Digital Commons Network^™

Lifespan Of Male And Female App/Ps1 And Appnl-F/Nl-F Mouse Models Of Alzheimer's Disease, Hannah Roberts, Yimin Fang, Kathleen Quinn, Tiarra Hill, Mackenzie R Peck, Andrzej Bartke, Kevin N Hascup, Erin R Hascup

Articles

Alzheimer's disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APP^NL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in male APP^NL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

Effectiveness Of Intrapartum Azithromycin To Prevent Infections In Planned Vaginal Births In Low-Income And Middle-Income Countries: A Post-Hoc Analysis Of Data From A Multicentre, Randomised, Double-Blind Placebo-Controlled Trial, Waldemar A. Carlo, Alan T.N. Tita, Janet L. Moore, Musaku Mwenechanya, Elwyn Chomba, Jennifer J. Hemingway-Foday, Avinash Kavi, Mrityunjay C. Metgud, Shivaprasad S. Goudar, Richard J. Derman, Adrien Lokangaka, Antoinette Tshefu, Melissa Bauserman, Jackie K. Patterson, Poonam Shivkumar, Manju Waikar, Archana Patel, Patricia L. Hibberd, Paul Nyongesa, Fabian Esamai, Osayame Austine Ekhaguere, Sherri Bucher, Saleem Jessani, Shiyam Sunder Tikmani, Sarah Saleem, Robert L. Goldenberg, Sk Masum Billah, Ruth Lennox, Rashidul Haque, William Petri, Manolo Mazariegos, Nancy F. Krebs, Denise C. Babineau, Elizabeth M. Mcclure, Marion Koso-Thomas, A-Plus Trial Group

Global Health Articles

Background

In 2023, the Azithromycin Prevention in Labor Use (A-PLUS) trial showed intrapartum azithromycin reduces maternal sepsis or death in women with planned vaginal delivery in low-resource settings, but whether it reduces maternal infection is unknown. We aimed to evaluate the effectiveness of intrapartum azithromycin in reducing maternal infection.

Methods

We performed a post-hoc analysis of the multicentre, facility-based, randomised, double-blind, placebo-controlled A-PLUS trial. This trial compared prophylactic intrapartum single oral dose of 2 g azithromycin versus placebo on maternal morbidity and mortality in low-resource settings in southeast Asia and Africa from Sept 9, 2020, to Aug 18, 2022. The …

Cost-Effectiveness Of Intrapartum Azithromycin To Prevent Maternal Infection, Sepsis, Or Death In Low-Income And Middle-Income Countries: A Modelling Analysis Of Data From A Randomised, Multicentre, Placebo-Controlled Trial, Jackie K. Patterson, Simon Neuwahl, Sydney Kirsch, Janet L. Moore, Alan T.N. Tita, Waldemar A. Carlo, Adrien Lokangaka, Antoinette Tshefu, Musaku Mwenechanya, Elwyn Chomba, Avinash Kavi, Mrityunjay C. Metgud, Shivaprasad S. Goudar, Richard J. Derman, Poonam Shivkumar, Manju Waikar, Archana Patel, Patricia L. Hibberd, Paul Nyongesa, Fabian Esamai, Osa A. Ekhaguere, Sherri Bucher, Saleem Jessani, Shiyam S. Tikmani, Sarah Saleem, Blair J. Wylie, Robert L. Goldenberg, Sk Masum Billah, Ruth Lennox, Rashidul Haque, William A. Petri, Manolo Mazariegos, Nancy F. Krebs, Jennifer J. Hemingway-Foday, Denise Babineau, Marion Koso-Thomas, Elizabeth M. Mcclure, Melissa Bauserman

Global Health Articles

BACKGROUND: Sepsis is one of the leading causes of maternal mortality globally. In 2023, the Azithromycin Prevention in Labor Use (A-PLUS) trial showed intrapartum azithromycin for women planning a vaginal birth reduced the risk of maternal sepsis or death and infection. We aimed to evaluate the cost-effectiveness of intrapartum azithromycin for pregnant people planning a vaginal birth in low-income and middle-income countries (LMICs) using A-PLUS trial data.

METHODS: We compared the benefits and costs of intrapartum azithromycin versus standard care across 100 000 model simulations using data from the A-PLUS trial and a probabilistic decision tree model that included 24 …

Combined Targeting Of Glioblastoma Stem Cells Of Different Cellular States Disrupts Malignant Progression, Chenfei Lu, Tao Kang, Junxia Zhang, Kailin Yang, Yang Liu, Kefan Song, Qiankun Lin, Deobrat Dixit, Ryan C Gimple, Qian Zhang, Zhumei Shi, Xiao Fan, Qiulian Wu, Daqi Li, Danyang Shan, Jiancheng Gao, Danling Gu, Hao You, Yangqing Li, Junlei Yang, Linjie Zhao, Zhixin Qiu, Hui Yang, Ningwei Zhao, Wei Gao, Weiwei Tao, Yingmei Lu, Yun Chen, Jing Ji, Zhe Zhu, Chunsheng Kang, Jianghong Man, Sameer Agnihotri, Qianghu Wang, Fan Lin, Xu Qian, Stephen C Mack, Zhibin Hu, Chaojun Li, Michael D Taylor, Ning Liu, Nu Zhang, Ming Lu, Yongping You, Jeremy N Rich, Wei Zhang, Xiuxing Wang

Faculty, Staff and Students Publications

Glioblastoma (GBM) is the most lethal primary brain tumor with intra-tumoral hierarchy of glioblastoma stem cells (GSCs). The heterogeneity of GSCs within GBM inevitably leads to treatment resistance and tumor recurrence. Molecular mechanisms of different cellular state GSCs remain unclear. Here, we find that classical (CL) and mesenchymal (MES) GSCs are enriched in reactive immune region and high CL-MES signature informs poor prognosis in GBM. Through integrated analyses of GSCs RNA sequencing and single-cell RNA sequencing datasets, we identify specific GSCs targets, including MEOX2 for the CL GSCs and SRGN for the MES GSCs. MEOX2-NOTCH and SRGN-NFκB axes play important …

Cell-Matrix Feedback Controls Stretch-Induced Cellular Memory And Fibroblast Activation, Yuan Hong, Xiangjun Peng, Haomin Yu, Delaram Shakiba, Yuxuan Huang, Chengqing Qu, Aliza Mujahid, Yin-Yuan Huang, Jacob A Sandler, Kenneth M Pryse, Justin M Sacks, Elliot L Elson, Guy M Genin, Et Al.

2020-Current year OA Pubs

Mechanical stretch can activate long-lived changes in fibroblasts, increasing their contractility and initiating phenotypic transformations. This activation, critical to wound healing and procedures such as skin grafting, increases with mechanical stimulus for cells cultured in two-dimensional but is highly variable in cells in three-dimensional (3D) tissue. Here, we show that static mechanical stretch of cells in 3D tissues can either increase or decrease fibroblast activation depending upon recursive cell-extracellular matrix (ECM) feedback and demonstrate control of this activation through integrated in vitro and mathematical models. ECM viscoelasticity, signaling dynamics, and cell mechanics combine to yield a predictable, but nonmonotonic, relationship …

Effects Of Intensive Blood Pressure Treatment On Orthostatic Hypertension: Individual Level Meta-Analysis, Stephen P Juraschek, Jiun-Ruey Hu, Jennifer L Cluett, Carol Mita, Lewis A Lipsitz, Lawrence J Appel, Nigel S Beckett, Barry R Davis, Rury R Holman, Edgar R Miller, Kenneth J Mukamal, Ruth Peters, Jan A Staessen, Addison A Taylor, Jackson T Wright, William C Cushman

Faculty, Staff and Students Publications

Objective: To determine the effects of intensive blood pressure treatment on orthostatic hypertension.

Design: Systematic review and individual participant data meta-analysis.

Data sources: MEDLINE, Embase, and Cochrane CENTRAL databases through 13 November 2023.

Inclusion criteria: Population: ≥500 adults, age ≥18 years with hypertension or elevated blood pressure; intervention: randomized trials of more intensive antihypertensive drug treatment (lower blood pressure goal or active agent) with duration ≥6 months; control: less intensive antihypertensive drug treatment (higher blood pressure goal or placebo); outcome: measured standing blood pressure.

Main outcomes: Orthostatic hypertension, defined as an increase in systolic blood pressure ≥20 mm Hg or …

Spatial And Seasonal Dynamics Of Mosquito Species In Harris County, Texas, Highlight Risk Of Arbovirus Introduction And Transmission, Morgan Jibowu, Maximea Vigilant, Andre Luis Costa-Da-Silva, Alisa Nelson, Heather T Essigmann, Eric L Brown, Sarah M Gunter

Faculty, Staff and Student Publications

Mosquito-borne diseases pose a significant public health threat, particularly in densely populated urban areas. Climate change, urbanization, and global connectivity have fueled the expansion of mosquitoes and their associated pathogens, increasing the disease burden. Harris County, Texas, is among the most vulnerable regions in the United States for mosquito-borne disease outbreaks, underscoring the critical need for localized insights into mosquito population dynamics to inform vector surveillance and control strategies. This study provides a comprehensive analysis of the population dynamics of mosquito species in Harris County by exploring their species composition, spatial distribution, and seasonal patterns. Our findings reveal the extensive …

Haploinsufficiency Of Itsn1 Is Associated With A Substantial Increased Risk Of Parkinson’S Disease, Thomas P Spargo, Chloe F Sands, Isabella R Juan, Jonathan Mitchell, Vida Ravanmehr, Jessica C Butts, Ruth B De-Paula, Youngdoo Kim, Fengyuan Hu, Quanli Wang, Dimitrios Vitsios, Manik Garg, Lawrence Middleton, Michal Tyrlik, Mirko Messa, Guillermo Del Angel, Daniel G Calame, Hiba Saade, Laurie Robak, Ben Hollis, Vishnu A Cuddapah, Huda Y Zoghbi, Joshua M Shulman, Slavé Petrovski, Ismael Al-Ramahi, Ioanna Tachmazidou, Ryan S Dhindsa

Faculty, Staff and Students Publications

Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10

Care Guided By Tissue Oxygenation And Haemodynamic Monitoring In Off-Pump Coronary Artery Bypass Grafting (Bottomline-Cs): Assessor Blind, Single Centre, Randomised Controlled Trial, Jiange Han, Wenqian Zhai, Zhenhua Wu, Zhao Zhang, Tao Wang, Min Ren, Ziyue Liu, Daniel I Sessler, Zhigang Guo, Lingzhong Meng

Faculty, Staff and Student Publications

Objective: To assess whether perioperative management guided by near-infrared spectroscopy to determine tissue oxygen saturation and haemodynamic monitoring reduces postoperative complications after off-pump coronary artery bypass grafting.

Design: Assessor blinded, single centre, randomised controlled trial (Bottomline-CS trial).

Setting: A tertiary teaching hospital in China.

Participants: 1960 patients aged 60 years or older who were scheduled for elective off-pump coronary artery bypass grafting.

Interventions: All patients had multisite monitoring of tissue oxygen saturation (bilateral forehead and unilateral forearm brachioradialis) and haemodynamic monitoring. Both groups received usual care, including arterial blood pressure, central venous pressure, electrocardiography, and transoesophageal echocardiography when indicated. Guided …

Sexual Health In The Era Of Artificial Intelligence: A Scoping Review Of The Literature, Elia Abou Chawareb, Brian H. Im, Sherry Lu, Muhammed A.M. Hammad, Tiffany R. Huang, Henry Chen, Faysal A. Yafi

Student Papers, Posters & Projects

INTRODUCTION: Artificial Intelligence (AI) has witnessed significant growth in the field of medicine, leveraging machine learning, artificial neuron networks, and large language models. These technologies are effective in disease diagnosis, education, and prevention, while raising ethical concerns and potential challenges. However, their utility in sexual medicine remains relatively unexplored.

OBJECTIVE: We aim to provide a comprehensive summary of the status of AI in the field of sexual medicine.

METHODS: A comprehensive search was conducted using MeSH keywords, including "artificial intelligence," "sexual medicine," "sexual health," and "machine learning." Two investigators screened articles for eligibility within the PubMed and MEDLINE databases, with …

Prediction Of Persistent Incomplete Occlusion Of Intracranial Aneurysms Treated With Woven Endobridge Device, Muhammed Amir Essibayi, Mohamed Sobhi Jabal, Hasan Jamil, Hamza Adel Salim, Basel Musmar, Nimer Adeeb, Mahmoud Dibas, Nicole M. Cancelliere, Jose Danilo Bengzon, Oktay Algin, Sherief Ghozy, Sovann V. Lay, Adrien Guenego, Leonardo Renieri, Joseph Carnevale, Guillaume Saliou, Panagiotis Mastorakos, Kareem El Naamani, Eimad Shotar, Markus Möhlenbruch, Michael Kral, Charlotte Chung, Mohamed M. Salem, Ivan Lylyk, Paul M. Foreman, Hamza Shaikh, Vedran Župančić, Muhammad U. Hafeez, Joshua Catapano, Muhammad Waqas, Muhammed Said Besler, Yasin Celal Gunes, James D. Rabinov, Julian Maingard, Clemens M. Schirmer, Mariangela Piano, Anna L. Kühn, Caterina Michelozzi, Robert M. Starke, Ameer Hassan, Mark Ogilvie, Anh Nguyen, Jesse Jones, Waleed Brinjikji, Marie T. Nawka, Marios Psychogios, Christian Ulfert, Bryan Pukenas, Jan-Karl Burkhardt, Thien Huynh, Juan Carlos Martinez-Gutierrez, Sunil A. Sheth, Diana Slawski, Rabih Tawk, Benjamin Pulli, Boris Lubicz, Pietro Panni, Ajit S. Puri, Guglielmo Pero, Eytan Raz, Christoph J. Griessenauer, Hamed Asadi, Adnan Siddiqui, Elad I. Levy, Deepak Khatri, Neil Haranhalli, Andrew F. Ducruet, Felipe C. Albuquerque, Robert W. Regenhardt, Christopher J. Stapleton, Peter Kan, Vladimir Kalousek, Pedro Lylyk, Srikanth Boddu, Jared Knopman, Stavropoula I. Tjoumakaris, Hugo H. Cuellar-Saenz, Pascal Jabbour, Frédéric Clarençon, Nicola Limbucci, Vitor Mendes Pereira, Aman B. Patel, David J. Altschul, Adam A. Dmytriw, Worldwideweb Consortium Collaborators

Department of Neurosurgery Faculty Papers

While the Woven EndoBridge (WEB) device has transformed the treatment of wide-neck intracranial aneurysms, incomplete occlusion remains a significant challenge requiring better understanding of contributing factors. A retrospective analysis was conducted on multicenter data from patients who underwent WEB device treatment for intracranial aneurysms between January 2011 and December 2022. Using machine learning models, Cox regression, and time-stratified analyses, we evaluated factors associated with persistent incomplete occlusion, defined as non-improving Raymond-Roy Occlusion Classification grade 2 or 3 at final follow-up. Among 813 patients (607 with < 24 months follow-up, 206 with ≥ 24 months), machine learning analysis identified aneurysm height, Acom location, neck diameter, and pretreatment mRS as predictors of persistent incomplete occlusion. On Cox regression. larger aneurysm neck diameter (HR 1.13, 95% CI 1.01-1.27, p = 0.027) and height (HR 1.14, 95% CI 1.02-1.26, p = 0.017), and radial …

Gene Expression Profiling Of Pancreatic Ductal Adenocarcinoma Cells In Hypercapnia Identifies Siah3 As A Novel Prognostic Biomarker, Nitzan Zohar, Ryan Maguire, Saed Khalilieh, Aditi Jain, Dmitriy Bosykh, Wilbur B. Bowne, Harish Lavu, Charles J. Yeo, Avinoam Nevler

Department of Surgery Faculty Papers

Hypercapnia is a key feature of the respiratory microenvironment in many pathologic conditions. It occurs both as a regional and as a systemic process, and it is associated with multiple metabolic changes such as mitochondrial dysfunction, decreased ATP production, and metabolic shift from glycolytic energy production to fatty acid metabolism. In the cancer tumor microenvironment, hypercapnia has been linked at times to enhanced cell migration, invasion, and chemoresistance. Our previous work has shown that hypercapnia-associated gene signatures can be used as prognostic biomarkers. However, unlike the hypoxia-inducible factor pathway, there are no validated targets to quantify hypercapnia. In this study, …

Protocol For Unlocking Alternative Polyadenylation Insights From Bulk Rna-Seq Data With Polyaminer-Bulk, Venkata Jonnakuti, Sriya Jonnakuti, Hari Krishna Yalamanchili

Duncan NRI Faculty and Staff Publications

PolyAMiner-Bulk, a deep-learning-based algorithm to decode alternative polyadenylation (APA) dynamics from bulk RNA sequencing (RNA-seq) data, enables scientists to identify and quantify APA events from processed bulk RNA-seq data. The protocol allows researchers to explore differential APA usage between two conditions and gain a better understanding of post-transcriptional regulatory mechanisms. The major steps involve input data preparation, executing PolyAMiner-Bulk, and interpreting the results. A basic familiarity with pre-processing bulk RNA-seq data and command-line tools is suggested.

For complete details on the use and execution of this protocol, please refer to Jonnakuti et al.¹

Rare Damaging Ccr2 Variants Are Associated With Lower Lifetime Cardiovascular Risk, Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S De Vries, Martin Dichgans

Faculty, Staff and Student Publications

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested …

Delivering Guideline-Directed Medical Therapy For Heart Failure With Reduced Ejection Fraction As An Over-Encapsulated Polypill: Rationale And Protocol For The Combo-Hf-X Pilot Crossover Randomised Clinical Trial, Colette Dejong, Mark D Huffman, Anubha Agarwal, Et Al.

2020-Current year OA Pubs

INTRODUCTION: A four-drug regimen of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) is underused, in part due to prescriber inertia and low patient adherence. Although fixed-dose combination pills ('polypills') have improved adherence and clinical outcomes for other conditions, there are no polypills available that combine multiple classes of GDMT for HFrEF. Pharmacy-level over-encapsulation, in which several tablets are combined into one capsule, offers an opportunity to create customised HFrEF polypills with the goal of improving delivery of HFrEF therapies.

METHODS AND ANALYSIS: In the COMBO-HF-X pilot crossover randomised clinical trial, we will enrol 30-40 patients …

Dependence Of Mitochondrial Calcium Signalling And Dynamics On The Disaggregase, Clpb, Donato D'Angelo, Víctor H. Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R. Cupo, Hilda Delgado De La Herran, Giorgia Ghirardo, James Shorter, Ron A. Wevers, Saskia B. Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. …

Ppdpf: Preventing Kidney Disease Through Nad+, Shin-Ichiro Imai

2020-Current year OA Pubs

Researchers have discovered PPDPF, a critical cellular factor that controls NAD

Inhibition Of The Metalloprotease Adam19 As A Novel Senomorphic Strategy To Ameliorate Gut Permeability And Senescence Markers By Modulating Senescence-Associated Secretory Phenotype (Sasp)., Sudipta Bar, Tyler A U Hilsabeck, B Pattavina, José Alberto López-Domínguez, Nathan Basisty, Joanna Bons, Mark Watson, Birgit Schilling, Judith Campisi, Pankaj Kapahi, Amit Sharma

Faculty Research 2025

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition …

Using The 5ms Framework To Advance Aging-Responsive Care For Heart Failure With Reduced Ejection Fraction, Abigail Latimer, Debra K. Moser, Jia-Rong Wu, Kim K. Birtcher, Malachy J. Clancy, Jennifer D. Portz, Joanna Paladino, Daniel D. Matlock, Christopher E. Knoepke

Department of Occupational Therapy Faculty Papers

Complexity of care is the inevitable consequence of an aging population and is particularly true in instances where patients are managing chronic conditions such as heart failure with reduced ejection fraction (HFrEF). HFrEF itself is complex, with an undulating course of illness, increased risk of sudden cardiac death, and myriad accompanying treatment considerations. Generalist management of HFrEF among older patients is further complicated by competing comorbidities, potential for financial toxicity, potential for mental health symptoms, and risk of care with does not align with goals and preferences. The 5Ms (multicomplexity, mind, mobility, medications, and matters most) is a holistic conceptualization …

Adipose Progenitor Cell-Derived Extracellular Vesicles Suppress Macrophage M1 Program To Alleviate Midlife Obesity, Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang

Children’s Nutrition Research Center Staff Publications

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs …

Evaluation And Surgical Management Of Pediatric Cutaneous Melanoma And Atypical Spitz And Non-Spitz Melanocytic Tumors (Melanocytomas): A Report From Children's Oncology Group, Michael R Sargen, Raymond L Barnhill, David E Elder, Susan M Swetter, Victor G Prieto, Jennifer S Ko, Armita Bahrami, Pedram Gerami, Arivarasan Karunamurthy, Alberto S Pappo, Lynn M Schuchter, Philip E Leboit, Iwei Yeh, John M Kirkwood, Melinda Jen, Ira J Dunkel, Megan M Durham, Emily R Christison-Lagay, Mary T Austin, Jennifer H Aldrink, Casey Mehrhoff, Elena B Hawryluk, Emily Y Chu, Klaus J Busam, Vernon Sondak, Jane Messina, Susana Puig, Andrew J Colebatch, Carrie C Coughlin, Kristen G Berrebi, Theodore W Laetsch, Sarah G Mitchell, Brittani Seynnaeve

Faculty, Staff and Student Publications

Purpose: The purpose of this study was to develop recommendations for the diagnostic evaluation and surgical management of cutaneous melanoma (CM) and atypical Spitz tumors (AST) and non-Spitz melanocytic tumors (melanocytomas) in pediatric (age 0-10 years) and adolescent (age 11-18 years) patients.

Methods: A Children's Oncology Group-led panel with external, multidisciplinary CM specialists convened to develop recommendations on the basis of available data and expertise.

Results: Thirty-three experts from multiple specialties (cutaneous/medical/surgical oncology, dermatology, and dermatopathology) established recommendations with supporting data from 87 peer-reviewed publications.

Recommendations: (1) Excisional biopsies with 1-3 mm margins should be performed when feasible for clinically …

Dna Damage Response Signatures Are Associated With Frontline Chemotherapy Response And Routes Of Tumor Evolution In Extensive Stage Small Cell Lung Cancer, Benjamin B Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R Tyson, Kyle Concannon, Kavya Ramkumar, C Allison Stewart, Robert J Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V Heymach, Barzin Y Nabet, David S Shames, Carl M Gay, Lauren A Byers

Faculty, Staff and Student Publications

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.

Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is …

Deciphering The Dark Cancer Phosphoproteome Using Machine-Learned Co-Regulation Of Phosphosites, Wen Jiang, Eric J Jaehnig, Yuxing Liao, Zhiao Shi, Tomer M Yaron-Barir, Jared L Johnson, Lewis C Cantley, Bing Zhang

Faculty, Staff and Students Publications

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, yet our limited knowledge about the regulation and function of most phosphosites hampers the extraction of meaningful biological insights. To address this challenge, we integrate machine learning with phosphoproteomic data from 1195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network that maps the co-regulation of 26,280 phosphosites. By incorporating network features from CoPheeMap into a second machine learning model, namely CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA uncovers 24,015 associations between 9399 phosphosites and 104 serine/threonine kinases, shedding light on many unannotated phosphosites and …

Attitudes And Barriers Toward Antiretroviral Therapeutic Drug Monitoring Among Infectious Disease Providers, Hongmei Wang, Cecilia M Torres, Thomas P Giordano, Bich N Dang, Dong Liang

Faculty, Staff and Students Publications

Background/Objectives: Effective HIV treatment and prevention rely heavily on patient adherence to the prescribed regimen. Therapeutic drug monitoring (TDM), which involves measuring medication concentrations in blood circulation, offers an objective method to evaluate toxic or ineffective drug levels. TDM is not routinely used in HIV treatment in clinical practice. Therefore, the purpose of this study is to survey infectious disease providers’ attitudes and barriers toward therapeutic drug monitoring for antiretroviral therapy in people living with HIV. Materials and

Methods: A 15-item online survey was distributed to infectious disease providers in the Greater Houston area, including physicians, pharmacists, and mid-level practitioners …

Mathematical Modeling To Address Questions In Breast Cancer Screening: An Overview Of The Breast Cancer Models Of The Cancer Intervention And Surveillance Modeling Network, Oguzhan Alagoz, Jennifer L Caswell-Jin, Harry J De Koning, Hui Huang, Xuelin Huang, Sandra J Lee, Yisheng Li, Sylvia K Plevritis, Swarnavo Sarkar, Clyde B Schechter, Natasha K Stout, Amy Trentham-Dietz, Nicolien Van Ravesteyn, Kathryn P Lowry

Faculty, Staff and Student Publications

The National Cancer Institute-funded Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer mathematical models have been increasingly utilized by policymakers to address breast cancer screening policy decisions and influence clinical practice. These well-established and validated models have a successful track record of use in collaborations spanning over 2 decades. While mathematical modeling is a valuable approach to translate short-term screening performance data into long-term breast cancer outcomes, it is inherently complex and requires numerous inputs to approximate the impacts of breast cancer screening. This review article describes the 6 independently developed CISNET breast cancer models, with a particular focus …

Near-Infrared Fluorescence Imaging With An Met-Targeting Probe For Biopsy Site Selection In Patients With Oral Potentially Malignant Disorders, Jingbo Wang, Xuemin Shen, Qifan Ma, Lin Yang, Xiaoyu Zhou, Luting Wang, Junqi Cui, Chunye Zhang, Guojun Li, Neil Gross, Siyi Li, Ruimin Huang, Changyou Zhan, Zhen Cheng, Kun Wang, Jie Tian, Ying Yuan, Xiaofeng Tao

Faculty, Staff and Student Publications

Accurate detection of malignant transformation in oral potentially malignant disorders (OPMDs) is crucial for guiding effective treatment and improving patient management. This study evaluates the potential of MET-binding peptide-indocyanine green (cMBP-ICG), a mesenchymal-epithelial transition factor (MET)-targeted near-infrared fluorescence imaging (NIRFI) probe, for biopsy site selection in OPMDs. Preclinical results demonstrate the superior accuracy of NIRFI-assisted biopsy over conventional oral examination (COE)-based biopsy in detecting high-grade dysplasia (HGD) or squamous cell carcinoma (SCC) and reducing missed detection rates. In a clinical trial with 50 patients, NIRFI-assisted biopsy achieves significantly higher diagnostic accuracy compared to COE-based biopsy (91% vs. 72%, p = …

Icos-Expressing Car-T Cells Mediate Durable Eradication Of Triple-Negative Breast Cancer And Metastasis, Shelley Herbrich, Mehdi Chaib, Padmanee Sharma

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes. In their recent study, Cao et al introduced a B7H3-specific chimeric antigen receptor (CAR)-T cell with constitutive inducible co-stimulator (ICOS) expression (ICOS-B7H3-CAR-T), which demonstrated eradication of TNBC, including metastases, in preclinical models. These CAR-T cells exploit the expression of ICOS ligand on TNBC cells, enhancing antitumor cytotoxicity through ICOS signaling. Compared with conventional B7H3-CAR-T cells, the ICOS-B7H3-CAR-T cells exhibited superior antitumor efficacy, increased cytokine secretion, and prolonged survival in xenograft murine models. This study highlights ICOS as a promising co-stimulatory molecule for improving CAR-T …

Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation And Sensitizes Leukemias To Menin Inhibition, Xiangguo Shi, Minhua Li, Zian Liu, Jonathan Tiessen, Yuan Li, Jing Zhou, Yudan Zhu, Swetha Mahesula, Qing Ding, Lin Tan, Mengdie Feng, Yuki Kageyama, Yusuke Hara, Jacob J Tao, Xuan Luo, Kathryn A Patras, Philip L Lorenzi, Suming Huang, Alexandra M Stevens, Koichi Takahashi, Ghayas C Issa, Md Abul Hassan Samee, Michalis Agathocleous, Daisuke Nakada

Faculty, Staff and Student Publications

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding …

Gamifying Anatomy Outreach: An Underexplored Opportunity, Mikaela L. Stiver, Aamna Naveed, John Chilton, Siobhan M. Moyes

Peninsula Medical School

This article explores the underutilized potential of incorporating gamified approaches into anatomy outreach initiatives. While gamification and game-based learning approaches have been widely adopted in formal educational settings, there is a surprising lack of research on their application for community-based public engagement with anatomy. We emphasize the importance of involving community partners from the outset to co-design gamified outreach activities. A collaborative approach tailors the final products to the needs, preferences, and resources of the target audiences. By actively involving end users, co-design fosters a sense of ownership, relevance, and long-term sustainability for the educational resources. This article also presents …

Emerging Clostridioides Difficile Ribotypes Have Divergent Metabolic Phenotypes, Firas S Midani, Heather A Danhof, Nathanael Mathew, Colleen K Ardis, Kevin W Garey, Jennifer K Spinler, Robert A Britton

Faculty, Staff and Students Publications

Clostridioides difficile is a gram-positive spore-forming pathogen that commonly causes diarrheal infections in the developed world. Although C. difficile is a genetically diverse species, certain ribotypes are overrepresented in human infections, and it is unclear if metabolic adaptations are essential for the emergence of these epidemic ribotypes. To identify ribotype-specific metabolic differences, we therefore tested carbon substrate utilization by 88 C. difficile isolates and looked for differences in growth between 22 ribotypes. As expected, C. difficile was capable of growing on a variety of carbon substrates. Further, C. difficile strains clustered by phylogenetic relationship and displayed ribotype-specific and clade-specific …