Digital Commons Network^™

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8

Genotype-Phenotype Correlations Of Monoallelic Pfic Variants In Pediatric Liver Disease: A Multicenter Retrospective Cohort Study., Brett J. Hoskins, Tiziano Pramparo, Chaowapong Jarasvaraparn, Michael J. Wilsey, Voytek Slowik, Lakshmi Kunam, Janis M. Stoll, Ruben E. Quiros-Tejeira, Simon Lam, Wikrom Karnsakul

Manuscripts, Articles, Book Chapters and Other Papers

Progressive familial intrahepatic cholestasis (PFIC) is classically caused by biallelic pathogenic variants, yet monoallelic variants of uncertain significance (VUS) in PFIC-associated genes are increasingly identified in children with cholestasis, creating diagnostic uncertainty. We conducted a multicenter cohort study of children with liver disease and/or cholestasis harboring monoallelic VUS in ATP8B1, ABCB11, ABCB4, TJP2, or NR1H4. Clinical and longitudinal data were analyzed, and variant frequencies were compared with population data from gnomAD. Twenty-six children with 37 monoallelic PFIC-gene VUS met inclusion criteria, and multigenic variant burden was common (73.1%). PFIC-like biochemical patterns were observed in 42.3% but were frequently transient, and …

Characterizing Children With Chronic Kidney Disease And Severe Proteinuria In The United States: A Retrospective Analysis Using Electronic Health Records., Bradley A. Warady, Simone Heeg, Alfredo E. Farjat, Rachel Knapp, Siir Su Saydam, Alexander Vowinkel, Alain Gay, James Potts, Andrea Scalise, Gordana Atanackovic, Sascha Van Boemmel-Wegmann

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: In recent years, real-world data have been increasingly used to enrich data from interventional studies on treatment effectiveness. To explore the viability of hybrid study designs in pediatric chronic kidney disease (CKD), we assessed the feasibility of identifying a real-world cohort of children with CKD and severely increased proteinuria who satisfied adapted eligibility criteria from the FIONA trial.

METHODS: We used data from the Optum® de-identified Electronic Health Record dataset (Optum® EHR) to identify and characterize children with CKD and severely increased proteinuria in records from January 2013 to December 2022. Patients were identified based on two sets of …

Ambulatory Arterial Stiffness Index Among Children And Adolescents With Chronic Kidney Disease: A Report From The Chronic Kidney Disease In Children Study., Susan M. Halbach, Jennifer Roem, Michael F. Schneider, Joshua Samuels, Susan L. Furth, Bradley A. Warady, Joseph T. Flynn, Ckid Study Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: To quantify the association between ambulatory arterial stiffness index (AASI) and hypertensive status, and to identify additional predictors of AASI, including body mass index (BMI), proteinuria, and mineral metabolism, in children and adolescents with chronic kidney disease (CKD).

METHODS: We analyzed data collected from 654 participants during 1283 study visits in the Chronic Kidney Disease in Children (CKiD) prospective cohort study. AASI was calculated from ambulatory blood pressure monitoring (ABPM) data as 1 minus the slope coefficient from a least squares linear regression of diastolic blood pressure (BP) on systolic BP. Hypertensive status was determined by clinic BP and …

In-Hospital Mortality Patterns And Readmissions In Patients With Chronic Obstructive Pulmonary Disease: An Analysis Of The Role Of Pulmonary Hypertension, Saad Afzal Khan, Trishna Parikh, Adishwar Rao, Akriti Agrawal, Aarohi Parikh, Sarah Shin, Maulin Patel, Kha Dinh, Bela Patel, Bindu Akkanti

Faculty, Staff and Student Publications

Chronic obstructive pulmonary disease (COPD) may be complicated by pulmonary hypertension (PH). We aimed to understand the impact of PH on in-hospital mortality and quantify the 30-day readmission rate among patients with COPD. For this cross-sectional study, we used the Nationwide Readmissions Database from 2017-2020 to identify adults ≥18 years with COPD. Patients were stratified according to PH diagnosis. Baseline characteristics between groups were compared using the Pearson chi-square test and two-sample t-test. Predictors of in-hospital mortality were determined using multivariate logistic regression analysis adjusted for demographics and confounders. The 30-day readmission rate and prevalence of PH subgroups by baseline …

Emotional Urgency And Lack Of Perseverance Are Linked To Anxiety Sensitivity And Improve During Early Recovery From Opioid Use Disorder., Breanna A. Mcnaughton-Long, Abigail J. Pleiman, Carmen Buchfink, Chrysantha B. Davis, Rayus Kuplicki, Martin P. Paulus, Hung-Wen Yeh, Maëlle C M Gueguen, Jennifer L. Stewart

Manuscripts, Articles, Book Chapters and Other Papers

Few studies have identified how facets of impulsivity relate to recovery in opioid use disorder (OUD). Treatment-enrolled individuals with OUD (n = 167) and healthy controls (CTL; n = 46) completed the Urgency, Premeditation, Perseverance, Sensation Seeking, Positive Urgency (UPPS-P) Impulsive Behavior Scale along with demographic and clinical measures at visit 1. Over the next three months, abstinence and return to use were documented for participants with OUD (via self-report, alcohol breathalyzer, urine drug screen, and secondary contact communication). Participants with OUD who returned to use (n = 59) did not complete further study visits, whereas those who remained abstinent …

Natural History Of Pi-Rads 3 Lesions On Serial Prostate Mpmri, Ron Marom, Yuval Rand, Meitar Atias, Sophie Barnes, Ibrahim Fahoum, Gal Keren-Paz, Mario Sofer, Ofer Yossepowitch, Snir Dekalo, Avi Beri, Roy Mano

Faculty, Staff and Students Publications

Objective: PI-RADS 3 lesions on prostate multiparametric MRI (mpMRI) are indeterminate findings with debated management. We evaluated their radiologic evolution on follow-up mpMRI and correlated imaging changes with biopsy outcomes.

Methods: We retrospectively identified 166 men with at least one PI-RADS 3 lesion on initial mpMRI and at least one follow-up mpMRI without intervening treatment. Lesions were classified at follow-up as regressed (downgraded to PI-RADS ≤ 2), stable (remained PI-RADS 3), or progressed (upgraded to PI-RADS 4-5). Lesions were stratified by zonal location. MRI-targeted biopsy results were reviewed when available (n = 64).

Results: On follow-up, 52% of lesions regressed, …

Fgfr1/Klb-Mfg-E8 Maintains Microvascular Integrity And Adaptive Cardiac Remodeling, Sanskruti R Gare, Nasser H Alatawi, Xinyi Chen, Jiayan Zhang, Claire Ross, Oveena Fonseka, Yihua Han, Namrita Kaur, Andrea Ruiz-Velasco, Xiangjun Zhao, Yingjuan Liu, Riham R E Abouleisa, Susanne S Hille, Tao Wang, Sabu Abraham, Bernard D Keavney, Martin K Rutter, Elizabeth J Cartwright, Gareth Howell, Tamer M A Mohamed, Oliver J Müller, Wei Liu

Faculty, Staff and Students Publications

Background: Endothelial defects in the heart are a contributor to cardiac pathological remodeling and dysfunction, which can be influenced by cardiomyocytes. Here, we explore cardioprotective crosstalk between cardiomyocytes and endothelial cells under diabetic conditions.

Methods: Type 2 diabetes was induced in male and female mice using a high-fat, high-sucrose diet in conjunction with low-dose streptozotocin. Cardiomyocyte-specific deletion of FGFR1 (fibroblast growth factor receptor 1) or KLB (beta-Klotho) was achieved by crossing floxed mice with αMHC (alpha-myosin heavy chain)-Cre transgenic mice, while the treatment potential was assessed by recombinant adeno-associated virus 9 delivery systems or administration of recombinant protein. Various in …

Altered Sperm Dna Methylation Provides An Epigenetic Route From Overweight And Older Men To Intergenerational Disease Transmission., Mathieu Schulz, Xiaojian Shao, Romain Lambrot, Christine Lafleur, Donovan Chan, Marie-Charlotte Dumargne, Amanda J. Macfarlane, Sergey Moskovtsev, Guillaume Bourque, Tomi Pastinen, Clifford Librach, Hope Weiler, Jacquetta Trasler, Sarah Kimmins

Manuscripts, Articles, Book Chapters and Other Papers

The occurrence of childhood neurodevelopmental disorders has been steadily increasing for decades, yet we have little understanding of modes of inheritance implicated in these diseases. Epidemiology studies have revealed an association between an elevated paternal Body Mass Index (BMI) and age as factors implicated in increased risk for neurodevelopmental disorders in children. Epigenetic regulation of gene expression by DNA methylation at cytosines is susceptible to environmental, diet, and lifestyle changes. Yet, whether a man's BMI and age influence the sperm methylome and potentially impact offspring development remains unresolved. Using MethylC capture sequencing, we identified over 38,000 differentially methylated CpGs in …

A Phase 2, Open-Label, Multicenter Study Of The Safety And Efficacy Of Tak-007 In Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma, Justin Darrah, Indumathy Varadarajan, Amitkumar Mehta, Jennifer Saultz, Matthew Mckinney, Monalisa Ghosh, Usama Gergis, Andrew Krueger, Kevin Galinsky, Girish Bende, Ajeetha Ramachandran, Varsha Sundaresan, Siddha Kasar, Bradley Hupf, Sharon Chen, Leopold Sellner, Reem Karmali

Department of Medical Oncology Faculty Papers

In relapsed/refractory large B-cell lymphoma (LBCL), chimeric antigen receptor (CAR)-natural killer (NK) cell therapies offer potential advantages over CAR-T-cell therapies, including off-the-shelf availability and scalable manufacturing. We performed a phase 2 study of single-dose TAK-007, a cryopreserved, cord blood-derived, off-the-shelf CD19 CAR-NK cell therapy, in 26 heavily pre-treated patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Adverse events were manageable, with limited grade 1-2 cytokine release syndrome (11.5%). Overall response rate with TAK-007 800 x106 CD19 CAR+ viable NK cells (n=14) was 60.9% (95% CI: 38.5-80.3). Median progression-free survival was 2.0 months (95% CI: 0.99-3.58) in LBCL (n=10) and 5.6 months …

Application Of Close-Kin Mark-Recapture To An American Black Bear Population Using Harvest Samples, Anthony Sévêque, Robert C. Lonsinger, Lisette P. Waits, Kristin E. Brzeski, Sarah L. Mayhew, D Cody Norton, Maya Weissman, Et Al.

Michigan Tech Publications

Close-kin mark-recapture (CKMR) offers a promising alternative to traditional mark-recapture methods for estimating wildlife population parameters. CKMR estimates demographic parameters by identifying genetic relationships between individuals, effectively "recapturing" parental genotypes through their offspring's genetic profiles. One key advantage of CKMR over traditional methods is the ability to estimate abundance without recapture, facilitating the use of lethally collected biological samples. Here, we present an application of CKMR to a terrestrial species using samples collected from harvested individuals. We analyzed genetic data from 1767 American black bears (Ursus americanus) harvested over two consecutive years in Michigan's Upper Peninsula. Using Genotyping-in-Thousands by sequencing …

Study Of Blood Linear Rna Nominates Cd55 And Dld As Early-Stage Biomarkers For Parkinson's Disease, Aleksandra Beric, Sarp Sahin, Santiago Sanchez, Zining Yang, Ravindra Kumar, Isabel Alfradique-Dunham, Jessie Sanford, Daniel Western, Bridget Phillips, John P Budde, Richard J Perrin, Paul T Kotzbauer, Joel S Perlmutter, Scott A Norris, Carlos Cruchaga, Laura Ibanez

2020-Current year OA Pubs

Parkinson's disease (PD) is the second leading neurodegenerative disease, pathologically characterized by the accumulation of alpha-synuclein in the brain and the loss of dopaminergic neurons in the substantia nigra pars compacta. Despite the intensive efforts to identify diagnostic biomarkers for PD and nominating prospective candidates such as such as CSF α-synuclein seed amplification assay or α-/β-synuclein ratio, establishment of minimally invasive biomarkers remains the focus of PD research. We leveraged transcriptomic data from 4343 participants from four independent datasets to robustly identify PD-associated transcripts. Following the differential abundance analyses, we integrated our findings with several brain transcriptomic, CSF proteomic, plasma …

Immune Hallmarks Of Recurrent Immune Checkpoint Inhibitor-Mediated Inflammatory Arthritis, Synat Keam, Yuanteng Jeff Li, Yanshuo Chu, Jean H Tayar, Huifang Lu, Michael Wu, Sandeep K Agarwal, Nitin Jain, Pavlos Msaouel, Adi Diab, Linghua Wang, Cara Haymaker, Roza Nurieva, Sang T Kim

Faculty, Staff and Students Publications

Immune checkpoint inhibitor (ICI) therapy is often associated with immune-related adverse events including inflammatory arthritis (IA). However, the mechanisms underlying ICI-mediated IA (ICI-IA), especially its recurrence, are not well understood. In this study, we sought to elucidate mechanisms of recurrent ICI-IA by analyzing longitudinal synovial fluid (SF) samples from patients with ICI-IA. SF samples were collected from six patients with ICI-IA at the first and second occurrences of ICI-IA and analyzed with single-cell RNA sequencing (n = 3), single-cell T-cell receptor sequencing (n = 3), single-cell B-cell receptor sequencing (n = 3), and flow cytometry (n = 6). SF samples …

Peritoneal Dialysis Catheter Complications In Neonates With Kidney Failure., Shannon Reinert, Maanasa Yarlagadda, Alexander Bondoc, Donna Claes, Stefanie Riddle, Meredith P. Schuh

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Neonates with kidney failure require placement of a peritoneal dialysis catheter (PD-C) shortly after birth. PD-C malfunction and peritonitis, both common in this population, are associated with PD failure. The aim of this study was to describe our center's PD-C-related practices and outcomes in neonates with kidney failure.

METHODS: We performed a retrospective chart review of neonates who required kidney replacement therapy (KRT) within the first 30 days of life from 01/2018-12/2023. We evaluated for PD-C duration, PD-C replacement or revision, and peritonitis.

RESULTS: Twenty-four neonates had PD-C placed for chronic dialysis at a median of 9.7 days and …

A Rare Recurring Gain-Of-Function Variant In Bmpr2 Causes Neurodevelopmental Phenotypes In Humans And Flies, Zhi Tan, Ariel Brautbar, Maria Descartes, Erica T Gray, Alejandro Iglesias, Scott D Mclean, Morgan Nutter, Olivia Daugherty, Amber Begtrup, Ingrid M Wentzensen, Yufeng Shen, Damian W Young, Martin M Matzuk, Oguz Kanca, Michael F Wangler, Hugo J Bellen, Wendy K Chung, Shinya Yamamoto

Faculty, Staff and Students Publications

Bone morphogenetic protein receptor type 2 (BMPR2) encodes an evolutionarily conserved serine/threonine kinase that phosphorylates type-1 BMP receptors to mediate intercellular communication upon ligand binding. Loss-of-function variants in BMPR2 are known to cause pulmonary arterial hypertension and other cardiovascular disorders. Here, we report a rare recurrent missense variant in BMPR2 (c.1126G>A [GenBank: NM_001204] [p.Glu376Lys]) identified in six individuals, who all present with neurodevelopmental phenotypes including autism spectrum disorder and global developmental delay. Trio analysis demonstrates de novo occurrence of this variant in at least five of the individuals. Using the fruit fly Drosophila melanogaster, we show that this variant …

A Genetic Risk Variant Associated With The Risk Of Primary Biliary Cholangitis Is Inherited From Neanderthals, Heather J Cordell, George F Mells, Richard N Sandford, David E Jones, Gideon Hirschfield, Katherine A Siminovitch, M Eric Gershwin, Brian D Juran, Elizabeth J Atkinson, Angela Cheung, Mariza De Andrade, Aris Baras, Konstantinos N Lazaridis, Rosanna Asselta, Pietro Invernizzi, Manuela Sironi, Sriram Sankararaman, Canadian‐Us Pbc Consortium, Uk‐Pbc Consortium, Italian Pbc Genetics Study Group

Faculty, Staff and Students Publications

Background: Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal-derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored.

Objective: We investigate whether archaic alleles influence PBC risk.

Design: Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE-mc and temporal haplotype dynamics were assessed using ancient …

The Epidemiology Of Kidney And Urinary Tract Infections In Pediatric Chronic Kidney Disease: Prevalence, Risk Factors And Association With Gfr Decline In The Chronic Kidney Disease In Children Study., Derek K. Ng, Andrea R. Molino, Siyao Zhang, Emily J. Stonebrook, Craig S. Wong, Pratyush Gyawali, Kimberly J. Reidy, Susan L. Furth, Bradley A. Warady, Jeffrey J. Fadrowski, Ckid Study Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Urinary tract and kidney infections are potential complications in pediatric chronic kidney disease (CKD), especially among patients with congenital anomalies of the kidney and urinary tract (CAKUT). We characterized the prevalence of self-reported infections from childhood through young adulthood; evaluated risk factors; and quantified the association with CKD progression.

METHODS: Infections in the past year were self-reported at annual Chronic Kidney Disease in Children (CKiD) study visits. Age-specific infection prevalences were stratified by sex and CKD diagnoses (glomerular, non-glomerular non-CAKUT, CAKUT low-risk for infections, and three CAKUT high-risk categories: reflux nephropathy, obstructive uropathy, and other high-risk). Repeated measures logistic …

A Prospective Natural History Study Protocol For Clinical Trial Readiness In Synaptic Disorders, Joeylynn Coyne, Ian Mcsalley, Michael C Kaufman, Bintou Bane, Torrey Chisari, Jonathan Toib, Carlyn Glatts, Sarah Tefft, Julie M Orlando, Viveknarayanan Padmanabhan, Alexander K Gonzalez, Alicia Harrison, Charlene Woo, Stephanie A Zbikowski, Rency Dhaduk, Johanna Mercurio, Macie Mccarthy, Jan H Magielski, Zachary Grinspan, Megan Abbott, Juliet Knowles, Hsiao-Tuan Chao, Katherine Xiong, Elizabeth Berry-Kravis, Sepideh Tabarestani, J Michael Graglia, Kathryn Helde, Virginie Mcnamar, Charlene Son Rigby, James Goss, Scott Demarest, Andrea Miele, Benjamin Prosser, Michael J Boland, Samuel R Pierce, Ingo Helbig

Faculty, Staff and Students Publications

Objective: STXBP1-related disorder (STXBP1-RD) and SYNGAP1-related disorder (SYNGAP1-RD) are two common genetic synaptopathies that are associated with epilepsy, developmental delay, intellectual developmental disorder, and behavioral problems. Both STXBP1-RD and SYNGAP1-RD are potential targets for disease-modifying therapies, but there is limited information in the literature describing the natural history of either disorder, which impedes outcome selection for future clinical trials. The objective of this study is to develop a framework to better define and outline the clinical spectrum and longitudinal trajectories of STXBP1-RD and SYNGAP1-RD natural history, including development, behavior, seizure histories, and electrophysiology.

Methods: Here, we describe a protocol, regulatory …

Unveiling Functional-Metabolic Synergy In The Healthy Brain: Multivariate Integration Of Dynamic [18f]Fdg-Pet And Resting-State Fmri, Claudia Tarricone, Giulia Vallini, Giorgia Baron, Massimiliano Facca, Erica Silvestri, Tommaso Volpi, Andrei G Vlassenko, Manu S Goyal, Alessandra Bertoldo

2020-Current year OA Pubs

Despite accounting for only 2% of body weight, the human brain requires significant amounts of glucose, even at rest, underscoring the importance of functional-metabolic relationships. Previous studies revealed moderate associations between resting-state fMRI functional connectivity (FC) and local metabolism via [

Ambulatory Blood Pressure Thresholds And Left Ventricular Hypertrophy In Children Aged 6-12 Years: A Pediatric Nephrology Research Consortium Study., Afsana Jahan, Matthew Schuchman, Mahie Abdullah, Meghan Mclaughlin, Emilia Maria Cadiz, Eshanika Manchanda, Aftab Chishti, Maggie Murphy, Sarah Twichell, Alexandra Mazo, Dmitry Samsonov, Aesha Maniar, Hannah Kim, Francis Lomanta, Ashok Chakravarthy Patibandla, Rachel Frank, Tarak Srivastava, Ikuyo Yamaguchi, Christine Sethna

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To evaluate the diagnostic performance of ambulatory blood pressure monitoring (ABPM) thresholds for predicting left ventricular hypertrophy (LVH) in children aged 6-12 years.

STUDY DESIGN: A retrospective, multicenter study was conducted across 11 Pediatric Nephrology Research Consortium sites and included children aged 6-12 years who underwent ABPM and 2-dimensional echocardiography for diagnostic assessment of elevated BP. The diagnostic accuracy of fixed ABPM thresholds and the current 95th percentile for sex and height were assessed using area under the receiver operating characteristic, sensitivity, specificity, and Youden index. Multivariable logistic regression models, adjusted for age, sex, and body mass index z-score, …

Characterization Of The Genotypic And Phenotypic Spectrum Of Tcf7l2-Related Neurodevelopmental Disorder (Trnd)., Sally Nijim, Mimi Kim, Melissa Denish, Michael V Gonzalez, Joseph Zinski, Claudine Rieubland, Dominique Braun, Elsebet Ostergaard, Amelle Shillington, Laurence Faivre, Julien Maraval, Aurore Garde, Christophe Philippe, Fréderic Tran-Mau-Them, Amy Crunk, Uci Gregor Site, Megan Hawley, Bert Callewaert, Maria Iascone, Anna Cereda, Cecilia Daolio, Tova Hershkovitz, Jean-Marc Good, Katharina Steindl, Tanja Frey, Anita Rauch, Alexandra Afenjar, Cyril Mignot, Jean-Madeleine De Sainte Agathe, Nicolette Den Hollander, Yvonne Hilhorst-Hofstee, Saskia Koene, Gijs Santen, Emilia K. Bijlsma, Sara Berger, Lakshmi Mehta, Radka Stoeva, Clara Houdayer, Paul Gueguen, Helene Faust, Sabine Specht, Annick Klabunde-Cherwon, Melik Malek Khelifa, Anke Bergmann, Carol J. Saunders, Magdalena Krygier, Diana Carrasco, Kay Metcalfe, Stephan J. Sanders, David Y. Zhang, Renae Judy, Wes Nijim, David Exposito-Alonso, Christine X. Deng, Jusung Kim, Jozef Gecz, Corrado Romano, Cindy Skinner, Angie Lichty, Ellen Linebaugh, Steven A. Skinner, Maria Chahrour, Tianyun Wang, Kun Xia, Hui Guo, Sien Van Daele, Gert Van Goethem, Christina Fagerberg, Jesper Graakjaer, Susanne Anders, Heike Fink, D Isum Ward, Dorothy K. Grange, Alanna Strong, Petra Zwijnenburg, Meghan Towne, René G. Feichtinger, Jennifer Morrison, Aditi Dagli, Jonathan Levy, Yline Capri, Rebecca C. Spillman, Sarah Hart, Vandana Shashi, Boris Keren, Tjitske Kleefstra, Rolph Pfundt, Christian Gilissen, Evan E. Eichler, Melanie Brugger, Michael Zech, Wendy K. Chung, Maria Fasolino, Holly C. Dow, Daniel J. Rader, Edward S. Brodkin, Maja Bucan, Eric D. Marsh, Caroline Dias, David C. Fajgenbaum

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ β-Catenin pathway. In 2021, 11 pediatric patients with monoallelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features-herein referred to as TCF7L2-related neurodevelopmental disorder-is urgently needed.

METHODS: We leveraged multiple methods (eg, GeneMatcher, DECIPHER, literature review, and public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n …

High-Grade Astrocytoma With Piloid Features: A Clinical And Genomic Analysis Of Prognostic Factors Using A Large Cohort, Shuodan Zhang, Omar H Butt, Sonika Dahiya, Et Al.

2020-Current year OA Pubs

BACKGROUND: High-grade astrocytoma with piloid features (HGAP) is a recently defined tumor type that is not well understood. Prognostic factors of clinical outcomes are not well established.

METHODS: Methylation profiling was performed on tumor samples, many at the National Cancer Institute (NCI) Laboratory of Pathology, and others from publicly available sources. Methylation classifier scores of ≥0.90 to the HGAP class on the NCI-Bethesda classifier version 3 were included. Clinical features were collected from the medical record. Survival analyses were performed using the Kaplan-Meier and Cox-proportional hazards methods.

RESULTS: The cohort comprised 421 patients. There were high rates of ATRX alteration …

Efficacy And Safety Of Frail Patients Treated With Ciltacabtagene Autoleucel In The Real World: A Center For International Blood And Marrow Transplant Research Analysis., Hira Mian, Muhammad Salman Faisal, Tiening Chen, Ruta Brazauskas, Temitope Oloyede, Nausheen Ahmed, Aimaz Afrough, Larry D Anderson, Rahul Banerjee, Jesus Berdeja, Aram Bidikian, Jakob Devos, Binod Dhakal, Ajoy Dias, Danai Dima, Yvonne A Efebera, Lohith Gowda, Doris K Hansen, Hamza Hashmi, Heather J Landau, Lazaros Lekakis, Abu-Sayeef Mirza, Ravi Narra, Krina Patel, Ashley E Rosko, Mark Schroeder, Surbhi Sidana, Saad Usmani, Marcelo C Pasquini, Taiga Nishihori, Othman Salim Akhtar, Meera Mohan

Oncology Articles

Background: Ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy, is approved for relapsed/refractory multiple myeloma (RRMM).

Methods: Using the Center for International Blood and Marrow Transplant Research registry, this study evaluated outcomes of frail patients receiving commercial cilta-cel from March 2022 to December 2023. Frailty was defined by an adapted simplified score incorporating age, performance status, and comorbidities.

Results: Among 541 patients with available frailty status, 183 (33.8%) were frail and 358 (66.2%) were nonfrail. Overall response rates were comparable (frail 82.8% vs. nonfrail 88.5%). However, frail patients had inferior progression-free survival (PFS) (12-month …

Clinical Decision Support For Fall Prevention In Primary Care: The Esteps Cluster Randomized Clinical Trial, Nancy K Latham, Erin Hommel, Mackenzie Kiesman, Stuart R Lipsitz, David W Bates, Diane L Carroll, Alexandra C Frost, Pamela M Garabedian, Julia V Loewenthal, Michael Sainlaire, Lipika Samal, Wenyu Song, Matthew Wien, Patricia C Dykes

Faculty, Staff and Students Publications

Importance: Falls are a leading cause of injury among older adults. Although exercise reduces fall risk, implementation in primary care remains limited.

Objective: To assess whether an electronic health record-integrated clinical decision support intervention, Electronic Strategies for Tailored Exercise to Prevent Falls (eSTEPS), reduces falls among older primary care patients at increased risk.

Design, setting, and participants: This matched-pair cluster randomized clinical trial was conducted from June 9, 2023, to May 8, 2025, with 12 to 23 months of follow-up at primary care practices within an integrated health system in the US. Adults aged 65 years or older with a …

Cadherin-11 Regulation Of Type Ii Alveolar Epithelial Cells During Pulmonary Fibrosis, Mesias Pedroza, Sarah To, Jennifer Smith, Tingting W Mills, Thandiwe Chavula, Harry Karmouty-Quintana, Sandeep K Agarwal

Faculty, Staff and Students Publications

Type II alveolar epithelial cell (AT2) injury has been hypothesized to contribute to pulmonary fibrosis. Cadherin-11 (CDH11) is a mediator of fibrosis and is upregulated on AT2s during lung fibrosis. Herein, the regulation of AT2 by CDH11 during pulmonary fibrosis was investigated. CDH11 levels were increased in lung samples from patients with idiopathic pulmonary fibrosis compared with those from healthy controls. CDH11 expression was inversely correlated with lung function. Cdh11-deficient mice were compared with wild-type mice in the intraperitoneal bleomycin model (IP BLM), and the role of AT2 was investigated using Cdh11 floxed-SPC-Cre mice and in vitro techniques. In …

Nemp1 Organizes The Meiotic Telomere-Linc Interface To Control Chromosome Movement And Telomere Integrity, Andrea Jurisicova, Helen Mcneill

Faculty, Staff and Students Publications

Nuclear Envelope Membrane Protein 1 (NEMP1) is highly expressed in oocytes and required for fertility, yet its meiotic function remains poorly understood. Here, we identify NEMP1 as a critical organizer of meiotic telomere-nuclear envelope coupling and chromosome dynamics. Loss of NEMP1 causes telomere aggregation, loss of shelterin protection, telomere shortening, persistent DNA damage, aberrant non-homologous end joining, and chromosome end-to-end fusion, ultimately leading to aneuploidy in mouse oocyte. NEMP1 is required during early fetal meiotic prophase I for telomere-nuclear envelope attachment, bouquet formation, homolog pairing, and synapsis. Live-cell imaging revealed robust rapid prophase movements in wild-type meiocytes, which were nearly …

Operative Vs Non-Operative Management Of Ventral Hernia: A Population Based Study Of Long-Term Benefits And Consequences, Sourav Podder, Julia A. Baran, Scott H. Koeneman, Francesco Palazzo, Nicole L. Dugan, Christopher Keating, Sami Tannouri

Department of Surgery Faculty Papers

Purpose: Ventral hernia (VH) management has progressed beyond simply physical repair of the defect. It now involves a strategy that purposefully restores abdominal core function and prevents future complications. This study investigates the association between ventral hernia repair (VHR) and functional disorders related to the abdominal core in addition to bowel obstruction, opioid misuse, and physical therapy utilization.

Methods: This retrospective cohort study used administrative codes from the TriNetX database. The outcomes of interest were spine and pelvic floor dysfunction, constipation, incontinence, genital prolapse, bowel obstruction, opioid misuse, and physical therapy utilization.

Results: A total of 587 384 patients were …

Validation Of Next‑Generation Sequencing‑Derived Circulating Mrna Variants As Potential Diagnostic Tools In Hepatocellular Carcinoma And Cholangiocarcinoma, Daniel Zezulinski, Maarouf A. Hoteit, David E. Kaplan, Tingting Zhan, Cataldo Doria, Timothy M. Block, Aejaz Sayeed

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Liquid biopsy can transform oncology practice through early detection and real‑time monitoring of cancer progression and response to treatment. Circulating cell‑free tumor RNA offers promise as a novel and emerging alternative to circulating cell‑free tumor DNA for detecting the presence and understanding the biology of liver tumors. Both circulating DNA and RNA, which predominantly reside in extracellular vesicles, carry evidence of vital germline and somatic mutations. High impact single nucleotide changes, insertions and deletions in circulating RNA (ctRNA) serve a key role in cancer development and progression. Tumor cells exploit the RNA splicing machinery to induce structural and functional changes …

Association Between Nonsyndromic Congenital Heart Disease And Childhood Cancer In A Population-Based, Retrospective Cohort Of 11 Million Children, Sonja A Rasmussen, Emily J Mason, Tania A Desrosiers, Charles J Shumate, Wendy N Nembhard, Mahsa M Yazdy, Eirini Nestoridi, Amanda E Janitz, Jean Paul Tanner, Russell S Kirby, Jason L Salemi, Chad D Huff, Sharon E Plon, Shaine A Morris, Philip J Lupo

Faculty, Staff and Students Publications

Background: Epidemiologic studies have demonstrated associations between congenital heart disease (CHD) and childhood cancer. However, these assessments have not fully accounted for the pathogenetic and clinical heterogeneity of CHD, limiting their capacity to inform pathogenetic studies and the clinical management of children with CHD.

Methods: To achieve a more detailed understanding of cancer risk in children with nonsyndromic CHD, we evaluated 60 cardiac lesions in 7 categories in a cohort of 11 million children from Massachusetts, North Carolina, Oklahoma, and Texas. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) and 95% CIs of cancer in children …

Androgens Mediate Sexual Dimorphism In Pilarowski-Bjornsson Syndrome., Kimberley Jade Anderson, Eirny Tholl Thorolfsdottir, Ilana M. Nodelman, Sara Tholl Halldorsdottir, Stefania Benonisdottir, Malak A. Alghamdi, Naif A M Almontashiri, Brenda J. Barry, Matthias Begemann, Jacquelyn F. Britton, Sarah Burke, Benjamin Cogne, Ana S A Cohen, Carles De Diego Boguñá, Evan E. Eichler, Elizabeth C. Engle, Jill A. Fahrner, Laurence Faivre, Mélanie Fradin, Nico Fuhrmann, Christine W. Gao, Gunjan Garg, Dagmar Grečmalová, Mina Grippa, Jacqueline R. Harris, Kendra Hoekzema, Tova Hershkovitz, Sydney Hubbard, Katrien Janssens, Julie A. Jurgens, Stanislav Kmoch, Cordula Knopp, Meral Aktas Koptagel, Farah A. Ladha, Pablo Lapunzina, Tobias Lindau, Marije Meuwissen, Andreina Minicucci, Emily Neuhaus, Mathilde Nizon, Lenka Nosková, Kristen Park, Chirag Patel, Rolph Pfundt, Pankaj Prasun, Nils Rahner, Nathaniel H. Robin, Carey Ronspies, Jasmin Roohi, Jill Rosenfeld, Margarita Saenz, Carol J. Saunders, Zornitza Stark, Isabelle Thiffault, Sarah Thull, Danita Velasco, Clara Velmans, Jolijn Verseput, Antonio Vitobello, Tianyun Wang, Karin Weiss, Ingrid M. Wentzensen, Genay Pilarowski, Thor Eysteinsson, Madelyn Gillentine, Kári Stefánsson, Agnar Helgason, Gregory D. Bowman, Hans Tomas Bjornsson

Manuscripts, Articles, Book Chapters and Other Papers

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1^R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1^R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants …