tbuckley/cabot-search huggingface dataset:
Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection Fraction
Authors: Erik B. Schelbert, Yaron Fridman, Timothy C. Wong, Hussein Abu Daya, Kayla M. Piehler, Ajay Kadakkal, Christopher A. Miller, Martin Ugander, Maren Maanja, Peter Kellman, Dipan J. Shah, Kaleab Z. Abebe, Marc A. Simon, Giovanni Quarta, Michele Senni, Javed Butler, Javier Diez, Margaret M. Redfield, Mihai Gheorghiade
Journal: JAMA Cardiology (2017)

Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function.To investigate whether myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes.Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19).Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures.Baseline BNP; subsequent hospitalization for heart failure or death.Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were "at risk" for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not.Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.
Abstract 3182: Cytoskeletal modulation results in increased tumor survival and drug resistance through attenuation of p53 dependent apoptosis
Authors: Victoria E. Wang, John Doench, David Root, Rene Bernards, Jeffrey Settleman, Frank McCormick
Journal: Cancer Research (2017)

Abstract One of the major challenges to eradicating cancer involves the evolution of drug resistant clones and persistence of residual disease that escapes our current limit of detection but may proliferate upon cessation of therapy. These microscopic foci of residual diseases often exhibit stem-cell like properties and are intrinsically more resistant to drug therapy. A better understanding of the mechanisms underlying the innate drug resistance of these cellular populations may lead to improved treatment strategies, resulting in more durable remissions and ultimately improved patient survival. We utilize functional genomic platforms to identify mechanisms responsible for the persistence of drug tolerant cells. A genome wide shRNA enrichment screen was performed using the c-Met addicted cell line GTL-16 to identify genes whose knockdown conferred DTP survival. Inhibition of the RhoA-ROCK-myosin pathway promotes drug resistance in a variety of tumor models, including those treated with either targeted therapy or conventional chemotherapy. Furthermore, pharmacological validation using multiple small molecule inhibitors of ROCK1 phenocopied both myosin heavy chain (MYH9) and light chain (MYL12) shRNA knockdown. More recently, utilizing a combination of gene expression and biochemical approaches, we have identified attenuation of p53 induced apoptosis to be a key event in mediating survival of these drug tolerant persisters. Reactivation of p53 using nutlin results in increased cell death. These findings demonstrate that modulation of cytoskeleton is an important, but underappreciated, mechanism of drug resistance across many tumor types. These downstream effectors may serve as novel therapeutic targets for intervention and also biomarkers to stratify patients and their response to treatment. Citation Format: Victoria E. Wang, John Doench, David Root, Rene Bernards, Jeffrey Settleman, Frank McCormick. Cytoskeletal modulation results in increased tumor survival and drug resistance through attenuation of p53 dependent apoptosis [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 3182. doi:10.1158/1538-7445.AM2017-3182
Abstract 4361: An integrated genome-wide methylation analysis with gene expression in normal breast tissues identifies differentially methylated CpG loci associated with obesity
Authors: Daniel Y. Weng, Min-Ae Song, Theodore M. Brasky, Catalin Marian, Renny S. Lan, Adana A. Llanos, Scott L. Spear, Bhaskar V. Kallakury, Jo L. Freudenheim, Peter G. Shields
Journal: Cancer Research (2017)

Abstract Introduction: Obesity is a risk factor for breast cancer, but the underlying mechanisms for this are only partially understood, and there has been only limited study of breast tissues molecularly before cancer develops. Methods: Breast tissues from healthy women undergoing reduction mammoplasty and epidemiologic interviews (n=121) were profiled for the whole genome transcriptome (Affymetrix Human Transcriptome Arrays) and genome-wide DNA methylation (Infinium HumanMethylation 450 BeadChip array). Results: After adjusting for confounding by age and race, 12,210 CpG dinucleotides with altered methylation levels correlated with body mass index (BMI) (10,808 positive correlations and1,402 negative correlations, FDR&amp;lt;0.05). Among them 4,170 BMI-associated hypermethylated CpG dinucleotides (-1.5 kb from transcription start site, 1st Exon, and 5’UTR) and 443 BMI-associated hypomethylated CpG dinucleotides were located in promoter regions. By integrating DNA methylation and mRNA expression data, we identified 310 methylated genes that correlated with gene expression (FDR&amp;lt;0.05). Of these, 242 genes had higher methylation status showing concurrent down-regulation in obese women, and 68 genes had lower methylation status showing concurrent up-regulation in obese women. Among the affected genes involved in diseases and disorders for inflammatory response, hereditary disorder, and immunological disease. Conclusions: This study provides evidence that obesity epigenetically deregulates genes potentially involved in breast cancer that have functional relationships to gene expression. Citation Format: Daniel Y. Weng, Min-Ae Song, Theodore M. Brasky, Catalin Marian, Renny S. Lan, Adana A. Llanos, Scott L. Spear, Bhaskar V. Kallakury, Jo L. Freudenheim, Peter G. Shields. An integrated genome-wide methylation analysis with gene expression in normal breast tissues identifies differentially methylated CpG loci associated with obesity [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 4361. doi:10.1158/1538-7445.AM2017-4361
Abstract 3820: Hepatitis B virus gene pre-S2 mutant as a high risk serum marker for hepatoma recurrence after a hepatic resection
Authors: Wen-Ya Huang
Journal: Cancer Research (2017)

Abstract Background: Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study aimed to evaluate the serum pre-S2 mutant LHBS as a high-risk recurrence marker in HCC patients after a hepatic resection. Methods: The pre-S gene chip was used to analyze 175 patients with HBV-related HCC who underwent a hepatic resection between 2008 and 2012. Thirty independent pre-S clones in every patient were analyzed for a semi-quantitative detection. Results: Multivariate regression analysis showed that the serum pre-S2 mutant level (≥ 5%) and the American Joint Committee on Cancer (AJCC) tumor stage were two independent high-risk factors for HCC recurrence. A Cox proportional hazards analysis also showed that the combined evaluations of the AJCC stage and serum pre-S2 mutant level provided a reliable predictive marker for HCC recurrence after primary surgery. We developed a Cox prediction model, which indicated the recurrence-free survival rates along with the time after surgery. This model was validated in an independent HCC cohort. Receiver operating characteristic curve analysis revealed that the model showed close sensitivities in the main and validation cohorts (AUC values: 0.741 and 0.704, respectively). Conclusions: The relative level of pre-S2 mutant in serum is, independently of tumor stage, an important predictive high-risk marker for HCC recurrence after a primary hepatic resection. The combined evaluations of the AJCC tumor stage and serum pre-S2 mutant level potentially serve as a convenient high-risk predictive marker for HCC prognosis. Citation Format: Wen-Ya Huang. Hepatitis B virus gene pre-S2 mutant as a high risk serum marker for hepatoma recurrence after a hepatic resection [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 3820. doi:10.1158/1538-7445.AM2017-3820
Abstract 2004: Epigenetic targeting of CD276 expression in medullolbastoma
Authors: Maheedhara R. Guda, Jose R. Castellanos, Collin M. Labak, Ramadevi Sanam, David J. Daniels, Sarah E. Martin, Julian J. Lin, Andrew J. Tsung, Kiran K. Velpula, Swapna Asuthkar
Journal: Cancer Research (2017)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for 20% of pediatric CNS tumors. Following surgery and treatment with chemotherapy and radiation, MBs recur in a significant proportion of patients. Moreover, survivors experience comorbidities related to the tumor and/or its treatment. New insights into MB tumor pathogenesis are needed for improving the survivorship and outcome of MB. Epigenetic silencing, including histone modification and DNA methylation, is an important tumorigenic mechanism in MB. However, its role in cancer immunopathology is poorly understood. Using datamining and immunohistochemistry analysis, we show that B7-H3 (CD276), an important immune checkpoint member of the B7 and CD28 families, is highly upregulated in all four molecular subtypes of MB compared to normal tissue. Based on the clinical success of inhibitory immune checkpoint blockades (CTLA-4, PD-1, and PD-L1), CD276 appears to be a promising therapeutic target for cancer immunotherapy. Moreover, we observed that increased expression of CD276 correlates significantly with the expression of Enhancer of Zeste Homologue 2 (EZH2), a histone H3-methylating (H3K27me3) catalytic subunit in the human MB specimens. We hypothesize that combined targeting of CD276 and EZH2 may have greater impact on tumor progression and immune cell response in MB. Simultaneously, we performed LC/MS analysis to identify novel interaction partners of CD276 in MB tumor. These findings taken together suggest that CD276 is strongly associated with several epigenetic markers, indicating a strong relationship between cancer immune evasion and epigenetic mechanisms. Citation Format: Maheedhara R. Guda, Jose R. Castellanos, Collin M. Labak, Ramadevi Sanam, David J. Daniels, Sarah E. Martin, Julian J. Lin, Andrew J. Tsung, Kiran K. Velpula, Swapna Asuthkar. Epigenetic targeting of CD276 expression in medullolbastoma [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 2004. doi:10.1158/1538-7445.AM2017-2004
Abstract 2724: Brush biopsy miRNA based OSCC detection and diagnosis
Authors: Guy R. Adami, Joel L. Schwartz, Yalu Zhou, Jessica L. Tang, Michael Markiewicz, Gina D. Jefferson, Joel Epstein, Antonia Kolokythas
Journal: Cancer Research (2017)

Abstract RNA based diagnosis and prognosis of squamous cell carcinoma has been slow to come to the clinic. Improvements in RNA measurement, statistical evaluation, and sample preservation still have not made these methods accurate enough to allow truly independent external validation. We propose that in the case of squamous cell carcinoma of the oral cavity that a chief source of variability is sample dissection which leads to variable amounts of stroma mixed in with tumor epithelium. We have used brush biopsy of suspicious lesions to characterize miRNA expression in OSCC epithelium. We used it to show an 11 miRNA signature for OSCC that can differentiate OSCC in both smokers and never smokers from normal tissue. We will report on efforts to optimize this classifier to distinguish OSCC from benign oral lesions such as lichen planus and leukoplakia that can be mistaken for OSCC. We also provide evidence that body fluid samples show similar changes in RNAs with OSCC that are seen in brush biopsy samples -suggesting much of the RNA is coming from the same source tumor epithelium. Finally, using a variation of mirPath designed to eliminate false positive, we have identified the neurotrophin signaling pathway as disregulated in most OSCC epithelium, and for the first time highlight the miRNAs that may control this pathway in OSCC, miR-486-5p, miR-7-5p, miR-146-5p, miR-101-3p, miR-18b-5p, miR-10b-5p, miR-21-5p, miR-20b-5p, miR-126-3p and miR-31-5p. Citation Format: Guy R. Adami, Joel L. Schwartz, Yalu Zhou, Jessica L. Tang, Michael Markiewicz, Gina D. Jefferson, Joel Epstein, Antonia Kolokythas. Brush biopsy miRNA based OSCC detection and diagnosis [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 2724. doi:10.1158/1538-7445.AM2017-2724
Abstract 400: NCI's CPTAC Phase III, proteogenomic analysis of additonal cancer types
Authors: Linda I. Hannick
Journal: Cancer Research (2017)

Abstract The Clinical Proteomics Tumor Analysis Consortium (CPTAC) is a National Cancer Institute initiative that seeks to uncover the molecular basis of cancer using a proteogenomic approach to study prospective cancer specimens. Leidos Biomed provides an infrastructure for supporting the collection of high quality biospecimens and data, in addition to project and subcontract management for the program. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. Phase II of CPTAC, completed in 2016, collected over 500 cases from breast, colon and ovarian patients. In early 2016, CPTAC Phase III began to collect and analyze 200 cases of each of ten additional cancers. The goal is to collect 200 qualified cases of five to six tumor types over a five-year period, although the program is currently accruing from ten. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to a sequencing center and tissues to proteomics groups. Data are combined and analyzed by translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons. Proteomic data are made available through the Data Coordinating Center. We report here on progress in collection of tissues and clinical data, and use of biorepository, proteomics and genomics and analysis centers. Citation Format: Linda I. Hannick. NCI's CPTAC Phase III, proteogenomic analysis of additonal cancer types [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 400. doi:10.1158/1538-7445.AM2017-400
Abstract 3362: PBRM1 regulates the transcription of cell adhesion genes in ccRCC
Authors: Basudev Chowdhury
Journal: Cancer Research (2017)

Abstract Advances in parallel sequencing have facilitated the recent identification of Polybromo-1 (PBRM1), a component of the PBAF (Polybromo-associated-BRG1- or BRM-associated factors) chromatin remodeling complex, as the second most frequently mutated gene in clear-cell renal cell Carcinoma (ccRCC). While several studies have described the diversity of PBRM1 mutations in ccRCC and established the mutation of PBRM1 as a “driver” of ccRCC carcinogenesis, little is known about the biological significance of PBRM1. With the intent of shedding light on the mechanistic roles of PBRM1, we have employed Next Generation Sequencing to delineate the transcriptional profile of cellular models of ccRCC with or without PBRM1 expression and identified genes associated with cell adhesion to be regulated by PBRM1 in 2D monolayer cultures. Since 2D cultures lack the architectural complexities to support studies pertaining to cellular adhesion, we evaluated the role of PBRM1 in 3D culture on Basement Membrane Matrix to provide a physiologically relevant analysis of gene expression and the resulting cellular phenotype. The results showed that of the 97 cell adhesion genes identified to be upregulated by PBRM1 in 2D cultures, 45 were also upregulated in 3D cultures and a subset of 32/45 genes underwent increased gene expression in 3D with respect to 2D cultures. The gene expression profile of candidate genes were verified by qPCR and Western Blotting. Mining The Cancer Genome Atlas (TCGA) publicly available data, we were able to correlate the gene expression profiles of cell adhesion genes identified in 3D cultures with those of ccRCC patients bearing at least 1 copy of the PBRM1 gene. Furthermore, we performed a PBRM1-ChIP-seq to map the genome-wide targets of PBRM1 and revealed the association of PBRM1 occupancy at proximal regulatory regions of 8/45 cell adhesion genes. All of these taken together, indicate a role for PBRM1 in regulating the gene expression of cell adhesion genes which act as important players in cellular morphogenesis and responsiveness to changes in the external environment. Disruption of cell adhesion is believed to affect signal transduction and pave the way facilitating metastasis in neoplastic cells. Currently we are investigating the effect of loss-of-PBRM1 on Epithelial to Mesenchymal Transition (EMT) and metastasis in ccRCC. Note: This abstract was not presented at the meeting. Citation Format: Basudev Chowdhury. PBRM1 regulates the transcription of cell adhesion genes in ccRCC [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 3362. doi:10.1158/1538-7445.AM2017-3362
SAT0488 Comparative effectiveness of ayurveda and conventional care in knee osteoarthritis – a randomized controlled trial
Authors: CS Kessler, K Dhiman, A Kumar, T Ostermann, S Gupta, A Morandi, M Mittwede, E Stapelfeldt, M Spoo, K Icke, A Michalsen, C Witt
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Traditional Indian Medicine Ayurveda is used to treat knee osteoarthritis (OA) despite limited evidence. <h3>Objectives</h3> We aimed to evaluate the effectiveness of complex Ayurvedic treatment compared to complex conventional care in knee OA patients. <h3>Methods</h3> According to ACR criteria patients with knee OA were included in a multicenter randomized, controlled trial and treated in 2 hospital outpatient clinics and 2 private outpatient clinics in Germany with 5 physicians and 20 therapists participating. Patients received either Ayurvedic treatment (n=77) or conventional care (n=74) with 15 treatments over 12 weeks. Primary outcome was the change on the Western Ontario and McMaster University Osteoarthritis (WOMAC) Index after 12 weeks (validated German version). Secondary outcomes included the WOMAC subscales; a pain disability index, numeric rating scales for pain and sleep quality, a pain experience scale, a quality-of-life index, a profile of mood index, rescue medication use, and safety issues. <h3>Results</h3> A total of 151 patients (Ayurveda n=77, conventional care n=74) were included. Changes of the WOMAC Index from baseline to 12 weeks were more pronounced in the Ayurveda group (mean difference 61.0 [95% CI 52.4;69.6]) than in the conventional group (32.0 [95% CI 21.4;42.6]) resulting in a significant difference between groups (p&lt;0.001) and a clinically relevant effect size (Cohen9s d 0.68 [95% CI 0.35;1.01]). Similar tendencies were observed for all secondary outcomes at week 12. Effects were sustainable at follow-ups after 6 and 12 months. <h3>Conclusions</h3> The results suggest that a complex Ayurvedic treatment might be clinically superior to a complex conventional intervention in the treatment of OA of the knee. <h3>Disclosure of Interest</h3> None declared
Abstract 1382: A novel BET family bromodomain inhibitor NHWD-870 represents a promising therapeutic agent for a broad spectrum of cancers
Authors: Nenghui Wang, Mingzhu Yin, Qin Yan
Journal: Cancer Research (2017)

Abstract Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins have emerged as a promising option for cancer therapy. NHWD-870 is a potent and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2/3/4/T. NHWD-870 exhibited robust single agent activity in cell viability assay across cancer cell lines derived from solid tumors, leukemia and lymphomas. Further characterization of cancer cell responses to NHWD-870 indicated that NHWD-870 manifested diverse mechanisms of action in different cancer settings. These include: 1) inhibition of tumor cell growth by downregulating the PDGFRβ, MEK1/2 and STAT1/MYC signaling in tumor cells; 2) inhibition of tumor angiogenesis by decreasing PDGF production in tumor cells and the PDGFRβ and MEK1/2 signaling in endothelial cells. Consistent with its broad spectrum of activities in vitro, NHWD-870 has potent tumor suppressive efficacies in xenograft mouse models of small cell lung cancer, triple negative breast cancer and ovarian cancer. These results support its further development for diverse solid tumor indications in the clinic. Citation Format: Nenghui Wang, Mingzhu Yin, Qin Yan. A novel BET family bromodomain inhibitor NHWD-870 represents a promising therapeutic agent for a broad spectrum of cancers [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 1382. doi:10.1158/1538-7445.AM2017-1382