bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 87: Targeting androgen receptor acetylation as a treatment for castrate-resistant prostate cancer
Authors: Heine Erin , Merry Diane E. , Dehm Scott , Knudsen Karen E. , Montie Heather L. 
Published: August 2015

Abstract
The goal of our studies is to determine the potential of targeting androgen receptor (AR) acetylation as a means to counter androgen-independent prostate cancer (PCa). AR lysine residues 630/632/633 are acetylated in response to androgen-binding. This AR modification has been shown to enhance the transcriptional function of AR and to contribute to prostate tumorigenesis. These observations are supported by the discovery of an AR mutation that mimics this modification in a subset of prostate cancer patients (K630T), as well as increased levels of AR acetyltransferases in some advanced cases. We are specifically interested in the role of this modification in castrate-resistant prostate cancer, and we hypothesize that acetylation contributes to aberrant AR activation in castrate-resistant prostate cancer and possibly in androgen receptor antagonist resistant disease. We are utilizing genetic and pharmacological approaches to determine the function of AR acetylation in PCa, both in cell culture and in in vivo models. We have generated C4-2 cell lines within which we have stably knocked down endogenous AR (shRNA) and replaced it with acetylation-mutant AR (acetylation-null, acetylation-mimic, or lysine-intact controls). We have been performing growth and transcription assays to assess the effect of AR acetylation on these attributes of castrate-resistant PCa. Cells expressing acetylation-mimic AR have increased expression of select AR target gene transcripts, compared to cells expressing AR, null for acetylation. Enhanced AR transcriptional activity corresponds with a growth advantage of acetylation-mimic AR-expressing cells, whereas acetylation-null AR expressing cells undergo a substantial growth inhibition. Studies in mouse xenografts will further clarify whether AR acetylation is a driver of castrate-resistant disease and whether targeting AR acetylation is a rational strategy to treat this advanced disease state. Continued studies will also validate the potential of targeting AR acetylation as a means to combat AR antagonist resistant disease. The growth inhibition of cells expressing acetylation-null AR suggests that reducing AR acetylation may be a means to treat castrate-resistant PCa.
Citation Format: Erin Heine, Diane E. Merry, Scott Dehm, Karen E. Knudsen, Heather L. Montie. Targeting androgen receptor acetylation as a treatment for castrate-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 87. doi:10.1158/1538-7445.AM2015-87
Abstract 888: Reproductive and hormonal factors and mortality risk among women with colorectal cancer in the NIH-AARP Diet and Health Study
Authors: Arem Hannah , Park Yikyung , Felix Ashley , Zervoudakis Alice , Brinton Louise A. , Matthews Charles E. , Gunter Marc J. 
Published: August 2015

Abstract
Introduction
Women in the US have lower rates of colorectal cancer than men, which has prompted research into the role of estrogen in carcinogenesis. While use of menopausal hormone therapy (MHT) and other hormonally-related factors have been associated with lower risk of colorectal cancer (CRC), associations between these factors and colorectal cancer survival are not well defined.
Methods
The NIH-AARP cohort includes 566,398 AARP members (aged 50-71 years) who resided in one of six US states or two metropolitan areas and completed a mailed baseline questionnaire in 1995-1996. Among 2,053 women with incident colorectal cancer in the NIH-AARP Diet and Health Study, we examined associations of age at menarche, age at menopause, age at first birth, parity, oral contraceptive use, and menopausal hormone therapy use with overall and disease-specific mortality. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and disease-specific mortality, adjusting for tumor stage and grade, treatment, years since diagnosis, body mass index, marital status, smoking status, diabetes, and physical activity.
Results
There were 759 deaths (332 due to CRC) over a median 7.7 years of follow-up. We observed a suggestive, but not statistically significant, lower risk of all-cause mortality among women who were 13 years or older at menarche compared to those 12 or younger (HR = 0.89, 95% CI 0.77-1.03), but no associations for age at menopause, age at first live birth, parity, or oral contraceptive use. Compared to never MHT use former MHT use was not associated with mortality risk, but we found an inverse association among current users at study entry for both all-cause mortality (HR = 0.80, 95% CI 0.67-0.94) and colorectal cancer-specific mortality (HR = 0.72, 95% CI 0.56-0.93). These associations were stronger among those who reported fewer than five years of MHT use at baseline than among those with a longer duration of use.
Conclusion
We found evidence of an inverse association between MHT use at study entry and all-cause and colorectal cancer-specific mortality risk. Future studies should focus on how varying usage patterns, including types of preparation used, affect tumor progression and colorectal cancer survival.
Citation Format: Hannah Arem, Yikyung Park, Ashley Felix, Alice Zervoudakis, Louise A. Brinton, Charles E. Matthews, Marc J. Gunter. Reproductive and hormonal factors and mortality risk among women with colorectal cancer in the NIH-AARP Diet and Health Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 888. doi:10.1158/1538-7445.AM2015-888
Abstract 890: Effects of Lewis lung carcinoma on trabecular microstructural changes in wild-type and plasminogen activator inhibitor-1 deficient mice fed a high-fat diet
Authors: Yan Lin 
Published: August 2015

Abstract
Bone is a major target organ of metastasis. The present study investigated the effects of Lewis lung carcinoma (LLC) on trabecular microstructural changes, using tomographic analysis, in distal femur and lumbar 4 vertebra from LLC-bearing wild-type and plasminogen activator inhibitor-1 (PAI-1) deficient mice (C57BL/6J background) fed the AIN93G diet or a high-fat diet; a group of AIN93G-fed non-tumor-bearing wild-type mice were used as controls. Compared to AIN93G-fed non-tumor-bearing wild-type mice, LLC significantly reduced bone volume fraction (BV/TV), connective density (Conn.D), trabecular number (Tb.N), trabecular thickness (Tb.Th) and bone mineral density (BMD) and significantly increased trabecular separation (Tb.Sp) in distal femurs of AIN93G-fed wild-type mice. In high-fat diet-fed mice, compared to the AIN93G-fed ones, LLC resulted in significantly greater reductions BV/TV, Conn.D, Tb.N and BMD and significantly greater increases in structure model index (SMI) and Tb.Sp. Deficiency in PAI-1, compared to wild-type mice, significantly increased BV/TV, Conn.D, Tb.N and significantly reduced SMI. In vertebra, LLC resulted in similar trabecular changes compared to the non-tumor-bearing wild-type controls, the high-fat diet reduced BV/TV and BMD and increased SMI, whereas PAI-1 deficiency did not affect trabecular microstructure in vertebrae. These results demonstrated (1) that LLC is detrimental to trabecular bone which may make it more vulnerable to malignant invasion, (2) that high-fat diet enhances LLC-induced trabecular deterioration and (3) that the improvement in trabecular microstructure by PAI-1 deficiency indicates that PAI-1 may play a role in trabecular microarchitectural deterioration during malignant progression.
Citation Format: Lin Yan. Effects of Lewis lung carcinoma on trabecular microstructural changes in wild-type and plasminogen activator inhibitor-1 deficient mice fed a high-fat diet. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 890. doi:10.1158/1538-7445.AM2015-890
Abstract 902: RNA-Seq profiling of silibinin effects on bladder cancer cells
Authors: Yamamura Soichiro , Mitsui Yozo , Bucay Nathan , Saini Sharanjot , Majid Shahana , Deng Guoren , Shahryary Varahram , Dahiya Rajvir , Tanaka Yuichiro 
Published: August 2015

Abstract
Silibinin is the major active constituent of silymarin, an extract of the milk thistle seeds, containing a mixture of flavonolignans such as silibinin and isosilibinin. Silibinin has been shown to have significant anti-cancer effects in a variety of cancer types, including bladder, kidney, prostate, skin, breast, lung and colon cancer. Silibinin (10 μM) significantly suppressed proliferation and invasion of T24 and UM-UC-3 bladder cancer cells. Western blot analysis showed that silibinin significantly reduces expression of vimentin and slug in these bladder cells. Vimentin is overexpressed in various cancers and is known to promote tumor growth, invasion, and poor prognosis. Slug, a transcriptional repressor which mediates epithelial to mesenchymal transition (EMT), has been implicated in tumor metastasis. These results indicate that silibinin inhibits proliferation and invasion by suppressing vimentin and slug in bladder cancer cells. We studed the anti-cancer effects of silibinin in bladder cancer cells using RNA-Seq, a transcriptome profiling technique that uses deep-sequencing to quantitatively investigate the global behavior of transcriptomes. We will discuss the RNA-Seq profiling of the anti-cancer effects of silibinin in bladder cancer cells, including the vimentin and slug networks.
Citation Format: Soichiro Yamamura, Yozo Mitsui, Nathan Bucay, Sharanjot Saini, Shahana Majid, Guoren Deng, Varahram Shahryary, Rajvir Dahiya, Yuichiro Tanaka. RNA-Seq profiling of silibinin effects on bladder cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 902. doi:10.1158/1538-7445.AM2015-902
Abstract 905: Influence of high fat diet and APC status on epigenetic regulation of FXR in colon cells
Authors: Selmin Ornella I. , Lyon Adam M. , Fang Changming , Doetschman Tom C. , Thompson Patricia A. , Martinez Jesse D. , Smith Jeffrey , Lance Peter M. , Romagnolo Donato F. 
Published: August 2015

Abstract
Bile acids (BAs) not recycled through the enterohepatic system can be modified in the colon into cancer-promoting secondary BAs such as deoxycholic acid (DCA). The farnesoid-X-receptor (FXR) regulates hepatic and intestinal BA homeostasis. However, in intestinal cells carrying defective adenomatous polyposis coli (Apc) gene the expression of FXR is reduced through yet unknown mechanisms. To investigate if Western high-fat diet (HFD) and Apc status influence epigenetic regulation of the Fxr in colonic mucosa. Weaned C57BL/6J male mice were fed a HFD (22% safflower oil = SO) or control low fat diet (LFD; 5% SO) for 6 wks. We examined the effects on CpG pmethylation of Fxr, and expression of FXR, peroxisome-proliferator activated receptor-gamma (PPARγ), and cyclooxygenase-2 (COX-2) mRNA. Also, we studied the influence of APC status on CpG methylation of the Fxr gene, and expression of FXR, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and COX-2 mRNA in normal colonic mucosa and colon tumors from APCMin/+ mice. Mice fed the HFD had reduced (60%) Fxr promoter methylation and increased (2∼3-fold) FXR, COX-2, and PPARγ mRNA levels. Conversely, APC-deficiency was associated with constitutive hypermethylation of the Fxr gene, elevation of COX-2, and reduced (60-90%) baseline FXR, IBABP, and SHP mRNA. In human HCT-116 colon cells, siRNA knock-down of APC reduced (50%) basal FXR mRNA expression, which was further reduced to 80% by DCA. We conclude that APC deficiency leads to constitutive epigenetic silencing of Fxr increasing the risk of inflammation and colon cancer associated with a Western HFD.
Note: This abstract was not presented at the meeting.
Citation Format: Ornella I. Selmin, Adam M. Lyon, Changming Fang, Tom C. Doetschman, Patricia A. Thompson, Jesse D. Martinez, Jeffrey Smith, Peter M. Lance, Donato F. Romagnolo. Influence of high fat diet and APC status on epigenetic regulation of FXR in colon cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 905. doi:10.1158/1538-7445.AM2015-905
Abstract 933: Circulating biomarkers of B vitamins in relation to lung cancer risk in the Lung Cancer Cohort Consortium
Authors: Fanidi Anouar , Muller David.C , Prentice Ross , Demetrius Albanes , Yuan Jian-Min , Stevens Victoria , Weinstein Stephanie J , Johansson Mattias , Brennan Paul ,   Lung Cancer Cohort Consortium (LC3)
Published: August 2015

Abstract
Background - B vitamins and factors related to one-carbon metabolism help to maintain DNA and regulate gene expression. Some epidemiological data suggest that factors related to the one-carbon metabolism are important in the pathogenesis of several cancers, including lung cancer.
Methods - Within the NCI Cohort Consortium, we designed a prospective case-control study including a total of 5,546 case-control pairs nested within 20 prospective cohorts. Centralized biochemical analyses of all study participants were performed to measure circulating concentrations of vitamin B6, folate and methionine, which were subsequently evaluated in relation to lung cancer risk using conditional logistic regression models.
Results - We observed an overall increased risk of lung cancer of 25% among study participants having a deficiency in circulating B6 concentrations compared to those with normal concentrations, the odds ratio (OR) being 1.23 95% confidence interval [CI] = 1.10 - 1.38. This association was primarily evident seen among men (OR 1.38 95% CI 1.20 - 1.60), but not among women (OR 1.03 95% CI 0.85-1.24), as well as for ever ever smokers (OR 1.32 95% CI 1.10 - 1.60). Subgroup analyses by histological sub-site indicated particularly strong association for squamous cell carcinoma type, with about 50% risk increase overall when comparing subjects with vitamin B6 deficiency to normal levels. No association was evident for methionine. Detailed results will be presented at the conference.
Conclusion - Our results are compatible with the hypothesis that vitamin B6 deficiency is associated with increased lung cancer risk, although the risk increase appears to be moderate.
Citation Format: Anouar Fanidi, David.C Muller, Ross Prentice, Albanes Demetrius, Jian-Min Yuan, Victoria Stevens, Stephanie J Weinstein, Mattias Johansson, Paul Brennan, Lung Cancer Cohort Consortium (LC3). Circulating biomarkers of B vitamins in relation to lung cancer risk in the Lung Cancer Cohort Consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 933. doi:10.1158/1538-7445.AM2015-933
Abstract 938: Circulating biomarkers of gut barrier function: Correlates and responses to calcium supplementation among sporadic colorectal adenoma patients in a dose-response randomized controlled trial
Authors: Yang Baiyu , Bostick Roberd M. , Gewirtz Andrew T. , Tran Hao Quang , Fedirko Veronika 
Published: August 2015

Abstract
Gut barrier dysfunction contributes to several gastrointestinal disorders, including inflammatory bowel diseases and colorectal cancer, but factors associated with intestinal hyperpermeability have rarely been assessed in human populations, and there is very limited clinical trial evidence on whether gut barrier function may be modified by dietary factors. To address these gaps, we 1) evaluated factors associated with baseline circulating biomarkers of gut barrier function, and 2) tested the effect of calcium on these biomarkers over a 4-month treatment period among patients with previous colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). Patients were randomized to placebo (n = 66), 1.0 g calcium (n = 64), or 2.0 g calcium (n = 63) daily. Circulating levels of anti-flagellin and anti-lipopolysaccharide (LPS) immunoglobulins (Igs) as markers of colonic hyperpermeability were measured at baseline and at 4-month follow-up via ELISA. At baseline, mean levels of anti-flagellin and anti-LPS IgA but not IgG were higher among men and those with a larger body mass index (BMI), a larger waist circumference, and higher levels of plasma C-reactive protein. Mean anti-flagellin IgG levels were higher among those with higher proinflammatory cytokine scores. We did not observe effects of calcium on anti-flagellin or anti-LPS Igs: the relative change of a combined permeability score (defined as the sum of the optical densities of all biomarkers) from baseline to follow-up was 0.07 (95% confidence interval [CI] -0.13, 0.27) for each treatment group relative to the placebo group (p-values ≥ 0.5). Our results suggest that 1) men and those with a larger BMI or waist circumference may have greater gut permeability, 2) markers of gut permeability and systemic inflammation may be directly associated with one another, and 3) supplemental calcium administered for 4 months may not modify circulating levels of biomarkers of gut barrier function.
Citation Format: Baiyu Yang, Roberd M. Bostick, Andrew T. Gewirtz, Hao Quang Tran, Veronika Fedirko. Circulating biomarkers of gut barrier function: Correlates and responses to calcium supplementation among sporadic colorectal adenoma patients in a dose-response randomized controlled trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 938. doi:10.1158/1538-7445.AM2015-938
Abstract 943: The critical role of CDK2 activation in determining the differential sensitivity of cell lines to Chk1 and Wee1 inhibitors
Authors: Sakurikar Nandini , Thompson Ruth , Montano Ryan , Eastman Alan 
Published: August 2015

Abstract
Anticancer DNA damaging agents activate checkpoints that halt the cell cycle to prevent further DNA replication and mitosis until the damage has been repaired. One of the important regulatory proteins activated in this pathway is Checkpoint kinase 1 (Chk1). Hence, Chk1 inhibitors have emerged as promising novel therapeutics. In clinical trials, Chk1 inhibitors are primarily being evaluated in combination with various DNA damaging agents. However, Chk1 inhibitors also show single agent activity in a subset of cell lines, and this provides a unique therapeutic opportunity to target these tumors. The goal of this study is to define the mechanism of this sensitivity, and identify biomarkers that would permit selection of appropriate patients for clinical trials. From screening a large panel of cancer cell lines, we observed that 15% were sensitive to the Chk1 inhibitor MK-8776, with rapid (&lt;6 h) induction of DNA double-strand breaks (DSB) in S phase cells. Most of the resistant cell lines were sensitive to the Wee1 inhibitor, MK-1775 (AZD1775), while all the cell lines were sensitive to the Wee1/Myt1 dual inhibitor, PD-166285. Wee1 suppresses activation of CDK1 and CDK2, suggesting that MK-1775-mediated activation of one or other (or both) of these kinases leads to DSB. MK-8776 did not activate CDK1, so we hypothesized that activation of CDK2 was critical. To differentiate between the role of CDK1 and CDK2 in cell lines sensitive or resistant to MK-8776, we used inhibitors to CDK1/2. We found that CVT-313 was a selective inhibitor of CDK2 at low concentrations, but that Ro-3306 failed to discriminate between these two kinases in cells. CVT-313 prevented DSB and the associated phosphorylation of histone-H2AX induced by MK-8776 and MK-1775. Cyclin E is a direct target of CDK2; phosphorylation of cyclin E leads to its degradation which was only observed in sensitive cells and prior to the formation of DSB. The acute cytotoxicity was dependent on cyclin A rather than cyclin E, as siRNA-mediated knockdown of cyclin A but not cyclin E, prevented DSB. We conclude that activation of cyclin A/CDK2 determines the sensitivity of cells to MK-8776. Resistance to MK-8776 results from failure to activate CDK2, presumably through failure to activate the upstream CDC25A phosphatase. MK-1775 can circumvent this resistance by directly activating CDK2. The untimely and abnormal activation of CDK2 is then cytotoxic to cancer cells.
Citation Format: Nandini Sakurikar, Ruth Thompson, Ryan Montano, Alan Eastman. The critical role of CDK2 activation in determining the differential sensitivity of cell lines to Chk1 and Wee1 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 943. doi:10.1158/1538-7445.AM2015-943
Abstract 949: An ER-α36 monoclonal antibody exhibits anticancer activity in triple-negative breast cancer cells
Authors: Lin Qingcong , Zhou Junma , Wang Jing , Wang Zonghui , Wang Jun , Chen Feng , Qian Xueming , Shang Xiao , Bao Jun , Wang Zhaoyi , Meng Kun 
Published: August 2015

Abstract
ER-α36 is a novel variant of ER-α, plays an important role in mitogenic estrogen signaling and tamoxifen resistance in both ER-positive and -negative breast cancer. ER-α36 is highly expressed on the plasma membrane of both ER-positive and -negative breast cancer stem/progenitor cells and critical for maintenance of the breast cancer stem/progenitor cells, which make it a promising target for antibody-based breast cancer treatment. In this study, we have screened and identified a candidate of therapeutic antibody named 3C11 that specifically recognizes ER-α36 at its unique C-terminal residues. The antibody 3C11 showed pM affinity to ER-α36 in the BiaCore assay and potent growth inhibitory activity in multiple breast cancer cell lines in vitro. In addition, 3C11 also showed dose-dependent inhibition of tumor growth in a xenograft model formed by a triple-negative breast cancer cell line SUM159 that was generated from a refractory breast cancer. Furthermore, we found that 3C11 was quickly and efficiently internalized into cells, which makes it a potential candidate for development of the antibody-drug conjugate approaches. These results demonstrated that ER-α36 is promising cancer target for development of antibody-based therapeutic approaches.
Citation Format: Qingcong Lin, Junma Zhou, Jing Wang, Zonghui Wang, Jun Wang, Feng Chen, Xueming Qian, Xiao Shang, Jun Bao, Zhaoyi Wang, Kun Meng. An ER-α36 monoclonal antibody exhibits anticancer activity in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 949. doi:10.1158/1538-7445.AM2015-949