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HoC_dynamic_1_shot_test

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HoC_dynamic_1_shot300

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;resisting cell death INPUT: 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-κB DNA-binding activity in lung cancer cells and in alveolar macrophages of tumor bearing mice and especially decreased the release of inflammatory factors including TNFα , 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-κB activation , as well as induction of TNFα and IL-6 . TLR2:TLR6 complexes mediate the effect of NF-κB inactivation by CDA-2 . In conclusion , CDA-2 potently inhibits lung tumor development by reduction of the inflammation in lung through suppression of NF-κB activation in myeloid cells , associating with modulation of TLR2 signaling . OUTPUT:

activating invasion and metastasis;resisting cell death;tumor promoting inflammation

HoC_dynamic_1_shot301

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 &lt ; 0.05 ) and indices of lipid peroxidation were greater ( P &lt ; 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 &lt ; 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 . OUTPUT: avoiding immune destruction INPUT: Ovarian cancer , one of inflammation-associated cancers , is the fifth leading cause of cancer deaths among women . Inflammation in the tumor microenvironment is associated with peritoneal tumor dissemination and massive ascites , which contribute to high mortality in ovarian cancer . Tumor suppressor p53 is frequently deleted or mutated in aggressive and high-grade ovarian cancer , probably aggravating cancer progression and increasing mortality . We therefore investigated the influence of p53 on proinflammatory chemokines in ovarian cancer cells . A PCR array of the chemokine network revealed that ovarian cancer cells with low or mutated p53 expression expressed high levels of proinflammatory chemokines such as CXCL1 , 2 , 3 and 8 . Transient transfection of p53 into p53-null ovarian cancer cells downregulated proinflammatory chemokines induced by tumor necrosis factor-α ( TNF ) , a proinflammatory cytokine abundantly expressed in ovarian cancer . Furthermore , p53 restoration or stabilization blocked TNF-induced NF-κB promoter activity and reduced TNF-activated IκB . Restoration of p53 increased ubiquitination of IκB , resulting from concurrently reduced proteasome activity followed by stability of IκB . A ubiquitination PCR array on restoration of p53 did not reveal any significant change in expression except for Mdm2 , indicating that the balance between p53 and Mdm2 is more important in regulating NF-κB signaling rather than the direct effect of p53 on ubiquitin-related genes or IκB kinases . In addition , nutlin-3 , a specific inducer of p53 stabilization , inhibited proinflammatory chemokines by reducing TNF-activated IκB through p53 stabilization . Taken together , these results suggest that p53 inhibits proinflammatory chemokines in ovarian cancer cells by reducing proteasomal degradation of IκB . Thus , frequent loss or mutation of p53 may promote tumor progression by enhancing inflammation in the tumor microenvironment . OUTPUT:

genomic instability and mutation;tumor promoting inflammation

HoC_dynamic_1_shot302

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: enabling replicative immortality;evading growth suppressors;genomic instability and mutation;tumor promoting inflammation;sustaining proliferative signaling INPUT: Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis . Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy . Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches . Here , we identified harmine ( β-carboline alkaloid ) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth . Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction . Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells . Moreover , harmine not only induced endothelial cell cycle arrest and apoptosis , but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay . Finally , harmine inhibited tumor growth by reducing tumor angiogenesis , as demonstrated by a xenograft tumor model . Our results suggested a novel mechanism and bioactivity of harmine , which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells . OUTPUT:

evading growth suppressors;inducing angiogenesis;resisting cell death;sustaining proliferative signaling

HoC_dynamic_1_shot303

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: Hormone-dependent estrogen receptor positive ( ER+ ) breast cancers generally respond well to anti-estrogen therapy . Unfortunately , hormone-independent estrogen receptor negative ( ER- ) breast cancers are aggressive , respond poorly to current treatments and have a poor prognosis . New approaches and targets are needed for the prevention and treatment of ER- breast cancer . The NF-κB signaling pathway is strongly implicated in ER- tumor genesis , constituting a possible target for treatment . Hydrogen sulfide-releasing aspirin ( HS-ASA ) , a novel and safer derivative of aspirin , has shown promise as an anti-cancer agent . We examined the growth inhibitory effect of HS-ASA via alterations in cell proliferation , cell cycle phase transitions , and apoptosis , using MDA-MB-231 cells as a model of triple negative breast cancer . Tumor xenografts in mice , representing human ER- breast cancer , were evaluated for reduction in tumor size , followed by immunohistochemical analysis for proliferation , apoptosis and expression of NF-κB . HS-ASA suppressed the growth of MDA-MB-231 cells by induction of G(0)/G(1) arrest and apoptosis , down-regulation of NF-κB , reduction of thioredoxin reductase activity , and increased levels reactive oxygen species . Tumor xenografts in mice , were significantly reduced in volume and mass by HS-ASA treatment . The decrease in tumor mass was associated with inhibition of cell proliferation , induction of apoptosis and decrease in NF-κB levels in vivo . HS-ASA has anti-cancer potential against ER- breast cancer and merits further study . OUTPUT: resisting cell death;sustaining proliferative signaling;tumor promoting inflammation INPUT: Hormone antagonist therapy for estrogen receptor positive ( ER+ ) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. 1α,25-dihydroxyvitamin D(3) [ 1α,25(OH)(2)D(3) ] is a potent antitumor agent in pre-clinical studies , but caused hypercalcemia when its effective antitumor doses were used . Therefore , we investigated the effects of a less-calcemic 1α,25(OH)(2)D(3) analog , 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D(3 )(MART-10 ) , on ER+MCF-7 cells . We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)(2)D(3) in inhibiting cell growth in a dose- and time-dependent manner . MART-10 is also much more potent in arresting MCF-7cell cycle progression at G(0)/G(1) phase as compared to 1α,25(OH)(2)D(3) , possibly mediated by a greater induction of p21 and p27 expression . Moreover , MART-10 is more active than 1α,25(OH)(2)D(3) in causing cell apoptosis , likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol . Based on our in vitro findings , MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer , for example , ER+ patients , to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens . Thus , further in vivo animal study is warranted . OUTPUT:

evading growth suppressors;sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot304

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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�10(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 μmol/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 μmol/L ) . In B16F10 cells , luteolin up-regulated E-cadherin at least partly via inhibiting the β3 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 β3 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 β3 integrin , suggesting that luteolin may be applied as a potential anticancer chemopreventative and chemotherapeutic agent . OUTPUT: activating invasion and metastasis INPUT: 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�1.72 μM 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 . OUTPUT:

sustaining proliferative signaling;resisting cell death

HoC_dynamic_1_shot305

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: genomic instability and mutation;tumor promoting inflammation INPUT: 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)(•-) &gt ; H(2)O(2) &gt ; NF-κB ( JNK/c-Jun ) >p53&gt ; loss ΔΨ(m)&gt ; caspase-3 , AIF &gt ; 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 . OUTPUT:

resisting cell death;tumor promoting inflammation

HoC_dynamic_1_shot306

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 ∼1.5μM and 40μM ) . 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 . OUTPUT: evading growth suppressors;sustaining proliferative signaling;resisting cell death INPUT: The Punica granatum L. var. granatum ( pomegranate ) has been demonstrated to exert antitumor effects on various types of cancer cells . The present study aimed to evaluate the medicinal herbs Punica granatum L. var. spinosa ( apple punice ) that are native to Iran . This study was determined to test the possible cytotoxic activity and induction of apoptosis on human prostate cell lines . The effect of ethanol extracts of the herbs on the inhibition of cell proliferation was assessed by MTT colorimetric assay . PC3 cell lines treated with the extracts were analyzed for the induction of apoptosis by cell death detection ( ELISA ) and TUNEL assay . Dye exclusion analysis was performed for viability rate . Our results demonstrated that the Punica granatum L. var. spinosa extract dose dependently suppressed the proliferation of PC3 cells ( IC(50)= 250.21 μg/mL ) when compared with a chemotherapeutic anticancer drug ( Toxol ) ( Vesper Pharmaceuticals ) with increased nucleosome production from apoptotic cells . The Punica granatum L. var. spinosa extract attenuated the human prostate cell proliferation in vitro possibly by inducing apoptosis . The Punica granatum L. var. spinosa is likely to be valuable for the treatment of some forms of human prostate cell line . OUTPUT:

resisting cell death

HoC_dynamic_1_shot307

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: resisting cell death;enabling replicative immortality INPUT: 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-α , 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 &lt ; 0.001 ) , formation of CPDs ( P &lt ; 0.001 ) and sunburn cells ( P &lt ; 0.001 ) , and the epidermal thickness and number of epidermal cell layers ( P &lt ; 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 &lt ; 0.001 ) and sunburn cells ( P &lt ; 0.001 ) . The administration of Cv via hydrogel may be a viable method for chemoprevention. . OUTPUT:

genomic instability and mutation;tumor promoting inflammation

HoC_dynamic_1_shot308

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 Cδ ( PKCδ)-dependent p53 activation to maintain cell survival after growth factor withdrawal . In contrast , DNA damage-induced p53 activation was PKCδ 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 . OUTPUT: cellular energetics;sustaining proliferative signaling;genomic instability and mutation INPUT: We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells . In this work , we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway.To investigate the role of this pathway in mifepristone-induced growth inhibition , human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor , LY294002 . The activation of Akt in ovarian cancer cells , as marked by its phosphorylation on Ser473 , was not modified by cytostatic concentrations of mifepristone , but it was blocked upon treatment with LY294002 . The combination mifepristone/LY294002 , but not the individual drugs , killed ovarian cancer cells via apoptosis , as attested by genomic DNA fragmentation and cleavage of caspase-3 , and the concomitant down-regulation of anti-apoptotic proteins Bcl-2 and XIAP . From a pharmacological standpoint , when assessing cell growth inhibition using a median-dose analysis algorithm , the interaction between mifepristone and LY294002 was synergistic . The lethality caused by the combination mifepristone/LY294004 in two dimensional cell cultures was recapitulated in organized , tri-dimensional spheroids . This study demonstrates that mifepristone and LY294002 , when used individually , cause cell growth arrest , yet when combined , they cause lethality . OUTPUT:

resisting cell death

HoC_dynamic_1_shot309

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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-κB)-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-κB 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-κB 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-κB-regulated inflammatory pathway , by pomegranate phytoconstituents to achieve chemoprevention of HCC . OUTPUT: tumor promoting inflammation INPUT: 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-κB protein and TNF-α 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-α expression , NF-κB activation , and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats . OUTPUT:

genomic instability and mutation;tumor promoting inflammation

HoC_dynamic_1_shot310

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 �M ) 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 . OUTPUT: resisting cell death;sustaining proliferative signaling INPUT: Previously , we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide ( H2S ) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating H2S generation . Because the incubation of endothelial cells with H2S has been known to enhance their angiogenic activities , we hypothesized that the amelioration of H2S-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells ( HUVECs ) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis . The expression of inflammatory mediators , angiogenic growth factors , and angiogenic activities in the absence or presence of Korean red ginseng extracts ( KRGE ) were evaluated in HUVECs stimulated with the H2S generator sodium hydrogen sulfide ( NaHS ) . KRGE efficiently decreased the expression of cystathionine β-synthase and cystathionine γ-lyase , enzymes that are essential for H2S synthesis . Concomitantly , a significant decrease in the expression of inflammatory mediators , including cyclooxygenase-2 and inducible nitric oxide synthase , and several angiogenic factors , including interleukin ( IL)-8 , hypoxia inducible factor-1a , vascular endothelial growth factor , IL-6 , and matrix metalloproteinases , was observed ; all of these factors are normally induced after NaHS . An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells , whereas KRGE pretreatment significantly attenuated tube formation . NaHS activated p38 and Akt , increasing the expression of angiogenic factors and the proliferation of HUVECs , whereas KRGE effectively abrogated this H2S-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells . In conclusion , KRGE was able to mitigate H2S-induced angiogenesis , implying that antagonistic action against H2S-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection . OUTPUT:

inducing angiogenesis;tumor promoting inflammation

HoC_dynamic_1_shot311

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 &gt ; 3.4 ng/ml and presence of lymphovascular invasion(LVI) . According to a multivariate analysis , with Cox regression , found an elevation of serum CEA &gt ; 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 &lt ; 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 &gt ; 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 . OUTPUT: activating invasion and metastasis INPUT: 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 ( χ΂ = 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% ; χ(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 ( χ² = 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 ( χ² = 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 . OUTPUT:

activating invasion and metastasis

HoC_dynamic_1_shot312

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: BACKGROUND &amp ; AIMS Hepatocytes are considered an exception of the paradigmatic inverse correlation between cell proliferation and terminal differentiation . In fact , hepatic vital functions are guaranteed by proliferating parenchymal cells during liver regeneration . However , a fine molecular characterization of the relationship between proliferation and differentiation in hepatocytes has been hampered by the lack of reliable in vivo or in vitro models . METHODS The hepatocyte terminal differentiation program was characterized in the immortalized , untransformed and differentiated hepatocytic cell line MMH , using several techniques . Particularly , two-dimensional difference gel electrophoresis combined to tandem mass spectrometry proteomic approach was used . Cell cycle and cell adhesion properties of MMH have been altered using either myc-overexpression and MEK1/2 inhibition or a constitutive active beta-catenin mutant , respectively . RESULTS The hepatocyte terminal differentiation program is stimulated by the exit from the cell cycle induced by cell-cell contact . Comparative proteomic analysis of proliferating versus quiescent hepatocytes validated the importance of contact inhibition , identifying 68 differently expressed gene products , representing 49 unique proteins . Notably , enzymes involved in important liver functions such as detoxification processes , lipid metabolism , iron and vitamin A storage and secretion , anti-inflammatory response and exocytosis were found significantly up-regulated in quiescent hepatocytes . Finally , we found that : ( i ) cell cycle arrest induced by MEK1/2 inhibition is not sufficient to induce hepatic product expression ; ( ii ) constitutive activation of beta-catenin counteracts the contact inhibition-induced terminal differentiation . CONCLUSION The hepatocyte terminal differentiation program requires a quiescent state maintained by cell-cell contact through the E-cadherin/beta-catenin pathway , rather than the inhibition of proliferation . OUTPUT: evading growth suppressors INPUT: 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 . OUTPUT:

tumor promoting inflammation;activating invasion and metastasis;cellular energetics

HoC_dynamic_1_shot313

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: In cancer cells , glucose is often converted into lactic acid , which is known as the ' Warburg effect ' . The reason that cancer cells have a higher rate of aerobic glycolysis , but not oxidative phosphorylation , remains largely unclear . Herein , we proposed an epigenetic mechanism of the Warburg effect . Fructose-1,6-bisphosphatase-1 ( FBP1 ) , which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells . Restoration of FBP1 expression suppressed anchorage-independent growth , indicating the relevance of FBP1 downregulation in carcinogenesis . Indeed , FBP1 was downregulated in gastric carcinomas ( P<0.01 , n=22 ) and gastric cancer cell lines ( 57% , 4/7 ) . Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells . Moreover , FBP1 downregulation was reversed by pharmacological demethylation . Its promoter was hypermethylated in gastric cancer cell lines ( 57% , 4/7 ) and gastric carcinomas ( 33% , 33/101 ) . Inhibition of NF-kappaB restored FBP1 expression , partially through demethylation of FBP1 promoter . Notably , Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer ( hazard ratio : 3.60 , P=0.010 ) . In summary , we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1 . Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer . Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect . OUTPUT: cellular energetics INPUT: 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 . OUTPUT:

cellular energetics

HoC_dynamic_1_shot314

***TASK*** The task is to perform a semantic classification of the article according to the hallmarks of cancer based on its abstract. ***INPUT*** The input is an abstract text. ***DOCUMENTATION*** There are 10 cancer hallmarks you will need to decide whether the article is related to, including: activating invasion and metastasis sustaining proliferative signaling resisting cell death cellular energetics genomic instability and mutation evading growth suppressors inducing angiogenesis enabling replicative immortality avoiding immune destruction tumor promoting inflammation ***OUTPUT*** The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics. ***EXAMPLES*** INPUT: 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 . OUTPUT: cellular energetics INPUT: BACKGROUND Aerobic glycolysis , namely the Warburg effect , is the main hallmark of cancer cells . Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift . This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression , some of which rely on functional mitochondria . In this framework , the role of mitochondrial complex I is still debated , in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism . The aim of this work is to provide the proof of concept that functional complex I is necessary to sustain tumor progression . METHODS Complex I-null osteosarcoma cells were complemented with allotopically expressed complex I subunit 1 ( MT-ND1 ) . Complex I re-assembly and function recovery , also in terms of NADH consumption , were assessed . Clones were tested for their ability to grow in soft agar and to generate tumor masses in nude mice . Hypoxia levels were evaluated via pimonidazole staining and hypoxia-inducible factor-1α ( HIF-1α ) immunoblotting and histochemical staining. 454-pyrosequencing was implemented to obtain global transcriptomic profiling of allotopic and non-allotopic xenografts . RESULTS Complementation of a truncative mutation in the gene encoding MT-ND1 , showed that a functional enzyme was required to perform the glycolytic shift during the hypoxia response and to induce a Warburg profile in vitro and in vivo , fostering cancer progression . Such trigger was mediated by HIF-1α , whose stabilization was regulated after recovery of the balance between α-ketoglutarate and succinate due to a recuperation of NADH consumption that followed complex I rescue . CONCLUSION Respiratory complex I is essential for the induction of Warburg effect and adaptation to hypoxia of cancer cells , allowing them to sustain tumor growth . Differently from other mitochondrial tumor suppressor genes , therefore , a complex I severe mutation such as the one here reported may confer anti-tumorigenic properties , highlighting the prognostic values of such genetic markers in cancer . OUTPUT:

cellular energetics;genomic instability and mutation