bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual inhibition of phosphatidylinositol 3‐kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin
Authors: Khan Naghma , Afaq Farrukh , Khusro Fatima H. , Mustafa Adhami Vaqar , Suh Yewseok , Mukhtar Hasan 
Published: May 2011

AbstractLung cancer is one of the most commonly occurring malignancies. It has been reported that mammalian target of rapamycin (mTOR) is phosphorylated in lung cancer and its activation was more frequent in tumors with overexpression of phosphatidylinositol 3‐kinase (PI3K)/Akt. Therefore, dual inhibitors of PI3K/Akt and mTOR signaling could be valuable agents for treating lung cancer. In the present study, we show that fisetin, a dietary tetrahydroxyflavone inhibits cell growth with the concomitant suppression of PI3K/Akt and mTOR signaling in human nonsmall cell lung cancer (NSCLC) cells. Using autodock 4, we found that fisetin physically interacts with the mTOR complex at two sites. Fisetin treatment was also found to reduce the formation of A549 cell colonies in a dose‐dependent manner. Treatment of cells with fisetin caused decrease in the protein expression of PI3K (p85 and p110), inhibition of phosphorylation of Akt, mTOR, p70S6K1, eIF‐4E and 4E‐BP1. Fisetin‐treated cells also exhibited dose‐dependent inhibition of the constituents of mTOR signaling complex such as Rictor, Raptor, GβL and PRAS40. There was an increase in the phosphorylation of AMPKα and a decrease in the phosphorylation of TSC2 on treatment of cells with fisetin. We also found that treatment of cells with mTOR inhibitor rapamycin and mTOR‐siRNA caused decrease in phosphorylation of mTOR and its target proteins which were further downregulated on treatment with fisetin, suggesting that these effects are mediated in part, through mTOR signaling. Our results show that fisetin suppressed PI3K/Akt and mTOR signaling in NSCLC cells and thus, could be developed as a chemotherapeutic agent against human lung cancer.
Pathological complete remission in patients with oesophagogastric cancer receiving preoperative 5‐fluorouracil, oxaliplatin and docetaxel
Authors: Homann Nils , Pauligk Claudia , Luley Kim , Werner Kraus Thomas , Bruch Hans‐Peter , Atmaca Akin , Noack Frank , Altmannsberger Hans‐Michael , Jäger Elke , Al‐Batran Salah‐Eddin 
Published: May 2011

AbstractThe aim of this study was to determine the pathological complete remission (pCR) rate, and its relationship to clinical outcome, in patients with adenocarcinoma of the stomach or oesophagogastric junction receiving preoperative 5‐fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) every 2 weeks. Data from these patients who received at least one cycle of preoperative FLOT followed by surgery were prospectively collected in three German centres. Outcome analyses were conducted and tumour samples were evaluated for pathological remission by a central pathologist. A total of 46 patients were included in this analysis. All patients had clinical T3‐ and/or N+‐stages and 11 (23.9%) had distant metastases (M1). After a median of 4 (range 2–8) preoperative cycles, 8 of 46 patients (17.4%) achieved a pCR. The pCR rate was highest in tumours of intestinal type histology (30.8%) and in those located in the oesophagogastric junction (30.4%) and lowest in patients with diffuse/mixed type tumours (0%) or tumours located in the stomach (4.3%; p < 0.05 for both comparisons). Patients with pCR had 100% probability of overall and disease‐free survival (DFS) during the observation period, which was significantly higher (p = 0.037 and p = 0.009, respectively) than the survival probability in patients without pCR. In conclusion, treatment intensification using FLOT was associated with significant pCR rates in patients with oesophagogastric cancer. The distribution of pCR appeared to be significantly different according to histological type and location of the tumours.
Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer
Authors: Ohlsson Lina , Israelsson Anne , Öberg Åke , Palmqvist Richard , Stenlund Hans , Hammarström Marie‐Louise , Hammarström Sten , Lindmark Gudrun 
Published: May 2011

AbstractThe aim was to explore the utility for staging and prognostic impact of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor, and bone morphogenic protein 1) containing domain protein 1 (CDCP1) and mucin 2 (MUC2) mRNA levels in mesenteric lymph nodes of colorectal cancer (CRC) patients. Lymph nodes were collected at surgery and bisected; one half was subjected to biomarker mRNA analysis using real‐time quantitative RT‐PCR and the other half to routine histopathology. Lymph nodes from 174 CRC patients and 24 controls were analyzed. The median follow‐up time was 59 (range 17–131) months. Cut‐off levels were defined by analyzing quintiles by Cox regression model. CEA mRNA showed the best discriminating power between patients with recurrence in CRC after surgery and patients who were apparently disease‐free (p = 0.015). The risk of recurrence for the CEA(+) patients was 4.6 times greater than for the CEA(−) patients (p < 0.0001). The other biomarkers gave lower hazard ratios. Cumulative survival analysis demonstrated that the average survival time was 99 months for CEA(−) patients compared to 39 months for CEA(+) patients, a difference of 60 months (p < 0.0001). Six to nine percent of the Stage I and Stage II patients [H&E(−)] had CEA(+), CK20(+), GCC(+) and/or MUC2(+) lymph nodes. Two of these patients died from recurrent CRC. Low lymph node MUC2/CEA mRNA ratio identified patients with high risk for recurrence (p = 0.011). Thus, quantitative reverse transcriptase‐polymerase chain reaction of CEA mRNA is a sensitive method to identify tumor cells in lymph nodes of CRC patients and, in combination with MUC2 mRNA, allows improved prediction of clinical outcome.
Cisplatin increases B‐cell‐lymphoma‐2 expression via activation of protein kinase C and Akt2 in endometrial cancer cells
Authors: Rouette Alexandre , Parent Sophie , Girouard Julie , Leblanc Valérie , Asselin Eric 
Published: May 2011

AbstractHuman carcinomas often show resistance to cisplatin and Bcl‐2 is associated with resistance to cisplatin. However, Bcl‐2 regulation on cisplatin treatment in human cancers is unknown. Here, we show a novel mechanism by which cisplatin treatment promotes resistance by increasing the expression of Bcl‐2 mRNA. Bcl‐2 mRNA and protein expression was increased in cisplatin‐resistant endometrial cancer cell lines (KLE and HEC‐1‐A), but not in cisplatin‐sensitive cell line (Ishikawa). Cisplatin‐mediated increase in Bcl‐2 expression was blocked by combination with either actinomycin D or cycloheximide. In addition, Bcl‐2 inhibition by HA14‐1 led to increased cisplatin‐induced apoptosis in KLE and HEC‐1‐A, whereas Bcl‐2 overexpression in Ishikawa led to decreased cisplatin‐induced apoptosis. Inhibition of protein kinase C (PKC) activity prevented cisplatin‐dependant increase in Bcl‐2 mRNA, and induced apoptosis in KLE cells. Furthermore, PKC inhibition was associated with decreased Akt and NF‐κB activity. Cells stably expressing shRNA for Akt isoforms revealed that Akt2 was involved in cisplatin‐dependant increase in Bcl‐2 and apoptosis. Overexpression of Akt2 in Akt2‐deficient cells led to increased Bcl‐2 expression on cisplatin treatment. Our data suggest a novel regulation pathway of Bcl‐2 by cisplatin, via the activation of PKC and Akt2, which has a profound impact on resistance to cisplatin‐induced apoptosis in endometrial cancer cells.
Dietary lignan and proanthocyanidin consumption and colorectal adenoma recurrence in the Polyp Prevention Trial
Authors: Bobe Gerd , Murphy Gwen , Albert Paul S. , Sansbury Leah B. , Lanza Elaine , Schatzkin Arthur , Cross Amanda J. 
Published: May 2011

AbstractLignans and proanthocyanidins are plant polyphenols that have shown protective properties against colorectal neoplasms in some human studies. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to prospectively evaluate the association between lignan and proanthocyanidin intake, estimated from databases linked to a food frequency questionnaire, and adenoma recurrence in 1,859 participants of the Polyp Prevention Trial. Overall, individual or total lignans or proanthocyanidins were not associated with colorectal adenoma recurrence. However, in sex‐specific analyses, total lignan intake was positively associated with any adenoma recurrence in women (highest vs. lowest lignan intake quartile OR = 2.07, 95% CI: 1.22–3.52, p trend = 0.004) but not in men (p interaction = 0.04). To conclude, dietary lignan and proanthocyanidin consumption were not generally related to colorectal adenoma recurrence; however, high lignan intake may increase the risk of adenoma recurrence in women.
Is mortality after childhood cancer dependent on social or economic resources of parents? A population‐based study
Authors: Syse Astri , Lyngstad Torkild Hovde , Kravdal Oystein 
Published: May 2011

AbstractDiagnostic and treatment protocols for childhood cancer are generally standardized, and therefore, survival ought to be fairly equal across social strata in societies with free public health care readily available. Nevertheless, our study explores whether there are disparities in mortality after childhood cancer in Norway depending on socioeconomic status of parents. Limited knowledge on differentials exists from earlier analyses. Discrete‐time hazard regression models for all‐cause mortality for the first 10 years after diagnosis were estimated for all Norwegian children (younger than 20 years), who were diagnosed with cancer during 1974–2007 (N = 6,280), using data from five national registers. Mortality was reduced by about 15% for children with highly educated mothers and children without siblings. These effects were most pronounced for cancers predicted to encompass intense, long‐lasting treatments resulting in chronic health problems. Neither earnings nor the marital status of parents affected children's survival. This large, registry‐based study suggests that time constraints and various noneconomic rewards of parents from their education appears to have an impact on childhood cancer survival. It may be that children with resourceful parents are healthier at the outset and/or are more likely to avoid later health problems. It may also be that children of well‐informed and strongly involved parents are offered better treatment or are able to make better use of what is offered, for instance, by adhering more closely to recommendations for follow‐up treatment. The possibility of such differentials in offered and actual treatment should be addressed in future research.
Kinesin family member 14: An independent prognostic marker and potential therapeutic target for ovarian cancer
Authors: Thériault Brigitte L. , Pajovic Sanja , Bernardini Marcus Q. , Shaw Patricia A. , Gallie Brenda L. 
Published: May 2011

AbstractThe novel oncogene KIF14 (kinesin family member 14) shows genomic gain and overexpression in many cancers including OvCa (ovarian cancer). We discovered that expression of the mitotic kinesin KIF14 is predictive of poor outcome in breast and lung cancers. We now determine the prognostic significance of KIF14 expression in primary OvCa tumors, and evaluate KIF14 action on OvCa cell tumorigenicity in vitro. Gene‐specific multiplex PCR and real‐time QPCR were used to measure KIF14 genomic (109 samples) and mRNA levels (122 samples) in OvCa tumors. Association of KIF14 with clinical variables was studied using Kaplan–Meier survival and Cox regression analyses. Cellular effects of KIF14 overexpression (stable transfection) and inhibition (stable shRNA knockdown) were studied by proliferation (cell counts), survival (Annexin V immunocytochemistry) and colony formation (soft‐agar growth). KIF14 genomic gain (>2.6 copies) was present in 30% of serous OvCas, and KIF14 mRNA was elevated in 91% of tumors versus normal epithelium. High KIF14 in tumors independently predicted for worse outcome (p = 0.03) with loss of correlation with proliferation marker expression and increased rates of recurrence. Overexpression of KIF14 in OvCa cell lines increased proliferation and colony formation (p < 0.01), whereas KIF14 knockdown induced apoptosis and dramatically reduced colony formation (p < 0.05). Our findings indicate that KIF14 mRNA is an independent prognostic marker in serous OvCa. Dependence of OvCa cells on KIF14 for maintenance of in vitro colony formation suggests a role of KIF14 in promoting a tumorigenic phenotype, beyond its known role in proliferation.
Let‐7 modulates acquired resistance of ovarian cancer to Taxanes via IMP‐1‐mediated stabilization of multidrug resistance 1
Authors: Boyerinas Benjamin , Park Sun‐Mi , Murmann Andrea E. , Gwin Katja , Montag Anton G. , Zillhardt Marion , Hua You‐Jia , Lengyel Ernst , Peter Marcus E. 
Published: May 2011

AbstractOvarian cancer patients frequently develop resistance to chemotherapy regiments using Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol‐based therapy is multidrug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let‐7 family of miRNAs are downregulated in many human cancers, and low let‐7 expression has been correlated with resistance to microtubule targeting drugs (Taxanes), although little is known that would explain this activity. We now provide evidence that, although let‐7 is not a universal sensitizer of cancer cells to Taxanes, it affects acquired resistance of cells to this class of drugs by targeting IMP‐1, resulting in destabilization of the mRNA of MDR1. Introducing let‐7g into ADR‐RES cells expressing both IMP‐1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin, a non‐MDR1 substrate. This effect could be reversed by reintroducing IMP‐1 into let‐7g high/MDR1 low cells causing MDR1 to again become stabilized. Consistently, many relapsed ovarian cancer patients tested before and after chemotherapy were found to downregulate let‐7 and to co‐upregulate IMP‐1 and MDR1, and the increase in the expression levels of both proteins after chemotherapy negatively correlated with disease‐free time before recurrence. Our data point at IMP‐1 and MDR1 as indicators for response to therapy, and at IMP‐1 as a novel therapeutic target for overcoming multidrug resistance of ovarian cancer.
Male circumcision is associated with a lower prevalence of human papillomavirus‐associated penile lesions among Kenyan men
Authors: Backes Danielle M. , Bleeker Maaike C.G. , Meijer Chris J.L.M. , Hudgens Michael G. , Agot Kawango , Bailey Robert C. , Ndinya‐Achola J.O. , Hayombe Juma , Hogewoning Cornelis J.A. , Moses Stephen , Snijders Peter J.F. , Smith Jennifer S. 
Published: May 2011

AbstractHuman papillomavirus (HPV)‐associated penile lesions in men may increase the risk of HPV transmission to their female partners. Risk factor data on HPV‐associated penile lesions are needed from regions with a high burden of cervical cancer. Visual inspection of the penis was conducted using a colposcope at the 24‐month visit among participants in a randomized controlled trial of male circumcision in Kenya, from May 2006 to October 2007. All photos were read independently by two observers for quality control. Penile exfoliated cells sampled from the glans/coronal sulcus and the shaft were tested for HPV DNA using GP5+/6+ PCR and for HPV16, 18 and 31 viral loads using a real time PCR assay. Of 275 men, 151 were circumcised and 124 uncircumcised. The median age was 22 years. Circumcised men had a lower prevalence of flat penile lesions (0.7%) versus uncircumcised (26.0%); adjusted odds ratio (OR) = 0.02; 95% confidence interval (CI) = 0.003–0.1. Compared to men who were HPV negative, men who were HPV DNA positive (OR = 6.5; 95% CI = 2.4–17.5) or who had high HPV16/18/31 viral load (OR = 5.2; 95% CI = 1.1–24.4) had higher odds of flat penile lesions. Among men with flat penile lesions, HPV56 (29.0%) and 16 (25.8%) were the most common types within single or multiple infections. Flat penile lesions are much more frequent in uncircumcised men and associated with higher prevalence of HPV and higher viral loads. This study suggests that circumcision reduces the prevalence of HPV‐associated flat lesions and may ultimately reduce male‐to‐female HPV transmission.
Demethylation of the FOXP3 gene in human melanoma cells precludes the use of this epigenetic mark for quantification of Tregs in unseparated melanoma samples
Authors: Lucas Sophie , van Baren Nicolas , de Smet Charles , Coulie Pierre G. 
Published: May 2011

AbstractThe human suppressive T cells that stably express transcription factor FOXP3, or regulatory T cells (Tregs), are thought to suppress antitumor immune responses. The most specific marker for human Tregs is the demethylation of CpG dinucleotides located in the first intron of FOXP3 (FOXP3i1). FOXP3i1 is completely methylated in other hematopoietic cells, including nonsuppressive T cells that transiently express FOXP3 after activation. Previously, we and others reported estimations of the frequency of Tregs in the blood of melanoma patients using a FOXP3i1 methylation‐specific qPCR assay. Here, we attempted to quantify Tregs inside tumor samples using this assay. However, we found demethylated FOXP3i1 sequences in the melanoma cells themselves. This demethylation was not associated with substantial FOXP3 mRNA or protein expression, even though the demethylation extended to the promoter and terminal regions of the gene in some melanoma cells. Our results imply that analyzing Treg frequencies by quantification of demethylated FOXP3i1 will require that tumor‐infiltrating T cells be separated from melanoma cells.
IGF binding protein‐6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis
Authors: Zhang Chunyang , Lu Ling , Li Yun , Wang Xianlei , Zhou Jianfeng , Liu Yunzhang , Fu Ping , Gallicchio Marisa A. , Bach Leon A. , Duan Cunming 
Published: May 2011

AbstractHypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here, we report that hypoxia induced the expression of insulin‐like growth factor binding protein‐6 (IGFBP‐6), a tumor repressor, in human and rodent vascular endothelial cells (VECs) via a hypoxia‐inducible factor (HIF)‐mediated mechanism. Addition of human IGFBP‐6 to cultured human VECs inhibited angiogenesis in vitro. An IGFBP‐6 mutant with at least 10,000‐fold lower binding affinity for IGFs was an equally potent inhibitor of angiogenesis, suggesting that this action of IGFBP‐6 is IGF‐independent. The functional relationship between IGFBP‐6 and vascular endothelial growth factor (VEGF), a major hypoxia‐inducible angiogenic molecule, was examined. While VEGF alone increased angiogenesis in vitro, co‐incubation with IGFBP‐6 abolished VEGF‐stimulated angiogenesis. The in vivo role of IGFBP‐6 in angiogenesis was tested in flk1:GFP zebrafish embryos, which exhibit green fluorescence protein in developing vascular endothelium, permitting visualization of developing blood vessels. Injection of human IGFBP‐6 mRNA reduced the number of embryonic inter‐segmental blood vessels by ∼40%. This anti‐angiogenic activity is conserved in zebrafish because expression of zebrafish IGFBP‐6b had similar effects. To determine the anti‐angiogenic effect of IGFBP‐6 in a tumor model, human Rh30 rhabdomyosarcoma cells stably transfected with IGFBP‐6 were inoculated into athymic BALB/c nude mice. Vessel density was 52% lower in IGFBP‐6‐transfected xenografts than in vector control xenografts. These results suggest that the expression of IGFBP‐6 in VECs is up‐regulated by hypoxia and IGFBP‐6 inhibits angiogenesis in vitro and in vivo.
Three‐residue loop closure in proteins: A new kinematic method reveals a locus of connected loop conformations
Authors: Nekouzadeh Ali , Rudy Yoram 
Published: May 2011

AbstractThe closure of a three‐residue loop was studied using a developed kinematic method. It was shown that there are infinite number of three‐residue loops (a locus of conformations), which can connect two segments of a polypeptide. This adds to the current understanding of a finite number of conformations for three‐residue loop‐closure. In the developed method, some of the equations can be solved analytically to reduce the computation cost. Benefiting from the reduced computation time, we determined all the relative positions of two polypeptide segments that can be connected by a three‐residue loop. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011
Attenuation of MicroRNA‐22 derepressed PTEN to effectively protect rat cardiomyocytes from hypertrophy
Authors: Xu Xu‐Dong , Song Xiao‐Wei , Li Qing , Wang Guo‐Kun , Jing Qing , Qin Yong‐Wen 
Published: May 2011

AbstractCardiac hypertrophy, which is characterized by the enlargement of cell size, reactivation of fetal genes, remains one of the most important triggers to heart failure. Increasing evidence shows that microRNA (miRNA) is extensively involved in the pathogenesis of cardiac hypertrophy. But the effects of miRNAs on cardiomyocyte hypertrophy have not been completely solved yet. Here, we showed that a collection of miRNAs was aberrantly expressed in hypertrophic cardiomyocytes induced by phenylephrine (PE) or angiotensin II (Ang II). Among them, miR‐22 was the most strikingly up‐regulated miRNA. To investigate the role of miR‐22 in hypertrophy, both over‐expression and knock‐down assays were performed on cardiomyocytes. The results showed that up‐regulation of miR‐22 significantly increased the cell size and markedly influenced the expression of hypertrophic markers, including induction of nppa and reduction of myh6. In contrast, reduction of miR‐22 level attenuated either PE‐ or Ang II‐induced hypertrophic reaction. Furthermore, several genes, including PTEN, were identified as potential targets of miR‐22 by bioinformatic algorithms. Using luciferase analysis, miR‐22 could significantly suppress the luciferase activity of reporter fused with 3′ untranslated region of PTEN mRNA. Furthermore, up‐regulation of miR‐22 could suppress the protein level of PTEN and reduction of miR‐22 level markedly increased the protein level of PTEN in cardiomyocytes by Western blot analysis, suggesting that the contribution of miR‐22 to cardiomyocyte hypertrophy may be partially through targeting PTEN. Taken together, miRNAs were dynamically regulated in cardiomyocyte hypertrophy and attenuation of miR‐22 in rat cardiomyocytes efficiently protected from hypertrophic effects through derepressing PTEN. J. Cell. Physiol. 227: 1391–1398, 2012. © 2011 Wiley Periodicals, Inc.