Medical Specialties Commons^™

Cd5 Expression In Ctcl And Its Implications For Anti-Cd5 Car T-Cell Therapy, Leena Wardeh, Madeline Williams, Courtney Prestwood, Zachary Wolner, Neda Nikbakht

Department of Dermatology and Cutaneous Biology Faculty Papers

Cutaneous T-Cell Lymphomas (CTCL) are a heterogenous group of T-cell malignancies in the skin and have poor treatment outcomes in advanced stages. CD5, a surface glycoprotein expressed on most mature T cells, has emerged as a promising target for chimeric antigen receptor (CAR) T-cell therapy in systemic T-cell lymphomas. However, its expression profile in CTCL and relevance for targeted therapy remain unclear. Notably, in CTCL, the cell surface expression of receptors, such as CD7 and CD26, tends to become downregulated on the surfaces of malignant T cells In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from patients at …

A Novel Approach To Calculating Expected Total Fetal Lung Volume In Fetuses With Isolated Congenital Diaphragmatic Hernia And Fetal Growth Restriction: A Theoretical Computational Simulation, Morcos Hanna, Jonathan Davies, Amaryllis Fernandes, Pamela M Ketwaroo, Amy R Mehollin-Ray, Roopali Donepudi, Alice King, Joseph Hagan, Sundeep G Keswani, Sharada H Gowda, Caraciolo J Fernandes

Faculty, Staff and Students Publications

Objectives: Congenital diaphragmatic hernia (CDH) often coexists with fetal growth restriction (FGR). The observed-to-expected (O/E) total fetal lung volume (TFLV) is used to assess CDH severity, predict outcomes, and direct fetal interventions. Expected TFLV measurements traditionally rely only on gestation age (GA). This simulation assesses how incorporating weight-adjusted GA norms affects O/E TFLV calculations in patients with isolated CDH and FGR.

Methods: A simulated dataset (n=1,005) utilized published mean fetal weight and TFLV references. Computer-generated variables included observed weights (3rd-10th %ile), O/E TFLV (10-65 %), and percent liver herniation (0-42 %). GA estimates were corrected by weight and used to …

Signs, Symptoms, And Health-Related Quality Of Life In Melas: Measuring What’S Important From The Patient And Clinician Perspectives, Paolo Medrano, Benjamin Banderas, Marisa Brimmer, Lily Settel, Sari Berger, Alan Shields, Amy Goldstein, Amel Karaa, Austin Larson, Sumit Parikh, Fernando Scaglia, Karra Danyelle Harrington, Chris James Edgar, Pamela Ventola, Matthew Webster, Jennifer Chickering, Chad Gwaltney, Phebe Wilson, Chad Glasser

Faculty, Staff and Students Publications

Background and objectives: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare genetic syndrome mostly associated with pathogenic variants in mitochondrial DNA. As there is limited research on the life experience of patients with MELAS, this study aimed to develop an understanding of the patient experience of MELAS through qualitative interviews to identify, describe, and substantiate important and relevant signs, symptoms, and health-related quality-of-life (HRQoL) impact (S/S/I) concepts.

Methods: Clinician and patient interviews were conducted virtually using semi-structured interview guides. During 60-minute interviews with five experts in the United States, clinicians were asked for their perspective on …

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes, Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Kymme Wang, Nick Sisneros, Megha Muraleedharan, Anantha Kethireddy, Marco Corbo, Harsha Gowda, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Matthew W Mitchell, Kevin A Peterson, Amjad Horani, Jill A Rosenfeld, Weimin Bi, Pawel Stankiewicz, Hsiao-Tuan Chao, Jennifer E Posey, Christopher M Grochowski, Zain Dardas, Erik G Puffenberger, Christopher E Pearson, Frank Kooy, Dale Annear, A Micheil Innes, Michael Heinz, Richard Head, Robert Fulton, Stephan Toutain, 9p-Arch, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner

Faculty, Staff and Students Publications

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

Racial Disparities In Clonal Hematopoiesis And Their Impact On Hematologic Malignancies, Zijian Zhang, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for hematologic malignancies (HM), but its distribution and clinical implications across diverse ancestries remain poorly characterized. In this study, we investigated CHIP and its progression to HM in a large, racially diverse cohort from the All of Us Research Program, comprising 245,388 participants. We identified 10,446 CHIP driver mutations in 9,476 individuals. Our analysis revealed clear racial disparities in CHIP prevalence and mutational profiles: African American (AA) individuals had higher odds of CHIP and exhibited distinct mutation patterns compared to White American (WA) individuals. Consistent with prior studies, CHIP …

Transdiagnostic Alterations In White Matter Microstructure Associated With Suicidal Thoughts And Behaviours In The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Lejla Colic, Zuriel Ceja, Maria R Dauvermann, Luca M Villa, Hannah S Savage, Yara J Toenders, Niousha Dehestani, Alyssa H Zhu, Adrian I Campos, Lauren E Salminen, Martin Alda, Ingrid Agartz, Nina Alexander, Rosa Ayesa-Arriola, Elizabeth D Ballard, Nerisa Banaj, Carlotta Barkhau, Zeynep Başgöze, Jochen Bauer, Francesco Benedetti, Klaus Berger, Bianca Besteher, Katharina Brosch, Manuel Canal-Rivero, Simon Cervenka, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Philippe Courtet, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Jeremy Deverdun, Ana M Diaz-Zuluaga, Lorielle M F Dietze, Jennifer W Evans, Negar Fani, Kira Flinkenflügel, Naomi P Friedman, Ian H Gotlib, Nynke A Groenewold, Dominik Grotegerd, Tomas Hajek, Alexander S Hatoum, Marco Hermesdorf, Ian B Hickie, Yoshiyuki Hirano, Tiffany C Ho, Yuki Ikemizu, Frank Iorfino, Jonathan C Ipser, Yuko Isobe, Andrea P Jackowski, Fabrice Jollant, Tilo Kircher, Melissa Klug, Sheri-Michelle Koopowitz, Anna Kraus, Axel Krug, Emmanuelle Le Bars, Elisabeth J Leehr, Meng Li, Elizabeth T C Lippard, Carlos Lopez-Jaramillo, Ivan I Maximov, Andrew M Mcintosh, Katie A Mclaughlin, Sean R Mcwhinney, Susanne Meinert, Elisa Melloni, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Stener Nerland, Emilie Olie, Victor Ortiz-García De La Foz, Pedro M Pan, Fabricio Pereira, Fabrizio Piras, Federica Piras, Sara Poletti, Andrew E Reineberg, Gloria Roberts, Rafael Romero-García, Matthew D Sacchet, Giovanni A Salum, Anca-Larisa Sandu, Carl M Sellgren, Eiji Shimizu, Harry R Smolker, Jair C Soares, J Douglas Steele, Frederike Stein, Dan J Stein, Benjamin Straube, Lea Teutenberg, Florian Thomas-Odenthal, Paula Usemann, Romain Valabregue, Johanna Valencia-Echeverry, Gerd Wagner, Gordon Waiter, Martin Walter, Heather C Whalley, Mon-Ju Wu, Tony T Yang, Carlos A Zarate, Andre Zugman, Giovana B Zunta-Soares, Kees Van Heeringen, Sanne J H Van Rooij, Nic Van Der Wee, Steven Van Der Werff, Paul M Thompson, Hilary P Blumberg, Anne-Laura Van Harmelen, Miguel E Rentería, Neda Jahanshad, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of …

Distinct Spatiotemporal Patterns Of White Matter Hyperintensity Progression, Jinyong Chung, Gilsoon Park, Wi-Sun Ryu, Dawid Schellingerhout, Hang-Rai Kim, Dong-Seok Gwak, Elizabeth Haddad, Neda Jahanshad, Beom Joon Kim, Keun-Sik Hong, Hyerin Oh, Sang-Wuk Jeong, Joon-Tae Kim, Man Seok Park, Kang-Ho Choi, Kyungbok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Moon-Ku Han, Yong-Jin Cho, Byung-Chul Lee, Philip M Bath, Joanna M Wardlaw, Hee-Joon Bae, Hosung Kim, Dong-Eog Kim

Faculty, Staff and Student Publications

White matter hyperintensity, a key imaging biomarker for brain health, has prognostic implications for stroke. Using a multicenter MRI dataset of 9179 stroke patients plus the UK Biobank (n = 36,210 low/high risk controls), we employ Subtype and Stage Inference modeling and identify three distinct white matter hyperintensity progression subtypes: fronto-parietal, radial, and temporo-occipital. Longitudinal validation confirms classification stability. The fronto-parietal subtype shows delayed onset and more hypertension, while the temporo-occipital subtype has more atrial fibrillation and coronary heart disease. The fronto-parietal and radial subtypes are linked to small vessel stroke, while the temporo-occipital subtype is linked to cardioembolism. The …

Cdk4/6 Inhibitors In Breast Cancer-Who Should Receive Them?, Anran Chen, Ze-Yi Zheng, Meenakshi Anurag, Ahmed Elkhanany, Natalie C Chen, Eric C Chang

Faculty, Staff and Students Publications

More than 70% of breast cancers are estrogen receptor-positive (ER+). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 …

Genome-Wide Association Study Of Childhood B-Cell Acute Lymphoblastic Leukemia Reveals Novel African Ancestry-Specific Susceptibility Loci, Cindy Im, Andrew R Raduski, Lauren J Mills, Kashi Raj Bhattarai, Robert J Mobley, Kelly R Barnett, Zhanni Lu, Kenneth Liao, Nathan Anderson, Rebecca A Johnson, Erica Langer, Anthony J Hooten, Alix E Seif, Kathrin M Bernt, Matthew Tsang, Brandon A Mamou, Luis Gil-De-Gómez, Julie A Wolfson, Danielle N Friedman, Neerav Shukla, Laura J Klesse, Erin L Marcotte, Lingyun Ji, Alice Dang, Minjie Luo, Yiming Zhong, Jalen Langie, Charleston W K Chiang, Adam De Smith, Joseph L Wiemels, Andrew Dewan, Xiaomei Ma, Catherine Metayer, Zhaoming Wang, Heather H Nelson, Nathan Pankratz, Tianzhong Yang, Saonli Basu, Lucie M Turcotte, Jun J Yang, Daniel Savic, Michael E Scheurer, Logan G Spector

Faculty, Staff and Students Publications

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P <  5 × 10−8) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10−3). Novel risk variants were also associated with subtype-specific disease (P <  0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

A Hybrid Model For Youth Engagement In Adolescent Health Studies: Insights From The Teen Research Advisors Program At A Midwestern Pediatric Academic Medical Center In The United States., John Tumberger, Alaina N. Burns, Michael Bartkoski, Mariah E. Brewe, Amelia Whittier, Kendyll Gethers, Ailisi Bogdon, Emerie Peterson, Stephani L. Stancil

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Engaging adolescents in research ensures studies are relevant, ethical, and beneficial while fostering authentic and applicable findings. Traditional in-person advisory boards face barriers to equitable participation, highlighting the need for innovative, flexible models tailored to specific research programs and individuals with lived experience. The primary aim of this article is to describe a novel hybrid youth advisory board suitable for informing ongoing operations of a research program while supporting youths' education and career exploration. Our secondary aim was to evaluate initial impact over the first 2 years of the program (2023-2024).

METHODS: Adolescents aged 12-21 with prior involvement in …

Everolimus And Low-Dose Tacrolimus After Heart Transplant In Children: A Randomized Clinical Trial, Christopher S Almond, Kevin P Daly, Erin L Albers, Juan C Alejos, Rebecca Ameduri, Scott R Auerbach, Lynsey Barkoff, Aliessa P Barnes, Matthew J Bock, Arene Butto, Waldemar F Carlo, Chesney D Castleberry, Maryanne R Chrisant, Shriprasad R Deshpande, William J Dreyer, Melanie D Everitt, Brian Feingold, Selena Gonzales, Seth A Hollander, Steven J Kindel, Gloria L Klein, Ashwin K Lal, Jacqueline M Lamour, Joanne Lee, Minmin Lu, Irene D Lytrivi, Shelley D Miyamoto, Elfriede Pahl, David M Peng, Thomas D Ryan, Tajinder P Singh, Jennifer A Su, David L Sutcliffe, A Marian Ybarra, Steven Zangwill, Joseph W Rossano, Lynn A Sleeper

Faculty, Staff and Students Publications

Importance: Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.

Objective: To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in …

Sexually Dimorphic Sail Feathers In The Mandarin Duck As A Model For Lifelong Developmental Modulation, Pin-Chi Tang, Hsu-Chen Cheng, Gee-Way Lin, Yung-Chih Lai, Ya-Chen Liang, Ping Wu, Tzu-Chiao Lin, Chen Siang Ng, Isheng Jason Tsai, Ang Li, Wen Hsiung Li, Chih-Feng Chen, Cheng-Ming Chuong, Randall Widelitz

Faculty, Staff and Student Publications

Developmental processes extend beyond embryogenesis to support lifelong tissue adaptations. Avian feather follicles, with their resident stem cells and capacity for cyclic regeneration, provide a dynamic model for postnatal tissue remodeling. Here, we propose the Mandarin duck (Aix galericulata) as an ideal model to study lifelong developmental modulation, focusing on the sexually dimorphic "sail feather"-a secondary flight feather in males that undergoes seasonal transformation into a strikingly asymmetric, ornamented phenotype during the breeding season. We identified asymmetric morphogen expression in regenerating male sail feathers and used transcriptome and H3K27ac ChIP-seq to uncover male and female signaling pathways and regulatory elements. …

Influences On Emergency Clinician Use Of Health Information Exchange: Interview Study, Brian E. Dixon, Umesh Ghimire, Benjamin Richter, Corinne Bowditch, Saurabh Rahurkar, John T. Finnell, Joshua R. Vest

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Health information exchange (HIE) supports clinical decision-making in emergency medicine settings. Despite evidence and policies that encourage the adoption of HIE, use by clinicians is limited. Moreover, few studies examine HIE use years after adoption by hospitals or clinics.

OBJECTIVE: This study aims to examine the perceptions and use of a mature, operational HIE system by emergency department clinicians years after its implementation.

METHODS: We interviewed 21 clinicians in various roles (eg, attending physician and nurse practitioner) across multiple health systems that participate in a statewide HIE network. We asked questions about their use of the HIE system and …

Biallelic Loss-Of-Function Variants In C19orf44 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen

Faculty, Staff and Students Publications

Background: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.

Methods: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to …

Cep76 Impairment At The Centrosome-Cilium Interface Contributes To A Spectrum Of Ciliopathies, Kamal Khan, Erika Tavares, Katherine Bishara, Aysegul Ozanturk, Leila Qebibo, Stephan Frangakis, Daniel G Calame, Isabelle Meunier, Béatrice Bocquet, Rafal Ploski, Mohammad Ayman Al Khateeb, Dana Marafi, Luke Mansard, Lena Damaj, Richard A Lewis, Farid Ullah, Thomas Arbogast, Jackson P Ogden, Madeleine Harion, Marjolaine Willems, Maha S Zaki, Tobias Bartolomaeus, Anne-Françoise Roux, James R Lupski, Malgorzata Rydzanicz, Rami Abou Jamra, Francis Ramond, Elise Heon, Lydie Burglen, Erica E Davis

Faculty, Staff and Students Publications

Dysfunction at the centrosome-cilium interface underlies a broad range of ciliopathies. Here, we identify biallelic variants in CEP76, encoding a centrosomal protein, in eight unrelated individuals presenting with neurodevelopmental, ocular, and variable additional multisystem features. Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits, including impaired cilium formation and length, disrupted transition zone architecture, and impaired IFT88-mediated anterograde intraflagellar transport. Zebrafish cep76 mutants recapitulate key clinical phenotypes, and in vitro complementation assays confirm pathogenicity for all tested human disease-associated variants. Proteomics analysis identifies CEP76 interactors, including known partners CCP110 and CEP97, and highlights clinically and functionally relevant candidates, including …

Metabolic Impact Of Dietary Glycine Supplementation In Individuals With Severe Obesity, Hong Chang Tan, Jean W Hsu, E Shyong Tai, Shaji Chacko, Vieon Wu, Paul M Yen, Jean-Paul Kovalik, Farook Jahoor

Faculty, Staff and Students Publications

Glycine plays a central role in human metabolism, and an adequate supply is required for synthesizing glutathione (GSH), eliminating excess metabolites as acylglycine via the glycine conjugation detoxification pathway, and maintaining 1-carbon cycle activity. However, glycine is deficient in individuals with severe obesity, which may compromise these pathways and metabolic health. This exploratory study examines whether dietary glycine supplementation could correct glycine deficiency and impairments in glycine-dependent metabolic pathways. 19 participants with severe obesity (BMI 38.3 ± 5.3 kg/m2) were treated with dietary glycine (100 mg/kg/day) for two weeks. We found that treatment significantly increased the plasma concentration of glycine …

Alterations Of The Upper Respiratory Microbiome Among Children Living With Hiv Infection In Botswana, Sweta M Patel, John Farirai, Mohamed Z Patel, Sifelane Boiditswe, Leabaneng Tawe, Shimane Lekalake, Mogomotsi Matshaba, Andrew P Steenhoff, Tonya Arscott-Mills, Kristen A Feemster, Samir S Shah, Nathan Thielman, Coleen K Cunningham, Lawrence A David, David M Murdoch, Matthew S Kelly

Faculty, Staff and Students Publications

Children living with HIV (CLWH) are at high risk of colonization and infection by respiratory pathogens, though this risk can be reduced by other microbes in the upper respiratory microbiome. The impact of HIV infection on the pediatric upper respiratory microbiome is poorly understood, and we sought to address this knowledge gap by identifying associations between HIV infection and the nasopharyngeal microbiomes of Batswana children. We enrolled Batswana CLWH (< 5 years) and age- and sex-matched HIV-exposed, uninfected and HIV-unexposed, uninfected children in a cross-sectional study. We used shotgun metagenomic sequencing to compare nasopharyngeal microbiomes by HIV status. Among the 143 children in this study, HIV and HIV-associated immunosuppression were associated with alterations in nasopharyngeal microbiome composition, including lower abundances of Corynebacterium species associated with resistance to bacterial pathogen colonization. These findings suggest that the upper respiratory microbiome may contribute to the high risk of respiratory infections among CLWH.

Stereoelectroencephalography Reveals Neural Signatures Of Multisensory Integration In The Human Superior Temporal Sulcus During Audiovisual Speech Perception, Yue Zhang, John F Magnotti, Xiang Zhang, Zhengjia Wang, Yingjia Yu, Kathryn A Davis, Sameer A Sheth, H Isaac Chen, Daniel Yoshor, Michael S Beauchamp

Faculty, Staff and Students Publications

Human speech perception is multisensory, integrating auditory information from the talker's voice with visual information from the talker's face. BOLD fMRI studies have implicated the superior temporal gyrus (STG) in processing auditory speech and the superior temporal sulcus (STS) in integrating auditory and visual speech, but as an indirect hemodynamic measure, fMRI is limited in its ability to track the rapid neural computations underlying speech perception. Using stereoelectroencephalography (sEEG) electrodes, we directly recorded from the STG and STS in 42 epilepsy patients (25F, 17M). Participants identified single words presented in auditory, visual, and audiovisual formats with and without added auditory …

Tng260 Is A Small-Molecule Corest Inhibitor That Sensitizes Stk11-Mutant Tumors To Anti-Pd-1 Immunotherapy, Leanne G Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S Patel, Ke Geng, Reshmee Bhattacharya, Gerald S Falchook, Jonathan W Goldman, Alexander I Spira, Salman R Punekar, David R Spigel, Judy S Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M Powell, Alfonso Lopez, Michela Ranieri, Magdalena A Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick Mccarren, Alice Tsai, Suleman S Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M Das, Lauren R Flynn, Julie A Shields, Laney Danielczyk, Brian J Mcmillan, Andre Mignault, Samuel R Meier, Hsin-Jung Wu, David J Guerin, Douglas A Whittington, Chengyin Min, Iga Sienczylo, John P Maxwell, Heather J Dibenedetto, Hideo Watanabe, Brian B Haines, Alan Huang, Adam Crystal, Jannik N Andersen, Xinyuan Wu, Kwok-Kin Wong

Faculty, Staff and Student Publications

Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11 …

Preoperative Brain Mapping Predicts Language Outcomes After Eloquent Tumor Resection, Matthew T Muir, Kyle Noll, Sarah Prinsloo, Hayley Michener, Jeffrey I Traylor, Vinodh A Kumar, Chibawanye I Ene, Sherise Ferguson, Ho-Ling Liu, Jeffrey S Weinberg, Frederick Lang, Brian A Taylor, Stephanie J Forkel, Sujit S Prabhu

Faculty, Staff and Student Publications

When operating on gliomas near critical language regions, surgeons risk either leaving residual tumor or inducing permanent postoperative language deficits (PLDs). Despite the advent of intraoperative mapping techniques, subjective judgments frequently determine important surgical decisions. We aim to inform data-driven surgery by constructing a non-invasive mapping approach that quantitatively predicts the impact of individual surgical decisions on long-term language function. This study included 79 consecutive patients undergoing resection of language-eloquent gliomas. Patients underwent preoperative navigated transcranial magnetic stimulation (TMS) language mapping to identify language-positive sites ("TMS points") and their associated white matter tracts ("TMS tracts") as well as formal language …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …

Landscape And Clinicopathologic Features Of Ras Pathway Mutations In Chronic Myelomonocytic Leukemia, Guillermo Montalban-Bravo, Sanam Loghavi, Ziyi Li, Kelly Chien, Rashmi Kanagal-Shamanna, Alex Bataller, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Koji Sasaki, Gautam Borthakur, Mahesh Swaminathan, Courtney Dinardo, Tapan Kadia, Farhad Ravandi, Naval Daver, Nicholas Short, Naveen Pemmaraju, Ghayas Issa, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford Csizmar, Hassan Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, Carlos Bueso-Ramos, Ayalew Tefferi, Hagop Kantarjian, Guillermo Garcia-Manero, Mrinal M Patnaik

Faculty, Staff and Student Publications

RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty For Below-The-Knee Peripheral Artery Disease: 2-Year Results From The Life-Btk Trial., Brian G Derubertis, Ramon L Varcoe, Prakash Krishnan, Marc P Bonaca, David J O'Connor, Richard Pin, David C Metzger, Andrew Holden, Jen-Kuang Lee, Osamu Iida, Ehrin J Armstrong, Steven W C Kum, Raghu Kolluri, Danielle R Bajakian, Lawrence A Garcia, Mehdi H Shishehbor, Shawn Yu, Karine Ruster, Brad J Martinsen, Zsuzsanna Igyarto, Sahil A Parikh

Heart and Vascular Articles

BACKGROUND: Limited treatment options exist for infrapopliteal disease in patients with chronic limb-threatening ischemia (CLTI), a condition associated with a high risk of limb loss. Interventional management of diseased infrapopliteal vessels with percutaneous transluminal angioplasty (PTA) is associated with high rates of restenosis and reintervention. In the LIFE-BTK randomized controlled trial (Pivotal Investigation of Safety and Efficacy of BRS Treatment-Below the Knee), the drug-eluting resorbable scaffold (DRS) demonstrated superior 12-month efficacy compared with PTA in a selected CLTI population with predominantly noncomplex, mildly to moderately calcified lesions. This report presents the 2-year safety and efficacy outcomes of the Esprit BTK …

Advancements In Prenatal Genetic Screening And Testing: Emerging Technologies And Evolving Applications, Mona M Makhamreh, Mei Ling Chong, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Advancements in genomic technologies have transformed prenatal genetic testing, offering more accurate, comprehensive, and noninvasive approaches to reproductive care. This review provides an in-depth overview of current methodologies and emerging innovations, including expanded carrier screening (ECS), cell-free DNA (cfDNA) testing, chromosomal microarray analysis (CMA), and sequencing-based diagnostics. We highlight how next-generation sequencing (NGS) technologies have revolutionized carrier screening and fetal genome analysis, enabling detection of a broad spectrum of genetic conditions. The clinical implementation of cfDNA has expanded from common aneuploidies to include copy number variants (CNVs), and single-gene disorders. Diagnostic testing has similarly evolved, with genome sequencing outperforming traditional …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Just-In-Time Adaptive Intervention To Improve Hiv Prevention And Substance Use In Youth Experiencing Homelessness (My-Ride): Protocol For A Randomized Controlled Trial, Diane Santa Maria, Nikhil Padhye, Michael Businelle, Natasha Slesnick, Stefani Ricondo, Marguerita Lightfoot

Faculty, Staff and Students Publications

Background: Youth who are experiencing homelessness face a higher risk of HIV infection compared to their housed peers, and suicide and overdose remain the leading causes of death among homeless youth. Just-in-Time Adaptive Interventions (JITAIs) are gaining momentum for HIV prevention and substance use research. Yet, most interventions for homeless youth have not addressed modifiable real-time factors.

Objective: This paper describes the development and implementation of a randomized attention-controlled trial to assess the efficacy of motivating youth to reduce infections, disconnections, and emotional dysregulation (MY-RIDE), a JITAI to improve HIV prevention and substance use in homeless youth.

Methods: This study …

The Effect Of Type 2 Diabetes Genetic Predisposition On Non-Cardiovascular Comorbidities, Ana Luiza Arruda, Ozvan Bocher, Henry J Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C Wood, Ken Suzuki, Josep M Mercader, Cassandra N Spracklen, James B Meigs, Marijana Vujkovic, George Davey Smith, Jerome I Rotter, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini

Faculty, Staff and Students Publications

Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts …

Development And Validation Of Clinical Screening Systems For Cushing Disease In The United States, Jorge E. Salcedo-Sifuentes, Sonal Mehta, Carter M. Suryadevara, Marvin Bergsneider, Kevin C. J. Yuen, Paul A. Gardner, Julie M. Silverstein, Albert H. Kim, James J. Evans, Garni Barkhoudarian, Juan C. Fernandez-Miranda, William T. Couldwell, Robert C. Rennert, Varun R. Kshettry, Kyle C. Wu, Carolina Benjamin, Gabriel Zada, Michael R. Chicoine, Jamie J. Van Gompel, Michael P. Catalino, Michael Karsy, Adam Mamelak, Ildiko Torok, Trevor Low, Won Kim, Donato R. Pacione, Nidhi Agrawal

Department of Neurosurgery Faculty Papers

PURPOSE: Clinical screening systems (CSSs) for Cushing syndrome (CS) validated in Europe have not been evaluated for CS or Cushing disease (CD) in the United States (US). We aimed to evaluate existing CSSs in US patients and develop two new symptom-based CSSs to identify patients with high pre-test probability of disease warranting referral for definitive biochemical workup-one for broad CS screening and one specifically for CD.

METHODS: Data were obtained from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID)-comprising 615 patients who underwent transnasal transsphenoidal resection for CD at one of 11 US pituitary centers, the Centers …