tbuckley/cabot-search huggingface dataset:
Perinatal iron deficiency and a high salt diet cause long-term kidney mitochondrial dysfunction and oxidative stress
Authors: Andrew G Woodman, Richard Mah, Danae L Keddie, Ronan M N Noble, Claudia D Holody, Sareh Panahi, Ferrante S Gragasin, Helene Lemieux, Stephane L Bourque
Journal: Cardiovascular Research (2019)

Perinatal iron deficiency (ID) alters developmental trajectories of offspring, predisposing them to cardiovascular dysfunction in later life. The mechanisms underlying this long-term programming of renal function have not been defined. We hypothesized perinatal ID causes hypertension and alters kidney metabolic function and morphology in a sex-dependent manner in adult offspring. Furthermore, we hypothesized these effects are exacerbated by chronic consumption of a high salt diet.Pregnant Sprague Dawley rats were fed either an iron-restricted or replete diet prior to and throughout pregnancy. Adult offspring were fed normal or high salt diets for 6 weeks prior to experimentation at 6 months of age. Blood pressure (BP) was assessed via indwelling catheters in anaesthetized offspring; kidney mitochondrial function was assessed via high-resolution respirometry; reactive oxygen species and nitric oxide were quantified via fluorescence microscopy. Adult males, but not females, exhibited increased systolic BP due to ID (P = 0.01) and high salt intake (P = 0.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P = 0.003), while succinate-dependent respiration was reduced by ID (P < 0.05). The combination of perinatal ID and high salt reduced complex IV activity in the cortex of males (P = 0.01). Perinatal ID increased cytosolic superoxide generation (P < 0.001) concomitant with reduced nitric oxide bioavailability (P < 0.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P = 0.04) and cytosolic superoxide within the cortex (P = 0.01). Male offspring exhibited glomerular basement membrane thickening (P < 0.05), increased collagen deposition (P < 0.05), and glomerular hypertrophy (interaction, P = 0.02) due to both perinatal ID and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or ID.Perinatal ID causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.
Abstract 18221: Choosing Wisely: Does It Apply to Prescription Drugs? A Cost Analysis of Utilization of Angiotensin Converting Enzyme Inhibitors Class of Drug Amongst Medicare Part D Beneficiaries
Authors: Anuradha Sethi, Maninder Singh, Dwight Stapleton
Journal: Circulation (2016)

Introduction: ACE-Is were amongst top 10 most frequently prescribed medications in 2010 for Medicare part D beneficiaries. There are multiple generic agents available (10 in the US) in this class. ...
Prospective trial of functional liver image-guided hepatic therapy (FLIGHT) with hepatobiliary iminodiacetic acid (HIDA) scans and update of institutional experience.
Authors: David Emmert Long, Colin Huang, Mark Tann, Benjamin Dawson, Gregory Bartlett, Mary A. Maluccio, Ryan Rhome, Feng-Ming Spring Kong, Susannah G. Ellsworth
Journal: Journal of Clinical Oncology (2019)

373 Background: Functional liver image-guided hepatic therapy (FLIGHT) is a novel stereotactic body radiation therapy (SBRT) planning technique. A functional map, generated from hepatobiliary iminodiacetic acid (HIDA) scans, is used to maximize the functional residual capacity of liver receiving &lt; 15 Gy (FRC 15 HIDA). We present initial results of a prospective trial evaluating FLIGHT vs standard planning and update our institutional experience. Methods: Eligible patients were ≥ 18 yo with 1 o or 2 o liver malignancy and Child-Pugh ≤ B7. Liver function was assessed with HIDA and blood chemistry at baseline, mid-treatment, and 3, 6, and 12 months post SBRT. Both standard and FLIGHT (optimized to avoid high functioning liver) plans were generated for each patient. Treating MDs were blinded to planning technique before selecting the treatment plan. The primary endpoint was to show &gt; 5% increase in FRC 15 HIDA in 3/15 pts. Secondary endpoints included the rate FLIGHT plans were selected and changes in HIDA and other liver function tests. Prior institutional experience included 27 pts with FLIGHT planned retrospectively. Paired t-test was used to compare dosimetric endpoints for FLIGHT vs. standard plans, including: FRC 15 HIDA, mean liver dose, effective uniform dose (EUD), and functional EUD (FEUD). Results: Fifteen pts were enrolled. The primary endpoint was met, as 4/15 pts had &gt; 5% improvement in FRC 15 HIDA (mean 5.2%, range -2.3-19.8%). Notably, the FLIGHT plan was selected in 11/15. The mean improvements in FRC 15 HIDA (5.2 vs 5.0%), mean liver dose (11.9 vs. 13.0%), EUD (5.1 vs 5.2%), and FEUD (6.9 vs 7.1%) were similar between prospective and retrospective cohorts (p &gt; 0.5). In the entire cohort (n = 42), FLIGHT improved FRC 15 HIDA, mean liver dose, EUD, and FEUD ( p ≤ 0.001). There were &gt; 5% improvements in FRC 15 HIDA in 15, mean liver dose in 31, EUD in 19, and FEUD in 27. Conclusions: FLIGHT with HIDA led to improvements in all analyzed dosimetric parameters. The extent of benefit was similar in both cohorts, and there was individual variation in the extent of benefit. Longer follow-up is required to determine the effect of FLIGHT on post-SBRT liver function. Clinical trial information: NCT03338062.
Abstract 19608: Real-World Comparisons of Major Bleeding Risk for Commercially Insured Non-Valvular Atrial Fibrillation Patients Initiating Apixaban, Dabigatran, Rivaroxaban, or Warfarin
Authors: Alpesh Amin, Allison Keshishian, Lien Vo, Jack Mardekian, Shalabh Singhal, Chad Patel, Kevin Odell, Jeffrey Trocio
Journal: Circulation (2016)

Objective: Clinical trials have demonstrated that non-VKA oral anticoagulants (NOACs) are at least as effective as warfarin for risk reduction of stroke or systemic embolism and are associated with similar or lower bleeding rates. This study compared the risk of major bleeding among non-valvular atrial fibrillation (NVAF) patients initiating oral anticoagulants. Methods: Commercially-insured adult patients in the Optum database prescribed apixaban, rivaroxaban, dabigatran, or warfarin were selected from 01JAN2013 -30SEP2015. Patients were required to have an AF diagnosis (ICD-9-CM code: 427.31), continuous health plan enrollment for ≥12 months, and no OAC use in the 12 months before the index date (first OAC claim date). Patients with claims suggestive of valvular heart disease, cardiac surgery, venous thromboembolism, reversible AF, or evidence of pregnancy were excluded. Major bleeding, defined as bleeding requiring hospitalization, was compared using a Cox proportional hazards model adjusted for age, s...
Anagrelide Inhibits Proliferation and Platelet Generation in Immortalized Megakaryocyte Progenitor Cell Lines Established from Human Induced Pluripotent Stem Cells
Authors: Koji Takaishi, Masahiro Takeuchi, Shokichi Tsukamoto, Naoya Takayama, Motohiko Oshima, Yusuke Isshiki, Kensuke Kayamori, Kenji Kimura, Yutaro Hino, Nagisa Oshima-Hasegawa, Shio Mitsukawa, Yusuke Takeda, Naoya Mimura, Chikako Ohwada, Tohru Iseki, Sou Nakamura, Koji Eto, Atsushi Iwama, Koutaro Yokote, Chiaki Nakaseko, Emiko Sakaida
Journal: Blood (2018)
TP53 Clonal and Subclonal Architecture in Chronic Lymphocytic Leukemia Patients Under Ibrutinib Treatment
Authors: Ilaria Del Giudice, Luciana Cafforio, Luca Vincenzo Cappelli, Caterina Ilari, Sara Raponi, Maria Stefania De Propris, Paola Mariglia, Francesca Romana Mauro, Marco Vignetti, Anna Guarini, Robin Foà
Journal: Blood (2018)
Accurate prediction of cell type-specific transcription factor binding
Authors: Jens Keilwagen, Stefan Posch, Jan Grau
Journal: Genome biology (2019)

Prediction of cell type-specific, in vivo transcription factor binding sites is one of the central challenges in regulatory genomics. Here, we present our approach that earned a shared first rank in the "ENCODE-DREAM in vivo Transcription Factor Binding Site Prediction Challenge" in 2017. In post-challenge analyses, we benchmark the influence of different feature sets and find that chromatin accessibility and binding motifs are sufficient to yield state-of-the-art performance. Finally, we provide 682 lists of predicted peaks for a total of 31 transcription factors in 22 primary cell types and tissues and a user-friendly version of our approach, Catchitt, for download.
The Challenge of Unexplained Splenomegalies: Preliminary Data of the French Prospective Multi-Center Splenomegaly Study (SMS)
Authors: Guillaume Denis, Laurence Sanhes, Jean-Marc Ziza, Frederic Bauduer, Marc G. Berger, Regis T. Costello, Kawkab Mehdi, Martin Michaud, Geoffrey Urbanski, Christian Rose
Journal: Blood (2018)
Reproductive factors and risk of melanoma: a population‐based cohort study
Authors: N.C. Støer, E. Botteri, R. Ghiasvand, M. Busund, S. Vangen, E. Lund, M.B. Veierød, E. Weiderpass
Journal: British Journal of Dermatology (2019)

The association between reproductive factors and risk of cutaneous melanoma (CM) is unclear. We investigated this issue in the Norwegian Women and Cancer cohort study.To examine the association between the reproductive factors age at menarche, menstrual cycle length, parity, age at first and last birth, menopausal status, breastfeeding duration and length of ovulatory life, and CM risk, overall and by histological subtypes and anatomical site.We followed 165 712 women aged 30-75 years at inclusion from 1991-2007 to the end of 2015. Multivariable Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).The mean age at cohort enrolment was 49 years. During a median follow-up of 18 years, 1347 cases of CM were identified. No reproductive factors were clearly associated with CM risk. When stratifying by histological subtype we observed significant heterogeneity (P = 0·01) in the effect of length of ovulatory life on the risk of superficial spreading melanoma (HR 1·02, 95% CI 1·01-1·04 per year increase) and nodular melanoma (HR 0·97, 95% CI 0·94-1·01 per year increase). When stratifying by anatomical site, menopausal status (HR 0·54, 95% CI 0·31-0·92, postmenopausal vs. premenopausal) and menstrual cycle length (HR 1·07, 95% CI 1·01-1·13, per day increase) were associated with CM of the trunk, and significant heterogeneity between anatomical sites was observed for menopausal status (P = 0·04).In this large population-based Norwegian cohort study, we did not find convincing evidence of an association between reproductive factors and risk of CM.
Abstract 046: Cardiorespiratory Fitness, Physical Activity, and Television Viewing Before Pregnancy and Risk of Gestational Diabetes: A Longitudinal Analysis From the CARDIA Study
Authors: Kara M Whitaker, Katherine H Ingram, Duke Appiah, Wanda K Nicholson, Wendy L Bennett, Cora E Lewis, Jared P Reis, Pamela J Schreiner, Erica P Gunderson
Journal: Circulation (2018)

Introduction: Low levels of cardiorespiratory fitness, moderate-to-vigorous-intensity physical activity (MVPA), and excess sedentary behaviors are associated with a greater risk of type 2 diabetes. Less is known about the role of fitness, MVPA, and sedentary behaviors before pregnancy with subsequent development of gestational diabetes mellitus (GDM), a strong risk factor for future diabetes and cardiovascular disease. Objective: To assess the associations of pre-pregnancy fitness, MVPA, and time spent watching television (a surrogate for sedentary behavior) with risk of GDM. Methods: Participants were 1,333 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study who did not have diabetes at baseline (1985-86) or before post-baseline births. Baseline fitness was estimated using a graded symptom-limited maximal treadmill test and expressed in metabolic equivalent units (METS). Baseline MVPA (exercise units/day) was measured using the CARDIA physical activity history questionnaire, and television viewing (hours/day) was assessed by self-report in 1990-91. Logistic regression analysis was used to calculate odds ratios and 95% confidence intervals, adjusting for study center, baseline age, race, parity, education, family history of diabetes, smoking, alcohol, dietary fat, pre-pregnancy body mass index, HOMA-IR, HDL-cholesterol, and time from baseline to delivery. Results: Over 25 years of follow up, 164 women developed GDM. As shown in the Table , the odds of developing GDM were 22% lower for each 1 standard deviation increment in baseline fitness after adjustment (2.3 METS; OR 0.78, 95% CI: 0.65, 0.95, p=0.013). MVPA and television viewing were not statistically significantly associated with developing GDM. Conclusions: This is one of the first studies to report an inverse association between objectively measured pre-pregnancy fitness and subsequent development of GDM. Improved pre-conception fitness may benefit women at risk for GDM.
JAK2 R1063H Variant Enhances V617F Constitutive Signaling and Favors Development of Essential Thrombocythemia with Increased Hemoglobin and Neutrophils
Authors: Cristina Mambet, Jean-Philippe Defour, Olga Babosova, Emilie Leroy, Laura Necula, Oana Stanca, Aurelia Tatic, Daniel Coriu, Monika Belickova, Barbora Kralova, Lucie Lanikova, Pascale Saussoy, Violaine Havelange, Carmen C. Diaconu, Vladimir Divoky, Stefan N Constantinescu
Journal: Blood (2018)
Follicular lymphoma–associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR
Authors: Fangyang Wang, Damián Gatica, Zhang Xiao Ying, Luke F. Peterson, Peter Kim, Denzil Bernard, Kamlai Saiya-Cork, Shaomeng Wang, Mark S. Kaminski, Alfred E. Chang, Tycel Phillips, Daniel J. Klionsky, Sami N. Malek
Journal: Journal of Clinical Investigation (2019)

The discovery of recurrent mutations in subunits of the vacuolar-type H+-translocating ATPase (v-ATPase) in follicular lymphoma (FL) highlights a role for the amino acid- and energy-sensing pathway to mTOR in the pathogenesis of this disease. Here, through the use of complementary experimental approaches involving mammalian cells and Saccharomyces cerevisiae, we have demonstrated that mutations in the human v-ATPase subunit ATP6V1B2 (also known as Vma2 in yeast) activate autophagic flux and maintain mTOR/TOR in an active state. Engineered lymphoma cell lines and primary FL B cells carrying mutated ATP6V1B2 demonstrated a remarkable ability to survive low leucine concentrations. The treatment of primary FL B cells with inhibitors of autophagy uncovered an addiction for survival for FL B cells harboring ATP6V1B2 mutations. These data support the idea of mutational activation of autophagic flux by recurrent hotspot mutations in ATP6V1B2 as an adaptive mechanism in FL pathogenesis and as a possible new therapeutically targetable pathway.
A Stemness Screen Reveals C3ORF54/INKA1 As a Gate-Keeper of Human Stem Cell Latency
Authors: Kerstin B. Kaufmann, Laura Garcia Prat, Shin-Ichiro Takayanagi, Jessica McLeod, Olga I. Gan, Kristele Pan, Stephanie Zhi-Juan Xie, John E. Dick
Journal: Blood (2018)
Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner
Authors: Matt L. Harlow, Maggie H. Chasse, Elissa A. Boguslawski, Katie M. Sorensen, Jenna M. Gedminas, Susan M. Kitchen-Goosen, Scott B. Rothbart, Cenny Taslim, Stephen L. Lessnick, Anderson S. Peck, Zachary B. Madaj, Megan J. Bowman, Patrick J. Grohar
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The successful clinical translation of compounds that target specific oncogenic transcription factors will require an understanding of the mechanism of target suppression to optimize the dose and schedule of administration. We have previously shown trabectedin reverses the gene signature of the EWS-FLI1 transcription factor. In this report, we establish the mechanism of suppression and use it to justify the reevaluation of this drug in the clinic in patients with Ewing sarcoma. Experimental Design: We demonstrate a novel epigenetic mechanism of trabectedin using biochemical fractionation and chromatin immunoprecipitation sequencing. We link the effect to drug schedule and EWS-FLI1 downstream target expression using confocal microscopy, qPCR, Western blot analysis, and cell viability assays. Finally, we quantitate target suppression within the three-dimensional architecture of the tumor in vivo using 18F-FLT imaging. Results: Trabectedin evicts the SWI/SNF chromatin-remodeling complex from chromatin and redistributes EWS-FLI1 in the nucleus leading to a marked increase in H3K27me3 and H3K9me3 at EWS-FLI1 target genes. These effects only occur at high concentrations of trabectedin leading to suppression of EWS-FLI1 target genes and a loss of cell viability. In vivo, low-dose irinotecan is required to improve the magnitude, penetrance, and duration of target suppression in the three-dimensional architecture of the tumor leading to differentiation of the Ewing sarcoma xenograft into benign mesenchymal tissue. Conclusions: These data provide the justification to evaluate trabectedin in the clinic on a short infusion schedule in combination with low-dose irinotecan with 18F-FLT PET imaging in patients with Ewing sarcoma.
Exhalation Delivery System (EDS) Intranasal Steroid vs Conventional Inhaled Nasal Steroids (INS): Patient Preference, Comfort and Ease of Use
Authors: Dareen D. Siri, John C. Messina, Jennifer L. Carothers, Harry J. Sacks, Ramy A. Mahmoud
Journal: Journal of Allergy and Clinical Immunology (2019)
Therapeutic Manipulation of Cancer Cell Metabolism with the Mitochondrial Metabolism Inhibitor Cpi-613 in Addition to Chemotherapy Abrogates the Adverse Prognostic Effect of Age in Relapsed and Refractory AML
Authors: Timothy Pardee, Scott Isom, Leslie Renee Ellis, Dianna S. Howard, Rupali Bhave, Megan Manuel, Sarah Dralle, Susan Lyerly, Bayard L. Powell
Journal: Blood (2018)
Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors
Authors: Shirin Moossavi, Shadi Sepehri, Bianca Robertson, Lars Bode, Sue Goruk, Catherine J. Field, Lisa M. Lix, Russell J. de Souza, Allan B. Becker, Piushkumar J. Mandhane, Stuart E. Turvey, Padmaja Subbarao, Theo J. Moraes, Diana L. Lefebvre, Malcolm R. Sears, Ehsan Khafipour, Meghan B. Azad
Journal: Cell Host & Microbe (2019)
Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology
Authors: Silvia Pozzi, Sai Sampath Thammisetty, Philippe Codron, Reza Rahimian, Karine Valérie Plourde, Geneviève Soucy, Christine Bareil, Daniel Phaneuf, Jasna Kriz, Claude Gravel, Jean-Pierre Julien
Journal: Journal of Clinical Investigation (2019)

The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD.
Association of Fetal Growth With General and Specific Mental Health Conditions
Authors: Erik Pettersson, Henrik Larsson, Brian D’Onofrio, Catarina Almqvist, Paul Lichtenstein
Journal: JAMA Psychiatry (2019)

It is unclear if the associations between fetal growth and later mental health conditions remain after controlling for familial factors and psychiatric comorbidity.To examine the associations between fetal growth and general and specific mental health conditions, controlling for familial factors.This register-based study conducted in Sweden analyzed 546 894 pairs of full siblings born between January 1, 1973, and December 31, 1998. Sibling pairs were followed up through December 31, 2013. First, population-based and within-sibling pair associations (which controlled for time-invariant familial confounders) between fetal growth and the outcomes were estimated. Second, exploratory factor analysis was applied to the outcomes to derive 1 general factor and 4 specific and independent factors. Third, the general and specific factors were regressed on fetal growth. Statistical analysis was performed from March 27, 2017, to October 27, 2018.The outcomes were 11 psychiatric diagnoses (depression, anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, bipolar disorder, alcohol abuse, drug use, attention-deficit/hyperactivity disorder, autism, schizophrenia, and schizoaffective disorder) and court convictions of violent crimes. Birth weight (in kilograms) statistically adjusted for gestational age was the exposure.The mean (SD) age of the 1 093 788 participants was 27.2 (6.8) years (range, 15.1-40.9 years) and 51.5% were male. Nine outcomes were significantly associated with birth weight in the population at large: depression (odds ratio [OR], 0.96; 95% CI, 0.95-0.98), anxiety (OR, 0.94; 95% CI, 0.92-0.95), posttraumatic stress disorder (OR, 0.91; 95% CI, 0.89-0.93), bipolar disorder (OR, 0.94; 95% CI, 0.89-1.00), alcohol abuse (OR, 0.89; 95% CI, 0.87-0.91), drug use (OR, 0.83; 95% CI, 0.80-0.85), violent crimes (OR, 0.85; 95% CI, 0.83-0.86), attention-deficit/hyperactivity disorder (OR, 0.88; 95% CI, 0.86-0.90), and autism (OR, 0.95; 95% CI, 0.92-0.97). Only depression (OR, 0.95; 95% CI 0.92-0.98), obsessive-compulsive disorder (OR, 0.93; 95% CI, 0.87-0.99), attention-deficit/hyperactivity disorder (OR, 0.86; 95% CI, 0.82-0.89), and autism (OR, 0.72; 95% CI, 0.69-0.76) remained significantly associated within sibling pairs. An exploratory factor analysis indicated that 1 general and 4 specific factors (capturing anxiety, externalizing, neurodevelopmental, and psychotic conditions) fit the outcomes well. Across almost all sensitivity analyses, an increase in birth weight by 1 kg significantly reduced the general (β, -0.047; 95% CI, -0.071 to -0.023) and the specific neurodevelopmental factors (β, -0.159; 95% CI, -0.190 to -0.128) within sibling pairs.Controlling for familial confounders, reduced fetal growth was associated with a small but significant increase in the general factor of psychopathology and a moderate increase in a specific neurodevelopmental factor.