Digital Commons Network^™

Genomic Analysis Of 11,555 Probands Identifies 60 Dominant Congenital Heart Disease Genes, Michael C Sierant, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent-offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to …

Acute Trem2 Inhibition Depletes Mafb-High Microglia And Hinders Remyelination, Jinchao Hou, Roberta Magliozzi, Yun Chen, Junjie Wu, John Wulf Ii, Gregory Strout, Xiangming Fang, Marco Colonna

2020-Current year OA Pubs

We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor that activates microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the

Patient- And Community-Level Characteristics Associated With Respiratory Syncytial Virus Vaccination, Diya Surie, Jennie H Kwon, Et Al.

2020-Current year OA Pubs

IMPORTANCE: In 2023, the first respiratory syncytial virus (RSV) vaccines were recommended for US adults 60 years or older, but few data are available about which patients were most likely to receive vaccine to inform future RSV vaccine outreach efforts.

OBJECTIVE: To assess patient- and community-level characteristics associated with RSV vaccine receipt and patient knowledge and attitudes related to RSV disease and RSV vaccines.

DESIGN, SETTING, AND PARTICIPANTS: During the first season of RSV vaccine use from October 1, 2023, to April 30, 2024, adults 60 years or older hospitalized with RSV-negative acute respiratory illness were enrolled in this cross-sectional …

Single-Cell Transcriptomic Analysis Of Kaposi Sarcoma, Daniel A. Rauch, Paula Valiño Ramos, Mariam Khanfar, John Harding, Ancy Joseph, Anam Fahad, Paul Simonson, Isabel Risch, Obi Griffith, Malachi Griffith, Lee Ratner

2020-Current year OA Pubs

Kaposi Sarcoma (KS) is a complex tumor caused by KS-associated herpesvirus 8 (KSHV). Histological analysis reveals a mixture of "spindle cells", vascular-like spaces, extravasated erythrocytes, and immune cells. In order to elucidate the infected and uninfected cell types in KS tumors, we examined twenty-five skin and blood samples from sixteen subjects by single cell RNA sequence analyses. Two populations of KSHV-infected cells were identified, one of which represented a CD34-negative proliferative fraction of endothelial cells, and the second representing CD34-positive cells expressing endothelial genes found in a variety of cell types including high endothelial venules, fenestrated capillaries, and endothelial tip …

Women’S Health Considerations In Traumatic Brain Injury, Sindhoori Nalla

Department of Rehabilitation Medicine Faculty Papers

Purpose of Review: Biological sex differences are an important factor to consider when treating TBI, as there can be a disproportionate manifestation of symptoms and recovery process when comparing females to males. Historically, these differences have not been well studied, and there is still much to be understood as to why these differences exist. Recent Findings: A number of factors are thought to contribute to disparities with women who have a TBI, including lack of well-designed research studies focused on women, hormonal fluctuations at the time of and as a result of a TBI, psychosocial comorbidities, and societal norms/expectations. While …

Oral Decitabine Cedazuridine With And Without Venetoclax In Higher-Risk Myelodysplastic Syndromes Or Chronic Myelomonocytic Leukemia: A Propensity Score-Matched Study, Alex Bataller, Koji Sasaki, Samuel Urrutia, Guillermo Montalban-Bravo, Alexandre Bazinet, Kelly Chien, Danielle Hammond, Ian M Bouligny, Mahesh Swaminathan, Ghayas Issa, Nicholas Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gail J Roboz, Michael Savona, Elizabeth A Griffiths, James Mccloskey, Olatoyosi Odenike, Aram Oganesian, Harold N Keer, Mohammad Azab, Hagop Kantarjian, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Hypomethylating agents (HMA) are indicated in the treatment of higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The combination of hypomethylating agents with venetoclax (Ven) has demonstrated promising results in these diseases, although randomized clinical trials are needed for validation. In this retrospective study, we compared two matched cohorts of patients with MDS or CMML: one receiving oral decitabine-cedazuridine (DEC-C, n = 73) and one receiving DEC-C and Ven (DEC-C-Ven, n = 51), in three contemporary clinical trials. The aim is to determine the impact of the addition of Ven to HMA in MDS and CMML. Individuals were matched …

Cigarette Smoke Induces Angiogenic Activation In The Cancer Field Through Dysregulation Of An Endothelial Microrna, Asawari Korde, Anuradha Ramaswamy, Seth Anderson, Lei Jin, Jian-Ge Zhang, Buqu Hu, Walter V Velasco, Lixia Diao, Jing Wang, Margaret A Pisani, Maor Sauler, Daniel J Boffa, Jonathan T Puchalski, Xiting Yan, Seyed Javad Moghaddam, Shervin S Takyar

Faculty, Staff and Student Publications

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial …

Characterization Of Hepatic Pathology During Azoxymethane-Induced Acute Liver Failure, Shadikchhya Maya Bhattarai, Ashwin Jhawer, Gabriel Frampton, Eleonora Troyanovskaya, Sharon Demorrow, Matthew Mcmillin

Faculty, Staff and Students Publications

Background: Acute liver failure (ALF) is a loss of liver function due to a severe hepatic insult. Studies utilizing the azoxymethane (AOM) mouse model of ALF, which also generates hepatic encephalopathy, have primarily focused on development of neurological deficits. However, the molecular processes that generate liver damage have not been fully characterized. Therefore, a more comprehensive characterization of the hepatic consequences of AOM toxicity is needed to better understand this disease model.

Aim: To identify molecular pathology contributing to hepatic injury during the progression of AOM-induced ALF.

Methods: C57BL/6 mice were injected with AOM to produce ALF and hepatic encephalopathy. …

Dock2 Deficiency And Gata2 Haploinsufficiency Can Underlie Critical Coronavirus Disease 2019 (Covid-19) Pneumonia, Sajjad Biglari, Leila Youssefian, Mohammad Amin Tabatabaiefar, Amir Hossein Saeidian, Bahareh Abtahi-Naeini, Erfan Khorram, Roya Sherkat, Atefeh Sohanforooshan Moghaddam, Fatemeh Mohaghegh, Maziyar Rahimi, Hamid Rahimi, Sharareh Babaei, Mohammad Shahrooei, Nikoo Mozafari, Shirin Zaresharifi, Fatemeh Vahidnezhad, Vida Homayouni, Lam C Tsoi, Johann E Gudjonsson, Hakon Hakonarson, Jean-Laurent Casanova, Emmanuelle Jouanguy, Vivien Béziat, Qian Zhang, Aurélie Cobat, Hassan Vahidnezhad

Faculty, Staff and Students Publications

The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80-85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon …

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.

Pmp2+ Schwann Cells Maintain The Survival Of Large-Caliber Motor Axons, Mikolaj M Kozlowski, Amy Strickland, Ana Morales Benitez, Robert E Schmidt, A Joseph Bloom, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing

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 …

Radial Glia Integrin Avb8 Regulates Cell Autonomous Microglial Tgfβ1 Signaling That Is Necessary For Microglial Identity, Gabriel Mckinsey, Nicolas Santander, Xiaoming Zhang, Kilian Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E. S. Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky, Thomas Arnold

Department of Medicine Faculty Papers

Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers …

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, …

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 …

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 …

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 …

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 = …

Impact Of Vascular Geometry On Thrombosis In Pediatric Patients With Modified Blalock-Taussig-Thomas Shunt: A Pilot Study, Ethan Penn, Yi Qiao, Kimsey Platten, Scott M Bugenhagen, Ram Rohatgi, Jacob R Miller, Jiaxiao Fang, Kelsey Mercer, Blaire Kulp, Jinli Wang, Guy M Genin, David Bark, Edon J Rabinowitz

2020-Current year OA Pubs

BACKGROUND: Thrombosis in modified Blalock-Taussig-Thomas shunts (mBTTS) poses a life-threatening risk for infants with shunt-dependent congenital heart disease. Although hemodynamics influence thrombosis, the specific geometric contributors remain unclear. This study aimed to identify key variables to inform future hemodynamic analysis, hypothesizing that brachiocephalic, subclavian artery, mBTTS, and/or pulmonary artery (PA) geometry play a critical role in clot formation.

METHODS AND RESULTS: We retrospectively analyzed 11 infants with hypoplastic left heart syndrome who underwent mBTTS placement. Using computed tomography and magnetic resonance imaging, we generated 3-dimensional models of the shunt and surrounding vasculature. Geometric variables related to shunt positioning and vascular …

Exploring Profiles Of Fathers Integrating Food And Physical Activity Parenting Practices, John A Jimenez-Garcia, Louise C Mâsse, Robert L Newton, Salma M Musaad, Alicia Beltran, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Objective: This study aims to identify fathers' profiles integrating food parenting practices (FPP) and physical activity parenting practices (PAPP).

Design: We analysed cross-sectional data. The fathers completed the reduced FPP and PAPP item banks and socio-demographic and family dynamics (co-parenting and household responsibility) questionnaires. We identified fathers' profiles via latent profile analysis. We explored the influence of social determinants, child characteristics and family dynamics on fathers' profiles using multinomial logistic regression.

Setting: Online survey in the USA.

Participants: Fathers of 5-11-year-old children.

Results: We analysed data from 606 fathers (age = 38 ± 8·0; Hispanic = 37·5 %). Most fathers …

An Exosome-Based Liquid Biopsy Predicts Depth Of Response And Survival Outcomes To Cetuximab And Panitumumab In Metastatic Colorectal Cancer: The Exonerate Study, Caiming Xu, Alessandro Mannucci, Francis Esposito, Helena Oliveres, Vicente Alonso-Orduña, Alfonso Yubero, Carlos Fernández-Martos, Antonieta Salud, Javier Gallego, Marta Martín-Richard, Julen Fernández-Plana, Mónica Guillot, Jorge Aparicio, Marwan Fakih, Scott Kopetz, Jaime Feliu, Joan Maurel, Ajay Goel

Faculty, Staff and Student Publications

Purpose: The EXOsome and cell-free miRNAs of anti-EGFR ResistAnce (EXONERATE) study was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC).

Patients and methods: Patients with newly diagnosed RAS wild-type, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in two nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRCs to predict PFS, OS, and ORR.

Results: Genome-wide …

Impact Of Co-Mutations And Transcriptional Signatures In Non-Small Cell Lung Cancer Patients Treated With Adagrasib In The Krystal-1 Trial, Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach

Faculty, Staff and Student Publications

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: …

Ca-125 As A Biomarker In Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, And Prospective Clinical Validation, Sandra L Grimm, Menuka Karki, Kyle A Blum, Jean-Philippe Bertocchio, Rong He, Durga N Tripathi, Niki M Zacharias, Justin M Lebenthal, Rahul A Sheth, Priya Rao, Giannicola Genovese, Zhen Lu, Robert C Bast, Davis R Ingram, Rossana Lazcano, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Nizar M Tannir, Cheryl L Walker, Cristian Coarfa, Pavlos Msaouel

Faculty, Staff and Student Publications

Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC.

Experimental design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA sequencing and histone chromatin immunoprecipitation sequencing. The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. …

Identification Of Lysosomal Lipolysis As An Essential Noncanonical Mediator Of Adipocyte Fasting And Cold-Induced Lipolysis, Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Et Al.

2020-Current year OA Pubs

Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. …

Effect Of Testosterone Treatment During Puberty In Boys With Klinefelter Syndrome (The Tipy Study): Protocol For A Nationwide Randomised, Double-Blinded, Placebo-Controlled Study, Ida Dyhr Caspersen, Andrés Felipe Østergaard Fritzbøger, Jørgen Holm Petersen, Niels Birkebæk, Ann-Margrethe Rønholt Christensen, Anders Jørgen Schou, Kurt Kristensen, Judith L. Ross, Shanlee Davis, Gary Butler, Sophie Van Rijn, Anders Juul, Lise Aksglaede

Department of Pediatrics Faculty Papers

INTRODUCTION: Klinefelter syndrome (KS) is a genetic condition characterised by the presence of an extra X chromosome in males (47,XXY). KS is associated with various phenotypic characteristics in adult life, including infertility, hypogonadism and increased risk of type II diabetes, cardiovascular disease and osteoporosis. Additionally, individuals with KS often experience mental health challenges and functional impairments that significantly impact their quality of life. Currently, testosterone replacement therapy (TRT) in adolescence is considered the first-line treatment by some physicians for patients with KS and biochemical signs of hypogonadism. However, comprehensive evidence on its effectiveness in preventing typical phenotypic traits associated with …

Inflammation And Gut Barrier Function-Related Genes And Colorectal Cancer Risk In Western European Populations, Hannah B Mandle, Mazda Jenab, Marc J Gunter, Anne Tjønneland, Anja Olsen, Christina C Dahm, Jie Zhang, Pierre-Emmanuel Sugier, Joseph Rothwell, Gianluca Severi, Rudolf Kaaks, Verena A Katzke, Matthias B Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Carlotta Sacerdote, Catalina Bonet, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Marcela Guevara, Richard Palmqvist, Thyra Löwenmark, Aurora Perez-Cornago, Elisabete Weiderpass, Alicia K Heath, Amanda J Cross, Paolo Vineis, David J Hughes, Veronika Fedirko

Faculty, Staff and Student Publications

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set …