tbuckley/cabot-search huggingface dataset:
Abstract LB-097: DNA methylation at enhancers distinguishes distinct breast cancer lineages
Authors: Thomas Fleischer, Xavier Tekpli, Anthony Mathelier, Shixiong Wang, Daniel Nebdal, Hari P. Dhakal, Kristine Kleivi Sandberg, Ellen Schliting, Anne-Lise Børresen-Dale, Elin Borgen, Bjørn Naume, Ragnhild Eskeland, Arnoldo Frigessi, Jörg Tost, Antoni Hurtado, Vessela N. Kristensen
Journal: Cancer Research (2017)

Abstract Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression we applied genome-wide expression-methylation quantitative trait loci (emQTL) analysis between 5meCpG and gene expression. We find that on a whole genome scale, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association, both in cis and in trans, which lead to identify distinct transcriptional networks and specific disease cell lineages deviating from the normal tissue. In three breast cancer cohorts (n=104, n=253 and n=330), we invariably identify enhancers whose DNA methylation tethers the binding of three key transcription factors in breast cancer in a lineage specific manner. Our emQTL analysis also identifies tumor infiltrating immune cell signatures. Using ChromHMM segmentation and ChIP-seq associated TF binding regions, we identify enhancers and TF binding sites around emQTLs-CpGs. We functionally validate the genes associated with these CpGs using knock-down by siRNA and applying GRO-seq analysis after transcriptional stimulation with estrogen. DNA methylation at TF binding regions is considered an early event during normal breast cell transformation into estrogen dependent breast cancer. Two distinct key gene regulatory networks reported here are prominently altered by DNA methylation. Citation Format: Thomas Fleischer, Xavier Tekpli, Anthony Mathelier, Shixiong Wang, Daniel Nebdal, Hari P. Dhakal, Kristine Kleivi Sandberg, Ellen Schliting, Oslo Breast Cancer Research Consortium (OSBREAC), Anne-Lise Børresen-Dale, Elin Borgen, Bjørn Naume, Ragnhild Eskeland, Arnoldo Frigessi, Jörg Tost, Antoni Hurtado, Vessela N. Kristensen. DNA methylation at enhancers distinguishes distinct breast cancer lineages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-097. doi:10.1158/1538-7445.AM2017-LB-097
Abstract 651: Evaluation of the expression and function of TIM-3 relative to PD-1 in human tumors
Authors: Kristen McEachern, Srimoyee Ghosh, Yonghong Zhao, Qiyao Zhang, Norman Zhang, David W. Jenkins
Journal: Cancer Research (2017)

Abstract While immunotherapies directed against PD-1 and PD-L1 have proven effective across multiple indications, there is still a large unmet medical need for therapies for patients who do not respond or who develop acquired resistance during the course of treatment. There are several emerging hypotheses to explain the lack of response, including the overall presence and localization of immune cells, as well as the up-regulation of additional T-cell checkpoints, including TIM-3 in tumor infiltrating lymphocytes. To investigate the potential role of TIM-3, we set out to evaluate the expression and function of TIM-3 and the relationship to PD-1 in several systems. Firstly, we developed a flow cytometry methodology to enumerate T-cell, including CD4 and CD8 positive cells, as well as other immune cell populations in a panel of human tumor samples, including non-small cell lung cancer (NSCLC). In these samples, we investigated the expression profiles of TIM-3 and PD-1 in both T-cell and non-T-cell populations. In addition, we performed complementary genomic studies to explore gene expression profiles of not only the bulk tumor samples but also of isolated PD1 positive/TIM-3 negative versus PD1 and TIM-3 double positive cell populations. The profiling identified tumors with a range of tumor infiltrating lymphocyte content and also differences in PD1 and TIM-3 expression. It was found that in addition to T-cells, TIM-3 was expressed on myeloid cell populations and furthermore, that there were distinct differences in the gene expression profiles of PD1 single positive versus PD1 and TIM-3 double positive cells. Building on the expression studies, the functional role of Tim-3 in T-cells and also on myeloid-derived cells was explored. Taken together, these studies provide further evidence for TIM-3 as an important immunological checkpoint and as a relevant therapeutic target for the treatment of cancer with the potential for biological effects in both the T-cell and myeloid compartments of the tumor microenvironment. Citation Format: Kristen McEachern, Srimoyee Ghosh, Yonghong Zhao, Qiyao Zhang, Norman Zhang, David W. Jenkins. Evaluation of the expression and function of TIM-3 relative to PD-1 in human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2017-651
Abstract 4243: Epigenome-wide association study of metabolic syndrome in African-Americans
Authors: Tomi Akinyemiju
Journal: Cancer Research (2017)

Abstract Background: The epidemic of obesity among US adults has resulted in significant increases in associated metabolic disorders such as diabetes, dyslipidemia and high blood pressure. Together, these disorders constitute metabolic syndrome, a clinically defined condition highly prevalent among African-Americans. Identifying epigenetic alterations associated with metabolic syndrome, including DNA methylation changes may provide information on biological pathways that are dysregulated and may potentially act as early biomarkers in cancer. Methods: Data on cardio-metabolic risk factors and DNA methylation was assessed on 606 African-Americans from the Hypertension Genetic Epidemiology Network (HyperGEN) study. Metabolic syndrome was defined using the joint harmonized criteria of at least three of: elevated waist circumference, high triglycerides, low HDL-cholesterol, high fasting blood glucose and high blood pressure. DNA methylation was assessed using the Illumina HumanMethylation 450K Bead Chip assay on DNA extracted from buffy coat. Linear mixed effects regression models were used to examine the association between CpG methylation and metabolic syndrome in crude and adjusted (for age, alcohol, smoking, sex) analyses. Replication using DNA from 76 African-Americans in the REason for Geographic and Racial Disparities in Cancer (REGARDS) study, as well as meta-analysis combining both cohorts was conducted. Results: Two differentially methylated CpG sites in the IGF2BP1 gene on chromosome 17 (cg06638433; β =0.01, p-value=3.10x10-7) and the ABCG1 gene on chromosome 21 (cg06500161; β: 0.018, p-value=2.60x10-8) were identified in models adjusted for age, sex, alcohol and smoking. Methylation of CpG sites on the TXNIP gene on chr 1 (p=2.83 x 10-9), and CPT1A gene on chr 11 (p=1.39 x 10-4) were also significantly associated with metabolic syndrome in unadjusted models. Results for the ABCG1 gene remained statistically significant in the replication set and meta-analysis. Conclusion: Metabolic syndrome was consistently associated with focal DNA hypermethylation in the ABCG1gene, a region of the chromosome that encodes proteins in the ATP-binding cassette transporter family, and is involved intra- and extra- cellular signaling. Alterations in the ABCG1 gene was observed in 40% of invasive breast cancer tumors in the TCGA, providing a potential epigenetic link between metabolic syndrome and breast cancer that deserves further study. Note: This abstract was not presented at the meeting. Citation Format: Tomi Akinyemiju. Epigenome-wide association study of metabolic syndrome in African-Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4243. doi:10.1158/1538-7445.AM2017-4243
Abstract 2342: TNFAIP8 promotes prostate cancer cell survival by modulating autophagy
Authors: Suresh Niture, Malathi Ramalinga, Habib Kedir, Deepak Kumar
Journal: Cancer Research (2017)

Abstract TNF-α inducible protein (TNFAIP8) is an antiapoptotic protein with roles in tumor cell growth and survival. Mechanisms of cell survival by TNFAIP8 remains elusive. In the current study, we investigated the role and molecular mechanism related to TNFAIP8 in the modulation of cell/cycle, autophagy and drug resistance/cell survival in prostate cancer cells. Microarray data from PC3 prostate cancer cells ectopically expressing TNFAIP8 demonstrated modulation of cell cycle related genes such as CDKs, CDCs and PCNA. Immunoblotting data from overexpression of TNFAIP8 in PC3 cells shows upregulation of cell cycle proteins cyclin A, cyclin B1, Myt1 and Chk1. However, no change in cell cycle was found. Phosphorylation of Histone-S10, CDC2-Tyr15 and Wee1-S642] was also observed. Autophagy plays an important role in tumor cell survival. We evaluated the effects of TNFAIP8 in modulating autophagy. Overexpression of TNFAIP8 leads to induction of autophagy. TNFAIP8 positively modulates the expression/stabilization of autophagy markers and effectors such as LC3β I/II, Beclin1, 4EBP1, oncogene p62 and SIRT1. Knockdown of TNFAIP8 inhibits autophagy induced by nutrient starvation in PC3 prostate and MCF7 breast cancer cells. We also evaluated cell growth and survival in PC3 cells. We demonstrate that TNFAIP8 promotes cell growth and proliferation in PC3, LNCaP and C4-2 prostate cancer cells. Furthermore, we have found that TNFAIP8 increase resistance against anticancer drugs docetaxel and doxorubicin. These data collectively suggest that by the creation of cellular autophagy events TNFAIP8 promotes cell survival and drug resistance in prostate cancer cells. Citation Format: Suresh Niture, Malathi Ramalinga, Habib Kedir, Deepak Kumar. TNFAIP8 promotes prostate cancer cell survival by modulating autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2342. doi:10.1158/1538-7445.AM2017-2342
Enhanced B-Cell Differentiation and Increased Production of Antibodies Targeting Surface Membrane Antigens in Patients with Chronic Graft-Versus-Host Disease
Authors: Kathy S. Wang, Corey S. Cutler, Sarah Nikiforow, Vincent T. Ho, John Koreth, Edwin P. Alyea, Philippe Armand, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz
Journal: Blood (2016)
Abstract 5361: Predesigned gene content for rapid deployment of custom oncology panels
Authors: Andrew J. Barry, Amy Emerman, Sarah Bowman, Kruti Patel, Eileen Dimalanta, Scott Adams, Noa Henig, Fiona Stewart, Cynthia Hendrickson, Theodore Davis, Charles Elfe
Journal: Cancer Research (2017)

Abstract Efficient utilization of targeted gene panels for oncology research is challenged by the wide variation in gene constituents specific to a given study. While focused gene panels efficiently provide the necessary depth of coverage for low frequency variant detection, the high costs and design challenges associated with de novo panel design present challenges. The NEBNext DirectTM technology utilizes a novel approach to selectively enrich nucleic acid targets ranging from a single gene to several hundred genes, without sacrificing specificity. The approach rapidly hybridizes both strands of genomic DNA with biotinyated probes prior to strepdavidin bead capture, enzymatic removal of off-target sequence, and conversion of captured molecules into sequencer-ready libraries. This results in a unique read coverage profile that results in uniform coverage across a given target. Unlike alternative hybridization methods, the approach does not necessitate upfront library preparation, and instead converts the captured molecules into dual-indexed illumina sequencer compatible libraries containing an 8 basepair sample ID and a 12bp Unique Molecule Index (UMI). The UMI individually tags each molecule prior to the final PCR amplification of the library, enabling identification of PCR duplicate molecules. The result is a 1-day protocol that enables the preparation of sequence-ready libraries from purified genomic DNA specific to the gene content included in the panel. We have designed and developed baits specific to the full exonic content of 450 genes associated with cancer. These are designed, balanced, and pooled on a per gene basis, and can be combined into customized panels, allowing rapid turnaround of specific custom gene subsets. Here, we present the ability to rapidly deploy custom gene panels across a variety of panel sizes and content, while maintaining high specificity, uniformity of coverage across target content, and sensitivity to detect nucleic acid variants from tumor samples. Citation Format: Andrew J. Barry, Amy Emerman, Sarah Bowman, Kruti Patel, Eileen Dimalanta, Scott Adams, Noa Henig, Fiona Stewart, Cynthia Hendrickson, Theodore Davis, Charles Elfe. Predesigned gene content for rapid deployment of custom oncology panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5361. doi:10.1158/1538-7445.AM2017-5361
Abstract 4416: Studies on role of acyl-CoA cholesterol acyltransferase (ACAT) expression in ovarian/endometrial cancer progression - An invitro study
Authors: Vijayalakshmi N. Ayyagari, Xinjia Wang, Laurent Brard
Journal: Cancer Research (2017)

Abstract INTRODUCTION: Cancer progression and tumorigenesis have been linked to alterations in cellular metabolic pathways of lipid and cholesterol synthesis in many cancers. Increased levels of cholesterol esters (CE) have been reported in breast cancer, leukemia, glioma and prostate cancer, but not exploited in detail in ovarian and endometrial cancers. Inside cells, excess free cholesterol is esterified by acyl-CoA cholesterol acyltransferase (ACAT) and stored as cholesteryl ester (CE) in lipid droplets (LDs). Cholesteryl ester accumulation may be a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway as observed in pancreatic cancer. In the present study, we focused on the role of ACAT and cholesterol esters in altered cholesterol metabolism in ovarian/endometrial cancer cell lines. METHODS: We studied the effect of abrogation of cholesterol esterification either by an ACAT-1 inhibitor/shRNA knockdown or via inhibition of PI3K/AKT/mTOR pathways and subsequent effect on ovarian/endometrial cancer cells proliferation, invasion, cell migration and tumorigenesis. The expression of ACAT was studied at the protein and mRNA levels in a panel of ovarian/ endometrial cancer cell lines and also in normal and ovarian cancer clinical samples. ACAT expression was assessed by western blotting, ELISA, quantitative RT-PCR and immunostaining techniques. RESULTS: Our results reveal an elevated expression of ACAT-1 at both protein and mRNA levels in ovarian and endometrial cancer cell lines as compared to primary cells. Our results also provide preliminary data on involvement of ACAT and cholesterol esters in the progression and metastasis of ovarian cancer. CONCLUSION: These studies may aid in the development of new biomarkers or treatment targets for ovarian/endometrial cancer. Citation Format: Vijayalakshmi N. Ayyagari, Xinjia Wang, Laurent Brard. Studies on role of acyl-CoA cholesterol acyltransferase (ACAT) expression in ovarian/endometrial cancer progression - An invitro study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4416. doi:10.1158/1538-7445.AM2017-4416
ENVIRONMENTAL RADIATION
Journal: JAMA (1964)

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Abstract 14476: Vitamin D Level and Driveline Infection in Patients Undergoing Left Ventricular Assist Device Implantation
Authors: Fadi Abou Obeid, Abdelhadi Rifai, Antone Tatooles, Erin Drever, Gardner Yost, Geetha Bhat
Journal: Circulation (2016)

Introduction:  Vitamin D has been identified as a hormone that acts on bone health and calcium homeostasis. It is also an important hormone that regulates cardiac myocytes. It has been implicated in the immune system and the inflammatory cascade led by B and T cells. Deficient levels of vitamin D have also been found to correlate with sepsis. Patients undergoing left ventricular assist device (LVAD) implantation are at increased risk of driveline infection. It is considered one of the major adverse events after LVAD implantation.   Hypothesis:  Vitamin D levels are associated with increased risk of driveline infection after LVAD implantation.   Methods:  We retrospectively reviewed the charts of 212 consecutive LVAD patients between Jan 1, 2010 and Jan 1, 2015. A total of 29 patients on ECMO and biventricular assist devices were excluded. Demographics showed a mean age of 59.7 years, 76.8% male and 52% Caucasian. We measured 25-OH vitamin D levels within one week prior to LVAD implantation and investigated its association with driveline infection during 1 year follow up. Vitamin D level was classified into 3 categories listed as Normal (>30 ng/ml), Insufficient (20-30 ng/ml) and Deficient (   Results:  Lower vitamin D levels were independently associated with a significant increase in the rate of driveline infection (Table 1).   Conclusions:  In conclusion, these findings reflect the clinical impact of vitamin D levels on patients undergoing LVAD implantation. Patients with decreased vitamin D levels had a significant increase in driveline infection. This can result in increased readmissions and morbidity. Further studies are needed to determine if vitamin D repletion regimens could decrease driveline infections.
Abstract 493: Pathologic findings at RRSO in germline <i>BRCA</i> mutation carriers with breast cancer: significance of bilateral RRSO at the optimal age in germline <i>BRCA</i> mutation carriers
Authors: YoungJae Lee, YongMan Kim, ShinWha Lee
Journal: Cancer Research (2017)

Abstract Objective: Most BRCA1/2 carriers do not undergo risk-reducing salpingo-oophorectomy (RRSO) by the recommended age. This study aimed to find the incidence of precursor lesions and cancer after RRSO. Methods: We retrospectively reviewed breast cancer patients identified as BRCA mutation carriers who underwent RRSO at Asan Medical Center, Seoul, Korea, from 2010 to 2014. From 2013, all cases were examined according to the SEE/FIM protocol and underwent immunohistochemically (IHC) staining. RRSO was performed in 63 patients, 27 in 2010-2012 and 36 in 2013-2014. Results: The median age at RRSO was 46.5 years (32-73 years). Occult invasive cancer was detected in 8 patients, of ovarian origin in 5 and of tubal origin in 3. All occult invasive cancer cases with metastasis were detected in patients older than 40 years. Of the 36 patients from the 2013-2014 cohort, 7 showed p53 overexpression, 1 showed Ki-67 overexpression, 2 showed serous tubal intraepithelial carcinoma (STIC), and 3 showed occult cancer. The detection rate of precursor lesions or cancer was 36.1% (13/36). In the analysis according to age, precursor lesions were more common in BRCA1 mutation carriers younger than 40 years old (66.7% vs 20.0%). In BRCA2 mutation carriers, precursor lesions were only detected in those older than 40 years of age, indicating the possible faster occurrence of precursor lesions in BRCA1 mutation carriers. Conclusions: Many patients still tend to delay RRSO until after they are 40 years old. Our findings support the significance of RRSO before the age of 40 in germline BRCA mutation carriers. Citation Format: YoungJae Lee, YongMan Kim, ShinWha Lee. Pathologic findings at RRSO in germline BRCA mutation carriers with breast cancer: significance of bilateral RRSO at the optimal age in germline BRCA mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 493. doi:10.1158/1538-7445.AM2017-493
Abstract 5455: Novel miRNA-based therapeutic approach to selectively target mutant p53 in cancer
Authors: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract Tumor suppressor p53, guardian of the genome, is frequently mutated or functionally dysregulated in more than 50% of human tumors. p53 mutation is a later event in tumorigenesis and a number of p53 mutants have “Gain of Function” (GOF) properties that have been shown to promote invasive and more aggressive phenotypes in cancer cells. Mutant p53 has been an attractive and promising therapeutic target for advanced stages of tumors. Yet, mutant p53 has proved to be one of the most undruggable targets. Thus, there is continued interest in understanding the GOF properties of mutant p53 and in designing novel strategies to target mutant p53 and/or key GOF pathways. Mature MicroRNAs (miRNAs) are ~22 nt endogenous, non-coding RNA sequences that bind to 3’UTR of their target genes and inhibit their translation. miRNA mimics are emerging therapeutics and attractive tools for mapping pathway networks. We developed a novel functional high throughput screening (HTS) assay to identify miRNAs that selectively target mutant p53-expressing cell lines. The HTS was performed in isogenic TP53+/+ (wild-type), TP53-/- (null) and TP53 R175H (mutant) HCT-116 colorectal cancer cell lines. Cell viability was used as the HTS read-out of our functional screen. Of 2754 miRNA mimics screened, we identified 56 miRNAs that selectively target TP53 R175H (mutant) cells. Our ongoing work is directed to further validating and identifying which of these miRNA mimics selectively induce apoptosis in mutant p53-expressing cells. We are also using reporter-based assays to identify a fraction of the 56 miRNAs that can bind to the p53 3’UTR. Our long-term goal is to selectively target mutant p53-expressing cells using miRNA mimics as single agents or in combination with FDA-approved or experimental therapeutics. Our strategy is may provide a unique opportunity for development of targeted therapy for TP53 mutant tumors. Citation Format: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, David T. Dicker, Wafik S. El-Deiry. Novel miRNA-based therapeutic approach to selectively target mutant p53 in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5455. doi:10.1158/1538-7445.AM2017-5455