Digital Commons Network^™

Dietary Fiber And Gut Bacteria Shape Infection Susceptibility, Aqsa Mohammed, Robert R Jenq

Faculty, Staff and Student Publications

Gut microbiota composition has been reported to affect pathogen susceptibility but its specific effects, the underlying mechanisms and the potential influence of the diet remain unexplored. In their recent study, Desai and colleagues (Wolter et al, 2024), explore the complex interaction between diet, the gut microbiota and pathogen susceptibility, highlighting a diet-dependent role of the mucin-degrading microbe Akkermansia muciniphila.

Predictive Capacity Of Immune-Related Adverse Events And Cytokine Profiling In Neoadjuvant Immune Checkpoint Inhibitor Trials For Head And Neck Squamous Cell Carcinoma\, Angela E Alnemri, Sruti Tekumalla, Annie E Moroco, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, Tingting Zhan, David M Cognetti, Joseph M Curry, Athanassios Argiris, Alban Linnenbach, Andrew P South, Larry A Harshyne, Jennifer M Johnson, Adam J Luginbuhl

Faculty, Staff and Student Publications

OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status.

METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival …

Stmnd1 Is A Phylogenetically Ancient Stathmin Which Localizes To Motile Cilia And Exhibits Nuclear Translocation That Is Inhibited When Soluble Tubulin Concentration Increases, Xiang Deng, Bryan O Seguinot, Gary Bradshaw, Jong Suk Lee, Shannon Coy, Marian Kalocsay, Sandro Santagata, Timothy Mitchison

Faculty, Staff and Student Publications

Stathmins are small, unstructured proteins that bind tubulin dimers and are implicated in several human diseases, but whose function remains unknown. We characterized a new stathmin, STMND1 (Stathmin Domain Containing 1) as the human representative of an ancient subfamily. STMND1 features a N-terminal myristoylated and palmitoylated motif which directs it to membranes and a tubulin-binding stathmin-like domain (SLD) that contains an internal nuclear localization signal. Biochemistry and proximity labeling showed that STMND1 binds tubulin, and live imaging showed that tubulin binding inhibits translocation from cellular membranes to the nucleus. STMND1 is highly expressed in multiciliated epithelial cells, where it localizes …

A Bayesian Quasi-Likelihood Design For Identifying The Minimum Effective Dose And Maximum Utility Dose In Dose-Ranging Studies, Feng Tian, Ruitao Lin, Li Wang, Ying Yuan

Faculty, Staff and Student Publications

Most existing dose-ranging study designs focus on assessing the dose-efficacy relationship and identifying the minimum effective dose. There is an increasing interest in optimizing the dose based on the benefit-risk tradeoff. We propose a Bayesian quasi-likelihood dose-ranging design that jointly considers safety and efficacy to simultaneously identify the minimum effective dose and the maximum utility dose to optimize the benefit-risk tradeoff. The binary toxicity endpoint is modeled using a beta-binomial model. The efficacy endpoint is modeled using the quasi-likelihood approach to accommodate various types of data (e.g. binary, ordinal or continuous) without imposing any parametric assumptions on the dose-response curve. …

Adaptive Bayesian Information Borrowing Methods For Finding And Optimizing Subgroup-Specific Doses, Jingyi Zhang, Ruitao Lin, Xin Chen, Fangrong Yan

Faculty, Staff and Student Publications

In precision oncology, integrating multiple cancer patient subgroups into a single master protocol allows for the simultaneous assessment of treatment effects in these subgroups and promotes the sharing of information between them, ultimately reducing sample sizes and costs and enhancing scientific validity. However, the safety and efficacy of these therapies may vary across different subgroups, resulting in heterogeneous outcomes. Therefore, identifying subgroup-specific optimal doses in early-phase clinical trials is crucial for the development of future trials. In this article, we review various innovative Bayesian information-borrowing strategies that aim to determine and optimize subgroup-specific doses. Specifically, we discuss Bayesian hierarchical modeling, …

Forecasting Acute Kidney Injury And Resource Utilization In Icu Patients Using Longitudinal, Multimodal Models, Yukun Tan, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Holly Hill, Elmer Bernstam, Ken Chen

Faculty, Staff and Student Publications

Background: Advances in artificial intelligence (AI) have realized the potential of revolutionizing healthcare, such as predicting disease progression via longitudinal inspection of Electronic Health Records (EHRs) and lab tests from patients admitted to Intensive Care Units (ICU). Although substantial literature exists addressing broad subjects, including the prediction of mortality, length-of-stay, and readmission, studies focusing on forecasting Acute Kidney Injury (AKI), specifically dialysis anticipation like Continuous Renal Replacement Therapy (CRRT) are scarce. The technicality of how to implement AI remains elusive.

Objective: This study aims to elucidate the important factors and methods that are required to develop effective predictive models of …

Utilization Of Biologic Disease-Modifying Antirheumatic Therapy In Patients With Rheumatoid Arthritis And Recently Diagnosed Breast Cancer, Juan I Ruiz, Xiudong Lei, Chi-Fang Wu, Hui Zhao, Sharon H Giordano, Suja S Rajan, Maria E Suarez-Almazor

Faculty, Staff and Student Publications

Objective: Biologic disease-modifying antirheumatic drugs (bDMARDs) are immunosuppressants, and there have been concerns that they might impact tumor immunity in patients with cancer with rheumatoid arthritis (RA). The purpose of this study was to describe the utilization trends of bDMARD in patients with RA after breast cancer (BC) diagnosis.

Methods: We performed a retrospective cohort study of adults with RA and BC (2008 onward) from Optum's de-identified Clinformatics® Data Mart Database (CDM); the Surveillance, Epidemiology, and End Results Program (SEER) Medicare; and the Texas Cancer Registry (TCR) Medicare databases. We evaluated bDMARD utilization trends during the first three years after …

Stat5b Mutations In Myeloid Neoplasms Differ By Disease Subtypes But Characterize A Subset Of Chronic Myeloid Neoplasms With Eosinophilia And/Or Basophilia, C Cameron Yin, Wayne Tam, Serena M Walker, Amandeep Kaur, Madhu M Ouseph, Wei Xie, Olga K Weinberg, Peng Li, Zhuang Zuo, Mark J Routbort, Simon Chen, L Jeffrey Medeiros, Tracy I George, Attilio Orazi, Daniel A Arber, Adam Bagg, Robert P Hasserjian, Sa A Wang

Faculty, Staff and Student Publications

STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low, <0.5%, but mutations were detected in all categories of such neoplasms, including myelodysplastic syndrome (MDS, 28%), acute myeloid leukemia (AML, 26%), myelodysplastic/myeloproliferative neoplasm (MDS/MPN, 18%), Philadelphia chromosome-negative classic MPN (12%), systemic mastocytosis (1%), and, with a notably high frequency, chronic eosinophilic leukemia, not otherwise specified (CEL-NOS, 15%). STAT5B mutations occurred preferentially in the SH2 domain (95%), involved 12 different codons, with the N642H hotspot being the most common (78%). Co-mutations were present in all cases and clonal hierarchy analysis showed that STAT5B mutations tended to be subclonal in AML, MPN, and MDS, but frequently dominant/co-dominant in CEL-NOS (83%), followed by MDS/MPN (40%). Across the group, eosinophilia and/or basophilia were common (41%), frequently observed in cases in which STAT5B mutations were detected at initial diagnosis (P<0.0001), with a high variant allele frequency (median 42.5%, P=0.0001), as a dominant/ co-dominant clone (P<0.0001), involving the canonical N642H (P=0.0607), and associated with fewer co-mutations (P=0.0009). Our data show that the characteristics and importance of a STAT5B mutation differ among myeloid neoplasms, but if present as a dominant mutation and detected at initial diagnosis, it appears to be a driver mutation in a subgroup of chronic myeloid neoplasms, preferentially promoting a proliferation of eosinophils and basophils.

Current Methods For Hyperpolarized [1-Current Methods For Hyperpolarized [1-13c]Pyruvate Mri Human Studies, Peder E Z Larson, Jenna M L Bernard, James A Bankson, Nikolaj Bøgh, Robert A Bok, Albert P Chen, Charles H Cunningham, Jeremy W Gordon, Jan-Bernd Hövener, Christoffer Laustsen, Dirk Mayer, Mary A Mclean, Franz Schilling, James B Slater, Jean-Luc Vanderheyden, Cornelius Von Morze, Daniel B Vigneron, Duan Xu

Faculty, Staff and Student Publications

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is …

Adding 6 Months Of Androgen Deprivation Therapy To Postoperative Radiotherapy For Prostate Cancer: A Comparison Of Short-Course Versus No Androgen Deprivation Therapy In The Radicals-Hd Randomised Controlled Trial, Chris C Parker, Noel W Clarke, Adrian D Cook, Howard Kynaston, Charles N Catton, William R Cross, Peter M Petersen, Rajendra A Persad, Fred Saad, Lorna C Bower, John Logue, Heather Payne, Silvia Forcat, Cindy Goldstein, Claire Murphy, Juliette Anderson, Maroie Barkati, David M Bottomley, Jennifer Branagan, Ananya Choudhury, Peter W M Chung, Lyn Cogley, Chee L Goh, Peter Hoskin, Vincent Khoo, Shawn C Malone, Lindsey Masters, Stephen L Morris, Abdenour Nabid, Aldrich D Ong, Rakesh Raman, Kathryn L Tarver, Alison C Tree, Jane Worlding, James P Wylie, Anjali M Zarkar, Wendy R Parulekar, Mahesh K B Parmar, Matthew R Sydes, Radicals Investigators

Faculty, Staff and Student Publications

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear.

METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy …

Contemporary Approach To Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors, Angela C Hirbe, Carina A Dehner, Eva Dombi, Vanessa Eulo, Andrea M Gross, Taylor Sundby, Alexander J Lazar, Brigitte C Widemann

Faculty, Staff and Student Publications

Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this …

Escalated-Dose Radiotherapy For Unresected Locally Advanced Pancreatic Cancer: Patterns Of Care And Survival In The United States, Christopher Shi, Brian De, Hop S Tran Cao, Suyu Liu, Marcus A Florez, Ramez Kouzy, Adam J Grippin, Matthew H G Katz, Ching-Wei D Tzeng, Naruhiko Ikoma, Michael P Kim, Sunyoung Lee, Jason Willis, Sonal S Noticewala, Bruce D Minsky, Grace L Smith, Emma B Holliday, Cullen M Taniguchi, Albert C Koong, Prajnan Das, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes.

METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 …

Statistical And Practical Considerations In Planning And Conduct Of Dose-Optimization Trials, Ying Yuan, Heng Zhou, Suyu Liu

Faculty, Staff and Student Publications

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In …

Mortality In Recipients Of Allogeneic Haematopoietic Cell Transplantation In The Era Of Cytomegalovirus Primary Prophylaxis: A Single-Centre Retrospective Experience, Anthony Febres-Aldana, Fareed Khawaja, Oscar Morado-Aramburo, Terri Lynn Shigle, Gabriela Rondon, Joseph Sassine, Amy Spallone, Krithika Srinivasan, Jeremy Ramdial, Amin Alousi, Richard Champlin, George Chen, May Daher, Katayoun Rezvani, Ella J Ariza-Heredia, Elizabeth J Shpall, Roy F Chemaly

Faculty, Staff and Student Publications

Objectives: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes.

Methods: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, …

Autologous Her2-Specific Car T Cells After Lymphodepletion For Advanced Sarcoma: A Phase 1 Trial, Meenakshi Hegde, Shoba Navai, Christopher Derenzo, Sujith K Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z Gad, Katherine A Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R Mathew, Huimin Zhang, Birju Mehta, Raksha R Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta Kalra, Rikhia Chakraborty, Sachin G Thakkar, Olga Dakhova, Vita S Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K Brenner, Helen E Heslop, Winfried S Wels, M John Hicks, Stephen Gottschalk, Nabil Ahmed

Faculty, Staff and Students Publications

In this prospective, interventional phase I study (NCT00902044) for patients with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T-cells (HER2-CART) after lymphodepletion with cyclophosphamide (Cy) +/− fludarabine (Flu): 1×108 T-cells/m2 after Flu (cohort A) or Flu/Cy (cohort B), and 1×108 CAR-positive T-cells/m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2-CART after lymphodepletion. The determination of antitumor responses was the secondary outcome. Thirteen patients were treated in 14 enrollments with 7 receiving multiple infusions. HER2-CART expanded after 19 of 21 infusions. Nine of 12 patients in cohorts A and …

Persistent ∆Fosb Expression Limits Recurrent Seizure Activity And Provides Neuroprotection In The Dentate Gyrus Of App Mice, Gabriel S Stephens, Jin Park, Andrew Eagle, Jason You, Manuel Silva-Pérez, Chia-Hsuan Fu, Sumin Choi, Corey P St Romain, Chiho Sugimoto, Shelly A Buffington, Yi Zheng, Mauro Costa-Mattioli, Yin Liu, A J Robison, Jeannie Chin

Faculty, Staff and Student Publications

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection …

Immune Infiltration At The Primary Tumor Is Associated With Clinical Outcome Of Patients With Extranodal Extension Of Lymph Node Metastasis In Oral Cancer, Chieko Michikawa, Frederico O Gleber-Netto, Curtis R Pickering, Xiayu Rao, Jing Wang, Andrew G Sikora, Jeffrey N Myers, Mitchell J Frederick

Faculty, Staff and Student Publications

Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown.

Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival.

Results: Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The …

The Association Of Self-Reported Sleep And Circadian Measures With Glycemic Control And Diabetes Complications Among Young Adults With Type 2 Diabetes, Dorit Koren, Kristen L Knutson, Brian K Burke, Kimberly L Drews, Fida Bacha, Lorraine Katz, Marsha D Marcus, Siripoom Mckay, Kristen Nadeau, Babak Mokhlesi, Today Study Group

Children’s Nutrition Research Center Staff Publications

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were …

Ascc1 Structures And Bioinformatics Reveal A Novel Helix-Clasp-Helix Rna-Binding Motif Linked To A Two-Histidine Phosphodiesterase, Naga Babu Chinnam, Roopa Thapar, Andrew S Arvai, Altaf H Sarker, Jennifer M Soll, Tanmoy Paul, Aleem Syed, Daniel J Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H Silverman, Nima Mosammaparast, Susan E Tsutakawa, John A Tainer

Faculty, Staff and Student Publications

Activating signal co-integrator complex 1 (ASCC1) acts with ASCC-ALKBH3 complex in alkylation damage responses. ASCC1 uniquely combines two evolutionarily ancient domains: nucleotide-binding K-Homology (KH) (associated with regulating splicing, transcriptional, and translation) and two-histidine phosphodiesterase (PDE; associated with hydrolysis of cyclic nucleotide phosphate bonds). Germline mutations link loss of ASCC1 function to spinal muscular atrophy with congenital bone fractures 2 (SMABF2). Herein analysis of The Cancer Genome Atlas (TCGA) suggests ASCC1 RNA overexpression in certain tumors correlates with poor survival, Signatures 29 and 3 mutations, and genetic instability markers. We determined crystal structures of Alvinella pompejana (Ap) ASCC1 and Human (Hs) …

Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino): Study Protocol, James J Crowley, Carolina Cappi, Marcos E Ochoa-Panaifo, Renee M Frederick, Minjee Kook, Andrew D Wiese, Diana Rancourt, Elizabeth G Atkinson, Paola Giusti-Rodriguez, Jacey L Anderberg, Latin American Trans‐Ancestry Initiative For Ocd Genomics, Brazilian Obsessive‐Compulsive Spectrum Disorder Working Group, Jonathan S Abramowitz, Victor R Adorno, Cinthia Aguirre, Gilberto S Alves, Gustavo S Alves, Naeshia Ancalade, Alejandro A Arellano Espinosa, Paul D Arnold, Daphne M Ayton, Izabela G Barbosa, Laura Marcela Barón Castano, Cynthia N Barrera, María Celeste Berardo, Dayan Berrones, John R Best, Tim B Bigdeli, Christie L Burton, Joseph D Buxbaum, Jennifer L Callahan, Maria Cecília B Carneiro, Sandra L Cepeda, Evelyn Chazelle, Jessica M Chire, Macarena Churruca Munoz, Pamela Claisse Quiroz, Journa Cobite, Jonathan S Comer, Daniel L Costa, Jennifer Crosbie, Victor O Cruz, Guillermo Dager, Luisa F Daza, Anabel De La Rosa-Gómez, Daniela Del Río, Fernanda Z Delage, Carolina B Dreher, Lucila Fay, Tomas Fazio, Ygor A Ferrão, Gabriela M Ferreira, Edith G Figueroa, Leonardo F Fontenelle, Diego A Forero, Daniele T H Fragoso, Bharathi S Gadad, Sheldon R Garrison, Andres González, Laura D Gonzalez, Marco A González, Polaris Gonzalez-Barrios, Wayne K Goodman, Dorothy E Grice, Jerry Guintivano, Daniel G Guttfreund, Andrew G Guzick, Matthew W Halvorsen, Joseph D Hovey, Hailiang Huang, Jonathan Irreño-Sotomonte, Reinhard Janssen-Aguilar, Matias Jensen, Alexandra Z Jimenez Reynolds, Joali Alexandra Juárez Lujambio, Nasim Khalfe, Madison A Knutsen, Caleb Lack, Nuria Lanzagorta, Monicke O Lima, Melanie O Longhurst, David A Lozada Martinez, Elba S Luna, Andrea H Marques, Molly S Martinez, Maria De Los Angeles Matos, Caitlyn E Maye, Joseph F Mcguire, Gabriela Menezes, Charlene Minaya, Tomás Miño, Sara M Mithani, Circe Montes De Oca, Alonso Morales-Rivero, Maria E Moreira-De-Oliveira, Olivia J Morris, Sandra I Muñoz, Zainab Naqqash, Ambar A Núñez Bracho, Belinda E Núñez Bracho, Maria Corina Ochoa Rojas, Luis A Olavarria Castaman, Trinidad Olivos Balmaceda, Iliana Ortega, Darpan I Patel, Ainsley K Patrick, Mariel Paz Y Mino, Jose L Perales Orellana, Bárbara Perdigão Stumpf, Tamara Peregrina, Tania Pérez Duarte, Kelly L Piacsek, Maritza Placencia, María Belén Prieto, Lucas C Quarantini, Yana Quarantini-Alvim, Renato T Ramos, Iaroslava C Ramos, Vanessa R Ramos, Kesley A Ramsey, Elise V Ray, Margaret A Richter, Bradley C Riemann, Juan C Rivas, Maria C Rosario, Camilo J Ruggero, Angel A Ruiz-Chow, Alejandra Ruiz-Velasco, Melisa N Sagarnaga, Aline S Sampaio, Leonardo C Saraiva, Russell J Schachar, Sophie C Schneider, Ethan J Schweissing, Laura D Seligman, Roseli G Shavitt, Keaton J Soileau, S Evelyn Stewart, Shaina B Storch, Emily R Strouphauer, Vissente Tapia Cuevas, Kiara R Timpano, Beatriz Treviño-De La Garza, Alexie Vallejo-Silva, Javier Vargas-Medrano, María I Vásquez, Guadalupe Vidal Martinez, Saira A Weinzimmer, Mauricio A Yanez, Gwyneth Zai, Lina M Zapata-Restrepo, Luz M Zappa, Raquel M Zepeda-Burgos, Anthony W Zoghbi, Euripedes C Miguel, Carolyn I Rodriguez, Mayra C Martinez Mallen, Pablo R Moya, Tania Borda, María Beatriz Moyano, Manuel Mattheisen, Stacey Pereira, Gabriel Lázaro-Muñoz, Karen G Martinez-Gonzalez, Michele T Pato, Humberto Nicolini, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we …

Phase Ii Study Of Ulixertinib In Children And Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: Apec1621j Of The National Cancer Institute-Children's Oncology Group Pediatric Match Trial, Kieuhoa T Vo, Amit J Sabnis, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Alok Jaju, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons

Center for Medical Ethics and Health Policy Staff Publications

Purpose: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.

Methods: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day …

Contextual Factors Influencing The Association Between The Affordable Care Act’S Medicaid Expansion And Veteran Va-Medicaid Dual Enrollment, Patrick N O'Mahen, Chase S Eck, Cheng Rebecca Jiang, Laura A Petersen

Center for Medical Ethics and Health Policy Staff Publications

Objective: To evaluate changes in dual enrollment after Affordable Care Act Medicaid expansion by VA priority group, (e.g., service connection), sex, and type of state expansion.

Study setting: Our cohort was all Veterans ages 18-64 enrolled in VA and eligible for benefits due to military service-connection or low income from 2011 to 2016; the unit of analysis was person-year.

Study design: Difference-in-difference and event-study analysis. The outcome was dual VA-Medicaid enrollment for at least 1 month annually. Medicaid expansion, VA priority status, whether a state expanded by a Section 1115 waiver, and sex were independent variables. We controlled for race, …

Individual Disruption Of 12 Testis-Enriched Genes Via The Crispr/Cas9 System Does Not Affect The Fertility Of Male Mice, Akira Suzuki, Norikazu Yabuta, Keisuke Shimada, Daisuke Mashiko, Keizo Tokuhiro, Yuki Oyama, Haruhiko Miyata, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

More than 1200 genes have been shown in the database to be expressed predominantly in the mouse testes. Advances in genome editing technologies such as the CRISPR/Cas9 system have made it possible to create genetically engineered mice more rapidly and efficiently than with conventional methods, which can be utilized to screen genes essential for male fertility by knocking out testis-enriched genes. Finding such genes related to male fertility would not only help us understand the etiology of human infertility but also lead to the development of male contraceptives. In this study, we generated knockout mice for 12 genes (Acrv1, Adgrf3, …

Continuous Renal Replacement Therapy: Current State And Future Directions For Worldwide Practice, Katja M Gist, Dana Y Fuhrman, Akash Deep, Taiki Haga, Demet Demirkol, Michael J Bell, Ayse Akcan-Arikan

Faculty, Staff and Students Publications

No abstract provided.

Social Connectedness And Adolescent Suicide Risk, Alejandra Arango, David Brent, Jacqueline Grupp-Phelan, Bradley J Barney, Anthony Spirito, Megan M Mroczkowski, Rohit Shenoi, Melinda Mahabee-Gittens, T Charles Casper, Cheryl King

Faculty, Staff and Students Publications

Background: Despite evidence of the importance of interpersonal connectedness to our understanding of suicide risk, relatively little research has examined the protective and buffering effects of connectedness among adolescents. The aims of this study were to determine: (a) whether overall connectedness (composite of family, peer, and school) and specific domains of connectedness were related to a lower likelihood of suicide attempts, and (b) whether these factors buffer the prospective risk of suicide attempt for high-risk subgroups (i.e., recent suicidal ideation and/or lifetime history of suicide attempt, peer victimization, or sexual and gender minority status).

Methods: Participants were 2,897 adolescents (64.7% …

Generation Of A Humanized Mace2 And A Conditional Hace2 Mouse Models Permissive To Sars-Cov-2 Infection, I-Wen Song, Megan Washington, Carolina Leynes, Jason Hsu, Kempaiah Rayavara, Yangjin Bae, Nele Haelterman, Yuqing Chen, Ming-Ming Jiang, Aleksandra Drelich, Vivian Tat, Denise G Lanza, Isabel Lorenzo, Jason D Heaney, Chien-Te Kent Tseng, Brendan Lee, Ronit Marom

Faculty, Staff and Students Publications

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to …

Unveiling Microbial Diversity: Harnessing Long-Read Sequencing Technology, Daniel P Agustinho, Yilei Fu, Vipin K Menon, Ginger A Metcalf, Todd J Treangen, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Long-read sequencing has recently transformed metagenomics, enhancing strain-level pathogen characterization, enabling accurate and complete metagenome-assembled genomes, and improving microbiome taxonomic classification and profiling. These advancements are not only due to improvements in sequencing accuracy, but also happening across rapidly changing analysis methods. In this Review, we explore long-read sequencing's profound impact on metagenomics, focusing on computational pipelines for genome assembly, taxonomic characterization and variant detection, to summarize recent advancements in the field and provide an overview of available analytical methods to fully leverage long reads. We provide insights into the advantages and disadvantages of long reads over short reads and …

Preparing Patients For Oral Immunotherapy (Ppoint): International Delphi Consensus For Procedural Preparation And Consent, Douglas P Mack, Timothy E Dribin, Paul J Turner, Richard L Wasserman, Mariam A Hanna, Marcus Shaker, Mimi L K Tang, Pablo Rodríguez Del Río, Brad Sobolewski, Elissa M Abrams, Aikaterini Anagnostou, Stefania Arasi, Sakina Bajowala, Philippe Bégin, Scott B Cameron, Edmond S Chan, Sharon Chinthrajah, Andrew T Clark, Paul Detjen, George Du Toit, Motohiro Ebisawa, Arnon Elizur, Jeffrey M Factor, Justin Greiwe, Jonathan O'B Hourihane, Sarah W Hughes, Douglas H Jones, Antonella Muraro, Anna Nowak-Wegrzyn, Nandinee B Patel, Amy M Scurlock, Atul N Shah, Sayantani B Sindher, Stephen Tilles, Brian P Vickery, Julie Wang, Hugh H Windom, Matthew Greenhawt

Faculty, Staff and Students Publications

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process.

OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form.

METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was …

Unswitched Memory B Cell Deficiency In Children With Sickle Cell Disease And Response To Pneumococcal Polysaccharide Vaccine, Venée N Tubman, Daniel Maysonet, Norma Estrada, Tripti Halder, Lindsey Ramos, Sameera Bhamidipati, Alexandre F Carisey, Charles G Minard, Carl E Allen

Faculty, Staff and Students Publications

Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with …

Cadherin-11 Targeted Cell-Specific Liposomes Enabled Skin Fibrosis Treatment By Inducing Apoptosis, Himanshu N Bhatt, Rimpy Diwan, Igor L Estevao, Rui Dong, Jennifer Smith, Chuan Xiao, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Continuous and aberrant activation of myofibroblasts is the hallmark of pathological fibrosis (e.g., abnormal wound healing). The deposition of excessive extracellular matrix (ECM) components alters or increases the stiffness of tissue and primarily accounts for multiple organ dysfunctions. Among various proteins, Cadherin-11 (CDH11) has been reported to be overexpressed on myofibroblasts in fibrotic tissues. Anti-apoptotic proteins such as (B cell lymphoma-2) (BCL-2) are also upregulated on myofibroblasts. Therefore, we hypothesize that CDH11 could be a targeted domain for cell-specific drug delivery and targeted inhibition of BCL-2 to ameliorate the development of fibrosis in the skin. To prove our hypothesis, we …