bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2650: A combined bioinformatics and GWAS approach identifies a functional 3′UTR insertion/deletion in YES1 associated with bladder cancer risk
Authors: Wei Hua , Hildebrandt Michelle AT , Gu Jian , Ye Yuanqing , Huang Maosheng , Dinney Colin P. , Wu Xifeng 
Published: August 2012

Abstract
Bladder cancer (BC) is diagnosed in over 70,000 individuals each year and its incidence is rising. There is a need for biomarkers to identify those at high risk, as well as for early detection. Large genome-wide association studies have identified multiple susceptibility loci; however, individually and combined, these variants only explain a small portion of the variation in BC risk. One possibility to explain the missing heritability is the effect of small insertions and deletions (INDELs). Because of the nature of these variations, they have a high likelihood for functional effects. Therefore, the purpose of study was to determine whether common INDELs are associated with BC risk. We retrieved 0.73 million INDELs and 7.72 million single nucleotide polymorphisms (SNPs) from the 1000 Genomes Pilot Project. Tagging-SNPs were identified for 0.48 million of these INDELs with r2 &gt; 0.80 by PLINK. We then evaluated each tagging-SNP for association with BC risk in 969 BC cases and 957 controls. Using this approach, 5,110 INDELs were shown to be associated with BC risk (P &lt; 0.05). We next focused on potentially functional INDELs located in exons, 3′ UTRs, 5′ UTRs or promoters. Approximately 50 INDELs fit this criterion, with a 2 basepair INDEL rs56342716 (-/AT) located in the 3′ UTR of YES1, a src kinase oncogene, being highly significant. The tagging-SNP for this INDEL, rs3786347, was associated with a 1.27-fold increase in BC risk (OR 1.27, 95% CI, 1.10-1.43, P = 6.08x10−4). These results were confirmed by direct genotyping of the INDEL in 822 BC cases and 802 healthy controls (OR 1.20, 95% CI, 1.04-1.38, P = 0.01). Reporter gene assay results revealed that the variant allele (AT) of rs56342716 disrupted the inhibitory effects of three microRNAs (miR-548e, miR-548f, and miR-548a-3p), providing a potential biological mechanism for the association with BC risk through increased YES1 levels. Together, these results provide evidence supporting a connection between a functional INDEL and BC risk while implicating YES1 in bladder cancer pathogenesis through a microRNA-mediated mechanism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2650. doi:1538-7445.AM2012-2650
Abstract 2697: Role of a novel flavonoid enriched in ocimum sanctum linn for prostate cancer chemoprevention and therapy
Authors: Singhal Sharad S. , Nagaprashantha Lokesh , Singhal Jyotsana , Awasthi Sanjay 
Published: August 2012

Abstract
The present study was conducted to determine the efficacy of novel flavonoid vicenin-2 (VCN-2), an active constituent of the medicinal herb Ocimum Sanctum Linn or Tulsi, as a single agent and in combination with docetaxel (DTL) in carcinoma of prostate (CaP). VCN-2 effectively induced anti-proliferative, anti-angiogenic and pro-apoptotic effect in CaP cells (PC-3, DU-145 and LNCaP) irrespective of their androgen responsiveness or p53 status. VCN-2 inhibited EGFR/Akt/mTOR/ p70S6K pathway along with decreasing c-Myc, cyclin D1, cyclin B1, CDK4, PCNA and hTERT in vitro. VCN-2 reached a level of 2.6 + 0.3 μM in serum after oral administration in mice which reflected that VCN-2 is orally absorbed. The i.v. administration of docetaxel (DTL), current drug of choice in androgen-independent CaP, is associated with dose-limiting toxicities like febrile neutropenia which has lead to characterization of alternate routes of administration and potential combinatorial regimens. In this regard, VCN-2 in combination with DTL synergistically inhibited the growth of prostate tumors in vivo with a greater decrease in the levels of AR, pIGF1R, pAkt, PCNA, cyclin D1, Ki67, CD31, and increase in E-cadherin. VCN-2 has been investigated for radio-protection and anti-inflammatory properties. This is the first study on the anti-cancer effects of VCN-2. In conclusion, our investigations collectively provide strong evidence that VCN-2 is effective against CaP progression along with indicating that VCN-2 and DTL co-administration is more effective than either of the single agents in androgen-independent prostate cancer. (Supported in part by NIH grant CA 77495)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2697. doi:1538-7445.AM2012-2697
Abstract 2715: Treatment of disseminated HER-2 carcinomas with a HER-2-retargeted oncolytic herpes virus
Authors: Lollini Pier-Luigi , Menotti Laura , Giovanni Carla De , Ianzano Marianna , Palladini Arianna , Grosso Valentina , Croci Stefania , Nicoletti Giordano , Landuzzi Lorena , Gatta Valentina , Fiume Gabriella Campadelli , Nanni Patrizia 
Published: August 2012

Abstract
Oncolytic viruses hold the promise to spare normal cells and to selectively seek and destroy tumor cells within the body. Until now numerous viruses where successfully engineered to confer or enhance tumor selectivity, however the effective targeting of disseminated tumor cells in vivo remains a major hurdle. We have retargeted herpes simpex virus (HSV) through the replacement of key gD sequences with sequences encoding a HER-2-specific single chain antibody derived from trastuzumab. The HER-2 retargeted virus (designated here as HER2-HSV) did not bind HSV natural receptors (HVEM and nectin-1), and exclusively infected and killed tumor cells expressing high levels of human HER-2 oncoprotein p185 (PNAS, 106: 9039, 2009). Intratumor injection of HER2-HSV inhibited the growth of HER-2+ human ovarian and breast carcinomas in immunodeficient mice. The aim of the present work was to assess the curative potential of HER2-HSV against disseminated tumors in realistic mouse models reflecting tumor spread in human patients. Human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally in immunodeficient Rag2−/−;Il2rg−/− mice give rise to a progressive peritoneal carcinomatosis similar to the fatal condition developing in advanced human patients. Intraperitoneal (i.p.) administrations of HER2-HSV (108 pfu weekly for 4 weeks) strongly inhibited carcinomatosis resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Visceral organs are a common target of metastatic spread of breast cancer, therefore we studied whether HER2-HSV administred i.p. could treat visceral metastases of HER-2+ MDA-MB-453 breast carcinomas in Rag2−/−;Il2rg−/− mice. The incidence of ovarian metastases was reduced from 89% to 30% by HER2-HSV treatment. Interestingly, the antimetastatic activity of HER2-HSV was not confined to the peritoneal cavity. In the same mice we found also a significant reduction in brain metastases but not in bone marrow infiltration. In practice, HER2-HSV administered i.p. inhibited both visceral (ovary) and distant (brain) HER-2+ breast cancer metastases, presumably reflecting both intraperitoneal diffusion of the virus and the neurotropism of herpesviruses. We are currently studying whether the intravenous administration of HER2-HSV could achieve a more widespread control of metastatic growth.In conclusion, the results show that a HER-2-redirected oncolytic herpesvirus could effectively target disseminated ovarian and breast carcinomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2715. doi:1538-7445.AM2012-2715
Abstract 2717: Reolysin: A novel reovirus-based agent that induces endoplasmic reticular stress in RAS-activated pancreatic cancer
Authors: Carew Jennifer S. , Espitia Claudia M. , Kelly Kevin R. , Coffey Matt , Freeman James W. , Nawrocki Steffan T. 
Published: August 2012

Abstract
Mutations in the RAS oncogene are associated with transformation and proliferation and are prevalent in many tumor types. Since RAS is frequently hyperactivated in pancreatic cancer and plays an essential role in tumor progression, it is an ideal therapeutic target. Reoviruses are naturally occurring viruses that are non-pathogenic and have been reported to specifically replicate in cancer cells with an activated RAS pathway, but not in normal tissue. To take advantage of this observation therapeutically, the reovirus-based anticancer agent Reolysin was recently developed. Reolysin has already progressed into clinical trials, but its mechanisms of action have not been fully elucidated. We hypothesized that Reolysin exposure would result in the production of viral products, stimulate endoplasmic reticular (ER) stress, and induce apoptosis. Reolysin treatment triggered the selective replication of reoviruses as visualized by immunocytochemistry and electron microscopy in KRAS-transformed immortalized human pancreatic duct epithelial cells and in a panel of pancreatic cancer cell lines. Reovirus accumulation was associated with an increase in the expression of ER stress-related genes as assessed by microarray and quantitative RT-PCR analyses, cleavage of caspase-4, and induction of apoptosis. In support of our hypothesis that Reolysin induces ER stress-mediated apoptosis, co-treatment with tunicamycin or brefeldin A further augmented Reolysin-induced cell death. Previous studies have demonstrated that the proteasome inhibitor bortezomib causes ER stress-mediated apoptosis. Here we show that co-treatment with bortezomib and Reolysin stimulates the simultaneous accumulation of ubiquitinated and viral proteins resulting in enhanced levels of ER stress-related gene expression, caspase-4 cleavage, and apoptosis. The role of caspase-4 as a regulator of therapeutic sensitivity to these agents was investigated by targeting caspase-4 expression with siRNA. Knockdown of caspase-4 blunted apoptosis stimulated by Reolysin, bortezomib, and the combination. Importantly, bortezomib also dramatically augmented the anticancer activity of Reolysin in xenograft models of pancreatic cancer in vivo. Analysis of tumor specimens from mice treated with Reolysin and bortezomib displayed reovirus accumulation, enhanced expression of GRP78/Bip, a marker of ER stress and increased levels of apoptosis. Collectively, our results demonstrate that the abnormal protein accumulation induced by Reolysin and bortezomib promotes heightened ER stress and apoptosis in pancreatic cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2717. doi:1538-7445.AM2012-2717
Abstract 2800: Dual PI3K/mTOR inhibitor NVP BEZ-235 suppresses translation of hypoxia-inducible factor (HIF)-1α and increases cell death under hypoxia
Authors: Karar Jayashree , Cerniglia George J. , Koumenis Constantinos , Maity Amit 
Published: August 2012

Abstract
Our goal was to investigate the effects of the Novartis compound NVP-BEZ235, a dual PI3K/mTOR inhibitor, on hypoxia-inducible factor-1 alpha (HIF-1α) expression. NVP-BEZ235 was much more potent than either the mTOR inhibitor rapamycin or the PI3K inhibitor LY294002 in blocking the hypoxic induction of HIF-1α in vitro, due to decreased protein translation. 7-methyl GTP chromatography showed that NVP-BEZ235 led to a robust recruitment of 4E-BP1 to eIF4E and a near absence of binding of eIF4G, consistent with inhibition of protein translation. NVP-BEZ235 also decreased expression of several proteins regulated by eIF4E including cyclin B1 and D1, survivin, and vascular endothelial growth factor. NVP-BEZ235 specifically decreased eIF4G but not eIF4E expression. As HIF-1α has been associated with adaptation under hypoxia, we examined the effect of NVP-BEZ235 on cell survival in low pO2 conditions. The drug increased killing of cells under hypoxia as measured by both short-term (MTT) and long-term (clonogenic) assays. To understand the mechanism behind this observation, we performed immunoblotting for factors associated with cell survival. In normoxia, Akt S473 phosphorylation decreased within an hour of NVP-BEZ235 treatment, but then increased by 24 hours. In contrast, under hypoxia, NVP-BEZ235 caused a prolonged suppression of Akt phosphorylation. Furthermore, we found a greater increase in PARP cleavage in hypoxic cells treated 1-16 hours after drug treatment than in normoxic cells, consistent with increased apoptosis. This was confirmed using an ELISA assay that measures cytoplasmic oligonucleosomes. We also found that NVP-BEZ235 increases autophagy as measured by (i) LC3-I to LC3-II conversion on immunoblotting, (ii) degradation of p62 and (iii) GFP-LC3 subcellular localization detected by immunofluorescence. Treatment of cells with the drug under hypoxia further increased autophagy, although it is unclear at this point whether this actually contributes to cell death or is a pro-survival mechanism. In conclusion, we have found that NVP-BEZ235 blocks HIF-1α induction and increases cell killing under hypoxia, which may have important implications for the use of this drug in cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2800. doi:1538-7445.AM2012-2800
Abstract 2806: BRAF and MEK inhibitor profiling across 240 tumor cell lines to correlate with sensitivity and resistant biomarkers
Authors: Bernards Karen , Ovechkina Yulia , Cheng Jushun , Kushleika John , Angione Alison , Hnilo James , O'Day Christine 
Published: August 2012

Abstract
Activated kinases that induce cell proliferation have been attractive targets for targeted cancer therapy development. Cancer cells could become dependent on tumor-specific activated kinases and this tendency has been coined oncogene addiction. Here, we investigated three activated kinase inhibitors: BRAF inhibitor, PLX-4032 analog, and the MEK inhibitors, CI1040 and PD0325901. We established a high throughput cellular approach to profile 240 human tumor cell lines identifying genotype-correlated sensitivity or resistance. Proliferative, apoptotic and cell cycle arrest responses were measured using multiplexed high content screening with automated fluorescence microscopy and image analysis based technology. Growth index was measured using nuclear dye. Activated caspase 3 antibodies were used for the apoptosis induction detection. Phospho-histone H3 antibodies were used to measure the cell cycle block. We generated cell line profiles to reveal drug sensitivity and resistance patterns that may correlate with the clinical genotype responses. Cell lines with BRAFV600E mutations showed overlapping sensitivity to all three MEK and BRAF inhibitors. RAS mutations confer resistance to the BRAF inhibitor and confer sensitivity to both MEK inhibitors. In addition, we used Alphascreen technology to measure phosphoERK across the 240 non-treated tumor cell line panel. We found that the majority of PLX-4032 sensitive cell lines expressed high levels of phosphoERK. In addition, we investigated BRAF, MEK and EGFR inhibitor combinations to evaluate potential synergies. This preclinical approach can be used to predict mechanisms of susceptibility or resistance to these agents which in turn could be used for the optimization of targeted cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2806. doi:1538-7445.AM2012-2806
Abstract 2823: PHA-739358, a pan-Aurora kinase inhibitor, induces apoptosis and inhibits invasion in melanoma cell lines
Authors: Xie Lifang , Meyskens Frank 
Published: August 2012

Abstract
Cutaneous melanoma (CM) is the most lethal form of skin cancer and is highly invasive and markedly resistant to conventional therapy. The incidence of malignant melanoma has been increasing worldwide for the past three decades, however, the standard care for patients with metastatic melanoma has not changed significantly, therefore, new strategies for treatment of metastatic melanoma are urgently needed. Significant insights have recently been gained into the molecular events underpinning the development of melanoma. Aurora kinases play an essential role as key mitotic regulators, controlling chromosome alignment, segregation, centrosomal maturation, mitotic spindle formation, and cytokinesis during mitosis, and are frequently overexpressed in various human cancers including that of CM making them ideal targets for anti-cancer therapy. Several small molecule inhibitors of the aurora kinases have been developed and tested in vivo and in vitro, and some of them have shown promising clinical efficacy in a number of early phaseI/II clinical trials. Among those, one of the most advanced clinical compounds currently is PHA-739358 (PHA). The goal of this study is to investigate the anti-proliferative and anti-invasive features of PHA in three melanoma cell lines including WM3211, Lu1205, and SK-Mel28. The results showed a time- and dose- dependent growth inhibition in all the cell lines tested with low μM IC50s upon PHA treatment, and significant induction of caspase activity was observed as well. FACScan cell cycle analysis showed significant induction of G2/M population of cells in all three cell lines and increased polyploidy proportion of cells in WM3211 cell line. For the first time, we showed that PHA inhibits melanoma cell invasion in a dose- and time- dependent manor using a Matrigel Invasion Assay. More interestingly, addition of PHA enhanced Temozolomide (TMZ)-induced caspase activation in melanoma cell lines indicating a potential combination therapeutic strategy for the treatment of melanoma. Thus, targeting aurora kianses with PHA is a promising therapeutic strategy administered alone or in combination with TMZ for patients with advanced stages of CM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2823. doi:1538-7445.AM2012-2823
Abstract 2837: Assay development for the discovery of semaphorin 3B-inducing agents from natural product sources
Authors: Yong Yeonjoong , Pan Li , Ren Yulin , Kinghorn A. Douglas , Swanson Steven M. , de Blanco Esperanza J. Carcache 
Published: August 2012

Abstract
The family of semaphorins has been found to regulate cell adhesion and cell motility, the immune response, angiogenesis, and tumor progression. The semaphorins are emerging as regulators of key processes of tumor progression. Semaphorin 3B, in particular, has been found to inhibit proliferation and promote apoptosis. Since there is yet no screening assay available to be used in drug discovery for this crucial target, the present study focuses on the development of a new absorbance-based bioassay to search for new semaphorin 3B inducers from natural sources. Among the parameters considered include the type of cancer cell line, the time of incubation, the type of lysis buffer, secondary effects that affect absorbance levels, and ways to minimize false positives. Vitamin D and actinomycin are being used as controls in this assay. Vitamin D acts as a positive control since it is a semaphorin 3B inducer. Comparison of the levels of induction of the active substances to that of the positive control provides an indication about the level of potential a hit will have if being developed as a drug. Actinomycin inhibits transcription by binding to DNA at the transcription initiation level. When using actinomycin in this assay, its effect is considered to be proportional to that of semaphorin 3B inhibitors. Hence, actinomycin serves as a negative control to discriminate inducers from inhibitors of semaphorin 3B. The use of both controls, therefore, offers the opportunity to discover selective and highly potent semaphorin 3B inducers of natural origin. The assay has been standardized in a 96-well plate format to optimize sensitivity, selectivity, accuracy, robustness, and cost effectiveness. A library of natural product compounds isolated from higher plants, filamentous fungi, and cyanobacteria is currently being screened using this new bioassay. A total of 50 samples have been tested already with two samples exhibiting low induction levels. The most active substances will be further tested using a series of immunoblot secondary assays to validate the potential hits. Additionally, the screening assay presented could be modified to discover new small molecules or drug-like scaffolds as inhibitors or inducers of other semaphorins. Thus, an assay to identify compounds that selectively and potently affect this pathway may lead to new ways of understanding the cell signaling mechanism of these agents, which could be beneficial for the discovery of new natural product leads for cancer treatment. Program project grant P01-CA125066-S1 funded by the National Cancer Institute, NIH.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2837. doi:1538-7445.AM2012-2837