Medicine and Health Sciences Commons^™

Association Between The 2022 Aha/Acc/Hfsa Heart Failure Staging And Cardiovascular And Kidney Outcomes In Patients With Diabetes And Kidney Disease: A Post Hoc Analysis Of The Scored Randomized Controlled Trial, Ayodele Odutayo, Deepak L Bhatt, Vikas S Sridhar, Michael Szarek, Christopher P Cannon, Lawrence A Leiter, Darren K Mcguire, Julia B Lewis, Renato D Lopes, Benjamin M Scirica, Kausik K Ray, Michael J Davies, Phillip Banks, Manon Girard, Subodh Verma, Jacob A Udell, Bertram Pitt, Ph Gabriel Steg, David Z I Cherney

Faculty, Staff and Student Publications

Background: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure (HF) classification incorporates cardiac biomarkers to identify early risk of HF. The HF stages may also guide the prognosis and management of cardiovascular and kidney-related events.

Methods: SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) was a randomized trial in diabetes with kidney disease comparing sotagliflozin versus placebo on cardiovascular death, HF hospitalizations, and urgent HF visits. SCORED participants were grouped by HF stage post hoc. Stage A: no …

Single-Photon Emission Computed Tomography Functional Liver Imaging To Facilitate Reirradiation For Liver Malignancies: A Phase I Trial, Enoch Chang, Emma B Holliday, Janio Szklaruk, William D Erwin, Ethan B Ludmir, Sonal S Noticewala, Prajnan Das, Albert C Koong, Bruce D Minsky, Grace L Smith, Gabriel O Sawakuchi, Rachael M Martin-Paulpeter, Joshua S Niedzielski, Luis A Perles, Sam Beddar, Veronica S Valino, Joshua L Nguyen, Kanwal P S Raghav, Milind Javle, Ahmed O Kaseb, Arvind N Dasari, Michael J Overman, Christine M Parseghian, Bruno C Odisio, Armeen Mahvash, Joshua D Kuban, Shu-En Shen, Xin S Wang, Aashish C Gupta, Mais M Al Taie, Kristy K Brock, Ching-Wei D Tzeng, Jean-Nicolas Vauthey, Franklin C L Wong, Eugene J Koay

Faculty, Staff and Student Publications

Background & aims: This phase I trial evaluated the safety of hypofractionated liver reirradiation (reRT) with preferential sparing of functional liver identified by technetium-99m sulfur colloid single-photon emission computed tomography (Tc-99m SC SPECT; hereafter SPECT) for patients previously treated with external beam radiotherapy or transarterial radioembolization.

Methods: A 3+3 design evaluated the safety of two escalating SPECT-based functional liver volumetric dose constraints. Dose-limiting toxicities (DLTs), liver segment volumes, and MRI functional liver imaging score, relative liver enhancement, and elastography were assessed.

Results: Thirteen patients were enrolled from 2018 to 2021. Median reRT gross tumor volume was 61 cm3 (range 1-677 …

The Gene Encoding Ornithine Decarboxylase For Putrescine Biosynthesis Is Essential For The Viability Of Fusobacterium Nucleatum, Shiqi Xu, Bibek G C, Alex Phan, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is a Gram-negative anaerobe associated with periodontitis and colorectal cancer. It secretes putrescine, a polyamine that promotes biofilm formation by oral co-colonizers and enhances the proliferation of cancer cells. However, the physiological importance of putrescine for F. nucleatum itself remains unexplored. Here, we show that putrescine biosynthesis, mediated by the ornithine decarboxylase gene oda, is essential for F. nucleatum viability. Deletion of oda was only possible when a functional copy was provided in trans, and CRISPR interference of oda expression resulted in complete growth defects. The essentiality of oda was conserved across multiple subspecies. Supplementation with …

Disease-Specific And Overall Survival For Patients With Lacrimal Gland Adenoid Cystic Carcinoma In Recent Decades, Bita Esmaeli, Zhouxuan Li, Tracy J Lu, Hila Goldberg, Jing Ning, James Matthew Debnam, Steven Jay Frank, Renata Ferrarotto

Faculty, Staff and Student Publications

Purpose: To evaluate the presenting symptoms, and the overall survival (OS) and disease-specific survival (DSS) in patients with lacrimal gland adenoid cystic carcinoma (LGACC).

Methods: This retrospective single-centre cohort study included all consecutive patients with LGACC treated by the primary author from November 1998 through August 2024. Demographic data, presenting symptoms, the histological subtype of LGACC, type of surgical treatment, adjuvant radiotherapy or chemotherapy, T category at presentation and survival data were reviewed. Correlations between histological subtypes, T-category, type of surgery (eye sparing vs orbital exenteration), and DSS and OS were analysed.

Results: 52 patients had a median age of …

Cdk2 Inhibitor Blu-222 Synergizes With Cdk4/6 Inhibitors In Drug Resistant Breast Cancers Through P21/P27 Induction, Linjie Luo, Yan Wang, Tuyen Bui, Xiaoting Jiang, Mei-Kuang Chen, Xiayu Rao, Sepideh Mohammadhosseinpour, Mi Li, Serena Kim, Rachel Y Kim, Saba Kamaliasl, Carmen W Ulizio, Spyros Tsavachidis, Juliana Navarro-Yepes, Nicole M Kettner, Hannah Wingate, Funda Meric-Bernstam, Kelly K Hunt, Jing Wang, Kerrie Faia, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated …

Prehospital Transfusion Strategies In Haemorrhagic Shock, Brian Burns, Brodie Nolan, Ian Ferguson, Michael Peddle, Christopher Partyka, Geoff Healy, Stacy Shackelford, Bryan Cotton

Faculty, Staff and Student Publications

Background: Massive transfusion protocols are established in-hospital practices for managing haemorrhagic shock, yet critical bleeding accounts for up to 40% of trauma deaths, with half occurring before hospital arrival. This has driven interest in prehospital transfusion, a concept originating in military settings where early blood product administration during prolonged evacuations demonstrated significant survival benefits. Despite compelling military evidence showing improved 24-h and 30-day survival with prehospital transfusion, civilian adoption faces substantial challenges. Global interest in this domain is increasing, particularly in regions with trauma populations remote from immediate access to major trauma centres.

Main body: Current prehospital transfusion strategies have …

Cdk2 Inhibitor Blu-222 Synergizes With Cdk4/6 Inhibitors In Drug Resistant Breast Cancers Through P21/P27 Induction, Linjie Luo, Yan Wang, Tuyen Bui, Xiaoting Jiang, Mei-Kuang Chen, Xiayu Rao, Sepideh Mohammadhosseinpour, Mi Li, Serena Kim, Rachel Y Kim, Saba Kamaliasl, Carmen W Ulizio, Spyros Tsavachidis, Juliana Navarro-Yepes, Nicole M Kettner, Hannah Wingate, Funda Meric-Bernstam, Kelly K Hunt, Jing Wang, Kerrie Faia, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated …

Cross-Ancestry Comparison Of Aptamer And Antibody Protein Measures, Jayna C Nicholas, Daniel H Katz, Usman A Tahir, Catherine L Debban, Francois Aguet, Thomas Blackwell, Russell P Bowler, K Alaine Broadaway, Jingsha Chen, Clary B Clish, Josef Coresh, Elaine Cornell, Daniel E Cruz, Rajat Deo, Margaret F Doyle, Peter Durda, Lynette Ekunwe, James S Floyd, Dipender Gill, Xiuqing Guo, Ron C Hoogeveen, Craig Johnson, Leslie A Lange, Yun Li, Alisa Manning, James B Meigs, Michael Y Mi, Josyf C Mychaleckyj, Nels C Olson, Katherine A Pratte, Brucy M Psaty, Alexander P Reiner, Peifeng Ruan, Magdalena Sevilla-Gonzalez, Amil M Shah, Quan Sun, Russell P Tracy, Jia Wen, Alexis C Wood, James G Wilson, Kristin L Young, Bing Yu, Mary R Rooney, Ani Manichaikul, Ruth Dubin, Karen L Mohlke, Stephen S Rich, Jerome I Rotter, Peter Ganz, Robert E Gerszten, Kent D Taylor, Laura M Raffield

Faculty, Staff and Student Publications

Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants and phenotypes. Here, we examine 2157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2157 proteins follow a bimodal distribution (median r = 0.30). We evaluate protein measure associations with genetic variants, and find approximately 25-30% of the signals on each platform are likely driven by protein-altering variants. We highlight 80 proteins that correlate differently across ancestry groups likely in part due …

Single-Cell Atlas Of Human Lung Aging Identifies Cell Type Dyssynchrony And Increased Transcriptional Entropy, Ruben De Man, John E Mcdonough, Taylor S Adams, Fadi Nikola, Reina Rangel, Sabina Anderson, Edward P Manning, Juan Cala Garcia, Benjamin Moss, Alan Waich, Fernando Poli, Rafael Cardenas, Cristian Coarfa, Qi Song, Ziv Bar-Joseph, Bart M Vanaudenaerde, Wim A Wuyts, Laura Niklason, Micha Sam B Raredon, Xiting Yan, Ivan O Rosas, Naftali Kaminski

Faculty, Staff and Students Publications

Age is a major risk factor for lung disease. We characterized the changing cellular, transcriptional, and genomic landscape of human lung aging using single-cell RNA sequencing. We find that lung aging is cell-type dyssynchronous, with alveolar epithelial and endothelial cells exhibiting the greatest transcriptional changes. Among alveolar epithelial cells, aging is associated with a decreased relative proportion of surfactant-expressing SPChigh AT2 cells. Among alveolar capillary cells, we observed loss of differentiation and capillary function. Analysis of somatic mutations called from single-cell data revealed an increase with aging, with alveolar epithelial and endothelial cell types exhibiting greater mutation burdens. Transcriptional entropy …

Metabolome Contribution To Sex Differences In The Link Between Alcohol Consumption And Type 2 Diabetes: A Prospective Analysis In The Hispanic Community Health Study/Study Of Latinos (Hchs/Sol), Brian Wang, Kai Luo, Wenyan Ma, Yanbo Zhang, Christina Cordero, Amber Pirzada, Martha Daviglus, Krista M Perreira, Bing Yu, Eric Boerwinkle, Robert C Kaplan, Qibin Qi

Faculty, Staff and Student Publications

Background: Light-to-moderate alcohol consumption has been linked to improved insulin resistance and lower type 2 diabetes (T2D) risk predominantly in females but not males. Potential mechanisms underlying this sex difference remain unclear.

Objective: This study evaluated associations of sex-specific alcohol-associated metabolomic signatures (AMSs) with insulin resistance and T2D risk in US Hispanic/Latino adults.

Methods: We analyzed serum metabolome data in the HCHS/SOL, a prospective, multicenter, community-based study of Hispanics/Latinos, aged 18 to 74 years old, enrolled from four U.S. metropolitan areas between 2008 and 2011. Sex-specific AMSs were developed using Elastic Net to identify serum metabolites uniquely associated with alcohol …

Qsox1: A Mysterious Golgi-Localized Disulfide Bond Catalyst And An Emerging Cancer Regulator, Shike Wang, Guan-Yu Xiao, Xiaochao Tan

Faculty, Staff and Student Publications

Quiescin sulfhydryl oxidase 1 (QSOX1) is a disulfide bond-forming enzyme with both disulfide isomerase and oxidoreductase activities. It plays an important role in protein folding, stability, and secretion. Growing evidence demonstrates that QSOX1 is upregulated in multiple cancer types and influences key behaviors of cancer cells, including proliferation, migration, invasion, and metastasis. Elevated QSOX1 expression is also associated with tumor malignancy and disease relapse. However, the molecular mechanisms by which QSOX1 drives cancer progression remain incompletely understood. In this review, we summarize current knowledge of QSOX1 expression and regulation in cancer, discuss its functional roles, and highlight key unanswered questions …

Low Intensity Vibration With Zoledronate Reduces Musculoskeletal Weakness And Adiposity In Estrogen Deprived Female Mice, Gabriel M Pagnotti, Trupti Trivedi, Laura E Wright, Sutha K John, Sreemala Murthy, Ryan R Pattyn, Monte S Willis, Yun She, Sukanya Suresh, Aji F Touray, William R Thompson, Clinton T Rubin, Khalid S Mohammad, Theresa A Guise

Faculty, Staff and Student Publications

Aromatase inhibitors are widely used in the treatment of hormone-sensitive breast cancer, but their suppression of estrogen production accelerates bone loss, increases fracture risk, and negatively impacts muscle and fat metabolism. Here, we demonstrate that daily low intensity vibration, serving as a non-drug mimetic for exercise, protects musculoskeletal health in skeletally immature, female mice under complete estrogen deprivation. Subsequent improvements in vertebral bone density are paralleled by greater and leaner skeletal muscle mass and function alongside reduced fat accretion and circulating metabolites. In mature, estrogen deprived mice, vibration enhances weekly bisphosphonate treatment, improving bone density, cortical thickness, and mechanical resistance …

What Needs To Be Standardized For Reliable, Reproducible, And Robust Tractography?, Jon Haitz Legarreta, Simona Schiavi, Wei Tang, Garrett Banks, Matthew Cieslak, Kurt Schilling, Alberto De Luca, Jacques-Donald Tournier, John Kruper, Francois Rheault, Stamatios N Sotiropoulos, Franco Pestilli, Jelle Veraart, Joseph Yuan-Mou Yang, Maxime Descoteaux, Sarah Heilbronner, Ariel Rokem

Faculty, Staff and Students Publications

Tractography is a key component of efforts to map brain connectivity. As a rapidly evolving field of neuroscience, current tractography methods are diverse, often varying across research laboratories and different software pipelines. Therefore, it suffers from a lack of standardization, leading to inconsistencies in results, which can limit reproducibility and affect the robustness needed for research and clinical applications of these methods. Variability in data acquisition procedures, inconsistencies in spatial referencing schemes and implementations, and anatomical heterogeneity-at the individual level, across the lifespan, and across species-hinder comparative analyses. Additionally, the lack of consensus on best practices complicates the development of …

Maturity-Onset Diabetes Of The Young (Mody) In A Racially/Ethnically Diverse Pediatric Population, Shilpi Relan, Guido Alarcon, Danielle Guffey, Charles G Minard, Mary E Fang, Kelly Timmons, Rona Y Sonabend, Mustafa Tosur, Maria J Redondo, Jennifer E Posey

Faculty, Staff and Students Publications

Context: Current practice guidelines recommend considering a diagnosis of maturity-onset diabetes of the young (MODY) in patients with diabetes with an affected parent but without typical features of type 1 or type 2 diabetes.

Objective: To test if these criteria apply to a real-world cohort of racially/ethnically diverse children with diabetes.

Methods: We performed a retrospective case review of electronic medical records of youth diagnosed with MODY in a large academic pediatric hospital in Southwestern United States. Cases were ascertained based on the identification of a molecular diagnosis of MODY.

Results: We studied 50 genetically confirmed cases of MODY: 60% …

Diagnostic Performance Of Non-Hyperemic Pressure Ratios Versus Fractional Flow Reserve Stratified By Coronary Artery: A Systematic Review And Meta-Analysis Of Individual Patient Data, Tatyana Storozhenko, Damien Collison, Nils P Johnson, Koshiro Sakai, Takuya Mizukami, Toshiro Shinke, Hitoshi Matsuo, Daniel Munhoz, Dimitri Buytaert, Hirohiko Ando, Brian Ko, Abdul Ihdayhid, Simone Biscaglia, Fernando Rivero, Thomas Engstrøm, Ketina Arslani, Antonio Maria Leone, Lokien X Van Nunen, William F Fearon, Evald Høj Christiansen, Bjarne L Nørgaard, Michael Maeng, Liyew Desta, Andy Yong, Hiromasa Otake, Yu Takahashi, Daniele Andreini, Jonathon Leipsic, Bon-Kwon Koo, Paola Monique Barbato, Jozef Bartunek, Emanuele Barbato, Jeroen Sonck, Bernard De Bruyne, Carlos Collet

Faculty, Staff and Student Publications

BACKGROUND: In the assessment of coronary physiology, non-hyperemic pressure ratios (NHPRs) provide an alternative to fractional flow reserve (FFR) without the need for hyperemic agents, reducing procedural time, side effects, and costs. However, it remains unclear whether NHPRs have similar diagnostic performance in the different coronary arteries. This study evaluates the diagnostic performance of NHPRs compared with FFR, stratified by coronary artery, in stable patients with coronary artery disease.

METHODS: We conducted a systematic review and individual patient-level data meta-analysis from prospective studies involving patients with intermediate to severe coronary stenosis who underwent physiological assessment with NHPRs and FFR. NHPRs …

Simulated Complex Cells Contribute To Object Recognition Through Representational Untangling, Mitchell B Slapik, Harel Z Shouval

Faculty, Staff and Student Publications

The visual system performs a remarkable feat: it takes complex retinal activation patterns and decodes them for object recognition. This operation, termed "representational untangling," organizes neural representations by clustering similar objects together while separating different categories of objects. While representational untangling is usually associated with higher-order visual areas like the inferior temporal cortex, it remains unclear how the early visual system contributes to this process-whether through highly selective neurons or high-dimensional population codes. This article investigates how a computational model of early vision contributes to representational untangling. Using a computational visual hierarchy and two different data sets consisting of numerals …

Long-Term Mpox Sequelae 11 To 18 Months After Acute Illness : A Cohort Study In Two Us Cities, Preetam A Cholli, Jason Zucker, Karen J Vigil, Faisal S Minhaj, Paul J Weidle, Melanie M Taylor, Brett Gray, Dana L Haberling, Agha Ajmal, Agam K Rao, Anyelina Cantos, Sarah Anne J Guagliardo, Max Flanagan, Gilhen H Rodriguez, Irene Tamí-Maury, Siobhán M O'Connor

Faculty, Staff and Student Publications

Background: Little was known about persistent sequelae of mpox before the 2022 multinational clade II mpox virus outbreak.

Objective: To characterize post-mpox sequelae 11 to 18 months after acute mpox diagnosis and compare outbreak-associated psychosocial and behavioral impact between at-risk persons who had or did not have mpox.

Design: Cohort study.

Setting: New York City, New York, and Houston, Texas.

Participants: Adults attending HIV, pre-exposure prophylaxis, or sexually transmitted infection clinics diagnosed with mpox during May 2022 to January 2023 (post-mpox) or at risk for but never diagnosed with mpox (no-mpox).

Measurements: All participants completed psychosocial and behavioral self-assessments. A …

Pseudoamniotic Band Sequence Risk Factors Following Fetoscopic Laser For Twin-Twin Transfusion Syndrome, Felicia V Lemoine, Sami Backley, Gustavo Vilchez-Lagos, Jimmy Espinoza, Edgar Hernandez-Andrade, Anthony Johnson, Ramesha Papanna, Eric Bergh

Faculty, Staff and Student Publications

Introduction: Pseudoamniotic band sequence (PABS) is a rare but serious complication following fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). We aim to explore associations between perioperative factors and PABS in monochorionic, diamniotic twins undergoing FLP for TTTS.

Methods: A secondary analysis was conducted using a prospective cohort of 816 FLP procedures performed between 2011 and 2024 at a single fetal therapy center. All cases had confirmed absence of PABS prior to FLP via ultrasound and fetoscopic evaluation. PABS was diagnosed postnatally or suspected after FLP and confirmed after birth. Clinical and perioperative variables were compared between cases with …

Genomics Define Malignant Transformation In Myeloma Precursor Conditions, Francesco Maura, P Leif Bergsagel, Bachisio Ziccheddu, Shaji Kumar, Kylee Maclachlan, Andriy Derkach, Juan-Jose Garces, Ross Firestone, Esteban Braggio, Yan Asmann, Michael Durante, Benjamin T Diamond, Marios Papadimitriou, Malin Hultcrantz, Alessio Marella, Giancarlo Castellano, Akihiro Maeda, Marta Lionetti, Antonio Matera, Stefania Pioggia, Matteo Claudio Da Vià, Claudio De Magistris, Daniel Leongamornlert, Danny Deavila, Praneeth Reddy Sudalagunta, Rafael Renatino Canevarolo, Erin M Siegel, Phaedra Agius, Jamie Teer, Andrew Mcpherson, Yusuke Yamashita, Ariosto S Silva, Patrick Blaney, Rachid Baz, Krina K Patel, Peter Campbell, Gareth Morgan, Rafael Fonseca, Ola Landgren, Robert Z Orlowski, Kenneth H Shain, Niccolo Bolli, Saad Usmani, S Vincent Rajkumar

Faculty, Staff and Student Publications

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify …

The Influence Of Bapineuzumab And Semagacestat On Rapid Progressors: A Retrospective Cohort Study, Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M Farrell, Xiaoqian Jiang, Yejin Kim, Paul E Schulz

Faculty, Staff and Student Publications

Background: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.

Objectives: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.

Design: Retrospective cohort study.

Setting: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data …

Ionic Mechanisms Of Two-Pore Channel Regulation Of Vesicle Trafficking, Heng Zhang, Michael X Zhu

Faculty, Staff and Student Publications

The endolysosomal system plays a pivotal role in cellular function. Before reaching lysosomes for degradation, the endocytosed cargoes are sorted at various stages of endosomal trafficking for recycling and/or rerouting. The proper execution of these processes depends on tightly regulated ion fluxes across endolysosomal membranes. Recent studies have demonstrated the importance of two-pore channels (TPCs), including TPC1 and TPC2, in endolysosomal trafficking. These channels are expressed in the membranes of distinct populations of endosomes and lysosomes, where they respond to nicotinic acid adenine dinucleotide phosphate (NAADP) and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] to conduct Ca2+ and Na+ release from these acidic organelles. …

B Lymphocytes Impede Tregs To Erode Islet Tolerance In Type 1 Diabetes, Christopher S Wilson, Blair T Stocks, Alexander C Falk, Daniel J Moore

Faculty, Staff and Students Publications

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and …

The Evolution Of Public Health Statistical Modeling Approaches And How To Advance Their Incorporation Into Modern Arboviral Surveillance, Maggie Mccarter, Stella C W Self, Alex Ewing, Mufaro Kanyangarara, Sarah M Gunter, Melissa S Nolan

Faculty, Staff and Students Publications

Statistical modeling of infectious disease transmission patterns has been in existence since the mid-1700s, evolving in their utility as the scientific and technological revolutions progressed. Despite the expansion of emerging mathematical and statistical methodologies over the past 250 yr, their usage has largely remained restricted to academic settings. This forum article will discuss the evolution of disease modeling techniques, the most common types of models in use today, and recommendations on how key archetypes can be incorporated into future public health practice. With the recent global impetus to predict and forecast novel pathogens, this article raises the question: Why are …

The Use Of Artificial Intelligence In Decreasing Vaccine Skepticism And Hesitancy, Nathaniel Wolf, Nhan Nguyen, Rojelio Mejia

Faculty, Staff and Students Publications

Purpose of review: Recent advances in artificial intelligence (AI) coincide with decreases in confidence in vaccines. This review examines studies that analyze and mitigate vaccine skepticism by implementing artificial intelligence strategies in various ways.

Recent findings: Studies have explored public attitudes towards vaccines using AI to analyze language in social media postings and interactions, scrutinize AI responses to vaccine-related queries, and attempt to use AI to directly influence vaccine hesitancy. Findings show that AI can be effective in addressing vaccine hesitancy in various ways, including, but not limited to, directly interacting with vaccine-hesitant groups, identifying reasons for vaccine hesitancy, and …

Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis And Apoptosis Cancer Cell Death Pathways, Christopher Egbulefu, Kvar Black, Xinming Su, Partha Karmakar, Lemoyne Habimana-Griffin, Gail Sudlow, Julie Prior, Ezugo Onejeme, Alex Zheleznyak, Baogang Xu, Yalin Xu, Alison Esser, Matthew Mixdorf, Evan Moss, Brad Manion, Cody Hongsermeier, Nisha Gamadia, Nicole Blasi, Luke Stallings, Chidube Alagbaoso, Nathan Reed, Matthew M Gubin, Chieh-Yu Lin, Robert Schreiber, Katherine Weilbaecher, Samuel Achilefu

Faculty, Staff and Student Publications

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth …

Comprehensive Metabolic Profiling Across Five Lifespan Stages In Murine Hippocampus And Cortex Reveals Sex-Related Variation In Age-Related Cognitive Decline, Xi Long, Wuping Liu, Changhan Chen, Qi Guo, Yidan Wang, Fang Yu, Yujin Zhang, Rodney E Kellems, Yang Xia

Faculty, Staff and Student Publications

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and 13C6-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. 13C6-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. …

Successful Bacteriophage Treatment Of A Recalcitrant Intra-Abdominal Infection Caused By Multi-Drug-Resistant Pseudomonas Aeruginosa In A 2-Year-Old Child, Sanchi Malhotra, Keiko C Salazar, Neema Pithia, Ishminder Kaur, Kristina Adachi, Nanda Ramachandar, Austin L Terwilliger, Anthony Maresso, Robert S Venick, Suzanne V Mcdiarmid, John S Bradley

Faculty, Staff and Students Publications

Antimicrobial resistance is life-threatening to complex pediatric patients who receive multiple courses of broad-spectrum antibiotics. Bacteriophages offer a safe treatment alternative when our antibiotic armamentarium is no longer sufficient. We describe successful use of bacteriophage therapy on a patient with a recalcitrant Pseudomonas aeruginosa infection after receiving a multi-organ transplant.

Pesticides Associated With Incident Diabetes Among Licensed Private Pesticide Applicators In The Agricultural Health Study Cohort (1993–2021), Christine G Parks, Qian Xiao, Jesse Wilkerson, Jonathan N Hofmann, Laura E Beane Freeman, Dale P Sandler

Faculty, Staff and Student Publications

Background: Growing evidence suggests pesticides may increase risk of type 2 diabetes, but data are limited on many specific chemicals.

Methods: In 29,527 private pesticide applicators in the Agricultural Health Study cohort (enrolled 1993-1997 in Iowa and North Carolina), 3,847 incident diabetes cases were identified by self-report during follow-up surveys in 1999-2003, 2005-2010, 2013-2015, and 2019-2021. We examined 50 pesticides reported at enrollment, updated in 1999-2003 or 2005-2010, prior to diabetes diagnosis or end of follow-up, using log-binomial regression to calculate relative risks (RR) and 95% confidence intervals (CI) for ever-use and intensity-weighted lifetime days (IWLD) use (tertiles, T1-3), adjusting …

Reducing Work-Related Screen-Time In Healthcare Workers During Leisure Time (Reduce Screen) - A Randomized Controlled Trial, Karsten Bartels, Karan Shah, Emelind Sanchez Rodriguez, Julie T Hoffman, Megan L Rolfzen, Juana Mora Valdovinos, Afton L Hassett, Daniel I Sessler

Faculty, Staff and Student Publications

The ubiquitous availability of work-related applications on personal devices makes healthcare workers prone to working during leisure time. We tested the hypothesis that an intervention to reduce work-related screen time during a weekend off reduces stress in healthcare workers in a pragmatic parallel design randomized controlled trial between November 2021 and November 2023. Healthcare workers using a smartphone with a work email application were eligible. Randomization was 1:1 to no treatment or a threefold educational intervention to: 1) activate automated responses to emails received, 2) reduce screen time, and 3) uninstall work applications from personal devices. The primary outcome was …

Foxo1 Inhibition And Fadd Knockdown Have Opposing Effects On Anticancer Drug-Induced Cytotoxicity And P21 Expression In Osteosarcoma Cells, Danielle Walker, Antanay Hall, Alexis Bonwell, Nancy Gordon, Danielle Robinson, Mario G Hollomon

Faculty, Staff and Student Publications

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and …