bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knockdown of hTERT by SiRNA suppresses growth of Capan‐2 human pancreatic cancer cell via the inhibition of expressions of Bcl‐2 and COX‐2
Authors: ZHONG Ying Qiang , XIA Zhong Sheng , FU Yu Ru , ZHU Zhao Hua 
Published: March 2010

OBJECTIVE:  To investigate the effects of human telomerase reverse transcriptase (hTERT) on the growth of Capan‐2 human pancreatic cancer cell and apoptosis.METHODS:  Cell proliferation, apoptosis and cell cycle were analyzed by cell counting and flow cytometry. mRNA and protein expressions of hTERT, Bcl‐2 and cyclooxygenase (COX)‐2 were assessed by real time PCR and Western blot.RESULTS:  Cell growth was significantly inhibited by 26.39 percent 24 h after hTERT‐small interference RNA (siRNA) transfection (50 nmol/L) with a 100 percent silencing efficiency (P < 0.05). The inhibition rates of cell proliferation were 46.77 percent, 70.61 percent, 84.71 percent and 85.99 percent at 2, 3, 5 and 7 days after transfection, respectively (P < 0.001). Early and late apoptotic cells increased significantly (especially 24 h after transfection) (P < 0.001). The cell cycle was suppressed significantly as manifested by the increase of cells in the G0/G1 phase and the decrease of cells in the S phase and G2/M phase (P < 0.01). The expressions of Bcl‐2 mRNA and COX‐2 mRNA were inhibited significantly 48 h after transfection: the inhibition rates were 86.86 percent and 100 percent, respectively (P < 0.001). Levels of Bcl‐2 protein were downregulated by 58.54 percent and 63.44 percent and the levels of COX‐2 protein were downregulated by 50.06 percent and 82.77 percent at 48 h and 72 h after transfection, respectively.CONCLUSION:  Knockdown of hTERT by siRNA can inhibit the growth of Capan‐2 cell. The inhibitory effect is associated with the downregulation of Bcl‐2 and COX‐2.
Ensemble forecasting shifts in climatically suitable areas for Tropidacris cristata (Orthoptera: Acridoidea: Romaleidae)
Authors: DINIZ‐FILHO JOSE ALEXANDRE F. , NABOUT JOÃO CARLOS , BINI LUIS MAURICIO , LOYOLA RAFAEL DIAS , RANGEL THIAGO FERNANDO , NOGUES‐BRAVO DAVID , ARAÚJO MIGUEL B. 
Published: March 2010

Abstract.  1. The effects of climate change on species’ ranges have been usually inferred using niche‐based models creating bioclimatic envelopes that are projected into geographical space. Here, we apply an ensemble forecasting approach for niche models in the Neotropical grasshopper Tropidacris cristata (Acridoidea: Romaleidae). A novel protocol was used to partition and map the variation in modelled ranges due to niche models, Atmosphere‐Ocean Global Circulation Models (AOGCM), and emission scenarios.2. We used 112 records of T. cristata and four climatic variables to model the species’ niche using five niche models, four AOGCMs and two emission scenarios. Combinations of these effects (50 cross‐validations for each of the 15 subsets of the environmental variables) were used to estimate and map the occurrence frequencies (EOF) across all analyses. A three‐way anova was used to partition and map the sources of variation.3. The projections for 2080 show that the range edges of the species are likely to remain approximately constant, but shifts in maximum EOF are forecasted. Suitable climatic conditions tend to disappear from central areas of Amazon, although this depends on the AOGCM and the niche model. Most of the variability around the mapped consensus projections came from using distinct niche models and AOGCMs.4. Although our analyses are restricted to a single species, they provide new conceptual and methodological insights in the application of ensemble forecasting and variance partition approaches to understand the origins of uncertainty in studies assessing species responses to climate change in the tropics.
Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study
Authors: Vestbo Jørgen , Anderson Julie Anne , Calverley Peter Mark Anthony , Celli Bartolomé , Ferguson Gary Thomas , Jenkins Christine , Yates Julie Carol , Jones Paul Wyatt 
Published: March 2010

AbstractIntroduction:  Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates.Objectives:  We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial.Methods:  We did an observational study nested in the TORCH trial, a placebo‐controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal.Results:  There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal.Conclusion:  Significant bias may occur in long‐term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal.Please cite this paper as: Vestbo J, Anderson JA, Calverley PMA, Celli B, Ferguson GT, Jenkins C, Yates JC, Jones PW. Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study. Clin Respir J 2011; 5: 44–49.
Portal vein thrombosis in Egyptian patients with liver cirrhosis: Role of methylenetetrahydrofolate reductase C677T gene mutation
Authors: Gabr Mamdouh Ahmed , Bessa Sahar Saad El‐Din , El‐Zamarani Enas Arafa 
Published: March 2010

Aim:  The pathogenesis of non‐malignant portal vein thrombosis (PVT) in cirrhotic patients is not clearly defined. This case‐control study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation in the pathogenesis of PVT in Egyptian cirrhotic patients.Methods:  Plasma homocysteine was measured and MTHFR C677T gene mutation was detected in 76 cirrhotic patients (21 with PVT, 55 without PVT) and 20 healthy controls.Results:  The frequency of CC genotype (wide type) in cirrhotic patients with PVT was lower than controls and cirrhotics without PVT. However, the frequency of TT genotype (homozygous mutation) was elevated in cirrhotic patients with PVT as compared to controls and those without PVT. Cirrhotic patients with PVT had significantly higher homocysteine than those without PVT. Cirrhotic patients with TT genotype are at a significant risk for PVT (odds ratio = 7.7, 95% confidence interval, 1.50–42.81) when compared with CC genotype. Moreover, subjects carrying TT genotype had a higher homocysteine than those carrying CC genotype.Conclusions:  The TT genotype of MTHFR is associated with an increased risk of PVT in Egyptian cirrhotic patients. Hyperhomocysteinemia could be considered as a relatively new risk factor for PVT in cirrhotic patients and plasma homocysteine should be investigated particularly in patients with PVT of unexplained etiology. The important clinical implication is that the readily available therapy of folate, vitamin B6 and B12 supplementation may reduce homocysteine and prevent further thrombotic complications in cirrhotic patients carrying the TT genotype.
Genetic Screen Identifies Insulin-like Growth Factor Binding Protein 5 as a Modulator of Tamoxifen Resistance in Breast Cancer
Authors: Ahn Bo Young , Elwi Adam N. , Lee Byoungchun , Trinh Diane L.N. , Klimowicz Alexander C. , Yau Annie , Chan Jennifer A. , Magliocco Anthony , Kim Sung-Woo 
Published: March 2010

AbstractTamoxifen resistance is one of the overarching challenges in the treatment of patients with estrogen receptor (ER)–positive breast cancer. Through a genome-wide RNA interference screen to discover genes responsible for tamoxifen resistance in vitro, we identified insulin-like growth factor binding protein 5 (IGFBP5) as a determinant of drug sensitivity. Specific knockdown of IGFBP5 by retroviral infection with short hairpin RNA–expressing cassette in MCF7 human breast cancer cells (pRS-shIGFBP5) conferred tamoxifen resistance in vitro due to concomitant loss of ERα expression and signaling. IGFBP5 expression was also reduced in MCF7 cells selected for tamoxifen resistance in culture (TAMR). Both tamoxifen-resistant MCF7-TAMR and MCF7-pRS-shIGFBP5 cells could be resensitized to drug by treatment with exogenous recombinant IGFBP5 (rIGFBP5) protein. Treatment with rIGFBP5 protein in mouse tumor xenografts reversed the in vivo tamoxifen resistance of MCF7-pRS-shIGFBP5 cell–derived tumors by reducing tumor cell proliferation. IGFBP5 immunohistochemical staining in a cohort of 153 breast cancer patients showed that low IGFBP5 expression was associated with shorter overall survival after tamoxifen therapy. Thus, IGFBP5 warrants investigation as an agent to reverse tamoxifen resistance. Cancer Res; 70(8); 3013–9. ©2010 AACR.
Noscapine, a Benzylisoquinoline Alkaloid, Sensitizes Leukemic Cells to Chemotherapeutic Agents and Cytokines by Modulating the NF-κB Signaling Pathway
Authors: Sung Bokyung , Ahn Kwang Seok , Aggarwal Bharat B. 
Published: March 2010

AbstractNoscapine, a benzylisoquinoline alkaloid derived from opium, was recently reported to exhibit activity against a variety of cancers through a poorly understood mechanism. Because the transcription factor NF-κB has been linked with inflammation, survival, proliferation, invasion, and angiogenesis in tumors, we hypothesized that noscapine mediates its effects by modulating the NF-κB activation pathway. We found that noscapine potentiates apoptosis induced by cytokines and chemotherapeutic agents in tumor cells. Noscapine alone suppressed proliferation of human leukemia and myeloma cells and downregulated the constitutive expression of cell survival proteins. Noscapine also abrogated the inducible expression of proteins involved in survival, proliferation, invasion, and angiogenesis, all of which are regulated by NF-κB. Noscapine suppressed both inducible and constitutive NF-κB activation in tumor cells through inhibition of IκB kinase, leading to inhibition of phosphorylation and degradation of IκBα. Noscapine also suppressed phosphorylation and nuclear translocation of p65, leading to inhibition of NF-κB reporter activity induced by various components of the NF-κB activation pathway. Activity of the NF-κB–containing cyclooxygenase-2 promoter was also inhibited by noscapine. Thus, noscapine inhibits the proliferation of leukemia cells and sensitizes them to tumor necrosis factor and chemotherapeutic agents by suppressing the NF-κB signaling pathway. Cancer Res; 70(8); 3259–68. ©2010 AACR.
β-Ionone Enhances TRAIL-Induced Apoptosis in Hepatocellular Carcinoma Cells through Sp1-Dependent Upregulation of DR5 and Downregulation of NF-κB Activity
Authors: Kim Mun-Ock , Moon Dong-Oh , Kang Chang-Hee , Kwon Taeg Kyu , Choi Yung Hyun , Kim Gi-Young 
Published: March 2010

Abstract
β-Ionone (ION), an end-ring analogue of β-carotenoid, has been known to inhibit tumor cell growth and induce apoptosis in various types of cancer cells. Nevertheless, its apoptosis-related molecular mechanisms remain unclear. Here, we first investigated the molecular mechanisms by which ION sensitizes cancer cells to the therapeutic potential of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Notably, treatment with subtoxic concentrations of ION and TRAIL effectively inhibited cell viability in the hepatocellular carcinoma cell line Hep3B and other cancer cell lines such as colon carcinoma cell line HCT116 and leukemia cell line U937. Combined treatment with ION and TRAIL was also more effective in inducing DR5 expression, caspase activities, and apoptosis than treatment with either agent alone. ION-mediated sensitization to TRAIL was efficiently reduced by treatment with a chimeric blocking antibody or small interfering RNA specific for DR5. Electrophoretic mobility shift assay and a chromatin immunoprecipitation assay confirmed that ION treatment upregulates the binding of transcription factor Sp1 to its putative site within the DR5 promoter region, suggesting that Sp1 is an ION-responsive transcription factor. In addition, ION significantly increased hepatocellular carcinoma cell sensitivity to TRAIL by abrogating TRAIL-induced NF-κB activation and decreasing the expression of antiapoptotic proteins such as XIAP and IAP-1/2. Taken together, these data suggest that ION is a useful agent for TRAIL-based cancer treatments. Mol Cancer Ther; 9(4); 833–43. ©2010 AACR.
Subcellular Distribution of a Fluorescence-Labeled Combi-Molecule Designed to Block Epidermal Growth Factor Receptor Tyrosine Kinase and Damage DNA with a Green Fluorescent Species
Authors: Todorova Margarita I. , Larroque Anne-Laure , Dauphin-Pierre Sabine , Fang You-Qiang , Jean-Claude Bertrand J. 
Published: March 2010

AbstractTo monitor the subcellular distribution of mixed epidermal growth factor (EGF) receptor (EGFR)–DNA targeting drugs termed combi-molecules, we designed AL237, a fluorescent prototype, to degrade into a green fluorescent DNA damaging species and FD105, a blue fluorescent EGFR inhibitor. Here we showed that AL237 damaged DNA in the 12.5 to 50 μmol/L range. Despite its size, it blocked EGFR phosphorylation in an enzyme assay (IC50 = 0.27 μmol/L) and in MDA-MB468 breast cancer cells in the same concentration range as for DNA damage. This translated into inhibition of extracellular signal-regulated kinase 1/2 or BAD phosphorylation and downregulation of DNA repair proteins (XRCC1, ERCC1). Having shown that AL237 was a balanced EGFR-DNA targeting molecule, it was used as an imaging probe to show that (a) green and blue colors were primarily colocalized in the perinuclear and partially in the nucleus in EGFR- or ErbB2-expressing cells, (b) the blue fluorescence associated with FD105, but not the green, was colocalized with anti-EGFR red-labeled antibody, (c) the green fluorescence of nuclei was significantly more intense in NIH 3T3 cells expressing EGFR or ErbB2 than in their wild-type counterparts (P &lt; 0.05). Similarly, the growth inhibitory potency of AL237 was selectively stronger in the transfectants. In summary, the results suggest that AL237 diffuses into the cells and localizes abundantly in the perinuclear region and partially in the nucleus where it degrades into EGFR and DNA targeting species. This bystander-like effect translates into high levels of DNA damage in the nucleus. Sufficient quinazoline levels are released in the cells to block EGF-induced activation of downstream signaling. Mol Cancer Ther; 9(4); 869–82. ©2010 AACR.
Inhibition of Aldose Reductase Prevents Growth Factor–Induced G1-S Phase Transition through the AKT/Phosphoinositide 3-Kinase/E2F-1 Pathway in Human Colon Cancer Cells
Authors: Ramana Kota V. , Tammali Ravinder , Srivastava Satish K. 
Published: March 2010

AbstractColon cancer is the leading cause of cancer death in both men and women worldwide. The deregulated cell cycle control or decreased apoptosis of normal epithelial cells leading to uncontrolled proliferation is one of the major features of tumor progression. We have previously shown that aldose reductase (AR), a NADPH-dependent aldo-keto reductase, has been shown to be involved in growth factor–induced proliferation of colon cancer cells. Herein, we report that inhibition of AR prevents epidermal growth factor (EGF)– and basic fibroblast growth factor (bFGF)–induced HT29 cell proliferation by accumulating cells at G1 phase of cell cycle. Similar results were observed in SW480 and HCT-116 colon cancer cells. Treatment of HT29 cells with AR inhibitor, sorbinil or zopolrestat, prevented the EGF- and bFGF-induced DNA binding activity of E2F-1 and phosphorylation of retinoblastoma protein. Inhibition of AR also prevented EGF- and bFGF-induced phosphorylation of cyclin-dependent kinase (cdk)-2 and expression of G1-S transition regulatory proteins such as cyclin D1, cdk4, proliferating cell nuclear antigen, cyclin E, and c-myc. More importantly, inhibition of AR prevented the EGF- and bFGF-induced activation of phosphoinositide 3-kinase/AKT and reactive oxygen species generation in colon cancer cells. Further, inhibition of AR also prevented the tumor growth of human colon cancer cells in nude mouse xenografts. Collectively, these results show that AR mediates EGF- and bFGF-induced colon cancer cell proliferation by activating or expressing G1-S phase proteins such as E2F-1, cdks, and cyclins through the reactive oxygen species/phosphoinositide 3-kinase/AKT pathway, indicating the use of AR inhibitors in the prevention of colon carcinogenesis. Mol Cancer Ther; 9(4); 813–24. ©2010 AACR.
Phospholipase A2 Activity of Peroxiredoxin 6 Promotes Invasion and Metastasis of Lung Cancer Cells
Authors: Ho Jin-Nyoung , Lee Seung Bum , Lee Seung-Sook , Yoon Sung Hwan , Kang Ga Young , Hwang Sang-Gu , Um Hong-Duck 
Published: March 2010

Abstract
Peroxiredoxins (PRDX) are a family of thiol-dependent peroxidases. Among the six mammalian members of this family, PRDX6 is the only protein that additionally exhibits phospholipase A2 (PLA2) activity. The physiologic role of this interesting PRDX6 feature is largely unknown at present. In this study, we show that PRDX6 increases the metastatic potential of lung cancer cells. Functional analyses of the enzymatic activities of PRDX6, using specific pharmacologic inhibitors and mutagenesis studies, reveal that both peroxidase and PLA2 activities are required for metastasis. Specifically, peroxidase activity facilitates the growth of cancer cells, and PLA2 activity promotes invasiveness. Further investigation of the latter event discloses that PLA2 activity promotes accumulation of arachidonic acid, which, in turn, induces the invasive pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and urokinase-type plasminogen activator. This study is the first to define the functions of the enzymatic activities of PRDX6 in metastasis and to show the involvement of arachidonic acid in PRDX6 action in intact cells. These novel findings provide a significant step toward elucidating the role of PRDX6 in cancer and the mechanism of its action. Mol Cancer Ther; 9(4); 825–32. ©2010 AACR.
Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line
Authors: Shi Zhanzhong , Hodges Vivien M. , Dunlop Elaine A. , Percy Melanie J. , Maxwell Alexander P. , El-Tanani Mohamed , Lappin Terry R.J. 
Published: March 2010

AbstractErythropoietin (Epo), the major regulator of erythropoiesis, and its cognate receptor (EpoR) are also expressed in nonerythroid tissues, including tumors. Clinical studies have highlighted the potential adverse effects of erythropoiesis-stimulating agents when used to treat cancer-related anemia. We assessed the ability of EpoR to enhance tumor growth and invasiveness following Epo stimulation. A benign noninvasive rat mammary cell line, Rama 37, was used as a model system. Cell signaling and malignant cell behavior were compared between parental Rama 37 cells, which express few or no endogenous EpoRs, and a modified cell line stably transfected with human EpoR (Rama 37-28). The incubation of Rama 37-28 cells with pharmacologic levels of Epo led to the rapid and sustained increases in phosphorylation of signal transducers and activators of transcription 5, Akt, and extracellular signal-regulated kinase. The activation of these signaling pathways significantly increased invasion, migration, adhesion, and colony formation. The Epo-induced invasion capacity of Rama 37-28 cells was reduced by the small interfering RNA–mediated knockdown of EpoR mRNA levels and by inhibitors of the phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways with adhesion also reduced by Janus-activated kinase 2/signal transducers and activators of transcription 5 inhibition. These data show that Epo induces phenotypic changes in the behavior of breast cancer cell lines and establishes links between individual cell signaling pathways and the potential for cancer spread. Mol Cancer Res; 8(4); 615–26. ©2010 AACR.
Prostaglandin E2 Promotes Lung Cancer Cell Migration via EP4-βArrestin1-c-Src Signalsome
Authors: Kim Jae Il , Lakshmikanthan Vijayabaskar , Frilot Nicole , Daaka Yehia 
Published: March 2010

Abstract
Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. However, despite these encouraging outcomes, the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer drugs. Hence, a better understanding of the molecular signals downstream of COX-2 is needed for the elucidation of drug targets that may improve cancer therapy. Here, we show that the COX-2 product prostaglandin E2 (PGE2) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE2 enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE2-mediated lung cancer cell migration. PGE2 affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression. Proximal EP4 effectors include heterotrimeric Gs and βArrestin proteins. Knockdown of βArrestin1 expression with shRNA significantly impaired the PGE2-induced c-Src activation and cell migration. Together, these results support the idea that increased expression of the COX-2 product PGE2 in the lung tumor microenvironment may initiate a mitogenic signaling cascade composed of EP4, βArrestin1, and c-Src which mediates cancer cell migration. Selective targeting of EP4 with a ligand antagonist may provide an efficient approach to better manage patients with advanced lung cancer. Mol Cancer Res; 8(4); 569–77. ©2010 AACR.