Medical Specialties Commons^™

Epigenome-Wide Association Study Of Lung Cancer Among Never Smokers In Two Prospective Cohorts In Shanghai, China, Mohammad L Rahman, Charles E Breeze, Xiao-Ou Shu, Jason Y Y Wong, Batel Blechter, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas A Bell, Wei Zheng, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted.

METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse …

Hiv/Aids-Associated Knowledge And Attitudes Towards Treating Disadvantaged Communities Among Pre-Community-Based Dental Education Dental Students In The Us, Aditi Tomar, Hannah Balcezak, Shirley Lewis Miranda, Marie C Latortue, Richa Chinchkhandi, Lisa Wigfall

Faculty, Staff and Student Publications

This study examines HIV/AIDS-associated knowledge and attitudes towards treating disadvantaged communities among predoctoral dental students in U.S. dental schools who have not yet commenced their Community-Based Dental Education (CBDE) training. It also compares the difference in the knowledge and attitudes between students with reported community engagement with PLWHA and those without. Our study comprised 89 predoctoral dental students within their D1-D3 years of dental school who had not yet initiated their Community-Based Dental Education (referred to as pre-CBDE dental students). Their responses were collected via an online survey. The participants were 68% females, 94% heterosexual, and with a mean age …

Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, And Cardiovascular Disease Risk In Us Hispanics And Latinos: Results From Hchs/Sol, Yi Wang, Guo-Chong Chen, Zheng Wang, Kai Luo, Yanbo Zhang, Yang Li, Amanda C Mcclain, Marta M Jankowska, Krista M Perreira, Josiemer Mattei, Carmen R Isasi, Maria M Llabre, Bharat Thyagarajan, Martha L Daviglus, Linda Van Horn, David Goldsztajn Farelo, Luis E Maldonado, Steven R Levine, Bing Yu, Eric Boerwinkle, Rob Knight, Robert D Burk, Robert C Kaplan, Qibin Qi, Brandilyn A Peters

Faculty, Staff and Student Publications

Background: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults.

Methods: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14 172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US …

Clear Thrombectomy Score: An Index To Estimate The Probability Of Good Functional Outcome With Or Without Endovascular Treatment In The Late Window For Anterior Circulation Occlusion, James E Siegler, Manisha Koneru, Muhammad M Qureshi, Mohamed Doheim, Raul G Nogueira, Nicolas Martinez-Majander, Simon Nagel, Mary Penckofer, Jelle Demeestere, Volker Puetz, Marc Ribo, Mohamad Abdalkader, João Pedro Marto, Alhamza R Al-Bayati, Hiroshi Yamagami, Diogo C Haussen, Marta Olive-Gadea, Simon Winzer, Mahmoud H Mohammaden, Robin Lemmens, Kanta Tanaka, Pekka Virtanen, Anne Dusart, Flavio Bellante, Daniel P O Kaiser, Francois Caparros, Hilde Henon, João Nuno Ramos, Santiago Ortega-Gutierrez, Sunil A Sheth, Stefania Nannoni, Lieselotte Vandewalle, Johannes Kaesmacher, Sergio Salazar-Marioni, Liisa Tomppo, Rita Ventura, Syed F Zaidi, Mouhammad Jumaa, Alicia C Castonguay, Milagros Galecio-Castillo, Ajit S Puri, Adnan Mujanovic, Piers Klein, Liqi Shu, Behzad Farzin, Hannah Moomey, Hesham E Masoud, Jessica Jesser, Markus A Möhlenbruch, Peter A Ringleb, Daniel Strbian, Osama O Zaidat, Shadi Yaghi, Davide Strambo, Patrik Michel, Daniel Roy, Shinichi Yoshimura, Kazutaka Uchida, Jean Raymond, Thanh N Nguyen

Faculty, Staff and Student Publications

Background: With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6-24 hours after last known well), we aimed to derive a score to predict favorable outcomes associated with EVT versus best medical management.

Methods and results: A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014-2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9-point score for predicting good functional outcome (modified Rankin Scale score 0-2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity …

Early Bolus Epinephrine Administration During Pediatric Cardiopulmonary Resuscitation For Bradycardia With Poor Perfusion: An Icu-Resuscitation Study, Amanda O'Halloran, Ron Reeder, Robert Berg, Tageldin Ahmed, Michael Bell, Robert Bishop, Matthew Bochkoris, Candice Burns, Joseph Carcillo, Todd Carpenter, J. Michael Dean, J. Wesley Diddle, Myke Federman, Richard Fernandez, Ericka Fink, Deborah Franzon, Aisha Frazier, Stuart Friess, Kathryn Graham, Mark Hall, David Hehir, Christopher M Horvat, Leanna Huard, Martha Kienzle, Todd Kilbaugh, Tensing Maa, Arushi Manga, Patrick Mcquillen, Kathleen Meert, Peter Mourani, Vinay Nadkarni, Maryam Naim, Daniel Notterman, Murray Pollack, Anil Sapru, Carleen Schneiter, Matthew Sharron, Neeraj Srivastava, Bradley Tilford, Alexis Topjian, Shirley Viteri, David Wessel, Heather Wolfe, Andrew Yates, Athena Zuppa, Robert Sutton, Ryan Morgan

Department of Pediatrics Faculty Papers

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness.

METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status.

RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness …

Implementation, Enrollment, And Engagement In An Opt-Out Telehealth Pharmacist-Assisted Tobacco Treatment Program For Patients Seen In Oncology Outpatient Clinics, K. Michael Cummings, Benjamin A. Toll, Vincent Talbot, Avery Roberson, Dianne Wilson, Martha Dunlap, Emily C. Ware, Amanda M. Palmer, Asia A. Bliss, Vincent S. Anokye, Graham Warren

Markey Cancer Center Faculty Publications

OBJECTIVE: To describe the workflow, reach, cost, and self-reported quit rates for an opt-out tobacco treatment program (TTP) for patients seen in 43 oncology outpatient clinics.

METHODS: Between May 25, 2021, and December 31, 2022, adult patients (≥18 years) visiting clinics affiliated with the Medical University of South Carolina Hollings Cancer Center were screened for smoking status. Those currently smoking were referred to a telehealth pharmacy-assisted TTP. An attempt was made to contact referred patients by phone. Patients reached were offered free smoking cessation counseling and a 2-week starter kit of nicotine replacement medication. A random sample of 420 patients …

Brain-Age Prediction: Systematic Evaluation Of Site Effects, And Sample Age Range And Size, Yuetong Yu, Hao-Qi Cui, Shalaila S Haas, Faye New, Nicole Sanford, Kevin Yu, Denghuang Zhan, Guoyuan Yang, Jia-Hong Gao, Dongtao Wei, Jiang Qiu, Nerisa Banaj, Dorret I Boomsma, Alan Breier, Henry Brodaty, Randy L Buckner, Jan K Buitelaar, Dara M Cannon, Xavier Caseras, Vincent P Clark, Patricia J Conrod, Fabrice Crivello, Eveline A Crone, Udo Dannlowski, Christopher G Davey, Lieuwe De Haan, Greig I De Zubicaray, Annabella Di Giorgio, Lukas Fisch, Simon E Fisher, Barbara Franke, David C Glahn, Dominik Grotegerd, Oliver Gruber, Raquel E Gur, Ruben C Gur, Tim Hahn, Ben J Harrison, Sean Hatton, Ian B Hickie, Hilleke E Hulshoff Pol, Alec J Jamieson, Terry L Jernigan, Jiyang Jiang, Andrew J Kalnin, Sim Kang, Nicole A Kochan, Anna Kraus, Jim Lagopoulos, Luisa Lazaro, Brenna C Mcdonald, Colm Mcdonald, Katie L Mcmahon, Benson Mwangi, Fabrizio Piras, Raul Rodriguez-Cruces, Jessica Royer, Perminder S Sachdev, Theodore D Satterthwaite, Andrew J Saykin, Gunter Schumann, Pierluigi Sevaggi, Jordan W Smoller, Jair C Soares, Gianfranco Spalletta, Christian K Tamnes, Julian N Trollor, Dennis Van't Ent, Daniela Vecchio, Henrik Walter, Yang Wang, Bernd Weber, Wei Wen, Lara M Wierenga, Steven C R Williams, Mon-Ju Wu, Giovana B Zunta-Soares, Boris Bernhardt, Paul Thompson, Sophia Frangou, Ruiyang Ge, Enigma‐Lifespan Working Group

Faculty, Staff and Student Publications

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain‐age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain‐age has highlighted the need for robust and publicly available brain‐age models pre‐trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain‐age model. Here we expand this work to develop, empirically validate, and disseminate a pre‐trained brain‐age model to cover most of the human lifespan. To achieve this, we selected the …

Bayesian Varying-Effects Vector Autoregressive Models For Inference Of Brain Connectivity Networks And Covariate Effects In Pediatric Traumatic Brain Injury, Yangfan Ren, Nathan Osborne, Christine B Peterson, Dana M Demaster, Linda Ewing-Cobbs, Marina Vannucci

Faculty, Staff and Student Publications

In this article, we develop an analytical approach for estimating brain connectivity networks that accounts for subject heterogeneity. More specifically, we consider a novel extension of a multi-subject Bayesian vector autoregressive model that estimates group-specific directed brain connectivity networks and accounts for the effects of covariates on the network edges. We adopt a flexible approach, allowing for (possibly) nonlinear effects of the covariates on edge strength via a novel Bayesian nonparametric prior that employs a weighted mixture of Gaussian processes. For posterior inference, we achieve computational scalability by implementing a variational Bayes scheme. Our approach enables simultaneous estimation of group-specific …

Clinical And Genomic Landscape Of Ras Mutations In Gynecologic Cancers, Ji Son, Yingao Zhang, Heather Lin, Oriol Mirallas, Pablo Alvarez Ballesteros, Mirella Nardo, Natalie Clark, R Tyler Hillman, Erick Campbell, Vijaykumar Holla, Amber M Johnson, Amadeo B Biter, Ying Yuan, Lauren P Cobb, David M Gershenson, Amir A Jazaeri, Karen H Lu, Pamela T Soliman, Shannon N Westin, Elizabeth D Euscher, Barrett C Lawson, Richard K Yang, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Experimental design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model.

Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and …

Intratumoral Microbiome Of Adenoid Cystic Carcinomas And Comparison With Other Head And Neck Cancers, Tatiana V Karpinets, Yoshitsugu Mitani, Chia-Chi Chang, Xiaogang Wu, Xingzhi Song, Ivonne I Flores, Lauren K Mcdaniel, Yasmine M Hoballah, Fabiana J Veguilla, Renata Ferrarotto, Lauren E Colbert, Nadim J Ajami, Robert R Jenq, Jianhua Zhang, Andrew P Futreal, Adel K El-Naggar

Faculty, Staff and Student Publications

Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the …

Transcriptomic Analysis Reveals The Anti-Cancer Effect Of Gestational Mesenchymal Stem Cell Secretome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Jing Xiao, Seydou Yao, Richard H Finnell, Robert S Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties …

Associations Of Ambulatory Blood Pressure Measurements With High-Sensitivity Troponin And Natriuretic Peptide Levels In Sprint, Nikit Venishetty, Jarett D Berry, James A De Lemos, Elaine Wu, Minjae Lee, Paul E Drawz, Vijay Nambi, Christie M Ballantyne, Anthony A Killeen, Joachim H Ix, Michael G Shlipak, Simon B Ascher

Faculty, Staff and Students Publications

Background: Nighttime blood pressure (BP) has greater prognostic importance for cardiovascular disease (CVD) than daytime BP, but less is known about nighttime and daytime BP associations with measures of subclinical CVD.

Methods: Among 897 Systolic Blood Pressure Intervention Trial Study (SPRINT) participants with 24-hour ambulatory BP monitoring obtained near the 27-month study visit, 849 (95%) had N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) measured at the 24-month study visit. Multivariable linear regression analyses were performed to evaluate the associations of nighttime and daytime BP with cardiac biomarker levels.

Results: The mean age was 69 ± 12 …

Tractography-Based Modeling Explains Treatment Outcomes In Patients Undergoing Deep Brain Stimulation For Obsessive-Compulsive Disorder, Ron Gadot, Ningfei Li, Ben Shofty, Michelle Avendano-Ortega, Sarah Mckay, Kelly R Bijanki, Meghan E Robinson, Garrett Banks, Nicole Provenza, Eric A Storch, Wayne K Goodman, Andreas Horn, Sameer A Sheth

Faculty, Staff and Students Publications

BACKGROUND: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ventrolateral prefrontal regions to the subthalamic nucleus could be an effective neuromodulatory target.

METHODS: We tested this concept by attempting to retrospectively explain through predictive modeling the ranks of clinical improvement as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in 10 patients with obsessive-compulsive disorder who underwent DBS to the ventral anterior limb of internal capsule with subsequent programming uninformed by the putative target tract.

RESULTS: Rank …

Beta Activity In Human Anterior Cingulate Cortex Mediates Reward Biases, Jiayang Xiao, Joshua A Adkinson, John Myers, Anusha B Allawala, Raissa K Mathura, Victoria Pirtle, Ricardo Najera, Nicole R Provenza, Eleonora Bartoli, Andrew J Watrous, Denise Oswalt, Ron Gadot, Adrish Anand, Ben Shofty, Sanjay J Mathew, Wayne K Goodman, Nader Pouratian, Xaq Pitkow, Kelly R Bijanki, Benjamin Hayden, Sameer A Sheth

Faculty, Staff and Students Publications

The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for …

Multiparametric Mri-Based Radiomic Models For Early Prediction Of Response To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Rania M Mohamed, Bikash Panthi, Beatriz E Adrada, Medine Boge, Rosalind P Candelaria, Huiqin Chen, Mary S Guirguis, Kelly K Hunt, Lei Huo, Ken-Pin Hwang, Anil Korkut, Jennifer K Litton, Tanya W Moseley, Sanaz Pashapoor, Miral M Patel, Brandy Reed, Marion E Scoggins, Jong Bum Son, Alastair Thompson, Debu Tripathy, Vicente Valero, Peng Wei, Jason White, Gary J Whitman, Zhan Xu, Wei Yang, Clinton Yam, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between …

Patient-Reported Quality Of Life At Diagnosis In Adolescent And Young Adults With Cancer, Goldy C George, Clark Andersen, Xiaohui Tang, Elizabeth Rodriguez, Midhat Jafry, Maria C Swartz, Sairah Ahmed, Carlos H Barcenas, J Andrew Livingston, Michael E Roth, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors.

Patients and methods: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores < 50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models.

Results: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% …

27-Hydroxycholesterol Acts On Estrogen Receptor Α Expressed By Pomc Neurons In The Arcuate Nucleus To Modulate Feeding Behavior, Hui Ye, Xiaohua Yang, Bing Feng, Pei Luo, Valeria C Torres Irizarry, Leslie Carrillo-Sáenz, Meng Yu, Yongjie Yang, Benjamin P Eappen, Marcos David Munoz, Nirali Patel, Sarah Schaul, Lucas Ibrahimi, Penghua Lai, Xinyue Qi, Yuliang Zhou, Maya Kota, Devin Dixit, Madeline Mun, Chong Wee Liew, Yuwei Jiang, Chunmei Wang, Yanlin He, Pingwen Xu

Faculty, Staff and Students Publications

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of …

Monoallelic De Novo Ajap1 Loss-Of-Function Variants Disrupt Trans-Synaptic Control Of Neurotransmitter Release, Simon Früh, Sami Boudkkazi, Peter Koppensteiner, Vita Sereikaite, Li-Yuan Chen, Diego Fernandez-Fernandez, Pascal D Rem, Daniel Ulrich, Jochen Schwenk, Ziyang Chen, Elodie Le Monnier, Thorsten Fritzius, Sabrina M Innocenti, Valérie Besseyrias, Luca Trovò, Michal Stawarski, Emanuela Argilli, Elliott H Sherr, Bregje Van Bon, Erik-Jan Kamsteeg, Maria Iascone, Alba Pilotta, Maria R Cutrì, Mahshid S Azamian, Andrés Hernández-García, Seema R Lalani, Jill A Rosenfeld, Xiaonan Zhao, Tiphanie P Vogel, Herda Ona, Daryl A Scott, Peter Scheiffele, Kristian Strømgaard, Mehdi Tafti, Martin Gassmann, Bernd Fakler, Ryuichi Shigemoto, Bernhard Bettler

Faculty, Staff and Students Publications

Adherens junction–associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed …

Chronic Eosinophilic Leukemia With A Novel Jak1 Mutation Responds Well To The Jak1/2 Inhibitor Ruxolitinib, Qing Wei, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

Msl2 Variants Lead To A Neurodevelopmental Syndrome With Lack Of Coordination, Epilepsy, Specific Dysmorphisms, And A Distinct Episignature, Remzi Karayol, Maria Carla Borroto, Sadegheh Haghshenas, Anoja Namasivayam, Jack Reilly, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley Mcconkey, Maria Shvedunova, Andrea K Petersen, Kari Magnussen, Christiane Zweier, Georgia Vasileiou, André Reis, Juliann M Savatt, Meghan R Mulligan, Louise S Bicknell, Gemma Poke, Aya Abu-El-Haija, Jessica Duis, Vickie Hannig, Siddharth Srivastava, Elizabeth Barkoudah, Natalie S Hauser, Myrthe Van Den Born, Uri Hamiel, Noa Henig, Hagit Baris Feldman, Shane Mckee, Ingrid P C Krapels, Yunping Lei, Albena Todorova, Ralitsa Yordanova, Slavena Atemin, Mihael Rogac, Vivienne Mcconnell, Anna Chassevent, Kristin W Barañano, Vandana Shashi, Jennifer A Sullivan, Angela Peron, Maria Iascone, Maria P Canevini, Jennifer Friedman, Iris A Reyes, Janell Kierstein, Joseph J Shen, Faria N Ahmed, Xiao Mao, Berta Almoguera, Fiona Blanco-Kelly, Konrad Platzer, Ariana-Berenike Treu, Juliette Quilichini, Alexia Bourgois, Nicolas Chatron, Louis Januel, Christelle Rougeot, Deanna Alexis Carere, Kristin G Monaghan, Justine Rousseau, Kenneth A Myers, Bekim Sadikovic, Asifa Akhtar, Philippe M Campeau

Faculty, Staff and Students Publications

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding …

Psmd11 Loss-Of-Function Variants Correlate With A Neurobehavioral Phenotype, Obesity, And Increased Interferon Response, Wallid Deb, Cory Rosenfelt, Virginie Vignard, Jonas Johannes Papendorf, Sophie Möller, Martin Wendlandt, Maja Studencka-Turski, Benjamin Cogné, Thomas Besnard, Léa Ruffier, Bérénice Toutain, Léa Poirier, Silvestre Cuinat, Amy Kritzer, Amy Crunk, Janette Dimonda, Jaime Vengoechea, Sandra Mercier, Lotte Kleinendorst, Mieke M Van Haelst, Linda Zuurbier, Telma Sulem, Hildigunnur Katrínardóttir, Rún Friðriksdóttir, Patrick Sulem, Kari Stefansson, Berglind Jonsdottir, Shimriet Zeidler, Margje Sinnema, Alexander P A Stegmann, Natali Naveh, Cara M Skraban, Christopher Gray, Jill R Murrell, Sedat Isikay, Davut Pehlivan, Daniel G Calame, Jennifer E Posey, Mathilde Nizon, Kirsty Mcwalter, James R Lupski, Bertrand Isidor, François V Bolduc, Stéphane Bézieau, Elke Krüger, Sébastien Küry, Frédéric Ebstein

Faculty, Staff and Students Publications

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be …

Predictive Value Of Has-Bled And Hemorr2hages Bleeding Risk Scores After Percutaneous Coronary Intervention, Ianis Doomun, Daphné Doomun, Sara Schukraft, Diego Arroyo, Selma T Cook, Tibor Huwyler, Jean-Jacques Goy, Jean-Christophe Stauffer, Mario Togni, Serban Puricel, Stéphane Cook

The Texas Heart Institute Journal

BACKGROUND: Various scoring systems have been developed to assess the risk of bleeding in medical settings. HAS-BLED and HEMORR2HAGES risk scores are commonly used to estimate bleeding risk in patients receiving anticoagulation for atrial fibrillation, but data on their predictive value in patients undergoing percutaneous coronary intervention (PCI) are limited.

METHODS: This study evaluated and compared the predictive abilities of the HAS-BLED and HEMORR2HAGES bleeding risk scores in all-comer patients undergoing PCI. The PARIS score, specifically designed for patients undergoing PCI, was used as a comparator. The scores were calculated at baseline and compared with the occurrence of events during …

Costs And Impact Of Disease In Adults With Sickle Cell Disease: A Pilot Study, Sophie Lanzkron, Nicole Crook, Joanne Wu, Sarah Hussain, Randall G. Curtis, Derek Robertson, Judith R. Baker, Diane Nugent, Amit Soni, Jonathan C. Roberts, Megan M. Ullman, Julie Kanter, Michael B. Nichol

Cardeza Foundation for Hematologic Research

We assessed the feasibility to estimate illness burden in adults with SCD, investigated factors associated with health-related quality of life (HRQoL), and estimated societal burden. We recruited 32 participants and collected data on fatigue, HRQoL, and work productivity and activity impairment via patient survey. Health care utilization was abstracted for the 12 months before enrollment using medical chart review. Mean age was 36.7 years; 84.4% of participants had hemoglobin SS or Sβthal0 disease, and 81.3% reported chronic pain (experiencing pain on ≥3 days per week in the past 6 months). Mean EQ-5D-3L visual analogue scale score was 63.4 and the …

Tsg-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses And Impair Anti-Tumor Response To Immune Checkpoint Therapy In Pancreatic Cancer, Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma

Faculty, Staff and Student Publications

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. …

Radiation Therapy With Or Without Cisplatin For Local Recurrences Of Endometrial Cancer: Results From An Nrg Oncology/Gog Prospective Randomized Multicenter Clinical Trial, Ann H Klopp, Danielle Enserro, Matthew Powell, Marcus Randall, Julian C Schink, Robert S Mannel, Laura Holman, David Bender, Christina L Kushnir, Floor Backes, Susan L Zweizig, Steven Waggoner, Kristin A Bradley, Lana Desouza Lawrence, Parviz Hanjani, Christopher J Darus, William Small, Higinia R Cardenes, Jonathan M Feddock, David S Miller

Faculty, Staff and Student Publications

Purpose: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy.

Materials and methods: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS.

Results: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to …

Longitudinal Program Evaluation Of An Inter-Institutional Mentorship Network For Pediatric Rheumatology Using A Quality Improvement Framework, Kristen Hayward, Alexi Grom, Eyal Muscal, Peter A Nigrovic, Kelly A Rouster-Stevens, Kaveh Ardalan, Linda Hiraki, L Nandini Moorthy

Faculty, Staff and Students Publications

BACKGROUND: The American College of Rheumatology (ACR)/Childhood Arthritis and Rheumatology Research Alliance (CARRA) Mentoring Interest Group (AMIGO) is an inter-institutional mentorship program launched to target mentorship gaps within pediatric rheumatology. Initial program evaluation indicated increased mentorship access. Given the small size of the pediatric rheumatology workforce, maintaining a consistent supply of mentors was a potential threat to the longevity of the network. Our aims were to: (i) describe the sustainability of AMIGO over the period 2011-2018, (ii) highlight ongoing benefits to participants, and (iii) describe challenges in the maintenance of a mentorship network.

METHODS: A mixed-methods approach centered on a …

The Cns Relapse In T-Cell Lymphoma Index Predicts Cns Relapse In Patients With T- And Nk-Cell Lymphomas, Rahul S Bhansali, Fredrik Ellin, Thomas Relander, Miao Cao, Wenrui Li, Qi Long, Nivetha Ganesan, Robert Stuver, Steven M Horwitz, Kitsada Wudhikarn, Steven R Hwang, N Nora Bennani, Julio Chavez, Lubomir Sokol, Hayder Saeed, Frank Duan, Pierluigi Porcu, Priyanka Pullarkat, Neha Mehta-Shah, Jasmine M Zain, Miguel Ruiz, Jonathan E Brammer, Rishab Prakash, Swaminathan P Iyer, Adam J Olszewski, Ajay Major, Peter A Riedell, Sonali M Smith, Caroline Goldin, Bradley Haverkos, Bei Hu, Tony Z Zhuang, Pamela B Allen, Wael Toama, Murali Janakiram, Taylor R Brooks, Deepa Jagadeesh, Nisha Hariharan, Aaron M Goodman, Gabrielle Hartman, Paola Ghione, Fatima Fayyaz, Joanna M Rhodes, Elise A Chong, James N Gerson, Daniel J Landsburg, Sunita D Nasta, Stephen J Schuster, Jakub Svoboda, Mats Jerkeman, Stefan K Barta

Faculty, Staff and Student Publications

Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. …

Tfeb Safeguards Trophoblast Syncytialization In Humans And Mice, Wanshan Zheng, Yue Zhang, Peiqun Xu, Zexin Wang, Xuan Shao, Chunyan Chen, Han Cai, Yinan Wang, Ming-An Sun, Wenbo Deng, Fan Liu, Jinhua Lu, Xueqin Zhang, Dunjin Cheng, Indira U Mysorekar, Haibin Wang, Yan-Ling Wang, Xiaoqian Hu, Bin Cao

Faculty, Staff and Students Publications

The formation of multinucleated syncytiotrophoblast (STB) through cell fusion of cytotrophoblast, also termed syncytialization, ensures the proper placental structure and functions. Nutrient insufficiency and inactivation of the mechanistic target of rapamycin complex 1 (mTORC1) in trophoblasts have been shown to enhance STB formation; however, the underlying mechanism remains elusive. Here, we showed that the deficiency of a mTORC1 downstream transcriptional factor, TFEB, significantly impaired STB formation in human trophoblasts and knock-out mice. TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 and thereby promoted trophoblast syncytialization. Additionally, TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth …

Incidence And Types Of Cardiac Arrhythmias In The Peri-Ictal Period In Patients Having A Generalized Convulsive Seizure, Laura Vilella, Christina Y Miyake, Ganne Chaitanya, Johnson P Hampson, Shirin Jamal Omidi, Manuela Ochoa-Urrea, Blanca Talavera, Oscar Mancera, Norma J Hupp, Jaison S Hampson, M R Sandhya Rani, Nuria Lacuey, Shiqiang Tao, Rup K Sainju, Daniel Friedman, Maromi Nei, Catherine A Scott, Brian Gehlbach, Stephan U Schuele, Jennifer A Ogren, Ronald M Harper, Beate Diehl, Lisa M Bateman, Orrin Devinsky, George B Richerson, Guo-Qiang Zhang, Samden D Lhatoo

Faculty, Staff and Students Publications

Background and objectives: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases.

Methods: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during …

Ai-Assisted Segmentation Tool For Brain Tumor Mr Image Analysis, Myungeun Lee, Jong Hyo Kim, Wookjin Choi, Ki Hong Lee

Department of Radiation Oncology Faculty Papers

TumorPrism3D software was developed to segment brain tumors with a straightforward and user-friendly graphical interface applied to two- and three-dimensional brain magnetic resonance (MR) images. The MR images of 185 patients (103 males, 82 females) with glioblastoma multiforme were downloaded from The Cancer Imaging Archive (TCIA) to test the tumor segmentation performance of this software. Regions of interest (ROIs) corresponding to contrast-enhancing lesions, necrotic portions, and non-enhancing T2 high signal intensity components were segmented for each tumor. TumorPrism3D demonstrated high accuracy in segmenting all three tumor components in cases of glioblastoma multiforme. They achieved a better Dice similarity coefficient (DSC) …