Medicine and Health Sciences Commons^™

Momentum: Momelotinib Vs Danazol In Patients With Myelofibrosis Previously Treated With Jaki Who Are Symptomatic And Anemic, Srdan Verstovsek, Stephen T Oh, Et Al

2020-Current year OA Pubs

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is …

Reduction In Unplanned Hospitalizations Associated With A Physician Focused Intervention To Reduce Potentially Inappropriate Medication Use Among Older Adults: A Population-Based Cohort Study., M Alcusky, R B Thomas, N Jafari, Scott W Keith, A Kee, S Del Canale, M Lombardi, Vittorio Maio

College of Population Health Faculty Papers

BACKGROUND: A multimodal general practitioner-focused intervention in the Local Health Authority (LHA) of Parma, Italy, substantially reduced the prevalence of potentially inappropriate medication (PIM) use among older adults. Our objective was to estimate changes in hospitalization rates associated with the Parma LHA quality improvement initiative that reduced PIM use.

METHODS: This population-based longitudinal cohort study was conducted among older residents (> 65 years) using the Parma LHA administrative healthcare database. Crude and adjusted unplanned hospitalization rates were estimated in 3 periods (pre-intervention: 2005-2008, intervention: 2009-2010, post-intervention: 2011-2014). Multivariable negative binomial models estimated trends in quarterly hospitalization rates among individuals at …

Myocardial T1 And T2 Mapping By Magnetic Resonance In Patients With Immune Checkpoint Inhibitor-Associated Myocarditis., Paaladinesh Thavendiranathan, Lili Zhang, Amna Zafar, Zsofia D Drobni, Syed S Mahmood, Marcella Cabral, Magid Awadalla, Anju Nohria, Daniel A Zlotoff, Franck Thuny, Lucie M Heinzerling, Ana Barac, Ryan J Sullivan, Carol L Chen, Dipti Gupta, Michael C Kirchberger, Sarah E Hartmann, Jonathan W Weinsaft, Hannah K Gilman, Muhammad A. Rizvi Md, Bojan Kovacina, Caroline Michel, Gagan Sahni, Ana González-Mansilla, Antonio Calles, Francisco Fernández-Avilés, Michael Mahmoudi, Kerry L Reynolds, Sarju Ganatra, Juan José Gavira, Nahikari Salterain González, Manuel García De Yébenes Castro, Raymond Y Kwong, Michael Jerosch-Herold, Otavio R Coelho-Filho, Jonathan Afilalo, Eduardo Zataraín-Nicolás, A John Baksi, Bernd J Wintersperger, Oscar Calvillo-Arguelles, Stephane Ederhy, Eric H Yang, Alexander R Lyon, Michael G Fradley, Tomas G Neilan

Hematology-Medical Oncology Division

BACKGROUND: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.

OBJECTIVES: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.

METHODS: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major …

Opioids Are Not A Major Cause Of Death Of Patients With Sickle Cell Disease., Samir K. Ballas

Cardeza Foundation for Hematologic Research

According to the Center of Disease Control and Prevention (CDC) database, the total number of deaths due to opioid overdose from 1999 through 2018 was 840,629. Given the alarming nature of these statistics, patients who requested prescription for opioids became targets of suspicion and possible accusation of maladaptive behavior. Patients with sickle cell disease (SCD) were often not exempt from such accusations and became guilty by association. In order to clarify the effect of opioids on the mortality of patients with SCD, the mortality rates for children and adults with SCD were investigated using the CDC Wide-ranging Online Data for …

Longitudinal Accumulation Of Cerebral Microhemorrhages In Dominantly Inherited Alzheimer Disease, Nelly Joseph-Mathurin, Guoqiao Wang, Eric Mcdade, Jason Hassenstab, Tyler M Blazey, Brian A Gordon, Gengsheng Chen, Parinaz Massoumzadeh, Russ C Hornbeck, Beau M Ances, Carlos Cruchaga, Celeste M Karch, Richard J Perrin, Chengjie Xiong, John C Morris, Randall J Bateman, Tammie L S Benzinger, Et Al

2020-Current year OA Pubs

OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with …

Intradural Extramedullary Capillary Hemangioma Of The Cauda Equina: Case Report Of A Rare Spinal Tumor., Liam P Hughes, Garrett Largoza, Thiago S Montenegro, Caio M Matias, Anthony Stefanelli, Mark T Curtis, James S Harrop

Department of Neurosurgery Faculty Papers

INTRODUCTION: Intradural extramedullary capillary hemangiomas of the cauda equina are exceedingly rare, with only 20 previous cases reported. In the adult population, these tumors are rare and can arise in the central and peripheral nervous systems from the dura or spinal nerve roots. Intradural capillary hemangiomas of the cauda equina can yield symptoms such as lower extremity weakness, pain, and bladder and bowel dysfunction. The clinical symptomology and surgical management of this rare spinal lesion are reviewed in this case report.

CASE PRESENTATION: A 50-year-old male presented with progressive bilateral lower extremity weakness for 2 years, with recent bladder and …

Affective Temperaments, Panic Disorder And Their Bipolar Connections, Zsuzsanna Belteczki, Zoltan Rihmer, Sandor Rozsa, Julia Ujvari, Maurizio Pompili, Xenia Gonda, Péter Dome

2020-Current year OA Pubs

No abstract provided.

Clustering Of Patients With Overactive Bladder Syndrome, James Gross, Joel M Vetter, H Henry Lai

2020-Current year OA Pubs

BACKGROUND: Overactive bladder is a heterogenous condition with poorly characterized clinical phenotypes. To discover potential patient subtypes in patients with overactive bladder (OAB), we used consensus clustering of their urinary symptoms and other non-urologic factors.

METHODS: Clinical variables included in the k-means consensus clustering included OAB symptoms, urinary incontinence, anxiety, depression, psychological stress, somatic symptom burden, reported childhood traumatic exposure, and bladder pain.

RESULTS: 48 OAB patients seeking care of their symptoms were included. k-means consensus clustering identified two clusters of OAB patients: a urinary cluster and a systemic cluster. The systemic cluster, which consisted of about half of the …

Neurological Manifestations As The Predictors Of Severity And Mortality In Hospitalized Individuals With Covid-19: A Multicenter Prospective Clinical Study, Man Amanat, Nima Rezaei, Mehrdad Roozbeh, Maziar Shojaei, Abbas Tafakhori, Anahita Zoghi, Ilad Alavi Darazam, Mona Salehi, Ehsan Karimialavijeh, Behnam Safarpour Lima, Amir Garakani, Alex R. Vaccaro, Mahtab Ramezani

Department of Orthopaedic Surgery Faculty Papers

BACKGROUNDS: The reports of neurological symptoms are increasing in cases with coronavirus disease 2019 (COVID-19). This multi-center prospective study was conducted to determine the incidence of neurological manifestations in hospitalized cases with COVID-19 and assess these symptoms as the predictors of severity and death.

METHODS: Hospitalized males and females with COVID-19 who aged over 18 years were included in the study. They were examined by two neurologists at the time of admission. All survived cases were followed for 8 weeks after discharge and 16 weeks if their symptoms had no improvements.

RESULTS: We included 873 participants. Of eligible cases, 122 …

The Predictive Value Of Absolute Lymphocyte Counts On Tumor Progression And Pseudoprogression In Patients With Glioblastoma, Jing Xi, Bilal Hassan, Ruth G N Katumba, Karam Khaddour, Akshay Govindan, Jingqin Luo, Jiayi Huang, Jian L Campian

2020-Current year OA Pubs

BACKGROUND: Differentiating true glioblastoma multiforme (GBM) from pseudoprogression (PsP) remains a challenge with current standard magnetic resonance imaging (MRI). The objective of this study was to explore whether patients' absolute lymphocyte count (ALC) levels can be utilized to predict true tumor progression and PsP.

METHODS: Patients were considered eligible for the study if they had 1) GBM diagnosis, 2) a series of blood cell counts and clinical follow-ups, and 3) tumor progression documented by both MRI and pathology. Data analysis results include descriptive statistics, median (IQR) for continuous variables and count (%) for categorical variables, p values from Wilcoxon rank …

Severity Of Parkinsonism Associated With Environmental Manganese Exposure, Brad A Racette, Gill Nelson, Wendy W Dlamini, Pradeep Prathibha, Jay R Turner, Mwiza Ushe, Harvey Checkoway, Lianne Sheppard, Susan Searles Nielsen

2020-Current year OA Pubs

BACKGROUND: Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016-2020.

METHODS: A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an …

Generation Of A Biobank From Two Adult Thoroughbred Stallions For The Functional Annotation Of Animal Genomes Initiative, Callum G. Donnelly, Rebecca R. Bellone, Erin N. Hales, Annee Nguyen, Scott A. Katzman, Ghislaine A. Dujovne, Kelly E. Knickelbein, Felipe Avila, Theodore S. Kalbfleisch, Elena Giulotto, Nicole B. Kingsley, Jocelyn Tanaka, Elizabeth Esdaile, Sichong Peng, Anna Dahlgren, Anna Fuller, Michael J. Mienaltowski, Terje Raudsepp, Verena K. Affolter, Jessica L. Petersen, Carrie J. Finno

Maxwell H. Gluck Equine Research Center Faculty Publications

Following the successful creation of a biobank from two adult Thoroughbred mares, this study aimed to recapitulate sample collection in two adult Thoroughbred stallions as part of the Functional Annotation of the Animal Genome (FAANG) initiative. Both stallions underwent thorough physical, lameness, neurologic, and ophthalmic (including electroretinography) examinations prior to humane euthanasia. Epididymal sperm was recovered from both stallions immediately postmortem and cryopreserved. Aseptically collected full thickness skin biopsies were used to isolate, culture and cryopreserve dermal fibroblasts. Serum, plasma, cerebrospinal fluid, urine, and gastrointestinal content from various locations were collected and cryopreserved. Under guidance of a board-certified veterinary anatomic …

Whole-Genome Sequencing Of African Americans Implicates Differential Genetic Architecture In Inflammatory Bowel Disease, Hari K Somineni, Rodney D Newberry, Et Al.

2020-Current year OA Pubs

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 …

Association Of Blood Pressure Variability And Diuretics With Cardiovascular Events In Patients With Chronic Kidney Disease Stages 1-5, L Parker Gregg, S Susan Hedayati, Hui Yang, Peter N Van Buren, Subhash Banerjee, Sankar D Navaneethan, Salim S Virani, Wolfgang C Winkelmayer, Carlos A Alvarez

Faculty, Staff and Students Publications

Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events in the general population. Data are scarce in chronic kidney disease (CKD). We hypothesized that BPV would be associated with cardiovascular outcomes, death, and end-stage kidney disease (ESKD) and that diuretics would modify these associations in patients with CKD.

We studied U.S. Veterans with non-dialysis CKD stages 1-5 and hypertension on non-diuretic antihypertensive monotherapy. At the time of second antihypertensive agent prescription, we propensity-matched for exposure to a loop or thiazide diuretic vs. any other antihypertensive. BPV was defined as the coefficient of variation of systolic blood pressure over …

Severe Acute Respiratory Syndrome Coronavirus 2-Induced Acute Aortic Occlusion: A Case Report, Artem Minalyan, Franklin L. Thelmo, Vincent Chan, Stephanie Tzarnas, Faizan Ahmed

Department of Medicine Faculty Papers

Background: Severe acute respiratory syndrome coronavirus 2 infection can lead to a constellation of viral and immune symptoms called coronavirus disease 2019. Emerging literature increasingly supports the premise that severe acute respiratory syndrome coronavirus 2 promotes a prothrombotic milieu. However, to date there have been no reports of acute aortic occlusion, itself a rare phenomenon. We report a case of fatal acute aortic occlusion in a patient with coronavirus disease 2019.

Case report: A 59-year-old Caucasian male with past medical history of peripheral vascular disease presented to the emergency department for evaluation of shortness of breath, fevers, and dry cough. …

Discovery And Characterization Of Bromodomain 2-Specific Inhibitors Of Brdt, Zhifeng Yu, Angela F Ku, Justin L Anglin, Rajesh Sharma, Melek Nihan Ucisik, John C Faver, Feng Li, Pranavanand Nyshadham, Nicholas Simmons, Kiran L Sharma, Sureshbabu Nagarajan, Kevin Riehle, Gundeep Kaur, Banumathi Sankaran, Marta Storl-Desmond, Stephen S Palmer, Damian W Young, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined …

Corneal Nonmyelinating Schwann Cells Illuminated By Single-Cell Transcriptomics And Visualized By Protein Biomarkers., Paola Bargagna-Mohan, Gwendolyn Schultz, Bruce Rheaume, Ephraim F Trakhtenberg, Paul Robson, Sonali Pal-Ghosh, Mary Ann Stepp, Katherine S Given, Wendy B Macklin, Royce Mohan

Anatomy and Regenerative Biology Faculty Publications

No abstract provided.

Point-Of-Care Lung Ultrasound For Covid-19: Findings And Prognostic Implications From 105 Consecutive Patients, Kosuke Yasukawa, Taro Minami, David R Boulware, Ayako Shimada, Ernest A Fischer

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: The prognostic value of point-of-care lung ultrasound has not been evaluated in a large cohort of patients with COVID-19 admitted to general medicine ward in the United States. The aim of this study was to describe lung ultrasound findings and their prognostic value in patients with COVID-19 admitted to internal medicine ward.

Method: This prospective observational study consecutively enrolled 105 hospitalized participants with COVID-19 at 2 tertiary care centers. Ultrasound was performed in 12 lung zones within 24 hours of admission. Findings were assessed relative to 4 outcomes: intensive care unit (ICU) need, need for intensive respiratory support, length …

A Brazilian National Preparedness Survey Of Anesthesiologists During The Coronavirus Pandemic, Vinícius Caldeira Quintão, Claudia Marquez Simões, Gibran Elias Harcha Munoz, Paul Barach, Maria José Carvalho Carmona, Brazilian Network For Research On Complications In Anesthesia Branca

College of Population Health Faculty Papers

No abstract provided.

Perfluorooctanoic Acid (Pfoa) Or Perfluorooctane Sulfonate (Pfos) And Dna Methylation In Newborn Dried Blood Spots In The Upstate Kids Cohort, Sonia L Robinson, Xuehuo Zeng, Weihua Guan, Rajeshwari Sundaram, Pauline Mendola, Diane L Putnick, Robert A Waterland, Chathura J Gunasekara, Kurunthachalam Kannan, Chongjing Gao, Erin M Bell, Edwina H Yeung

Children’s Nutrition Research Center Staff Publications

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants which may alter prenatal development, potentially through epigenetic modifications. Prior studies examining PFOS/PFOA and DNA methylation have relatively few subjects (n < 200) and inconsistent results. We examined relations of PFOA/PFOS with DNA methylation among 597 neonates in the Upstate KIDS cohort study. PFOA/PFOS were quantified in newborn dried blood spots (DBS) using high-performance liquid chromatography/tandem mass spectrometry. DNA methylation was measured using the Infinium MethylationEPIC BeadChip with DNA extracted from DBS. Robust linear regression was used to examine the associations of PFOA/PFOS with DNA methylation at individual CpG sites. Covariates included sample plate, estimated cell type, epigenetically derived ancestry, infant sex and plurality, indicators of maternal socioeconomic status, and prior pregnancy loss. In supplemental analysis, we restricted the analysis to 2242 CpG sites previously identified as Correlated Regions of Systemic Interindividual Variation (CoRSIVs) which include metastable epialleles. At FDR90th percentile was related to DNA methylation at cg15557840, near SCRT2, SRXN1; PFOS>90th percentile was related to 2 CpG sites in a sex-specific manner (cg19039925 in GVIN1 in boys and cg05754408 in ZNF26 in girls). When analysis was restricted to CoRSIVs, log-scaled, continuous PFOS concentration was related to DNA methylation at cg03278866 within PTBP1. In conclusion, there was limited evidence of an association between high concentrations of PFOA/PFOS and DNA methylation in newborn DBS in the Upstate KIDS cohort. These …

The Association Between Overnight Fasting And Body Mass Index In Older Adults: The Interaction Between Duration And Timing, Qian Xiao, Cici Bauer, Tracy Layne, Mary Playdon

Faculty, Staff and Student Publications

BACKGROUND: Circadian rhythms play an important role in the regulation of eating and fasting, and mistimed dietary intakes may be detrimental to metabolic health. Extended overnight fasting has been proposed as a strategy to better align the eating-fasting cycle with the internal circadian clock, and both observational and experimental studies have linked longer overnight fasting with lower body weight. However, it remains unclear if the timing of overnight fasting modifies the relationship between fasting duration and weight outcomes.

METHODS: The current study included 495 men and 499 women age 50-74 years. Dietary intake over 12 months was assessed by 24-h …

In Vivo Transplantation Of Human Intestinal Organoids Enhances Select Tight Junction Gene Expression, Mariaelena A Boyle, David J Sequeira, Eoin P Mcneill, Zachary K Criss, Noah F Shroyer, Allison L Speer

Faculty, Staff and Student Publications

BACKGROUND: Short bowel syndrome is a potentially fatal condition with inadequate management options. Tissue-engineered small intestine (TESI) is a promising solution, but confirmation of TESI function will be crucial before human application. We sought to define intestinal epithelial barrier function in human intestinal organoid (HIO)-derived TESI.

MATERIALS AND METHODS: HIOs were generated in vitro from human embryonic stem cells. After 1 mo, HIOs were collected for analysis or transplanted into the kidney capsule of immunocompromised mice. Transplanted HIOs (tHIOs) were harvested for analysis at 4 or 8 wk. Reverse transcription quantitative polymerase chain reaction and immunofluorescent staining were performed for …

A Biallelic Pathogenic Variant In The Ogdh Gene Results In A Neurological Disorder With Features Of A Mitochondrial Disease, Zheng Yie Yap, Klaudia Strucinska, Satoshi Matsuzaki, Sukyeong Lee, Yue Si, Kenneth Humphries, Mark A Tarnopolsky, Wan Hee Yoon

Faculty, Staff and Students Publications

2-Oxoglutarate dehydrogenase (OGDH) is a rate-limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in …

Deficiency Of Stat1 In Cd11c+ Cells Alters Adipose Tissue Inflammation And Improves Metabolic Dysfunctions In Mice Fed A High-Fat Diet, Antu Antony, Zeqin Lian, Xiaoyuan Dai Perrard, Jerry Perrard, Hua Liu, Aaron R Cox, Pradip Saha, Lothar Hennighausen, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 …

Pegylated Arginine Deiminase Depletes Plasma Arginine But Maintains Tissue Arginine Availability In Young Pigs, Mahmoud A Mohammad, Inka C Didelija, Barbara Stoll, Trung C Nguyen, Juan C Marini

Faculty, Staff and Students Publications

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (

Tbx5-Encoded T-Box Transcription Factor 5 Variant T223m Is Associated With Long Qt Syndrome And Pediatric Sudden Cardiac Death, Alexandra M Markunas, Perathu K R Manivannan, Jordan E Ezekian, Agnim Agarwal, William Eisner, Katherina Alsina, Hugh D Allen, Gregory A Wray, Jeffrey J Kim, Xander H T Wehrens, Andrew P Landstrom

Faculty, Staff and Students Publications

Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype-negative. Whole-exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype-negative LQTS and sudden death. The TBX5-T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen-2, Provean, …

Inhibition Of Camkk2 Impairs Autophagy And Castration-Resistant Prostate Cancer Via Suppression Of Ampk-Ulk1 Signaling, Chenchu Lin, Alicia M Blessing, Thomas L Pulliam, Yan Shi, Sandi R Wilkenfeld, Jenny J Han, Mollianne M Murray, Alexander H Pham, Kevin Duong, Sonja N Brun, Reuben J Shaw, Michael M Ittmann, Daniel E Frigo

Faculty, Staff and Students Publications

Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; …

Effect Of Aspirin On Cancer Incidence And Mortality In Older Adults, John J Mcneil, Yin Cao, Et Al.

2020-Current year OA Pubs

BACKGROUND: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.

METHODS: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal …

Impact Of Obesity On Day-Night Differences In Cardiac Metabolism, Sobuj Mia, Ravi Sonkar, Lamario Williams, Mary N Latimer, Isabelle Frayne Robillard, Abhinav Diwan, Stuart J Frank, Christine Des Rosiers, Martin E Young

2020-Current year OA Pubs

An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac metabolism also fluctuates across the 24-hours day, in association with diurnal sleep-wake and fasting-feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day-night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet-induced obesity disrupts cardiac "diurnal metabolic flexibility", which is normalized by time-of-day-restricted feeding. Chronic high fat feeding (20-wk)-induced …

Hepatotoxicity Following Administration Of Onasemnogene Abeparvovec (Avxs-101) For The Treatment Of Spinal Muscular Atrophy, Deepa Chand, Franziska Mohr, Hugh Mcmillan, Francis Fonyuy Tukov, Kyle Montgomery, Aaron Kleyn, Rui Sun, Sitra Tauscher-Wisniewski, Petra Kaufmann, Gerd Kullak-Ublick

2020-Current year OA Pubs

BACKGROUND & AIMS: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury.

METHODS: Data from 325 patients with SMA who had received OA through 31 December 2019, in …