Diseases Commons^™

Tubular-Specific Expression Of Hiv Protein Vpr Leads To Severe Tubulointerstitial Damage Accompanied By Progressive Fibrosis And Cystic Development, Yuqiang Chen, Ya Chen, Jia Fu, Zeguo Sun, Huilin Li, Wenzhen Xiao, Jing E, Benjamin Y Lo, Niansong Wang, Weijia Zhang, Mary E Klotman, Paul E Klotman, Jeffrey B Kopp, Vivette D D'Agati, John Cijiang He, Kyung Lee

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a …

Long-Chain Polyunsaturated Lipids Associated With Responsiveness To Anti-Pd-1 Therapy Are Colocalized With Immune Infiltrates In The Tumor Microenvironment, Mary E King, Robert Yuan, Jeremy Chen, Komal Pradhan, Isabel Sariol, Shirley Li, Ashish Chakraborty, Oscar Ekpenyong, Jennifer H Yearley, Janica C Wong, Luis Zúñiga, Daniela Tomazela, Maribel Beaumont, Jin-Hwan Han, Livia S Eberlin

Faculty, Staff and Students Publications

The programmed cell death protein-1 (PD-1) is highly expressed on the surface of antigen-specific exhausted T cells and, upon interaction with its ligand PD-L1, can result in inhibition of the immune response. Anti-PD-1 treatment has been shown to extend survival and result in durable responses in several cancers, yet only a subset of patients benefit from this therapy. Despite the implication of metabolic alteration following cancer immunotherapy, mechanistic associations between antitumor responses and metabolic changes remain unclear. Here, we used desorption electrospray ionization mass spectrometry imaging to examine the lipid profiles of tumor tissue from three syngeneic murine models with …

Asthma And Cardiovascular Disease: A Bidirectional Association?, Muhammad Adrish, Nicola A Hanania

Faculty, Staff and Students Publications

No abstract provided.

Association Of Long-Term Change In N-Terminal Pro-B-Type Natriuretic Peptide With Incident Heart Failure And Death, Xiaoming Jia, Mahmoud Al Rifai, Ron Hoogeveen, Justin B Echouffo-Tcheugui, Amil M Shah, Chiadi E Ndumele, Salim S Virani, Biykem Bozkurt, Elizabeth Selvin, Christie M Ballantyne, Vijay Nambi

Faculty, Staff and Students Publications

IMPORTANCE: Most studies, especially in primary prevention patients, have evaluated N-terminal B-type natriuretic peptide (NT-proBNP) at one time point. Evaluation of change in NT-proBNP may improve risk stratification for incident cardiovascular events.

OBJECTIVE: To assess the association between change in NT-proBNP and risk for incident heart failure (HF) and death.

DESIGN, SETTING, AND PARTICIPANTS: Participants were recruited from 4 US communities enrolled in the Atherosclerosis Risk in Community (ARIC) study. Individuals who attended ARIC visits 2 and 4 (approximately 6 years apart) with measurements of NT-proBNP and without prevalent HF were included. Assays of NT-proBNP were conducted between 2011 and …

Types Of Physical Activity In Nonalcoholic Fatty Liver Disease And All-Cause And Cardiovascular Mortality, Donghee Kim, Karn Wijarnpreecha, Brittany B Dennis, George Cholankeril, Aijaz Ahmed

Faculty, Staff and Students Publications

The impact of different types of physical activity (PA) on mortality in the context of nonalcoholic fatty liver disease (NAFLD) is not clearly defined and was investigated. This prospective study was performed using the 2007–2014 US National Health and Nutrition Examination Survey with mortality follow-up through 2019. Over a median follow-up of 8.6 years, leisure-time and transportation-related PA that fulfilled the criteria outlined in the PA guidelines (≥150 min/week) in NAFLD were associated with a risk reduction in all-cause mortality (hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.59–0.98 for leisure-time PA; HR: 0.62, 95% CI: 0.45–0.86 for transportation-related PA). …

Clic And Membrane Wound Repair Pathways Enable Pandemic Norovirus Entry And Infection, B Vijayalakshmi Ayyar, Khalil Ettayebi, Wilhelm Salmen, Umesh C Karandikar, Frederick H Neill, Victoria R Tenge, Sue E Crawford, Erhard Bieberich, B V Venkataram Prasad, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Globally, most cases of gastroenteritis are caused by pandemic GII.4 human norovirus (HuNoV) strains with no approved therapies or vaccines available. The cellular pathways that these strains exploit for cell entry and internalization are unknown. Here, using nontransformed human jejunal enteroids (HIEs) that recapitulate the physiology of the gastrointestinal tract, we show that infectious GII.4 virions and virus-like particles are endocytosed using a unique combination of endosomal acidification-dependent clathrin-independent carriers (CLIC), acid sphingomyelinase (ASM)-mediated lysosomal exocytosis, and membrane wound repair pathways. We found that besides the known interaction of the viral capsid Protruding (P) domain with host glycans, the Shell …

Mecp2 Regulates Gdf11, A Dosage-Sensitive Gene Critical For Neurological Function, Sameer S Bajikar, Ashley G Anderson, Jian Zhou, Mark A Durham, Alexander J Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral …

Developing Consensus On Clinical Outcomes For Children With Mild Pneumonia: A Delphi Study, Todd A Florin, Joy Melnikow, Melissa Gosdin, Ryan Ciuffetelli, Jillian Benedetti, Dustin Ballard, Marianne Gausche-Hill, Matthew P Kronman, Lisa A Martin, Rakesh D Mistry, Mark I Neuman, Debra L Palazzi, Sameer J Patel, Wesley H Self, Samir S Shah, Sonal N Shah, Susan Sirota, Andrea T Cruz, Richard Ruddy, Jeffrey S Gerber, Nathan Kuppermann

Faculty, Staff and Students Publications

BACKGROUND: The absence of consensus for outcomes in pediatric antibiotic trials is a major barrier to research harmonization and clinical translation. We sought to develop expert consensus on study outcomes for clinical trials of children with mild community-acquired pneumonia (CAP).

METHODS: Applying the Delphi method, a multispecialty expert panel ranked the importance of various components of clinical response and treatment failure outcomes in children with mild CAP for use in research. During Round 1, panelists suggested additional outcomes in open-ended responses that were added to subsequent rounds of consensus building. For Rounds 2 and 3, panelists were provided their own …

Impact Of Penicillin Allergy Labels On Children Treated For Outpatient Respiratory Infections, Torsten Joerger, Margaret G Taylor, Yun Li, Debra L Palazzi, Jeffrey S Gerber

Faculty, Staff and Students Publications

BACKGROUND: Penicillin allergy is the most common antibiotic allergy, yet most children labeled as allergic tolerate penicillin. The impact of inaccurate penicillin allergy labels (PALs) on pediatric outpatients is unknown. The objective of this study was to compare outcomes between children with and without a PAL after treatment for outpatient respiratory tract infections (RTI).

METHODS: A retrospective, longitudinal birth cohort study was performed in children who received care in 90 pediatric primary care practices in Philadelphia and Houston metropolitan areas. Prescribing and clinical outcomes of children with a PAL at the time of an RTI were compared to non-allergic children, …

Multitrait Genome-Wide Analyses Identify New Susceptibility Loci And Candidate Drugs To Primary Sclerosing Cholangitis, Younghun Han, Jinyoung Byun, Catherine Zhu, Ryan Sun, Julia Y Roh, Heather J Cordell, Hyun-Sung Lee, Vikram R Shaw, Sung Wook Kang, Javad Razjouyan, Matthew A Cooley, Manal M Hassan, Katherine A Siminovitch, Trine Folseraas, David Ellinghaus, Annika Bergquist, Simon M Rushbrook, Andre Franke, Tom H Karlsen, Konstantinos N Lazaridis, Kathryn A. Mcglynn, Katherine A Mcglynn, Lewis R Roberts, Christopher I Amos, International Psc Study Group

Faculty, Staff and Students Publications

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug …

A Modern Multimodal Pain Protocol Eliminates The Need For Opioids For Most Patients Following Total Knee Arthroplasty: Results From A Retrospective Comparative Cohort Study, Leland Van Deventer, Amy Bronstone, Claudia Leonardi, Matthew Bennett, Peter Yager, Vinod Dasa

School of Medicine Faculty Publications

Purpose: Modern multimodal analgesia has been shown to significantly reduce opioid use following total knee arthroplasty (TKA). This study was conducted to determine if changing TKA discharge opioid prescriptions from automatic to upon request resulted in more opioid free recoveries without compromising pain control. Methods: Between December 2019 and August 2021, an orthopedic surgeon performed 144 primary unilateral TKAs; patients received the same multimodal analgesia protocol except for postoperative opioid prescribing. The first consecutively-treated cohort automatically received an opioid prescription following discharge (automatic group) and the second cohort received opioid prescriptions only upon request (upon request group). Opioid prescription data …

Banking On Virus-Specific T Cells To Fulfill The Need For Off-The-Shelf Cell Therapies, David H Quach, Premal Lulla, Cliona M Rooney

Faculty, Staff and Students Publications

Adoptively transferred virus-specific T cells (VSTs) have shown remarkable safety and efficacy for the treatment of virus-associated diseases and malignancies in hematopoietic stem cell transplant (HSCT) recipients, for whom VSTs are derived from the HSCT donor. Autologous VSTs have also shown promise for the treatment of virus-driven malignancies outside the HSCT setting. In both cases, VSTs are manufactured as patient-specific products, and the time required for procurement, manufacture, and release testing precludes their use in acutely ill patients. Further, Good Manufacturing Practices-compliant products are expensive, and failures are common in virus-naive HSCT donors and patient-derived VSTs that are rendered anergic …

Intellectual Disability Related To De Novo Germline Loss Of The Distal End Of The P-Arm Of Chromosome 17: A Case Report, Eden Pope, Matthew Huertas, Amar Paul, Braden Cunningham, Matthew Jennings, Ryan Perry, Stephanie Chavez, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

Hypothesis/Purpose: In this report we present a case of a 20-year-old female with congenital intellectual disability, stunted growth, and hypothyroidism. Competitive genetic hybridization (CHG) revealed a loss of 17p13.3, and the deletion was not present in either parent. This deletion has not previously been characterized, but mutations on the p-arm of chromosome 17 are responsible for Miller-Dieker Syndrome and Isolated Lissencephaly Sequence, both of which share symptoms in common with the patient.

Methods: Peripheral mononuclear cells (PBMCs) were used for karyotyping and competitive genetic hybridization (CHG). Bioinformatic analysis was carried out using the Genome Data Viewer (ncbi.nlm.nih.gov/genome/gdv).

Results: Karyotype was …

Evofosfamide For The Treatment Of Human Papillomavirus-Negative Head And Neck Squamous Cell Carcinoma, Stephen Mf Jamieson, Peter Tsai, Maria K Kondratyev, Pratha Budhani, Arthur Liu, Neil N Senzer, E Gabriela Chiorean, Shadia I Jalal, John J Nemunaitis, Dennis Kee, Avik Shome, Way W Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M Kakadia, Nicholas S Knowlton, Courtney Rh Lynch, Cho R Hong, Tet Woo Lee, Reidar A Grénman, Laura Caporiccio, Trevor D Mckee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P Mcivor, John M Chaplin, Kevin O Hicks, Stefan K Bohlander, Bradly G Wouters, Charles P Hart, Cristin G Print, William R Wilson, Michael A Curran, Francis W Hunter

Faculty, Staff and Student Publications

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × …

Prevention Of Doxorubicin-Induced Cardiotoxicity By A Coumestan Analogue, Psoralidin, Mujtaba H. Shah, Myia Aiges, Kota V. Ramana

Annual Research Symposium

Natural phenolic compound Psoralidin limits cardiotoxicity associated with Doxorubicin

Lipoprotein(A) In Atherosclerotic Cardiovascular Disease And Aortic Stenosis: A European Atherosclerosis Society Consensus Statement, Florian Kronenberg, Samia Mora, Erik S G Stroes, Brian Ference Ference Ference, Benoit J. Arsenault, Lars Berglund, Marc R. Dweck, Marlys Koschinsky, Gilles Lambert, Salim S. Virani

Office of the Provost

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do …

Clinical Practice Guideline Recommendation Summaries For Pediatric Oncology Health Care Professionals: A Qualitative Study, Nancy Santesso, Melissa Beauchemin, Paula D. Robinson, Alexandra M. Walsh, Aaron J. Sugalski, Tammy Lo, Ha Dang, Brian T. Fisher, Allison C. Grimes, Andrea Rothfus Wrightson, Lolie C. Yu, Lillian Sung, L. Lee Dupuis

School of Medicine Faculty Publications

Objective To develop a summary format of clinical practice guideline (CPG) recommendations to improve understandability among health care professionals. Methods We developed a summary format based on current research and used the "Think Aloud"technique in one-on-one cognitive interviews to iteratively improve it. Interviews of health care professionals from Children's Oncology Group-member, National Cancer Institute Community Oncology Research Program sites were conducted. After every five interviews (a round), responses were reviewed, and changes made to the format until it was well understood and no new, substantive suggestions for revision were raised. We took a directed (deductive) approach to content analysis of …

Identification Of Small-Molecule Inhibitors Of The Salmonella Frab Deglycase Using A Live-Cell Assay, Anice Sabag-Daigle, Erin F Boulanger, Pankajavalli Thirugnanasambantham, Jamison D Law, Alex J Bogard, Edward J Behrman, Venkat Gopalan, Brian M M Ahmer

Faculty, Staff and Student Publications

Nontyphoidal salmonellosis is one of the most significant foodborne diseases in the United States and globally. There are no vaccines available for human use to prevent this disease, and only broad-spectrum antibiotics are available to treat complicated cases of the disease. However, antibiotic resistance is on the rise and new therapeutics are needed. We previously identified the Salmonella fraB gene, that mutation of causes attenuation of fitness in the murine gastrointestinal tract. The FraB gene product is encoded in an operon responsible for the uptake and utilization of fructose-asparagine (F-Asn), an Amadori product found in several human foods. Mutations in …

Lacrimal Gland Epithelial Cells Shape Immune Responses Through The Modulation Of Inflammasomes And Lipid Metabolism, Vanessa Delcroix, Olivier Mauduit, Menglu Yang, Amrita Srivastava, Takeshi Umazume, Cintia S De Paiva, Valery I Shestopalov, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren's syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren's syndrome models: diseased

Vitamin C Contributes To Epigenetic Regulation Of Genes Related To Diabetic Retinopathy In Retinal Endothelial Cells, Elizabeth L. Turner, Jonathon Reynolds, Walker Kay, Marianne Becnel, Matthew Conway, Alexander Kim, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

No abstract provided.

Development Of An Affordable, Manual Method Of Dna Extraction From Bones And Teeth ​, Varos Victer Manukyan, Lara Laughrey, Ryan V. Powers, Amar Paul, Davis Johnston, Dashon Eure, Todeh Toomians, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

No abstract provided.

The Immunomodulating Effects Of Morphine Dependence And Withdrawal In A Rat Model, Mark Stoll

Annual Research Symposium

Would you like to know what happens to the immune system during opioid drug withdrawal?

Carvacrol Regulates Endotoxin -Induced Arachidonic Acid Metabolism., Aliea M. Jalali, Spencer Norton

Annual Research Symposium

Plant-derived essential oil prevents endotoxin-induced inflammatory response

A Systematic Review: Toxoplasma Gondii Infection And Drugs Of Abuse, Amani Sastry

Annual Research Symposium

No abstract provided.

Sulopenem For The Treatment Of Complicated And Uncomplicated Bacterial Urinary Tract Infection (Uti), Aiyi Chen, Thanh-Liem Vu, Daniel J. Yang, Landon Olsen

Annual Research Symposium

No abstract provided.

Hypoglycemia: A Mimic Of Global Ischemic Injury, Zachary Leavitt, Jay Babu, Sannah Vasaya, Robert Balsinger, Aroucha Vickers

Annual Research Symposium

No abstract provided.

Lipomatosis Of Nerve, Mehruba Alam, Thomas Benjamin Lyle Wasden

Annual Research Symposium

Lipomatosis of nerve is a benign lesion with increased fibrofatty tissue infiltrating and surrounding nerves, usually occurring in children and young adults as a slowly progressive swelling or mass, which can clinically mimic a tumor or malignancy. Here we report a 59-year-old man who presented with pain in his right foot and a mass that has been mostly stable for years, but which seems to have grown slightly of late, and is clinically suspicious for ganglion cyst. The MRI revealed a fatty mass concerning for lipoma or atypical lipomatous tumor. Consequently, the patient underwent excisional biopsy. The H&E sections showed …

Efficacy Of Osteoporosis Education In Rural Populations, Mindy Cook, Jaden Arnold, Hannah Berhow, Rebekah Hans, Bivash Neupane, Alizon Pachas, Andrea Pham, Holly Radke, Mitchell Rush, Emily Schwartz, Hunter Stutz, Darell Schmick, David Sant Phd, Erika Noonan Md

Annual Research Symposium

No abstract provided.

A Multicenter Analysis Of Nucleic Acid Quantification Using Aqueous Humor Liquid Biopsy In Retinoblastoma: Implications For Clinical Testing, Deborah H Im, Sarah Pike, Mark W Reid, Chen-Ching Peng, Shreya Sirivolu, Hans E Grossniklaus, G Baker Hubbard, Alison H Skalet, Kellyn N Bellsmith, Carol L. Shields, Sara E Lally, Andrew W Stacey, Bibiana J Reiser, Aaron Nagiel, Rachana Shah, Liya Xu, Jesse L Berry

Wills Eye Hospital Papers

PURPOSE: Retinoblastoma (RB) is most often diagnosed with clinical features and not diagnosed with tumor biopsy. This study describes tumor-derived analyte concentrations from aqueous humor (AH) liquid biopsy and its use in clinical assays.

DESIGN: Case series study.

PARTICIPANTS: Sixty-two RB eyes from 55 children and 14 control eyes from 12 children from 4 medical centers.

METHODS: This study included 128 RB AH samples including: diagnostic (DX) samples, samples from eyes undergoing treatment (TX), samples after completing treatment (END), and during bevacizumab injection for radiation therapy after completing RB treatment (BEV). Fourteen-control AH were analyzed for unprocessed analytes (double-stranded DNA …

The Coronavirus Disease 2019 Pandemic Unmasked The Challenges Faced By Early-Stage Faculty In Infectious Diseases: A Call To Action, Erin M Scherer, Martin Backer, Karen Carvajal, Lara Danziger-Isakov, Sharon Frey, Leigh M Howard, Felicia Scaggs Huang, Angelica C Kottkamp, Tara Reid, Maria C Rodriguez-Barradas, Helen C Stankiewicz Karita, Zheyi Teoh, Anna Wald, Jennifer Whitaker, Zanthia Wiley, Igho Ofotokun, Kathryn M Edwards, Infectious Diseases Clinical Research Consortium (Idcrc) Mentorship Program Writing Group

Faculty, Staff and Students Publications

The coronavirus disease 2019 (COVID-19) pandemic and associated increase in family care responsibilities resulted in unsustainable personal and professional workloads for infectious diseases (ID) faculty on the front lines. This was especially true for early-stage faculty (ESF), many of whom had caregiving responsibilities. In addition, female faculty, underrepresented in medicine and science faculty and particularly ESF, experienced marked declines in research productivity, which significantly impacts career trajectories. When combined with staffing shortages due to an aging workforce and suboptimal recruitment and retention in ID, these work-life imbalances have brought the field to an inflection point. We propose actionable recommendations and …