Medical Specialties Commons^™

Safety And Tolerability Of Atogepant For The Preventive Treatment Of Migraine: A Post Hoc Analysis Of Pooled Data From Four Clinical Trials, Paul Rizzoli, Michael Marmura, Jennifer Robblee, Jennifer Mcvige, Sara Sacco, Stephanie Nahas, Jessica Ailani, Rosa De Abreu Ferreira, Julia Ma, Jonathan Smith, Brett Dabruzzo, Messoud Ashina

Department of Jefferson Headache Center Papers and Presentations

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders.

METHODS: This post hoc analysis was performed using data pooled …

Nf-Κb As An Inducible Regulator Of Inflammation In The Central Nervous System, Sudha Anilkumar, Elizabeth Wright-Jin

Department of Medicine Faculty Papers

The NF-κB (nuclear factor K-light-chain-enhancer of activated B cells) transcription factor family is critical for modulating the immune proinflammatory response throughout the body. During the resting state, inactive NF-κB is sequestered by IκB in the cytoplasm. The proteasomal degradation of IκB activates NF-κB, mediating its translocation into the nucleus to act as a nuclear transcription factor in the upregulation of proinflammatory genes. Stimuli that initiate NF-κB activation are diverse but are canonically attributed to proinflammatory cytokines and chemokines. Downstream effects of NF-κB are cell type-specific and, in the majority of cases, result in the activation of pro-inflammatory cascades. Acting as …

Immune Heterogeneity In Small-Cell Lung Cancer And Vulnerability To Immune Checkpoint Blockade, Barzin Y Nabet, Habib Hamidi, Myung Chang Lee, Romain Banchereau, Stefanie Morris, Leah Adler, Velimir Gayevskiy, Ahmed M Elhossiny, Minu K Srivastava, Namrata S Patil, Kiandra A Smith, Rajiv Jesudason, Caleb Chan, Patrick S Chang, Matthew Fernandez, Sandra Rost, Lisa M Mcginnis, Hartmut Koeppen, Carl M Gay, John D Minna, John V Heymach, Joseph M Chan, Charles M Rudin, Lauren A Byers, Stephen V Liu, Martin Reck, David S Shames

Faculty, Staff and Student Publications

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but …

Nanofibrous Multidomain Peptide Hydrogels Provide T Cells A 3d, Cytocompatible Environment For Cell Expansion And Antigen-Specific Killing, Viridiana Leyva-Aranda, Shailbala Singh, Maria J Telesforo, Simon Young, Cassian Yee, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

T cells have the ability to recognize and kill specific target cells, giving therapies based on their potential for treating infection, diabetes, cancer, and other diseases. However, the advancement of T cell-based treatments has been hindered by difficulties in their ex vivo activation and expansion, the number of cells required for sustained in vivo levels, and preferential localization following systemic delivery. Biomaterials may help to overcome many of these challenges by providing a combined means of proliferation, antigen presentation, and cell localization upon delivery. In this work, we studied self-assembling Multidomain Peptides (MDPs) as scaffolds for T cell culture, activation, …

Methodological Advances In Patient-Centered Rare Disease Research: The Uthealth Houston Turner Syndrome Society Of The United States Research Registry, Sara Mansoorshahi, Cindy Scurlock, Scientific Advisory Board Of The Turner Syndrome Society Of The United States Research Registry, Siddharth K Prakash

Faculty, Staff and Student Publications

BACKGROUND: Many different clinical specialists provide care to patients with Turner syndrome (TS), who have highly variable clinical manifestations. Therefore, a national TS registry is essential to inform a cohesive approach to healthcare and research. In 2015, the Turner Syndrome Society of the United States (TSSUS) created the Turner Syndrome Research Registry (TSRR) to engage directly with community participants who voluntarily provide longitudinal data about their experiences with TS. TSRR projects are collaborative partnerships between people with TS, TSSUS, and researchers.

RESULTS: To ensure that registry workflows conform to the data privacy choices of participants, TSSUS collaborated with UTHealth Houston …

High Response Rate With Extended Dosing Of Cemiplimab In Advanced Cutaneous Squamous Cell Carcinoma, Danny Rischin, Brett G M Hughes, Nicole Basset-Séguin, Dirk Schadendorf, Samantha Bowyer, Sabiha Trabelsi Messai, Friedegund Meier, Thomas K Eigentler, Victoria Casado Echarren, Brian Stein, Marie Beylot-Barry, Sophie Dalac, Brigitte Dréno, Michael R Migden, Axel Hauschild, Chrysalyne D Schmults, Annette M Lim, Suk-Young Yoo, Anne J Paccaly, Apostolos Papachristos, Jenny-Hoa Nguyen, Emmanuel Okoye, Frank Seebach, Jocelyn Booth, Israel Lowy, Matthew G Fury, Alexander Guminski

Faculty, Staff and Student Publications

BACKGROUND: Cemiplimab (Libtayo

METHODS: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review.

RESULTS: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n

CONCLUSIONS: Extended dosing of cemiplimab 600 mg intravenously Q4W …

Toward Generalizable Machine Learning Models In Speech, Language, And Hearing Sciences: Estimating Sample Size And Reducing Overfitting, Hamzeh Ghasemzadeh, Robert E Hillman, Daryush D Mehta

Faculty, Staff and Student Publications

PURPOSE: Many studies using machine learning (ML) in speech, language, and hearing sciences rely upon cross-validations with single data splitting. This study's first purpose is to provide quantitative evidence that would incentivize researchers to instead use the more robust data splitting method of nested

METHOD: First, the significant impact of different cross-validations on ML outcomes was demonstrated using real-world clinical data. Then, Monte Carlo simulations were used to quantify the interactions among the employed cross-validation method, the discriminative power of features, the dimensionality of the feature space, the dimensionality of the model, and the sample size. Four different cross-validation methods …

Integration Of Pan-Omics Technologies And Three-Dimensional In Vitro Tumor Models: An Approach Toward Drug Discovery And Precision Medicine., Anmi Jose, Pallavi Kulkarni, Jaya Thilakan, Murali Munisamy, Anvita Gupta Malhotra, Jitendra Singh, Ashok Kumar, Vivek M. Rangnekar, Neha Arya, Mahadev Rao

Markey Cancer Center Faculty Publications

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to …

Isoform Alterations In The Ubiquitination Machinery Impacting Gastrointestinal Malignancies, Srimathi Kasturirangan, Derek Nancarrow, Ayush Shah, Kiran Lagisetty, Theodore Lawrence, David Beer, Dipankar Ray

Department of Medicine Faculty Papers

The advancement of RNAseq and isoform-specific expression platforms has led to the understanding that isoform changes can alter molecular signaling to promote tumorigenesis. An active area in cancer research is uncovering the roles of ubiquitination on spliceosome assembly contributing to transcript diversity and expression of alternative isoforms. However, the effects of isoform changes on functionality of ubiquitination machineries (E1, E2, E3, E4, and deubiquitinating (DUB) enzymes) influencing onco- and tumor suppressor protein stabilities is currently understudied. Characterizing these changes could be instrumental in improving cancer outcomes via the identification of novel biomarkers and targetable signaling pathways. In this review, we …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

The Acceptance And Use Of Digital Technologies For Self-Reporting Medication Safety Events After Care Transitions To Home In Patients With Cancer: Survey Study, Yun Jiang, Misun Hwang, Youmin Cho, Christopher R Friese, Sarah T Hawley, Milisa Manojlovich, John C Krauss, Yang Gong

Faculty, Staff and Student Publications

BACKGROUND: Actively engaging patients with cancer and their families in monitoring and reporting medication safety events during care transitions is indispensable for achieving optimal patient safety outcomes. However, existing patient self-reporting systems often cannot address patients' various experiences and concerns regarding medication safety over time. In addition, these systems are usually not designed for patients' just-in-time reporting. There is a significant knowledge gap in understanding the nature, scope, and causes of medication safety events after patients' transition back home because of a lack of patient engagement in self-monitoring and reporting of safety events. The challenges for patients with cancer in …

Target: A Randomized, Noninferiority Trial Of A Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling For Prostate Cancer Germline Testing, Stacy Loeb, Scott Keith, Heather Cheng, Amy Leader, Laura Gross, Tatiana Sanchez Nolasco, Nataliya Byrne, Rebecca Hartman, Lauren Brown, Christopher Pieczonka, Leonard Gomella, William Kevin Kelly, Costas Lallas, Nathan Handley, Patrick Mille, James Mark, Gordon Brown, Sameer Chopra, Alexandra Mcclellan, David Wise, Lucas Hollifield, Veda Giri

Department of Urology Faculty Papers

PURPOSE: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services.

METHODS: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at …

Commentary On 2022 Guidelines On Clinical Trial Design In Cluster Headache And Further Suggestions, Ioana Medrea, Stewart J Tepper, Donliang Wang, Paul G Mathew, Mark Burish

Faculty, Staff and Student Publications

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies.

MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment.

CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Final Results Of Urelumab, An Anti-Cd137 Agonist Monoclonal Antibody, In Combination With Cetuximab Or Nivolumab In Patients With Advanced Solid Tumors, Nikhil I Khushalani, Patrick A Ott, Robert L Ferris, Tina Cascone, Dirk Schadendorf, Dung T Le, Manish R Sharma, Fabrice Barlesi, William Sharfman, Jason J Luke, Ignacio Melero, Deanne Lathers, Jaclyn Neely, Satyendra Suryawanshi, Abanti Sanyal, James L Holloway, Rasika Suryawanshi, Scott Ely, Neil H Segal

Faculty, Staff and Student Publications

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.

METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m

RESULTS: CA186-018: 66 patients received study treatment. The most frequent …

Rehabilitation Treatment Specification System For Voice Therapy: Application To Everyday Clinical Care, Jeremy Wolfberg, John Whyte, Patricia Doyle, Shirley Gherson, Jason Muise, Brian Petty, Carol Jorgensen Tolejano, Robert E Hillman, Tara Stadelman-Cohen, Jarrad H Van Stan

Faculty, Staff and Student Publications

PURPOSE: Rehabilitation intervention descriptions often do not explicitly identify active ingredients or how those ingredients lead to changes in patient functioning. The Rehabilitation Treatment Specification System (RTSS) provides guidance to identify the critical aspects of any rehabilitation therapy and supported the development of standardly named ingredients and targets in voice therapy (Rehabilitation Treatment Specification System for Voice Therapy [RTSS-Voice]). This study sought to test the content validity of the RTSS-Voice and determine if the RTSS-Voice can be used to identify commonalities and differences in treatment (criterion validity) across clinicians in everyday clinical practice.

METHOD: Five speech-language pathologists from different institutions …

Protein Biomarkers And Alternatively Methylated Cell-Free Dna Detect Early Stage Pancreatic Cancer, Roni Ben-Ami, Qiao-Li Wang, Jinming Zhang, Julianna G Supplee, Johannes F Fahrmann, Roni Lehmann-Werman, Lauren K Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth Shemer, Benjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E Clancy, Douglas A Rubinson, Kimmie Ng, John A Chabot, Fay Kastrinos, Michael Kluger, Andrew J Aguirre, Pasi A Jänne, Nabeel Bardeesy, Ben Stanger, Mark H O'Hara, Jacob Till, Anirban Maitra, Erica L Carpenter, Andrea J Bullock, Jeanine Genkinger, Samir M Hanash, Cloud P Paweletz, Yuval Dor, Brian M Wolpin

Faculty, Staff and Student Publications

Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.

Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.

Results: Comparative methylome analysis identified nine loci that were differentially …

Haploinsufficiency Of Zfhx3, Encoding A Key Player In Neuronal Development, Causes Syndromic Intellectual Disability, María Del Rocío Pérez Baca, Eva Z Jacobs, Lies Vantomme, Pontus Leblanc, Elke Bogaert, Annelies Dheedene, Laurenz De Cock, Sadegheh Haghshenas, Aidin Foroutan, Michael A Levy, Jennifer Kerkhof, Haley Mcconkey, Chun-An Chen, Nurit Assia Batzir, Xia Wang, María Palomares, Marieke Carels, Zfhx3 Consortium, Bart Dermaut, Bekim Sadikovic, Björn Menten, Bo Yuan, Sarah Vergult, Bert Callewaert

Faculty, Staff and Students Publications

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis. We describe 42 individuals with protein-truncating variants (PTVs) or (partial) deletions of ZFHX3, exhibiting variable intellectual disability and autism spectrum disorder, recurrent facial features, relative short stature, brachydactyly, and, rarely, cleft palate. ZFHX3 LoF associates with a specific methylation profile in whole blood extracted DNA. Nuclear abundance of ZFHX3 increases during human brain development and …

Heterogeneity And Overlap In The Continuum Of Linguistic Profile Of Logopenic And Semantic Variants Of Primary Progressive Aphasia: A Profile Analysis Based On Multidimensional Scaling Study, Gaia Chiara Santi, Francesca Conca, Valentina Esposito, Cristina Polito, Silvia Paola Caminiti, Cecilia Boccalini, Carmen Morinelli, Valentina Berti, Salvatore Mazzeo, Valentina Bessi, Alessandra Marcone, Sandro Iannaccone, Se-Kang Kim, Sandro Sorbi, Daniela Perani, Stefano F Cappa, Eleonora Catricalà

Faculty, Staff and Students Publications

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce.

METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [

RESULTS: Patients' profiles were distributed across a …

Variants In Zfx Are Associated With An X-Linked Neurodevelopmental Disorder With Recurrent Facial Gestalt\, James L Shepherdson, Katie Hutchison, Dilan Wellalage Don, George Mcgillivray, Tae-Ik Choi, Carolyn A Allan, David J Amor, Siddharth Banka, Donald G Basel, Laura D Buch, Deanna Alexis Carere, Renée Carroll, Jill Clayton-Smith, Ali Crawford, Morten Dunø, Laurence Faivre, Christopher P Gilfillan, Nina B Gold, Karen W Gripp, Emma Hobson, Alexander M Holtz, A Micheil Innes, Bertrand Isidor, Adam Jackson, Panagiotis Katsonis, Leila Amel Riazat Kesh, Genomics England Research Consortium;, Sébastien Küry, François Lecoquierre, Paul Lockhart, Julien Maraval, Naomichi Matsumoto, Julie Mccarrier, Josephine Mccarthy, Noriko Miyake, Lip Hen Moey, Andrea H Németh, Elsebet Østergaard, Rushina Patel, Kate Pope, Jennifer E Posey, Rhonda E Schnur, Marie Shaw, Elliot Stolerman, Julie P Taylor, Erin Wadman, Emma Wakeling, Susan M White, Lawrence C Wong, James R Lupski, Olivier Lichtarge, Mark A Corbett, Jozef Gecz, Charles M Nicolet, Peggy J Farnham, Cheol-Hee Kim, Marwan Shinawi

Duncan NRI Faculty and Staff Publications

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included …

Maternal And Perinatal Health Research During Emerging And Ongoing Epidemic Threats: A Landscape Analysis And Expert Consultation, Mercedes Bonet, Magdalena Babinska, Pierre Buekens, Shivaprasad S Goudar, Beate Kampmann, Marian Knight, Dana Meaney-Delman, Smaragda Lamprianou, Flor Muñoz Rivas, Andy Stergachis, Cristiana M Toscano, Joycelyn Bhatia, Sarah Chamberlain, Usman Chaudhry, Jacqueline Mills, Emily Serazin, Hannah Short, Asher Steene, Michael Wahlen, Olufemi T Oladapo

Faculty, Staff and Students Publications

INTRODUCTION: Pregnant women and their offspring are often at increased direct and indirect risks of adverse outcomes during epidemics and pandemics. A coordinated research response is paramount to ensure that this group is offered at least the same level of disease prevention, diagnosis, and care as the general population. We conducted a landscape analysis and held expert consultations to identify research efforts relevant to pregnant women affected by disease outbreaks, highlight gaps and challenges, and propose solutions to addressing them in a coordinated manner.

METHODS: Literature searches were conducted from 1 January 2015 to 22 March 2022 using Web of …

Early Estimate Of Nirsevimab Effectiveness For Prevention Of Respiratory Syncytial Virus-Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season - New Vaccine Surveillance Network, October 2023-February 2024, Heidi L Moline, Ayzsa Tannis, Ariana P Toepfer, John V Williams, Julie A Boom, Janet A Englund, Natasha B Halasa, Mary Allen Staat, Geoffrey A Weinberg, Rangaraj Selvarangan, Marian G Michaels, Leila C Sahni, Eileen J Klein, Laura S Stewart, Elizabeth P Schlaudecker, Peter G Szilagyi, Jennifer E Schuster, Leah Goldstein, Samar Musa, Pedro A Piedra, Danielle M Zerr, Kristina A Betters, Chelsea Rohlfs, Christina Albertin, Dithi Banerjee, Erin R Mckeever, Casey Kalman, Benjamin R Clopper, Meredith L Mcmorrow, Fatimah S Dawood

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants agedtrials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, …

De Novo Variants In Dennd5b Cause A Neurodevelopmental Disorder, Marcello Scala, Valeria Tomati, Matteo Ferla, Mariateresa Lena, Julie S Cohen, Ali Fatemi, Elly Brokamp, Anna Bican, John A Phillips, Mary E Koziura, Michael Nicouleau, Marlene Rio, Karine Siquier, Nathalie Boddaert, Ilaria Musante, Serena Tamburro, Simona Baldassari, Michele Iacomino, Paolo Scudieri, Undiagnosed Diseases Network, Jill A Rosenfeld, Gary Bellus, Sara Reed, Hind Al Saif, Rossana Sanchez Russo, Matthew B Walsh, Vincent Cantagrel, Amy Crunk, Stefano Gustincich, Sarah M Ruggiero, Mark P Fitzgerald, Ingo Helbig, Pasquale Striano, Mariasavina Severino, Vincenzo Salpietro, Nicoletta Pedemonte, Federico Zara

Faculty, Staff and Students Publications

The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal …

Single-Cell Cd4 And Cd8 T-Cell Secretome Profiling Reveals Temporal And Niche Differences In Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy, Jessica L Root, Poonam N Desai, Christopher Ly, Bofei Wang, Fatima Zahra Jelloul, Jing Zhou, Sean Mackay, Mansour Alfayez, Jairo Matthews, Sherry Pierce, Patrick K Reville, Naval Daver, Hussein A Abbas

Faculty, Staff and Student Publications

UNLABELLED: Acute myeloid leukemia (AML) is a heterogeneous malignancy of the blood primarily treated with intensive chemotherapy. The allogeneic T-cell antileukemic activity via donor lymphocyte infusions and stem cell transplantation suggests a potential role for checkpoint blockade therapy in AML. While clinical trials employing these treatments have fallen short of expected results, a deeper exploration into the functional states of T cells in AML could bridge this knowledge gap. In this study, we analyzed the polyfunctional activity of T cells in a cohort of patients with relapsed/refractory (RelRef) AML treated on the clinical trial (ClinicalTrials.gov identifier: NCT02397720) of combination therapy …

Chimeric Oncolytic Adenovirus Evades Neutralizing Antibodies From Human Patients And Exhibits Enhanced Anti-Glioma Efficacy In Immunized Mice, Dong Ho Shin, Hong Jiang, Andrew G Gillard, Debora Kim, Xuejun Fan, Sanjay K Singh, Teresa T Nguyen, Sagar S Sohoni, Andres R Lopez-Rivas, Akhila Parthasarathy, Chibawanye I Ene, Joy Gumin, Frederick F Lang, Marta M Alonso, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent …

Geographic Distribution Of Human Infections With Zoonotic Ancylostoma Ceylanicum And Anthropophilic Hookworms In Ecuador: A Retrospective Analysis Of Archived Stool Samples, Dayana Aguilar-Rodríguez, Victor Seco-Hidalgo, Andrea Lopez, Natalia Romero-Sandoval, Manuel Calvopiña, Angel Guevara, Lucy Baldeón, Alejandro Rodríguez, Rojelio Mejia, Thomas B Nutman, William J Sears, Philip J Cooper

Faculty, Staff and Students Publications

Zoonotic human infections with Ancylostoma ceylanicum have recently been reported in the Americas. We used archived human stool samples to study the geographic distribution of human infections with A. ceylanicum and anthropophilic hookworms in different geoclimatic regions (coastal, Andean, and Amazon) of Ecuador. We analyzed retrospectively archived human stool samples from five studies previously screened for hookworm infection by microscopy, of which four included hookworm-positive samples only and one involved hookworm-negative samples to increase geographic distribution of sampling. Stools were analyzed using multi-parallel quantitative polymerase chain reaction (qPCR) assays to detect Necator americanus, Ancylostoma duodenale, A. ceylanicum, Ascaris lumbricoides, Trichuris …

Enhancing Prognostic Power In Multiple Myeloma Using A Plasma Cell Signature Derived From Single-Cell Rna Sequencing, Jian-Rong Li, Shahram Arsang-Jang, Yan Cheng, Fumou Sun, Anita D'Souza, Binod Dhakal, Parameswaran Hari, Quillan Huang, Paul Auer, Yong Li, Raul Urrutia, Fenghuang Zhan, John D Shaughnessy, Siegfried Janz, Jing Dong, Chao Cheng

Faculty, Staff and Students Publications

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum …

Inactivation Of Adenosine Receptor 2a Suppresses Endothelial-To-Mesenchymal Transition And Inhibits Subretinal Fibrosis In Mice, Qiuhua Yang, Yongfeng Cai, Qian Ma, Albert Xiong, Peishan Xu, Zhidan Zhang, Jiean Xu, Yaqi Zhou, Zhiping Liu, Dingwei Zhao, John Asara, Wei Li, Huidong Shi, Ruth B Caldwell, Akrit Sodhi, Yuqing Huo

Faculty, Staff and Students Publications

Anti–vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (Adora2a), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury–induced CNV or mice with a deficiency in the …

Motivational Interviewing Skills Practice Enhanced With Artificial Intelligence, Paul J. Hershberger, Yong Pei, Dean A. Bricker, Timothy N. Crawford, Ashutosh Shivakumar, Angie Castle, Katharine Conway, Raveendra Medaramitta, Maria Rechtin, Josephine F. Wilson

Family Medicine Faculty Publications

Background: Finding time in the medical curriculum to focus on motivational interviewing (MI) training is a challenge in many medical schools. We developed a software-based training tool, “Real-time Assessment of Dialogue in Motivational Interviewing” (ReadMI), that aims to advance the skill acquisition of medical students as they learn the MI approach. This human-artificial intelligence teaming may help reduce the cognitive load on a training facilitator. Methods: During their Family Medicine clerkship, 125 third-year medical students were scheduled in pairs to participate in a 90-minute MI training session, with each student doing two role-plays as the physician. Intervention group students received …

Endovascular Thrombectomy For Large Ischemic Stroke Across Ischemic Injury And Penumbra Profiles., Amrou Sarraj, Ameer E Hassan, Michael G Abraham, Santiago Ortega-Gutierrez, Scott E Kasner, Muhammad Shazam Hussain, Michael Chen, Leonid Churilov, Hannah Johns, Clark W Sitton, Vignan Yogendrakumar, Felix C Ng, Deep K Pujara, Spiros Blackburn, Sophia Sundararajan, Yin C Hu, Nabeel A Herial, Juan F Arenillas, Jenny P Tsai, Ronald F Budzik, William J Hicks, Osman Kozak, Bernard Yan, Dennis J Cordato, Nathan W Manning, Mark W Parsons, Andrew Cheung, Ricardo A Hanel, Amin N Aghaebrahim, Teddy Y Wu, Pere Cardona Portela, Chirag D Gandhi, Fawaz Al-Mufti, Natalia Pérez De La Ossa, Joanna D Schaafsma, Jordi Blasco, Navdeep Sangha, Steven Warach, Timothy J Kleinig, Faris Shaker, Faisal Al Shaibi, Gabor Toth, Mohammad A Abdulrazzak, Gagan Sharma, Abhishek Ray, Jeffrey Sunshine, Amanda Opaskar, Kelsey R Duncan, Wei Xiong, Edgar A Samaniego, Laith Maali, Colleen G Lechtenberg, Arturo Renú, Nirav Vora, Thanh Nguyen, Johanna T Fifi, Stavropoula I Tjoumakaris, Pascal Jabbour, Georgios Tsivgoulis, Vitor Mendes Pereira, Maarten G Lansberg, Michael Degeorgia, Cathy A Sila, Nicholas Bambakidis, Michael D Hill, Stephen M Davis, Lawrence Wechsler, James C Grotta, Marc Ribo, Greg W Albers, Bruce C Campbell

Neuroscience Articles

IMPORTANCE: Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain.

OBJECTIVE: To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect.

DESIGN, SETTING, AND PARTICIPANTS: An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 …

Muc20 Regulated By Extrachromosomal Circular Dna Attenuates Proteasome Inhibitor Resistance Of Multiple Myeloma By Modulating Cuproptosis, Xiaobin Wang, Yingqing Shi, Hua Shi, Xiaoyu Liu, Aijun Liao, Zhuogang Liu, Robert Z Orlowski, Rui Zhang, Huihan Wang

Faculty, Staff and Student Publications

BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation.

METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay.

RESULTS: …