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https://www.readbyqxmd.com/read/28936969/systematic-integration-of-biomedical-knowledge-prioritizes-drugs-for-repurposing
#1
Daniel Scott Himmelstein, Antoine Lizee, Christine Hessler, Leo Brueggeman, Sabrina L Chen, Dexter Hadley, Ari Green, Pouya Khankhanian, Sergio E Baranzini
The ability to computationally predict whether a compound treats a disease would improve the economy and success rate of drug approval. This study describes Project Rephetio to systematically model drug efficacy based on 755 existing treatments. First, we constructed Hetionet (neo4j.het.io), an integrative network encoding knowledge from millions of biomedical studies. Hetionet v1.0 consists of 47,031 nodes of 11 types and 2,250,197 relationships of 24 types. Data was integrated from 29 public resources to connect compounds, diseases, genes, anatomies, pathways, biological processes, molecular functions, cellular components, pharmacologic classes, side effects, and symptoms...
September 22, 2017: ELife
https://www.readbyqxmd.com/read/28935542/phase-i-trial-of-veliparib-a-poly-adp-ribose-polymerase-inhibitor-plus-metronomic-cyclophosphamide-in-metastatic-her2-negative-breast-cancer
#2
Jesus Anampa, Alice Chen, John Wright, Margi Patel, Christine Pellegrino, Karen Fehn, Joseph A Sparano, Eleni Andreopoulou
BACKGROUND: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. METHODS: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer...
September 1, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28929254/root-chemistry-and-soil-fauna-but-not-soil-abiotic-conditions-explain-the-effects-of-plant-diversity-on-root-decomposition
#3
Hongmei Chen, Natalie J Oram, Kathryn E Barry, Liesje Mommer, Jasper van Ruijven, Hans de Kroon, Anne Ebeling, Nico Eisenhauer, Christine Fischer, Gerd Gleixner, Arthur Gessler, Odette González Macé, Nina Hacker, Anke Hildebrandt, Markus Lange, Michael Scherer-Lorenzen, Stefan Scheu, Yvonne Oelmann, Cameron Wagg, Wolfgang Wilcke, Christian Wirth, Alexandra Weigelt
Plant diversity influences many ecosystem functions including root decomposition. However, due to the presence of multiple pathways via which plant diversity may affect root decomposition, our mechanistic understanding of their relationships is limited. In a grassland biodiversity experiment, we simultaneously assessed the effects of three pathways-root litter quality, soil biota, and soil abiotic conditions-on the relationships between plant diversity (in terms of species richness and the presence/absence of grasses and legumes) and root decomposition using structural equation modeling...
September 19, 2017: Oecologia
https://www.readbyqxmd.com/read/28928360/tumor-associated-b-cells-induce-tumor-heterogeneity-and-therapy-resistance
#4
Rajasekharan Somasundaram, Gao Zhang, Mizuho Fukunaga-Kalabis, Michela Perego, Clemens Krepler, Xiaowei Xu, Christine Wagner, Denitsa Hristova, Jie Zhang, Tian Tian, Zhi Wei, Qin Liu, Kanika Garg, Johannes Griss, Rufus Hards, Margarita Maurer, Christine Hafner, Marius Mayerhöfer, Georgios Karanikas, Ahmad Jalili, Verena Bauer-Pohl, Felix Weihsengruber, Klemens Rappersberger, Josef Koller, Roland Lang, Courtney Hudgens, Guo Chen, Michael Tetzlaff, Lawrence Wu, Dennie Tompers Frederick, Richard A Scolyer, Georgina V Long, Manashree Damle, Courtney Ellingsworth, Leon Grinman, Harry Choi, Brian J Gavin, Margaret Dunagin, Arjun Raj, Nathalie Scholler, Laura Gross, Marilda Beqiri, Keiryn Bennett, Ian Watson, Helmut Schaider, Michael A Davies, Jennifer Wargo, Brian J Czerniecki, Lynn Schuchter, Dorothee Herlyn, Keith Flaherty, Meenhard Herlyn, Stephan N Wagner
In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28924597/endoscopic-sleeve-gastroplasty-the-learning-curve
#5
Christine Hill, Mohamad El Zein, Abhishek Agnihotri, Margo Dunlap, Angela Chang, Alison Agrawal, Sindhu Barola, Saowanee Ngamruengphong, Yen-I Chen, Anthony N Kalloo, Mouen A Khashab, Vivek Kumbhari
BACKGROUND AND STUDY AIMS:  Endoscopic sleeve gastroplasty (ESG) is gaining traction as a minimally invasive bariatric treatment. Concern that the learning curve may be slow, even among those proficient in endoscopic suturing, is a barrier to widespread implementation of the procedure. Therefore, we aimed to define the learning curve for ESG in a single endoscopist experienced in endoscopic suturing who participated in a 1-day ESG training program. PATIENTS AND METHODS:  Consecutive patients who underwent ESG between February 2016 and November 2016 were included...
September 2017: Endoscopy International Open
https://www.readbyqxmd.com/read/28920935/spinal-cord-injury-induced-immunodeficiency-is-mediated-by-a-sympathetic-neuroendocrine-adrenal-reflex
#6
Harald Prüss, Andrea Tedeschi, Aude Thiriot, Lydia Lynch, Scott M Loughhead, Susanne Stutte, Irina B Mazo, Marcel A Kopp, Benedikt Brommer, Christian Blex, Laura-Christin Geurtz, Thomas Liebscher, Andreas Niedeggen, Ulrich Dirnagl, Frank Bradke, Magdalena S Volz, Michael J DeVivo, Yuying Chen, Ulrich H von Andrian, Jan M Schwab
Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism...
September 18, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28903991/biology-and-etiology-of-young-onset-breast-cancers-among-premenopausal-african-american-women-results-from-the-amber-consortium
#7
Lynn Chollet-Hinton, Andrew F Olshan, Hazel B Nichols, Carey K Anders, Jennifer L Lund, Emma H Allott, Traci N Bethea, Chi-Chen Hong, Stephanie M Cohen, Thaer Khoury, Gary R Zirpoli, Virginia F Borges, Lynn A Rosenberg, Elisa V Bandera, Christine B Ambrosone, Julie R Palmer, Melissa A Troester
BACKGROUND: African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered. METHODS: We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (≥40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls)...
September 13, 2017: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/28903752/measurement-of-cortisol-in-saliva-a-comparison-of-measurement-error-within-and-between-international-academic-research-laboratories
#8
Jessica L Calvi, Frances R Chen, Victoria Brann Benson, Eleanor Brindle, Matt Bristow, Alpana De, Sonja Entringer, Helen Findlay, Christine Heim, Eric A Hodges, Heiko Klawitter, Sonia Lupien, Holly M Rus, Jitske Tiemensma, Silvanna Verlezza, Claire-Dominique Walker, Douglas A Granger
OBJECTIVE: Hundreds of scientific publications are produced annually that involve the measurement of cortisol in saliva. Intra- and inter-laboratory variation in salivary cortisol results has the potential to contribute to cross-study inconsistencies in findings, and the perception that salivary cortisol results are unreliable. This study rigorously estimates sources of measurement variability in the assay of salivary cortisol within and between established international academic-based laboratories that specialize in saliva analyses...
September 13, 2017: BMC Research Notes
https://www.readbyqxmd.com/read/28903137/nationwide-coverage-and-cost-sharing-for-pcsk9-inhibitors-among-medicare-part-d-plans
#9
Dhruv S Kazi, Christine Y Lu, Grace A Lin, Colette DeJong, R Adams Dudley, Randi Chen, Chien-Wen Tseng
No abstract text is available yet for this article.
September 13, 2017: JAMA Cardiology
https://www.readbyqxmd.com/read/28900195/genetic-interactions-with-age-sex-body-mass-index-and-hypertension-in-relation-to-atrial-fibrillation-the-afgen-consortium
#10
Lu-Chen Weng, Kathryn L Lunetta, Martina Müller-Nurasyid, Albert Vernon Smith, Sébastien Thériault, Peter E Weeke, John Barnard, Joshua C Bis, Leo-Pekka Lyytikäinen, Marcus E Kleber, Andreas Martinsson, Henry J Lin, Michiel Rienstra, Stella Trompet, Bouwe P Krijthe, Marcus Dörr, Derek Klarin, Daniel I Chasman, Moritz F Sinner, Melanie Waldenberger, Lenore J Launer, Tamara B Harris, Elsayed Z Soliman, Alvaro Alonso, Guillaume Paré, Pedro L Teixeira, Joshua C Denny, M Benjamin Shoemaker, David R Van Wagoner, Jonathan D Smith, Bruce M Psaty, Nona Sotoodehnia, Kent D Taylor, Mika Kähönen, Kjell Nikus, Graciela E Delgado, Olle Melander, Gunnar Engström, Jie Yao, Xiuqing Guo, Ingrid E Christophersen, Patrick T Ellinor, Bastiaan Geelhoed, Niek Verweij, Peter Macfarlane, Ian Ford, Jan Heeringa, Oscar H Franco, André G Uitterlinden, Uwe Völker, Alexander Teumer, Lynda M Rose, Stefan Kääb, Vilmundur Gudnason, Dan E Arking, David Conen, Dan M Roden, Mina K Chung, Susan R Heckbert, Emelia J Benjamin, Terho Lehtimäki, Winfried März, J Gustav Smith, Jerome I Rotter, Pim van der Harst, J Wouter Jukema, Bruno H Stricker, Stephan B Felix, Christine M Albert, Steven A Lubitz
It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF)...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899971/matrix-screen-identifies-synergistic-combination-of-parp-inhibitors-and-nicotinamide-phosphoribosyltransferase-nampt-inhibitors-in-ewing-sarcoma
#11
Christine M Heske, Mindy I Davis, Joshua T Baumgart, Kelli M Wilson, Michael V Gormally, Lu Chen, Xiaohu Zhang, Michele Ceribelli, Damien Duveau, Rajarshi Guha, Marc Ferrer, Fernanda I Arnaldez, Jiuping Jay Ji, Huong-Lan Tran, Yiping Zhang, Arnulfo Mendoza, Lee J Helman, Craig J Thomas
PURPOSE: While many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations. EXPERIMENTAL DESIGN: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class...
September 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28899888/protocol-for-a-systematic-review-of-instruments-for-the-assessment-of-quality-of-life-and-well-being-in-children-and-adolescents-with-cerebral-palsy
#12
Christine Mpundu-Kaambwa, Gang Chen, Elisabeth Huynh, Remo Russo, Julie Ratcliffe
INTRODUCTION: Cerebral palsy is the most common cause of physical disability in children and adolescents and is associated with impairments that may reduce the quality of life (QOL) of this population. Patient-reported outcome measures (PROMs) can facilitate the assessment of the effect of disease and treatment on QOL, from a patient viewpoint. The purpose of this systematic review is to identify PROMs that are used to measure QOL and subjective well-being (SWB) outcomes in young people with cerebral palsy and to evaluate the suitability of these PROMs for application in economic evaluations within this population...
September 11, 2017: BMJ Open
https://www.readbyqxmd.com/read/28878000/dissecting-hematopoietic-and-renal-cell-heterogeneity-in-adult-zebrafish-at-single-cell-resolution-using-rna-sequencing
#13
Qin Tang, Sowmya Iyer, Riadh Lobbardi, John C Moore, Huidong Chen, Caleb Lareau, Christine Hebert, McKenzie L Shaw, Cyril Neftel, Mario L Suva, Craig J Ceol, Andre Bernards, Martin Aryee, Luca Pinello, Iain A Drummond, David M Langenau
Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA-protein kinase catalytic subunit (prkdc), interleukin-2 receptor γ a (il2rga), and double-homozygous-mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants...
September 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28833888/stereospecific-electrophilic-fluorination-of-alkylcarbastannatrane-reagents
#14
Xinghua Ma, Mohamed Diane, Glenn Ralph, Christine Chen, Mark R Biscoe
We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site-specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds...
August 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28833638/design-synthesis-and-characterization-of-brequinar-conjugates-as-probes-to-study-dhodh-inhibition
#15
Joseph T Madak, Christine R Cuthbertson, Wenmin Chen, Hollis D Showalter, Nouri Neamati
Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar-based DHODH inhibition and DHODH's therapeutic relevance in cancer, we have developed novel brequinar-based probes. We disclose a 16-step convergent synthesis of the first brequinar-PROTAC and a 4-step approach towards the first mitochondrial-directed brequinar probe. A PROTAC and mitochondria-directed probe of brequinar both possess cytotoxicity that is superior to brequinar in a colony formation assay...
August 21, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28821559/synergy-of-wee1-and-mtor-inhibition-in-mutant-kras-driven-lung-cancers
#16
Josephine Hai, Shengwu Liu, Lauren Bufe, Khanh Do, Ting Chen, Xiaoen Wang, Christine Ng, Shuai Li, Ming-Sound Tsao, Geoffrey I Shapiro, Kwok-Kin Wong
PURPOSE: KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. EXPERIMENTAL DESIGN: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28819565/genomic-and-immune-heterogeneity-are-associated-with-differential-responses-to-therapy-in-melanoma
#17
Alexandre Reuben, Christine N Spencer, Peter A Prieto, Vancheswaran Gopalakrishnan, Sangeetha M Reddy, John P Miller, Xizeng Mao, Mariana Petaccia De Macedo, Jiong Chen, Xingzhi Song, Hong Jiang, Pei-Ling Chen, Hannah C Beird, Haven R Garber, Whijae Roh, Khalida Wani, Eveline Chen, Cara Haymaker, Marie-Andrée Forget, Latasha D Little, Curtis Gumbs, Rebecca L Thornton, Courtney W Hudgens, Wei-Shen Chen, Jacob Austin-Breneman, Robert Szczepaniak Sloane, Luigi Nezi, Alexandria P Cogdill, Chantale Bernatchez, Jason Roszik, Patrick Hwu, Scott E Woodman, Lynda Chin, Hussein Tawbi, Michael A Davies, Jeffrey E Gershenwald, Rodabe N Amaria, Isabella C Glitza, Adi Diab, Sapna P Patel, Jianhua Hu, Jeffrey E Lee, Elizabeth A Grimm, Michael T Tetzlaff, Alexander J Lazar, Ignacio I Wistuba, Karen Clise-Dwyer, Brett W Carter, Jianhua Zhang, P Andrew Futreal, Padmanee Sharma, James P Allison, Zachary A Cooper, Jennifer A Wargo
Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort...
2017: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/28798985/nanostring-based-breast-cancer-risk-prediction-for-women-with-sclerosing-adenosis
#18
Stacey J Winham, Christine Mehner, Ethan P Heinzen, Brendan T Broderick, Melody Stallings-Mann, Aziza Nassar, Robert A Vierkant, Tanya L Hoskin, Ryan D Frank, Chen Wang, Lori A Denison, Celine M Vachon, Marlene H Frost, Lynn C Hartmann, E Aubrey Thompson, Mark E Sherman, Daniel W Visscher, Amy C Degnim, Derek C Radisky
PURPOSE: Sclerosing adenosis (SA), found in ¼ of benign breast disease (BBD) biopsies, is a histological feature characterized by lobulocentric proliferation of acini and stromal fibrosis and confers a two-fold increase in breast cancer risk compared to women in the general population. We evaluated a NanoString-based gene expression assay to model breast cancer risk using RNA derived from formalin-fixed, paraffin-embedded (FFPE) biopsies with SA. METHODS: The study group consisted of 151 women diagnosed with SA between 1967 and 2001 within the Mayo BBD cohort, of which 37 subsequently developed cancer within 10 years (cases) and 114 did not (controls)...
August 10, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28798024/fabry-disease-in-families-with-hypertrophic-cardiomyopathy-clinical-manifestations-in-the-classic-and-later-onset-phenotypes
#19
Berglind Adalsteinsdottir, Runolfur Palsson, Robert J Desnick, Marianna Gardarsdottir, Polakit Teekakirikul, Martin Maron, Evan Appelbaum, Ulf Neisius, Barry J Maron, Michael A Burke, Brenden Chen, Silvere Pagant, Christoffer V Madsen, Ragnar Danielsen, Reynir Arngrimsson, Ulla Feldt-Rasmussen, Jonathan G Seidman, Christine E Seidman, Gunnar Th Gunnarsson
BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes)...
August 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/28795536/corrigendum-sustainable-gel-electrolyte-containing-pyrazole-as-corrosion-inhibitor-and-dendrite-suppressor-for-aqueous-zn-limn2-o4-battery
#20
Tuan K A Hoang, The Nam Long Doan, Julie Hyeonjoo Cho, Jane Ying Jun Su, Christine Lee, Changyu Lu, P Chen
No abstract text is available yet for this article.
August 10, 2017: ChemSusChem
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