Medical Specialties Commons^™

Interim Estimates Of 2024-2025 Seasonal Influenza Vaccine Effectiveness - Four Vaccine Effectiveness Networks, United States, October 2024-February 2025, Aaron M Frutos, Seana Cleary, Emily L Reeves, Haris M Ahmad, Ashley M Price, Wesley H Self, Yuwei Zhu, Basmah Safdar, Ithan D Peltan, Kevin W Gibbs, Matthew C Exline, Adam S Lauring, Sarah W Ball, Malini Desilva, Sara Y Tartof, Kristin Dascomb, Stephanie A Irving, Nicola P Klein, Brian E Dixon, Toan C Ong, Ivana A Vaughn, Stacey L House, Kiran A Faryar, Mary Patricia Nowalk, Manjusha Gaglani, Karen J Wernli, Vel Murugan, Olivia L Williams, Rangaraj Selvarangan, Geoffrey A Weinberg, Mary A Staat, Natasha B Halasa, Leila C Sahni, Marian G Michaels, Janet A Englund, Marie K Kirby, Diya Surie, Fatimah S Dawood, Benjamin R Clopper, Heidi L Moline, Ruth Link-Gelles, Amanda B Payne, Elizabeth Harker, Kristina Wielgosz, Zachary A Weber, Duck-Hye Yang, Nathaniel M Lewis, Jennifer Decuir, Samantha M Olson, Jessie R Chung, Brendan Flannery, Lisa A Grohskopf, Carrie Reed, Shikha Garg, Sascha Ellington, Cdc Influenza Vaccine Effectiveness Collaborators

Faculty, Staff and Students Publications

Annual influenza vaccination is recommended for all persons aged ≥6 months in the United States. Interim influenza vaccine effectiveness (VE) was calculated among patients with acute respiratory illness–associated outpatient visits and hospitalizations from four VE networks during the 2024–25 influenza season (October 2024–February 2025). Among children and adolescents aged <18 years, VE against any influenza was 32%, 59%, and 60% in the outpatient setting in three networks, and against influenza-associated hospitalization was 63% and 78% in two networks. Among adults aged ≥18 years, VE in the outpatient setting was 36% and 54% in two networks and was 41% and 55% against hospitalization in two networks. Preliminary estimates indicate that receipt of the 2024–2025 influenza vaccine reduced the likelihood of medically attended influenza and influenza-associated hospitalization. CDC recommends annual receipt of an age-appropriate influenza vaccine by all eligible persons aged ≥6 months as long as influenza viruses continue to circulate locally.

A Review Of Gut Failure As A Cause And Consequence Of Critical Illness, Danielle E. Soranno, Craig M. Coopersmith, Jessica F. Brinkworth, Faith N. F. Factora, Julia H. Muntean, Monty G. Mythen, Jacob Raphael, Andrew D. Shaw, Vidula Vachharajani, Jeannette S. Messer

Department of Anesthesiology Faculty Papers

In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of …

Impact Of Measurable Residual Disease Clearance Kinetics In Patients With Aml Undergoing Intensive Chemotherapy, Wei-Ying Jen, Koji Sasaki, Farhad Ravandi, Tapan M Kadia, Sa A Wang, Wei Wang, Sanam Loghavi, Naval G Daver, Courtney D Dinardo, Ghayas C Issa, Hussein A Abbas, Cedric Nasnas, Alex Bataller, Samuel Urrutia, Omer S Karrar, Sherry Pierce, Hagop M Kantarjian, Nicholas J Short

Faculty, Staff and Student Publications

The prognostic impact of measurable residual disease (MRD) in acute myeloid leukemia (AML) is unequivocal; however, the optimal time point for achieving undetectable MRD is unclear. We retrospectively studied patients with newly diagnosed (ND) AML who achieved remission with frontline intensive chemotherapy and had MRD assessed by flow cytometry after induction (time point 1 [TP1]) and after cycles 2 or 3 (TP2). Cases were grouped into MRD negative (Neg)/Neg, positive (Pos)/Neg, or Pos/Pos at TP1 and TP2, respectively. Of 1980 patients with ND AML, 277 met the inclusion criteria and were included in this analysis. The median relapse-free survival (RFS) …

Incidence And Predictors Of Woven Endobridge (Web) Shape Modification Following Treatment Of Intracranial Aneurysms In A Large Multicenter Study, Nimer Adeeb, Hamza Adel Salim, Basel Musmar, Assala Aslan, Christian Swaid, Miguel Cuellar, Mahmoud Dibas, Nicole Cancelliere, Jose Danilo Bengzon Diestro, Oktay Algin, Sherief Ghozy, Sovann Lay, Adrien Guenego, Leonardo Renieri, Joseph Carnevale, Guillaume Saliou, Panagiotis Mastorakos, Kareem El Naamani, Eimad Shotar, Markus Möhlenbruch, Michael Kral, Charlotte Chung, Mohamed Salem, Ivan Lylyk, Paul Foreman, Hamza Shaikh, Vedran Župančić, Muhammad U Hafeez, Joshua Catapano, Muhammad Waqas, Muhammet Arslan, Onur Ergun, James Rabinov, Yifan Ren, Clemens Schirmer, Mariangela Piano, Anna Kühn, Caterina Michelozzi, Robert Starke, Ameer Hassan, Mark Ogilvie, Anh Nguyen, Jesse Jones, Waleed Brinjikji, Marie Nawka, Marios Psychogios, Christian Ulfert, Bryan Pukenas, Jan-Karl Burkhardt, Thien Huynh, Juan Carlos Martinez-Gutierrez, Muhammed Amir Essibayi, Sunil Sheth, Diana Slawski, Rabih Tawk, Benjamin Pulli, Boris Lubicz, Pietro Panni, Ajit Puri, Guglielmo Pero, Eytan Raz, Christoph Griessenauer, Hamed Asadi, Adnan Siddiqui, Elad Levy, Neil Haranhalli, David Altschul, Andrew Ducruet, Felipe Albuquerque, Robert Regenhardt, Christopher Stapleton, Peter Kan, Vladimir Kalousek, Pedro Lylyk, Srikanth Boddu, Jared Knopman, Stavropoula Tjoumakaris, Pascal Jabbour, Frédéric Clarençon, Nicola Limbucci, Vivek Yedavalli, Max Wintermark, Vitor Mendes Pereira, Aman Patel, Hugo Cuellar-Saenz, Adam Dmytriw

Department of Neurosurgery Faculty Papers

The Woven EndoBridge (WEB) device is FDA-approved for the treatment of bifurcation aneurysms. Despite its wide popularity, it has been under scrutiny for its association with potential aneurysm recanalization and retreatment due to device shape modification. This study aims to analyze the shape modification rate of WEB devices and identify factors associated with this phenomenon, as well as its correlation with aneurysm retreatment. We conducted a retrospective review of the WorldWide WEB Consortium database, including adult patients treated for intracranial aneurysms with the WEB device. We assessed aneurysm occlusion using the WEB Occlusion Scale and defined WEB shape modification as …

The Spatial Landscape Of Cancer Hallmarks Reveals Patterns Of Tumor Ecological Dynamics And Drug Sensitivity, Mustafa Sibai, Sergi Cervilla, Daniela Grases, Eva Musulen, Rossana Lazcano, Chia-Kuei Mo, Veronica Davalos, Arola Fortian, Adrià Bernat, Margarita Romeo, Collin Tokheim, Jordi Barretina, Alexander J Lazar, Li Ding, Dutreneo Study Investigators, Enrique Grande, Francisco X Real, Manel Esteller, Matthew H Bailey, Eduard Porta-Pardo

Faculty, Staff and Student Publications

Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we …

Immunological Biomarkers Of Response And Resistance To Treatment With Cabozantinib And Nivolumab In Recurrent Endometrial Cancer, Vladimir Roudko, Diane Marie Del Valle, Emir Radkevich, Geoffrey Kelly, Xie Hui, Manishkumar Patel, Edgar Gonzalez-Kozlova, Kevin Tuballes, Howard Streicher, Swati Atale, Lisa Wang, Benito Czinczin, Seunghee Kim-Schulze, Ignacio I Wistuba, Cara L Haymaker, Gheath Al-Atrash, Ganiraju Manyam, Jianjun Zhang, Ryan Thompson, Mayte Suarez-Farinas, Stephanie Lheureux, Sacha Gnjatic

Faculty, Staff and Student Publications

Background: Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.

Methods and results: Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific …

Conformational Flexibility Is A Critical Factor In Designing Broad-Spectrum Human Norovirus Protease Inhibitors, Son Pham, Boyang Zhao, Neetu Neetu, Banumathi Sankaran, Ketki Patil, Sasirekha Ramani, Yongcheng Song, Mary K Estes, Timothy Palzkill, B V Venkataram Prasad

Faculty, Staff and Students Publications

UNLABELLED: Human norovirus (HuNoV) is a leading cause of gastroenteritis worldwide and is associated with significant morbidity, mortality, and economic impact. There are currently no licensed antiviral drugs for the treatment of HuNoV-associated gastroenteritis. The HuNoV protease plays a critical role in the initiation of virus replication by cleaving the polyprotein. Thus, it is an ideal target for developing antiviral small-molecule inhibitors. While rupintrivir, a potent small-molecule inhibitor of several picornavirus proteases, effectively inhibits GI.1 protease, it is an order of magnitude less effective against GII protease. Other GI.1 protease inhibitors also tend to be less effective against GII proteases. …

2′-Fucosyllactose Inhibits Human Norovirus Replication In Human Intestinal Enteroids, Ketki Patil, B Vijayalakshmi Ayyar, Nicole M Hayes, Frederick H Neill, Lars Bode, Mary K Estes, Robert L Atmar, Sasirekha Ramani

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide. Currently, there are no targeted antivirals for the treatment of HuNoV infection. Histo-blood group antigens (HBGAs) on the intestinal epithelium are cellular attachment factors for HuNoVs; molecules that block the binding of HuNoVs to HBGAs thus have the potential to be developed as antivirals. Human milk oligosaccharides (HMOs) are glycans in human milk with structures analogous to HBGAs. HMOs have been shown to act as decoy receptors to prevent the attachment of multiple enteric pathogens to host cells. Previous X-ray crystallography studies have demonstrated the binding of HMO 2′-fucosyllactose …

Pskh1 Kinase Activity Is Differentially Modulated Via Allosteric Binding Of Ca2+ Sensor Proteins, Christopher R Horne, Toby A Dite, Samuel N Young, Lucy J Mather, Laura F Dagley, Jared L Johnson, Tomer M Yaron-Barir, Emily M Huntsman, Leonard A Daly, Dominic P Byrne, Antonia L Cadell, Boaz H Ng, Jumana Yousef, Dylan H Multari, Lianju Shen, Luke M Mcaloon, Gerard Manning, Mark A Febbraio, Anthony R Means, Lewis C Cantley, Maria C Tanzer, David R Croucher, Claire E Eyers, Patrick A Eyers, John W Scott, James M Murphy

Children’s Nutrition Research Center Staff Publications

Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed in prostate, lung, and kidney cancers. However, little is known about PSKH1 regulatory mechanisms, leading to its classification as a “dark” kinase. Here, we used biochemistry and mass spectrometry to define PSKH1’s consensus substrate motif, protein interactors, and how interactors, including Ca2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca2+-Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca2+ sensor of the Cab45, Reticulocalbin, Erc55, Calumenin (CREC) family, Reticulocalbin-3, suppressed PSKH1 catalytic activity. In …

Training Clinicians To Facilitate Diabetes Group Visits, Moe Ameri, Layla Abdul Jabbar, Stephanie Kim, Mukaila Raji, Susan L Samson, Elizabeth M Vaughan

Faculty, Staff and Students Publications

Introduction: Managing diabetes in community clinics often presents substantial challenges. Diabetes group visits, shared medical appointments involving a clinician, offer a potential solution to these challenges. However, there is a need for training clinicians to effectively lead and facilitate these group visits.

Aim: The aim of this study is to develop and assess a training program designed to equip clinician learners with the skills to facilitate diabetes group visits.

Methods: Using the ADDIE model (Analysis, Design, Development, Implementation, Evaluation) as a guiding framework, we developed a 3-hour virtual training program for clinician learners at two community clinics. The training covered …

Associations Of Long-Term Exposure To Temperature With Coronary Artery Calcification Risk Among Middle-Aged Adults: The Coronary Artery Risk Development In Young Adults (Cardia) Study, Dandan Zhao, Jie Yao, Yuanfei Li, David R Jacobs, Yinan Zheng, Chunyu Liu, Yingbin Fu, Margaret M Deangelis, Donald Lloyd-Jones, Lifang Hou, Kai Zhang

Faculty, Staff and Students Publications

BACKGROUND: The impact of ambient temperature on population health has drawn increasing attention as climate change drives more extreme temperatures globally. However, little research has investigated its connection to subclinical cardiovascular diseases. This study aims to examine the impact of long-term exposure to temperature on coronary artery calcification (CAC) among middle-aged Black and White adults in four U.S. areas with varying climate and weather conditions.

METHODS: This study compiled long-term environmental temperature data and individual coronary artery Agatston score (0 vs. >0) from the Coronary Artery Risk Development in Young Adults study. It employed logistic regression and examined the influences …

Clostridioides Difficile Colonization Is Not Mediated By Bile Salts And Utilizes Stickland Fermentation Of Proline In An In Vitro Model, Xiaoyun Huang, April E Johnson, Joshua N Brehm, Thi Van Thanh Do, Thomas A Auchtung, Hugh C Mccullough, Armando I Lerma, Sigmund J Haidacher, Kathleen M Hoch, Thomas D Horvath, Joseph A Sorg, Anthony M Haag, Jennifer M Auchtung

Faculty, Staff and Students Publications

Treatment with antibiotics is a major risk factor for Clostridioides difficile infection, likely due to depletion of the gastrointestinal microbiota. Two microbiota-mediated mechanisms thought to limit C. difficile colonization include the conversion of conjugated primary bile salts into secondary bile salts toxic to C. difficile growth and competition between the microbiota and C. difficile for limiting nutrients. Using a continuous flow model that simulates the nutrient conditions of the distal colon, we investigated how treatment with 6 clinically used antibiotics influenced susceptibility to C. difficile infection in 12 different microbial communities cultivated from healthy individuals. Antibiotic treatment reduced microbial richness; …

Mapping Snorna-Target Rna Interactions In An Rna-Binding Protein-Dependent Manner With Chimeric Eclip, Zhuoyi Song, Bongmin Bae, Simon Schnabl, Fei Yuan, Thareendra De Zoysa, Maureen V Akinyi, Charlotte A Le Roux, Karine Choquet, Amanda J Whipple, Eric L Van Nostrand

Faculty, Staff and Students Publications

Background: Small nucleolar RNAs (snoRNAs) are non-coding RNAs that function in ribosome and spliceosome biogenesis, primarily by guiding modifying enzymes to specific sites on ribosomal RNA (rRNA) and spliceosomal RNA (snRNA). However, many orphan snoRNAs remain uncharacterized, with unidentified or unvalidated targets, and studies on additional snoRNA-associated proteins are limited.

Results: We adapted an enhanced chimeric eCLIP approach to comprehensively profile snoRNA-target RNA interactions using both core and accessory snoRNA-binding proteins as baits. Using core snoRNA-binding proteins, we confirmed most annotated snoRNA-rRNA and snoRNA-snRNA interactions in mouse and human cell lines and called novel, high-confidence interactions for orphan snoRNAs. While …

Regulating Chemoresistance And Cancer Stemness: The Cdh17-Yap Pathway In Distinct Cellular States Of Lung Cancer Ctc Clusters, Zujun Que, Dan Qi, Yun Yang, Wang Yao, Jiajun Liu, Yan Li, Yuanyuan Yu, Luyao Wang, Fangfei Li, Ge Zhang, Erxi Wu, Jianhui Tian

Children’s Nutrition Research Center Staff Publications

Background: Drug resistance in metastatic lung cancer significantly contributes to patient mortality. This study explores the role of circulating tumor cells (CTCs), the precursors to metastasis, in driving this resistance. We aim to delineate the unique biological traits of CTC clusters in lung cancer and elucidate the mechanisms underlying their resistance to chemotherapy.

Methods: We used an ultralow adsorption plate to establish a CTC suspension culture system. Comparisons between adherent and suspension cultures of CTC-TJH-01 cells were made via Cell Counting Kit-8 (CCK-8), western blot, immunofluorescence, and flow cytometry assays to evaluate cell proliferation, drug resistance, and cancer stemness. The …

Ultra-Low Extracorporeal Volume Microfluidic Leukapheresis Is Safe And Effective In A Rat Model, Mubasher Iqbal, Alexandra L Mclennan, Anton Mukhamedshin, Mai T P Dinh, Qisheng Liu, Jacob J Junco, Arvind Mohan, Poyyapakkam R Srivaths, Karen R Rabin, Thomas P Fogarty, Sean C Gifford, Sergey S Shevkoplyas, Fong W Lam

Faculty, Staff and Students Publications

Leukapheresis is a potentially life-saving therapy for children with symptomatic hyperleukocytosis. However, the standard centrifugation-based approach exposes pediatric patients to significant complications due to its large extracorporeal volume, high flow rates, and considerable platelet loss. Here, we tested whether performing cell separation with a high-throughput microfluidic technology could alleviate these limitations. In vitro, our microfluidic devices removed ~85% of large leukocytes and ~90% of spiked leukemic blasts from undiluted human whole blood, while minimizing platelet losses. Multiplexed devices connected in parallel allowed for faster, clinically relevant flow rates in vitro with no difference in leukocyte collection efficiency. When connected to …

Pitavastatin Is Well-Tolerated With No Detrimental Effects On Physical Function, Kristine M Erlandson, Triin Umbleja, Heather J Ribaudo, Jennifer A Schrack, Edgar T Overton, Carl J Fichtenbaum, Kathleen V Fitch, Jhoanna C Roa, Marissa R Diggs, Kenneth Wood, Markella V Zanni, Gerald S Bloomfield, Carlos Malvestutto, Judith A Aberg, Maria C Rodriguez-Barradas, Rosalba Gomez Morones, Katherine Breaux, Pamela S Douglas, Steven K Grinspoon, Todd T Brown

Faculty, Staff and Students Publications

Background: Little is known about the potential benefits or harms of statins on physical function among people with human immunodeficiency virus (PWH).

Methods: REPRIEVE was a double-blind randomized controlled trial evaluating pitavastatin for primary prevention of major adverse cardiovascular events in PWH. Time to complete 10 chair rises, 4-m gait speed, grip strength, and a modified short physical performance test were assessed annually for up to 5 years in the ancillary study PREPARE and analyzed using linear mixed models.

Findings: Of 602 PWH, 52% were randomized to pitavastatin and 48% to placebo. Median age was 51 years; 18% were female …

Continued Nintedanib In Patients With Systemic Sclerosis-Associated Interstitial Lung Disease: 3-Year Data From Senscis-On, Yannick Allanore, Madelon C Vonk, Oliver Distler, Arata Azuma, Maureen D Mayes, Alexandra James, Veronika Kohlbrenner, Margarida Alves, Dinesh Khanna, Kristin B Highland

Faculty, Staff and Student Publications

Objective: We assessed adverse events and changes in forced vital capacity (FVC) in patients treated with open-label nintedanib over 148 weeks of SENSCIS-ON, the extension of the SENSCIS trial.

Methods: Adverse events and changes in FVC over 148 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON ('continued nintedanib' group) and in patients who received placebo in SENSCIS or received nintedanib for ≤28 days in a drug-drug interaction study and then received nintedanib in SENSCIS-ON ('initiated nintedanib' group).

Results: The continued nintedanib group comprised 197 patients, and the initiated nintedanib group comprised …

Memorability Of Novel Words Correlates With Anterior Fusiform Activity During Reading, Oscar Woolnough, Nitin Tandon

Faculty, Staff and Student Publications

Our memory for the words we already know is best predicted by their associated meanings. However, the factors that influence whether we will remember a new word after we see it for the first time are unclear. We record memory performance for 2100 novel pseudowords across 1804 participants during a continuous recognition task. Participants show significant agreement across individuals for which novel words were memorable or forgettable, suggesting an intrinsic memorability for individual pseudowords. Pseudowords that are similar to low-frequency known words, with sparse orthographic neighbourhoods and rarely occurring letter pairs, are more memorable. Further, using intracranial recordings in 36 …

The Heterogeneity Of 13q Deletions In Chronic Lymphocytic Leukemia: Diagnostic Challenges And Clinical Implications, Changqing Xia, Guang Liu, Jinglan Liu, Arash Ronaghy, Saber Tadros, Wei Wang, Hong Fang, Shanxiang Zhang, Joseph D Khoury, Zhenya Tang

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, particularly in Western countries. CLL can present indolently or aggressively, influenced by various factors, including chromosomal alterations. Fluorescent in situ hybridization (FISH), targeting specific genes/loci frequently affected in CLL patients, has established a standard for stratifying five CLL prognostic groups: del(11q)/ATM, trisomy 12, del(13q) as a sole aberration, del(17p)/TP53, and normal CLL FISH panel results. Among these, del(13q) as a sole aberration is associated with a favorable prognosis, while the others are considered intermediate (normal CLL FISH panel result and trisomy 12) or unfavorable …

Aberrant Choroid Plexus Formation Drives The Development Of Treatment-Related Brain Toxicity, Tamara Bender, Esther Schickel, Celine Schielke, Jürgen Debus, David R Grosshans, Marco Durante, Insa S Schroeder

Faculty, Staff and Student Publications

Brain tumors are commonly treated with radiotherapy, but the efficacy of the treatment is limited by its toxicity to the normal tissue including post-irradiation contrast enhanced lesions often linked to necrosis. The poorly understood mechanisms behind such brain lesions were studied using cerebral organoids. Here we show that irradiation of such organoids leads to dose-dependent growth retardation and formation of liquid-filled cavities but is not correlated with necrosis. Instead, the radiation-induced changes comprise of an enhancement of cortical hem markers, altered neuroepithelial stem cell differentiation, and an increase of ZO1+/AQP1+/CLDN3+-choroid plexus (CP)-like structures accompanied by an upregulation of IGF2 mRNA, …

Pulmonopoly: A Game-Based Approach To Teach And Reinforce Basic Concepts Of Pulmonary Medicine To Medical Students, Michael Dong, James Uricheck, Urvashi Vaid

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

INTRODUCTION: Pulmonopoly is an innovative active-learning medical board game addressses core pulmonary concepts in an engaging, competitive style. The strength of Pulmonopoly lies in its ability to combine ease of setup and play with comprehensive content coverage that comprises a significant proportion of national board examinations, offering a gamification experience that can be readily applied in different settings and modified for learner levels.

METHODS: We created an instructional game, Pulmonopoly, based on pulmonary content delivered to preclinical medical students and required for national board examinations. We invited first-year medical students to participate in 60-minute small-group sessions. Content addressed pulmonary subject …

The Mutational Landscape And Functional Effects Of Noncoding Ultraconserved Elements In Human Cancers, Recep Bayraktar, Yitao Tang, Mihnea P Dragomir, Cristina Ivan, Xinxin Peng, Linda Fabris, Jianhua Zhang, Alessandro Carugo, Serena Aneli, Jintan Liu, Mei-Ju M Chen, Sanjana Srinivasan, Iman Sahnoune, Emine Bayraktar, Kadir C Akdemir, Meng Chen, Pranav Narayanan, Wilson Huang, Leonie Florence Ott, Agda Karina Eterovic, Oscar Eduardo Villarreal, Mohammad Moustaf Mohammad, Michael D Peoples, Danielle M Walsh, Jon Andrew Hernandez, Margaret B Morgan, Kenna R Shaw, Jennifer S Davis, David Menter, Constantine S Tam, Paul Yeh, Sarah-Jane Dawson, Laura Z Rassenti, Thomas J Kipps, Tanja Kunej, Zeev Estrov, Simon A Joosse, Luca Pagani, Catherine Alix-Panabières, Klaus Pantel, Alessandra Ferajoli, Andrew Futreal, Ignacio I Wistuba, Milan Radovich, Scott Kopetz, Michael J Keating, Giulio F Draetta, John S Mattick, Han Liang, George A Calin

Faculty, Staff and Student Publications

The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) …

At-Home Stroke Neurorehabilitation: Early Findings With The Neuroexo Bci System, Juan José González-España, Lianne Sánchez-Rodríguez, Maxine Annel Pacheco-Ramírez, Jeff Feng, Kathryn Nedley, Shuo-Hsiu Chang, Gerard E Francisco, Jose L Contreras-Vidal

Faculty, Staff and Student Publications

Background: Democratized access to safe and effective robotic neurorehabilitation for stroke survivors requires innovative, affordable solutions that can be used not only in clinics but also at home. This requires the high usability of the devices involved to minimize costs associated with support from physical therapists or technicians.

Methods: This paper describes the early findings of the NeuroExo brain-machine interface (BMI) with an upper-limb robotic exoskeleton for stroke neurorehabilitation. This early feasibility study consisted of a six-week protocol, with an initial training and BMI calibration phase at the clinic followed by 60 sessions of neuromotor therapy at the homes of …

Immune Checkpoint Inhibitors Plus Debulking Surgery For Patients With Metastatic Renal Cell Carcinoma: Clinical Outcomes And Immunological Correlates Of A Prospective Pilot Trial, Sangeeta Goswami, Jianjun Gao, Sreyashi Basu, Daniel D Shapiro, Jose A Karam, Rebecca Slack Tidwell, Kamran Ahrar, Matthew T Campbell, Yu Shen, Alexandro E Trevino, Aaron T Mayer, Alexsandra B Espejo, Christian Seua, Marc D Macaluso, Yulong Chen, Wenbin Liu, Zhong He, Shalini S Yadav, Ying Wang, Priya Rao, Li Zhao, Jianhua Zhang, Sonali Jindal, Nizar M Tannir, Andrew Futreal, Linghua Wang, Padmanee Sharma

Faculty, Staff and Student Publications

Surgical removal of primary tumors reverses tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT), is not understood. We report the first prospective, pilot, non-comparative clinical trial (NCT02210117) to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma. Primary safety endpoint of this trial has been met, with 43 patients completing cytoreductive surgery, 36 patients undergoing …

Characterization Of Rationally Designed Crispr/Cas9-Based Dna Methyltransferases With Distinct Methyltransferase And Gene Silencing Activities In Human Cell Lines And Primary Human T Cells, Rosa Selenia Guerra-Resendez, Samantha Legoff Lydon, Alex J Ma, Guy C Bedford, Daniel R Reed, Sunghwan Kim, Erik R Terán, Tomoki Nishiguchi, Mario Escobar, Andrew R Dinardo, Isaac B Hilton

Faculty, Staff and Students Publications

Nuclease-deactivated Cas (dCas) proteins can be used to recruit epigenetic effectors, and this class of epigenetic editing technologies has revolutionized the ability to synthetically control the mammalian epigenome and transcriptome. DNA methylation is one of the most important and well-characterized epigenetic modifications in mammals, and while many different forms of dCas-based DNA methyltransferases (dCas-DNMTs) have been developed for programmable DNA methylation, these tools are frequently poorly tolerated and/or lowly expressed in mammalian cell types. Further, the use of dCas-DNMTs has largely been restricted to cell lines, which limits mechanistic insights in karyotypically normal contexts and hampers translational utility in the …

Invasion And Metastasis In Cancer: Molecular Insights And Therapeutic Targets, Yongxing Li, Fengshuo Liu, Qingjin Cai, Lijun Deng, Qin Ouyang, Xiang H-F Zhang, Ji Zheng

Faculty, Staff and Students Publications

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is …

Antibiotic-Induced Loss Of Gut Microbiome Metabolic Output Correlates With Clinical Responses To Car T-Cell Therapy, Rishika Prasad, Abdur Rehman, Lubna Rehman, Faezeh Darbaniyan, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Eli Zamir, Sabine Schmidt, Tomo Hayase, Chia-Chi Chang, Lauren Mcdaniel, Ivonne Flores, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E Fayad, Sairah Ahmed, Swaminathan P Iyer, Michael Wang, Preetesh Jain, Loretta J Nastoupil, Jason Westin, Reetakshi Arora, Joel Turner, Fareed Khawaja, Ranran Wu, Jennifer B Dennison, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Marco L Davila, Peter Dreger, Felix Korell, Anita Schmitt, Mark R Tanner, Richard E Champlin, Christopher R Flowers, Elizabeth J Shpall, Samir Hanash, Sattva S Neelapu, Michael Schmitt, Marion Subklewe, Johannes Francois-Fahrmann, C K Stein-Thoeringer, Eran Elinav, Michael D Jain, Eiko Hayase, Robert R Jenq, Neeraj Y Saini

Faculty, Staff and Student Publications

Antibiotic (ABX)–induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, …

Aif3 Splicing Variant Elicits Mitochondrial Malfunction Via The Concurrent Dysregulation Of Electron Transport Chain And Glutathione-Redox Homeostasis, Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang

Faculty, Staff and Student Publications

Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases …

Zika Virus Ns1 Drives Tunneling Nanotube Formation For Mitochondrial Transfer And Stealth Transmission In Trophoblasts, Rafael T Michita, Long B Tran, Steven J Bark, Deepak Kumar, Shay A Toner, Joyce Jose, Indira U Mysorekar, Anoop Narayanan

Faculty, Staff and Students Publications

Zika virus (ZIKV) is unique among orthoflaviviruses in its vertical transmission capacity in humans, yet the underlying mechanisms remain incompletely understood. Here, we show that ZIKV induces tunneling nanotubes (TNTs) in placental trophoblasts which facilitate transfer of viral particles, proteins, mitochondria, and RNA to neighboring uninfected cells. TNT formation is driven exclusively via ZIKV non-structural protein 1 (NS1). Specifically, the N-terminal 1-50 amino acids of membrane-bound ZIKV NS1 are necessary for triggering TNT formation in host cells. Trophoblasts infected with TNT-deficient ZIKV

Oral Inflammation And Microbiome Dysbiosis Exacerbate Chronic Graft-Versus-Host Disease, Yui Kambara, Hideaki Fujiwara, Akira Yamamoto, Kazuyoshi Gotoh, Shuma Tsuji, Mari Kunihiro, Tadashi Oyama, Toshiki Terao, Ayame Sato, Takehiro Tanaka, Daniel Peltier, Keisuke Seike, Hisakazu Nishimori, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshihiko Soga, Pavan Reddy, Yoshinobu Maeda

Faculty, Staff and Students Publications

The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated …