Digital Commons Network^™

Chromatin Environment And Cellular Context Specify Compensatory Activity Of Paralogous Mef2 Transcription Factors, Shahriyar P Majidi, Naveen C Reddy, Michael J Moore, Hao Chen, Tomoko Yamada, Milena M Andzelm, Timothy J Cherry, Linda S Hu, Michael E Greenberg, Azad Bonni

Open Access Publications

Compensation among paralogous transcription factors (TFs) confers genetic robustness of cellular processes, but how TFs dynamically respond to paralog depletion on a genome-wide scale in vivo remains incompletely understood. Using single and double conditional knockout of myocyte enhancer factor 2 (MEF2) family TFs in granule neurons of the mouse cerebellum, we find that MEF2A and MEF2D play functionally redundant roles in cerebellar-dependent motor learning. Although both TFs are highly expressed in granule neurons, transcriptomic analyses show MEF2D is the predominant genomic regulator of gene expression in vivo. Strikingly, genome-wide occupancy analyses reveal upon depletion of MEF2D, MEF2A occupancy robustly increases …

A Comprehensive Resource For Induced Pluripotent Stem Cells From Patients With Primary Tauopathies, Celeste M Karch, Rita Martinez, Jacob A Marsh, Simon Hsu, Nupur Ghoshal, Joanne Norton, Nigel J Cairns, Et Al

Open Access Publications

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP …

Validation Of A 5-Item Tool To Measure Patient Assessment Of Clinician Compassion In The Emergency Department, Praveen Sabapathi, Michael B Roberts, Brian M Fuller, Michael A Puskarich, Christopher W Jones, J Hope Kilgannon, Valerie Braz, Christina Creel-Bulos, Nathaniel Scott, Kristina L Tester, Anthony Mazzarelli, Stephen Trzeciak, Brian W Roberts

Open Access Publications

BACKGROUND: To test if the 5-item compassion measure (a tool previously validated in the outpatient setting to measure patient assessment of clinician compassion) is a valid and reliable tool to quantify a distinct construct (i.e. clinical compassion) among patients evaluated in the emergency department (ED).

METHODS: Cross-sectional study conducted in three academic emergency departments in the U.S. between November 2018 and April 2019. We enrolled adult patients who were evaluated in the EDs of the participating institutions and administered the 5-item compassion measure after completion of care in the ED. Validity testing was performed using confirmatory factor analysis. Cronbach's alpha …

Human Monoclonal Antibodies Against Chikungunya Virus Target Multiple Distinct Epitopes In The E1 And E2 Glycoproteins, Jose A. Quiroz, Ryan J. Malonis, Larissa B. Thackray, Courtney A. Cohen, Jesper Pallesen, Rohit K. Jangra, Rebecca S. Brown, Daniel Hofmann, Frederick W. Holtsberg, Sergey Shulenin, Elisabeth K. Nyakatura, Lorellin A. Durnell, Vinayak Rayannavar, Johanna P. Daily, Andrew B. Ward, M. Javad Aman, John M. Dye, Kartik Chandran, Michael S. Diamond, Margaret Kielian, Jonathan R. Lai

Open Access Publications

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two …

Comparative Genomic Analysis And Molecular Examination Of The Diversity Of Enterotoxigenic Escherichia Coli Isolates From Chile, David A. Rasko, Felipe Del Canto, Qingwei Luo, James M. Fleckenstein, Roberto Vidal, Tracy H. Hazen

Open Access Publications

Enterotoxigenic Escherichia coli (ETEC) is one of the most common diarrheal pathogens in the low- and middle-income regions of the world, however a systematic examination of the genomic content of isolates from Chile has not yet been undertaken. Whole genome sequencing and comparative analysis of a collection of 125 ETEC isolates from three geographic locations in Chile, allowed the interrogation of phylogenomic groups, sequence types and genes specific to isolates from the different geographic locations. A total of 80.8% (101/125) of the ETEC isolates were identified in E. coli phylogroup A, 15.2% (19/125) in phylogroup B, and 4.0% (5/125) in …

30-Day Emergency Department Revisit Rates Among Older Adults With Documented Dementia, Tyler Kent, Adriane Lesser, Juhi Israni, Ula Hwang, Christopher Carpenter, Kelly J Ko

Open Access Publications

OBJECTIVES: Published literature on national emergency department (ED) revisit rates among older adults with dementia is sparse, despite anecdotal evidence of higher ED utilization. Thus we evaluated the odds ratio (OR) of 30-day ED revisits among older adults with dementia using a nationally representative sample.

DESIGN: We assessed the frequency of claims associated with a 30-day ED revisit among Medicare beneficiaries with and without a dementia diagnosis before or at index ED visit. We used a logistic regression model controlling for dementia, age, sex, race, region, Medicaid status, transfer to a skilled nursing facility after ED, primary care physician use …

Dc-Script Deficiency Delays Mouse Mammary Gland Development And Branching Morphogenesis, Chunling Tang, Renske J E Van Den Bijgaart, Maaike W G Looman, Nina Tel-Karthaus, Annemarie M A De Graaf, Susan Gilfillan, Marco Colonna, Marleen Ansems, Gosse J Adema

Open Access Publications

Mammary glands are unique organs in which major adaptive changes occur in morphogenesis and development after birth. Breast cancer is the most common cancer and a major cause of mortality in females worldwide. We have previously identified the loss of expression of the transcription regulator DC-SCRIPT (Zfp366) as a prominent prognostic event in estrogen receptor positive breast cancer patients. DC-SCRIPT affects multiple transcriptional events in breast cancer cells, including estrogen and progesterone receptor-mediated transcription, and promotes CDKN2B-related cell cycle arrest. As loss of DC-SCRIPT expression appears an early event in breast cancer development, we here investigated the role of DC-SCRIPT …

Gene Expression Analysis To Detect Disseminated Tumor Cells In The Bone Marrow Of Triple-Negative Breast Cancer Patients Predicts Metastatic Relapse, Chidananda M Siddappa, Sreeraj G Pillai, Jackie Snider, Patsy Alldredge, Kathyrn Trinkaus, Mark A Watson, Rebecca Aft

Open Access Publications

PURPOSE: Disseminated tumor cells (DTCs) in the BM of breast cancer patients predict early disease relapse, but the molecular heterogeneity of these cells is less well characterized. Expression of a 46-gene panel was used to detect DTCs and classify patient BM samples to determine whether a composite set of biomarkers could better predict metastatic relapse.

METHODS: Using a high-throughput qRT-PCR assay platform, BM specimens collected from 70 breast cancer patients prior to neoadjuvant therapy were analyzed for the expression of 46 gene transcripts. Gene expression was scored positive (detectable) relative to a reference pool of 16 healthy female control BM …

Association Of Intestinal Alkaline Phosphatase With Necrotizing Enterocolitis Among Premature Infants, Maya Heath, Rebecca Buckley, Zeromeh Gerber, Porcha Davis, Laura Linneman, Qingqing Gong, Brian Barkemeyer, Zhide Fang, Misty Good, Duna Penn, Sunyoung Kim

Open Access Publications

Importance: Necrotizing enterocolitis (NEC) in preterm infants is an often-fatal gastrointestinal tract emergency. A robust NEC biomarker that is not confounded by sepsis could improve bedside management, lead to lower morbidity and mortality, and permit patient selection in randomized clinical trials of possible therapeutic approaches.

Objective: To evaluate whether aberrant intestinal alkaline phosphatase (IAP) biochemistry in infant stool is a molecular biomarker for NEC and not associated with sepsis.

Design, Setting, and Participants: This multicenter diagnostic study enrolled 136 premature infants (gestational age, <37 weeks) in 2 hospitals in Louisiana and 1 hospital in Missouri. Data were collected and analyzed from May 2015 to November 2018.

Exposures: Infant stool samples were collected between 24 and 40 or more weeks postconceptual age. Enrolled infants …

Tfeb Activation In Macrophages Attenuates Postmyocardial Infarction Ventricular Dysfunction Independently Of Atg5-Mediated Autophagy, Ali Javaheri, Geetika Bajpai, Antonino Picataggi, Smrithi Mani, Layla Foroughi, Hosannah Evie, Attila Kovacs, Carla J Weinheimer, Krzystztof Hyrc, Qingli Xiao, Andrea Ballabio, Jin-Moo Lee, Scot J Matkovich, Babak Razani, Joel D Schilling, Kory J Lavine, Abhinav Diwan

Open Access Publications

Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation …

Genome-Wide Analysis Of Heterogeneous Nuclear Ribonucleoprotein (Hnrnp) Binding To Hiv-1 Rna Reveals A Key Role For Hnrnp H1 In Alternative Viral Mrna Splicing, Sebla B Kutluay, Ann Emery, Srinivasa R Penumutchu, Dana Townsend, Kasyap Tenneti, Michaela K Madison, Amanda M Stukenbroeker, Chelsea Powell, David Jannain, Blanton S Tolbert, Ronald I Swanstrom, Paul D Bieniasz

Open Access Publications

Alternative splicing of HIV-1 mRNAs increases viral coding potential and controls the levels and timing of gene expression. HIV-1 splicing is regulated in part by heterogeneous nuclear ribonucleoproteins (hnRNPs) and their viral target sequences, which typically repress splicing when studied outside their native viral context. Here, we determined the location and extent of hnRNP binding to HIV-1 mRNAs and their impact on splicing in a native viral context. Notably, hnRNP A1, hnRNP A2, and hnRNP B1 bound to many dispersed sites across viral mRNAs. Conversely, hnRNP H1 bound to a few discrete purine-rich sequences, a finding that was mirrored

Defining Components Of Early Functional Rehabilitation For Acute Achilles Tendon Rupture: A Systematic Review, Jennifer A Zellers, Marianne Christensen, Inge Lunding Kjær, Michael Skovdal Rathleff, Karin Grävare Silbernagel

Open Access Publications

Background: Early functional rehabilitation is frequently discussed in treating Achilles tendon rupture. A consistent definition of what constitutes early functional rehabilitation has not been established across the literature, despite studies supporting its efficacy. A standardized definition would be helpful to pool data across studies, allow for between-study comparisons, and ultimately work toward developing clinical guidelines.

Purpose: To define early functional rehabilitation (including when it is initiated and what it entails) when used to treat Achilles tendon rupture and to identify outcome measures for evaluating the effect of treatment.

Study Design: Systematic review; Level of evidence, 4.

Methods: Ovid MEDLINE, EMBASE, …

Bimodal Release Ondansetron For Acute Gastroenteritis Among Adolescents And Adults: A Randomized Clinical Trial, Robert A. Silverman, Stacey L. House, Andrew C. Meltzer, Barry Hahn, Luis M. Lovato, Jahn Avarello, Joseph B. Miller, Ira N. Kalfus, Reza Fathi, Gilead Raday, Terry F. Plasse, Eric C. Yan

Open Access Publications

Importance: Vomiting resulting from acute gastroenteritis is commonly treated with intravenous antiemetics in acute care settings. If oral treatment were beneficial, patients might not need intravenous administered hydration or medication. Furthermore, a long-acting treatment could provide sustained relief from nausea and vomiting.

Objective: To determine whether an experimental long-acting bimodal release ondansetron tablet decreases gastroenteritis-related vomiting and eliminates the need for intravenous therapy for 24 hours after administration.

Design, Setting, and Participants: This placebo-controlled, double-blind, randomized clinical trial included patients from 19 emergency departments and 2 urgent care centers in the United States from December 8, 2014, to February 17, …

Neurosteroids As Novel Antidepressants And Anxiolytics: Gaba-A Receptors And Beyond, Charles F Zorumski, Steven M Paul, Douglas F Covey, Steven Mennerick

Open Access Publications

The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic neurosteroids focusing on their actions as positive allosteric modulators of GABA

Diffusion Basis Spectrum Imaging For Identifying Pathologies In Ms Subtypes, Afsaneh Shirani, Peng Sun, Kathryn Trinkaus, Dana C Perantie, Ajit George, Robert T Naismith, Robert E Schmidt, Sheng-Kwei Song, Anne H Cross

Open Access Publications

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal-appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and …

Surgical Treatment Of Gluteus Medius Tears Augmented With Allograft Human Dermis, Cecilia Pascual-Garrido, Maria T Schwabe, Jorge Chahla, Masahiko Haneda

Open Access Publications

Greater trochanteric pain syndrome can be caused by gluteus medius and minimus tendinopathy/tears and chronic trochanteric bursitis. Specifically, moderate-to-severe abductor tendon tears can cause severe lateral hip pain, limp, and abnormal gait. A variety of open and endoscopic techniques to treat glut abductors hip tears have been described. The use of scaffolds, such as acellular human dermal allograft, to augment tendon repair, already has been successfully reported in rotator cuff repairs of the shoulder. Still, the use of acellular human dermal allograft in the hip has been limited. However, there are some clinical scenarios in which augmentation of abductors hip …

Svtools: Population-Scale Analysis Of Structural Variation, David E Larson, Haley J Abel, Colby Chiang, Abhijit Badve, Indraniel Das, James M Eldred, Ryan M Layer, Ira M Hall

Open Access Publications

SUMMARY: Large-scale human genetics studies are now employing whole genome sequencing with the goal of conducting comprehensive trait mapping analyses of all forms of genome variation. However, methods for structural variation (SV) analysis have lagged far behind those for smaller scale variants, and there is an urgent need to develop more efficient tools that scale to the size of human populations. Here, we present a fast and highly scalable software toolkit (svtools) and cloud-based pipeline for assembling high quality SV maps-including deletions, duplications, mobile element insertions, inversions and other rearrangements-in many thousands of human genomes. We show that this pipeline …

Cabozantinib Versus Sunitinib For Untreated Patients With Advanced Renal Cell Carcinoma Of Intermediate Or Poor Risk: Subgroup Analysis Of The Alliance A031203 Cabosun Trial, Daniel J George, Colin Hessel, Susan Halabi, M Dror Michaelson, Olwen Hahn, Meghara Walsh, Joel Picus, Eric J Small, Shaker Dakhil, Darren R Feldman, Milan Mangeshkar, Christian Scheffold, Michael J Morris, Toni K Choueiri

Open Access Publications

Cabozantinib treatment prolonged progression-free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, …

Conservation And Global Distribution Of Non-Canonical Antigens In Enterotoxigenic Escherichia Coli, F. Matthew Matthew Kuhlmann, John Martin, Tracy H. Hazen, Tim J. Vickers, Madeline Pashos, Pablo C. Okhuysen, Oscar G. Gómez-Duarte, Elizabeth Cebelinski, Dave Boxrud, Felipe Del Canto, Roberto Vidal, Firdausi Qadri, Makedonka Mitreva, David A. Rasko, James M. Fleckenstein

Open Access Publications

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) cause significant diarrheal morbidity and mortality in children of resource-limited regions, warranting development of effective vaccine strategies. Genetic diversity of the ETEC pathovar has impeded development of broadly protective vaccines centered on the classical canonical antigens, the colonization factors and heat-labile toxin. Two non-canonical ETEC antigens, the EtpA adhesin, and the EatA mucinase are immunogenic in humans and protective in animal models. To foster rational vaccine design that complements existing strategies, we examined the distribution and molecular conservation of these antigens in a diverse population of ETEC isolates.

METHODS: Geographically diverse ETEC isolates (n = …

Neoadjuvant Cryotherapy Improves Dysphagia And May Impact Remission Rates In Advanced Esophageal Cancer, Tilak Shah, Vladimir Kushnir, Pritesh Mutha, Mankanchan Majhail, Bhaumik Patel, Matthew Schutzer, Drew Mogahanaki, George Smallfield, Milan Patel, Alvin Zfass

Open Access Publications

No abstract provided.

Sotatercept Safety And Effects On Hemoglobin, Bone, And Vascular Calcification, Daniel W Coyne, Hem N Singh, William T Smith, Ana Carolina Giuseppi, Jamie N Connarn, Matthew L Sherman, Frank Dellanna, Hartmut H Malluche, Keith A Hruska

Open Access Publications

Introduction: Patients with end-stage kidney disease (ESKD) exhibit anemia, chronic kidney disease‒mineral bone disorder (CKD-MBD), and cardiovascular disease. The REN-001 and REN-002 phase II, multicenter, randomized studies examined safety, tolerability, and effects of sotatercept, an ActRIIA-IgG1 fusion protein trap, on hemoglobin concentration; REN-001 also explored effects on bone mineral density (BMD) and abdominal aortic vascular calcification.

Methods: Forty-three patients were treated in REN-001 (dose range: sotatercept 0.3‒0.7 mg/kg or placebo subcutaneously [s.c.] for 200 days) and 50 in REN-002 (dose range: 0.1‒0.4 mg/kg i.v. and 0.13‒0.5 mg/kg s.c. for 99 days).

Results: In REN-001, frequency of achieving target hemoglobin response …

Vav1 Inhibits Rankl-Induced Osteoclast Differentiation And Bone Resorption., Jin Sun Jang, In Soon Kang, Young-Nam Cha, Zang Hee Lee, Mary C Dinauer, Young-June Kim, Chaekyun Kim

Open Access Publications

Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1-/-) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor. Therefore, Vav1 may play a …

Burden Of Cause-Specific Mortality Associated With Pm2.5 Air Pollution In The United States, Benjamin Bowe, Yan Xie, Yan Yan, Ziyad Al-Aly

Open Access Publications

Importance: Ambient fine particulate matter (PM2.5) air pollution is associated with increased risk of several causes of death. However, epidemiologic evidence suggests that current knowledge does not comprehensively capture all causes of death associated with PM2.5 exposure.

Objective: To systematically identify causes of death associated with PM2.5 pollution and estimate the burden of death for each cause in the United States.

Design, Setting, and Participants: In a cohort study of US veterans followed up between 2006 and 2016, ensemble modeling was used to identify and characterize morphology of the association between PM2.5 and causes of death. Burden of death associated …

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic And Calcium Response Of Offspring To Somatosensory Stimuli, Rachel M Rahn, Susan E Maloney, Lindsey M Brier, Joseph D Dougherty, Joseph P Culver

Open Access Publications

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (HbO

Noda-Like Rna Viruses Infecting Caenorhabditis Nematodes: Sympatry, Diversity, And Reassortment, Lise Frézal, Hyeim Jung, Stephen Tahan, David Wang, Marie-Anne Félix

Open Access Publications

Three RNA viruses related to nodaviruses were previously described to naturally infect the nematode

Clinical Outcomes And Toxicity Of Proton Beam Radiation Therapy For Re-Irradiation Of Locally Recurrent Breast Cancer, Prashant Gabani, Hetal Patel, Maria A Thomas, Beth Bottani, S Murty Goddu, William Straube, Julie A Margenthaler, Laura Ochoa, Jeff D Bradley, Imran Zoberi

Open Access Publications

Purpose: Repeat radiation therapy (RT) using photons/X-rays for locally recurrent breast cancer results in increased short and long-term toxicity. Proton beam RT (PBRT) can minimize dose to surrounding organs, thereby potentially reducing toxicity. Here, we report the toxicity and clinical outcomes for women who underwent re-irradiation to the chest wall for locally recurrent breast cancer using PBRT.

Materials and methods: This was a retrospective study analyzing 16 consecutive patients between 2013 and 2018 with locally recurrent breast cancer who underwent re-irradiation to the chest wall with PBRT. For the recurrent disease, patients underwent maximal safe resection, including salvage mastectomy, wide …

Integrated Proteogenomic Characterization Of Clear Cell Renal Cell Carcinoma, David J Clark, Yize Li, Yige Wu, Matthew A Wyczalkowski, Sunantha Sethuraman, Song Cao, Feng Chen, James J Hsieh, Li Ding, Et Al

Open Access Publications

To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale …

Cholesterol Accessibility At The Ciliary Membrane Controls Hedgehog Signaling, Maia Kinnebrew, Ellen J. Iverson, Bhaven B. Patel, Ganesh V. Pusapati, Jennifer H. Kong, Kristen A. Johnson, Giovanni Luchetti, Kaitlyn M. Eckert, Jeffrey G. Mcdonald, Douglas F. Covey, Christian Siebold, Arun Radhakrishnan, Rajat Rohatgi

Open Access Publications

Previously we proposed that transmission of the hedgehog signal across the plasma membrane by Smoothened is triggered by its interaction with cholesterol (Luchetti et al., 2016). But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find that Smoothened activation and Hedgehog signaling are driven by a biochemically-defined, small fraction of membrane cholesterol, termed accessible cholesterol. Increasing cholesterol accessibility by depletion of sphingomyelin, which sequesters cholesterol in complexes, amplifies Hedgehog signaling. Hedgehog ligands increase cholesterol accessibility in …

Changes In Serum Albumin And Other Nutritional Markers When Using Sucroferric Oxyhydroxide As Phosphate Binder Among Hemodialysis Patients: A Historical Cohort Study, Kamyar Kalantar-Zadeh, Linda H Ficociello, Vidhya Parameswaran, Nicolaos V Athienites, Claudy Mullon, Robert J Kossmann, Daniel W Coyne

Open Access Publications

BACKGROUND: Elevated serum phosphorus concentrations are common among maintenance hemodialysis patients. Protein is a major source of dietary phosphate, but restriction of protein intake can result in hypoalbuminemia and protein-energy wasting. We hypothesized that sucroferric oxyhydroxide (SO), a potent phosphate binder with a low pill burden, may reduce serum phosphorus levels in hemodialysis patients with hypoalbuminemia without adversely impacting albumin levels or dietary intake of protein.

METHODS: We retrospectively examined de-identified data from 79 adult, in-center hemodialysis patients with baseline hypoalbuminemia (≤ 3.5 g/dL) switched to SO as part of routine clinical care for at least 1 year. Temporal changes …

Targeting Tauopathy With Engineered Tau-Degrading Intrabodies, Gilbert Gallardo, Connie H Wong, Sara M Ricardez, Carolyn N Mann, Kent H Lin, Cheryl E G Leyns, Hong Jiang, David M Holtzman

Open Access Publications

BACKGROUND: The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology. Although these and other studies demonstrate that conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the …