Medicine and Health Sciences Commons^™

Lxr/Cd38 Activation Drives Cholesterol-Induced Macrophage Senescence And Neurodegeneration Via Nad+ Depletion, Ryo Terao, Tae Jun Lee, Jason Colasanti, Charles W Pfeifer, Joseph B Lin, Andrea Santeford, Keitaro Hase, Shinobu Yamaguchi, Daniel Du, Brian S Sohn, Yo Sasaki, Mitsukuni Yoshida, Rajendra S Apte

2020-Current year OA Pubs

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD

Nivolumab Plus Brentuximab Vedotin For Relapsed/Refractory Peripheral T-Cell Lymphoma And Cutaneous T-Cell Lymphoma, Pier Luigi Zinzani, Neha Mehta-Shah, Et Al.

2020-Current year OA Pubs

No abstract provided.

Induced Cd8Α Identifies Human Nk Cells With Enhanced Proliferative Fitness And Modulates Nk Cell Activation, Celia C. Cubitt, Pamela Wong, Hannah K. Dorando, Jennifer A. Foltz, Jennifer Tran, Lynne Marsala, Nancy D. Marin, Mark Foster, Timothy Schappe, Hijab Fatima, Michelle Becker-Hapak, Alice Y. Zhou, Kimberly Hwang, Miriam T. Jacobs, David A. Russler-Germain, Emily M. Mace, Melissa M. Berrien-Elliott, Jacqueline E. Payton, Todd A. Fehniger

2020-Current year OA Pubs

The surface receptor CD8α is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8α expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8α may affect critical NK cell functions. Here, we discovered that CD8α- NK cells had improved control of leukemia in xenograft models compared with CD8α+ NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8α expression was induced on approximately 30% of previously CD8α- NK cells …

Retrospective Study On The Efficacy And Safety Of Dulaglutide In Patients With Diabetes And Moderate-Advanced Chronic Kidney Disease, Sriya Kosaraju, Rong M Zhang

2020-Current year OA Pubs

No abstract provided.

Intrapartum Exposure To Synthetic Oxytocin, Maternal Bmi, And Neurodevelopmental Outcomes In Children Within The Echo Consortium, Lisa Kurth, T Michael O'Shea, Irina Burd, Anne L Dunlop, Lisa Croen, Greta Wilkening, Ting-Ju Hsu, Stephan Ehrhardt, Arvind Palanisamy, Monica Mcgrath, Marie L Churchill, Daniel Weinberger, Marco Grados, Dana Dabelea

2020-Current year OA Pubs

BACKGROUND: Synthetic oxytocin (sOT) is frequently administered during parturition. Studies have raised concerns that fetal exposure to sOT may be associated with altered brain development and risk of neurodevelopmental disorders. In a large and diverse sample of children with data about intrapartum sOT exposure and subsequent diagnoses of two prevalent neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), we tested the following hypotheses: (1) Intrapartum sOT exposure is associated with increased odds of child ADHD or ASD; (2) associations differ across sex; (3) associations between intrapartum sOT exposure and ADHD or ASD are accentuated in …

Radiotherapy Plan Quality Assurance In Nrg Oncology Trials For Brain And Head/Neck Cancers: An Ai-Enhanced Knowledge-Based Approach, Du Wang, Jeff M Michalski, Jiayi Huang, Et Al.

2020-Current year OA Pubs

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on …

Effect Of Genomic And Cellular Environments On Gene Expression Noise, Clarice K Y Hong, Avinash Ramu, Siqi Zhao, Barak A Cohen

2020-Current year OA Pubs

BACKGROUND: Individual cells from isogenic populations often display large cell-to-cell differences in gene expression. This "noise" in expression derives from several sources, including the genomic and cellular environment in which a gene resides. Large-scale maps of genomic environments have revealed the effects of epigenetic modifications and transcription factor occupancy on mean expression levels, but leveraging such maps to explain expression noise will require new methods to assay how expression noise changes at locations across the genome.

RESULTS: To address this gap, we present Single-cell Analysis of Reporter Gene Expression Noise and Transcriptome (SARGENT), a method that simultaneously measures the noisiness …

Biobank-Wide Association Scan Identifies Risk Factors For Late-Onset Alzheimer's Disease And Endophenotypes, Donghui Yan, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits …

Health Equity Engineering: Optimizing Hope For A New Generation Of Healthcare, Felicity T Enders, Joyce E Balls-Berry, Et Al.

2020-Current year OA Pubs

Medical researchers are increasingly prioritizing the inclusion of underserved communities in clinical studies. However, mere inclusion is not enough. People from underserved communities frequently experience chronic stress that may lead to accelerated biological aging and early morbidity and mortality. It is our hope and intent that the medical community come together to engineer improved health outcomes for vulnerable populations. Here, we introduce Health Equity Engineering (HEE), a comprehensive scientific framework to guide research on the development of tools to identify individuals at risk of poor health outcomes due to chronic stress, the integration of these tools within existing healthcare system …

Accessibility, Relevance, And Impact Of A Symptom Monitoring Tool For Home Hospice Care: Theory Elaboration And Qualitative Assessment, Karla T Washington, Debra Parker Oliver, Allison K Donehower, Patrick White, Jacquelyn J Benson, Patrick G Lyons, George Demiris

2020-Current year OA Pubs

BACKGROUND: Early users found Engagement and Visualization to Improve Symptoms in Oncology Care (ENVISION), a web-based application designed to improve home management of hospice patients' symptoms and support patients' and family caregivers' well-being, to be generally useful and easy to use. However, they also raised concerns about potential challenges users with limited technological proficiency might experience.

OBJECTIVE: We sought to concurrently accomplish two interrelated study aims: (1) to develop a conceptual framework of digital inclusivity for health information systems and (2) to apply the framework in evaluating the digital inclusivity of the ENVISION application.

METHODS: We engaged ENVISION users (N=34) …

Solutes Unmask Differences In Clustering Versus Phase Separation Of Fet Proteins, Mrityunjoy Kar, Laura T Vogel, Gaurav Chauhan, Suren Felekyan, Hannes Ausserwöger, Timothy J Welsh, Furqan Dar, Anjana R Kamath, Tuomas P J Knowles, Anthony A Hyman, Claus A M Seidel, Rohit V Pappu

2020-Current year OA Pubs

Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions of percolation are evident through the viscoelasticity of condensates and through the formation of heterogeneous distributions of nano- and mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that clusters formed in sub-saturated solutions of FET (FUS-EWSR1-TAF15) proteins are affected differently by glutamate versus chloride. These differences on the nanoscale, gleaned using a suite of methods deployed across a wide range of protein concentrations, are prevalent and can be unmasked even though the driving forces for phase separation remain unchanged in glutamate versus chloride. Strikingly, differences in anion-mediated …

Quantification Of Visceral Fat At The L5 Vertebral Body Level In Patients With Crohn's Disease Using T2-Weighted Mri, Favour Garuba, Aravinda Ganapathy, Spencer Mckinley, Karan H Jani, Adriene Lovato, Satish E Viswanath, Scott Mchenry, Parakkal Deepak, David H Ballard

2020-Current year OA Pubs

The umbilical or L3 vertebral body level is often used for body fat quantification using computed tomography. To explore the feasibility of using clinically acquired pelvic magnetic resonance imaging (MRI) for visceral fat measurement, we examined the correlation of visceral fat parameters at the umbilical and L5 vertebral body levels. We retrospectively analyzed T2-weighted half-Fourier acquisition single-shot turbo spin echo (HASTE) MR axial images from Crohn's disease patients who underwent MRI enterography of the abdomen and pelvis over a three-year period. We determined the area/volume of subcutaneous and visceral fat from the umbilical and L5 levels and calculated the visceral …

A Fungal Protein Organizes Both Glycogen And Cell Wall Glucans, Liza Loza, Tamara L Doering

2020-Current year OA Pubs

Glycogen is a glucose storage molecule composed of branched α-1,4-glucan chains, best known as an energy reserve that can be broken down to fuel central metabolism. Because fungal cells have a specialized need for glucose in building cell wall glucans, we investigated whether glycogen is used for this process. For these studies, we focused on the pathogenic yeast

Comprehensive Proteogenomic Characterization Of Rare Kidney Tumors, Ginny Xiaohe Li, Yize Li, Nataly Naser Al Deen, Feng Chen, Wagma Caravan, Andrew Houston, Siqi Chen, Li Ding, Et Al.

2020-Current year OA Pubs

Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC …

Feasibility, Acceptability And Preliminary Effect Of A Community-Led Hiv Self-Testing Model Among Adolescent Girls And Young Women In Rural Northern Uganda: A Quasi-Experimental Study Protocol, Ronald Olum, Elvin H Geng, Freddy E Kitutu, Philippa M Musoke

2020-Current year OA Pubs

BACKGROUND: Adolescent girls and young women (AGYW) in sub-Saharan Africa face a disproportionately higher HIV/AIDS burden despite the global decline in incidence. Existing interventions often fail to adequately address their unique social, economic, and cultural challenges, limiting access to essential HIV/AIDS services, including HIV testing. Emerging evidence indicates that HIV self-testing, a user-friendly and confidential method, enhances HIV diagnosis and linkage to care by targeting these barriers. This study aims to assess the feasibility, acceptability, and preliminary impact of a peer-delivered, community-health worker (CHW)-facilitated HIV self-testing intervention for AGYW in Northern Uganda.

METHODS: This mixed-methods quasi-experimental implementation science study will …

Molecular Insights Into The Prototypical Single-Stranded Dna-Binding Protein From E. Coli, Nina J Bonde, Alexander G Kozlov, Michael M Cox, Timothy M Lohman, James L Keck

2020-Current year OA Pubs

The SSB protein of

Graded Decisions In The Human Brain, Tao Xie, Markus Adamek, Hohyun Cho, Matthew A Adamo, Anthony L Ritaccio, Jon T Willie, Peter Brunner, Jan Kubanek

2020-Current year OA Pubs

Decision-makers objectively commit to a definitive choice, yet at the subjective level, human decisions appear to be associated with a degree of uncertainty. Whether decisions are definitive (i.e., concluding in all-or-none choices), or whether the underlying representations are graded, remains unclear. To answer this question, we recorded intracranial neural signals directly from the brain while human subjects made perceptual decisions. The recordings revealed that broadband gamma activity reflecting each individual's decision-making process, ramped up gradually while being graded by the accumulated decision evidence. Crucially, this grading effect persisted throughout the decision process without ever reaching a definite bound at the …

Gilteritinib As Post-Transplant Maintenance For Aml With Internal Tandem Duplication Mutation Of Flt3, Mark J Levis, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of

METHODS: Adults with

RESULTS: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided

CONCLUSION: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable

Common Single-Base Insertions In The Vntr Of The Carboxyl Ester Lipase (Cel) Gene Are Benign And Also Likely To Arise Somatically In The Exocrine Pancreas, Ranveig S Brekke, Anny Gravdal, Khadija El Jellas, Grace E Curry, Jianguo Lin, Steven J Wilhelm, Solrun J Steine, Eric Mas, Stefan Johansson, Mark E Lowe, Bente B Johansson, Xunjun Xiao, Karianne Fjeld, Anders Molven

2020-Current year OA Pubs

The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in …

Liver Acox1 Regulates Levels Of Circulating Lipids That Promote Metabolic Health Through Adipose Remodeling, Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F. Semenkovich, Irfan J. Lodhi

2020-Current year OA Pubs

No abstract provided.

The Impact Of Behavior Change Counseling Delivered Via A Digital Health Tool Versus Routine Care Among Adolescents With Obesity: Pilot Randomized Feasibility Study, Maura Kepper, Callie Walsh-Bailey, Zoe M Miller, Min Zhao, Kianna Zucker, Angeline Gacad, Cynthia Herrick, Neil H White, Ross C Brownson, Randi E Foraker

2020-Current year OA Pubs

BACKGROUND: Youth overweight and obesity is a public health crisis and increases the risk of poor cardiovascular health (CVH) and chronic disease. Health care providers play a key role in weight management, yet few tools exist to support providers in delivering tailored evidence-based behavior change interventions to patients.

OBJECTIVE: The goal of this pilot randomized feasibility study was to determine the feasibility of implementing the Patient-Centered Real-Time Intervention (PREVENT) tool in clinical settings, generate implementation data to inform scale-up, and gather preliminary effectiveness data.

METHODS: A pilot randomized clinical trial was conducted to examine the feasibility, implementation, and preliminary impact …

Unintentionally Intentional: Unintended Effects Of Spinal Stimulation As A Platform For Multi-Modal Neurorehabilitation After Spinal Cord Injury, Gerson N Moreno Romero, Avery R Twyman, Maria F Bandres, Jacob Graves Mcpherson

2020-Current year OA Pubs

Electrical stimulation of spinal neurons has emerged as a valuable tool to enhance rehabilitation after spinal cord injury. In separate parameterizations, it has shown promise for improving voluntary movement, reducing symptoms of autonomic dysreflexia, improving functions mediated by muscles of the pelvic floor (e.g., bowel, bladder, and sexual function), reducing spasms and spasticity, and decreasing neuropathic pain, among others. This diverse set of actions is related both to the density of sensorimotor neural networks in the spinal cord and to the intrinsic ability of electrical stimulation to modulate neural transmission in multiple spinal networks simultaneously. It also suggests that certain …

Benefits And Advances Of Cone Beam Ct Use In Prostatic Artery Embolization: Review Of The Literature And Pictorial Essay, Nassir Rostambeigi, Daniel Crawford, Jafar Golzarian

2020-Current year OA Pubs

Prostatic artery embolization (PAE) has proven to be an efficacious treatment for urinary symptoms of benign prostatic hyperplasia. PAE is performed in a complex and challenging anatomical field which may pose difficulties from procedural standpoint. Cone beam computed tomography (CBCT) has been proposed as an invaluable tool during the PAE procedure. A review of different techniques and advancements, as well as demonstration of CBCT benefits via a pictorial overview of the salient examples is lacking. The techniques of CBCT are discussed herein and the virtual injection technology as an advancement in CBCT is discussed. To show the merits of CBCT …

Quantitative T2 Mapping-Based Longitudinal Assessment Of Brain Injury And Therapeutic Rescue In The Rat Following Acute Organophosphate Intoxication, Alita Jesal D Almeida, Brad A Hobson, Naomi Saito, Donald A Bruun, Valerie A Porter, Danielle J Harvey, Joel R Garbow, Abhijit J Chaudhari, Pamela J Lein

2020-Current year OA Pubs

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T

Mv140 Mucosal Vaccine Induces Targeted Immune Response For Enhanced Clearance Of Uropathogenic E. Coli In Experimental Urinary Tract Infection, Paula Saz-Leal, Marianne Morris Ligon, Carmen María Diez-Rivero, Diego García-Ayuso, Soumitra Mohanty, Marcos Viñuela, Irene Real-Arévalo, Laura Conejero, Annelie Brauner, José Luis Subiza, Indira Uppugunduri Mysorekar

2020-Current year OA Pubs

MV140 is an inactivated whole-cell bacterial mucosal vaccine with proven clinical efficacy against recurrent urinary tract infections (UTIs). These infections are primarily caused by uropathogenic

Causes And Attributable Fraction Of Death From Ards In Inflammatory Phenotypes Of Sepsis, Bruno Evrard, Pratik Sinha, Et Al.

2020-Current year OA Pubs

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAF

METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAF

RESULTS: The PAF

CONCLUSIONS: The PAF

Acute Pulmonary Injury In Hematology Patients Supported With Pathogen-Reduced And Conventional Platelet Components, Allison P Wheeler, Ronald Jackups, Et Al.

2020-Current year OA Pubs

Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded …

Radiological And Pulmonary Results Of Surgical Treatment Of Severe Idiopathic Scoliosis Using Preoperative Halo Gravity Traction Compared With Less Invasive Temporary Internal Distraction In Staged Surgery In Adolescents, Pawel Grabala, Michael A Galgano, Michal Grabala, Jacob M Buchowski

2020-Current year OA Pubs

No abstract provided.

Targeting Cathepsin C Ameliorates Murine Acetaminophen-Induced Liver Injury, Jessica Raith, Malte Bachmann, Sina Gonther, Hendrik Stülb, Ali A Aghdassi, Christine T N Pham, Heiko Mühl

2020-Current year OA Pubs

Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene expression during murine APAP-induced ALI by 3'mRNA sequencing (massive analysis of cDNA ends, MACE), we observed splenic mRNA accumulation encoding for the neutrophil serine proteases cathepsin G, neutrophil elastase, and proteinase-3 - all are hierarchically activated by cathepsin C (CtsC). This, along with increased serum levels of these proteases in diseased mice, concurs with the established phenomenon of myeloid cell mobilization during APAP intoxication.

Reverse Genetics Of Murine Rotavirus: A Comparative Analysis Of The Wild-Type And Cell-Culture-Adapted Murine Rotavirus Vp4 In Replication And Virulence In Neonatal Mice, Takahiro Kawagishi, Liliana Sánchez-Tacuba, Ningguo Feng, Harry B Greenberg, Siyuan Ding

2020-Current year OA Pubs

Small-animal models and reverse genetics systems are powerful tools for investigating the molecular mechanisms underlying viral replication, virulence, and interaction with the host immune response in vivo. Rotavirus (RV) causes acute gastroenteritis in many young animals and infants worldwide. Murine RV replicates efficiently in the intestines of inoculated suckling pups, causing diarrhea, and spreads efficiently to uninoculated littermates. Because RVs derived from human and other non-mouse animal species do not replicate efficiently in mice, murine RVs are uniquely useful in probing the viral and host determinants of efficient replication and pathogenesis in a species-matched mouse model. Previously, we established an …