Medical Specialties Commons^™

A Quantitative, Bayesian-Informed Approach To Gene-Specific Variant Classification: Updated Expert Panel Recommendations Improve Classification Of Tp53 Germline Variants For Li-Fraumeni Syndrome, Cristina Fortuno, Megan N Frone, Jessica Mester, Miguel De La Hoya, Phuong L Mai, Tina Pesaran, Maria Isabel Achatz, Rebecca Bassett, Carolina Bustamante, Stephanie Crowley, Kelvin Cesar De Andrade, D Gareth Evans, Bingjian Feng, Laura Fuqua, Maria Isabel Harrell, Jessica N Hatton, Robert Huether, Chimene Kesserwan, Kristy Lee, Suzanne P Macfarland, Jamie L Maciaszek, Kara Maxwell, Kelly Mcgoldrick, Maureen Murphy, Bita Nehoray, Judith Penkert, Emilia Modolo Pinto, Sharon E Plon, Alison Schwartz-Levine, Ashley S Thompson, Wenyi Wang, Gerard P Zambetti, Kristin Zelley, Paul A James, Sharon A Savage, Christian P Kratz, Amanda B Spurdle

Faculty, Staff and Students Publications

Background: Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.

Methods: The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of …

Injectable Microparticle-Nanoliposome Hydrogel For Extended Release Of Small Hydrophilic Molecules, Gil Aizik, Wonmin Choi, Claire A Ostertag-Hill, Matthew Torre, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Achieving sustained local release of small hydrophilic drugs is challenging and is particularly important when the drugs are toxic. To address these challenges, we developed a hybrid system comprising drug-containing microparticles embedded within a nanoliposomal hydrogel matrix. This system forms through salt-induced gelation using physiologically relevant sodium chloride concentrations (0.9%), allowing for microparticle encapsulation without harsh chemical processes. In vitro, the hybrid system exhibited a slower release of encapsulated cargo compared to microparticles or hydrogel alone. In vivo proof of principle was provided with tetrodotoxin (TTX), a small hydrophilic and ultrapotent local anesthetic, which can cause systemic toxicity if the …

Review Of Diffusion Models And Its Applications In Biomedical Informatics, Jiawei Luo, Liren Yang, Yan Liu, Changbao Hu, Grant Wang, Yan Yang, Tie-Lin Yang, Xiaobo Zhou

Faculty, Staff and Student Publications

The diffusion model, a cutting-edge deep generative technique, is gaining traction in biomedical informatics, showcasing promising applications across various domains. This review presents an overview of the working principles, categories, and numerous applications of diffusion models in biomedical research. In medical imaging, these models, through frameworks like Denoising Diffusion Probabilistic Models (DDPMs) and Stochastic Differential Equations (SDE), offer advanced solutions for image generation, reconstruction, segmentation, and denoising. Notably, they’ve been employed in synthesizing 2D/3D medical images, MRI, and PET image reconstruction, and segmentation tasks such as labeled MRI generation. In the realm of structured Electronic Health Records (EHR) data, diffusion …

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. …

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 …

Apoa1 Binding Protein Promotes Lymphatic Cell Fate And Lymphangiogenesis By Relieving Caveolae-Mediated Inhibition Of Vegfr3 Signaling, Jun-Dae Kim, Surbhi Chaudhary, Weiqing Chen, Jonathan Astin, Philip S Crosier, Pengchun Yu, John P Cooke, Henry J Pownall, Hugo J Bellen, Nhat-Tu Le, Daniel L Kiss, Guangyu Wang, Stanley G Rockson, Hong Chen, Longhou Fang

Faculty, Staff and Students Publications

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 …

Sperm And Offspring Production In A Nonobstructive Azoospermia Mouse Model Via Testicular Mrna Delivery Using Lipid Nanoparticles, Daisuke Mashiko, Chihiro Emori, Yuki Hatanaka, Daisuke Motooka, Chen Pan, Yuki Kaneda, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Microsurgical testicular sperm extraction (microTESE) with intracytoplasmic sperm injection (ICSI) represents the current standard treatment for nonobstructive azoospermia (NOA). However, cures remain unavailable for NOA patients lacking retrievable haploid cells. mRNA supplementation could be a potential treatment for genetic defects leading to impaired spermatogenesis. Lipid nanoparticles (LNPs) have emerged as mRNA delivery vehicles with minimal risk of genome integration; however, their ability to selectively deliver mRNA to specific cell types remains limited. To overcome this, microRNA (miRNA) target sequences were incorporated into mRNA constructs to restrict expression specifically to germ cells. Using pyruvate dehydrogenase E1 subunit alpha 2 (PDHA2) knockout …

Emergency Department-Initiated Palliative Care Screening Among Older Adults: A Systematic Review And Meta-Analysis Protocol, Dimitri E Lin, Satheesh Gunaga, Fabrice I Mowbray, Eric D Isaacs, Daniel Markwalter, Naomi George, Alison E Hay, Rita Manfredi, Erica Westlake, Murtaza Akhter, Jason K Bowman, Naomi Rebollo-Lee, Brian Gacioch, Alexander D Ginsburg, Justin Kenneth Brooten, Sarah Pajka, Katie Selman, Paul Bain, Joshua J Davis, Shan Liu, Kei Ouchi

Faculty, Staff and Students Publications

Introduction: The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer's disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient's trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. …

Insights, Opportunities, And Challenges Provided By Large Cell Atlases, Martin Hemberg, Federico Marini, Shila Ghazanfar, Ahmad Al Ajami, Najla Abassi, Benedict Anchang, Bérénice A Benayoun, Yue Cao, Ken Chen, Yesid Cuesta-Astroz, Zachary Debruine, Calliope A Dendrou, Iwijn De Vlaminck, Katharina Imkeller, Ilya Korsunsky, Alex R Lederer, Jessica Jingyi Li, Pieter Meysman, Clint L Miller, Kerry A Mullan, Uwe Ohler, Pratibha Panwar, Nikolaos Patikas, Jonas Schuck, Jacqueline H Y Siu, Timothy J Triche, Alex Tsankov, Sander W Van Der Laan, Masanao Yajima, Jean Yang, Fabio Zanini, Ivana Jelic

Faculty, Staff and Student Publications

The field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome.

Clinical Course And Treatment Outcomes In Solid-Basaloid Adenoid Cystic Carcinoma Of The Breast: A Systematic Review And Case Report, Stephanie Kim, Kyle Sheth, Xiaoying Yu, Laura Porterfield, Elizabeth M Vaughan

Faculty, Staff and Students Publications

Background: Adenoid Cystic Carcinoma (ACC) is a rare, indolent subtype of triple-negative breast cancer, accounting for < 0.1 % of cases. The solid-basaloid subtype (SBACC), comprising approximately one-quarter of breast ACCs, has a poorer prognosis. While ACC is typically managed with surgery and is chemo-resistant, SBACC is more aggressive and often treated with chemotherapy and, more recently, immunotherapy-though supporting evidence remains limited.

Aim: To assess clinical characteristics and treatment outcomes of SBACC of the breast.

Methods: This study presents a case of breast SBACC and a systematic review of five databases (inception-September 10, 2024). Eligible studies reported clinical course, treatment, and outcomes. Exclusions included duplicates, non-SBACC focus, animal studies, and those lacking clinical or with only pathological data. Descriptive statistics were used for binary and categorical variables. Risk of bias was assessed using JBI tools, following PRISMA 2020 guidelines. The review is registered in PROSPERO.

Results: …

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 …

Regorafenib Pulmonary Toxicity: A Case Of Cavitary Lung Disease And Ards Treated With Infliximab, Michael Dong, Mackenzie Kramer, Tanmay Gandhi, Gautam George

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

Regorafenib-induced pneumonitis and acute respiratory distress syndrome (ARDS) are rare and poorly characterized toxicities. We describe a 43-year-old male with metastatic colorectal cancer who developed hypoxic respiratory failure after two cycles of regorafenib. Imaging revealed cavitary lung lesions and diffuse ground glass opacities. Despite antibiotics and high-dose corticosteroids, his condition deteriorated, requiring ICU admission and mechanical ventilation. Bronchoalveolar lavage revealed bacterial pathogens, and he was treated for pneumonia. After multidisciplinary discussion, he was assessed to have regorafenib-induced pneumonitis as a major driver of his respiratory failure, and after limited steroid response, infliximab was administered with marked respiratory improvement. However, he …

Intracellular Lactate Dynamics In Drosophila Neurons, Matthew S Price, Elham Rastegari, Richa Gupta, Katie Vo, Travis I Moore, Kartik Venkatachalam

Faculty, Staff and Student Publications

Rates of lactate production and consumption reflect the metabolic state of many cell types, including neurons. Here, we investigated the effects of nutrient deprivation on lactate dynamics in Drosophila neurons by leveraging the limiting effects of the unstirred layer, a diffusion barrier that forms around cells in culture. We found that neurons constitutively consume lactate when the availability of trehalose, a glucose disaccharide preferred by insects, is limited by the unstirred layer. Acute mechanical disruption of the unstirred layer reduced this reliance on lactate. Through kinetic modeling and experimental validation, we demonstrate that neuronal lactate consumption rates under unstirred layer …

Nucleotide Motif-Guided Selection Of Plasma Microrna Biomarkers In Trauma, Boyang Ren, Ruoxing Li, Chien-Yu Lin, Chanhee Park, Sheng Wang, Andrew O Suen, John Kessler, Shiming Yang, Rosemary Kozar, Lin Zou, Brittney Williams, Ziyi Li, Peter Hu, Wei Chao

Faculty, Staff and Student Publications

Trauma remains a leading cause of morbidity and mortality in part due to complex pathophysiological responses. Yet our abilities to predict these changes are limited. Plasma miRNAs have been proposed as DAMPs that drive immune response and organ injury. Here, we test a panel of plasma miRNAs-selected based on next-generation sequencing and nucleotide motifs identified via a machine-learning algorithm-for their abilities to predict subclinical pathophysiological injuries. We find marked and severity-dependent increases in the miRNA biomarkers following trauma, which are closely associated with various injury markers. AUROC indicates that these biomarkers possess strong diagnostic and predictive abilities in overall trauma …

Visualization Of Lysosomal Membrane Proteins By Cryo Electron Tomography, Bridget M Mcveigh, José J De Jesús-Pérez, Dirk H Siepe, Prerana Gogoi, Shrawan Kumar Mageswaran, Marian Kalocsay, Elaine M Mihelc, Vera Y Moiseenkova-Bell

Faculty, Staff and Student Publications

Lysosomes are essential organelles for cellular homeostasis and signaling, with dysfunction linked to neurological disorders, lysosomal storage diseases, and cancer. While proteomics has advanced our understanding of lysosomal composition, the structural characterization of lysosomal membrane proteins in their native environment remains a significant challenge. Here, we developed a cryo electron tomography workflow to visualize lysosomal membrane proteins within intact, native lysosomal membranes. We isolated endolysosomes by independently targeting two lysosomal membrane proteins, transient receptor potential mucolipin 1 and transmembrane protein 192, enriching organelles that exhibited the expected morphology and proteomic composition of the endolysosomal system. Sub-tomogram averaging enabled the structural …

The Fast And The Very Fast: High-Frequency Oscillations In Alzheimer's Disease, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease increases the risk of developing epilepsy together with cognitive decline. Early diagnosis or prediction of parameters associated with epileptic activity can greatly help in managing disease outcomes. Network hyperexcitability is a candidate of interest as a neurophysiological biomarker of Alzheimer's disease. High-frequency oscillations are increasingly recognized as potential biomarkers of hyperexcitability and epileptic activity. However, they have not yet been identified in Alzheimer's disease. In this study, we measured high-frequency oscillations via magnetoencephalography recordings in Alzheimer's disease patients with and without epileptic activity, as part of a Phase 2a randomized, double blind clinical trial of the efficacy of …

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 …

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 …

Dietary Patterns For Weight And Glycemic Management In Persons With Type 1 Diabetes: A Meta-Analysis Of Clinical Trials, Daria Igudesman, Laura M Nally, Alyssa A Grimshaw, Craig G Gunderson, Elizabeth G Considine, Laura M Jacobsen, Mustafa Tosur, Peter A Gottlieb, Irl B Hirsch, Lori M Laffel, Jennifer L Sherr, Chantal Mathieu, Richard E Pratley

Children’s Nutrition Research Center Staff Publications

Background: Medical nutrition therapy is fundamental for managing glycemia and weight in type 1 diabetes, yet dietary guidance specific to this population and relevant subgroups is lacking.

Purpose: We synthesized the interventional literature investigating diet patterns for glycemic and weight management in youth and adults with type 1 diabetes, with attention to interindividual variation that suggests the need for precision approaches. The protocol was prospectively registered (CRD42024519941).

Data sources: AMED, CINAHL, Cochrane Library, Ovid MEDLINE, Ovid Embase, Google Scholar, and Web of Science Core Collection were searched from January 2011 to June 2024.

Study selection: Clinical trials ≥4 weeks with …

Protocol For Isolating Patient-Derived Ascites Cells And Extracellular Vesicles From Gastric Cancer Peritoneal Metastases, Yibo Fan, Jody V Vykoukal, Shumei Song, Melissa Pool Pizzi, Gengyi Zou, Katsuhiro Yoshimura, Jiankang Jin, Hiroyuki Katayama, George A Calin, Rebecca E Waters, Qiong Gan, Linghua Wang, Samir Hanash, Shilpa S Dhar, Jaffer A Ajani

Faculty, Staff and Student Publications

Peritoneal carcinomatosis (PC) cells and extracellular vesicles (EVs) from gastric cancer ascites are valuable for studying tumor-stroma interactions. Here, we present a protocol for isolating PC cells and EVs from patient ascites. We describe steps for PC cell culture, iodixanol-based EV purification, electron microscopy, nanoparticle tracking analysis, flow cytometry, and proteomic profiling. This protocol also includes TD-139 loading into exosomes for functional assays to evaluate their role in modulating the tumor microenvironment. For complete details on the use and execution of this protocol, please refer to Fan et al.

Equal Survival For Black Americans With Multiple Myeloma When Appropriately Matched To White Americans, David E Mery, Guido Tricot, Samer Al Hadidi, Yihao Zhan, Cody Ashby, Clyde Bailey, Eric R Siegel, Daisy V Alapat, Hongwei Xu, Sandra Mattox, Caroline Schinke, Maurizio Zangari, Sharmilan Thanendrarajan, Qing Yi, Robert Z Orlowski, Frits Van Rhee, John D Shaughnessy, Fenghuang Zhan

Faculty, Staff and Student Publications

No abstract provided.

Genetic Determinants And Genomic Consequences Of Non-Leukemogenic Somatic Point Mutations, Joshua S Weinstock, Sharjeel A Chaudhry, Maria Ioannou, Maria Viskadourou, Paula Reventun, Yasminka A Jakubek, L Alexander Liggett, Cecelia Laurie, Jai G Broome, Alyna Khan, Kent D Taylor, Xiuqing Guo, Patricia A Peyser, Eric Boerwinkle, Nathalie Chami, Eimear E Kenny, Ruth J Loos, Bruce M Psaty, Russell P Tracy, Jennifer A Brody, Jeong H Yun, Michael H Cho, Ramachandran S Vasan, Sharon L Kardia, Jennifer A Smith, Laura M Raffield, Aurelian Bidulescu, Emily C O'Brien, Mariza De Andrade, Jerome I Rotter, Stephen S Rich, Russell P Tracy, Yii Der Ida Chen, C Charles Gu, Chao A Hsiung, Charles Kooperberg, Bernhard Haring, Rami Nassir, Rasika Mathias, Alex Reiner, Vijay G Sankaran, Charles J Lowenstein, Thomas W Blackwell, Goncalo R Abecasis, Albert V Smith, Hyun M Kang, Pradeep Natarajan, Siddhartha Jaiswal, Alexander Bick, Wendy S Post, Paul Scheet, Paul Auer, Theodoros Karantanos, Alexis Battle, Marios Arvanitis

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as leukemogenic point mutations or mosaic chromosomal alterations (mCAs), are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we use 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic …

Two Commonly Reported Incidental Variants In Otc Are Associated With Late-Onset Disease, Steven H Lang, Russell S Lo, Gareth A Cromie, Aimée M Dudley, Nicholas Ah Mew, Kara Simpson, Vernon Reid Sutton, Sandra Darilek, Saima Ali, Matthew T Snyder, Brendan Lee, Ronit Marom, Sandesh C S Nagamani, Lindsay C Burrage

Faculty, Staff and Students Publications

Asymptomatic individuals with pathogenic variants in OTC, the gene encoding ornithine transcarbamylase are increasingly being identified through cascade testing, carrier screening, or as secondary findings from genome-wide sequencing tests. However, guidance for counseling and management of such individuals is currently lacking. We selected two common OTC variants for phenotypic and functional characterization: NM_000531.6:c.118C>T p.(Arg40Cys) and NM_000531.6:c.1061T>G p.(Phe354Cys). The former is the most frequently reported pathogenic/likely pathogenic missense variant present in gnomAD, and the latter has been frequently encountered in our clinical practice. We performed a retrospective chart review at our center, queried the database of the Urea Cycle …

Cerebellar Dysfunction In Glaucoma Patients, Anisha Kasi, Ji Won Bang, Vivek Trivedi, Jeannie Au, Ian Conner, Gadi Wollstein, Joel Schuman, Rakie Cham, Kevin Chan

Wills Eye Hospital Papers

Glaucoma patients often have higher injurious fall rates compared to healthy older adults. However, little is known about the underlying neural mechanisms. Recent evidence shows cerebral changes beyond the visual pathway of glaucoma patients, yet it remains unclear whether the cerebellum, which plays an important role in balance and motor control, is involved in glaucoma. In this study, we sought to investigate cerebellar functional connectivity changes in glaucoma by comparing 32 glaucoma subjects and 10 age-matched healthy control subjects who underwent resting-state functional magnetic resonance imaging at 3 Tesla with eyes closed. After conducting both regions-of-interest and seed-to-voxel analyses, we …

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 …

Resilience And Vulnerabilities Of Tumor Cells Under Purine Shortage Stress, Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael A Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

Purpose: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.

Experimental design: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.

Results: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multiprotein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. Although this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the …

Sub-Ciliary Localization Of Cep290 And Effects Of Its Loss In Mouse Photoreceptors During Development, Abigail R. Moye, Michael A. Robichaux, Melina A. Agosto, Alexandre P. Moulin, Alexandra Graff-Meyer, Carlo Rivolta, Theodore G. Wensel

Faculty, Staff and Students Publications

No abstract provided.

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.

Differential Bk Channel Potentiation By Vanzacaftor Enantiomers Enables Therapy For Modulator-Ineligible People With Cystic Fibrosis, Nathalie Baumlin, Sumedha Gunewardena, Scott H Randell, Frank T Horrigan, Matthias Salathe

Faculty, Staff and Students Publications

No abstract provided.