Digital Commons Network^™

Nemvaleukin Alfa Monotherapy In Patients With Advanced Melanoma And Renal Cell Carcinoma: Results From The Phase 1/2 Non-Randomized Artistry-1 Trial, Emiliano Calvo, Valentina Boni, Olivier Dumas, Sang Joon Shin, Seth D Rosen, Arvind Chaudhry, Philip R Debruyne, Xiaomin He, Ulka N Vaishampayan, David F Mcdermott

School of Nursing and Midwifery

BACKGROUND: Despite improved outcomes with immune checkpoint inhibitors (ICIs) and their combinations in advanced solid tumors, a subset of patients remains unresponsive or progresses, highlighting an unmet need for novel treatments with durable benefit. Nemvaleukin alfa (nemvaleukin, ALKS 4230) demonstrated manageable safety and antitumor activity, alone and in combination with pembrolizumab, across heavily pretreated advanced solid tumors in the ARTISTRY-1 study. We report in-depth antitumor activity, safety, pharmacokinetics, and pharmacodynamics of nemvaleukin monotherapy at the recommended phase 2 dose (RP2D) in advanced melanoma and renal cell carcinoma (RCC) cohorts from ARTISTRY-1.

METHODS: ARTISTRY-1 was a three-part (A, B, and C), …

Depletion Of Effector Regulatory T Cells Associates With Major Response To Induction Dual Immune Checkpoint Blockade, Xianli Jiang, Nils-Petter Rudqvist, Bo Jiang, Shengbin Ye, Shan He, Qingnan Liang, Jinzhuang Dou, Michelle D Williams, Joe Dan Dunn, Jason M Johnson, Keiko Akagi, Weihong Xiao, Shaoheng Liang, Satvik Elayavalli, Baohua Sun, Edwin R Parra, Renata Ferrarotto, Adam S Garden, Clifton David Fuller, Jay Reddy, Neil D Gross, Miriam N Lango, Cheuk Hong Leung, Suyu Liu, Diane D Liu, Meng Li, J Jack Lee, Michael A Curran, Jack Phan, Ken Chen, Maura L Gillison

Faculty, Staff and Student Publications

In a phase II trial, patients with local-regionally advanced human papillomavirus-positive oropharyngeal carcinoma (n = 35) received ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Coprimary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. …

An Ethanol-Induced Loss Of The Lipid Droplet-Associated Segregase Vcp/P97 Leads To Hepatic Steatosis, Sandhya Sen, Shaun Weller, Ryan J Schulze, Donglin Ding, Carol A Casey, Conrad Weihl, Mark A Mcniven

2020-Current year OA Pubs

The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17β13) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor …

Enhancing Patient Positioning Accuracy: Evaluating Daily Cone Beam Computed Tomography In The Halcyon System., Duong Thanh Tai, Luong Tien Phat, Tran Trung Kien, Nguyen Ngoc Anh, Nguyen Xuan Hai, Peter Sandwall, David Bradley, James C L Chow

Oncology Articles

BACKGROUND: Precise patient positioning is crucial for successful radiotherapy, ensuring accurate delivery of radiation to tumors while minimizing exposure to healthy tissues. Positional errors can significantly impact treatment efficacy and increase side effects. This study evaluates the effectiveness of daily cone beam computed tomography (CBCT) imaging in the Halcyon system for detecting and correcting patient misalignments across various cancer types and treatment sites.

METHODS: A retrospective analysis was conducted on 411 patients treated with the Varian Halcyon linear accelerator from August 2022 to August 2024. Patients were grouped based on tumor location: Head and Neck (118 patients), Chest (188 patients), …

Rsph4a-Pcdx: An Index To Predict Lung Function Decline In Primary Ciliary Dyskinesia, Gabriel Román-Ríos, Gabriel Rosario-Ortiz, Marcos J Ramos-Benitez, Ricardo A Mosquera, Wilfredo De Jesús-Rojas

Faculty, Staff and Student Publications

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder that impairs mucociliary clearance and leads to progressive lung disease. This study aimed to characterize lung function decline in a genetically homogeneous cohort of Puerto Rican patients with

Inhibition Of Epithelial Cell Yap-Tead/Lox Signaling Attenuates Pulmonary Fibrosis In Preclinical Models, Darcy Elizabeth Wagner, Hani N Alsafadi, Nilay Mitash, Aurelien Justet, Qianjiang Hu, Ricardo Pineda, Claudia Staab-Weijnitz, Martina Korfei, Nika Gvazava, Kristin Wannemo, Ugochi Onwuka, Molly Mozurak, Adriana Estrada-Bernal, Juan Cala-Garcia, Katrin Mutze, Rita Costa, Deniz Bölükbas, John Stegmayr, Wioletta Skronska-Wasek, Stephan Klee, Chiharu Ota, Hoeke A Baarsma, Jingtao Wang, John Sembrat, Anne Hilgendorff, Jun Ding, Andreas Günther, Rachel Chambers, Ivan Rosas, Stijn De Langhe, Naftali Kaminski, Mareike Lehmann, Oliver Eickelberg, Melanie Königshoff

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX …

Sporadic Als Induced Pluripotent Stem Cell Derived Neurons Reveal Hallmarks Of Tdp-43 Loss Of Function, Jeffrey D Rothstein, Olivia Keeley, Caroline Warlick, Timothy M Miller, Cindy V Ly, Jonathan D Glass, Alyssa N Coyne

2020-Current year OA Pubs

Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same …

Retinal Vascular Dysfunction In The Mthfr(677c>T) Mouse Model Of Cerebrovascular Disease, Alaina M Reagan, Michael Maclean, Travis L Cossette, Gareth R Howell

Faculty Research 2025

INTRODUCTION: Investigations of retinal biomarkers for Alzheimer's disease (AD) and AD and related dementias (ADRD), has increased significantly. We examine retinal vascular health in a mouse containing the ADRD risk variant Mthfr

METHODS: Morphology and function of retinal vasculature and neurons were assessed using in vivo imaging, immunohistochemistry, and pattern electroretinography. RNAscope and proteomics were employed to determine Mthfr gene expression and differential protein expression in mice carrying Mthfr

RESULTS: Mice show age- and sex-dependent retinal vascular deficits, displaying similarities to previously published brain data. Mthfr is widely expressed and co-localizes with vascular cell markers. Proteomics identified common molecular signatures …

Mitochondrial Complex I Deficiency Induces Alzheimer's Disease-Like Signatures That Are Reversible By Targeted Therapy., Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina

Faculty Research 2025

INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4

METHODS: Cortico-hippocampal tissue from Ndufs4

RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4

DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest …

Alternating Hemiplegia Of Childhood Associated Mutations In Atp1a3 Reveal Diverse Neurological Alterations In Mice., Markus Terrey, Georgii Krivoshein, Scott I Adamson, Elena Arystarkhova, Laura C. Anderson, John Szwec, Shelby Mckee, Holly Jones, Sara Perkins, Vijay Selvam, Pierre-Alexandre Piec, Dweet Chhaya, Ari Dehn, Aamir Zuberi, Stephen A Murray, Natalia S Morsci, Kathleen J Sweadner, David A Knowles, Else A Tolner, Arn M J M Van Den Maagdenberg, Cathleen Lutz

Faculty Research 2025

Pathogenic variants in the neuronal Na⁺/K⁺ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting …

Association Of Epigenetic Aging With Plasma Cbiomarkers Of Amyloid, Tau, Neurodegeneration, And Neuroinflammation In Hispanic/Latino Adults, Myriam Fornage, Wassim Tarraf, Martha L Daviglus, Charles Decarli, Kevin A Gonzalez, Carmen R Isasi, Sayaka Kuwayama, Melissa Lamar, Bonnie E Levin, Humberto Parada, Alberto R Ramos, Tatjana Rundek, Bharat Thyagarajan, Hector M González

The Brown Foundation: Institute of Molecular Medicine

Background: Blood-based biomarkers hold significant promise for the early detection and diagnosis of Alzheimer's disease (AD) and other dementias. Age-related changes in blood levels of AD biomarkers are well-documented but poorly understood. Epigenetic clocks are mathematical models based on DNA methylation patterns that reflect various aspects of the multidimensional aging process. We investigated the associations of epigenetic aging with five blood-based AD biomarkers in 2656 Hispanic/Latino adults (mean age 62.5 years; 65% females) from the Hispanic Community Health Study/Study of Latinos. We used multivariable linear regression models to estimate the associations of acceleration in each of five epigenetic clocks with …

The Impact Of Gender, Training Year, Medical Specialty And The Covid-19 Pandemic On Resident Wellness, Sara Beachy, Jessica Luzier, Chantel Weisenmuller, Kathleen Bors, Mary Ann Maurer, Amna Anees, Tiffany Lasky, Lisa Calderwood

Department of Family & Community Medicine Faculty Papers

INTRODUCTION: Data are limited as to which factors most strongly impact medical trainees' well-being, and few studies have assessed trainee's wellness at multiple time points during the COVID-19 pandemic. Additionally, much research has not taken an intersectional approach to understanding the ways in which different facets of a resident's identity impact their wellness. Thus, more person-centred, probability-driven statistical approaches that can produce distinct heterogenous groups of individuals are warranted to understand the way in which different identities are associated with resident wellness scores.

METHODS: A latent profile analysis was conducted using institutional data from resident surveys administered from 2019 to …

Multicenter Span Trial Of Fasudil In Ischemic Stroke, Takahiko Imai, Andreia Lopes De Morais, Xuyan Jin, Tao Qin, Jessica Lamb, Karisma A Nagarkatti, Mu-Hsun Chen, Ligia S B Boisserand, Rakesh B Patel, Mariia Kumskova, Anjali Chauhan, Krishnan M Dhandapani, Mohammad B Khan, Pradip K Kamat, Yanrong Shi, Suyi Cao, Basavaraju G Sanganahalli, Joseph B Mandeville, Patrick D Lyden, David C Hess, Enrique C Leira, Anil K Chauhan, Jaroslaw Aronowski, Louise D Mccullough, Raymond C Koehler, Lauren H Sansing, Márcio A Diniz, Cenk Ayata

Children’s Nutrition Research Center Staff Publications

Background: The SPAN (Stroke Preclinical Assessment Network) is a confirmatory multicenter trial network to test cerebroprotective interventions in experimental acute stroke. In a first-of-its-kind trial, SPAN tested 6 interventions in a rodent model of transient focal ischemic stroke. Here, we report the efficacy of fasudil, an isoform-nonselective rho-associated kinase inhibitor, on primary and secondary outcomes in the SPAN trial.

Methods: Fasudil was administered at 10 mg/kg intraperitoneally every 12 hours for 6 doses starting 5 minutes before reperfusion in a 60-minute endovascular filament middle cerebral artery occlusion model. The active treatment arm (n=345) was compared with the pooled intraperitoneal and …

Impaired Rest-Activity Rhythm Characteristics Predict Higher Risk Of Incident Type 2 Diabetes In Uk Biobank Participants, Chris Ho Ching Yeung, Alison K Wright, Daniel P Windred, Angus C Burns, Andrew J K Phillips, Sean W Cain, Martin K Rutter, Qian Xiao

Faculty, Staff and Student Publications

Objective: Circadian rhythms play a key role in metabolic health. Rest-activity rhythms, which are in part driven by circadian rhythms, may be associated with diabetes risk. There is a need for large prospective studies to comprehensively examine different rest-activity metrics to determine their relative strength in predicting risk of incident type 2 diabetes.

Research design and methods: In actigraphy data from 83,887 UK Biobank participants, we applied both parametric and nonparametric algorithms to derive 13 different metrics characterizing different aspects of rest-activity rhythm. Diabetes cases were identified using both self-reported data and health records. We used Cox proportional hazards models …

Linking Chronic Kidney Disease To Incident Heart Failure And Adverse Cardiac Remodeling Through The Plasma Proteome: The Aric Study, Leo F Buckley, Pranav Dorbala, Victoria Lamberson, Brian L Claggett, Yue Ren, Morgan E Grams, Josef Coresh, Kunihiro Matsushita, Ryan T Demmer, Ruth F Dubin, Rajat Deo, Peter Ganz, Christie M Ballantyne, Ron C Hoogeveen, Bing Yu, Amil M Shah

Faculty, Staff and Student Publications

Background: Investigation of circulating plasma proteins may reveal insights into molecular pathways that contribute to the development of heart failure (HF) among people with chronic kidney disease.

Objectives: The authors aimed to identify circulating kidney function-related plasma proteins that are associated with the risk of incident HF.

Methods: The authors studied participants of the ongoing longitudinal ARIC (Atherosclerosis Risk In Communities) study. Relative plasma concentrations of 4,697 unique proteins were measured with the use of an aptamer assay (Somalogic). Each protein was tested for associations with estimated glomerular filtration rate (eGFR), log-transformed urine albumin-to-creatinine ratio (UACR), and incident HF by …

Racial Disparities In The Receipt Of Therapies For Cancer, Hypertension, And Diabetes, And In Mortality In A Large Population-Based Cohort Of Older Men With Prostate Cancer, Zhuoyun Li, Xianglin L Du

Faculty, Staff and Student Publications

Background: Racial disparities in treatment and mortality were widely studied among prostate cancer patients; however, few studies considered the prevalence of hypertension and diabetes and their treatment status.

Objectives: To determine whether there are racial discrepancies in the use of anti-cancer, antihypertensive, and antidiabetic drugs in a cohort of long-term survivors of prostate cancer diagnosed in 2007-2015; and to examine racial disparities in mortality after adjustments for their differences in those treatments.

Methods: We used the SEER (Surveillance, Epidemiology, and End Results)-Medicare linked database and included records for patients with prostate cancer at age 65 years or older diagnosed from …

A Large-Scale Genome-Wide Study Of Gene-Sleep Duration Interactions For Blood Pressure In 811,405 Individuals From Diverse Populations, Pavithra Nagarajan, Thomas W Winkler, Amy R Bentley, Clint L Miller, Aldi T Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael R Brown, John L Morrison, Ayush Giri, Jeffrey R O'Connell, Traci M Bartz, Lisa De Las Fuentes, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Zhijie Huang, Mart Kals, Minjung Kho, Christophe Lefevre, Jian'an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Yuri Milaneschi, Nicholette D Palmer, Varun Rao, Rainer Rauramaa, Botong Shen, Stefan Stadler, Quan Sun, Jingxian Tang, Sébastien Thériault, Adriaan Van Der Graaf, Peter J Van Der Most, Yujie Wang, Stefan Weiss, Kenneth E Westerman, Qian Yang, Tabara Yasuharu, Wei Zhao, Wanying Zhu, Drew Altschul, Md Abu Yusuf Ansari, Pramod Anugu, Anna D Argoty-Pantoja, Michael Arzt, Hugues Aschard, John R Attia, Lydia Bazzanno, Max A Breyer, Jennifer A Brody, Brian E Cade, Hung-Hsin Chen, Yii-Der Ida Chen, Zekai Chen, Paul S De Vries, Latchezar M Dimitrov, Anh Do, Jiawen Du, Charles T Dupont, Todd L Edwards, Michele K Evans, Tariq Faquih, Stephan B Felix, Susan P Fisher-Hoch, James S Floyd, Mariaelisa Graff, Charles Gu, Dongfeng Gu, Kristen G Hairston, Anthony J Hanley, Iris M Heid, Sami Heikkinen, Heather M Highland, Michelle M Hood, Mika Kähönen, Carrie A Karvonen-Gutierrez, Takahisa Kawaguchi, Setoh Kazuya, Tanika N Kelly, Pirjo Komulainen, Daniel Levy, Henry J Lin, Peter Y Liu, Pedro Marques-Vidal, Joseph B Mccormick, Hao Mei, James B Meigs, Cristina Menni, Kisung Nam, Ilja M Nolte, Natasha L Pacheco, Lauren E Petty, Hannah G Polikowsky, Michael A Province, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Stephen S Rich, Renata L Riha, Lorenz Risch, Martin Risch, Edward A Ruiz-Narvaez, Rodney J Scott, Colleen M Sitlani, Jennifer A Smith, Tamar Sofer, Maris Teder-Laving, Uwe Völker, Peter Vollenweider, Guanchao Wang, Ko Willems Van Dijk, Otis D Wilson, Rui Xia, Jie Yao, Kristin L Young, Ruiyuan Zhang, Xiaofeng Zhu, Jennifer E Below, Carsten A Böger, David Conen, Simon R Cox, Marcus Dörr, Mary F Feitosa, Ervin R Fox, Nora Franceschini, Sina A Gharib, Vilmundur Gudnason, Sioban D Harlow, Jiang He, Elizabeth G Holliday, Zoltan Kutalik, Timo A Lakka, Deborah A Lawlor, Seunggeun Lee, Terho Lehtimäki, Changwei Li, Ching-Ti Liu, Reedik Mägi, Fumihiko Matsuda, Alanna C Morrison, Brenda Wjh Penninx, Patricia A Peyser, Jerome I Rotter, Harold Snieder, Tim D Spector, Lynne E Wagenknecht, Nicholas J Wareham, Alan B Zonderman, Kari E North, Myriam Fornage, Million Veteran Program, Adriana M Hung, Alisa K Manning, James Gauderman, Han Chen, Patricia B Munroe, Dabeeru C Rao, Diana Van Heemst, Susan Redline, Raymond Noordam, Heming Wang

Faculty, Staff and Student Publications

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health …

Accelerometer-Measured Chronoactivity And Type 2 Diabetes Risk: A Prospective Study In Uk Biobank Participants, Qiuyu Feng, Gali Albalak, Ko Willems Van Dijk, Jeroen H P M Van Der Velde, Qian Xiao, Raymond Noordam, Diana Van Heemst

Faculty, Staff and Student Publications

Objective: We assessed whether timing of physical activity, independent from the total activity amount, - which we refer to as chronoactivity - is associated with type 2 diabetes (T2D) risk.

Methods: We included UK Biobank participants with valid accelerometry data (UK, exposure measurement: 2013-2015, follow-up till November 2023) and without diabetes mellitus at baseline (N = 89,439; mean age: 61.7 [SD:7.9] years). Relative hourly physical activity was calculated by dividing the average hourly clock time physical activity by the average hourly physical activity in a week. Participants were categorized into different chronoactivity clusters using k-means cluster analysis on relative hourly …

Transcriptomic Analysis Of Localized High-Risk Prostate Cancer Improves Prognostication And Identifies Benefit From Adding Docetaxel To Definitive Radiotherapy With Androgen Suppression In The Nrg Oncology/Rtog 0521 Phase 3 Trial, Ryan M Phillips, James A Proudfoot, Elai Davicioni, Yang Liu, Daniel E Spratt, Jeff M Simko, Robert B Den, Alan Pollack, Seth A Rosenthal, A Oliver Sartor, Christopher J Sweeney, Gerhardt Attard, Leslie Longoria, Samir Patel, Michael W Straza, Jason A Efstathiou, Amit B Shah, Karen E Hoffman, Joseph P Rodgers, Howard M Sandler, Felix Y Feng, Phuoc T Tran

Faculty, Staff and Student Publications

Background and objective: NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response.

Methods: Decipher GC scores and basal-luminal cellular subtypes were generated for specimens from …

Bayesian Counterfactual Machine Learning Individualizes Radiation Modality Selection To Mitigate Immunosuppression, Duo Yu, Michael J Kane, Yiqing Chen, Steven H Lin, Radhe Mohan, Brian P Hobbs

Faculty, Staff and Student Publications

Purpose: Lymphocytes play critical roles in cancer immunity and tumor surveillance. Radiation-induced lymphopenia (RIL) is a common side effect observed in patients with cancer undergoing chemoradiation therapy (CRT), leading to impaired immunity and worse clinical outcomes. Although proton beam therapy (PBT) has been suggested to reduce RIL risk compared with intensity-modulated radiation therapy (IMRT), this study used Bayesian counterfactual machine learning to identify distinct patient profiles and inform personalized radiation modality choice.

Methods: A novel Bayesian causal inferential technique is introduced and applied to a matched retrospective cohort of 510 patients with esophageal cancer undergoing CRT to identify patient profiles …

Inhibition Of Methylthioadenosine Phosphorylase Protects From Experimental Acute Kidney Injury, Afaf Saliba, Yidong Chen, Jonathan W Nelson, Abhinav Vetcha, Wei Wei Wang, Li Kang, Nagarjunachary Ragi, Soumya Maity, Hamid Rabb, W Brian Reeves, Kumar Sharma

Faculty, Staff and Student Publications

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfusion and cisplatin-induced acute kidney injury (AKI). MTAP inhibition was confirmed by accumulation of methylthioadenosine (MTA). Treated mice showed reduced renal injury and decreased tubular damage. Transcriptomic analysis revealed protection from inflammatory and stress pathways, while maintaining oxidative phosphorylation, fatty acid metabolism, and epithelial integrity-related genes. Analysis of human single-cell RNA-seq data from the Kidney Precision Medicine Project indicated that MTAP is highly expressed in kidney injury marker-positive adaptive proximal tubule …

Associative Coding Of Conditioned Fear In The Thalamic Nucleus Reuniens In Rodents And Humans, Tuğçe Tuna, Michael S Totty, Muhammad Badarnee, Flávio Afonso Gonçalves Mourão, Shaun Peters, Mohammad R Milad, Stephen Maren

Faculty, Staff and Student Publications

The nucleus reuniens (RE) is a midline thalamic structure interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Recent work in both rodents and humans implicates the RE in the adaptive regulation of emotional memories, including the suppression of learned fear. However, the neural correlates of aversive learning in the RE of rodents and humans remain unclear. To address this, we recorded RE activity in humans (BOLD fMRI) and rats (fiber photometry) during Pavlovian fear conditioning and extinction. In both rats and humans, we found that conditioned stimulus (CS)-evoked activity in RE reflects the associative value of the CS. …

Associations Between Prostate Cancer And Dementia: A Nationwide Study In Sweden, Casey Crump, Pär Stattin, James D Brooks, Jan Sundquist, Jingkai Wei, Weiva Sieh, Kristina Sundquist

Faculty, Staff and Student Publications

Background and objective: Prostate cancer (PC) and dementia may commonly co-occur; yet, prior evidence for bidirectional associations is inconsistent. This study aims to determine the associations between PC and dementia in large population-based studies, which may further inform clinical care.

Methods: To assess the dementia risk in men with PC, a national cohort study was conducted in 178 746 men diagnosed with PC in 1998-2017 and 1 787 460 age-matched control men in Sweden without prior dementia. Cox regression was used to estimate hazard ratios (HRs) for Alzheimer's disease (AD) and vascular dementia (VaD) through 2018. Subanalyses explored differences by …

White Matter Abnormalities And Cognition In Aging And Alzheimer Disease, Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R Pechman, Abigail W Workmeister, T Bryan Jackson, Yuankai Huo, Shubhabrata Mukherjee, Jesse Mez, Logan C Dumitrescu, Katherine A Gifford, Corey J Bolton, Leslie S Gaynor, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun-Turgut, Mohamad Habes, Di Wang, Arthur W Toga, Paul M Thompson, Panpan Zhang, Kurt G Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Barbara B Bendlin, Sterling C Johnson, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Paul K Crane, Michael L Cuccaro, Timothy J Hohman, Derek B Archer, Dimitrios Zaras, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Seo-Eun Choi, Brandon Klinedinst, Michael L Lee, Phoebe Scollard, Emily H Trittschuh, Elizabeth A Sanders

Faculty, Staff and Student Publications

Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).

Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.

Design setting and participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were …

The Significance Of Detecting An Unusual Myeloblast Immunophenotype In A Presumptive Clinical Diagnosis Of Myelodysplastic Syndromes, Fnu Sameeta, Wei Wang, Fatima Zahra Jelloul, Okechukwu V Nwogbo, Beenu Thakral, Jie Xu, Shaoying Li, Chi Young Ok, Guilin Tang, Fuli Jia, L Jeffrey Medeiros, Sanam Loghavi, Jeffrey L Jorgensen, Sa A Wang

Faculty, Staff and Student Publications

Context.—: Blasts in myelodysplastic syndromes (MDSs) typically have a primitive myeloid immunophenotype (CD34+CD117+CD13+CD33+HLA-DR+). On rare occasions, blasts were found to be CD34 negative or minimally expressed in a presumptive MDS.

Objective.—: To investigate the occurrence of these cases, and to examine any unique molecular genetic features, and clinical relevance.

Design.—: More than 2000 flow cytometry immunophenotyping tests for MDS performed during a 5-year period were retrospectively reviewed. Chronic myelomonocytic leukemia and overt acute myeloid leukemia (AML) (≥20% blasts) were excluded.

Results.—: Approximately 800 cases had abnormal myeloblasts consistent with myeloid neoplasms; 96% of cases showed a typical primitive phenotype, but …

Single-Cell Proteomic Analysis Reveals Multiple Myeloma Heterogeneity And The Dynamics Of The Tumor Immune Microenvironment In Precursor And Advanced States, Mohamed Kamal, Stephanie N Shishido, Jeremy Mason, Krina Patel, Elisabet E Manasanch, Robert Z Orlowski, Peter Kuhn

Faculty, Staff and Student Publications

Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone …

Optimization Of Mhealth Behavioral Interventions For Patients With Chronic Lymphocytic Leukemia: The Health4cll Study, Che Young Lee, Max J Gordon, Melissa M Markofski, Emily C Lavoy, Susan K Peterson, Liang Li, Sara Fares, Miranda Baum, Margaret Pace, Danielle Walsh, Alessandra Ferrajoli, Karen Basen-Engquist

Faculty, Staff and Student Publications

Purpose: This pilot study of a diet and physical activity intervention (HEALTH4CLL) was conducted to reduce fatigue and improve physical function (PF) in patients with chronic lymphocytic leukemia (CLL).

Methods: The HEALTH4CLL study used a randomized factorial design based on the multiphase optimization strategy (MOST). Patients received diet, exercise, and body weight management instructional materials plus a Fitbit and were randomized to undergo one of 16 combinations of 4 evidence-based mHealth intervention strategies over 16 weeks. Patients' fatigue, PF, health-related quality of life, behavior changes, and program satisfaction and retention were assessed. Paired t-tests were used to examine changes in …

Orp2 Regulates Free Cholesterol Accumulation In Hepatocytes During Mash, Jin Wu, Yudi Zhao, Liwen Qiu, Qiaoli Chen, Xiaowei Wang, Jingwen Gu, Yan Liang, Yingjie Zhang, Hong-Yu Wang, Yang Liu, Xiaoqin Wu, Shuai Chen, Feng-Jung Chen, Mingming Gao, Hongyuan Yang

Faculty, Staff and Student Publications

Background: Cholesterol crystals in hepatocytes are known to strongly associate with human metabolic dysfunction-associated steatohepatitis. However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation and the formation of cholesterol crystals in hepatocytes. In cultured cell lines, oxysterol-binding protein-related protein 2 (ORP2) functions to deliver cholesterol to the plasma membrane from endosomal compartments.

Methods: Here, we generated liver-specific ORP2 knockout (ORP2-LKO) mice and characterized their metabolic phenotypes on chow and high-fat diet.

Results: The ORP2-LKO mice developed much more severe hepatic steatosis than floxed control mice after high-fat diet feeding. They also demonstrated more severe liver inflammation and damage. …

Computed Tomography Radiomics-Based Cross-Sectional Detection Of Mandibular Osteoradionecrosis In Head And Neck Cancer Survivors, Serageldin Kamel, Laia Humbert-Vidan, Zaphanlene Kaffey, Sarah Mirbahaeddin, Abdulrahman Abusaif, David T A Fuentes, Kareem Wahid, Cem Dede, Mohamed A Naser, Renjie He, Ahmed W Moawad, Khaled M Elsayes, Melissa M Chen, Adegbenga O Otun, Jillian Rigert, Mark S Chambers, Andrew Hope, Erin Watson, Kristy K Brock, Katherine Hutcheson, Lisanne Van Dijk, Amy C Moreno, Stephen Y Lai, Clifton D Fuller, Abdallah S R Mohamed, Md Anderson Head And Neck Cancer Symptom Working Group

Faculty, Staff and Student Publications

Purpose: This study aims to identify radiomic features from contrast-enhanced CT (CECT) scans that differentiate osteoradionecrosis (ORN) from normal mandibular bone in head and neck cancer (HNC) patients treated with radiotherapy (RT).

Materials and methods: CECT images from 150 patients with confirmed ORN diagnosis (2008-2018) at MD Anderson Cancer Center (MDACC) were analyzed (80 % train, 20 % test). Radiomic features were extracted using PyRadiomics from manually segmented ORN regions and automated contralateral healthy mandible regions. Correlation analysis (r > 0.95) reduced features for model training. A random Forest (RF) classifier with Recursive Feature Elimination identified discriminative features. Explainability was assessed …

Genetic Diversity And Expanded Phenotypes In Dystonia: Insights From Large-Scale Exome Sequencing, Mirja Thomsen, Fabian Ott, Sebastian Loens, Gamze Kilic-Berkmen, Ai Huey Tan, Shen-Yang Lim, Ebba Lohmann, Kaja M Schröder, Lea Ipsen, Lena A Nothacker, Linn Welzel, Alexandra S Rudnik, Frauke Hinrichs, Thorsten Odorfer, Kirsten E Zeuner, Friederike Schumann, Andrea A Kühn, Simone Zittel, Marius Moeller, Robert Pfister, Christoph Kamm, Anthony E Lang, Yi Wen Tay, Ana Luísa De Almeida Marcelino, Marie Vidailhet, Emmanuel Roze, Joel S Perlmutter, Jeanne S Feuerstein, Victor S C Fung, Florence Chang, Richard L Barbano, Steven Bellows, Aparna A Wagle Shukla, Alberto J Espay, Mark S Ledoux, Brian D Berman, Stephen Reich, Andres Deik, Andre Franke, Michael Wittig, Sören Franzenburg, Jens Volkmann, Norbert Brüggemann, H A Jinnah, Tobias Bäumer, Christine Klein, Hauke Busch, Katja Lohmann

Faculty, Staff and Students Publications

Objective: Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex.

Methods: Exome sequencing was conducted on 1924 genetically unsolved, mainly late-onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia (n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible.

Results: We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG …