Digital Commons Network^™

Genome-Wide Discovery Of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity, Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan

Faculty, Staff and Students Publications

Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use Massively Parallel Reporter Assays to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our …

Low Mutation Rate But High Male-Bias In The Germline Of A Short-Lived Opossum, Yadira Peña-García, Richard J Wang, Muthuswamy Raveendran, R Alan Harris, Paul B Samollow, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

Age and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than 6 mo of age. Whole-genome sequencing of 22 trios reveals one of the lowest mutation rates per generation …

Stereotactic Body Radiation Therapy Utilization Trends For Stage I Non-Small Cell Lung Cancer, Sara Sakowitz, Haley I Tupper, Lawrence N Benjamin, Scott Oh, Tao He, Reza Ronaghi, Colleen L Channick, Brian J Rosenberg, Ramin Salehi-Rad, Malcolm I Smith, Joanne M Bando, Timothy J Young, Igor Barjaktarvic, Maria A Velez Velez, Arjan Gower, Amy L Cummings, Jonathan Goldman, Aaron E Lisberg, Edward B Garon, Jane Yanagawa, Emily A Cameron, Bryan M Burt, Sha'shonda L Revels, Paul Toste, Jay M Lee, Alan Lee, Jie Deng, Hanjoo Lee, Peyman Benharash, Drew Moghanaki

Faculty, Staff and Students Publications

No abstract provided.

Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla

Faculty, Staff and Students Publications

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD …

Real-World Outcomes Of Infections Following Tisagenlecleucel In Patients With B-Cell All: A Cibmtr Analysis, Hemalatha G Rangarajan, Prakash Satwani, Megan M Herr, Min Chen, Michael J Martens, Kitsada Wudhikarn, Samuel John, Vanessa A Fabrizio, Emily M Hsieh, Amar H Kelkar, Erin Doherty, David I Marks, Olle Ringden, Brian Friend, Matthew S Kelly, Nosha Farhadfar, Tim Prestidge, Nasheed M Hossain, Hongtao Liu, Shahrukh Hashmi, Dipenkumar Modi, Lena E Winestone, Zeinab El Boghdadly, Hemant S Murthy, Miguel-Angel Perales, Roy F Chemaly, Christopher E Dandoy, Joshua A Hill, Anna Huppler, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. …

‘In Texas, Everybody Wants Antibiotics’: Reducing Inappropriate Antibiotic Expectations And Use With A Provider-Patient Communication Tool In Primary Care, Ashley Collazo, Paige Wermuth, Johanan Luna Rodriguez, Kiara Olmeda, Azalia Mancera, Fabrizia Faustinella, Michael K Paasche-Orlow, Roger Zoorob, Barbara Wells Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Background/objective: Patients often expect antibiotics for self-limiting diseases, pressuring providers to prescribe antibiotics unnecessarily. These expectations also contribute to the unsafe practice of taking antibiotics without a prescription (non-prescription use), such as pills retained from prior prescriptions or antibiotics from non-medical sources. Previous work shows that non-prescription use is due to strong, widely held misconceptions regarding the curative power of antibiotics. To reduce unnecessary use of antibiotics, we developed and pilot-tested a patient-focused, bilingual (English and Spanish) educational tool with patient and provider stakeholder input. The tool, a trifold brochure, included information on safe antibiotic use, potential antibiotic harms and …

Infection After Cd19 Chimeric Antigen Receptor T-Cell Therapy For Large B-Cell Lymphoma: Real-World Analysis From Cibmtr, Kitsada Wudhikarn, Megan M Herr, Min Chen, Michael J Martens, John H Baird, Lohith Gowda, Hemalatha G Rangarajan, Muhammad Bilal Abid, Mohamed A Kharfan-Dabaja, Kirsten M Williams, Siddhartha Ganguly, Jo-Anne H Young, Akshay Sharma, Giancarlo Fatobene, Tania Jain, Christopher G Kanakry, Dipenkumar Modi, Natalie S Grover, Baheyeldin Salem, Marjorie Vieira Batista, Paschalis Vergidis, Dwight E Yin, Amer M Beitinjaneh, Amar H Kelkar, Taiga Nishihori, Jennifer Holter Chakrabarty, Usama Gergis, Melody Smith, Zeinab El Boghdadly, Christopher E Dandoy, Hemant S Murthy, Anna R Huppler, Miguel-Angel Perales, Roy F Chemaly, Joshua A Hill, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, …

Reducing Moral Distress Through Interdisciplinary Collaboration: The Impact Of A Weekly Palliative Care And Neonatology Conference, Kirthi Devireddy, Riddhi Shukla, Rachel Boren, James E Slaven, Rebecca A Baker, Jayme D Allen, Karen M Moody

Faculty, Staff and Student Publications

Background: Moral distress is the experience of knowing what ethically right action to take, but being unable to act accordingly, due to external factors. It is an experience common to providers working in the neonatal intensive care unit (NICU) where care for infants, often born at the edges of viability or with other life-limiting diagnoses, includes life and death medical decision-making in the context of uncertain prognoses. Palliative care, which aims to reduce suffering, can assist with staff moral distress by providing space for conversations regarding goals-of-care and end-of-life decision making.

Methods: The palliative care and NICU teams co-developed a …

Hepatic Ischemia-Reperfusion Injury: Underlying Mechanisms And Concepts In Liver Surgery And Liver Transplantation, Jie Zhao, Lidan Hou, Kenneth J Dery, Xiaoyi Yuan, Kang Ho Kim, Jerzy W Kupiec-Weglinski, David R Hall, Caitlin J Thornley, Mark J Hobeika, Holger K Eltzschig, Cynthia Ju

Faculty, Staff and Student Publications

Hepatic ischemia-reperfusion injury (H-IRI) is a critical complication in liver surgery and liver transplantation, contributing to graft dysfunction and poor clinical outcomes. When hepatocyte protective mechanisms are insufficient to counteract energy depletion and oxidative stress during ischemia, cell death occurs. Tissue damage during H-IRI leads to the release of damage-associated molecular patterns (DAMPs), which recruit and activate immune cells such as neutrophils and monocytes, orchestrating the initiation, progression, and eventual resolution of sterile inflammation. Extended criteria donor (ECD) livers, particularly steatotic ones, are more vulnerable to H-IRI, leading to poorer outcomes and limiting expansion of the donor pool. However, the …

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

Comparison Of Bare Metal Vs Covered Proximal Stent Fixation During Fenestrated Endovascular Aortic Repair Of Complex Abdominal Aortic Aneurysms, Guilherme B Lima, Ying Huang, Lucas Ruiter Kanamori, Emanuel R Tenorio, Bruno P Schmid, Steven Maximus, Naveed Saqib, Thanila A Macedo, Bernardo C Mendes, Gustavo S Oderich

Faculty, Staff and Students Publications

Purpose: Fenestrated stent-grafts with proximal bare-metal fixation stent (BMFS) may provide better rotational movement to facilitate vessel catheterization, but novel designs with covered fixation stents (CFSs) have been increasingly utilized with lower profile fabric. This study aimed to evaluate procedural metrics and outcomes of fenestrated endovascular repair (FEVAR) using BMFS and CFS devices.

Methods: Clinical data of 502 consecutive patients enrolled in a prospective, non-randomized investigational device exemption (IDE) study were reviewed. Patients with 4-vessel fenestrated stent-grafts with BMFS or CFS for treatment of complex abdominal aortic aneurysms (CAAAs) and Extent IV thoracoabdominal aortic aneurysms (TAAAs) were included. Patients with …

Weight Loss And A Shunt On “Off”: An Odd Case Of Overshunting In An Idiopathic Intracranial Hypertension Patient Illustrative Case, Thomas Hamre, Ashley Ricciardelli, Alex Flores, Ashwin Viswanathan

Faculty, Staff and Students Publications

Background: CSF diversion with ventriculoperitoneal (VP) shunts is a common treatment for idiopathic intracranial hypertension (IIH). Rarely, overshunting can occur. Diagnosing and managing overshunting in an IIH patient with a shunt can be challenging. The authors present a unique etiology of overshunting successfully treated with shunt ligation.

Observations: A 48-year-old female with IIH who had undergone VP shunt placement with a programmable Certas valve presented with symptoms concerning for low-pressure headaches following a 25-kg weight loss. Intracranial pressure (ICP) monitoring along with an inpatient headache diary facilitated the diagnosis of intracranial hypotension secondary to CSF overdrainage through the shunt. Following …

Peripheral Microvascular And Cerebral White Matter Dysfunction In Schizophrenia: Implications Of A Body-Brain Endothelial Pathophysiology, Eric L Goldwaser, Alexa Yuen, Wyatt Marshall, Bhim M Adhikari, Joshua Chiappelli, Andrew Van Der Vaart, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Heather Bruce, Patrick Donnelly, Braxton Mitchell, Charles Hong, Danny J J Wang, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

Background and hypothesis: Schizophrenia spectrum disorder (SSD) is a chronic neuropsychiatric illness accompanied by significant brain structural and functional abnormalities and higher rate of cardio- and cerebrovascular comorbidities. We hypothesized that genetic and environmental risk factors that led to SSD act throughout the body and demonstrated the association between lower integrity of peripheral vascular endothelium and white matter (WM) microstructure.

Study design: Microvascular endothelial function was evaluated using brachial artery post-occlusive reactive hyperemia (PORH), in which endothelial responses are measured under reduced blood flow and after blood flow is restored. White matter microstructure was assessed by multi-shell diffusion tensor imaging …

Whole-Exome Sequencing-Based Linkage Analysis Of Multiple Myeloma (Mm) And Monoclonal Gammopathy Of Undetermined Significance (Mgus) Pedigrees, Alyssa I Clay-Gilmour, Nicola J Camp, Xiaomu Wei, Angel Earle, Aaron Norman, Jason Sinnwell, Delphine Demangel, Rosalie Griffin, Charles Dumontet, James Mckay, Ken Offit, Vijai Joseph, Siwei Chen, Daniel O'Brien, Vincent Rajkumar, Robert Klein, Shaji Kumar, Steve Lipkin, Celine M Vachon

Faculty, Staff and Student Publications

Background/objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis.

Methods: Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander-Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, …

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Development Of A Targeted Bioprotac Degrader Selective For Misfolded Sod1, Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke Mcalary, Jeremy S Lum, Justin J Yerbury

Faculty, Staff and Student Publications

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we …

Social Determinants Of Health Patterns In Children With Severe Disease Due To Sars-Cov-2 Infection-An Exploratory Approach, Joshua Prabhu, Sebastian Acosta, Fabio Savorgnan, Ananth V Annapragada, Usha Sethuraman

Faculty, Staff and Students Publications

Background/Objectives: Research on the association of adverse social determinants of health (SDOH) with severe pediatric coronavirus disease (COVID-19) is limited. We examined associations between SDOH patterns and COVID-19 severity in children.

Methods: We conducted a prospective, observational study of children (< 18 years) with symptomatic SARS-CoV-2 infection evaluated in an urban pediatric emergency department (March 2021-April 2022) in Detroit, Michigan. Caregivers completed a 34-item survey based on the Healthy People 2030 framework. Severe disease was defined as the occurrence of respiratory/cardiac failure or death within four weeks of diagnosis. Continuous and categorical variables were described using medians and percentages, respectively. Associations between disease severity and risk factors were determined using chi-square tests. Association rule mining was used for feature selection, followed by multivariate logistic regression.

Results: We analyzed data from 354 children [6-12 years: 31.1%, Female: 51.1%, Black: 59%, not Hispanic: 84.7%, public insurance: 77.1%, chronic condition: 27.4%]. Of the total, 113 children had severe disease. Most caregivers were 30-44 years old (53.1%), had less than a college degree (70.4%), and income < USD 50,000 (75.2%). Adverse SDOH reported included food/housing insecurity (24.6%), no support (64.7%), unmet childcare needs (35.9%), and lack of transportation (12.7%). After controlling for age, sex, medical history, income, and obesity, severe disease was associated with caregiver use of drugs/alcohol (OR:5.92, p < 0.001) and social discrimination/lack of support (OR: 1.74, p = 0.030).

Conclusions: Two SDOH patterns (caregiver use of drugs/alcohol …

Hyperoxia During Neonatal Cardiopulmonary Bypass Is Associated With Worse Clinical Outcomes: A Multi-Institutional Study, Asaad G Beshish, David M Kwiatkowski, Nathaniel Sznycer-Taub, John M Costello, Andrew Jergel, Scott Gillespie, Katherine Cashen, Ahmed Asfari, Maria Batsis, Jason R Buckley, Meghan M Chlebowski, Saul Flores, Nimrod Goldshtrom, Karl Migally, Kimberly I Mills, Monique R Radman, Chetana Reddy, Brittany Shutes, Christine M Riley, Sukumar Suguna Narasimhulu, Dana Mueller, Venugopal Amula, Raji Venkitachalam, Brian F Joy, Karan B Karki, Scott M Leopold, Jennifer E Schramm, Christine A Capone, Scott I Aydin, Adnan M Bakar, Kieran Leong, Agnieszka Kulikowska, Sarah Wing, Christopher W Mastropietro, Collaborative Research From The Pediatric Intensive Care Society (Core‐Pcics) Investigators

Faculty, Staff and Students Publications

Background: Exposure to supraphysiologic oxygen concentrations, or hyperoxia, during neonatal cardiopulmonary bypass (CPB) has been associated with worse outcomes in single-center studies. We aimed to describe variation in oxygen exposure during CPB and determine if hyperoxia is associated with worse outcomes in a multicenter cohort of neonates undergoing cardiac surgery.

Methods: We conducted a retrospective study of neonates who underwent surgery with CPB between January 2021 and December 2022 at 29 centers. Primary outcomes were operative mortality and major adverse cardiovascular events (MACE), which included CPR, extracorporeal support, stroke, and mortality. Logistic regression assessed the associations between median PaO2 during …

Rbm39 Contributes To Mgmt Maintenance In Response To Temozolomide-Induced Dna Damage, Vahid Khalaj, Jack T Adams, Solmaz Aghaamiri, Servando Hernandez Vargas, Tyler M Bateman, Sukhen C Ghosh, Majid Momeny, Ali Azhdarinia

The Brown Foundation: Institute of Molecular Medicine

Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. In this study, we investigated the effect of RNA-binding motif protein 39 (RBM39) downregulation on MGMT protein levels, based on prior observations suggesting an association between these two proteins. Pharmacological depletion or siRNA-mediated knockdown of RBM39 led to a marked reduction in MGMT protein levels in MGMT-expressing cancer cells. We further showed that dual targeting of RBM39 (using indisulam) and MGMT (with O6-benzylguanine) synergistically enhanced MGMT depletion. Functionally, combined indisulam and TMZ treatment significantly …

Ezhip Boosts Neuronal-Like Synaptic Gene Programs And Depresses Polyamine Metabolism, Elham Hasheminasabgorji, Huey-Miin Chen, Taylor A Gatesman, Subhi Talal Younes, Gabrielle A Nobles, Farhang Jaryani, Heather Mao, Kwanha Yu, Benjamin Deneen, Wee Yong, Michael D Taylor, Sameer Agnihotri, Marco Gallo

Faculty, Staff and Students Publications

It is currently understood that the characteristic loss of the repressive histone mark H3K27me3 in PFA ependymoma and diffuse midline glioma (DMG) are caused by complementary mechanisms mediated by EZHIP and the oncohistone H3K27M, respectively. To support the complementarity of these mechanisms, rare H3K27M-negative DMGs express EZHIP. Interestingly, EZHIP is one of the few genes recurrently mutated in PFA. The significance of EZHIP mutations in PFA, and whether EZHIP has wider functions in addition to repression of H3K27me3 deposition, are not known. Here, we investigated the mutational landscape of EZHIP in pediatric brain tumors. We found that EZHIP mutations occur …

Standardizing And Scaffolding Health Care Ai-Chatbot Evaluation: Systematic Review, Yining Hua, Winna Xia, David Bates, George Luke Hartstein, Hyungjin Tom Kim, Michael Li, Benjamin W Nelson, Charles Stromeyer Iv, Darlene King, Jina Suh, Li Zhou, John Torous

Faculty, Staff and Students Publications

Background: Health care chatbots are rapidly proliferating, while generative artificial intelligence (AI) outpaces existing evaluation standards.

Objective: We aimed to develop a structured, stakeholder-informed framework to standardize evaluation of health care chatbots.

Methods: PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses)-guided searches across multiple databases identified 266 records; 152 were screened, 21 full texts were assessed, and 11 frameworks were included. We extracted 356 questions (refined to 271 by deduplication and relevance review), mapped items to Coalition for Health AI constructs, and organized them with iterative input from clinicians, patients, developers, epidemiologists, and policymakers.

Results: We developed the Health …

The Utility Of Ultra-Deep Rna Sequencing In Mendelian Disorder Diagnostics, Sen Zhao, Jefferson C Sinson, Shenglan Li, Jill A Rosenfeld, Gladys Zapata, Kristina Macakova, Mezthly Pena, Becky Maywald, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William Craigen, Lisa Emrick, Undiagnosed Diseases Network, Tyson Clark, Gila Yanai Lithwick, Zohar Shipony, Christine Eng, Brendan Lee, Pengfei Liu

Faculty, Staff and Students Publications

RNA sequencing (RNA-seq) has emerged as a powerful tool for resolving variants of uncertain significance (VUSs), particularly those affecting gene expression and splicing. However, most reference datasets and diagnostic protocols employ relatively modest sequencing depths (∼50-150 million reads), which may fail to detect low-abundance transcripts and rare splicing events critical for accurate diagnosis. We evaluated the diagnostic and translational utility of ultra-high-depth (up to ∼1 billion unique reads) RNA-seq in four clinically accessible tissues using the Ultima sequencing platform. After validating the performance of Ultima RNA-seq, we investigated how increasing sequencing depth affects gene and isoform detection, splicing variant discovery, …

Genetic Architecture And Analysis Practices Of Circulating Metabolites In The Nhlbi Trans-Omics For Precision Medicine Program, Nannan Wang, Franklin P Ockerman, Laura Y Zhou, Megan L Grove, Taryn Alkis, John Barnard, Russell P Bowler, Clary B Clish, Shinhye Chung, Emily Drzymalla, Anne M Evans, Nora Franceschini, Robert E Gerszten, Madeline G Gillman, Scott R Hutton, Rachel S Kelly, Charles Kooperberg, Martin G Larson, Jessica Lasky-Su, Deborah A Meyers, Prescott G Woodruff, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Ramachandran S Vasan, Scott T Weiss, Kari E Wong, Alexis C Wood, Lang Wu, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Ronit Yarden, Thomas W Blackwell, Albert V Smith, Han Chen, Laura M Raffield, Bing Yu

Faculty, Staff and Students Publications

Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse …

Compadre: Combined Pedigree-Aware Distant Relatedness Estimation For Improved Pedigree Reconstruction, Grahame F Evans, James T Baker, Lauren E Petty, Alexander S Petty, Hannah G Polikowsky, Ryan J Bohlender, Hung-Hsin Chen, Che-Yu Chou, Kathryn Z Viljoen, Janet M Beilby, Shelly Jo Kraft, Wanying Zhu, Joshua M Landman, Autumn R Morrow, Dayi Bian, Alyssa C Scartozzi, Chad D Huff, Jennifer E Below

Faculty, Staff and Student Publications

Designing powerful and unbiased genomic studies requires accurate assessment of familial relatedness even when this information is not captured from participants. Characterization of pairwise degrees of relatedness from participants' genetic data enables reconstruction of pedigrees, and several pedigree reconstruction tools have emerged in the last decade. However, limitations of these tools include high computational burden in large datasets, reliance on external information, reduced accuracy in admixed populations, and most notably, an inability to accurately reconstruct pedigrees when only a subset of family members is represented in the genetic data. To improve pedigree reconstruction in large-scale data and in pedigrees with …

Distinct Tumor-Associated Macrophage Signatures Shape The Immune Microenvironment And Patient Prognosis In Renal Cell Carcinoma, Youngsoo Han, Aidan Shen, Cheng-Chi Chao, Lucas Yeung, Aliesha Garrett, Jianming Zeng, Satoru Kawakita, Jesse Wang, Zhaohui Wang, Alireza Hassani, Xiling Shen, Chongming Jiang

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan-Meier survival plots, receiver operating characteristic (ROC) …

Menin Inhibitor Ds-1594b Drives Differentiation And Induces Synergistic Lethality In Combination With Venetoclax In Acute Myeloid Leukemia Cells With Rearranged Mixed-Lineage Leukemia And Mutated Nucleophosmin-1, Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva

Faculty, Staff and Student Publications

Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and …

Rising Metastatic Prostate Cancer Rates But Narrowing Racial Gap, Hanna Zurl, Zhiyu Qian, Klara K Pohl, Andrea Piccolini, Stephan M Korn, Muhieddine Labban, Stuart R Lipsitz, Mansoo Cho, Sean A Fletcher, Marianne Leitsmann, Sascha Ahyai, Quoc-Dien Trinh, Alexander P Cole

Faculty, Staff and Student Publications

Background: In recent years, there has been considerable interest in addressing racial disparities in prostate cancer (PCa) care including risk-adapted screening. This study examined trends in metastatic PCa incidence by race and placed them in context of changes in PSA screening recommendations.

Methods: We analyzed metastatic PCa incidence trends by race (using Surveillance Epidemiology and End Results data, 2005-2021) and PSA screening trends (using Behavioral Risk Factors Surveillance Survey data, 2012-2020). We fitted a generalized linear model with an interaction term for race and year of diagnosis and calculated annual incidence rate ratios (metastatic disease) and odds ratios (screening) for …

Distinguishing Syndromic And Nonsyndromic Cleft Palate Through Analysis Of Protein-Altering De Novo Variants In 818 Trios, Kelsey R Robinson, Sarah W Curtis, Justin E Paschall, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Gary M Shaw, Lina Moreno Uribe, Jeffrey C Murray, Harrison Brand, Seth M Weinberg, Mary L Marazita, Kimberly F Doheny, Elizabeth J Leslie-Clarkson

Faculty, Staff and Student Publications

De novo variants (DNs) are sporadically occurring variants found in an offspring but absent in both parents. DNs most commonly arise in the germline and are not under selective pressure; therefore, they may be enriched for disease-causing alleles. In fact, DNs have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a craniofacial congenital anomaly occurring in ∼1 in 1,700 live births. Genome-wide association studies have found fewer than a dozen CP-specific loci, while exome and targeted sequencing studies in family-based and case-control cohorts often lack statistical power to conclusively identify causal variants. We therefore hypothesized that CP …

Aberrant Expression Of A Disintegrin And Metalloproteinase With Thrombospondin Motifs 13 (Adamts13) In Pancreatic Cancer Leads To Dichotomic Functions, Stephanie Allmang, Hagen R. Witzel, Anne Hausen, Simone Marquard, Christoph Eckert, Nicole Marnet, Nina Hörner, Philipp Mayer, Stefan Heinrich, Hien Dang, Wilfried Roth, Matthias M. Gaida

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers characterized by highly invasive growth into the surrounding peripancreatic fat tissue, where tumor cells can directly interact with adipocytes. Due to poor response to the currently available (radio)chemotherapies, there is an urgent need for advanced therapy concepts. The present study shows that ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), a key factor in blood coagulation, is significantly overexpressed in human PDAC. Immunohistochemical analysis revealed that ADAMTS13 expression is associated with prolonged survival and negatively correlated with vascular density. In vitro and in vivo experiments demonstrate its partial …

Mutational Landscape And Clinical Impact Of Spen Mutations In Patients With Chronic Lymphocytic Leukemia, Priyatharsini Nirmalanantham, Andrés E Quesada, Anindita Ghosh, Pei Lin, Chi Y Ok, Richard K Yang, Hong Fang, Sofia Garces, Rashmi Kanagal-Shamanna, Sanam Loghavi, Mark J Routbort, Cameron Cheng Yin, Wang Wei, Sarah Pasyar, Roland Bassett, Siba El Hussein, Nitin Jain, Jan Burger, William G Wierda, Sa Wang, Carlos Bueso-Ramos, Keyur P Patel, Leonard Jeffrey Medeiros, Fatima Zahra Jelloul

Faculty, Staff and Student Publications

Background/objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis.

Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were …