirmed expression of the inserted gene and induction of telomerase activity in leiomyoma and myometrial cells . Analysis of cells for estrogen receptor-alpha and progesterone receptor proteins by Western blotting showed no change in expression of these proteins between the immortalized and parental leiomyoma and myometrial cells . Both immortalized and parental myometrial and leiomyoma cells expressed the smooth muscle-specific cytoskeletal protein alpha-actin and were negative for mutant p53 protein as evidenced by immunocytochemical staining . The immortalized leiomyoma and myometrial cells showed no anchorage-independent growth , with the exception of a small subpopulation of immortalized leiomyoma cells at a higher passage that did form two to three small colonies ( per 50,000 cells ) in soft agar . None of the immortalized cells were tumorigenic in nude mice . In conclusion , our data show the successful insertion of the hTERT gene into leiomyoma and myometrial cells and the immortalization of these cell lines without phenotypic alteration from the parental cell types ( up to 200 population doublings ) . These cells should help to advance research in understanding the molecular pathways involved in the conversion of a normal myometrial cell to a leiomyoma cell and the mechanisms responsible for the growth of uterine leiomyomas . Answers to these questions will undoubtedly lead to the development of more effective treatment and intervention regimens for clinical cases of uterine leiomyoma .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "12065682"}
{"sentence": "Photodynamic therapy ( PDT ) of hepatic tumours has been restricted owing to the preferential retention of photosensitizers in liver tissue . We therefore investigated interstitial tumour illumination as a means of selective PDT . A piece of colon carcinoma CC531 was implanted in the liver of Wag/Rij rats . Photofrin was administered ( 5 mg kg-1 i.v. ) 2 days before laser illumination . Tumours with a mean ( +/- s.e. ) diameter of 5.7 +/- 0.1 mm ( n = 106 , 20 days after implantation ) were illuminated with 625 nm light , at 200 mW cm-1 from a 0.5 cm cylindrical diffuser and either 100 , 200 , 400 , 800 or 1600 J cm-1 . Control groups received either laser illumination only , Photofrin only or diffuser insertion only . Short-term effects were studied on the second day after illumination by light microscopy and computer-assisted integration of the circumference of damaged areas . Long-term effects were studied on day 36 . To determine the biochemistry of liver damage and function , serum ASAT and ALAT levels were measured on day 1 and 2 , and antipyrine clearance on day 1 . Tumour and surrounding liver necrosis increased with light dose delivered ( P < 0.001 ) . Best long-term results were obtained at 800 J cm-1 with complete tumour remission in 4 out of 6 animals . No deterioration in liver function was found . The results of this study show the ability of interstitial PDT to cause major destruction of tumour tissue in the liver combined with minimal liver damage .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1457339"}
{"sentence": "A better understanding of the underlying mechanisms of DNA repair after exposure to ionizing radiation represents a research priority aimed at improving the outcome of clinical radiotherapy . Because of the close association with DNA double strand break ( DSB ) repair , phosphorylation of the histone H2AX protein ( \u03b3H2AX ) , quantified by immunodetection , has recently been used as a method to study DSB induction and repair at low and clinically relevant radiation doses . However , the lack of consistency in literature points to the need to further validate the role of H2AX phosphorylation in DSB repair and the use of this technique to determine intrinsic radiosensitivity . In the present study we used human mammary epithelial MCF10A cells , characterized by a radiosensitive phenotype due to reduced levels of the Ku70 and Ku80 repair proteins , and investigated whether this repair-deficient cell line displays differences in the phosphorylation pattern of H2AX protein compared to repair-proficient MCF10A cells . This was established by measuring formation and disappearance of \u03b3H2AX foci after irradiating synchronized cell populations with ( 60)Co \u03b3-rays . Our results show statistically significant differences in the number of \u03b3H2AX foci between the repair-deficient and -proficient cell line , with a higher amount of \u03b3H2AX foci present at early times post-irradiation in the Ku-deficient cell line . However , the disappearance of those differences at later post-irradiation times questions the use of this assay to determine intrinsic radiosensitivity , especially in a clinical setting .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "21116096"}
{"sentence": "The Salmonella type III secretion system ( T3SS ) efficiently translocates heterologous proteins into the cytosol of eukaryotic cells . This leads to an antigen-specific CD8 T-cell induction in mice orally immunized with recombinant Salmonella . Recently , we have used Salmonella's T3SS as a prophylactic and therapeutic intervention against a murine fibrosarcoma . In this study , we constructed a recombinant Salmonella strain translocating the immunogenic H-2D(b)-specific CD8 T-cell epitope VILTNPISM ( KDR2 ) from the murine vascular endothelial growth factor receptor 2 ( VEGFR2 ) . VEGFR2 is a member of the tyrosine protein kinase family and is upregulated on proliferating endothelial cells of the tumor vasculature . After single orogastric vaccination , we detected significant numbers of KDR2-tetramer-positive CD8 T cells in the spleens of immunized mice . The efficacy of these cytotoxic T cells was evaluated in a prophylactic setting to protect mice from challenges with B16F10 melanoma cells in a flank tumor model , and to reduce dissemination of spontaneous pulmonary melanoma metastases . Vaccinated mice revealed a reduction of angiogenesis by 62% in the solid tumor and consequently a significant decrease of tumor growth as compared to non-immunized mice . Moreover , in the lung metastasis model , immunization with recombinant Salmonella resulted in a reduction of the metastatic melanoma burden by approximately 60% .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22511934"}
{"sentence": "The 7WD4 and 7PA2 cell lines , widely used as cellular models for Alzheimer's disease ( AD ) , have been used to investigate the effects of amyloid-\\u03b2 protein precursor overexpression and amyloid-\\u03b2 ( A\\u03b2 ) oligomer accumulation on mitochondrial function . Under standard culture conditions , both cell lines , compared to Chinese hamster ovary ( CHO ) control cells , displayed an decrease of O2 respiration as sustained by endogenous substrates . Functional impairment of the respiratory chain was found distributed among the protein complexes , though more evident at the level of complex I and complex IV . Measurements of ATP showed that its synthesis by oxidative phosphorylation is decreased in 7WD4 and 7PA2 cells by this loss being partly compensated by glycolysis ( Warburg effect ) . Compensation proved to be more efficient in 7WD4 than in 7PA2 cells , the latter cell line displaying the highest reactive oxygen species production . The strongest deficit was observed in mitochondrial membrane potential that is almost 40% and 60% lower in 7WD4 and 7PA2 cells , respectively , in comparison to CHO controls . All functional parameters point to a severe bioenergetic impairment of the AD cells , with the extent of mitochondrial dysfunction being correlated to the accumulation of A\\u03b2 peptides and oligomers .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23948918"}
{"sentence": "In spite of numerous advances , the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed . PCH4 , a derivative of n-butylidenephthalide , has been investigated for its anti-tumor effects on oral squamous cell carcinoma ( OSCC ) . The aim of this study was to investigate the anti-tumor mechanism of a potential target gene , Nur77 , in OSCC cells , which can be induced by PCH4 treatment . Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells . When Nur77 translocation was blocked , the degree of tumor apoptosis caused by PCH4 was significantly inhibited ( p\u2009<\u20090.05 ) . Within the MAPK pathway , PCH4 only induced JNK phosphorylation . Furthermore , treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis ( p\u2009<\u20090.05 ) and decreased PCH4-induced Nur77 expression ( p\u2009<\u20090.05 ) . In a xenograft animal model , administration of PCH4 also showed anti-tumor effects . We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4 . These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20809206"}
{"sentence": "In mammalian cells more than 90% of double-strand breaks are repaired by NHEJ . Impairment of this pathway is associated with cell cycle arrest , cell death , genomic instability and cancer . Human diseases such as Nijmegen breakage syndrome , due to mutations in the NBS1 gene , produce defects in resection of double-strand breaks . NBS1 hypomorphic mutant mice are viable , and cells from these mice are defective in S phase and G2/M checkpoints . NBS1 polymorphisms have been associated with increased risk of breast cancer . We previously demonstrated that estradiol protected estrogen receptor ( ER)-positive ( + ) breast cancer cell lines against double-strand breaks and cell death . We now demonstrate that protection from double-strand break damage in ER+ cells is mediated via regulation by c-myc , p53 , CBP and SRC1 coactivators in intron 1 of the NBS1 gene . We concluded that NBS1 is responsible for estradiol-mediated protection from double-strand breaks in ER+ breast cancer cells .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23291854"}
{"sentence": "Cold atmospheric plasma ( CAP ) , a technology based on quasi-neutral ionized gas at low temperatures , is currently being evaluated as a new highly selective alternative addition to existing cancer therapies . Here , we present a first attempt to identify the mechanism of CAP action . CAP induced a robust G2/M increase in two different types of cancer cells with different degrees of tumorigenicity . We hypothesize that the increased sensitivity of cancer cells to CAP treatment is caused by differences in the distribution of cancer cells and normal cells within the cell cycle . The expression of \u03b3H2A.X ( pSer139 ) , an oxidative stress reporter indicating S-phase damage , is enhanced specifically within CAP treated cells in the S phase of the cell cycle . Together with a significant decrease in EdU-incorporation after CAP , these data suggest that tumorigenic cancer cells are more susceptible to CAP treatment .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22957140"}
{"sentence": "In aqueous media , photochemical excitation to S(1) of 3-phenylphenols 4-8 leads to deprotonation of the phenol OH , coupled with protonation of the benzyl alcohol and overall dehydration that delivers zwitterions 17-21 . The zwitterions react with nucleophiles ( CH(3)OH , CF(3)CH(2)OH and ethanolamine ) converting them in high quantum yields to the corresponding adducts and photosolvolysis products ( for photomethanolysis \\u03a6 Zwitterions 20 and 21 were characterized by laser flash photolysis in CH(3)CN-H(2)O ( \\u03c4 and 25 \\u03bcs , respectively ) and the associated quenching rate constants with nucleophiles azide and ethanolamine determined . In vitro studies of antiproliferative activity of the photochemicaly generated QMs and zwitterions formed from 2- , 3- and 4-phenylphenols were carried out on three human cancer cell lines HCT 116 ( colon ) , MCF-7 ( breast ) , and H 460 ( lung ) . Irradiation of cells incubated with 3 , 6 , and 26 showed enhanced antiproliferative activity compared to the cells that were not irradiated .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22212815"}
{"sentence": "Peroxisome proliferator activated receptor \u03b3 ( PPAR\u03b3 ) , a subgroup of ligand-activated nuclear receptors , plays critical roles in cell cycle regulation , differentiation , apoptosis and invasion . PPAR\u03b3 is involved in tumorigenesis and is a potent target for cancer therapy . PPAR\u03b3 transactivation of KLF4 has been demonstrated in various studies ; however , how PPAR\u03b3 regulates KLF4 expression is not clear . In this study , we revealed that PPAR\u03b3 regulates the expression of KLF4 by binding directly to the PPAR response element ( PPRE ) within the KLF4 promoter . The PPRE resided at -1657bp to -1669bp upstream of the KLF4 ATG codon , which is essential for the transactivation of TGZ-induced KLF4 expression . Furthermore , we found that stable silencing of KLF4 obviously suppressed the G1/S arrest and anti-proliferation effects induced by PPAR\u03b3 ligands . Taken together , our data indicated that upregulating KLF4 upon PPAR\u03b3 activation is mediated through PPRE in KLF4 promoter , thus providing further insights into PPAR\u03b3 signal transduction pathway as well as a novel cancer therapeutic strategy .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23275339"}
{"sentence": "Recent studies have highlighted an apparently paradoxical link between self-renewal and senescence triggered by DNA damage in certain cell types . In addition , the finding that TP53 can suppress senescence has caused a re-evaluation of its functional role in regulating these outcomes . To investigate these phenomena and their relationship to pluripotency and senescence , we examined the response of the TP53-competent embryonal carcinoma ( EC ) cell line PA1 to etoposide-induced DNA damage . Nuclear POU5F1/OCT4A and p21cip1 were upregulated in the same cells following etoposide-induced G 2M arrest . However , while accumulating in the karyosol , the amount of OCT4A was reduced in the chromatin fraction . Phosphorylated CHK2 and Rad51/\u03b3H2AX-positive nuclear foci , overexpression of Aurora B kinase and moderate macroautophagy were evident . Upon release from G 2M arrest , cells with repaired DNA entered mitoses , while the cells with persisting DNA damage remained at this checkpoint or underwent mitotic slippage and gradually senesced . Reduction of TP53 using sh- or si-RNA prevented the upregulation of OCT4A and p21cip1 and increased DNA damage . Subsequently , mitoses , micronucleation and senescence were all enhanced after TP53 reduction with senescence confirmed by upregulation of CDKN2A/p16ink4a and increased sa-\u03b2-galactosidase positivity . Those mitoses enhanced by TP53 silencing were shown to be multicentrosomal and multi-polar , containing fragmented and highly deranged chromosomes , indicating a loss of genome integrity . Together , these data suggest that TP53-dependent coupling of self-renewal and senescence pathways through the DNA damage checkpoint provides a mechanism for how embryonal stem cell-like EC cells safeguard DNA integrity , genome stability and ultimately the fidelity of self-renewal .", "label": [0, 0, 0, 1, 1, 1, 0, 0, 0, 0], "id": "23287532"}
{"sentence": "BACKGROUND To assess the potential mechanisms that may underlie increased local failure in triple negative ( TN ) breast cancers , an analysis was performed of the risk of residual carcinoma after lumpectomy with correlation to pathologic factors , including molecular phenotype . METHODS A review of pathologic specimens was performed for women with invasive breast cancer treated with lumpectomy followed by reexcision . Data were collected on age ; tumor size , grade , and nodal stage ; estrogen receptor , progesterone receptor , and human endothelial growth factor receptor 2 ( Her2 ) ; extensive intraductal component ; lymphovascular invasion ; margins ; and reexcision findings . Univariate and multivariate logistic regression analyses were performed to evaluate for associations between pathologic features of the lumpectomy specimen and reexcision findings . Molecular phenotypes were defined by conventionally used immunohistochemical pattern . RESULTS Data were collected on 369 patients with breast cancer . The median age was 57 years , median tumor size was 1.5 cm , 36% had positive margins , 32% had positive lymph nodes , 73.5% had the luminal A subtype , 9.5% had the luminal B subtype , 4.5% were Her2-enriched , and 12.5% were TN . Overall , 32% of patients had invasive cancer in their reexcision specimens , and 51% of those with the TN subtype had residual invasive disease on reexcision compared with 30% to 31% for other subtypes . On univariate analysis , age , tumor size , margin status , lymphovascular invasion , nodal status , and TN subtype were associated with elevated risk of residual invasive cancer . On multivariate analysis using a forward stepwise model , TN subtype maintained significance , with an odds ratio of 3.28 ( P = .002 ) . CONCLUSION TN subtype has a statistically significant association with an increased risk of residual tumor . This suggests the putative increase in the risk of local failure in TN patients may be related to increased residual tumor burden .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22864932"}
{"sentence": "Metastasis is a major cause of death of patients with malignant tumors . Matrix metalloproteinases ( MMPs ) are important for the migration and invasion of various types of cancer cell . Propofol is a known anesthetic agent , widely used for short-term anesthesia and for longer-term sedation . Propofol inhibits the proliferation of a variety of tumor cells , but there is no available information regarding propofol-inhibited migration and invasion of tumor cells in vitro . In this study , we investigated the effects of propofol on the migration and invasion of human lung carcinoma A549 cells . Wound healing assay and Boyden chamber assays indicated that propofol inhibited the migration and invasion of A549 cells in vitro . Gelatin zymographic analysis showed the inhibitory effect of propofol on the activation of expression MMP-2 . Western blot analysis also indicated that propofol suppressed the protein expiration of growth factor receptor-bound protein 2 ( GRB2 ) , Jun N-terminal kinases 1/2 ( p-JNK1/2 ) , p-p38 , MMP-2 and MMP-9 in A549 cells . Results from real-time PCR assay also showed that propofol inhibited the mRNA gene expression of MMP-2 , -7 and -9 , and enhanced that of tissue inhibitor of metalloproteinase 1 ( TIMP1 ) and TIMP2 in A549 cells . Taken together , these data show that propofol inhibits MMP-2 and -9 mRNA and protein expressions , resulting in suppression of lung cancer cell invasion and migration in vitro .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23155249"}
{"sentence": "Deregulation of D-type cyclin-dependent kinases ( CDK4 and 6 ) is widely observed in various human cancers , illustrating their importance in cell cycle control . Like other cyclin-dependent kinases ( CDKs ) , assembly with cyclins is the most critical step for activation of CDK4/6 . As previously reported elsewhere , we observed that the level of cyclinD1-CDK4 complex and its associated kinase activity were significantly low in asynchronously proliferating mouse embryo fibroblasts lacking both p21(Cip1) and p27(Kip1) ( p21/p27-null MEFs ) . These evidences imply that p21(Cip1) and p27(Kip1) CDK inhibitors are ' essential activators ' of cyclin D-kinases . We , however , discovered here that both the assembly and activation of cyclin D1-CDK4 complex occur when quiescent p21/p27-null MEFs were stimulated to re-enter the cell cycle . This mitogen-induced cyclin D1-kinase activity was blocked by overexpression of p16(INK4a) and resulted in the inhibition of S phase entry in p21/p27-null MEFs . Furthermore , ectopic expression of p34(SEI-1) , a mitogen-induced CDK4 binding protein , increased the levels of active cyclinD1-CDK4 complex in asynchronously proliferating p21/p27-null MEFs . Together , our results suggest that there are several independent ways to stimulate the assembly of cyclin D1-CDK4 kinases . Although p21(Cip1) and p27(Kip1) play a role in this process , our results demonstrate that additional mechanisms must occur in G0 to S phase transition .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12444543"}
{"sentence": "Human fibroblasts undergo cellular senescence after a finite number of divisions , in response to the erosion of telomeres . In addition to being terminally arrested in the cell cycle , senescent fibroblasts express genes that are normally induced upon wounding , including genes that remodel the extracellular matrix . We have identified the novel zinc finger protein APA-1 , whose expression increased in senescent human fibroblasts independent of telomere shortening . Extended passage , telomerase-immortalized fibroblasts had increased levels of APA-1 as well as the cyclin-dependent kinase inhibitor p16 . In fibroblasts , APA-1 was modified by the ubiquitin-like protein SUMO-1 , which increased APA-1 half-life , possibly by blocking ubiquitin-mediated degradation . Overexpression of APA-1 did not cause cell cycle arrest ; but , it induced transcription of the extracellular matrix-remodeling genes MMP1 and PAI2 , which are associated with fibroblast senescence . MMP1 and PAI2 transcript levels also increased in telomerase-immortalized fibroblasts that had high levels of APA-1 , demonstrating that the matrix-remodeling phenotype of senescent fibroblasts was not induced by telomere attrition alone . APA-1 was able to transactivate and bind to the MMP1 promoter , suggesting that APA-1 is a transcription factor that regulates expression of matrix-remodeling genes during fibroblast senescence .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 1, 0], "id": "12370286"}
{"sentence": "The secretion of immunosuppressive factors like transforming growth factor-beta ( TGF-beta ) by tumor cells has been recognized as one of the mechanisms involved in tumor immunological escape . This study aimed to examine whether dendritic cell ( DC ) immunization could reverse TGF-beta-induced immunosuppression by simulating the in vivo interaction among infused DCs , host T cells , and tumor-secreted TGF-beta in an in vitro study . We found that both immature and mature DCs were relatively resistant to TGF-beta . The addition of TGF-beta to naive human CD4+ T cells , which are required by genetically modified DC to elicit antitumor immunity , resulted in their hyporesponsiveness to DC stimulation in a dose-dependent manner . When activated by allogeneic DCs in the presence of TGF-beta , CD4+ T cells displayed a reduced capacity to proliferate . More importantly , activated CD4+ T cells induced by DC stimulation were very sensitive to TGF-beta , and this susceptibility was enhanced by their previous exposure to TGF-beta . The underlying mechanism was linked to TGF-beta-induced apoptosis of activated T cells . However , the presence of stimulation from DC or antibodies to CD3 plus CD28 could partly reverse the immunosuppressive effect of TGF-beta on activated CD4+ T cells . Taken together , our results indicate that the efficacy of DC immunization may be impaired by tumor-derived TGF-beta .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 1, 0], "id": "11781072"}
{"sentence": "Estrogens , acting through estrogen receptor \u03b1 ( ER\u03b1 ) , stimulate breast cancer proliferation , making ER\u03b1 an attractive drug target . Since 384-well format screens for inhibitors of proliferation can be challenging for some cells , inhibition of luciferase-based reporters is often used as a surrogate end point . To identify novel small-molecule inhibitors of 17\u03b2-estradiol ( E(2))-ER\u03b1-stimulated cell proliferation , we established a cell-based screen for inhibitors of E(2)-ER\u03b1 induction of an estrogen response element ( ERE)(3)-luciferase reporter . Seventy-five \" hits \" were evaluated in tiered follow-up assays to identify where hits failed to progress and evaluate their effectiveness as inhibitors of E(2)-ER\u03b1-induced proliferation of breast cancer cells . Only 8 of 75 hits from the luciferase screen inhibited estrogen-induced proliferation of ER\u03b1-positive MCF-7 and T47D cells but not control ER\u03b1-negative MDA-MB-231 cells . Although 12% of compounds inhibited E(2)-ER\u03b1-stimulated proliferation in only one of the ER\u03b1-positive cell lines , 40% of compounds were toxic and inhibited growth of all the cell lines , and exhibited little or no ability to inhibit E(2)-ER\u03b1-stimulated cell proliferation . Representative compounds were evaluated in more detail , and a lead ER\u03b1 inhibitor was identified .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22498909"}
{"sentence": "Alteration of the oxidative stress of hepatocellular carcinoma ( HCC ) cells can influence the expressions of genes favored angiogenesis . Quinone reductase 2 which can activate quinones leading to reactive oxygen species production is a melatonin receptor known as MT3 . Prazosin prescribed for benign prostate hyperplasia and hypertension is a potent antagonist for MT3 . This study was to investigate the influence of therapeutic concentrations of prazosin ( 0.01 and 0.1\u03bcM ) on cell proliferation and differential expressions of CCL2 , CCL20 , CXCL6 , CXCL10 , IL8 and IL6 genes related to inflammation and/or oxidative stress in human HCC cell lines . Two HCC cell lines including one without susceptible to amphotericin B-induced oxidative stress ( cell line A ; HCC24/KMUH ) and one with this effect ( cell line B ; HCC38/KMUH ) were investigated by 0.01 and 0.1\u03bcM prazosin . The premixed WST-1 cell proliferation reagent was applied for proliferation assay . Differential expressions of genes were examined by quantitative reverse transcriptase-polymerase chain reaction . Our results showed that both 0.01 and 0.1\u03bcM prazosin did not influence cell proliferation in both cell lines . Both 0.01 and 0.1\u03bcM prazosin in cell line A and 0.01\u03bcM prazosin in cell line B did not cause differential expressions of tested genes . However , 0.1\u03bcM prazosin caused remarkable up-regulation of IL6 gene and slightly up-regulation of CCL2 gene in cell line B. In conclusion , high therapeutic concentration of prazosin can up-regulate angiogenic IL6 and CCL2 genes in human HCC cells susceptible to amphotericin B-induced oxidative stress . Clinical application of prazosin in patients with HCC should consider this possibility .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 1], "id": "23089469"}
{"sentence": "Telomerase activity , a cardinal requirement for immortalization , is a crucial step in the development of cancer and has been studied in many kinds of malignant tumours for clinical diagnostic and/or prognostic utilities . Using a PCR-based TRAP assay , we investigated telomerase activity in 8 adenomatous polyps , 9 dysplastic polyps , and in 36 paired cancer-normal mucosa specimens , one liver and one spleen metastasis from patients resected for sporadic colorectal cancer . Telomerase was absent or very low in normal mucosa and in adenomatous polyps . Dysplastic polyps and adenocarcinoma samples showed telomerase activity , with higher levels in cancer tissues compared to dysplastic lesions . A high telomerase activity was shown to be associated with late-staged cancers and metastasis , providing arguments supporting the role of telomerase not only in the development but also in the progression of colorectal carcinoma . Moreover , telomerase evaluation may help to confirm the malignant transformation in polypoid colorectal lesions with different levels of dysplastic alterations .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12373297"}
{"sentence": "Autism is a childhood-onset neurodevelopmental disorder with complex genetic mechanism underlying its etiology . Recent studies revealed that a few single de novo copy number variants of genomic DNA ( copy number variants [ CNVs] ) are pathogenic and causal in some sporadic cases , adding support to the hypothesis that some sporadic autism might be caused by single rare mutation with large clinical effect . In this study , we report the detection of two novel private CNVs simultaneously in a male patient with autism . These two CNVs include a microduplication of Mb at chromosome 4q12-13.1 that was transmitted from his mother and a microdeletion of Mb at 5q32 that was transmitted from his father . Several genes such as LPHN3 , POU4F3 , SH3RF2 , and TCERG1 mapped to these two regions have psychiatric implications . However , the parents had only mild degree of attention deficit symptoms but did not demonstrate any obvious autistic symptoms or psychopathology . Our findings indicate that each of these two CNVs alone may not be pathogenic enough to cause clinical symptoms in their respective carriers , and hence they can be transmitted within each individual family . However , concomitant presence of these two CNVs might result in the clinical phenotypes of the affected patient reported here . Thus , our report of this family may represent an example to show that two hits of CNV and the presence of compound heterozygosity might be important mechanisms underlying the pathogenesis of autism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22778016"}
{"sentence": "The t(10;11)(p12;q23) chromosomal translocation in human acute myeloid leukemia results in the fusion of the MLL and AF10 genes . The latter codes for a novel leucine zipper protein , one of many MLL fusion partners of unknown function . In this report , we demonstrate that retroviral-mediated transduction of an MLL-AF10 complementary DNA into primary murine myeloid progenitors enhanced their clonogenic potential in serial replating assays and led to their efficient immortalization at a primitive stage of myeloid differentiation . Furthermore , MLL-AF10-transduced cells rapidly induced acute myeloid leukemia in syngeneic or severe combined immunodeficiency recipient mice . Structure/function analysis showed that a highly conserved 82-amino acid portion of AF10 , comprising 2 adjacent alpha-helical domains , was sufficient for immortalizing activity when fused to MLL . Neither helical domain alone mediated immortalization , and deletion of the 29-amino acid leucine zipper within this region completely abrogated transforming activity . Similarly , the minimal oncogenic domain of AF10 exhibited transcriptional activation properties when fused to the MLL or GAL4 DNA-binding domains , while neither helical domain alone did . However , transcriptional activation per se was not sufficient because a second activation domain of AF10 was neither required nor competent for transformation . The requirement for alpha-helical transcriptional effector domains is similar to the oncogenic contributions of unrelated MLL partners ENL and ELL , suggesting a general mechanism of myeloid leukemogenesis by a subset of MLL fusion proteins , possibly through specific recruitment of the transcriptional machinery .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "11986236"}
{"sentence": "\" Reactive \" or activated stroma characterizes many malignancies including breast cancers . Recently , we isolated a reactive mouse mammary gland stromal cell line called BJ3Z . These cells express alpha-smooth muscle actin and stromal cell-derived factor 1 ( SDF-1 ) and are tumorigenic when injected into mice . Here we show that , in vivo , BJ3Z cells influence the angiogenesis and proliferation of xenografted estrogen receptor ( ER)-positive MCF-7 human breast cancer cell-derived solid tumors . The growth-promoting effects of BJ3Z cells are equivalent to those of estradiol ( E(2) ) . BJ3Z cells also increase the proliferation of normal mouse mammary luminal cells adjacent to tumors . In vitro , BJ3Z cells reorganize and increase the proliferation of cocultured malignant MCF-7 and normal human breast MCF10A cells grown as organoids in three-dimensional culture . The effects of BJ3Z cells on MCF-7 cells are equivalent to those of E(2) . In contrast , BJ3Z cells do not alter the growth of highly aggressive ER-negative MDA-MB-231 human breast cancer cells . We show that BJ3Z cells secrete vascular endothelial growth factor ( VEGF ) . The growth of MCF-7 organoids induced by BJ3Z can be inhibited by antagonists of VEGF and SDF-1 . Conversely , recombinant VEGF stimulates the proliferation of MCF-7 , but not MDA-MB-231 , organoids . We conclude that , in addition to angiogenesis , VEGF released by activated stroma increases the growth of ER-positive malignant epithelial cells and of adjacent normal epithelium . Because activated stroma can substitute for E(2) and fosters hormone-independent growth of ER-positive tumors , we suggest that breast cancers exhibiting intrinsic hormone resistance may respond to antiangiogenic therapies .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "20332242"}
{"sentence": "Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth . We observed promoter methylation and loss of expression in neurofilament heavy polypeptide ( NEFH ) in a significant proportion of primary esophageal squamous cell carcinoma ( ESCC ) samples that were of a high tumor grade and advanced stage . RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo , whereas forced expression of NEFH significantly inhibited cell growth and colony formation . Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase , via activation of the Akt/beta-catenin pathway , resulting in enhanced aerobic glycolysis and mitochondrial dysfunction . The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of beta-catenin expression , and was decreased by the treatment of 2-Deoxyglucose , a glycolytic inhibitor , or API-2 , an Akt inhibitor . Loss of NEFH activates the Akt/beta-catenin pathway and increases glycolysis and mitochondrial dysfunction . Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20140245"}
{"sentence": "In traditional biochemical experiments , the behavior of individual proteins is obscured by ensemble averaging . To better understand the behavior of proteins that bind to and/or translocate on DNA , we have developed instrumentation that uses optical trapping , microfluidic solution delivery , and fluorescent microscopy to visualize either individual proteins or assemblies of proteins acting on single molecules of DNA . The general experimental design involves attaching a single DNA molecule to a polystyrene microsphere that is then used as a microscopic handle to manipulate individual DNA molecules with a laser trap . Visualization is achieved by fluorescently labeling either the DNA or the protein of interest , followed by direct imaging using high-sensitivity fluorescence microscopy . We describe the sample preparation and instrumentation used to visualize the interaction of individual proteins with single molecules of DNA . As examples , we describe the application of these methods to the study of proteins involved in recombination-mediated DNA repair , a process essential for the maintenance of genomic integrity .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20580968"}
{"sentence": "Methyleugenol ( MEG ) , a constituent of plants used in the human diet , is hepatocarcinogenic in rodents . In an experiment to elucidate its mode of action in rat liver , male F344 rats were administered MEG intragastrically at 3 doses per week for up to 16 weeks in an initiation phase , after which half the rats were fed 500 ppm phenobarbital ( PB ) in the diet to promote liver neoplasia and the other half were maintained on control diet for 24 weeks . At 8 and 16 week interim terminations , ( 32)P-nucleotide postlabeling assay revealed 3 adducts in livers of all MEG groups . The hepatocellular replicating fractions , measured by proliferating cell nuclear antigen immunohistochemistry , were doubled or more in all MEG groups . Hepatocellular altered foci , detected by glutathione S-transferase-placental type ( \\u03c0 ) immunohistochemistry , were present beginning with the high dose group at 8 weeks and extending to all MEG groups at 16 weeks . At the end of maintenance/promotion phase , the incidences , multiplicity and size of foci was similar between control and low dose groups , while those of mid and high dose groups were increased . Hepatocellular adenomas occurred in the mid and high dose groups , attaining higher multiplicity and size with PB . Thus , MEG had rapid initiating activity , reflecting the formation of DNA adducts and possibly cell proliferation .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 1, 0], "id": "23220513"}
{"sentence": "A stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-osyl ( Tempol ) is widely used as an antioxidant invitro and invivo . In this study , we investigated the effects of Tempol on the growth of As4.1 juxtaglomerular cells in relation to cell cycle and cell death . Tempol dose-dependently decreased the growth of As4.1 cells with an IC50 of at 48h . DNA flow cytometry analysis and BrdU staining indicated that Tempol induced S phase arrest , which is accompanied by a downregulation of cyclin A. Tempol also induced apoptotic cell death , which was accompanied by the loss of mitochondrial membrane potential ( MMP ; \\u2206\\u03a8m ) , an activation of caspase-3 and cleavage of poly(ADP-ribose)polymerase-1 ( PARP-1 ) . Furthermore , Tempol increased reactive oxygen species ( ROS ) levels , and the phosphorylation of extracellular signal-regulated kinase ( ERK ) and c-Jun N-terminal kinase ( JNK ) . MEK and JNK inhibitors significantly attenuated a growth inhibition in Tempol-treated As4.1 cells . In conclusion , Tempol inhibited the growth of As4.1 cells via cell cycle arrest and apoptosis . Tempol also activated ERK and JNK signaling , which was responsible for cell growth inhibition . Our present data provide useful information for the toxicological effects of Tempol in juxtaglomerular cells in relation to cell growth inhibition and cell death .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22024718"}
{"sentence": "In normal human cells , oncogene-induced senescence ( OIS ) depends on induction of DNA damage response . Oxidative stress and hyperreplication of genomic DNA have been proposed as major causes of DNA damage in OIS cells . Here , we report that down-regulation of deoxyribonucleoside pools is another endogenous source of DNA damage in normal human fibroblasts ( NHFs ) undergoing HRAS(G12V)-induced senescence . NHF-HRAS(G12V) cells underexpressed thymidylate synthase ( TS ) and ribonucleotide reductase ( RR ) , two enzymes required for the entire de novo deoxyribonucleotide biosynthesis , and possessed low dNTP levels . Chromatin at the promoters of the genes encoding TS and RR was enriched with retinoblastoma tumor suppressor protein and histone H3 tri-methylated at lysine 9 . Importantly , ectopic coexpression of TS and RR or addition of deoxyribonucleosides substantially suppressed DNA damage , senescence-associated phenotypes , and proliferation arrest in two types of NHF-expressing HRAS(G12V) . Reciprocally , short hairpin RNA-mediated suppression of TS and RR caused DNA damage and senescence in NHFs , although less efficiently than HRAS(G12V) . However , overexpression of TS and RR in quiescent NHFs did not overcome proliferation arrest , suggesting that unlike quiescence , OIS requires depletion of dNTP pools and activated DNA replication . Our data identify a previously unknown role of deoxyribonucleotides in regulation of OIS .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "23245831"}
{"sentence": "Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer . We examined peripheral blood lymphocyte ( PBL ) gene expression as a biomarker of illness and treatment effect using the Affymetrix Human Gene ST1 platform in patients with metastatic renal cell carcinoma ( mRCC ) who received combined treatment with IL-2 , interferon-?-2a and dendritic cell vaccine . We examined gene expression , cytokine levels in patient serum and lymphocyte subsets as determined by flow cytometry ( FCM ) . Pre-treatment PBLs from patients with mRCC exhibit a gene expression profile and serum cytokine profile consistent with inflammation and proliferation not found in healthy donors ( HD ) . PBL gene expression from patients with mRCC showed increased mRNA of genes involved with T-cell and T(REG)-cell activation pathways , which was also reflected in lymphocyte subset distribution . Overall , PBL gene expression post-treatment ( POST ) was not significantly different than pre-treatment ( PRE ) . Nevertheless , treatment related changes in gene expression ( post-treatment minus pre-treatment ) revealed an increased expression of T-cell and B-cell receptor signaling pathways in responding ( R ) patients compared to non-responding ( NR ) patients . In addition , we observed down-regulation of T(REG)-cell pathways post-treatment in R vs. NR patients . While exploratory in nature , this study supports the hypothesis that enhanced inflammatory cytotoxic pathways coupled with blunting of the regulatory pathways is necessary for effective anti-cancer activity associated with immune therapy . This type of analysis can potentially identify additional immune therapeutic targets in patients with mRCC .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23226513"}
{"sentence": "Ovarian cancer-related angiogenesis is a complex process orchestrated by many positive and negative regulators . Many growth factors are involved in the development of the tumor-associated vasculature , and from these , endocrine gland-derived vascular endothelial growth factor ( EG-VEGF ) seems to play a crucial role . EG-VEGF is the first organ-specific angiogenic factor and its effects are restricted to the endothelial cells of the endocrine glands . Although EG-VEGF was detected in both normal and neoplastic ovaries , its clinical significance remains controversial . In the present study , we analyzed 30 patients with epithelial ovarian cancer , and the immunohistochemical expression of EG-VEGF was compared with the conventional clinico-pathological parameters of prognosis . Neoplastic cells of the ovarian carcinoma expressed EG-VEGF in 73.33% of the cases , as a cytoplasmic granular product of reaction . We found a strong correlation between the expression of EG-VEGF at protein level and tumor stage , grade , and microscopic type . The expression of EG-VEGF was found in patients with stage III and IV , but not in stage II . The majority of serous adenocarcinoma , half of the cases with clear cell carcinoma and two cases with endometrioid carcinoma showed definite expression in tumor cells . No positive reaction was found in the cases with mucinous carcinoma . Our results showed that EG-VEGF expression is an indicator not only of the advanced stage , but also of ovarian cancer progression . Based on these data , we concluded that EG-VEGF expression in tumor cells of the epithelial ovarian cancer is a good marker of unfavorable prognosis and could be an attractive therapeutic target in patients with advanced-stage tumors , refractory conventional chemotherapy .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "22990536"}
{"sentence": "Leptin is thought to be involved in febrigenic signaling from the periphery to the brain . Zucker obese rats have a so-called fatty mutation in the leptin receptor gene and express a dysfunctional protein . Studies comparing the fever responses of fatty ( fa/fa ) rats and of their lean ( Fa/Fa and Fa/fa ) counterparts yield contradictory results . To resolve these contradictions , we evaluated the effect of fatty mutation on infectious and stress-associated fevers at thermoneutrality ( 29 degrees C ) and in a cool environment ( 20 degrees C ) . Zucker fa/fa and Fa/ ? rats were infused with Escherichia coli lipopolysaccharide ( LPS ; 10 microg/kg ) through a jugular catheter ( infectious fever ) or with saline through the catheter ( control ) or received a painful intramuscular injection of saline ( stress fever ) . At thermoneutrality , the colonic temperature ( T(c) ) responses of fatty rats to all stimuli tested were no different from the responses of lean rats . In a cool environment , T(c) responses of fatty rats to all stimuli were degrees C lower than those of lean rats . The observed attenuation of LPS-induced and stress-associated fevers in Zucker fatty rats in the cold agrees with the literature data showing that brown adipose tissue ( the major heat production effector ) is morphologically and functionally defective in these rats . The normal febrile responses of fatty Zucker rats to pyrogenic stimuli at thermoneutrality indicate that fatty mutation does not interrupt febrigenic signaling from the periphery to the brain .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "11742853"}
{"sentence": "Oxidative stress is the main etiological factor behind the pathogenesis of various diseases including inflammation , cancer , cardiovascular and neurodegenerative disorders . Due to the spin trapping abilities and various pharmacological properties of nitrones , their application as therapeutic agent has been gaining attention . Though the antioxidant properties of the nitrones are well known , the mechanism by which they modulate the cellular defense machinery against oxidative stress is not well investigated and requires further elucidation . Here , we have investigated the mechanisms of cytoprotection of the nitrone spin traps against oxidative stress in bovine aortic endothelial cells ( BAEC ) . Cytoprotective properties of both the cyclic nitrone 5,5-dimethyl-pyrroline N-oxide ( DMPO ) and linear nitrone \u03b1-phenyl N-tert-butyl nitrone ( PBN ) against H\u2082O\u2082-induced cytotoxicity were investigated . Preincubation of BAEC with PBN or DMPO resulted in the inhibition of H\u2082O\u2082-mediated cytotoxicity and apoptosis . Nitrone-treatment resulted in the induction and restoration of phase II antioxidant enzymes via nuclear translocation of NF-E2-related factor 2 ( Nrf-2 ) in oxidatively-challenged cells . Furthermore , the nitrones were found to inhibit the mitochondrial depolarization and subsequent activation of caspase-3 induced by H\u2082O\u2082 . Significant down-regulation of the pro-apoptotic proteins p53 and Bax , and up-regulation of the anti-apoptotic proteins Bcl-2 and p-Bad were observed when the cells were preincubated with the nitrones prior to H\u2082O\u2082-treatment . It was also observed that Nrf-2 silencing completely abolished the protective effects of nitrones . Hence , these findings suggest that nitrones confer protection to the endothelial cells against oxidative stress by modulating phase II antioxidant enzymes and subsequently inhibiting mitochondria-dependent apoptotic cascade .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "22580046"}
{"sentence": "BACKGROUND Epidemiologic data have shown that obesity independently increases colorectal cancer ( CRC ) risk , but the mechanisms are poorly understood . Obesity is an inflammatory state , and chronic colonic inflammation induces CRC . OBJECTIVE We conducted this proof-of-principle study to seek evidence of obesity-associated colorectal inflammation and to evaluate effects of diet-induced weight loss . DESIGN We measured inflammatory cytokines , gene arrays , and macrophage infiltration in rectosigmoid mucosal biopsies of 10 obese premenopausal women [ mean \u00b1 SD body mass index ( in kg/m(2) ) : 35 \u00b1 3.5 ] before and after weight loss induced by a very-low-calorie diet . RESULTS Subjects lost a mean ( \u00b1SD ) of 10.1 \u00b1 1% of their initial weight . Weight loss significantly reduced fasting blood glucose , total cholesterol , triglycerides , LDL , tumor necrosis factor-\u03b1 ( TNF-\u03b1 ) , and interleukin ( IL)-8 concentrations ( P < 0.05 ) . After weight loss , rectosigmoid biopsies showed a 25-57% reduction in TNF-\u03b1 , IL-1\u03b2 , IL-8 , and monocyte chemotactic protein 1 concentrations ( P < 0.05 ) . T cell and macrophage counts decreased by 28% and 42% , respectively ( P < 0.05 ) . Gene arrays showed dramatic down-regulation of proinflammatory cytokine and chemokine pathways , prostaglandin metabolism , and the transcription factors STAT3 ( signal transducer and activator of transcription 3 ) and nuclear transcription factor \u03baB . Weight loss reduced expression of FOS and JUN genes and down-regulated oxidative stress pathways and the transcription factors ATF ( activating transcription factor ) and CREB ( cyclic AMP response element-binding ) . CONCLUSIONS Our data show that diet-induced weight loss in obese individuals reduces colorectal inflammation and greatly modulates inflammatory and cancer-related gene pathways . These data imply that obesity is accompanied by inflammation in the colorectal mucosa and that diet-induced weight loss reduces this inflammatory state and may thereby lower CRC risk .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21147860"}
{"sentence": "Background/Aims : Cimetidine has been shown to play an important role in the treatment of cancer and the regulation of the immune system . Therefore , we aimed to observe the effects of cimetidine on the systematic immune response in the perioperative period . Methodology : Sixty patients with colorectal cancer were enrolled from Jan 2005 to Dec 2005 from Taizhou Hospital . The patients were administrated with cimetidine ( 0.8g\ufffdd-1 or 1.2g\ufffdd-1 ) or saline from the day of admission to the 10th POD . Venous blood sample was collected and the T- , B- and NK-lymphocyte subsets were determined by flow cytometry . The specimens were subjected to tumor-infiltrating lymphocytes ( TILs ) response examination . Results : The levels of CD3 and CD4 T-lymphocytes were increased significantly in both low and high dose cimetidine groups 10 days after operation . The number of CD19 B cells was also elevated by cimetidine . However , no significant changes were observed in the CD8 , CD4/CD8 value . TIL responses in the cimetidine groups were also enhanced significantly . Conclusions : Cimetidine can alleviate systematic immunosuppression and improve the local immune function of the colorectal cancer patients in the perioperative period .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22944376"}
{"sentence": "Glycol ethers are known reproductive and developmental toxins in laboratory animals , but little is known about their genotoxic effects in humans . In the current article , the authors tested the hypothesis that human in utero exposure to ethylene glycol monomethyl ether ( EGME ) is associated with the development of specific congenital anomalies and elevated levels of chromosome aberrations . The authors conducted a clinical and cytogenetic evaluation of 41 offspring of 28 females occupationally exposed to EGME for an average duration of 4.6 yr . Six offspring of 5 women who were occupationally exposed to EGME during pregnancy exhibited characteristic dysmorphic features that were not observed in 35 offspring of 23 women who worked in the same facility , but who were not pregnant at the time of exposure . Persistent cytogenetic damage was observed exclusively in all 6 in-utero-exposed offspring , but not in their 12 match non-in-utero-exposed controls . The study characterizes EGME as a human teratogen , as indicated by the prevalence of characteristic dysmorphic features and persistent cytogenetic damage in individuals exposed in utero to this chemical .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12530607"}
{"sentence": "The Sleeping Beauty ( SB ) transposon is a nonviral , integrating vector system with proven efficacy in preclinical animal models , and thus holds promise for future clinical applications . However , SB has a close-to-random insertion profile that could lead to genotoxic effects , thereby presenting a potential safety issue . We evaluated zinc finger ( ZF ) DNA-binding domains ( DBDs ) for their abilities to introduce a bias into SB's insertion profile . E2C , that binds a unique site in the erbB-2 gene , mediated locus-specific transposon insertions at low frequencies . A novel ZF targeting LINE1 repeats , ZF-B , showed specific binding to an 18-bp site represented by copies in the human genome . We mapped SB insertions using linear-amplification ( LAM)-PCR and Illumina sequencing . Targeted insertions with ZF-B peaked at approximately fourfold enrichment of transposition around ZF-B binding sites yielding overall frequency of insertion into LINE1 . A decrease in the ZF-B dataset with respect to transposon insertions in genes was found , suggesting that LINE1 repeats act as a sponge that \" soak up \" a fraction of SB insertions and thereby redirect them away from genes . Improvements in ZF technology and a careful choice of targeted genomic regions may improve the safety profile of SB for future clinical applications .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22776959"}
{"sentence": "The metastatic spread of malignant neoplasms is associated with active migration of cancer cells . The migration of neoplastic cells during the metastatic process may be affected by various extracellular factors , including chemoattractants , haptotactic signals , electric fields , substrate anisotropy , and cell-to-cell contacts . We examined the effect of homotypic collisions and heterotypic interactions with normal human skin fibroblasts on the motile activity of Walker carcinosarcoma cells . It was found that Walker carcinosarcoma cells moving in a dense population neither show contact inhibition of movement when colliding with one another nor increase their motile activity as a result of contact stimulation of motility . On the other hand , when plated onto the surface of aligned fibroblasts , Walker carcinosarcoma cells migrated mainly along the long axes of underlying fibroblasts as a result of contact guidance . The directional character of movement ( but not the speed of migration ) of Walker carcinosarcoma cells on the surface of aligned fibroblasts was completely effaced by RGD-containing synthetic peptide at a concentration of 1 mg/ml but not by 5 microM verapamil ( selective voltage-gated calcium channel inhibitor ) or 10 microM gadolinium chloride ( non-specific blocker of mechanosensitive ion channels ) . The suppression of directional character of migration of tumour cells by RGD-containing peptide was associated with the decrease in the amount of fibronectin macromolecules attached to fibroblasts . This suggests that alignment and anisotropic distribution of fibronectin macromolecules may be responsible for contact guidance of tumour cells moving on the surface of fibroblasts .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "12219835"}
{"sentence": "Previous studies have demonstrated that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ( NNK ) induced liver tumors in F344 rats but not in Syrian golden hamsters . The aim of this study was to determine whether there was a correlation between the persistence of O6-methylguanine ( O6-mGua ) adducts and the rate of recovery of O6-methylguanine-DNA methyltransferase ( O6-mGuaT ) after depletion in the liver and susceptibility to NNK in F344 rat and Syrian golden hamster injected s.c. with NNK ( 80 mg/kg ) . The levels of both 7-methylguanine and O6-mGua reached a maximum 24 h after NNK treatment . O6-mGua in NNK-treated rat liver was undetectable after 48 h . In the rat , the depletion of O6-mGuaT activity occurred within 4 h following NNK treatment . A subsequent rapid recovery of enzyme activity was observed 36 h after NNK exposure . In contrast , high levels of O6-mGua persisted in hamster liver DNA and no O6-mGuaT activity was detected up to 336 h after NNK injection . Thus , the persistence of O6-mGua in hamster liver is most likely related to a lack of recovery of the O6-mGuaT . These results suggested that factors other than O6-mGua may be determining NNK-induced hepatocarcinogenesis in rats . An aldehyde generated by alpha-hydroxylation of NNK , 4-oxo-4-(3-pyridyl)butanal , inhibited O6-mGuaT activity in rat hepatocytes , suggesting that this aldehyde contributes to the carcinogenicity of NNK by inhibiting this repair enzyme .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1423885"}
{"sentence": "In the central nervous system , levels of extraneuronal dopamine are controlled primarily by the action of the dopamine transporter ( DAT ) . Multiple signaling pathways regulate transport activity , substrate efflux , and other DAT functions through currently unknown mechanisms . DAT is phosphorylated by protein kinase C within a serine cluster at the distal end of the cytoplasmic N terminus , whereas recent work in model cells revealed proline-directed phosphorylation of rat DAT at membrane-proximal residue Thr(53) . In this report , we use mass spectrometry and a newly developed phospho-specific antibody to positively identify DAT phosphorylation at Thr(53) in rodent striatal tissue and heterologous expression systems . Basal phosphorylation of Thr(53) occurred with a stoichiometry of and was strongly increased by phorbol esters and protein phosphatase inhibitors , demonstrating modulation of the site by signaling pathways that impact DAT activity . Mutations of Thr(53) to prevent phosphorylation led to reduced dopamine transport V(max) and total apparent loss of amphetamine-stimulated substrate efflux , supporting a major role for this residue in the transport kinetic mechanism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22722938"}
{"sentence": "Pancreatic cancer remains the fourth most common cause of cancer-related death in the United States . Potent therapeutic strategies are urgently needed for pancreatic cancer . Cucurmosin is a novel type1 ribosome-inactivating protein ( RIP ) isolated from the sarcocarp of Cucurbita moschata ( pumpkin ) . Due to its cytotoxicity , cucurmosin can inhibit tumor cell proliferation through induction of apoptosis on tumor cells , but the specific mechanism is still unclear . We explored the function of cucurmosin in BxPC-3 pancreatic cancer cells using multiple cellular and molecular approaches such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay , flow cytometry , reverse transcription polymerase chain reaction ( RT-PCR ) , Western blotting and transmission electron microscopy for observing typical changes and formation of apoptotic bodies . We found that cucurmosin inhibited the proliferation of BxPC-3 cells in a time- and dose-dependent manner , and increased the cell population in the G0-G1 phase . With increasing concentration of cucurmosin , the expression of EGFR , p-PI3K , Akt , p-Akt , mTOR , p-mTOR , P70S6K-\u03b1 , p-P70S6K-\u03b1 , 4E-BP1 and p-4E-BP1 at the protein level was decreased , whereas the expression of p-Bad and caspase-9 was elevated . However , the mRNA expression of EGFR did not change . These findings suggest that cucurmosin can down-regulate the expression of EGFR by targeting . Cucurmosin induces the apoptosis of BxPC-3 pancreatic cancer cells via the PI3K/Akt/mTOR signaling pathway .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22139427"}
{"sentence": "Human esophageal adenocarcinoma ( EAC ) develops in a sequence from gastroesophageal reflux disease ( GERD ) , columnar-lined esophagus ( CLE ) , dysplasia , and eventually to EAC . We established a rat surgical EAC model with esophagogastroduodenal anastomosis ( EGDA ) to mimic the staged process of esophageal adenocarcinogenesis . Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 ( PGE2 ) , leukotriene B4 ( LTB4 ) , 15-hydroeicosatetraenoic acid ( HETE ) , 12-HETE , 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus , with PGE2 as the major metabolite . Consistent with this profile , cyclooxygenase 2 ( Cox2 ) was overexpressed in the basal cell layer of esophageal squamous epithelium , CLE cells and EAC tumor cells of the EGDA rats , as compared with the normal esophageal epithelium . Sulindac ( a Cox inhibitor ) , nordihydroguaiaretic acid ( NDGA , a lipoxygenase inhibitor ) and alpha-difluoromethylornithine ( DFMO , an ornithine decarboxylase inhibitor ) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model . In a short-term study ( for 4 weeks after surgery ) , dietary administration of both sulindac ( 300 and 600 p.p.m. ) and NDGA ( 100 p.p.m. ) effectively reduced the EGDA-induced inflammation . In a long-term chemoprevention study ( for 40 weeks after surgery ) , 300 p.p.m. sulindac , alone or in combination with 100 p.p.m . NDGA or 0.5% DFMO , decreased the tumor incidence from 57.7 to 26.9% , or 16.7 or 20% , respectively ( P < 0.05 ) . NDGA alone ( 100 and 200 p.p.m. ) slightly decreased the tumor incidence to 52.4 and 37% , respectively , although the difference was not statistically significant . DFMO alone did not show significant effects on tumor incidence . Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2 . In conclusion , sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "12507933"}
{"sentence": "Treacher-Collins-Franceschetti syndrome ( TCS ) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia , micrognathia , downslanting palpebral fissures , eyelid colobomata , and ear deformities that often lead to conductive deafness . A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene . In all , 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion . A further case had a novel in-frame deletion in the alternatively spliced exon 6A of uncertain pathogenicity . The majority of the pathogenic sequence changes were found to predict premature protein termination , however , four novel missense changes in the LIS1 homology motif at the 5 ' end of the gene were identified . The partial gene deletions of different sizes represent of all the pathogenic TCOF1 mutations identified , indicating that gene rearrangements account for a significant proportion of TCS cases . This is the first report of gene rearrangements resulting in TCS . These findings expand the TCOF1 mutation spectrum indicating that dosage analysis should be performed together with sequence analysis , a strategy that is predicted to have a sensitivity of 71% for patients in whom TCS is strongly suspected .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22317976"}
{"sentence": "BACKGROUND Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation . Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates . METHODOLOGY/PRINCIPAL FINDINGS We tested the effects of daily administered parathyroid hormone ( PTH ) on bone disease and myeloma growth , and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models . PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden , which reflected the dependence of primary myeloma cells on the bone marrow microenvironment . Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts . In myelomatous bone , PTH markedly increased the number of osteoblasts and bone-formation parameters , and the number of osteoclasts was unaffected or moderately reduced . Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression . Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling ; involvement of Wnt signaling was prominent . Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells , and altered expression of genes that control oxidative stress and inflammation . PTH receptors were not expressed by myeloma cells , and PTH had no effect on myeloma cell growth in vitro . CONCLUSIONS/SIGNIFICANCE We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption and myeloma growth ; mechanisms involve increased osteoblast production of anti-myeloma factors and minimized myeloma induction of inflammatory conditions .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21188144"}
{"sentence": "Evaluation of immune dysfunction during the tumor-bearing state is a critical issue in combating cancer . In this study , we initially found that IL-6 , one of the cachectic factors , suppressed CD4(+) T cell-mediated immunity through downregulation of MHC class II by enhanced arginase activity of dendritic cells ( DC ) in tumor-bearing mice . We demonstrated that administration of Ab against IL-6R ( anti-IL-6R mAb ) greatly enhanced T cell responses and inhibited the growth of tumor in vivo . We also found that IL-6 upregulated the expression of arginase-1 and arginase activity of DC in vitro . Tumor-infiltrating CD11c(+) DC exhibited upregulated mRNA expression of arginase-1 but reduced expression of MHC class II in parallel with the increase in serum IL-6 levels at the late stage in tumor-bearing hosts . However , the administration of anti-IL-6R mAb into tumor-bearing mice inhibited both the downmodulation of MHC class II and the upregulation of arginase-1 mRNA levels in DC . Furthermore , we noted that N(\u03c9)-hydroxy-L-arginine or L-arginine , an arginase-1 inhibitor , blocked the reduction in MHC class II levels on CD11c(+) DC during the tumor-bearing state . Finally , we demonstrated that the administration of N(\u03c9)-hydroxy-L-arginine at the peritumor site significantly enhanced CD4(+) T cell responses and inhibited tumor growth . Thus , IL-6-mediated arginase activation and the subsequent reduction in MHC class II expression on DC appeared to be critical mechanisms for inducing dysfunction of the immune system in the tumor-bearing state . Blockade of the IL-6-arginase cascade is a promising tool to overcome the dysfunction of antitumor immunity in tumor-bearing hosts .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23248265"}
{"sentence": "BACKGROUND Cholangiocarcinoma , a type of malignant tumor , originates from epithelial cells of the bile duct . Perineural invasion is common path for cholangiocarcinoma metastasis , and it is highly correlated with postoperative recurrence and poor prognosis . It has been reported that muscarinic acetylcholine receptor M3 ( mAChR M3 ) is widely expressed in digestive tract cancer , and may play an important role in the proliferation , differentiation , transformation and carcinogenesis of tumors . This study was to explore the effect of mAChR M3 on the growth of cholangiocarcinoma cells in vitro and provide a new approach to the pathogenesis and treatment of cholangiocarcinoma . METHODS Streptavidin-biotin complex immunohistochemistry was carried out to assess the expression of mAChR M3 in surgical specimens of cholangiocarcinomas ( 40 cases ) and normal bile duct tissues ( 9 ) , as well as to investigate nerve infiltration . The cholangiocarcinoma cells were treated with different concentrations of selective M-receptor agonist pilocarpine and M-receptor blocker atropine sulfate to induce changes in cell proliferation . The experimental data were analyzed by the Chi-square test . RESULTS The strongly-positive expression rate of mAChR M3 was much higher in poorly-differentiated ( 69% , 9/13 ) than in well- and moderately-differentiated cholangiocarcinomas ( 30% , 8/27 ) ( X2=5.631 , P<0.05 ) . The strongly-positive mAChR M3 expression rate in hilar cholangiocarcinoma ( 50% , 14/28 ) was higher than that in cholangiocarcinomas from the middle and lower common bile duct ( 25% , 3/12 ) ( X2=2.148 , P<0.05 ) . Cholangiocarcinomas with distant metastasis had a strongly-positive expression rate ( 75% , 9/12 ) , which was much higher than those without distant metastasis ( 29% , 8/28 ) ( X2=7.410 , P<0.01 ) . The absorbance value in the pilocarpine+atropine group was significantly higher than the corresponding value in the pilocarpine group . CONCLUSIONS The expression of mAChR M3 is influenced by the extent of differentiation , distant metastasis and the site of cholangiocarcinoma . It also plays a key role in the proliferation and metastasis of cholangiocarcinoma .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22893470"}
{"sentence": "Angiogenesis is a crucial step in the growth and metastasis of cancers , since it enables the growing tumor to receive oxygen and nutrients . Cancer prevention using natural products has become an integral part of cancer control . We studied the antiangiogenic activity of quercetin using ex vivo , in vivo and in vitro models . Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation , migration , invasion and tube formation of endothelial cells , which are key events in the process of angiogenesis . Most importantly , quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay ( CAM ) and matrigel plug assay . Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT , mTOR , and ribosomal protein S6 kinase in HUVECs . Quercetin ( 20 mg/kg/d ) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model , indicating that quercetin inhibited tumorigenesis by targeting angiogenesis . Furthermore , quercetin reduced the cell viability and induced apoptosis in prostate cancer cells , which were correlated with the downregulation of AKT , mTOR and P70S6K expressions . Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway , and could be used as a potential drug candidate for cancer therapy .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 0], "id": "23094058"}
{"sentence": "Several lines of evidence indicate that neuromuscular junction ( NMJ ) destruction and disassembly is an early phenomenon in amyotrophic lateral sclerosis ( ALS ) . Here we analyzed by confocal and electron microscopy the NMJ structure in the diaphragm of SOD1G93A mice at symptom onset . In these mice , which provide a model for familial ALS , diaphragm denervation ( as well as gastrocnemius denervation ( was found . In addition , the size of the synaptic vesicle pool was reduced and alterations of mitochondria were observed in approximately 40% of the remaining presynaptic terminals . Chronic treatment of SOD1G93A mice with the anabolic steroid nandrolone during the presymptomatic stage preserved the diaphragm muscle mass and features indicative of synaptic activity . These features were represented by the number of vesicles docked within 200 nm from the presynaptic membrane and area of acetylcholine receptor clusters . Structural preservation of mitochondria was documented in presynaptic terminals . However , innervation of diaphragm muscle fibers was only slightly increased in nandrolone-treated SOD1-mutant mice . Altogether the results point out and define fine structural alterations of diaphragm NMJs in the murine model of familial ALS at symptom onset , and indicate that nandrolone may prevent or delay structural alterations in NMJ mitochondria and stimulate presynaptic activity but does not prevent muscle denervation during the disease .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22800606"}
{"sentence": "The immune status of spleen and the effect of surgical treatment in advanced gastric cancer ( AGC ) patients were evaluated by means of testing NK cell activity , T-lymphocyte subsets and circulating immune complex ( CIC ) . The results showed ( 1 ) the significant impairment of NK cell activity and T-lymphocyte subsets , were decreased in CD3+ , CD4+ cells and increased in CD6+ cells resulting in CD4+/CD8+ cell ratio decrease in peripheral blood lymphocytes ( PBL ) , splenic venous blood lymphocytes ( SVL ) and spleen cells ( SC ) of AGC , as compared with PBL of normal population ; ( 2 ) NK cell activity or CD4+/CD8+ cell ratio of SVL and SC were significantly lower than those of PBL in AGC patients , mainly caused by marked decrease of CD4+ cells in SC ; ( 3 ) NK cell activity , CD4+ cells and CD4+/CD8+ cell ratio were significantly elevated in most of AGC cases receiving either radical gastrectomy ( R2+ ) or extensive radical gastrectomy ( R3 ) . A striking declination in CD8+ cells were found only after R3 operation ; ( 4 ) after a short period ( 10-14 days ) or a long period ( 2-4 years ) of radical gastrectomy , NK cell activity and T-lymphocyte subsets showed no significant differences between R2+ and R3 operation . As a rule , AGC would weaken immune function of patients , and along with the development of the tumor , the immunosuppression in the spleen would be generated gradually . For these reasons , a complete tumor resection would be necessary to improve the immunocompetence , and the combined splenectomy might be advisable if indicated .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "1332809"}
{"sentence": "BACKGROUND Dickkopf-related protein 1 ( DKK1 ) has been reported involved in metastasis and invasion in several tumors . This study sought to investigate the prognostic value of DKK1 in intrahepatic cholangiocarcinoma ( ICC ) and its role in promoting ICC metastasis . METHODS Tissue microarrays of 138 ICC patient samples were employed to detect DKK1 , vascular endothelial growth factor C ( VEGF-C ) , and matrix metalloproteinase 9 ( MMP9 ) expression using immunohistochemistry . The prognostic significances were assessed by Kaplan-Meier survival estimates . DKK1 expression was measured in an ICC cell line ( HCCC-9810 ) and ICC tissues by immunofluorescence assay , quantitative real-time polymerase chain reaction , and western blot . Serum levels of DKK1 from 37 ICC patients were tested by enzyme-linked immunosorbent assay . The role of DKK1 in proliferation , migration , invasion , and gene expression regulation was assessed by DKK1 depletion using small interfering RNA . RESULTS Multivariate analyses revealed that DKK1 was an unfavorable predictor for overall survival and time to recurrence . The prognostic significance was retained in ICC patients with low recurrence risk ( P < .05 ) . DKK1 expression was elevated in an ICC cell line , tumor samples , and patient sera . High levels of DKK1 in ICC tissues correlated with elevated MMP9 , VEGF-C , and metastasis of hepatic hilar lymph nodes . DKK1 depletion caused a decrease in cell migration and invasiveness , and down-regulation of MMP9 and VEGF-C expression . CONCLUSIONS DKK1 is a novel prognostic biomarker for ICC , and it enhances tumor cell invasion and promotes lymph node metastasis of ICC through the induction of MMP9 and VEGF-C . DKK1 may be a potential therapeutic target for ICC .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23132676"}
{"sentence": "Quercetin is a flavonoid with anticancer properties . In this study , we examined the effects of quercetin on cell cycle , viability , and proliferation of cancer cells , either singly or in combination with the microtubule-targeting drugs taxol and nocodazole . Although quercetin induced cell death in a dose-dependent manner , 12.5-50 \u03bcM quercetin inhibited the activity of both taxol and nocodazole to induce G2/M arrest in various cell lines . Quercetin also partially restored drug-induced loss in viability of treated cells for up to 72 h . This antagonism of microtubule-targeting drugs was accompanied by a delay in cell cycle progression and inhibition of the buildup of cyclin-B1 at the microtubule organizing center of treated cells . However , quercetin did not inhibit the microtubule targeting of taxol or nocodazole . Despite the short-term protection of cells by quercetin , colony formation and clonogenicity of HCT116 cells were still suppressed by quercetin or quercetin-taxol combination . The status of cell adherence to growth matrix was critical in determining the sensitivity of HCT116 cells to quercetin . We conclude that although long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival , the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21058190"}
{"sentence": "PURPOSE The cytotoxic effect of the combination treatment of TNF-alpha and hyperthermia on L929 and TNF-alpha-resistant L929 ( rL929 ) cells was investigated . MATERIALS AND METHODS L929 cells were treated with TNF-alpha ( 5 ng/mL ) , heating at 43 degrees C or the combination of TNF-alpha and heating . The cells were harvested at different time within the 24-hour period . The viability and the type of cell death of the harvested cells were examined . RESULTS When L929 cells were treated with a combination of TNF-alpha and heating the cells died quickly and apoptosis increased to an overwhelming extent , especially in the group pre-treated with TNF-alpha for 1 h prior to heating . Although rL929 cells were resistant to TNF-alpha alone , the cells became sensitive to TNF-alpha treatment when combined with heating . Similar to the L929 cell , the cells also died rapidly and exhibited apoptosis to a higher extent . Using an Annexin-V-FITC kit and flow cytometer , we found that both necrosis and apoptosis occurred . Agarose gel electrophoresis of DNA extracted from treated cells showed that the DNA fragments were multiples of approximately 200 bp . Furthermore , by studying the kinetics of cell death and apoptosis , we found that the loss of cell membrane integrity preceded the DNA fragmentation in both L929 and rL929 cells . CONCLUSION The results suggested that hyperthermia may enhance the necrotic and apoptotic effects of TNF-alpha on some tumour cells and overcome the resistance of some tumour cells to TNF-alpha .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20707650"}
{"sentence": "Activating c-KIT mutations ( exons 11 and 17 ) are found in 10-40% of testicular seminomas , the majority being missense point mutations ( codon 816 ) . Malignant ovarian dysgerminomas represent of all ovarian cancers in Western countries , resembling testicular seminomas , regarding chromosomal aberrations and c-KIT mutations . DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer , with gonadoblastoma as precursor progressing to dysgerminoma . Here we present analysis of c-KIT exon 8 , 9 , 11 , 13 and 17 , and PDGFRA exon 12 , 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis , confirmed by sequencing . The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases ( all found in pure ovarian dysgerminomas ) . A synonymous SNP ( rs 5578615 ) was detected in two patients , one DSD patient ( with bilateral disease ) and one patient with dysgerminoma . Next to these , three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas . In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD . In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma . No PDGFRA mutations were found . Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated , TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients . This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma , in which mutational status of c-KIT might parallel the presence of TSPY .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22937135"}
{"sentence": "Endothelial cells respond to hypoxic changes with resultant accumulation of several metabolites and switch over to angiogenic phenotype . Although certain intermediates of glycolytic and oxidative metabolic pathways have been known to affect angiogenesis , the effect of citrate , which accumulates in certain tumors , on angiogenesis is not known . Therefore , the effect of citrate on angiogenesis was studied using different model systems . Increased vascularization in chorioallantoic membrane assay , increased endothelial sprouting in rat aortic rings , and increased expression of CD31 , E-selectin in endothelial cells suggested a possible proangiogenic effect of citrate . Upregulation of angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor suggested that the effect of citrate involves modulation of expression of angiogenic growth factors . LY 294002 , an inhibitor of PI3K-Akt pathway , and wortmannin , an inhibitor of Akt pathway , reversed the effect of citrate in human umbilical vein endothelial cells . Citrate induced significant upregulation and activation of Akt in endothelial cells . Rapamycin , an inhibitor of mTOR , also reversed the effect of citrate in human umbilical vein endothelial cells and sprouting of aortic rings suggesting that the angiogenic effect of citrate involves activation of PI3K-Akt-mTOR pathway .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "23161184"}
{"sentence": "We have examined the effect of FK506 on the Adriamycin sensitivity of the multidrug resistant human chronic myelocytic leukemia cell line ( K562/ADM ) . In K562/ADM cells , 1.0 microgram/ml FK506 reversed the resistance of Adriamycin , and increased the IC50 value for Adriamycin up to 17 fold . However , IC50 value for the parent cells ( K562 ) increased only 1.5 fold . By cell cycle analysis , the accumulation in late S-G2M phase was confirmed on K562/ADM cells , treated with 1.0 microgram/ml FK506 and low-dose of Adriamycin . Cyclosporin A ( CsA ) could also restored the Adriamycin sensitivity in the K562/ADM cells , as previously reported. 1.0 microgram/ml FK506 as well as CsA significantly increased radioactive Adriamycin accumulation in K562/ADM cells and blocked [ 3H]azidopien photoaffinity labeling of P-glycoprotein . These results suggest that 1.0 microgram/ml FK506 could reverse the Adriamycin resistance in a MDR human leukemia cells through the interaction with P-glycoprotein .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1284834"}
{"sentence": "Metabolic reprogramming in cancer is manifested by persistent aerobic glycolysis and suppression of mitochondrial function and is known as the Warburg effect . The Warburg effect contributes to cancer progression and is considered to be a promising therapeutic target . Understanding the mechanisms used by cancer cells to suppress their mitochondria may lead to development of new approaches to reverse metabolic reprogramming . We have evaluated mitochondrial function and morphology in poorly respiring LM7 and 143B osteosarcoma ( OS ) cell lines showing the Warburg effect in comparison with actively respiring Saos2 and HOS OS cells and noncancerous osteoblastic hFOB cells . In LM7 and 143B cells , we detected markers of the mitochondrial permeability transition ( MPT ) , such as mitochondrial swelling , depolarization , and membrane permeabilization . In addition , we detected mitochondrial swelling in human OS xenografts in mice and archival human OS specimens using electron microscopy . The MPT inhibitor sanglifehrin A reversed MPT markers and increased respiration in LM7 and 143B cells . Our data suggest that the MPT may play a role in suppression of mitochondrial function , contributing to the Warburg effect in cancer .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "24100035"}
{"sentence": "PURPOSE Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative ( gemtuzumab ozogamicin , GO ) are a novel therapy option for acute myeloid leukaemia ( AML ) . Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies , including drug efflux or other mechanisms decreasing apoptosis . Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks ( DSBs ) accompanied by decreased DNA repair . METHODS We labelled anti-CD33 antibodies with the alpha-emitter ( 211)At and compared survival of leukaemic HL-60 and K-562 cells treated with the ( 211)At-labelled antibodies , GO or unlabelled antibodies as controls . We also measured caspase-3/7 activity , DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free ( 211)At . RESULTS The mean labelling ratio of ( 211)At-labelled antibodies was 1:1,090 +/- 364 ( range : 1:738-1:1,722 ) in comparison to 2-3:1 for GO . Tumour cell binding of ( 211)At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33 . ( 211)At-anti-CD33 decreased survival significantly more than did GO at comparable dilution ( 1:1,000 ) . No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after ( 211)At-anti-CD33 ( 1:1,090 ) versus GO ( 1:1 ) treatment . CONCLUSION Our results suggest that ( 211)At is a promising , highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody . Labelling techniques leading to higher chemical yield and specific activities must be developed to increase ( 211)At-anti-CD33 therapeutic effects .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "20107790"}
{"sentence": "The transcription factor NF-kappaB is constitutively active in pancreatic adenocarcinoma . Here we explore the contribution of NF-kappaB to the malignant phenotype of pancreatic cancer cells in addition to its anti-apoptotic role . Block of NF-kappaB signalling by non-destructible IkappaBalpha rendered cells resistant to TGF-beta-induced epithelial-mesenchymal transition ( EMT ) . In contrast , NF-kappaB activation by TNF-alpha or expression of constitutively active IKK2 induced an EMT-phenotype with up-regulation of vimentin and ZEB1 , and down-regulation of E-cadherin . EMT could also be induced in cells with defective TGF-beta signalling . Functional assays demonstrated reduced or strongly enhanced migration and invasion upon NF-kappaB inhibition or activation , respectively .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "20350779"}
{"sentence": "As a member of peroxiredoxin ( Prx ) family , PrxIII is predominantly located in mitochondria and plays an important role as a scavenger of reactive oxygen species ( ROS ) . Since previous reports demonstrated over-expression of PrxIII in cervical cancer , we conducted the present study to investigate the significance of PrxIII in cervical cancer development and/or progression . Cervical cancer cells were cultured from tissues derived from cervical cancer patients . After successful knockdown of PrxIII expression by small interfering RNA , we evaluated ROS level , viable cell number , and apoptosis of cervical cancer cells along with the culture time . The production of ROS was increased in cervical cancer cells as compared with normal cervical epithelia . Knockdown of PrxIII expression induced up-regulation of other Prx members including PrxI , PrxII , and PrxV . ROS level was higher in down-regulated cervical cancer cells than in controls and the difference was increasing with culture time . We also observed increased apoptosis and decreased viable cell number in down-regulated cervical cancer cells . Our results suggest that PrxIII is an indispensable ROS scavenger , which protects tumor cells against oxidative damage and subsequent apoptosis .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23772374"}
{"sentence": "Elevated insulin-like growth factor binding protein-related protein 1 ( IGFBP-rP1 ) mRNA in senescent human mammary epithelial cells suggested that the IGFBP-3 gene product may inhibit cell proliferation . To test this hypothesis , we used a retroviral vector to express IGFBP-rP1 cDNA in the IGFBP-rP1-deficient MCF-7 breast cancer cell line . Compared with control vector-transduced cells , cumulative cell numbers for IGFBP-rP1-transduced polyclonal or clonal cell cultures were reduced by 39 and 74% , respectively , after 1 week . Medium conditioned by IGFBP-rP1-producing cultures reduced cumulative cell numbers in parental MCF-7 cultures by 20% compared with medium from cultures of a control vector-transduced cell line . Nuclear fragmentation analysis and cell proliferation assays completed in the presence of the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone excluded apoptosis as the responsible mechanism . The percentage of cells containing senescence-associated beta-galactosidase activity was doubled compared with control cell cultures . Flow cytometry analysis indicated that twice as many noncycling cells were present in the IGFBP-rP1-transduced MCF-7 cell cultures compared with controls . These findings indicate that IGFBP-rP1 is an inhibitor of MCF-7 breast cancer cell proliferation and may act via a cellular senescence-like mechanism .", "label": [0, 0, 0, 1, 0, 0, 0, 1, 1, 0], "id": "12065244"}
{"sentence": "Animal studies indicate that the immune system is one of the most sensitive targets of the toxic effects of 2,3,7,8-tetrachloro-p-dibenzodioxin ( TCDD ) . TCDD inhibits immunoglobulin secretion and decreases resistance to bacterial , viral , and parasitic infections in exposed animals . Nearly 20 years after the Seveso , Italy , accident , we measured immunoglobulin and complement plasma levels in a random sample of the population in the most highly exposed zones ( n = 62 ) and in the surrounding noncontaminated area ( n = 58 ) . Plasma IgG levels decreased with increasing TCDD plasma concentration ( r = -0.35 , p = 0.0002 ) . Median IgG concentration decreased from 1,526 mg/dL in the group with the lowest ( < 3.5 ppt ) TCDD levels to 1,163 mg/dL in the group with the highest ( 20.1-89.9 ppt ) TCDD levels ( p = 0.002 ) . The association was significant ( p = 0.0004 ) after adjusting for age , sex , smoking , and consumption of domestic livestock and poultry in multiple regression analysis and persisted after exclusion of subjects with inflammatory diseases and those using antibiotics or nonsteroidal anti-inflammatory drugs . IgM , IgA , C3 , and C4 plasma concentrations did not exhibit any consistent association with TCDD levels . We performed a systematic review of all the articles published between 1966 and 2001 on human subjects exposed to TCDD reporting information on circulating levels of immunoglobulins and/or complement components . The literature indicates that the evidence for effects of TCDD on humoral immunity is sparse . Methodologic issues , results , and possible sources of variation between studies are discussed . The possible long-term immunologic effects of TCDD exhibited by the participants of the present study , coupled with the increased incidence of lymphatic tumors in the area of the accident , warrant further investigation .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12460794"}
{"sentence": "OBJECTIVE To design and develop a novel , sensitive and versatile method for in vivo foot printing and studies of DNA damage , such as DNA adducts and strand breaks . METHODS Starting with mammalian genomic DNA , single-stranded products were made by repeated primer extension , these products were ligated to a double-stranded linker having a randomized 3 ' overhang , and used for PCR . DNA breaks in p53 gene produced by restriction endonuclease AfaI were detected by using this new method followed by Southern hybridization with DIG-labeled probe . RESULTS This randomized terminal linker-dependent PCR ( RDPCR ) method could generate band signals many-fold stronger than conventional ligation-mediated PCR ( LMPCR ) , and it was more rapid , convenient and accurate than the terminal transferase-dependent PCR ( TDPCR ) . CONCLUSION DNA strand breakage can be detected sensitively in the gene level by RDPCR . Any lesion that blocks primer extension should be detectable .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12500660"}
{"sentence": "BACKGROUND Inactivation of p53 is involved in arsenite-induced tumorigenesis ; however , the molecular mechanisms remain poorly understood . OBJECTIVE We investigated the molecular mechanisms underlying the inactivation of p53 and neoplastic transformation induced by arsenite in human embryo lung fibroblast ( HELF ) cells . METHODS Anchorage-independent growth assays were performed , and tumorigenicity in intact animals was assessed to confirm arsenite-induced neoplastic transformation . We determined the levels and functions of p53 , nuclear factor-kappa B ( NF-B ; a key transcriptional regulator ) , and mot-2 ( a p53 inhibitor ) and their relationships in arsenite-induced transformed HELF cells by two-dimensional electrophoresis , reverse-transcriptase polymerase chain reaction , Western blot , immunofluorescence , and co-immunoprecipitation assays . RESULTS Exposure of HELF cells to low levels of arsenite increased their proliferation rate and anchorage-independent growth and disrupted normal contact inhibition . When introduced into nude mice , transformed cells were tumorigenic . We used proteomic analysis to identify proteins with altered expression between untreated and arsenite-exposed cells . We found decreased expression of NF-B repressing factor ( NKRF ; an inhibitor of NF-B-mediated gene transcription ) , increased expression of mot-2 , and increased activation of NF-B . Changes in cells exposed to 1.0 microM arsenite were more marked than changes in cells exposed to 0.5 or 2.0 microM arsenite . Inactivation of NF-B prevented malignant transformation induced by 1.0 microM arsenite . Moreover , we also identified a mechanism whereby NF-B regulated p53 . Specifically , activation of NF-B up-regulated mot-2 expression , which prevented nuclear translocation of p53 and switched the binding preference of the p53 and NF-B coactivator CBP [ cyclic AMP-responsive element binding protein ( CREB ) binding protein ] from p53 to NF-B . CONCLUSIONS mot-2-mediated cross talk between NF-B and p53 appears to be involved in arsenite-induced tumorigenesis of HELF cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20199942"}
{"sentence": "Pegylated Interferon-\u03b12b ( pIFN-\u03b1 ) is an integral part of the drug regimen currently employed against melanoma . Interferon Regulatory Factor-1 ( IRF-1 ) plays an important role in the transcriptional regulation of the IFN response , cell cycle and apoptosis . We have studied pIFN-\u03b1 induced responses when combined with the chemotherapy agent , vinblastine in tumor and endothelial cell lines and the connection to IRF-1 signaling . Levels of IRF-1/IRF-2 protein expression were found to be decreased in tumor versus normal tissues. pIFN-\u03b1 induced IRF-1 signaling in human melanoma ( M14 ) and endothelial ( EA.hy926 ) cells and enhanced cell death when combined with vinblastine . Upon combined IFN-\u03b1 and vinblastine treatment , p21 expression , PARP cleavage and activated Bak levels were increased in M14 cells . An increase in p21 and cyclin D1 expression occurred in EA.hy926 cells after 6 h of treatment with pIFN-\u03b1 which dissipated by 24 h . This biphasic response , characteristic of cellular senescence , was more pronounced upon combined treatment . Exposure of the EA.hy926 cells to pIFN-\u03b1 was associated with an enlarged , multinucleated , \u03b2-galactosidase-positive senescent phenotype . The overall therapeutic mechanism of IFN-\u03b1 combined with chemotherapy may be due to both direct tumor cell death via IRF-1 signaling and by premature senescence of endothelial cells and subsequent effects on angiogenesis in the tumor microenvironment .", "label": [0, 0, 0, 1, 1, 0, 1, 1, 0, 0], "id": "21197417"}
{"sentence": "We have evaluated DNA damage ( DNA adduct formation ) after feeding benzo[a]pyrene ( BP ) to wild-type ( WT ) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53 . DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry ( HPLC/ES-MS/MS ) , which measures r7,t8,t9-trihydroxy-c-10-(N ( 2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene ( BPdG ) , and a chemiluminescence immunoassay ( CIA ) , using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene ( BPDE)-DNA antiserum , which measures both BPdG and the other stable BP-DNA adducts . When mice were fed 100 ppm BP for 28 days , BP-induced DNA damage measured in esophagus , liver and lung was typically higher in Xpa(-/-)p53(+/-) mice , compared with WT mice . This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice . BPdG , the major DNA adduct associated with tumorigenicity , was the primary DNA adduct formed in esophagus ( a target tissue in the mouse ) , whereas total BP-DNA adducts predominated in higher levels in the liver ( a non-target tissue in the mouse ) . In an attempt to lower BP-induced DNA damage , we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin ( CHL ) in the BP-containing diet for 28 days . The addition of CHL resulted in an increase of BP-DNA adducts in esophagus , liver and lung of WT mice , a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice . Therefore , the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect , indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "22828138"}
{"sentence": "Amyloid precursor protein ( APP ) altered metabolism , A\\u03b2-overproduction/aggregation and oxidative stress are implicated in the development of Alzheimer's disease pathology . Based on our previous data indicating that administration of a polyphenol-rich ( PrB ) blueberry extract ( from wild Vaccinium angustifolium ) is memory enhancing in healthy mice and in order to delineate the neuroprotective mechanisms , this study investigated the antioxidant effects of PrB in H\\u2082O\\u2082-induced oxidative damage , A\\u03b2 peptide fibrillogenesis and APP metabolism . PrB suppressed H\\u2082O\\u2082-initiated oxidation ( DCF assay ) and cell death ( MTT assay ) in SH-SY5Y cells . Protective effects were observed on Chinese hamster ovary ( CHO ) cells overexpressing APP770 carrying the mutation Val717Phe only at high concentrations , while further damage on HEK293 cells was induced after co-treatment with 250\u2009\u00b5M H\\u2082O\\u2082 and PrB in comparison with H\\u2082O\\u2082 alone . Using the thioflavine T assay , blueberry polyphenols inhibited A\\u03b2-aggregation ( 15\u2009\u00b5g/mL ) in a time-dependent manner , while in the CHO(APP770) cells it had no effect on APP metabolism as assessed by western blot . The results suggest that blueberry polyphenols exhibit antioxidant and/or pro-oxidant properties according to the cellular environment and have no effect on APP metabolism .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22086824"}
{"sentence": "Dietary antioxidants , such as the carotenoids , may protect DNA from oxidative damage . This has been proposed to explain the epidemiological association between higher consumption of fruits and vegetables , which are rich in antioxidants , and lower incidence of cancer . However , this remains to be demonstrated conclusively . The effects of carotenoid supplementation on 1 ) baseline DNA damage , 2 ) susceptibility of cellular DNA to oxidative attack , and 3 ) DNA repair were measured in the human lymphocyte cell line Molt-17 . Baseline DNA damage , susceptibility to oxidant attack ( 100 mumol/l H2O2 for 5 min at 4 degrees C ) , and disappearance of DNA single-strand breaks ( SSB ) after oxidative challenge were monitored by single-cell gel electrophoresis . DNA repair patch synthesis activity in cell extracts was determined using assays that measure nucleotide incorporation during repair of oxidative lesions in template DNA . Unlike single-cell gel electrophoresis , the parameters measured with these assays are not dependent on strand break religation . There was no evidence that beta-carotene , lutein , or beta-cryptoxanthin supplementation protected cellular DNA from oxidation under basal conditions or after oxidative challenge . However , only carotenoid-supplemented cells exhibited a significant decrease in numbers of SSB over a 2-h period after treatment with H2O2 . Carotenoid supplementation did not provoke any detectable change in repair patch synthesis activity . We conclude that supplementation with carotenoids at 8 mumol/l does not provide significant antioxidant protection for DNA in Molt-17 lymphocytes but may enhance recovery of cells from oxidative challenge , as measured by loss of SSB . We argue that these data are most consistent with carotenoids acting to enhance DNA strand break repair .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 1], "id": "12588700"}
{"sentence": "In mice fed a diet supplemented with red clover isoflavones the prostatic epithelium displays a significant increase in the production of estrogen receptor beta and the adhesion protein E-cadherin but a decrease in transforming growth factor beta1 . These proteins are estrogenically-induced markers of proliferation , maintenance of histological architecture , preservation of cell phenotype and reduction of the potential for neoplastic and metastatic transformation . This study suggests that red clover isoflavones represent a non-toxic dietary treatment for prostatic hyperplasia and a reduction in the potential for neoplastic transformation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "15195125"}
{"sentence": "Treatment for glioblastoma multiforme includes the alkylating agent temozolomide combined with ionizing radiation . Persistent O6-guanine methylation by temozolomide in O6-methylguanine methyl transferase negative tumors causes cytotoxic lesions recognized by DNA mismatch repair , triggering apoptosis . Resistance ( intrinsic or acquired ) presents obstacles to successful temozolomide treatment , limiting drug efficacy and life expectancy . Two glioma cell lines , SNB19 and U373 , sensitive to temozolomide ( GI(50) values 36 and 68 microM , respectively ) were exposed to increasing temozolomide concentrations ( 1-100 microM ) . Variant cell lines ( SNB19VR , U373VR ) were generated that displayed acquired temozolomide resistance ( GI(50) values 280 and 289 microM , respectively ) . Cross-resistance to mitozolomide was observed in U373VR cells only . In clonogenic and MTT assays , methylguanine methyltransferase ( MGMT ) depletion using O6-benzylguanine sensitized U373VR cells to temozolomide , indicating the resistance mechanism involves MGMT re-expression . Indeed , Western blot analyses revealed MGMT protein in cell lysates . In SNB19VR cells , down-regulation of MSH6 message and protein expression may confer temozolomide tolerance . Inhibition of poly(ADP-ribose) polymerase-1 ( a key base excision repair ( BER ) enzyme ) partially restored sensitivity , and DNA repair gene arrays demonstrated up-regulation ( >5-fold ) of BER gene NTL1 in SNB19VR cells . In conclusion , we have developed two glioma cell lines whose distinct mechanisms of acquired resistance to temozolomide , involving expression of MGMT , or inactivation of DNA mismatch repair and recruitment of BER enzymes , are consistent with clinical observations . These cell lines provide valuable models for the development of strategies to combat temozolomide resistance .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20357518"}
{"sentence": "C-reactive protein is produced in response to cytokines such as interleukin ( IL)-6 . It is known that increased plasma IL-6 levels induce increased hepatic and intratumoral production of C-reactive protein . Cyclooxygenase enzyme-2 is induced by various stimuli , including inflammation and various growth factors . Expression of these two markers has not been well studied in clear cell renal cell carcinoma . The objective of this study is to correlate the expression of C-reactive protein and cyclooxygenase enzyme-2 in clear cell renal cell carcinoma with pathologic parameters . A search of the surgical pathology and consultation files at our institution was performed for nephrectomy specimens with clear cell renal cell carcinoma from 2007 to 2008 . Immunohistochemical stains for C-reactive protein and cyclooxygenase enzyme-2 were performed . Staining intensity was graded as 0 , 1+ , 2+ , and 3+ . The staining intensity was then correlated with pathologic stage and Fuhrman nuclear grade for each case . A total of 110 cases were identified . Strong expression of C-reactive protein was associated with higher Fuhrman nuclear grade and pathologic stage , and the strength of correlation was statistically significant ( p\u2009=\u20090.01 and p\u2009=\u20090.001 ) , respectively . However , cyclooxygenase enzyme-2 expression did not show statistically significant correlation with both pathologic stage and Fuhrman nuclear grade ( p\u2009=\u20090.1 and p\u2009=\u20090.15 ) , respectively . To our knowledge , this is the largest study to date correlating the expression of both C-reactive protein and cyclooxygenase enzyme-2 in tissue with pathologic parameters in patients with clear cell renal cell carcinoma , which could have significant prognostic and therapeutic implications .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "21086092"}
{"sentence": "OBJECTIVE To explore the adduct characteristics of styrene and DNA . METHODS The adduct reactions between styrene , urinary mandalic acid(MA) , phenylglyoxalic acid(PGA) , mercapturic acid of styrene ( UMA ) and DNA were studied by ultraviolet spectral analysis . The SO-DNA adducts by 32P-post labeled method , the chemical structures of SO-DNA adducts by GC-MS and NMR were also studied . RESULTS SO combined with DNA at O6 , N2 positions of dGMP to form six adducts , but styrene , urinary mandalic acid , phenylglyoxalic acid and mercapturic acid of styrene did not react with DNA to form adduct . CONCLUSIONS Styrene formed adduct with DNA through its active center metabolite--SO after entering the body . SO combined with DNA at O6 , N2 positions of dGMP to form adducts . If these DNA adducts are not repaired or are mis-repaired before cell duplication , the gene mutation and chemical damage would happen . No adduct reactions are seen among other metabolites of styrene .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "14694722"}
{"sentence": "Environmental or occupational exposure to low doses of arsenic induces a series of health problems including cancer . The molecular events in arsenic-induced carcinogenicity remain to be defined . In the NuLi-1 immortalized human lung epithelial cell line with p53 and pRb deficiency , exposure to low doses of arsenic trioxide for 72\u2009h promoted cell proliferation and upregulated the gene transcription levels of FOXM1 , CDC6 , CDC25A , and cyclin D1 , which are both critical cell cycle regulatory genes and proto-oncogenes . Continuous in vitro exposure to 1\u2009\ufffdM arsenic trioxide for 34 wks induced malignant cell transformation , as evidenced by enhanced anchorage-independent cell growth . The expression of FOXM1 , CDC6 , CDC25A , and Cyclin D1 was dynamically elevated at the gene transcription and protein levels in the process of cell transformation . The carcinogenic ability of transformed cell colonies coincides with the expression levels of FOXM1 in in vitro anchorage-independent growth assays and in vivo tumor xenograft formation assays . In reverse , the knockdown of FOXM1 in lung adenocarcinoma A549 cells or arsenic-transformed NuLi-1 cells significantly decreased anchorage-independent cell growth and tumor xenograft formation . The transformed NuLi-1 cells showed genomic instability in the form of copy number variation ( CNV ) at chromosome 1 , 5 , 6 , 18 , and 20 , but not loss of heterozygosity ( LOH ) . These results showed for the first time that chronic exposure to low doses of arsenic trioxide promoted lung carcinogenicity , in part by aberrantly upregulating FOXM1 and its associated oncogenes , when the tumor suppressor genes p53 and pRb were inactivated. \ufffd 2012 Wiley Periodicals , Inc .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23255470"}
{"sentence": "Vasohibin-1 ( VASH1 ) is isolated as an endothelial cell ( EC)-produced angiogenesis inhibitor . We questioned whether VASH1 plays any role besides angiogenesis inhibition , knocked-down or overexpressed VASH1 in ECs , and examined the changes of EC property . Knock-down of VASH1 induced premature senescence of ECs , and those ECs were easily killed by cellular stresses . In contrast , overexpression of VASH1 made ECs resistant to premature senescence and cell death caused by cellular stresses . The synthesis of VASH1 was regulated by HuR-mediated post-transcriptional regulation . We sought to define the underlying mechanism . VASH1 increased the expression of ( superoxide dismutase 2 ) SOD2 , an enzyme known to quench reactive oxygen species ( ROS ) . Simultaneously , VASH1 augmented the synthesis of sirtuin 1 ( SIRT1 ) , an anti-aging protein , which improved stress tolerance . Paraquat generates ROS and causes organ damage when administered in vivo . More VASH1 ( +/- ) mice died due to acute lung injury caused by paraquat . Intratracheal administration of an adenovirus vector encoding human VASH1 augmented SOD2 and SIRT1 expression in the lungs and prevented acute lung injury caused by paraquat . Thus , VASH1 is a critical factor that improves the stress tolerance of ECs via the induction of SOD2 and SIRT1 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "23056314"}
{"sentence": "Here we report that miR-93 , a miRNA in the miR-106B cluster , a paralog of the miR-17-92 cluster , was significantly upregulated in human breast carcinoma tissues . We stably expressed miR-93 in the MT-1 human breast carcinoma cell line and found that tumors formed by the miR-93 cells contained more blood vessels than those formed by the control cells . Co-culture experiments indicated that the MT-1 cells displayed a high activity of adhesion with endothelial cells and could form larger and more tube-like structures with endothelial cells . Lung metastasis assays were performed in a mouse metastatic model , and it was found that expression of miR-93 promoted tumor cell metastasis to lung tissue . In cell culture , expression of miR-93 enhanced cell survival and invasion . We examined the potential target that mediated miR-93's effects and found that the large tumor suppressor , homology 2 ( LATS2 ) was a target of miR-93 . Higher levels of LATS2 were associated with cell death in the tumor mass . Silencing LATS2 expression promoted cell survival , tube formation and invasion , while ectopic expression of LATS2 decreased cell survival and invasion . These findings demonstrated that miR-93 promoted tumor angiogenesis and metastasis by suppressing LATS2 expression . Our results suggest that the inhibition of miR-93 function may be a feasible approach to repress tumor metastasis .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23111389"}
{"sentence": "BACKGROUND & AIMS Hepatocellular carcinoma ( HCC ) is an aggressive malignancy with few treatment options . As the status of the tumour immune microenvironment can affect progression of established tumours , we evaluated potential immune mechanisms associated with survival in HCC . METHODS Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry . Tumour-infiltrating leukocytes ( TILs ) were isolated to verify the expression of immune genes and to identify proliferating TILs . These parameters were analyzed statistically in relation with patient survival and tumour phenotype ( apoptosis and proliferation ) . RESULTS The immune microenvironment within tumours was found to be heterogeneous , although globally more inert compared to the adjacent non-tumour liver tissue . Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival . TNF , IL6 and CCL2 are the most significant genes , with TNF being an independent predictor of survival in multivariate analysis . The gene set includes macrophage and NK-associated molecules such as TLR4 , TLR3 , CCR2 , NCR3 . Most of these molecules are expressed by TILs . Importantly , proliferating immune cells , predominantly NK and T cells , are present in tumours of patients with longer survival , and exclusively in areas devoid of proliferating tumour cells . NK and CD8(+) T cell densities are correlated positively with tumour apoptosis , and negatively with tumour proliferation . CONCLUSIONS Hence , an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "19720422"}
{"sentence": "Meningiomas constitute of primary intracranial tumors and are associated with increased mortality in NF2 patients . To evaluate potential medical therapies for these tumors , we have established a quantifiable orthotopic model for NF2-deficient meningiomas . We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein , merlin . We also demonstrated that AR-42 , a pan-histone deacetylase inhibitor , inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16INK4A , p21CIP1/WAF1 , and p27KIP1 . Also , AR-42 increased pro-apoptotic Bim expression and decreased anti-apoptotic BclXL levels . However , AR-42 predominantly arrested Ben-Men-1 cells at G2/M , while inducing cell-cycle arrest at G1 in meningeal cells . Consistently , AR-42 substantially decreased the levels of cyclin D1 , E , and A , and PCNA in meningeal cells while significantly reducing the expression of cyclin B , important for progression through G2 , in Ben-Men-1 cells . In addition , AR-42 decreased Aurora A and B expression . To compare the in vivo efficacies of AR-42 and AR-12 , a PDK1 inhibitor , we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time . While AR-12 treatment moderately slowed tumor growth , AR-42 caused regression of Ben-Men-1-LucB tumors . Importantly , AR-42-treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet . Together , these results suggest that AR-42 is a potential therapy for meningiomas . The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23151902"}
{"sentence": "It is still difficult to decide on the treatment modalities for advanced esophageal carcinoma when the prognostic factors of T4 esophageal cancer are not fully understood . In this article , we report that among 71 patients with T4 thoracic esophageal cancer , 49 underwent esophagectomy , 9 had curative resection ( R0 group ) , and 40 had palliative resection ( R1/2 group ) . A total of 22 patients had palliative treatments : bypass in 5 ( bypass group ) , gastrostomy or jejunostomy in 6 ( stoma group ) , and radiochemotherapy alone in 11 ( nonoperation group ) . Clinicopathologic characteristics were retrospectively investigated . Treatment-related deaths occurred in 7 ( 10% ) : none in R0 , 3 ( 8% ) in R1/2 , 3 ( 60% ) in bypass , and 1 ( 17% ) in stoma group . Swallowing was improved in 50 ( 70% ) patients : 9 ( 100% ) in R0 , 30 ( 75% ) in R1/2 , 1 ( 20% ) in bypass , 3 ( 50% ) in stoma , and 7 ( 64% ) in the nonoperation group . One- , two- , and three-year overall survival rates were 56% , 22% , and 22% in the R0 group and 35% , 19% and 6% in the R1/2 group , respectively ( p = 0.19 ) . In the bypass , stoma , and nonoperation groups , none survived 1.6 years . The factors influencing the survival rate of the 49 patients undergoing esophagectomy were grade of lymph node metastasis , amount of perioperative blood transfusion , lymph vessel , and blood vessel invasion . Among these , independent prognostic factors for survival were amount of blood transfusion ( -6 units vs. -7 units , p <0.0001 ) and grade of lymph node metastasis [ none- or peritumoral [ lymph nodes adjacent to the main tumor or at a nearby location ( <3 cm ) from the tumor ] metastasis vs. more distant metastasis [ lymph nodes at a distant location ( > 3 cm) ] , p = 0.016 ] . Bypass and stoma operation neither prolonged the survival nor improved the difficulty of swallowing compared with radiochemotherapy alone . Esophagectomy can achieve the best improvement of swallowing and the longest survival with an acceptable mortality rate . Esophageal carcinoma patients with T4 disease and distinct metastasis in the lymph nodes at a distant location ( >3 cm ) from the primary tumor may not benefit from an esophageal resection .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12355140"}
{"sentence": "The neurofibromatosis type 2 ( NF2 ) tumor suppressor gene encodes merlin , a membrane/cytoskeleton protein necessary for the maintenance of contact inhibition of growth in cells . Bi-allelic inactivation of NF2 is known to cause multiple cancers in both humans and mice . However , the mechanism through which merlin exerts its tumor-suppressive function remains obscure . In this report , we show that NF2 knockout mouse embryonic fibroblasts lost contact inhibition of cell proliferation and contained significantly increased canonical Wnt signaling . Inhibition of Rac1 , the activity of which is inversely regulated by NF2 , through the use of a dominant-negative mutant , small hairpin RNA or a small molecule inhibitor in NF2-deficient cells , was able to suppress elevated Wnt signals as shown by reduced activity of the T-cell factor 4 ( TCF4 ) transcription factor . Dominant-negative TCF4 or Rac1 mutant , as well as a small molecule inhibition of Wnt , were able to curb NF2 deficiency-elicited cell proliferation at the confluent state . Thus , Rac1-mediated canonical Wnt signaling is essential for the loss of contact inhibition in NF2-deficient cells .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "20154721"}
{"sentence": "Omeprazole is a proton pump inhibitor , a widely used drug to treat ulcers and gastroesophageal refluxdisease . We have evaluated colon cancer chemopreventive properties of omeprazole using azoxymethane ( AOM)-induced colonic aberrant crypt foci ( ACF ) in male F344 rats and analyzed cell growth inhibition and apoptosis induction in human colon cancer cells . Five-week-old male F344 rats were fed a control or experimental diet containing two doses of omeprazole ( 200 and 400ppm ) . After one week , all animals were s.c. injected with AOM ( 15mg/kg body weight , once weekly for two weeks ) . Rats continued on experimental diets for seven more weeks before being sacrificed . Colons were histopathologically evaluated for ACF . Human colon cancer HCT-116 and HCA-7 cells treated with omeprazole were evaluated for different markers associated with proliferation and apoptotic markers using Western blot technique . Rats fed with 200 and 400ppm of omeprazole significantly suppressed total colonic ACF formation ( P<0.001 ) and showed significant suppression of multi-crypt foci ( P<0.05-0.001 ) . Omeprazole produced significant dose-response effects on inhibition of multi-crypt foci ( \u22654 ) . Omeprazole treatment in human colon cancer cell lines HCT-116 and HCA-7 cells resulted in induction of p21waf1/cip1 and decreased the expression of anti-apoptotic proteins Bcl-2 , Bcl-XL and survivin in a dose-dependent manner . Anticancer properties observed in colon cancer cell lines suggest that omeprazole may induce key signaling molecules of antiproliferation and inhibition of anti-apoptotic proteins .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21956158"}
{"sentence": "Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression , and most human lung tumors express estrogen receptor \u03b2 ( ER\u03b2 ) as well as aromatase . To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen , alone or in combination with the ER antagonist fulvestrant , ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone ( NNK ) along with daily supplements of androstenedione , the substrate for aromatase . Placebo , anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis . The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors ( mean = 0.5 ) compared with placebo ( mean = 4.6 , P < 0.001 ) , fulvestrant alone ( mean = 3.4 , P < 0.001 ) or anastrozole alone ( mean = 2.8 , P = 0.002 ) . A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups . Beginning antiestrogen treatment after NNK exposure , when preneoplastic lesions had already formed , also yielded maximum antitumor effects with the combination . Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs , whereas ER\u03b2 was found in both macrophages and tumor cells . Antiestrogens , especially in combination , effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention . An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens , beginning early in the carcinogenesis process . ER\u03b2 expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22859269"}
{"sentence": "Splenic haemangiosarcomas ( HSAs ) from 122 dogs were characterized and classified according to their patterns of growth , survival time post splenectomy , metastases and chemotherapy . The most common pattern of growth was a mixture of cavernous , capillary and solid tumour tissue . Survival time post splenectomy was independent of the growth pattern ; however , it was influenced by chemotherapy and metastases . Immunohistochemical assessment of the expression of angiogenic factors ( fetal liver kinase-1 , angiopoietin-2 , angiopoietin receptor-2 and vascular endothelial growth factor A ) and conventional endothelial markers ( CD31 , factor VIII-related antigen ) revealed variable expression , particularly in undifferentiated HSAs . Therefore , a combination of endothelial markers should be used to confirm the endothelial origin of splenic tumours .", "label": [1, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23276383"}
{"sentence": "FZR1 is an anaphase-promoting complex ( APC ) activator best known for its role in the mitotic cell cycle at M-phase exit , in G1 , and in maintaining genome integrity . Previous studies also established that it prevents meiotic resumption , equivalent to the G2/M transition . Here we report that mouse oocytes lacking FZR1 undergo passage through meiosis I that is accelerated by h , and this is due to an earlier onset of spindle assembly checkpoint ( SAC ) satisfaction and APC(CDC20) activity . However , loss of FZR1 did not compromise SAC functionality ; instead , earlier SAC satisfaction was achieved because the bipolar meiotic spindle was assembled more quickly in the absence of FZR1 . This novel regulation of spindle assembly by FZR1 led to premature bivalent attachment to microtubules and loss of kinetochore-bound MAD2 . Bivalents , however , were observed to congress poorly , leading to nondisjunction rates of 25% . We conclude that in mouse oocytes FZR1 controls the timing of assembly of the bipolar spindle and in so doing the timing of SAC satisfaction and APC(CDC20) activity . This study implicates FZR1 as a major regulator of prometaphase whose activity helps to prevent chromosome nondisjunction .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22918942"}
{"sentence": "The aberrant expression of human epidermal growth factor receptor-2 ( HER-2 ) has been detected in ovarian cancer . However , the role of HER-2 in the development of ovarian cancer has not been sufficiently elucidated . The objective of this study was to determine the role of HER-2 in the apoptosis and metastasis of SKOV-3 ovarian cancer cells . SKOV-3 cells were transfected with three double\u2011stranded small interfering RNA ( siRNA ) molecules that target HER-2 . Various sequences were synthesized by T7 transcription invitro to select the most effective HER-2\u2011silencing siRNA . SKOV-3 cells were examined for growth inhibition using the MTT proliferation assay and apoptosis was assessed using flow cytometry and TUNEL assay . The Matrigel basement memebrane matrix was used to assess invasion and chemotactic mobility , as a model of tumor cell metastasis . Western blot analysis was used to detect the expression of matrix metallopeptidase-9 ( MMP-9 ) , E-cadherin , N-cadherin and vimentin. siRNA interference in HER-2 resulted in decreased cell proliferation and invasion and increased apoptosis . Western blot analysis demonstrated a marked increase in E-cadherin and MMP-9 and a reduction in N-cadherin and vimentin protein levels in the SKOV-3 cells . The suppression of HER-2 expression resulted in apoptosis and the inhibition of metastasis of SKOV-3 cells . Therefore , the overexpression of the HER-2 gene can enhance the metastatic potential of SKOV-3 cells by increasing the protein levels of MMP-9 . Epithelial-mesenchymal transition may be involved in the HER-2 siRNA-induced invasion and migration of SKOV-3 cells . Taken together , these results suggest that HER-2 functions as an oncogene and may thus be an attractive therapeutic target in SKOV-3 ovarian cancer cells .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "23292493"}
{"sentence": "BACKGROUND Exposure to high doses of ionizing radiation ( IR ) can lead to localized radiation injury of the skin and exposed cells suffer dsDNA breaks that may elicit cell death or stochastic changes . Little is known about the DNA damage response after high-dose exposure of the skin . Here , we investigate the cellular and DNA damage response in acutely irradiated minipig skin . METHODS AND FINDINGS IR-induced DNA damage , repair and cellular survival were studied in 15 cm(2) of minipig skin exposed in vivo to Co-60 \\u03b3 rays . Skin biopsies of control and 4 h up to 96 days post exposure were investigated for radiation-induced foci ( RIF ) formation using \\u03b3-H2AX , 53BP1 , and active ATM-p immunofluorescence . High-dose IR induced massive \\u03b3-H2AX phosphorylation and high 53BP1 RIF numbers 4 h , 20 h after IR . As time progressed RIF numbers dropped to a low of <1% of keratinocytes at 28-70 days . The latter contained large RIFs that included ATM-p , indicating the accumulation of complex DNA damage . At 96 days most of the cells with RIFs had disappeared . The frequency of active-caspase-3-positive apoptotic cells was 17-fold increased 3 days after IR and remained >3-fold elevated at all subsequent time points . Replicating basal cells ( Ki67+ ) were reduced 3 days post IR followed by increased proliferation and recovery of epidermal cellularity after 28 days . CONCLUSIONS Acute high dose irradiation of minipig epidermis impaired stem cell replication and induced elevated apoptosis from 3 days onward . DNA repair cleared the high numbers of DBSs in skin cells , while RIFs that persisted in <1% cells marked complex and potentially lethal DNA damage up to several weeks after exposure . An elevated frequency of keratinocytes with persistent RIFs may thus serve as indicator of previous acute radiation exposure , which may be useful in the follow up of nuclear or radiological accident scenarios .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22761813"}
{"sentence": "Geraniol ( GOH ) , a naturally occurring monoterpene , has been shown to have antiproliferative , cell cycle arrest and apoptosis-inducing effects , and represents a promising cancer chemopreventive agent . In the present study , we investigated the chemopreventive potential of GOH ( 50 and 100\u2009mg\u2009kg(-1) body weight ) against 7,12-dimethylbenz[a]anthracene ( DMBA)/12-O-tetradecanoylphorbol 13-acetate ( TPA)-mediated skin tumorigenesis in Swiss albino mice . The topical treatment of GOH , 30\u2009min prior to TPA ( 2\u2009\u00b5g per 200\u2009\u00b5l of acetone ) treatment significantly inhibited TPA-induced skin edema , hyperplasia , COX-2 induction and oxidative stress response . The GOH treatment also resulted in reduction of TPA-induced ornithine decarboxylase activity and [ (3) H ] thymidine incorporation by 53% ( P\u2009<\u20090.001 ) and 41% ( P\u2009<\u20090.001 ) , respectively . We found that GOH treatment significantly inhibited the tumor incidence and number of tumors ( P\u2009<\u20090.001 ) and extended the latency period from 4\u2009weeks in DMBA/TPA treatment group to 10\u2009weeks in GOH-pretreated mice . Furthermore , we observed that GOH treatment significantly suppressed the Ras/Raf/ERK1/2 signaling pathway in skin tumor . Consistently , GOH-treated skin tumors showed reduced expression of Bcl-2 and increased expression of Bax in these lesions . Thus , it was concluded that GOH inhibits DMBA/TPA-mediated skin tumorigenesis by attenuating the Ras proliferation pathway and inducing pro-apoptotic state via inhibition of oxidative stress response and inflammation .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "22760862"}
{"sentence": "The purpose of this study was to determine the impact of the non-steroidal anti-inflammatory drug tepoxalin on canine tumour cell growth and describe the changes associated with tepoxalin treatment . In vitro experiments were performed to assess tepoxalin-associated alterations in tumour cell growth . Clinically achievable tepoxalin concentrations did not significantly alter tumour cell growth in vitro . Vascular endothelial growth factor ( VEGF ) production and hypoxia-inducible factor-1\u03b1 dose-dependently increased in vitro in the presence of tepoxalin . A canine osteosarcoma xenograft was used to determine in vivo effects of tepoxalin on tumour growth and angiogenesis . Despite increased VEGF in vitro , there was a significant growth delay associated with tepoxalin treatment . Normal dogs were administered tepoxalin to assess effects on systemic VEGF production , but not found to have significantly increased VEGF . These data suggest that tepoxalin may moderately inhibit tumour growth and may be administered as an analgesic to tumour-bearing dogs .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "21569197"}
{"sentence": "Basal cell hyperplasia classically has been described as having bland cytologic features . During the past 2 years , we have seen 12 cases ( 11 in consultation ) with atypical features that were confused with adenocarcinoma of the prostate . Eleven of these 12 cases contained prominent nucleoli mimicking carcinoma ; in the 12th case , nuclei were enlarged , hyperchromatic , and moderately pleomorphic . Immunohistochemistry with antibodies against high-molecular-weight cytokeratin ( 34 beta E12 ) was performed in nine of the cases , verifying their basal cell nature . Additional findings in these cases were necrotic intraluminal secretions ( two cases ) , immature squamous metaplasia ( two cases ) , peculiar hyaline cytoplasmic globules ( two cases ) , adenosis ( one case ) , markedly atypical nuclei of uncertain nature occurring elsewhere in the specimen ( one case ) , and intraluminal blue mucin ( two cases ) . We analyzed nine cases of typical basal cell hyperplasia , all of which showed classic features of basal cell hyperplasia with benign cytology . Both atypical and classical basal cell hyperplasia were frequently infiltrated by lymphocytes such that the cytologic changes could not be attributable to inflammation . Atypical basal cell hyperplasia must be differentiated from ordinary adenocarcinoma of the prostate , prostatic intraepithelial neoplasia , and basaloid carcinoma ( adenoid cystic carcinoma ) of the prostate .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 1], "id": "1281386"}
{"sentence": "A rat colonic adenocarcinoma was implanted subcutaneously ( s.c. ) in nude mice . After 7 days , the animals were divided into different groups . Two groups received subcutaneous injections twice daily with 3 or 6 micro g/kg body weight octreotide , galanin and serotonin . Three groups were respectively treated with 20 , 30 , and 40 micro g/kg body weight of the previously mentioned bioactive substances . Control group received only saline solution in the same fashion as treated animals . The treatment lasted for 5 days . The tumour volume and weight , the relative density of blood vessels , of tumour necrotic tissue , of apoptotic nuclei and of proliferating nuclei were measured . Apoptosis was detected by in situ labelling of nuclear DNA fragmentation according to TUNEL method , and proliferation by immunocytochemistry . Morphometry was done with the classical stereological point-counting method . Food consumption , animal weight , faeces weight and its water content were measured for 3 days before and after treatment . Triple therapy with 3 and 6 micro g/kg body weight had no effect on any of the parameters measured , except in reducing the relative volume density of tumour blood vessels . Treatment with 20 , 30 and 40 micro g/kg body weight of the previously mentioned bioactive substances reduced the tumour volume , the relative volume density of blood vessels and increased the relative volume density of necrotic tissue and of apoptotic nuclei ( in the 20 micro g group ) . However , there was no difference between treated mice and controls regarding the relative volume density of proliferating nuclei . There was no statistical difference between treated animals regarding food consumption , body weight , faeces weight and its water content before and during treatment . The present study confirms that triple therapy with octreotide , galanin and serotonin causes regression of a rat colon carcinoma . It further showed that optimum treatment dose is 20 micro g/kg body weight of each bioactive substance . Moreover , this therapy regime does not show apparent side effects in the experiments carried out on mice .", "label": [0, 0, 0, 0, 0, 0, 1, 1, 0, 0], "id": "12220727"}
{"sentence": "Thyroid hormone ( T(3) ) mediates cellular growth , development , and differentiation by binding to the nuclear thyroid hormone receptor ( TR ) . Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma ( HCC ) independent from other major HCC risk factors . Dickkopf ( DKK ) 4 , a secreted protein , antagonizes the Wnt signal pathway . In this study , we demonstrate that T(3) may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA ( mRNA ) and protein levels . DKK4 was down-regulated in 67.5% of HCC cancerous tissues . The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues . Further , TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis . In function assays , stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro . Conversely , knocking down DKK4 restores cell invasiveness . DKK4-expressing J7 clones showed increased degradation of \u03b2-catenin , but down-regulation of CD44 , cyclin D1 , and c-Jun . To investigate the effect of DKK4 and TR on tumor growth in vivo , we established a xenograft of J7 cells in nude mice . J7-DKK4 and J7-TR\u03b11 overexpressing mice , which displayed growth arrest , lower lung colony formation index , and smaller tumor size than in control mice , supporting an inhibitory role of DKK4 in tumor progression . CONCLUSION : Taken together , these data suggest that the TR/DKK4/Wnt/\u03b2-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21994129"}
{"sentence": "Adults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia ( ALL ) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse , supporting the need to use alternative therapies . CRLF2 encodes the thymic stromal lymphopoietin ( TSLP ) receptor , which activates cell signaling in normal lymphocytes on binding its ligand , TSLP . We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway . In a large number of primary CRLF2-rearranged ALL samples , we observed increased basal levels of pJAK2 , pSTAT5 , and pS6 . We thus characterized the biochemical sequelae of CRLF2 and JAK alterations in CRLF2-rearranged ALL primary patient samples via analysis of TSLP-mediated signal transduction . TSLP stimulation of these leukemias further induced robust JAK/STAT and PI3K/mTOR pathway signaling . JAK inhibition abrogated phosphorylation of JAK/STAT and , surprisingly , of PI3K/mTOR pathway members , suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials . The PI3K/mTOR pathway inhibitors rapamycin , PI103 , and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway , suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "22685175"}
{"sentence": "Many cancer cells metabolize glucose preferentially via pyruvate to lactate instead to CO(2) and H(2)O ( oxidative phosphorylation ) even in the presence of oxygen ( Warburg effect ) . Dichloroacetate ( DCA ) is a drug which is able to shift pyruvate metabolism from lactate to acetyl-CoA ( tricarboxylic acid cycle ) by indirect activation of pyruvate dehydrogenase ( PDH ) . This can subsequently lead to an increased flow of oxygen in the respiratory chain , associated with enhanced generation of reactive oxygen species ( ROS ) which may cause apoptosis . In order to investigate if DCA may be suitable for neuroblastoma therapy , it was investigated on three human neuroblastoma cell lines whether DCA can reduce lactate production and enhance oxygen consumption . The data show , that DCA ( in the low millimolar range ) is able to reduce lactate production , but there was only a slight shift to increased oxygen consumption and almost no effect on cell vitality , proliferation and apoptosis of the three cell lines investigated . Therefore , DCA at low millimolar concentrations seems to be only of minor efficacy for neuroblastoma treatment .", "label": [0, 0, 1, 0, 0, 0, 0, 1, 0, 0], "id": "22508045"}
{"sentence": "Proton radiotherapy has gained more favor among oncologists as a treatment option for localized and deep-seated tumors . In addition , protons are a major constituent of the space radiation astronauts receive during space flights . The potential for these exposures to lead to , or enhance cancer risk has not been well studied . Our objective is to study the biological effects of low energy protons on epithelial cells and its propensity to enhance transforming growth factor beta 1 ( TGF\u03b21)-mediated epithelial-mesenchymal transition ( EMT ) , a process occurring during tumor progression and critical for invasion and metastasis . Non-transformed mink lung epithelial cells ( Mv1Lu ) and hTERT- immortalized human esophageal epithelial cells ( EPC ) were used in this study . EMT was identified by alterations in cell morphology , EMT-related gene expression changes determined using real-time PCR , and EMT changes in specific cellular markers detected by immunostaining and western blotting . Although TGF\u03b21 treatment alone is able to induce EMT in both Mv1Lu and EPC cells , low energy protons ( 5 MeV ) at doses as low as 0.1 Gy can enhance TGF\u03b21 induced EMT . Protons alone can also induce a mild induction of EMT . SD208 , a potent TGF\u03b2 Receptor 1 ( TGF\u03b2R1 ) kinase inhibitor , can efficiently block TGF\u03b21/Smad signaling and attenuate EMT induction . We suggest a model for EMT after proton irradiation in normal and cancerous tissue based on our results that showed that low and high doses of protons can sensitize normal human epithelial cells to mesenchymal transition , more prominently in the presence of TGF\u03b21 , but also in the absence of TGF\u03b21 .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22844446"}
{"sentence": "Immortalization ( senescence bypass ) is a critical rate-limiting step in the malignant transformation of mammalian somatic cells . Human cells must breach at least two distinct senescence barriers to permit unfettered clonal evolution during cancer development : ( 1 ) stress- or oncogene-induced premature senescence ( SIPS/OIS ) , mediated via the p16-Rb and/or ARF-p53-p21 tumour-suppressive pathways , and ( 2 ) replicative senescence triggered by telomere shortening . In contrast , because their telomerase is constitutively active , cells from small rodents possess only the SIPS/OIS barrier , and are therefore useful for studying SIPS/OIS bypass in isolation . Dermal fibroblasts from the Syrian hamster ( SHD cells ) are exceptionally resistant to spontaneous SIPS bypass , but it can be readily induced following exposure to a wide range of chemical and physical carcinogens . Here we show that a spectrum of carcinogen-specific mutational and epigenetic alterations involving the INK4A ( p16 ) , p53 and INK4B ( p15 ) genes are associated with induced SIPS bypass . With ionizing radiation , immortalization is invariably accompanied by efficient biallelic deletion of the complete INK4/CDKN2 locus . In comparison , SHD cells immortalized by the powerful polycyclic hydrocarbon carcinogen benzo(a)pyrene display transversion point mutations in the DNA-binding domain of p53 coupled with INK4 alterations such as loss of expression of p15 . Epimutational silencing of p16 is the primary event associated with immortalization by nickel , a human non-genotoxic carcinogen . As SIPS/OIS bypass is a prerequisite for the immortalization of normal diploid human epithelial cells , our results with the SHD model will provide a basis for delineating combinations of key molecular changes underpinning this important event in human carcinogenesis .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "22410783"}
{"sentence": "The ATM/ATR DNA damage checkpoint functions in the maintenance of genetic stability and some missense variants of the ATM gene have been shown to confer a moderate increased risk of prostate cancer . However , whether inactivation of this checkpoint contributes directly to prostate specific cancer predisposition is still unknown . Here , we show that exposure of non-malignant prostate epithelial cells ( HPr-1AR ) to androgen led to activation of the ATM/ATR DNA damage response and induction of cellular senescence . Notably , knockdown of the ATM gene expression in HPr-1AR cells can promote androgen-induced TMPRSS2 : ERG rearrangement , a prostate-specific chromosome translocation frequently found in prostate cancer cells . Intriguingly , unlike the non-malignant prostate epithelial cells , the ATM/ATR DNA damage checkpoint appears to be defective in prostate cancer cells , since androgen treatment only induced a partial activation of the DNA damage response . This mechanism appears to preserve androgen induced autophosphorylation of ATM and phosphorylation of H2AX , lesion processing and repair pathway yet restrain ATM/CHK1/CHK2 and p53 signaling pathway . Our findings demonstrate that ATM/ATR inactivation is a crucial step in promoting androgen-induced genomic instability and prostate carcinogenesis .", "label": [0, 0, 0, 1, 0, 1, 0, 0, 0, 0], "id": "23272087"}
{"sentence": "Paragangliomas are relatively uncommon neoplasms that arise in adrenal and extra-adrenal paraganglia of the autonomic nervous system . Parasympathetic paraganglioma develop predominantly in the head and neck . It is exceedingly uncommon to develop a primary intraparathyroid paraganglioma . There is only a single case report in the English literature . The information from the single previous case report ( Medline 1960-2009 ) was combined with this case report . Our patient was a 69 year old woman who presented with a thyroid gland mass , with extension into the substernal space . The patient had a history of renal cell carcinoma removed 18 months before . At surgery , a thyroid lobectomy and a parathyroidectomy were performed . The parathyroid tissue showed a very well defined zellballen arrangement of paraganglion cells within the parenchyma of the parathyroid gland . The cells had ample basophilic , granular cytoplasm . The nuclei were generally round to oval with ' salt-and-pepper ' nuclear chromatin distribution . There was a richly vascularized stroma . Mitotic figures , necrosis , invasive growth , and profound nuclear pleomorphism were absent . The neoplastic cells were strongly and diffusely immunoreactive with chromogranin , synaptophysin , CD56 , and focally with cyclin-D1 . The paraganglioma showed a delicate S-100 protein positive supporting sustentacular framework . Keratin , CD10 , PTH , calcitonin and RCC markers were negative . The patient showed no stigmata of Multiple Endocrine Neoplasia ( MEN ) and has no paraganglioma in any other anatomic site . She is alive without any additional findings 12 months after surgery . Isolated paraganglioma within the parathyroid is rare , and should be separated from parathyroid adenoma , hyperplasia or metastatic disease to assure appropriate management .", "label": [1, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20237987"}
{"sentence": "The goal of this study was to determine the prevalence of sequence variants in the class I beta-tubulin ( clone m40 ) gene and their occurrence in human tumors and cancer cell lines . DNA was isolated from 93 control individuals representing a wide variety of ethnicities , 49 paclitaxel-naive specimens ( 16 ovarian cancers , 17 non-small cell lung cancers , and 16 ovarian cancer cell lines ) , and 30 paclitaxel-resistant specimens ( 9 ovarian cancers , 9 ovarian cancer cell lines , and 12 ovarian cancer xenografts in nude mice ) . Denaturing high-performance liquid chromatography and direct sequence analysis detected two silent polymorphisms in exon 4 , Leu217Leu ( CTG/CTA ) and Gly400Gly ( GGC/GGT ) , with minor allele frequencies of 17 and 0.5% , respectively . Five nucleotide substitutions and one single-base deletion were detected in introns 1 , 2 , and 3 and in the 3 ' untranslated region . Analysis of 49 paclitaxel-naive and 30 paclitaxel-resistant specimens revealed no additional polymorphisms in the coding region . In addition , no amino acid replacements were found in chimpanzee , gorilla , and orangutan in comparison to human . Our data demonstrate a very high degree of sequence conservation in class I beta-tubulin , suggesting that all residues are important in tubulin structure and function . Individual variation in response to treatment with paclitaxel is not likely to be caused by genetic variations in the beta-tubulin drug target . Moreover , acquired mutations in class I beta-tubulin are unlikely to be a clinically relevant cause of drug resistance .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12467216"}
{"sentence": "OBJECTIVE Expression of N-myc downstream-regulated gene 1 ( NDRG1)/Cap43 is a prognostic indicator of human malignancies according to the tumor type in which it occurs . We investigated how NDRG1/Cap43 could affect tumor growth and angiogenesis in non-small-cell lung cancer ( NSCLC ) in vivo using an animal experimental model , and also how it could affect tumor angiogenesis and prognosis in NSCLC patients . METHODS AND RESULTS Knockdown of NDRG1/Cap43 in lung cancer cells using a specific small interfering RNA resulted in growth rates in culture that were similar to those of counterpart control cells , but decreased tumor growth rates in vivo markedly . Stable NDRG1/Cap43 knockdown did not induce consistent changes in the expression of Epidermal growth factor receptor ( EGFR ) family proteins and c-Met in two human lung cancer cell lines in vitro . However , cell lines with NDRG1/Cap43 knockdown showed markedly decreased production of the potent angiogenic factors vascular endothelial growth factor-A and interleukin-8 . Cells with knockdown of NDRG1/Cap43 showed marked reduction of tumor-induced angiogenesis . Using immunohistochemistry , we examined 182 surgically resected specimens of NSCLC for expression of NDRG1/Cap43 and tumor angiogenesis . High microvessel density in the tumor was significantly associated with nuclear positivity for NDRG1/Cap43 in both adenocarcinoma ( p = 0.003 ) and squamous cell carcinoma ( p=0.041 ) . For both adenocarcinoma ( p = 0.031 ) and squamous cell carcinoma ( p=0.034 ) , the survival curve of patients negative for nuclear NDRG1/Cap43 expression differed significantly from that of patients who were positive . CONCLUSION Therefore , the expression of NDRG1/Cap43 may be predictive of tumor angiogenesis and poor prognosis in NSCLC .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "22481237"}
{"sentence": "Hepatocellular carcinoma ( HCC ) is the most prevalent liver tumor and a deadly disease with limited therapeutic options . Dysregulation of cell signaling pathways is a common denominator in tumorigenesis , including hepatocarcinogenesis . The epidermal growth factor receptor ( EGFR ) signaling system is commonly activated in HCC , and is currently being evaluated as a therapeutic target in combination therapies . We and others have identified a central role for the EGFR ligand amphiregulin ( AR ) in the proliferation , survival and drug resistance of HCC cells . AR expression is frequently up-regulated in HCC tissues and cells through mechanisms not completely known . Here we identify the \u03b2-catenin signaling pathway as a novel mechanism leading to transcriptional activation of the AR gene in human HCC cells . Activation of \u03b2-catenin signaling , or expression of the T41A \u03b2-catenin active mutant , led to the induction of AR expression involving three specific \u03b2-catenin-Tcf responsive elements in its proximal promoter . We demonstrate that HCC cells expressing the T41A \u03b2-catenin active mutant show enhanced proliferation that is dependent in part on AR expression and EGFR signaling . We also demonstrate here a novel cross-talk of the EGFR system with fibroblast growth factor 19 ( FGF19 ) . FGF19 is a recently identified driver gene in hepatocarcinogenesis and an activator of \u03b2-catenin signaling in HCC and colon cancer cells . We show that FGF19 induced AR gene expression through the \u03b2-catenin pathway in human HCC cells . Importantly , AR up-regulation and EGFR signaling participated in the induction of cyclin D1 and cell proliferation elicited by FGF19 . Finally , we demonstrate a positive correlation between FGF19 and AR expression in human HCC tissues , therefore supporting in clinical samples our experimental observations . These findings identify the AR/EGFR system as a key mediator of FGF19 responses in HCC cells involving \u03b2-catenin signaling , and suggest that combined targeting of FGF19 and AR/EGFR may enhance therapeutic efficacy .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "23285165"}
{"sentence": "Myxoid leiomyosarcoma is an extremely rare variant of leiomyosarcoma , masquerading almost to perfection as a benign lesion . For , indeed , the tumor lacks the defining features of high mitotic activity , cellular atypia or necrosis , and the microscopic picture is dominated by abundant myxoid stroma containing sparse spindle cells . We report here such a case occurring in the uterus and discuss the differential diagnosis . The relevant literature is reviewed .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20882892"}
{"sentence": "High-grade prostate cancers express high levels of matrix metalloproteinases ( MMPs ) , major enzymes involved in tumor invasion and metastasis . However , the tumor cell lines commonly employed for prostate cancer research express only small amounts of MMPs when cultivated as monolayer cultures , in common culture media . The present study was conducted to ascertain whether culture conditions that include fibronectin can alter MMP2 and MMP9 expression by the human prostatic epithelial cell lines RWPE-1 , LNCaP and PC-3 . These cells were individually seeded at 2\u00d710(4) cells/cm(2) , cultivated until they reached 80% confluence , and then exposed for 4h to fibronectin , after which the conditioned medium was analyzed by gelatin zymography . Untreated cells were given common medium . Only RWPE-1 cells express detectable amounts of MMP9 when cultivated in common medium , whereas the addition of fibronectin induced high expression levels of pro and active forms of MMP2 in all tested cell lines . Our findings demonstrate that normal and tumor prostate cell lines express MMP2 activity when in contact with extracellular matrix components or blood plasma proteins such as fibronectin . Future studies of transcriptomes and proteomes in prostate cancer research using these cell lines should not neglect these important conclusions .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23261429"}
{"sentence": "DNA single-strand breaks and associated growth inhibition induced by the thymidylate synthase inhibitor N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazoline-6-ylmethyl)-N -methylamino]-2 - thenoyl)-L-glutamic acid ( ICI D1694 ) were quantitated using the human ileocecal adenocarcinoma cell line , HCT-8 . The effects of different concentrations and schedules of [ 6R,S]-5-formyltetrahydrofolate ( [ 6RS]LV ) and 2'-deoxy-thymidine ( dThd ) on drug growth inhibition and DNA damage were also evaluated . The drug concentrations for 50% inhibition of cell growth in culture following 2-h and 72-h exposures were 0.073 and 0.003 microM , respectively . After a 2-h drug exposure , the occurrence of DNA single-strand breaks ( SSBs ) was time dependent . It was detectable at 8 h and reached a maximum at about 24 h , 34 +/- 3 ( SD ) and 305 +/- 34 rad equivalents with 0.1 microM ( 50% inhibition concentration ) and 1.0 microM ( 90% inhibition concentration ) ICI D1694 , respectively . A significant level of DNA SSBs ( 101 +/- 13 rad equivalents ) was still detectable at 72 h after the 2-h treatment with 1 microM ICI D1694 . No significant level of DNA SSBs was detected when cells were exposed simultaneously to ICI D1694 and 20 microM [ 6RS]LV . Complete rescue of drug-induced DNA SSBs could be achieved when cells were exposed to 10 microM dThd starting no later than 4 h after drug treatment . The growth inhibition of ICI D1694 was abrogated by [ 6RS]LV in a concentration-dependent manner . Complete protection was achieved when cells were exposed simultaneously to 1 microM ICI D1694 and 5 microMs [ 6RS]LV or to 3 microMs dThd immediately after drug treatment . The results demonstrate that : ( a ) the growth inhibition of ICI D1694 is a function of time and schedule ; ( b ) the growth inhibition is accompanied by extensive DNA single-strand breaks and slow repair ; ( c ) at 1 microM ICI D1694 , 3 microMs dThd and 5 microMs [ 6RS]LV can completely rescue cells from drug effects when dThd is added up to 4 h following drug treatment or when [ 6RS]LV is given in combination with the drug ; ( d ) interference of [ 6RS]LV with ICI D1694 action may be occurring at the level of drug uptake and at intracellular targets , while dThd interferes with the drug action at intracellular targets .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1394217"}
{"sentence": "Taxol ( Paclitaxel ) is an important natural product for the treatment of solid tumors such as ovarian , breast , non-small-cell lung tumors , and some head and neck carcinomas . Different concentrations of taxol trigger distinct effects on cell death forms . In present study , cell counting kit ( CCK-8 ) assay , confocal fluorescence microscopy imaging , flow cytometry ( FCM ) and western blotting ( WB ) analysis were used to analyze the characteristics of cell death induced by low ( 35 nM ) and high ( 70 microM ) concentration of taxol respectively in human lung adenocarcinoma ( ASTC-a-1 ) cells . Our results showed that low concentration of taxol induced cell death dominantly in apoptotic fashion associated with nuclear fragmentation , protein synthesis , phosphatidylserine ( PS ) externalization , G2/M cell cycle arrest , Bax translocation into mitochondria and caspase-3 activation , whereas high concentration of this drug induced significant cytoplasm vacuolization , mitochondria swelling and paraptosis-like cell death form without protein synthesis that is necessary for paraptosis . Although the mechanism of high concentration of taxol-induced paraptosis-like cell death has not been clear , this finding might have a potential implication for cancer therapy , especially for apoptosis-resistant cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20714087"}
{"sentence": "Epigenetic changes in pediatric neuroblastoma may contribute to the aggressive pathophysiology of this disease , but little is known about the basis for such changes . In this study , we examined a role for the DNA methyltransferase DNMT3B , in particular , the truncated isoform DNMT3B7 , which is generated frequently in cancer . To investigate if aberrant DNMT3B transcripts alter DNA methylation , gene expression , and phenotypic character in neuroblastoma , we measured DNMT3B expression in primary tumors . Higher levels of DNMT3B7 were detected in differentiated ganglioneuroblastomas compared to undifferentiated neuroblastomas , suggesting that expression of DNMT3B7 may induce a less aggressive clinical phenotype . To test this hypothesis , we investigated the effects of enforced DNMT3B7 expression in neuroblastoma cells , finding a significant inhibition of cell proliferation in vitro and angiogenesis and tumor growth in vivo . DNMT3B7-positive cells had higher levels of total genomic methylation and a dramatic decrease in expression of the FOS and JUN family members that comprise AP1 transcription factors . Consistent with an established antagonistic relationship between AP1 expression and retinoic acid receptor activity , increased differentiation was seen in the DNMT3B7-expressing neuroblastoma cells following treatment with all-trans retinoic acid ( ATRA ) compared to controls . Our results indicate that DNMT3B7 modifies the epigenome in neuroblastoma cells to induce changes in gene expression , inhibit tumor growth , and increase sensitivity to ATRA .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "22815530"}
{"sentence": "BACKGROUND Cancer , much like most human disease , is routinely studied by utilizing model organisms . Of these model organisms , mice are often dominant . However , our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by Million Years ( MY ) of independent evolution between these species . For a given set of human disease related genes , it is therefore important to determine if functional equivalency has been retained between species . In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages . RESULTS Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations . We identified orthologs for these 22 genes across a set of high coverage ( >6X ) vertebrate genomes . Analysis of these orthologous datasets revealed significant levels of positive selection . Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages . Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11 , in the ancestral primate lineage for CDH1 , in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1 . CONCLUSION Identifying positive selection in the Primate , Hominidae , Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages . Analyses such as this , combining evolutionary theory and predictions - along with medically relevant data , can thus provide us with important clues for modeling human diseases .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22788692"}
{"sentence": "Vaccination is , in theory , a safe and effective approach for controlling disseminated or metastatic cancer due to the specificity of the mammalian immune system , yet its success in the clinic has been hampered thus far by the problem of immune tolerance to tumor self-antigen . Here we describe a DNA vaccination strategy that is able to control cancer by overcoming immune tolerance to tumor self-antigen . We engineered a DNA construct encoding a dimeric form of a secreted single chain trimer of major histocompatibility complex class I heavy chain , \u03b22-microglobulin , and peptide antigen linked to immunoglobulin G ( SCT-Ag/IgG ) . The chimeric protein was able to bind to antigen-specific CD8+ T cells with nearly 100% efficiency and strongly induce their activation and proliferation . In addition , the chimeric protein was able to coat professional antigen-presenting cells through the Fc receptor to activate antigen-specific CD8+ T cells . Furthermore , intradermal vaccination with DNA encoding SCT-Ag/IgG could generate significant numbers of cytotoxic effector T cells against tumor self-antigen and leads to successful therapeutic outcomes in a preclinical model of metastatic melanoma . Our data suggest that the DNA vaccine strategy described in the current study is able to break immune tolerance against endogenous antigen and result in potent therapeutic antitumor effects . Such strategy may be used in other antigenic systems for the control of infections and/or cancers .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23268564"}
{"sentence": "The functional and therapeutic importance of the Warburg effect is increasingly recognized , and glycolysis has become a target of anticancer strategies . We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism . We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents . Here , we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model . Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin . Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells ( RBC ) , which express Glut1 as their sole glucose transporter . Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein , intracellular ATP , and glycolytic enzymes . All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase ( AMPK ) and declines in cyclin E2 as well as phosphorylated retinoblastoma , resulting in cell-cycle arrest , senescence , and necrosis . Addition of extracellular ATP rescued compound-treated cancer cells , suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule . Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells . Thus , WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism .", "label": [0, 0, 1, 1, 0, 0, 0, 1, 1, 0], "id": "22689530"}
{"sentence": "Despite experimental evidence that sulforaphane can exert chemopreventive effects , whether these effects are specific for neoplastic cells is not known . Following our previous demonstration that sulforaphane induces cell cycle arrest and apoptosis in human T lymphoblastoid Jurkat leukemia cells and increases p53 and bax protein expression , we tested sulforaphane on non-transformed phytohemagglutinin-stimulated human lymphocytes . Here , we demonstrate that sulforaphane arrested cell cycle progression in G , phase , through a decrease in the protein expression of cyclin D3 . Moreover , sulforaphane induced apoptosis ( and also necrosis ) , mediated by an increase in the expression of p53 . These findings suggest that sulforaphane is a growth modulator for T cells . Our in vitro evidence that sulforaphane is active and even cytotoxic in normal as well as transformed lymphocytes raises important questions regarding its suitability for cancer chemoprevention .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "12530531"}
{"sentence": "Although anticancer effect of gambogic acid ( GA ) and its potential mechanisms were well documented in past decades , limited information is available on the anticancer effect of gambogenic acid ( GNA ) , another major active component of Gamboge . Here we performed a study to determine whether GNA possesses anticancer effect and find its potential mechanisms . The results suggested that GNA significantly inhibited the proliferation of several tumor cell lines in vitro and in vivo . Treatment with GNA dose and time dependently induced A549 cells apoptosis , arrested the cells to G0/G1 phase in vitro and down-regulated the expression of cyclin D1 and cyclooxygenase ( COX)-2 in mRNA level . In addition , anticancer effect was further demonstrated by applying xenografts in nude mice coupled with the characteristic of apoptosis in the GNA treated group . Taken together , these observations might suggest that GNA inhibits tumor cell proliferation via apoptosis-induction and cell cycle arrest .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 1], "id": "20190402"}
{"sentence": "The Msh2 DNA mismatch repair gene is one of five genes implicated in the pathogenesis of hereditary nonpolyposis colorectal cancer ( HNPCC ) . To address the possible mechanisms of the site-specific occurrence of HNPCC , the effect of Msh2 deficiency on mutations in different parts of the colon was investigated using the BC-1(lacI)/Msh2 double transgenic mouse . Compared to the Msh2(+/+) mice , Msh2(-/-) mice had an 8-9-fold increase of mutation frequency ( MF ) in the lacI gene from the cecum and the proximal and distal colon . The mutational spectra were also significantly different between Msh2(+/+) and Msh2(-/-) mice , with a significant increase in the frequency of -1 frameshifts and G:C-->A:T base substitutions in the repair-deficient mice . However , in spite of the site-specific predisposition of HNPCC in humans , we found no significant difference in the MF or mutation spectrum between the three parts of the colon in Msh2(+/+) , Msh2(+/-) , or Msh2(-/-) mice . In addition , 11 independent mutants harboring complex mutations within the lacI gene were recovered in the Msh2(-/-) mice . Interestingly , while the Msh2(+/-) mice displayed an overall MF similar to that observed in the wild-type mice , sequencing revealed a significantly different mutational spectrum between Msh2(+/+) and Msh2(+/-) mice , mainly characterized by an increase in -1 frameshifts . Due to the prevalence of frameshift mutations in HNPCC patients , this haploinsufficiency effect of the Msh2 gene in safeguarding genomic integrity may have important implications for human carrier status .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12489114"}
{"sentence": "The aryl hydrocarbon receptor ( AhR ) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds . Several reports have shown that the AhR plays an important role in the control of cell-cycle progression , and this function is thought to be partly associated with the tumor promotion activity of dioxin . However , the underling mechanisms are not fully understood . We have previously shown that overexpression of AhR , as well as AhR ligand treatment , stimulates cell proliferation of human lung cancer A549 cells . In AhR-activated cells , the expression levels of DNA synthesis-related genes such as proliferating cell nuclear antigen ( PCNA ) and RFC38 are notably increased . Expression of these genes is mainly regulated by E2F1 , a transcription factor that is crucial for transition of the cell cycle from G1 to S phase . We show here that the transcriptional activity of E2F1 is increased by the AhR agonist treatment and that this effect depends on the presence of AhR . Functional mapping of AhR showed that the Per-Arnt-Sim ( PAS ) B domain is required for promotion of E2F1 activity . The mechanism involves formation of a complex of AhR and E2F1 on the regulatory region in the E2F1 target gene , followed by recruitment of coactivator activator for thyroid hormone and retinoid receptors ( ACTR ) . Consequently , the results in this study indicate the physiological function of AhR as a potent transcriptional coactivator of E2F1-dependent transcription and implicate the AhR-E2F1 interaction as a part of the mechanism by which AhR/Arnt promotes cell proliferation .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "20190398"}
{"sentence": "Nine primary pulmonary carcinomas , one metastatic carcinoma , and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases ( MPs ) and tissue inhibitors of MPs ( TIMPs ) . In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells . While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs ( NNL ) as well as in carcinomas , stromelysin 3 ( ST3 ) , 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas . Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis . The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype . However , since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples , their expression is not a uniform feature of pulmonary carcinomas . The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "1457364"}
{"sentence": "PURPOSE The epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ZD1839 ( Iressa ; AstraZeneca Pharmaceuticals , Alderley Park , United Kingdom ) is under development as an anticancer agent . We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin , an EGFR-dependent tissue , in cancer patients participating in ZD1839 phase I clinical trials . PATIENTS AND METHODS We studied 104 pre- and/or on-ZD1839 therapy ( approximately at day 28 of therapy ) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839 . We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated ( phosphorylated ) EGFR . Effects on receptor signaling ( activated mitogen-activated protein kinase [ MAPK] ) , proliferation , p27(KIP1) , and maturation were also assessed . RESULTS Histopathologically , the stratum corneum of the epidermis was thinner during therapy ( P <.001 ) . In hair follicles , prominent keratin plugs and microorganisms were found in dilated infundibula . ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells ( P <.001 ) . In addition , ZD1839 inhibited MAPK activation ( P <.001 ) and reduced keratinocyte proliferation index ( P <.001 ) . Concomitantly , ZD1839 increased the expression of p27(KIP1) ( P <.001 ) and maturation markers ( P <.001 ) and increased apoptosis ( P <.001 ) . These effects were observed at all dose levels , before reaching dose-limiting toxicities . CONCLUSION ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo . These effects were profound at doses well below the one producing unacceptable toxicity , a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "11773160"}
{"sentence": "Prostaglandin E(2) ( PGE(2) ) receptor subtype EP(2) , which is coupled to cAMP metabolism , is known to mediate proliferation of primary human keratinocytes in vitro . The effect of gain or loss of EP(2) receptors in immortalized human keratinocytes ( HaCat cells ) was examined . HaCat keratinocytes were transfected with sense or anti-sense constructs of the EP(2) receptor . Loss or gain of EP(2) expression was documented by immunoblot and associated changes in agonist-stimulated cAMP production . Loss or gain of EP(2) receptor expression correlated with alterations in plating efficiencies but with modest affects on growth . When cell lines were studied in an organ culture model , anti-sense clones were highly invasive compared with vector controls and sense transfectants . A marked increase in prostaglandin production is commonly seen in malignant lesions . Because prostaglandin receptors are known to undergo ligand-induced receptor down-regulation , we sought to determine whether EP(2) receptor down-regulation results in increased invasiveness . In vector controls , invasiveness was reproduced by ligand-dependent EP(2) receptor down-regulation as assessed by immunohistochemistry . In addition , loss of EP(2) receptor expression was associated with decreased paxillin expression , a critical component of focal adhesion assembly . Thus , down-regulation of EP(2) receptors represents a potential mechanism for neoplastic progression to an invasive phenotype .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "12466123"}
{"sentence": "Telomere repeats are added onto chromosome ends by telomerase , consisting of two main core components : a catalytic protein subunit ( telomerase reverse trancriptase , TERT ) , and an RNA subunit ( telomerase RNA , TR ) . Here , we report for the first time evidence that HMGB1 ( a chromatin-associated protein in mammals , acting as a DNA chaperone in transcription , replication , recombination , and repair ) can modulate cellular activity of mammalian telomerase . Knockout of the HMGB1 gene ( HMGB1 KO ) in mouse embryonic fibroblasts ( MEFs ) results in chromosomal abnormalities , enhanced colocalization of \\u03b3-H2AX foci at telomeres , and a moderate shortening of telomere lengths . HMGB1 KO MEFs also exhibit significantly ( >5-fold ) lower telomerase activity than the wild-type MEFs . Correspondingly , enhanced telomerase activity is observed upon overexpression of HMGB1 in MEFs . HMGB1 physically interacts with both TERT and TR , as well as with active telomerase complex in vitro . However , direct interaction of HMGB1 with telomerase is most likely not accountable for the observed higher telomerase activity in HMGB1-containing cells , as revealed from the inability of purified HMGB1 protein to stimulate telomerase activity in vitro . While no transcriptional silencing of TERT is observed in HMGB1 KO MEFs , levels of TR are diminished ( providing possible explanation for the observed lower telomerase activity in HMGB1 KO cells . Interestingly , knockout of the HMGB2 gene elevates telomerase activity ( in MEFs , suggesting that the two closely related proteins of the HMGB family , HMGB1 and HMGB2 , have opposite effects on telomerase activity in the cell . The ability of HMGB1 to modulate cellular activity of telomerase and to maintain telomere integrity can help to understand some aspects of the protein involvement in chromosome stability and cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22544226"}
{"sentence": "Acute lymphoblastic leukemia is still an incurable disease with resistance to therapy developing in the majority of patients . We investigated the effect of TPEN , an intracellular zinc chelator , in Jurkat and in ex vivo acute lymphoblastic leukemia ( ALL ) cells resistant to chemotherapy . Changes of nuclei morphology , reactive oxygen species generation , presence of hypodiploid cells , phosphatidylserine translocation , mitochondrial membrane depolarization , immunohistochemical identification of cell death signalling molecules , and pharmacological inhibition were assayed to detect the apoptotic cell death pathways . We found that TPEN induces apoptosis in both types of cells by a molecular oxidative stress pathway involving O(2)(\u2022-) > H(2)O(2) > NF-\u03baB ( JNK/c-Jun ) >p53> loss \u0394\u03a8(m)> caspase-3 , AIF > chromatin condensation/DNA fragmentation . Interestingly , TPEN induced apoptosis independently of glucose ; leukemic cells are therefore devoid of survival capacity by metabolic resistance to treatment . Most importantly , TPEN cytotoxic effect can eventually be regulated by the antioxidant N-acetyl-cysteine and zinc ions . Our data suggest that TPEN can be used as a potential therapeutic prooxidant agent against refractory leukemia . These data contribute to understanding the importance of oxidative stress in the treatment of ALL .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "23320127"}
{"sentence": "BACKGROUND The circumscription of the avian superfamily Sylvioidea is a matter of long ongoing debate . While the overall inclusiveness has now been mostly agreed on and 20 families recognised , the phylogenetic relationships among the families are largely unknown . We here present a phylogenetic hypothesis for Sylvioidea based on one mitochondrial and six nuclear markers , in total kbp , for 79 ingroup species representing all currently recognised families and some species with uncertain affinities , making this the most comprehensive analysis of this taxon . RESULTS The resolution , especially of the deeper nodes , is much improved compared to previous studies . However , many relationships among families remain uncertain and are in need of verification . Most families themselves are very well supported based on the total data set and also by indels . Our data do not support the inclusion of Hylia in Cettiidae , but do not strongly reject a close relationship with Cettiidae either . The genera Scotocerca and Erythrocercus are closely related to Cettiidae , but separated by relatively long internodes . The families Paridae , Remizidae and Stenostiridae clustered among the outgroup taxa and not within Sylvioidea . CONCLUSIONS Although the phylogenetic position of Hylia is uncertain , we tentatively support the recognition of the family Hyliidae Bannerman , 1923 for this genus and Pholidornis . We propose new family names for the genera Scotocerca and Erythrocercus , Scotocercidae and Erythrocercidae , respectively , rather than including these in Cettiidae , and we formally propose the name Macrosphenidae , which has been in informal use for some time . We recommend that Paridae , Remizidae and Stenostiridae are not included in Sylvioidea . We also briefly discuss the problems of providing a morphological diagnosis when proposing a new family-group name ( or genus-group name ) based on a clade .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22920688"}
{"sentence": "We report clinical findings that extend the phenotype of the kb 16p11.2 microdeletion syndrome to include a rare , severe , and persistent pediatric speech sound disorder termed Childhood Apraxia of Speech ( CAS ) . CAS is the speech disorder identified in a multigenerational pedigree ( 'KE' ) in which half of the members have a mutation in FOXP2 that co-segregates with CAS , oromotor apraxia , and low scores on a nonword repetition task . Each of the two patients in the current report completed a 2-h assessment protocol that provided information on their cognitive , language , speech , oral mechanism , motor , and developmental histories and performance . Their histories and standard scores on perceptual and acoustic speech tasks met clinical and research criteria for CAS . Array comparative genomic hybridization analyses identified deletions at chromosome 16p11.2 in each patient . These are the first reported cases with well-characterized CAS in the 16p11.2 syndrome literature and the first report of this microdeletion in CAS genetics research . We discuss implications of findings for issues in both literatures .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22909774"}
{"sentence": "Lung cancer is the leading cause of cancer-related deaths in the world . Achaete-scute complex homolog-1 ( Ascl1 ) is a member of the basic helix-loop-helix ( bHLH ) transcription factor family that has multiple functions in the normal and neoplastic lung such as the regulation of neuroendocrine differentiation , prevention of apoptosis and promotion of tumor-initiating cells . We now show that Ascl1 directly regulates matrix metalloproteinase-7 ( MMP-7 ) and O(6)-methylguanine-DNA methyltransferase ( MGMT ) . Loss- and gain-of-function experiments in human bronchial epithelial and lung carcinoma cell lines revealed that Ascl1 , MMP-7 and MGMT are able to protect cells from the tobacco-specific nitrosamine NNK-induced DNA damage and the alkylating agent cisplatin-induced apoptosis . We also examined the role of Ascl1 in NNK-induced lung tumorigenesis in vivo . Using transgenic mice which constitutively expressed human Ascl1 in airway lining cells , we found that there was a delay in lung tumorigenesis . We conclude that Ascl1 potentially enhances DNA repair through activation of MMP-7 and MGMT which may impact lung carcinogenesis and chemoresistance . The study has uncovered a novel and unexpected function of Ascl1 which will contribute to better understanding of lung carcinogenesis and the broad implications of transcription factors in tobacco-related carcinogenesis .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "23300791"}
{"sentence": "Gefitinib , the specific inhibitor of the epidermal growth factor receptor ( EGFR ) , may cause growth delay in cancer cell lines . Thorough understanding of the downstream cellular signaling of gefitinib will facilitate the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies , and provide information for key targets for therapeutic intervention . In this study , we investigated the role of transducer of erbB2.1 ( TOB1 ) in gefitinib therapy . Using the lung carcinoma cell lines A549 and NCI-H1975 , the results suggested that gefitinib might mediate cell cycle arrest in lung cancer cells at least by targeting TOB1 expression . Gefitinib treatment caused cell cycle arrest predominantly at the G1 phase , which is associated with TOB1 nuclear translocation and its interaction with cyclin D1 . We also showed that knockdown of TOB1 expression by RNAi rescued lung cancer cells from gefitinib-induced cell-proliferative arrest . These results suggest that TOB1 interaction with cyclin D1 and nuclear translocation is directly involved in the gefitinib-induced anti-proliferative cell cycle arrest .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "23255952"}
{"sentence": "Understanding how arsenic exacts its diverse , global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis . A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic , and manifest as diverse diseases . Following an initial observation that arsenite-exposed cells in culture acidify their media more rapidly than control cells , the report here shows that low level exposure to arsenite ( 75ppb ) is sufficient to induce aerobic glycolysis ( the Warburg effect ) as a generalized phenomenon in cultured human primary cells and cell lines . Expanded studies in one such cell line , the non-malignant pulmonary epithelial line , BEAS-2B , established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate , an increased rate of extracellular acidification , and inhibition by the non-metabolized glucose analog , 2-deoxy-D-glucose . Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression , as well as protein accumulation of an established glycolysis master-regulator , hypoxia-inducible factor 1A . Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23648393"}
{"sentence": "This study is to investigate the effects of bortezomib on the angiogenesis of mesenchymal stem cells ( MSCs ) . We examined the effects of bortezomib on the cellular proliferation , migration , and capillary network formation of HUVECs cocultured with CMs of MSCs . We found that Bortezomib inhibited the cellular proliferation and tube formation of HUVECs cocultured with CMs in a dose-dependent fashion . Bortezomib also prevented the migration of HUVECs cocultured with CMs . In addition , bortezomib dose-dependently inhibited the growth of MSCs and prevented the production of angiogenic factors including VEGF ( vascular endothelial growth factor ) , HGF ( hepatocyte growth factor ) , and bFGF ( basic fibroblast growth factor ) in MSCs . In conclusion , bortezomib prevented the angiogenesis mediated by MSCs .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "23013101"}
{"sentence": "PURPOSE Although the adrenal gland is a common site of extrahepatic metastasis from hepatocellular carcinoma ( HCC ) , there are no definitive guidelines for the treatment of adrenal metastasis . This study examines the effectiveness of various treatments for this disease . METHODS We retrospectively analyzed 20 patients treated for adrenal metastasis of HCC by adrenalectomy ( n = 13 ) , transarterial chemoembolization ( TACE ) , or percutaneous ethanol injection therapy ( PEIT ) ( n = 7 ) . RESULTS There were no significant differences in cumulative survival rates between patients given adrenalectomy and those given TACE or PEIT , either after completing treatment for primary HCC or after the first treatment for adrenal metastasis . Six of seven patients with tumor thrombi in the inferior vena cava ( IVC ) from adrenal metastasis underwent adrenalectomy combined with intracaval thrombectomy , five of whom survived for more than 1 year after surgery , and two of whom are still alive without any recurrence more than 3 years after surgery . PEIT showed good results for small adrenal metastasis . CONCLUSION These findings suggest that therapeutic modalities should be chosen according to the clinical features of each individual , including the size of the metastatic tumor , whether there is invasion into the IVC , the function of the remaining liver , and the existence of intra- and/or nonadrenal extrahepatic lesions . Furthermore , intracaval tumor thrombectomy could be indicated for patients with IVC thrombus if they are suitable candidates for surgery .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "12541019"}
{"sentence": "Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior . The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear , however . We previously established two lines of mouse osteosarcoma cells : AX cells , which are able to form tumors in syngeneic mice , and AXT cells , which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development . We have now identified Igf2 mRNA-binding protein3 ( Imp3 ) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo . Imp3 is consistently up-regulated in tumors formed by AX cells , and its expression in these cells was found to confer malignant properties such as anchorage-independent growth , loss of contact inhibition , and escape from anoikis in vitro . The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells . The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism . Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "23226335"}
{"sentence": "Abstract Different cyclooxygenase ( COX)-2 inhibitors were known to cause different cell cycle changes . We investigated whether this different effect on cell cycle change was due to concentration-dependent effect . We investigated the effects of celecoxib , a COX-2 selective inhibitor , on cell cycle regulation in irradiated cancer cells that express high or low levels of COX-2 . Four stably COX-2 knocked-down or overexpressed cell lines were treated with various concentrations of celecoxib with or without radiation . Celecoxib differentially modulated the cell cycle according to the concentrations applied . G(1) arrest was induced at lower concentrations , whereas G(2)/M arrest was induced at higher concentrations in each cell line tested . Radiation-induced G(2)/M arrest was enhanced at lower concentrations but reduced at higher concentrations . The cutoff values to divide lower and higher concentrations were cell-type specific . Celecoxib treatment activated Cdc25C and inhibited p21 expression in both unirradiated and irradiated cells , regardless of COX-2 expression . Apoptosis was induced in irradiated cells 48 hours after treatment with celecoxib dependent of COX-2 . These results imply that celecoxib deactivates the G(2) checkpoint via both Cdc25C- and p21-dependent pathways in irradiated cells , which subsequently die by secondary apoptosis . Cell cycle modulating effects in irradiated cells resulting from treatment with celecoxib may have clinical importance with regard to the potential application of celecoxib in cancer patients undergoing radiotherapy .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "23268707"}
{"sentence": "The influence of cell shape on the expression of proto-oncogenes was examined in normal and malignant human cells that varied in their sensitivities to contact-inhibition of proliferation . Cells were constrained into varying degrees of roundness by plating onto culture surfaces coated with different concentrations of poly(2-hydroxyethyl methacrylate ) ( poly[HEMA] ) and assayed for proliferation capacity and levels of c-myc , c-ras , c-fos , and c-fes mRNAs . Proliferation of contact-inhibited normal CUA-1 fibroblasts and the variant HT-IFNr cells was highly coupled to cell shape . As these cells became more rounded , a critical degree of roundness was reached at which proliferation ceased . In contrast , proliferation of non-contact-inhibited malignant HT-1080 cells was independent of cell shape . Northern analysis revealed that expression of c-myc and c-ras was highly sensitive to cell shape in the normal CUA-1 cells but not in the malignant HT-1080 or variant HT-IFNr cells . Levels of c-myc and c-ras mRNAs declined to nearly undetectable levels in CUA-1 cells at degrees of roundness that correlated with loss of proliferative ability . Expression of c-fos and c-fes oncogenes were independent of cell shape in all cells tested . Quantification of transcription rates by the nuclear run-off assay showed that shape modulation of c-myc and c-ras oncogene expression occurred at the transcriptional level . These data suggest that changes in cell shape can modulate expression of certain oncogenes and that these changes correlate with the cell's ability to proliferate . Moreover , inability to regulate c-myc and c-ras oncogene expression is associated with loss of shape-dependent growth controls and contact inhibition but that loss of this regulation alone is not sufficient to release cells from contact-inhibited controls .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "1385453"}
{"sentence": "BACKGROUND: : Radiotherapy is an efficient remedy in the treatment of hepatocellular carcinoma ( Hca ) ; however , some cancer cells can still survive from the radiation and the therapeutic effect is to be improved . Regulatory T cell ( Tregs)-induced tumor tolerance and Akt expression play important roles in the tumor survival . This study aims to elucidate the role of radiation induces Akt expression in Tregs . METHODS: : A rat Hca model was developed . Hca tissue was collected from the rats with or without radiotherapy . The frequency of Treg and apoptotic Treg in Hca tissue was assessed by flow cytometry . A cell culture model was used to investigate the mechanism by which the tumor-infiltrating Tregs survive from irradiation . RESULTS: : After radiotherapy , the frequency of Treg was increased in Hca , the frequency of apoptotic Tregs was decreased and the expression of Akt was increased in the remaining Tregs . The results were reproduced in vitro with a cell culture model . The addition of Akt inhibitor blocked the irradiation-induced Treg survival . Tregs with high levels of Akt still preserve the immune suppressor function . CONCLUSIONS: : Akt plays an important role in the radiation-induced tumor-infiltrating Treg survival in Hca .", "label": [0, 1, 0, 0, 0, 0, 0, 1, 0, 0], "id": "23255243"}
{"sentence": "During mitotic exit , a small GTPase Tem1 needs to be activated . During most of the cell cycle , Tem1 activity is antagonized by a GTPase activating complex ( GAP ) composed of Bub2 and Bfa1 . Bfa1 protein has cell cycle regulated phosphorylation depending upon the Polo-like kinase Cdc5 . This phosphorylation dissociates Bfa1 from Tem1 and thus relieves the inhibition of Tem1 by the GAP complex . Bub2 and Bfa1 are also required to prevent mitotic exit when there is DNA damage , spindle damage or spindle misorientation at G(2)/M phase . While Cdc5 inhibits Bfa1/Bub2 , mutating the Cdc5 phosphorylation sites on Bfa1 does not have a strong activating effect on Bub2/Bfa1 , suggesting there must be additional regulation in this pathway . Here we report that Bub2 protein also has cell cycle regulated phosphorylation . This phosphorylation is partially dependent upon the Polo-like kinase Cdc5 and is consistent with negative regulation of the Bub2/Bfa1 GAP complex . Spindle damage or spindle misorientation prevents Bub2 phosphorylation . The spindle damage effect is dependent upon the spindle assembly checkpoint components Mad2 and Mps1 . Thus like Bfa1 , Bub2 protein is also controlled both during mitotic exit and in response to cell cycle checkpoints . Bub2 phosphorylation is likely to be controlled by a novel kinase .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "12461298"}
{"sentence": "The morphology characteristics of cell apoptosis of the malignant tumour cells in magnetic field-treated mouse was observed for the first time . The apoptotic cancer cell contracted , became rounder and divorced from adjacent cells ; the heterochromatin condensed and coagulated together along the inner side of the nuclear membrane ; the endoplasmic reticulums ( ER ) expanded and fused with the cellular membrane ; many apoptotic bodies which were packed by the cellular membrane appeared and were devoured by some lymphocytes and plasma . Apoptosis of cancer cells was detected by terminal deoxynucleotidyl transferase mediatedin situ nick end labeling ( TUNEL ) . It was found that the number of apoptosis cancer cells of the sample treated by the magnetic field is more than that of the control sample . The growth of malignant tumour in mice was inhibited and the ability of immune cell to dissolve cancer cells was improved by ultralow frequency ( ULF ) pulsed gradient magnetic field ; the nuclei DNA contents decreased , indicating that magnetic field can block DNA replication and inhibit mitosis of cancer cells . It was suggested that magnetic field could inhibit the metabolism of cancer cell , lower its malignancy , and restrain its rapid and heteromorphic growth . Since ULF pulsed gradient magnetic field can induce apoptosis of cancer cells and inhibit the growth of malignant tumour , it could be used as a new method to treat cancer .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "18763061"}
{"sentence": "Adoptive transfer of immunity against hepatitis B surface antigen ( HBsAg ) was previously shown to facilitate suppression of experimental human hepatocellular carcinoma ( HCC ) expressing HBsAg in athymic mice . We have shown that oral tolerance induces antigen-specific immune suppression of HBsAg by feeding hepatitis B virus ( HBV ) antigens . In the present study we evaluated the effect of oral tolerance induction toward HBV or HCC antigens on the growth of experimental HCC-expressing HBsAg in mice . Tolerance induction was induced in mice by 5 oral feedings of 1 microg HBV antigens or HCC-extracted proteins ( 50 microg protein ) before vaccination with recombinant HBsAg . Splenocytes ( 2 x 10(6) ) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 10(7) human hepatoma Hep3B cells . Adoptive transfer of splenocytes immunized toward HBsAg prevented tumor growth . At 4 weeks after splenocyte transplantation , tumor volume and serum alpha-fetoprotein ( AFP ) levels in athymic mice transplanted with splenocytes immunized to HBsAg were undetectable as compared with 1,048 +/- 738 mm(3) and 2,500 +/- 1,431 ng/ml in recipients of na\ufffdve splenocytes ( p < 0.0001 ) . Mice receiving splenocytes tolerized toward Hep3B cells , as manifested by reduced serum HBs antibody levels , reduced HBV-specific stimulation index and reduced HBV-specific-IFN gamma spot-forming cells , had early tumor growth evident by elevated AFP serum levels , weight loss and mortality , which were suppressed at 6 weeks . Mice transplanted with splenocytes tolerized toward HBV antigens did not have direct evidence of tumor growth . Induction of oral tolerance toward HCC-extracted proteins enabled transient tumor growth in this model . This effect was mediated through downregulation of the anti-HBV immune response .", "label": [0, 1, 0, 0, 0, 0, 0, 0, 0, 0], "id": "11774243"}
{"sentence": "IFN-\u03b3 is a master regulator of the immune responses that occur in the transplanted kidney , acting both on the immune system and on the graft itself . The cellular responses to IFN-\u03b3 are complex , and emerging evidence suggests that IFN-\u03b3 may regulate autophagic functions . Conversely , autophagy modulates innate and adaptive immune functions in various contexts . In this study , we identify a novel mechanism by which IFN-\u03b3 activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-\u03b3 . Our results indicate that IFN-\u03b3 promotes tryptophan depletion , activates the eIF2\u03b1 kinase general control nonderepressible-2 ( GCN2 ) , and leads to an increase in the autophagic flux . Further , tryptophan supplementation and RNA interference directed against GCN2 inhibited IFN-\u03b3-induced autophagy . This process is of functional relevance because autophagy regulates the secretion of inflammatory cytokines and growth factors by human kidney epithelial cells in response to IFN-\u03b3 . These findings assign to IFN-\u03b3 a novel function in the regulation of autophagy , which , in turn , modulates IFN-\u03b3-induced secretion of inflammatory cytokines .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 1], "id": "22896630"}
{"sentence": "Thrombopoietin ( TPO ) receptor agonists represent a new approach for the treatment of thrombocytopenia , which may develop as a consequence of immune thrombocytopenia , chemotherapy treatment , chronic hepatitis C infection , or myelodysplastic syndromes . There are concerns that use of certain growth factors can hasten disease progression in some types of hematologic malignancies and solid tumors . In this study , expression of MPL ( TPO-R ) mRNA was examined in tumor cell lines , patient tumor samples ( renal cell carcinoma , prostatic carcinoma , soft tissue and bony/cartilage sarcoma , colon cancer , and lymphoma ) , and normal tissues using microarray analysis and qRT-PCR . MPL mRNA is expressed at very low or undetectable levels compared with erythropoietin receptor ( EPOR ) , human epidermal growth factor ( ERBB2 ; HER2 ) , and insulin-like growth factor-1 receptor ( IGF1R ) in these patient samples . These data suggest TPO-R agonists will likely preferentially stimulate proliferation and differentiation of cells of megakaryocytic lineage , potentially demonstrating their utility for correcting thrombocytopenia in clinical settings .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "21318160"}
{"sentence": "The cytotoxicities of highly efficient salan-Ti(IV) complexes toward a range of cell lines , including drug-resistant cells , are reported along with preliminary mechanistic insights . Five salan-Ti(IV) complexes were investigated toward eight different human and murine cancer-derived cell lines , including colon , ovarian , lung , cervical , pancreatic , leukemic , skin , and breast . The salan complexes are more active toward the cells analyzed than cisplatin and the known titanium compound ( bzac)(2 ) Ti(OiPr)(2) , and no cell line resistant to the salan complexes was identified . Moreover , the salan-Ti(IV) complexes are highly active toward both cisplatin-sensitive ( A2780 ) and cisplatin-resistant ( A2780CisR ) human ovarian cancer cell lines . Similarly , the salan complexes are cytotoxic toward multi-drug-resistant ( ABCB1-expressing ) mouse lymphoma cell lines HU-1 and HU-2 . Importantly , minimal or no activity was observed toward primary murine cells ( bone marrow , heart , liver , kidney , spleen , and lung ) , supporting selectivity for cancer cells . Additionally , the salan complexes maintain high cytotoxicity for up to 24 h following exposure to cell culture medium , whereas reference complexes ( bzac)(2 ) Ti(OiPr)(2) and Cp(2) TiCl(2) rapidly lose much of their activity upon exposure to medium , within h . The upregulation of p53 followed by cell-cycle arrest in G(1) phase is likely one mechanism of action of the salan complexes . Taken together , the results indicate that these compounds are selectively toxic to cancer cells and are able to circumvent two independent mechanisms of drug resistance , thus expanding the scope of their potential medicinal utility .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22262543"}
{"sentence": "Radiotherapy for head and neck tumors often results in persistent loss of function in salivary glands . Patients suffering from impaired salivary function frequently terminate treatment prematurely because of reduced quality of life caused by malnutrition and other debilitating side-effects . It has been previously shown in mice expressing a constitutively active form of Akt ( myr-Akt1 ) , or in mice pretreated with IGF1 , apoptosis is suppressed , which correlates with maintained salivary gland function measured by stimulated salivary flow . Induction of cell cycle arrest may be important for this protection by allowing cells time for DNA repair . We have observed increased accumulation of cells in G2/M at acute time-points after irradiation in parotid glands of mice receiving pretreatment with IGF1 . As p21 , a transcriptional target of the p53 family , is necessary for maintaining G2/M arrest , we analyzed the roles of p53 and p63 in modulating IGF1-stimulated p21 expression . Pretreatment with IGF1 reduces binding of \u0394Np63 to the p21 promoter after irradiation , which coincides with increased p53 binding and sustained p21 transcription . Our data indicate a role for \u0394Np63 in modulating p53-dependent gene expression and influencing whether a cell death or cell cycle arrest program is initiated .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 1, 0], "id": "21480565"}
{"sentence": "BACKGROUND In this paper we propose a chemical physics mechanism for the initiation of the glycolytic switch commonly known as the Warburg hypothesis , whereby glycolytic activity terminating in lactate continues even in well-oxygenated cells . We show that this may result in cancer via mitotic failure , recasting the current conception of the Warburg effect as a metabolic dysregulation consequent to cancer , to a biophysical defect that may contribute to cancer initiation . MODEL Our model is based on analogs of thermodynamic concepts that tie non-equilibrium fluid dynamics ultimately to metabolic imbalance , disrupted microtubule dynamics , and finally , genomic instability , from which cancers can arise . Specifically , we discuss how an analog of non-equilibrium Rayleigh-Benard convection can result in glycolytic oscillations and cause a cell to become locked into a higher-entropy state characteristic of cancer . CONCLUSIONS A quantitative model is presented that attributes the well-known Warburg effect to a biophysical mechanism driven by a convective disturbance in the cell . Contrary to current understanding , this effect may precipitate cancer development , rather than follow from it , providing new insights into carcinogenesis , cancer treatment , and prevention .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "23758735"}
{"sentence": "A 39-year-old male without contributory medical history had sustained progressive double vision , ptosis , and trigeminal pain for 2 weeks . Physical examination revealed total ophthalmoplegia and visual field defect with normal blood examination and chest radiography . Cranial computed tomography revealed a hyperdense mass in the left frontotemporal fossae with bony erosion . Magnetic resonance imaging confirmed a broad-based , intensely enhanced extraaxial tumor of 4x4x4 cm diameter with dural tail sign . Cerebral angiography demonstrated insignificant blood supply both from the internal carotid and middle meningeal arteries . Nearly total tumor resection was achieved via orbitofrontotemporal craniotomy . Intraoperative findings revealed the extraaxial tumor with broad attachment to the dura mater and invasion to the optic and oculomotor nerves . Histological examination revealed hypercellular tumor with significant cell atypism , mitotic activity , and focal necrosis . Immunohistochemical staining was positive for AE1/3 and c-kit , but negative for glial fibrillary acidic protein . Systemic examination performed postoperatively revealed a thymic tumor without additional remote lesions . The final diagnosis was metastatic brain tumor from thymic carcinoma . Rapid progression of neurological impairment inconsistent with a benign extraaxial tumor needs prompt surgical intervention .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "20587979"}
{"sentence": "BACKGROUND The isothiocyanate sulforaphane ( SFN ) possesses interesting anticancer activities . However , recent studies reported that SFN promotes the formation of reactive oxygen species ( ROS ) as well as DNA breakage . METHODOLOGY/PRINCIPAL FINDINGS We investigated whether SFN is able to damage RNA , whose loss of integrity was demonstrated in different chronic diseases . Considering the ability of SFN to protect from genotoxicity , we also examined whether SFN is able to protect from RNA damage induced by different chemicals ( doxorubicin , spermine , S-nitroso-N-acetylpenicillamine , H(2)O(2) ) . We observed that SFN was devoid of either RNA damaging and RNA protective activity in human leukemic cells . It was able to potentiate the RNA damage by doxorubicin and spermine . In the first case , the effect was attributable to its ability of modulating the bioreductive activation of doxorubicin . For spermine , the effects were mainly due to its modulation of ROS levels produced by spermine metabolism . As to the cytotoxic relevance of the RNA damage , we found that the treatment of cells with a mixture of spermine or doxorubicin plus SFN increased their proapoptotic potential . Thus it is conceivable that the presence of RNA damage might concur to the overall toxic response induced by a chemical agent in targeted cells . CONCLUSIONS/SIGNIFICANCE Since RNA is emerging as a potential target for anticancer drugs , its ability to enhance spermine- and doxorubicin-induced RNA damage and cytotoxicity could represent an additional mechanism for the potentiating effects of SFN associated with anticancer drugs .", "label": [0, 0, 0, 0, 0, 1, 0, 1, 0, 0], "id": "22539965"}
{"sentence": "Amplification of the HER-2 ( c-erbB-2 ) gene and overexpression of the p185HER-2 gene product is found in approximately one-third of primary human breast and ovarian cancers and is associated with a poor clinical outcome of early relapse and death . The HER-2 gene encodes a cell-surface growth factor receptor with intrinsic tyrosine kinase activity . Wild-type human HER-2 has been shown to act as a potent oncogene when over-expressed in mouse fibroblasts . Recent data suggest that the mechanism by which HER-2 mediates transformation requires the interaction of the epidermal growth factor ( EGF ) receptor . To test whether overexpression of normal human HER-2 can transform cells independently of the EGF receptor , we have introduced multiple copies of HER-2 into the EGF receptor-negative cell line , NR6 , and have performed assays for both transformation and tumorigenicity . Engineered NR6 cells that overexpress the HER-2 gene product display a highly transformed and tumorigenic phenotype as compared with control cells . Additionally , a monoclonal antibody to the extracellular domain of the HER-2 receptor is able to inhibit the proliferation of the overexpressing cells in vitro as well as tumor growth in vivo . This study provides clear evidence that HER-2-mediated transformation can be achieved independently of the EGF receptor .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 1, 0], "id": "1354348"}
{"sentence": "BACKGROUND/AIMS The use of chemotherapy in hepatocellular carcinoma is still controversial . The aim of this study was to investigate whether the combined use of epirubicin and progesterone has a synergistic effect on cell proliferation and apoptosis in HepG2 cells . METHODOLOGY Different concentrations of epirubicin ( 0.1 microg/ml , 0.25 microg/ml and 0.5microg/ml ) or progesterone ( 12.5 microM , 25 microM and 50 microM ) were added to HepG2 cells either alone or in combinations consisting of different concentrations of the two . Their effects on HepG2 cells were studied by ( 1 ) XTT assay for analysis of cell proliferation , ( 2 ) 3H-Thymidine incorporation for DNA synthesis , ( 3 ) annexin V-FITC/ propidium iodide ( PI ) flowcytometery for cell apoptosis , ( 4 ) flowcytometry for cell cycle distributions , and ( 5 ) reverse transcription-polymerase chain reaction for expression of cell cycle modulator , cyclin D1 . RESULTS 50 microM progesterone increased both the cytotoxic and apoptotic effects of 0.1 microg/ml epirubicin on HepG2 cells at 48 hr culture due to 50 microM progesterone accumulated cells in S phase of the cell cycle and subsequently reduced cyclin D1 expression . These effects on HepG2 cells induced by this combination were comparable to those induced by 0.5 microg/ml epirubicin alone . CONCLUSIONS In vitro , progesterone can increase the cytotoxicity and apoptosis induced by epirubicin on HepG2 cells .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "20422883"}
{"sentence": "Semiconductor nanoparticles ( NPs ) became important and wide-used tool for cell imaging because of their unique remarkable properties . Nevertheless , all previous investigations in this area were done on proliferating cells . For the first time , this work demonstrates strong influence of cell active proliferation/contact inhibition of proliferation on uptake of NPs . In addition , we show that cell division plays key-role in penetration of silicon carbide based NPs ( SiC NPs ) inside the cell nucleus . This may very likely concern other types of NPs able to reach the cell nuclei . In particular , observed effect of cell division gives perspectives for future selective cancer treatment with NPs .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "22653530"}
{"sentence": "We show that sufficient concentrations of gold nanoparticles produced by an original synthesis method in EMT-6 and CT-26 cancer cells make it possible to detect the presence , necrosis and proliferation of such cells after inoculation in live mice . We first demonstrated that the nanoparticles do not interfere with the proliferation process . Then , we observed significant differences in the tumor evolution and the angiogenesis process after shallow and deep inoculation . A direct comparison with pathology optical images illustrates the effectiveness of this approach .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 1, 0], "id": "22934133"}
{"sentence": "The multi-kinase inhibitor dasatinib induced a variable but significant decrease of viability in both p53(wild-type) ( EHEB , JVM-2 , JVM-3 ) and p53(mutated) ( MEC-1 , MEC-2 , BJAB ) prolymphocytic B leukemic cells , due to a combination of cell cycle block in G1 and apoptosis . Antibody phospho-kinase array analysis revealed that dasatinib inhibited the phosphorylation of various kinases , including ERK1/2 and p38/MAPK as well as of STAT3 transcription factors , in both p53(wild-type) and p53(mutated) cells . Therefore , dasatinib might offer a novel therapeutic strategy not only for p53(wild-type) , but also for p53(mutated) B malignancies that have the worst prognosis and urgently need innovative therapeutic approaches .", "label": [0, 0, 0, 0, 1, 0, 0, 1, 1, 0], "id": "20953816"}
{"sentence": "Plasminogen activator inhibitor type 1 ( PAI-1 ) is a serpin protein , a natural inhibitor of urokinase ( uPA ) and tissue plasminogen activators ( tPA ) . By inhibiting uPA it can block growth of the cancer tumors by suppressing angiogenesis , while when acting on tPA in the blood it can avert conversion of plasminogen to plasmin preventing lysis of the clot . Furthermore , blocking PAI-1 activity can protect against thrombosis . Thus PAI-1 makes great impact on human homeostasis and is desirable for clinical application . Wild-type PAI-1 ( wt-PAI-1 ) has a short span of activity with a t1/2 of h , being spontaneously converted into a latent form . An enormous effort has been made to create a more stable molecule with >600 PAI-1 variants constructed to study its structure-function relationship . In the present study , we evaluate the structure of the active recombinant VLHL-PAI-1 ( very long half life , active >700 h ) which is glycosylated similarly to wt-PAI-1 at N232 and N288 , with the extended reactive center loop , intact engineered -S-S-bridge ( Q174C , G323C ) that precludes latency without affecting structure , and can be controlled by a reducing agent to terminate activity at will . We have already proven its usefulness to control cancer in human cancer cells , as well as preventing clot lysis in human whole blood and plasma and in a mouse model . Our results demonstrate the potential therapeutic applications ( topical or systemic ) of this protein in the treatment of cancer , for the trauma patients to ward off an excessive blood loss , or for people with the PAI-1 deficiency , especially during surgery .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "21947232"}
{"sentence": "Breast cancer is the most common malignancy in women , and many breast cancer patients fail conventional treatment strategies of chemotherapy , radiation , and antiestrogen therapy . Research into the molecular pathways and biomarkers involved in the development of breast cancer should yield information that will guide therapeutic decisions . Epidermal growth factor receptor ( EGFR ) and cyclooxygenase-2 ( COX-2 ) are involved in the carcinogenesis of breast cancer and exist tight crosstalk with estrogen receptor ( ER ) pathway . Combination of EGFR and COX-2 inhibitors , therefore , could be an effective strategy for reducing cell growth in estrogen-dependent breast cancer . In order to verify the effects of EGFR and COX-2 inhibitors , breast cancer cells MCF-7 and SKBR-3 were characterized for receptors status and then treated with respective inhibitors ( nimotuzumab and celecoxib ) alone and in combination . Both cell lines were sensitive to celecoxib , but not to nimotuzumab . However , combination of two drugs demonstrated synergistic effects on cell killing . Moreover , association of two drugs resulted in SKBR-3 cells , a further G0/G1 phase arrest than one drug alone . Downregulation of p-EGFR , p-Akt , p-mTOR , and amplified in breast cancer 1 ( AIB1 ) were observed in both cell lines , and upregulation of E-cadherin was only found in MCF-7 , after treatment with single agent or in combination . These studies suggest that nimotuzumab and celecoxib exert synergistic antiproliferation effects in breast cancer , which partly correlates with ER status . Due to Akt/mTOR , EMT and AIB1 pathways participate in this process , therefore , E-cadherin and AIB1 may be considered as possible biomarkers to predict response in ER-positive breast cancer cells treated with EGFR and COX-2 inhibitors .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 1, 0], "id": "22252523"}
{"sentence": "DNA damage induced by benzene and its metabolites is thought of as an important mechanism underlying benzene genotoxicity in chronic benzene poisoning ( CBP ) . Therefore , genetic variation in DNA repair genes may contribute to susceptibility to CBP in the exposed population . Since benzene-induced DNA damages include DNA adducts , we hypothesized that the polymorphisms of ERCC1 ( Excision repair cross complementation group 1 ) and ERCC2/XPD ( Excision repair cross complementation group 2/xeroderma pigmentosum group D ) are associated with the risk of CBP . A case-control study involving 102 benzene-poisoned patients and 204 none-benzene-poisoned controls occupationally exposed to benzene was carried out in the Northeast region of China . The polymorphisms of codon 118 ( rs11615 ) and C8092A ( rs3212986 ) of ERCC1 , codon 751 ( rs13181 ) , 312 ( rs1799793 ) and 156 ( rs238406 ) of ERCC2/XPD were genotyped by TaqMan(\u00ae) Real-time PCR . The results showed that individuals carrying the ERCC1 codon 118 TT genotype had an increased risk of CBP ( OR(adj)=3.390 ; 95%CI : 1.393-8.253 ; P=0.007 ) comparing with its CC genotype . After stratified by smoking , gender and exposure duration we found that the increased risk of CBP associated with the ERCC1 codon 118 TT genotype confined to nonsmokers ( OR=3.214 ; 95% CI : 1.359-7.601 ; P=0.006 ) , female ( OR=3.049 ; 95% CI : 1.235-7.529 ; P=0.013 ) and exposure duration> 12 years ( OR=3.750 ; 95% CI : 1.041-13.513 ; P=0.035 ) . Since ERCC1 and ERCC2/XPD are both located on chromosome 19q13.3 , haplotype analysis of all 5 SNPs was also conducted . However no correlations between the risks of CBP and other genotypes or haplotypes were found . Therefore , our findings suggest an important role of ERCC1 codon 118 polymorphisms for a biomarker to CBP in the Chinese occupational population .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "23147699"}
{"sentence": "The ultraviolet ( UV ) radiation present in sunlight is immune-suppressive . Recently we showed that solar-simulated UV radiation ( UVA + UVB ; 295-400 nm ) , applied after immunization , suppressed immunological memory and the elicitation of delayed-type hypersensitivity to the common opportunistic pathogen , Candida albicans . Further , we found that wavelengths in the UVA region of the solar spectrum ( 320-400 nm ) , devoid of UVB , were equally effective in activating immune suppression as UVA + UVB radiation . Here we report on the mechanisms involved . No immune suppression was found in UV-irradiated mice injected with monoclonal anti-interleukin ( IL)-10 antibody , or mice exposed to solar-simulated UV radiation and injected with recombinant IL-12 . Antigen-specific suppressor T cells were found in the spleens of mice exposed to UVA + UVB radiation . Applying liposomes containing bacteriophage T4N5 to the skin of mice exposed to solar-simulated UVA + UVB radiation or mice exposed to UVA radiation blocked immune suppression , demonstrating an essential role for UV-induced DNA damage in the suppression of established immune reactions . These findings indicate that UV radiation activates similar immunological pathways to suppress the induction , or the elicitation , of the immune response .", "label": [0, 1, 0, 0, 0, 1, 0, 0, 0, 0], "id": "12444953"}
{"sentence": "We demonstrate that reactive oxygen species ( ROS ) plays an important role in the process of apoptosis in human peripheral blood mononuclear cell ( PBMC ) which is induced by the radiation of 900 MHz radiofrequency electromagnetic field ( RFEMF ) at a specific absorption rate ( SAR ) of W/kg when the exposure lasts longer than two hours . The apoptosis is induced through the mitochondrial pathway and mediated by activating ROS and caspase-3 , and decreasing the mitochondrial potential . The activation of ROS is triggered by the conformation disturbance of lipids , protein , and DNA induced by the exposure of GSM RFEMF . Although human PBMC was found to have a self-protection mechanism of releasing carotenoid in response to oxidative stress to lessen the further increase of ROS , the imbalance between the antioxidant defenses and ROS formation still results in an increase of cell death with the exposure time and can cause about 37% human PBMC death in eight hours .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22778799"}
{"sentence": "Tobacco-induced oxidative stress leads to chronic inflammation and is implicated in the development of many human epithelial cancers , including head and neck cancer . Cigarette smoke exposure was shown to induce the expression of the \u0394Np63\u03b1 and nitric oxide synthase ( NOS)-2 in head and neck squamous cell carcinoma cells and immortalized oral keratinocytes . The NOS2 promoter was found to contain various cognate sequences for several transcription factors including interferon regulatory factor ( IRF)-6 and p63 , which were shown in vivo binding to the NOS2 promoter in response to smoke exposure . Small interfering ( si)-RNAs against both \u0394Np63\u03b1 and IRF6 decreased the induction of NOS2 promoter-driven reporter luciferase activity and were shown to inhibit NOS2 activity . Furthermore , both mainstream ( MSE ) and sidestream ( SSE ) smoking extracts induced changes in expression of autophagic marker , LC3B , while siRNA against \u0394Np63\u03b1 , IRF6 and NOS2 modulated these autophagic changes . Overall , these data support the notion that \u0394Np63\u03b1/IRF6 interplay regulates NOS2 transcription , thereby underlying the autophagic-related cancer cell response to tobacco exposure .", "label": [0, 0, 0, 0, 0, 0, 0, 1, 0, 0], "id": "21129360"}
{"sentence": "BACKGROUND The immune system plays an important role in the multifactorial biologic system during the development of neoplasias . However , the involvement of the inflammatory response in the promotion/control of malignant cells is still controversial , and the cell subsets and the mechanisms involved are poorly investigated . The goal of this study was to characterize the clinical-pathological status and the immunophenotyping profile of tumor infiltrating lymphocytes and their association with the animal survival rates in canine mammary carcinomas . METHODS Fifty-one animals with mammary carcinomas , classified as carcinomas in mixed tumors-MC-BMT = 31 and carcinomas-MC = 20 were submitted to systematic clinical-pathological analysis ( tumor size ; presence of lymph node and pulmonary metastasis ; clinical stage ; histological grade ; inflammatory distribution and intensity as well as the lymphocytic infiltrate intensity ) and survival rates . Twenty-four animals ( MC-BMT = 16 and MC = 8 ) were elected to the immunophenotypic study performed by flow cytometry . RESULTS Data analysis demonstrated that clinical stage II-IV and histological grade was I more frequent in MC-BMT as compared to MC . Univariate analysis demonstrated that the intensity of inflammation ( moderate/intense ) and the proportion of CD4+ ( > or = 66.7% ) or CD8+ T-cells ( <33.3% ) were not associated with worse survival rate . Multivariate analysis demonstrated that only lymphocytic infiltrate intensity > or = 600 ( P = 0.02 ) remained as independent prognostic factor . Despite the clinical manifestation , the lymphocytes represented the predominant cell type in the tumor infiltrate . The percentage of T-cells was higher in animals with MC-BMT without metastasis , while the percentage of B-lymphocytes was greater in animals with metastasized MC-BMT ( P < 0.05 ) . The relative percentage of CD4+ T-cells was significantly greater in metastasized tumors ( both MC-BMT and MC ) , ( P < 0.05 ) while the proportion of CD8+ T-cells was higher in MC-BMT without metastasis . Consequently , the CD4+/CD8+ ratio was significantly increased in both groups with metastasis . Regardless of the tumor type , the animals with high proportions of CD4+ and low CD8+ T-cells had decreased survival rates . CONCLUSION The intensity of lymphocytic infiltrate and probably the relative abundance of the CD4+ and CD8+ T-lymphocytes may represent important survival prognostic biomarkers for canine mammary carcinomas .", "label": [1, 1, 0, 0, 0, 0, 0, 0, 0, 1], "id": "20525350"}
{"sentence": "Phyllanthus urinaria is widely used as anti-inflammatory , antiviral , antibacterial , and anti-hepatotoxic medicines in almost every tropical country . However , scientific evidence supporting its use in cancer metastasis is limited , particularly osteosarcoma . We investigated the effect of P. urinaria extract ( PUE ) on cell viability , invasion , and migration in the human osteosarcoma Saos-2 cell line , and looked at the impact of PUE on several relevant proteases and signaling pathways . This study demonstrates that PUE , at a range of concentrations ( from 0 to 100 \u03bcg/ml ) , concentration-dependently inhibited the migration/invasion capacities of Saos-2 without cytotoxic effects . Zymographic and western blot analyses revealed that PUE inhibited the urokinase-type plasminogen activator ( u-PA ) and matrix metalloproteinase-2 ( MMP-2 ) enzyme activity , as well as protein expression . Western blot analysis also showed that PUE inhibits phosphorylation of ERK1/2 and Akt . Testing of mRNA level , quantitative real-time PCR , and promoter assays evaluated the inhibitory effects of PUE on u-PA expression in Saos-2 cells . The chromatin immunoprecipitation ( ChIP ) assay was reactive to the transcription protein SP-1 , which was inhibited by PUE . In conclusion , PUE suppresses human osteosarcoma Saos-2 cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways . Therefore , PUE produces anti-metastatic activity in Saos-2 cells .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23201449"}
{"sentence": "Biomaterials such as polyetherurethans ( PEUs ) are the scaffolding , which is indispensable for the development of the bio-artificial organs . However , PEUs can induce tumors in subcutaneous implantation sites in rat . We have shown that the different inhibitory potential of gap junctional intercellular communication ( GJIC ) on the surface of the biomaterials , including PEUs , is a key step in determining the tumorigenic potential . Here we show that suppression of a gap junctional protein connexin 43 ( Cx43 ) plays an important role in in vivo tumorigenesis induced by PEUs for the first time and that Cx43 transfection may be an effective strategy for preventing tumorigenesis induced by biomaterials . Rat tumor cell line U41 is derived from tumors in the subcutaneous implantation of PEU films . The GJIC and the expression of Cx43 were suppressed in U41 . The restoration of normal phenotype , such as reduction of growth rate , recovery of contact inhibition and loss of colony formation ability in soft agar , was achieved by Cx43 transfection . These results strongly suggest that suppression of Cx43 expression plays an important role in the development of rat malignant fibrous histiocytoma ( MFHC ) caused by PEUs and that Cx43 transfection is effective for prevention of tumorigenesis induced by PEUs .", "label": [0, 0, 0, 0, 1, 0, 0, 0, 0, 0], "id": "19003298"}
{"sentence": "The homodimeric bc(1) complexes are membrane proteins essential in respiration and photosynthesis . The distance between the two b(L)-hemes of the dimer opens the possibility of electron transfer between them , but contradictory reports make such inter-monomer electron transfer controversial . We have constructed in Rhodobacter sphaeroides a heterodimeric expression system similar to those used before , in which the bc(1) complex can be mutated differentially in the two copies of cyt b to test for inter-monomer electron transfer , but found that genetic recombination by cross-over then occurs to produce wild-type homodimer . Selection pressure under photosynthetic growth always favored the homodimer over heterodimeric variants enforcing inter-monomer electron transfer , showing that the latter are not competitive . These results , together with kinetic analysis of myxothiazol titrations , demonstrate that inter-monomer electron transfer does not occur at rates competitive with monomeric turnover . We examine the results from other groups interpreted as demonstrating rapid inter-monomer electron transfer , conclude that similar mechanisms are likely to be in play , and suggest that such claims might need to be re-examined .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22465023"}
{"sentence": "The oncogenic potential of a human papillomavirus type 16 ( HPV16 ) variant cloned from normal human cervical keratinocytes has been tested in vitro using primary rodent epithelial cells and human cervical keratinocytes . The HPV16 variant was able to extend the lifespan of , but failed to immortalize , human keratinocytes . It could however cooperate with an activated ras oncogene to transform primary rodent cells . Radioimmunoprecipitation assays of the rodent cells showed that they expressed the E7 protein . DNA sequence analysis of the URR/E6/E7 and E5 regions of the HPV16 showed them to be fully functional , but a deletion in the viral E2 open reading frame was detected . This truncated E2 only weakly stimulated transcription of the viral regulatory region . Complementation assays using the HPV16 variant and a full-length E2 enabled the cloned variant to immortalize human cervical keratinocytes with wild-type efficiency . These results suggest that other viral gene products in addition to E6/E7 may play an important role in the in vitro immortalization of cervical keratinocytes in HPV16 and the development of cervical cancer .", "label": [0, 0, 0, 1, 0, 0, 0, 0, 0, 0], "id": "1312701"}
{"sentence": "We studied the effects of double-strand breaks on intramolecular extrachromosomal homologous recombination in mammalian cells . Pairs of defective herpes thymidine kinase ( tk ) sequences were introduced into mouse Ltk- cells on a DNA molecule that also contained a neo gene under control of the SV40 early promoter/enhancer . With the majority of the constructs used , gene conversions or double crossovers , but not single crossovers , were recoverable . DNA was linearized with various restriction enzymes prior to transfection . Recombination events producing a functional tk gene were monitored by selecting for tk-positive colonies . For double-strand breaks placed outside of the region of homology , maximal recombination frequencies were measured when a break placed the two tk sequences downstream from the SV40 early promoter/enhancer . We observed no relationship between recombination frequency and either the distance between a break and the tk sequences or the distance between the tk sequences . The quantitative effects of the breaks appeared to depend on the degree of homology between the tk sequences . We also observed that inverted repeats recombined as efficiently as direct repeats . The data indicated that the breaks influenced recombination indirectly , perhaps by affecting the binding of a factor(s) to the SV40 promoter region which in turn stimulated or inhibited recombination of the tk sequences . Taken together , we believe that our results provide strong evidence for the existence of a pathway for extrachromosomal homologous recombination in mammalian cells that is distinct from single-strand annealing . We discuss the possibility that intrachromosomal and extrachromosomal recombination have mechanisms in common .", "label": [0, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "1459429"}
{"sentence": "The prediction of tumor behavior for patients with oral carcinomas remains a challenge for clinicians . The presence of lymph node metastasis is the most important prognostic factor but it is limited in predicting local relapse or survival . This highlights the need for identifying biomarkers that may effectively contribute to prediction of recurrence and tumor spread . In this study , we used one- and two-dimensional gel electrophoresis , mass spectrometry and immunodetection methods to analyze protein expression in oral squamous cell carcinomas . Using a refinement for classifying oral carcinomas in regard to prognosis , we analyzed small but lymph node metastasis-positive versus large , lymph node metastasis-negative tumors in order to contribute to the molecular characterization of subgroups with risk of dissemination . Specific protein patterns favoring metastasis were observed in the \" more-aggressive \" group defined by the present study . This group displayed upregulation of proteins involved in migration , adhesion , angiogenesis , cell cycle regulation , anti-apoptosis and epithelial to mesenchymal transition , whereas the \" less-aggressive \" group was engaged in keratinocyte differentiation , epidermis development , inflammation and immune response . Besides the identification of several proteins not yet described as deregulated in oral carcinomas , the present study demonstrated for the first time the role of cofilin-1 in modulating cell invasion in oral carcinomas .", "label": [1, 0, 0, 0, 0, 0, 1, 1, 1, 1], "id": "23227181"}
{"sentence": "Interferon-gamma ( IFN-gamma ) has pleiotropic activities other than its antivirus action , including cell growth inhibition , natural killer ( NK ) cell and cytotoxic T lymphocyte ( CTL ) activation , and angiogenesis inhibitory activity , and these activities are supposed to be involved in its antitumour activity . However , it has not been completely elucidated which activity is mainly involved in the tumour suppression in vivo . In this study , we analysed inhibitory mechanisms of endogenous IFN-gamma against B16 melanoma experimental metastasis . After intravenous injection of tumour cells , tumour deposits in the lungs and liver were increased and life span was shorter in IFN-gamma(-/-) mice , indicating important roles for IFN-gamma in antitumour mechanisms . Interestingly , tumour deposits were not increased in IFN-gamma receptor ( R)(-/- ) mice . Furthermore , only low levels of cell-mediated immunity against the tumour and activation of NK cells were observed , indicating that antimetastatic effects of IFN-gamma is not mediated by host cells . The survival period of B16 melanoma-bearing IFN-gamma R(-/-) mice was , however , shorter than wild-type mice . These observations suggest that IFN-gamma prevents B16 melanoma experimental metastasis by directly inhibiting the cell growth , although antitumour host functions may also be involved in a later phase .", "label": [1, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "11849319"}
{"sentence": "RAD51 is a key enzyme of homologous recombination and repair of DNA double-strand breaks . RAD51 mRNA expression levels are significantly increased in laser-microdissected mammary simple carcinomas and their lymph node metastases when compared to adenomas or nonneoplastic mammary gland of the same dog . Here , RAD51 protein expression was analyzed by immunohistochemistry in paraffin-embedded mammary carcinomas and their lymph node metastases of 40 dogs , adenomas of 48 dogs , and nonneoplastic mammary gland of 88 dogs . Number of cells with nuclear RAD51 expression was significantly ( P < or = .05 ) increased in carcinomas when compared to adenomas and metastases . In contrast , no significant differences in the number of RAD51-expressing cells were detected when metastases were compared with adenomas and nonneoplastic gland . RAD51 expression in carcinomas was correlated with expression in metastases but not with histologic grade . In conclusion , the increased number of RAD51-expressing cells in carcinomas might indicate genomic instability in these cells . Nevertheless , the increased RAD51 mRNA expression in metastases could not be confirmed by immunohistochemistry .", "label": [1, 0, 0, 0, 0, 1, 0, 0, 0, 0], "id": "20080488"}
{"sentence": "Despite recent population data , the influence of dietary folate supplementation on colon cancer risk remains controversial . This study examines the effects of folate deficiency , in combination with choline , methionine , and vitamin B12 depletion , on intestinal tumorigenesis in Apc(Min/+) mice . Methyl donor sufficient ( MDS ) and deficient ( MDD ) diets were started at five or 10 weeks of age and tumors evaluated at 16 weeks . MDD suppressed intestinal tumor formation in Apc(Min/+) mice ( when started at five weeks of age . The protective effect was lost when MDD was initiated at 10 weeks of age , indicating an important time dependency on cancer suppression . Concomitant with cancer protection , MDD restricted body weight gain . Therefore , a second study was conducted in which MDS was given ad libitum or pair-fed with MDD . Although small intestinal tumors were reduced 54% in pair-fed MDS mice , MDD caused a further reduction ( 96% ) . In colon , although MDD did not affect tumor numbers , tumor size was reduced . Gene expression profiling of normal-appearing colonic mucosa after 11 weeks on MDD identified a total of 493 significantly downregulated genes relative to the MDS group . Pathway analysis placed many of these genes within general categories of inflammatory signaling and cell-cycle regulation , consistent with recently published human data obtained during folate depletion . Further studies are warranted to investigate the complex interplay of methyl donor status and cancer protection in high-risk populations .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22677908"}
{"sentence": "The purpose of this study was to combine a three-dimensional NMR-compatible bioreactor with hyperpolarized ( 13)C NMR spectroscopy in order to probe cellular metabolism in real time . JM1 ( immortalized rat hepatoma ) cells were cultured in a three-dimensional NMR-compatible fluidized bioreactor . ( 31)P spectra were acquired before and after each injection of hyperpolarized [ 1-(13)C ] pyruvate and subsequent ( 13)C spectroscopy at 11.7 T . ( 1)H and two-dimensional ( 1)H-(1)H-total correlation spectroscopy spectra were acquired from extracts of cells grown in uniformly labeled ( 13)C-glucose , on a 16.4 T , to determine ( 13)C fractional enrichment and distribution of ( 13)C label . JM1 cells were found to have a high rate of aerobic glycolysis in both two-dimensional culture and in the bioreactor , with 85% of the ( 13)C label from uniformly labeled ( 13)C-glucose being present as either lactate or alanine after 23 h . Flux measurements of pyruvate through lactate dehydrogenase and alanine aminotransferase in the bioreactor system were 12.18 +/- 0.49 nmols/sec/10(8) cells and 2.39 +/- 0.30 nmols/sec/10(8) cells , respectively , were reproducible in the same bioreactor , and were not significantly different over the course of 2 days . Although this preliminary study involved immortalized cells , this combination of technologies can be extended to the real-time metabolic exploration of primary benign and cancerous cells and tissues prior to and after therapy .", "label": [0, 0, 1, 0, 0, 0, 0, 0, 0, 0], "id": "20099325"}
{"sentence": "Forkhead box protein O1 ( FOXO1 ) , a key member of the FOXO family of transcription factors , acts as a tumor suppressor and has been associated with various key cellular functions , including cell growth , differentiation , apoptosis and angiogenesis . Therefore , it is puzzling why FOXO protein expression is downregulated in cancer cells . MicroRNAs , non-coding 20 nucleotide single-stranded RNAs , result in translational repression or degradation and gene silencing of their target genes , and significantly contribute to the regulation of gene expression . In the current study , we report that miR-370 expression was significantly upregulated in five prostate cancer cell lines , compared to normal prostatic epithelial ( PrEC ) cells . Ectopic expression of miR-370 induced proliferation and increased the anchorage-independent growth and colony formation ability of DU145 and LNCaP prostate cancer cells , while inhibition of miR-370 reduced proliferation , anchorage-independent growth and colony formation ability . Furthermore , upregulation of miR-370 promoted the entry of DU145 and LNCaP prostate cancer cells into the G1/S cell cycle transition , which was associated with downregulation of the cyclin-dependent kinase ( CDK ) inhibitors , p27(Kip1) and p21(Cip1) , and upregulation of the cell-cycle regulator cyclin D1 mRNA . Additionally , we demonstrated that miR-370 can downregulate expression of FOXO1 by directly targeting the FOXO1 3'-untranslated region . Taken together , our results suggest that miR-370 plays an important role in the proliferation of human prostate cancer cells , by directly suppressing the tumor suppressor FOXO1 .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23029264"}
{"sentence": "Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans . Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations . However , no definitive case of adaptive introgression has yet been described . Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians ( but not sub-Saharan Africans ) has a sequence that closely matches that of the Neanderthal STAT2 . This haplotype , referred to as N , was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals . Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence ( thousand years ago ) and is found throughout Eurasia at an average frequency of Interestingly , N is found in Melanesian populations at higher frequency ( than in Eurasian populations . A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone . Although we are not able to pinpoint the precise target of positive selection , we identify nonsynonymous mutations in ERBB3 , ESYT1 , and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22883142"}
{"sentence": "BACKGROUND : It is unclear whether distinct weight-related trajectory classes , differing in course , demographics , and health characteristics , exist in the elderly population . METHODS : Data came from the 10-year ( 1986-1996 ) Duke Established Populations for Epidemiologic Studies of the Elderly study of 3,861 black ( 54% ) and white ( 46% ) participants aged 65-105 years . Latent-class trajectories of body mass index ( BMI : kg/m(2) ) based on self-reported weight and height at baseline , 3 , 6 , and 10 years later were determined using generalized mixture models . Polytomous logistic regression was used to identify baseline demographic and health characteristics that distinguished the trajectories , and 10-year postbaseline data to confirm the findings . RESULTS : We identified three trajectories : normal weight ( BMI 27.6% of the sample ) , overweight ( BMI 65.1% ) , and obese ( BMI 7.3% ) . Demographic characteristics distinguished the three trajectories : highest odds of blacks , women , and less education in the obese trajectory , lowest in the normal-weight trajectory . Obese and overweight differed adversely from normal-weight trajectories , but not significantly from each other on cognitive impairment , hypertension , and diabetes . Depressive symptomatology was more prevalent in the obese ; they were also younger . There was no association with cancer or heart disease . CONCLUSION : Distinct trajectories and course of BMI were present in this older population . Weight loss increased with increase in BMI class . Although demographic characteristics distinguished all trajectory classes , adverse health characteristics distinguished the overweight and obese classes from the normal-weight class , but not from each other . Problems associated with education and health are present at study entry and should be addressed earlier in life .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "23089335"}
{"sentence": "Molecular dynamics ( MD ) simulations of the single-stranded DNA trinucleotide TG*G* , with the G* guanines crosslinked by the antitumor drug cisplatin , were performed with explicit representation of the water as solvent . The purpose of the simulations was to explain previous NMR observations indicating that in single-stranded cisplatin-DNA adducts , the crosslinked guanines adopt a left-handed helical orientation , whereas in duplexes , the orientation is right-handed . The analysis of the MD trajectory of TG*G* has ascribed a crucial role to hydrogen-bonding ( direct or through-water ) interactions of the 5'-oriented NH(3) ligand of platinum with acceptor groups at the 5'-side of the crosslink , namely the TpG* phosphate and the terminal 5'-OH group . These interactions bring about some strain into the trinucleotide which is slightly but significantly ( 1-1.5 kcal.mol(-1) ) higher for the right-handed orientation than for the left-handed one . During the unconstrained , 3 ns long MD simulation , left-handed conformations were times more abundant than the right-handed ones . This sampling difference agrees roughly with the calculated energy difference in strain energy . Overall , these results show that the Pt-GG crosslink within single-stranded DNA is malleable and can access different conformations at a moderate energy cost . This malleability could be of importance in interactions between the platinated DNA and cellular proteins , in which the DNA is locally unwound .", "label": [0, 0, 0, 0, 0, 0, 0, 0, 0, 0], "id": "22947917"}
{"sentence": "An in vitro angiogenesis system was designed for screening angiogenic agonists and antagonists . In order to obtain large quantities of cells and reproducibility , human endothelial cells with extended life spans were developed by retroviral transfection . The resulting cells grown in a serum-free medium containing endothelial cell growth supplement ( ECGS ) have a telomerase activity , extended life spans of at least 21 passages , and an endothelial cell phenotype ( diI-acetylated-LDL upake , factor VIII-related antigen , VEGFR-1 and R-2 , and tissue-type plasminogen activator ( tPA) ) that resembled that of unaltered primary endothelial cells . Exceptions were ( i ) a higher expression of tPA , and ( ii ) a non-significant growth response to FGF-2 or VEGF stimulation . Within three-dimensional fibrin gels , specific cell clones rapidly formed tubular structures in a more reproducible manner than those observed with low-passage primary cells . Tube formation by primary endothelial cells and those with extended life spans was dependent upon FGF-2 and ECGS , respectively . Both cell types produced FGF-2 and VEGF cytokines . Increasing doses of suramin significantly decreased the size of microvessels formed by both cell lines . These functional results indicate that a vascular matrix system containing human cells with extended life spans can be successfully utilized as an in vitro assay for antiangiogenic compounds .", "label": [0, 0, 0, 0, 0, 0, 1, 0, 0, 0], "id": "12549857"}