tbuckley/cabot-search huggingface dataset:
Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape
Authors: Cankut Cubuk, Marta R. Hidalgo, Alicia Amadoz, Miguel A. Pujana, Francesca Mateo, Carmen Herranz, Jose Carbonell-Caballero, Joaquin Dopazo
Journal: Cancer Research (2018)

Abstract Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Significance: Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. Cancer Res; 78(21); 6059–72. ©2018 AACR.
Genetic testing referral, uptake, and results in a program for women age 40 or younger with breast cancer.
Authors: Asma Ali, Ellen Warner, Kimberley Hill
Journal: Journal of Clinical Oncology (2012)

1542 Background: PYNK: Breast Cancer Program for Young Woman is a novel program started in 2008 at our center to optimize management and promote research for women ≤ age 40 newly diagnosed with breast cancer. Clinical and epidemiological data including cancer family history (FH) is prospectively collected on each consenting patient. As Toronto’s population is uniquely multiethnic we sought to determine BRCA testing eligibility, uptake and results for PYNK patients. Methods: Of the 145 consecutive patients, data were available for 109, of whom 2 had testing prior to diagnosis. Our provincial BRCA testing criteria are age &lt; 35 at diagnosis; suspicious FH; or Ashkenazi Jewish (AJ) and age &lt; 50 at diagnosis. Results: Of the 107 previously untested patients, 40 were &lt; 35 at diagnosis. In 5 of the other 67 testing eligibility could not be assessed. 66 of the 102 (65%) were eligible and of those 65 (98%) were offered referral for counseling. One declined counseling, 9 were not yet seen, 2 declined testing, and 53 were tested. Test results are available for 47 as follows: 30 (64%) no mutation, 4 (8%) variant of uncertain significance (VUS), 7(15%) BRCA1 mutations and 6 (13%) BRCA2 mutations including 1 of the 4 AJ women. Ethnicity of the other 12 mutation carriers was: 1 Hispanic, 2 European, 2 African, 4 Asians, 1 mix, 1 unknown and 1 not recorded. Two (15%) of the mutation carriers had no FH of breast or ovarian cancer. Four additional women opted for counseling and testing despite ineligibility and none had mutations. Conclusions: A specialized program for young women facilitates appropriate referral for genetic testing and encourages high testing uptake, which is important given the high prevalence of mutations (28% of tested women). Further research is necessary to assess the psychological and management impact of having a VUS on young women compared to their older counterparts.
Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s disease
Authors: Ta-Chiang Liu, Justin T. Kern, Kelli L. VanDussen, Shanshan Xiong, Gerard E. Kaiko, Craig B. Wilen, Michael W. Rajala, Roberta Caruso, Michael J. Holtzman, Feng Gao, Dermot P.B. McGovern, Gabriel Nunez, Richard D. Head, Thaddeus S. Stappenbeck
Journal: Journal of Clinical Investigation (2018)

It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome. We hypothesized that CD susceptibility genes interact with cigarette smoking, a major CD environmental risk factor, to trigger Paneth cell defects. We found that both CD subjects and mice with ATG16L1T300A (T300A; a prevalent CD susceptibility allele) developed Paneth cell defects triggered by tobacco smoke. Transcriptional analysis of full-thickness ileum and Paneth cell–enriched crypt base cells showed the T300A-smoking combination altered distinct pathways, including proapoptosis, metabolic dysregulation, and selective downregulation of the PPARγ pathway. Pharmacologic intervention by either apoptosis inhibitor or PPARγ agonist rosiglitazone prevented smoking-induced crypt apoptosis and Paneth cell defects in T300A mice and mice with conditional Paneth cell–specific knockout of Atg16l1. This study demonstrates how explicit G+E can drive disease-relevant phenotype and provides rational strategies for identifying actionable targets.
Abstract 19746: Identification of Novel microRNA Profiles in Patients With Myxomatous Mitral Valve Disease
Authors: Michael A Hagler, Nassir M Thalji, Nate Russell, Michael Welge, Colleen Bushell, Matthew Berry, Bryan A White, Rakesh M Suri, Jordan D Miller
Journal: Circulation (2015)

Introduction: Myxomatous mitral valve disease (MMVD) is a degenerative condition characterized by tissue fibrosis and matrix remodeling which ultimately progresses to leaflet prolapse. While recent work has shown that transforming growth factor beta (TGF-β) signaling contributes to the pathogenesis of MMVD, upstream regulators of this and other pathways remain poorly understood. Hypothesis: We sought to use high-throughput RNA sequencing coupled with microRNA (miRNA) sequencing to identify novel molecular targets as well as upstream regulators contributing to MMVD. Methods: We conducted mRNA and miRNA sequencing on normal (n = 10) and myxomatous human mitral valve samples (n = 10). Differential expression was identified using linear modeling and parallel random forest analyses. Canonical pathways were identified by Ingenuity Pathway Analyses (IPA). Predicted miRNA targets were identified using TargetScanHuman 6.2. Results: We found 2784 mRNAs that were differentially expressed between normal and myxomatous mitral valves, which IPA largely categorized in to pro-fibrotic, matrix remodeling and cellular proliferation signaling. In miRNA sequenced from the same samples, 67 miRNAs were differentially-expressed between normal and myxomatous mitral valves. Increased expression of TGF-β ligands, collagen isoforms, and matrix metalloproteinases were associated with reductions in miRNAs predicted to target them. Conversely, mRNA levels of the “protective” genes TGFβ-induced factor homeobox 1, salt-inducible kinase 1, TIMP metallopeptidase inhibitor 4, and cyclin-dependent kinase inhibitor 1C mRNA levels were decreased in myxomatous tissue, and miRNAs predicted to target these genes (e.g., miR-656, miR-379-3p, miR-664a-3p, and miR-34c-5p) were significantly increased. Conclusions: Collectively, these data not only identify novel genes that are differentially regulated in MMVD, but also suggest miRNAs may play an active role in suppressing key protective molecules in MMVD. Thus, anti-mIRs therapy may be a viable therapeutic target to restore anti-fibrotic and anti-proliferative molecules in the valve and slow progression of MMVD. Future mechanistic studies will lay a critical foundation for translational work in these areas.
Abstract 20172: Identifying Hospital Cardiac Services for Acute Myocardial Infarction Using Individual Patient Claims Data
Authors: Tiffany E Chang, Shu-Xia Li, Isuru Ranasinghe, Harlan Krumholz
Journal: Circulation (2014)

Background: Hospital data on cardiac services provided is restricted to a limited number of services collected by the American Hospital Association (AHA) Survey. We developed an alternative method to identify hospital services using individual patient administrative claims data for acute myocardial infarction (AMI) in the Premier Database. Methods: We first determined inpatient cardiac services relevant for AMI care from guidelines. Then, we identified these services from patient claims using ICD-9, CPT, Medicare Revenue and provider specialty codes. Additionally, Premier Chargemaster and Physician Specialty Codes were used. A hospital was classified as providing a service if they had &gt;5 AMI patient claims for the service in the Premier database from 2009-2011. To measure the accuracy of the claims based method, we compared the percentage of hospitals that were shown to provide a service identified through the AHA survey for a subset of services identifiable from both sources. Results: We identified 32 services relevant for AMI care that could be defined using data with inpatient claims among 476 hospitals in the Premier database (Figure). The availability of these services ranged from 100% (for services such as chest x-ray) to 1% for heart transplant service. When compared to the subset of 12 services also collected in the AHA survey, a high percentage of agreement (≥80%) was noted for 10/16 (63%) services (such as a dedicated ED, general CT, coronary angiography, PCI, ICU, pharmacist and physio/OT services). Moderate agreement was seen for one service (coronary care unit), and 5/16 (31%) services showed low agreement (≤50%) (EP testing, inpatient cardiac surgical services, inpatient cardiac rehabilitation, transplant unit, and social worker). Conclusion: It is feasible to use claims data to determine in-hospital AMI services, but the accuracy of the method needs to be investigated further for certain services that have a low degree of agreement in our analysis.
Abstract 15185: Long Non-Coding RNA H19 Regulates Abdominal Aortic Aneurysm Development and Disease Progression
Authors: Yuhuang Li, Hong Jin, Albert Busch, Ekaterina Chernogubova, Jaroslav Pelisek, Per Eriksson, Joy Roy, Joshua M Spin, Philip S Tsao, Lars Maegdefessel
Journal: Circulation (2017)

Background: - Long noncoding RNAs (lncRNAs) have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize the ...
Strength training as superior, dose-dependent and safe prevention of acute and overuse sports injuries: a systematic review, qualitative analysis and meta-analysis
Authors: Jeppe Bo Lauersen, Thor Einar Andersen, Lars Bo Andersen
Journal: British Journal of Sports Medicine (2018)

Objective This review aims to analyse strength training-based sports injury prevention randomised controlled trials (RCT) and present best evidence recommendations for athletes and future research. A priori PROSPERO registration; CRD42015006970. Design Systematic review, qualitative analysis and meta-analysis. Sorting of studies and quality assessments were performed by two independent authors. Qualitative analyses, relative risk (RR) estimate with robustness and strength of evidence tests, formal tests of publication bias and post-hoc meta-regression were performed. Data sources PubMed, Embase, Web of Science and SPORTDiscus were searched to July 2017. Eligibility criteria for selecting studies RCTs on strength training exercises as primary prevention of sports injuries. Results Six studies analysed five different interventions with four distinct outcomes. 7738 participants aged 12–40 years were included and sustained 177 acute or overuse injuries. Studies were published in 2003–2016, five from Europe and one from Africa. Cluster-adjusted intention-to-treat analysis established RR 0.338 (0.238–0.480). The result was consistent across robustness tests and strength of evidence was high. A 10% increase in strength training volume reduced the risk of injury by more than four percentage points. Formal tests found no publication bias. Conclusion The included studies were generally well designed and executed, had high compliance rates, were safe, and attained consistently favourable results across four different acute and overuse injury outcomes despite considerable differences in populations and interventions. Increasing strength training volume and intensity were associated with sports injury risk reduction. Three characteristically different approaches to prevention mechanisms were identified and incorporated into contemporary strength training recommendations.
Robot-assisted AMS-800 Artificial Urinary Sphincter Bladder Neck Implantation in Female Patients with Stress Urinary Incontinence
Authors: Benoit Peyronnet, Grégoire Capon, Olivier Belas, Andrea Manunta, Clément Allenet, Juliette Hascoet, Jehanne Calves, Michel Belas, Pierre Callerot, Grégoire Robert, Aurélien Descazeaud, Georges Fournier
Journal: European Urology (2018)
Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer
Authors: Lanbo Xiao, Jean C. Tien, Josh Vo, Mengyao Tan, Abhijit Parolia, Yajia Zhang, Lisha Wang, Yuanyuan Qiao, Sudhanshu Shukla, Xiaoju Wang, Heng Zheng, Fengyun Su, Xiaojun Jing, Esther Luo, Andrew Delekta, Kristin M. Juckette, Alice Xu, Xuhong Cao, Ajjai S. Alva, Youngsoo Kim, A. Robert MacLeod, Arul M. Chinnaiyan
Journal: Cancer Research (2018)

Advanced prostate cancer initially responds to androgen deprivation therapy (ADT), but the disease inevitably recurs as castration-resistant prostate cancer (CRPC). Although CRPC initially responds to abiraterone and enzalutamide, the disease invariably becomes nonresponsive to these agents. Novel approaches are required to circumvent resistance pathways and to extend survival, but the mechanisms underlying resistance remain poorly defined. Our group previously showed the histone lysine-N-methyltransferase EZH2 to be overexpressed in prostate cancer and quantitatively associated with progression and poor prognosis. In this study, we screened a library of epigenetic inhibitors for their ability to render CRPC cells sensitive to enzalutamide and found that EZH2 inhibitors specifically potentiated enzalutamide-mediated inhibition of proliferation. Moreover, we identified antisense oligonucleotides (ASO) as a novel drug strategy to ablate EZH2 and androgen receptor (AR) expression, which may have advantageous properties in certain settings. RNA-seq, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin using sequencing demonstrated that EZH2 inhibition altered the AR cistrome to significantly upregulate AR signaling, suggesting an enhanced dependence of CRPC cells on this pathway following inhibition of EZH2. Combination treatment with ASO targeting EZH2 and AR transcripts inhibited prostate cancer cell growth in vitro and in vivo better than single agents. In sum, this study identifies EZH2 as a critical epigenetic regulator of ADT resistance and defines ASO-based cotargeting of EZH2 and AR as a promising strategy for the treatment of CRPC.Significance: Simultaneous targeting of lysine methyltransferase EZH2 and the AR with ASO proves a novel and effective therapeutic strategy in patients with CRPC. Cancer Res; 78(20); 5731-40. ©2018 AACR.
Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo
Authors: Kevin D. Courtney, Divya Bezwada, Tomoyuki Mashimo, Kumar Pichumani, Vamsidhara Vemireddy, Alexander M. Funk, Jennifer Wimberly, Sarah S. McNeil, Payal Kapur, Yair Lotan, Vitaly Margulis, Jeffrey A. Cadeddu, Ivan Pedrosa, Ralph J. DeBerardinis, Craig R. Malloy, Robert M. Bachoo, Elizabeth A. Maher
Journal: Cell Metabolism (2018)
Considerations in Epidemiologic Definitions of Undiagnosed Diabetes
Authors: Linda S. Geiss, Kai McKeever Bullard, Ralph Brinks, Edward W. Gregg
Journal: Diabetes Care (2018)

Accurately quantifying undiagnosed type 2 diabetes is an important challenge for conducting diabetes surveillance and identifying the potential missed opportunities for preventing complications. However, there has been little focused attention on how undiagnosed diabetes is defined in epidemiologic surveys and how limitations in methods used to ascertain undiagnosed diabetes may impact our understanding of the magnitude of this important public health problem. This Perspective highlights weaknesses in how undiagnosed diabetes is quantified in epidemiologic research and the biases and caveats that should be considered when using estimates of undiagnosed diabetes to influence public health policy.
Abstract 11800: Optimal Coronary Revascularization in Patients With Unstable Angina or Non-ST-Elevation Myocardial Infarction: 5-Year Outcomes of the CREDO-Kyoto PCI/CABG Registry Cohort-2
Authors: Akira Marui, Takeshi Kimura, Noboru Nishiwaki, Kazuaki Mitsudo, Tatsuhiko Komiya, Michiya Hanyu, Hiroki Shiomi, Shiro Tanaka, Ryuzo Sakata
Journal: Circulation (2014)

Background: SYNTAX trial revealed the long-term benefit of coronary artery bypass grafting (CABG) relative to percutaneous coronary intervention (PCI) using drug-eluting stent (DES) in patients with stable angina with complex coronary disease. However, long-term benefit of CABG relative to PCI in patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) has not been well elucidated. Methods and Results: We identified 673 patients with 3-vessel and/or left main disease with UA or NSTEMI among 15,939 patients undergoing first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG Registry Cohort-2 (PCI: n=425, CABG: n=238). Age was not different between the 2 groups (p=0.58). Rate of Killip class III or IV (pulmonary edema or cardiogenic shock) was not different between the 2 groups (14% vs. 11%, p=0.19). Number of treated lesion was higher in the CABG group (2.0±1.0 vs. 3.0±1.0, p&lt;0.001). Pre-procedural SYNTAX score was significantly higher in the CABG group (26.8±10.8 vs. 32.2±10.5, p&lt;0.001). Unadjusted 30-day mortality was 6.0% for PCI and 2.9% for CABG. [Table] Five-year outcomes revealed that all-cause mortality after PCI was significantly higher than after CABG (hazard ratio [95% confidence interval]; 1.59 [1.15-2.21], p=0.005). The risk of composite of death, stroke, or myocardial infarction (MACCE) after PCI were also higher than after CABG (1.63 [1.23-2.16], p&lt;0.001). In patients with 3-vessel disease without left main disease (n=465), the risks of death and MACCE after PCI were significantly higher than after CABG (1.59 [1.04-2.43], p=0.03 and 1.60 [1.10-2.34], p=0.01). Similarly the risks of death and MACCE after PCI were also higher than after CABG in patients with left main disease (n=208) Conclusions: In patients with UA or NSTEMI, 5-year outcomes revealed that CABG relative to PCI reduced the risk of death, MACCE, and any revascularization in the DES era both in patients with 3-vessel and left main disease.
5-day nitrofurantoin increased clinical resolution of uncomplicated UTIs in women vs 1-dose fosfomycin
Authors: John C. O’Horo, Aaron Tande
Journal: Annals of Internal Medicine (2018)

Source Citation Huttner A, Kowalczyk A, Turjeman A, et al. Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women: a randomized clinical trial. JAMA. 2018;319:1781-9. 29710295
Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes
Authors: Yoshihiro Hayashi, Yue Zhang, Asumi Yokota, Xiaomei Yan, Jinqin Liu, Kwangmin Choi, Bing Li, Goro Sashida, Yanyan Peng, Zefeng Xu, Rui Huang, Lulu Zhang, George M. Freudiger, Jingya Wang, Yunzhu Dong, Yile Zhou, Jieyu Wang, Lingyun Wu, Jiachen Bu, Aili Chen, Xinghui Zhao, Xiujuan Sun, Kashish Chetal, Andre Olsson, Miki Watanabe, Lindsey E. Romick-Rosendale, Hironori Harada, Lee-Yung Shih, William Tse, James P. Bridges, Michael A. Caligiuri, Taosheng Huang, Yi Zheng, David P. Witte, Qian-fei Wang, Cheng-Kui Qu, Nathan Salomonis, H. Leighton Grimes, Stephen D. Nimer, Zhijian Xiao, Gang Huang
Journal: Cancer Discovery (2018)

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS.Significance: We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. Cancer Discov; 8(11); 1438-57. ©2018 AACR.See related commentary by Chen and Steidl, p. 1355This article is highlighted in the In This Issue feature, p. 1333.