Digital Commons Network^™

In Vitro Activity Of Cefepime/Taniborbactam And Comparator Agents Against Gram-Negative Bacterial Bloodstream Pathogens Recovered From Patients With Cancer, Bahgat Gerges, Joel Rosenblatt, Y-Lan Truong, Ying Jiang, Samuel A Shelburne, Anne-Marie Chaftari, Ray Hachem, Issam Raad

Faculty, Staff and Student Publications

BACKGROUND: Taniborbactam is a β-lactamase inhibitor that, when combined with cefepime, may offer a potential treatment option for patients with serious and resistant Gram-negative bacterial (GNB) pathogens.

OBJECTIVES: This study evaluated

METHODS: A total of 270 GNB pathogens (2019-23) isolated from patients with cancer were tested against cefepime/taniborbactam and comparator agents commonly used for these patients. CLSI-approved broth microdilution methods were used. MIC

RESULTS: Cefepime/taniborbactam showed highly potent activity against tested Enterobacterales, including isolates producing ESBLs and carbapenem-resistant Enterobacterales. At a provisional breakpoint of ≤16/4 mg/L, cefepime/taniborbactam inhibited most tested species of GNB pathogens, with overall 98.9% susceptibility, which was …

Sphingosine-1-Phosphate Inhibition Increases Endoplasmic Reticulum Stress To Enhance Oxaliplatin Sensitivity In Pancreatic Cancer, Zachary Gao, Harinarayanan Janakiraman, Yang Xiao, Sung Wook Kang, Jiangling Dong, Jasmine Choi, Besim Ogretmen, Hyun-Sung Lee, Ernest Ramsay Camp

Faculty, Staff and Students Publications

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer resistant to current therapies, including oxaliplatin (Oxa). Growing evidence supports the ability of cancers to harness sphingolipid metabolism for survival. Sphingosine-1-phosphate (S1P) is an anti-apoptotic, pro-survival mediator that can influence cellular functions such as endoplasmic reticulum (ER) stress. We hypothesize that PDAC drives dysregulated sphingolipid metabolism and that S1P inhibition can enhance ER stress to improve therapeutic response to Oxa in PDAC.

METHODS: RNA sequencing data of sphingolipid mediators from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) datasets were analyzed. Murine and human PDAC cell lines were treated …

The Moderating Effects Of Hiv Relevant Factors On The Relationship Between Intimate Partner Violence And Intention To Start Hiv Pre-Exposure Prophylaxis (Prep) Among Cisgender Women, Shimrit Keddem, Victoria Frye, Annet Davis, Beryl A Koblin, Hong-Van Tieu, Rachele K Lipsky, Vijay Nandi, Anne M Teitelman

Faculty, Staff and Students Publications

Background:

Intimate partner violence (IPV) and HIV are serious and related public health problems that detrimentally impact women’s health. Because women who experience IPV are more likely to acquire HIV, it is critical to promote HIV prevention strategies, such as HIV pre-exposure prophylaxis (PrEP), that increase autonomy.

Setting:

This study of cis-gender women eligible for HIV PrEP took place between 2017 and 2019 in Philadelphia and New York City.

Methods:

This study aimed to examine the relationship between four types of IPV (control, psychological, psychological, physical, sexual) and intention to start PrEP among PrEP-eligible cisgender women; and assess the extent …

Does A Reduction In Receiving Assistance With Daily Activities Among Older Adults In Mexico Indicate An Increase In Unmet Needs Or A Decrease In Needs For Care?, Brian Downer, Rafael Samper-Ternent, Philip Cantu, Matthew Miller, Rebeca Wong

Faculty, Staff and Student Publications

OBJECTIVES: The percentage of older adults in Mexico with difficulty completing activities of daily living (ADL) who receive assistance from family appears to be decreasing. We compared 2 birth cohorts of older adults in Mexico to investigate whether this trend reflects an increase in unmet caregiving needs or a decrease in the need for care.

METHODS: We selected Mexican Health and Aging Study participants aged 60-76 in 2001 (n = 4,805) and 2018 (n = 6,494). ADL tasks were dressing, walking, bathing, getting in and out of bed, and toileting. Participants who reported difficulty with an ADL were asked if …

Potential Impact Of Annual Vaccination With Reformulated Covid-19 Vaccines: Lessons From The Us Covid-19 Scenario Modeling Hub, Sung-Mok Jung, Sara L Loo, Emily Howerton, Lucie Contamin, Claire P Smith, Erica C Carcelén, Katie Yan, Samantha J Bents, John Levander, Jessi Espino, Joseph C Lemaitre, Koji Sato, Clifton D Mckee, Alison L Hill, Matteo Chinazzi, Jessica T Davis, Kunpeng Mu, Alessandro Vespignani, Erik T Rosenstrom, Sebastian A Rodriguez-Cartes, Julie S Ivy, Maria E Mayorga, Julie L Swann, Guido España, Sean Cavany, Sean M Moore, T Alex Perkins, Shi Chen, Rajib Paul, Daniel Janies, Jean-Claude Thill, Ajitesh Srivastava, Majd Al Aawar, Kaiming Bi, Shraddha Ramdas Bandekar, Anass Bouchnita, Spencer J Fox, Lauren Ancel Meyers, Przemyslaw Porebski, Srini Venkatramanan, Aniruddha Adiga, Benjamin Hurt, Brian Klahn, Joseph Outten, Jiangzhuo Chen, Henning Mortveit, Amanda Wilson, Stefan Hoops, Parantapa Bhattacharya, Dustin Machi, Anil Vullikanti, Bryan Lewis, Madhav Marathe, Harry Hochheiser, Michael C Runge, Katriona Shea, Shaun Truelove, Cécile Viboud, Justin Lessler

Faculty, Staff and Student Publications

BACKGROUND: Coronavirus Disease 2019 (COVID-19) continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Here, we present projections of COVID-19 hospitalizations and deaths in the United States for the next 2 years under 2 plausible assumptions about immune escape (20% per year and 50% per year) and 3 possible CDC recommendations for the use of annually reformulated vaccines (no recommendation, vaccination for those aged 65 years and over, vaccination for all eligible age groups based on FDA approval).

METHODS AND FINDINGS: The COVID-19 Scenario Modeling Hub …

Concordance Of Human Papillomavirus Genotypes In Mailed Home-Based Self-Collected Versus Clinician-Collected Anal Swabs Among Sexual And Gender Minority Individuals, Jenna Nitkowski, Anna R Giuliano, Tim Ridolfi, Elizabeth Chiao, Maria E Fernandez, Vanessa Schick, Michael D Swartz, Jennifer S Smith, Alan G Nyitray

Faculty, Staff and Student Publications

Background: Home-based self-sampling may be a viable option for anal cancer screening among sexual minority men (SMM). Yet limited research has compared home-based self-collected with clinician-collected anal swabs for human papillomavirus (HPV) genotyping.

Methods: The Prevent Anal Cancer Self-Swab Study recruited SMM and transgender persons 25 years and over in Milwaukee, WI to participate in an anal cancer screening study. Participants were randomized to a home or clinic arm. Home-based participants were mailed an anal self-sampling kit to complete and return via postal mail. They were also asked to attend a clinic appointment where a clinician collected an anal swab. …

Randomized Phase 2 Trial Of Tremelimumab And Durvalumab In Combination Versus Sequentially In Recurrent Platinum-Resistant Ovarian Cancer, Emily M Hinchcliff, Anne Knisely, Naomi Adjei, Bryan Fellman, Ying Yuan, Ami Patel, Cai Xu, Shannon N Westin, Anil K Sood, Pamela T Soliman, Aaron Shafer, Nicole D Fleming, David M Gershenson, Raghunandan Vikram, Tharakeswara Bathala, David Vining, Dhakshina M Ganeshan, Karen H Lu, Charlotte C Sun, Larissa A Meyer, Amir A Jazaeri

Faculty, Staff and Student Publications

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC).

METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end …

Tumor-Resident Microbes: The New Kids On The Microenvironment Block, Le Li, Vidhi Chandra, Florencia Mcallister

Faculty, Staff and Student Publications

Tumor-resident microbes (TRM) are an integral component of the tumor microenvironment (TME). TRM can influence tumor growth, distant dissemination, and response to therapies by interfering with molecular pathways in tumor cells as well as with other components of the TME. Novel technologies are improving the identification and visualization of cell type-specific microbes in the TME. The mechanisms that mediate the role of TRM at the primary tumors and metastatic sites are being elucidated. This knowledge is providing novel perspectives for targeting microbes or using microbial interventions for cancer interception or therapy.

Abatacept Pharmacokinetics And Exposure Response In Patients Hospitalized With Covid-19, Stephen J Balevic, Daniel K Benjamin, William G Powderly, P Brian Smith, Daniel Gonzalez, Matthew W Mccarthy, Linda K Shaw, Christopher J Lindsell, Sam Bozzette, Daphne Williams, Benjamin P Linas, John Blamoun, Heta Javeri, Christoph P Hornik

Faculty, Staff and Student Publications

IMPORTANCE: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown.

OBJECTIVE: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments.

DESIGN, SETTING, AND PARTICIPANTS: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 …

Case Of Human Orthohantavirus Infection, Michigan, Usa, 2021, Samuel M Goodfellow, Robert A Nofchissey, Dustin Arsnoe, Chunyan Ye, Seonghyeon Lee, Jieun Park, Won-Keun Kim, Kartik Chandran, Shannon L M Whitmer, John D Klena, Jonathan W Dyal, Trevor Shoemaker, Diana Riner, Mary Grace Stobierski, Kimberly Signs, Steven B Bradfute

Faculty, Staff and Student Publications

Orthohantaviruses cause hantavirus cardiopulmonary syndrome; most cases occur in the southwest region of the United States. We discuss a clinical case of orthohantavirus infection in a 65-year-old woman in Michigan and the phylogeographic link of partial viral fragments from the patient and rodents captured near the presumed site of infection.

Clinical Epidemiological Characteristics And Risk Factors For Severity Of Sars-Cov-2 Pneumonia In Pediatric Patients: A Hospital-Based Study In Vietnam, Sang N Nguyen, Lam T Vu, Ha T Nguyen, Giang H Dao, Anh Ngoc T Nguyen

Faculty, Staff and Student Publications

Introduction Coronavirus disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which can cause organ failure in several organs, cardiac problems, or acute respiratory distress syndrome (ARDS). Identifying clinical epidemiological characteristics and risk factors for complications of COVID-19 allows clinicians to diagnose and treat promptly. Objectives This study aims to describe the clinical epidemiological characteristics of COVID-19 and assess risk factors for the severity of SARS-CoV-2 pneumonia in children treated at Haiphong Children's Hospital. Methods A descriptive cross-sectional study was conducted in Haiphong Children's Hospital, Haiphong, Vietnam, for one year, from January 1, 2022, to December 31, 2022. Results In …

Rfx Transcription Factor In The Human-Associated Yeast Candida Albicans Regulates Adhesion To Oral Epithelium, Diana L Rodríguez, Elena Lindemann-Perez, J Christian Perez

Faculty, Staff and Student Publications

Adhesion to mucosal surfaces is a critical step in many bacterial and fungal infections. Here, using a mouse model of oral infection by the human fungal pathobiont Candida albicans, we report the identification of a novel regulator of C. albicans adhesion to the oral mucosa. The regulator is a member of the regulatory factor X (RFX) family of transcription factors, which control cellular processes ranging from genome integrity in model yeasts to tissue differentiation in vertebrates. Mice infected with the C. albicans rfx1 deletion mutant displayed increased fungal burden in tongues compared to animals infected with the reference strain. High-resolution …

Large-Scale Phenotyping Of Patients With Long Covid Post-Hospitalization Reveals Mechanistic Subtypes Of Disease, Felicity Liew, Claudia Efstathiou, Sara Fontanella, Matthew Richardson, Ruth Saunders, Dawid Swieboda, Jasmin K Sidhu, Stephanie Ascough, Shona C Moore, Noura Mohamed, Jose Nunag, Clara King, Olivia C Leavy, Omer Elneima, Hamish J C Mcauley, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Victoria C Harris, Linzy Houchen-Wolloff, Neil J Greening, Nazir I Lone, Matthew Thorpe, A A Roger Thompson, Sarah L Rowland-Jones, Annemarie B Docherty, James D Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke S Howard, Daniel G Wootton, Jennifer K Quint, Thushan I De Silva, Antonia Ho, Christopher Chiu, Ewen M Harrison, William Greenhalf, J Kenneth Baillie, Malcolm G Semple, Lance Turtle, Rachael A Evans, Louise V Wain, Christopher Brightling, Ryan S Thwaites, Peter J M Openshaw, Phosp-Covid Collaborative Group, Isaric Investigators

Faculty, Staff and Student Publications

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers …

Cytoplasmic Redox Imbalance In The Thioredoxin System Activates Hsf1 And Results In Hyperaccumulation Of The Sequestrase Hsp42 With Misfolded Proteins, Davi Goncalves, Duong Long Duy, Sara Peffer, Kevin A Morano

Faculty, Staff and Student Publications

Cells employ multiple systems to maintain homeostasis when experiencing environmental stress. For example, the folding of nascent polypeptides is exquisitely sensitive to proteotoxic stressors including heat, pH, and oxidative stress, and is safeguarded by a network of protein chaperones that concentrate potentially toxic misfolded proteins into transient assemblies to promote folding or degradation. The redox environment itself is buffered by both cytosolic and organellar thioredoxin and glutathione pathways. How these systems are linked is poorly understood. Here, we determine that specific disruption of the cytosolic thioredoxin system resulted in constitutive activation of the heat shock response in Saccharomyces cerevisiae and …

Analytical Challenges In Omics Research On Asthma And Allergy: A National Institute Of Allergy And Infectious Diseases Workshop, Supinda Bunyavanich, Patrice M Becker, Matthew C Altman, Jessica Lasky-Su, Carole Ober, Karsten Zengler, Evgeny Berdyshev, Richard Bonneau, Talal Chatila, Nilanjan Chatterjee, Kian Fan Chung, Colleen Cutcliffe, Wendy Davidson, Gang Dong, Gang Fang, Patricia Fulkerson, Blanca E Himes, Liming Liang, Rasika A Mathias, Shuji Ogino, Joseph Petrosino, Nathan D Price, Eric Schadt, James Schofield, Max A Seibold, Hanno Steen, Lisa Wheatley, Hongmei Zhang, Alkis Togias, Kohei Hasegawa

Center for Medical Ethics and Health Policy Staff Publications

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes …

Effectiveness Of Cord Blood As A Strategy To Rule Out Conjugated Hyperbilirubinemia, Miray Kurtca, Sanjiv Harpavat, Sridevi Devaraj

Faculty, Staff and Students Publications

Early detection of biliary atresia is crucial for timely intervention and improved outcomes in infants with elevated conjugated bilirubin levels. This study aims to investigate the viability of cord blood gas analysis as a novel method for assessing conjugated bilirubin levels. Infants with high heel stick levels also showed elevated cord blood bilirubin levels, indicating that cord blood testing could replace the need for repeat heel stick tests, especially benefiting low birth weight infants. Ongoing research, including larger cohorts and alternative bilirubin measurement methods, will further validate this innovative screening approach. Infants with biliary atresia have high conjugated bilirubin levels …

Single-Center Outcomes After Liver Transplantation With Sars-Cov-2-Positive Donors: An Argument For Increased Utilization, Ashton A Connor, Max W Adelman, Constance M Mobley, Mozhgon Moaddab, Alexandra J Erhardt, David E Hsu, Elizabeth W Brombosz, Mansi Sanghvi, Yee Lee Cheah, Caroline J Simon, Mark J Hobeika, Ashish S Saharia, David W Victor, Sudha Kodali, Tamneet Basra, Edward A Graviss, Duc T Nguyen, Ahmed Elsaiey, Linda W Moore, Masayuki Nigo, Ashley L Drews, Kevin A Grimes, Cesar A Arias, Xian C Li, A Osama Gaber, R Mark Ghobrial

Faculty, Staff and Students Publications

Background: The COVID-19 pandemic has led to an increase in SARS-CoV-2-test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19-positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19-positive donors at a single center are presented here.

Methods: A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19-positive (n = 29 total; 25 index, 4 redo) and …

Re-Evaluation Of The Methodology For Estimating The Us Specialty Physician Workforce, W Stephen Black-Schaffer, David J Gross, Zakia Nouri, Aidan Delisle, Michael Dill, Jason Y Park, James M Crawford, Michael B Cohen, Rebecca L Johnson, Donald S Karcher, Thomas M Wheeler, Stanley J Robboy

Faculty, Staff and Students Publications

Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's …

Prescription And Dispensation Of Qt-Prolonging Medications In Individuals Receiving Hemodialysis, Virginia Wang, Chin-Hua Lily Wang, Magdalene M Assimon, Patrick H Pun, Wolfgang C Winkelmayer, Jennifer E Flythe

Faculty, Staff and Students Publications

IMPORTANCE: Individuals with dialysis-dependent kidney failure have numerous risk factors for medication-related adverse events, including receipt of care by multiple clinicians and initiation of some QT-prolonging medications with known risk of torsades de pointes (TdP), which is associated with higher risk of sudden cardiac death. Little is known about the prescription and dispensation patterns of QT-prolonging medications among people receiving dialysis, hindering efforts to reduce drug-related harm from these and other medications in this high-risk population.

OBJECTIVE: To examine prescription and dispensation patterns of QT-prolonging medications with known TdP risk and selected interacting medications prescribed to individuals receiving hemodialysis.

DESIGN, …

Relevance Of Lymphocyte Proliferation To Pha In Severe Combined Immunodeficiency (Scid) And T Cell Lymphopenia, Roshini S Abraham, Amrita Basu, Jennifer R Heimall, Elizabeth Dunn, Alison Yip, Malika Kapadia, Neena Kapoor, Lisa Forbes Satter, Rebecca Buckley, Richard O'Reilly, Geoffrey D E Cuvelier, Sharat Chandra, Jeffrey Bednarski, Sonali Chaudhury, Theodore B Moore, Hilary Haines, Blachy J Dávila Saldaña, Deepakbabu Chellapandian, Ahmad Rayes, Karin Chen, Emi Caywood, Shanmuganathan Chandrakasan, Mark Thomas Vander Lugt, Christen Ebens, Pierre Teira, Evan Shereck, Holly Miller, Victor Aquino, Hesham Eissa, Lolie C Yu, Alfred Gillio, Lisa Madden, Alan Knutsen, Ami J Shah, Kenneth Desantes, Jessie Barnum, Larisa Broglie, Avni Y Joshi, Gary Kleiner, Jasmeen Dara, Susan Prockop, Caridad Martinez, Talal Mousallem, Joseph Oved, Lauri Burroughs, Rebecca Marsh, Troy R Torgerson, Jennifer W Leiding, Sung Yun Pai, Donald B Kohn, Michael A Pulsipher, Linda M Griffith, Luigi D Notarangelo, Morton J Cowan, Jennifer Puck, Christopher C Dvorak, Elie Haddad

Faculty, Staff and Students Publications

Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had < 10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.02). Further, in patients with CD3+ T cell counts between 51 and 300 cells/μL, there was a higher proliferative response with the PHA flow assay compared to the 3H-T assay (p < 0.0001), suggesting that the method of analysis influences the resolution and interpretation of PHA results. Importantly, we observed many SCID patients with profound T cell lymphopenia having normal T cell proliferation when assessed by flow cytometry. We recommend this test be considered only as supportive in the diagnosis of typical SCID.

Association Of Nightly Fasting, Meal Frequency, And Skipping Meals With Metabolic Syndrome Among Kuwaiti Adults, Fatema Alkhulaifi, Suad Al-Hooti, Sameer Al-Zenki, Husam Alomirah, Qian Xiao, Wenyaw Chan, Fuqing Wu, Charles Darkoh

Faculty, Staff and Student Publications

Mounting evidence suggests that meal timing and frequency are associated with cardiometabolic health by influencing circadian rhythms. However, the evidence is inconsistent and limited, especially in non-Western cultures. This cross-sectional study aims to investigate the association between temporal habits of dietary intake, such as nightly fasting duration and meal frequency, and metabolic syndrome among Kuwaiti adults. A 24-hour recall was used to assess temporal habits of dietary intake. Meal frequency was defined as the number of daily eating episodes. The study included a total of 757 adults aged 20 years and older. The participants' mean age was 37.8 ± 12.3 …

Antitumor Efficacy And Safety Of Unedited Autologous Cd5car T Cells In Relapsed/Refractory Mature T-Cell Lymphomas, Laquisa C Hill, Rayne H Rouce, Mengfen J Wu, Tao Wang, Royce Ma, Huimin Zhang, Birju Mehta, Natalia Lapteva, Zhuyong Mei, Tyler S Smith, Lina Yang, Madhuwanti Srinivasan, Phillip M Burkhardt, Carlos A Ramos, Premal Lulla, Martha Arredondo, Bambi Grilley, Helen E Heslop, Malcolm K Brenner, Maksim Mamonkin

Center for Medical Ethics and Health Policy Staff Publications

Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5⁺ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety …

Digital Twins For Health: A Scoping Review, Evangelia Katsoulakis, Qi Wang, Huanmei Wu, Leili Shahriyari, Richard Fletcher, Jinwei Liu, Luke Achenie, Hongfang Liu, Pamela Jackson, Ying Xiao, Tanveer Syeda-Mahmood, Richard Tuli, Jun Deng

Faculty, Staff and Student Publications

The use of digital twins (DTs) has proliferated across various fields and industries, with a recent surge in the healthcare sector. The concept of digital twin for health (DT4H) holds great promise to revolutionize the entire healthcare system, including management and delivery, disease treatment and prevention, and health well-being maintenance, ultimately improving human life. The rapid growth of big data and continuous advancement in data science (DS) and artificial intelligence (AI) have the potential to significantly expedite DT research and development by providing scientific expertise, essential data, and robust cybertechnology infrastructure. Although various DT initiatives have been underway in the …

Intrathecal Gene Therapy For Giant Axonal Neuropathy, Diana X Bharucha-Goebel, Joshua J Todd, Dimah Saade, Gina Norato, Minal Jain, Tanya Lehky, Rachel M Bailey, Jessica A Chichester, Roberto Calcedo, Diane Armao, A Reghan Foley, Payam Mohassel, Eshetu Tesfaye, Bradley P Carlin, Beth Seremula, Melissa Waite, Wadih M Zein, Laryssa A Huryn, Thomas O Crawford, Charlotte J Sumner, Ahmet Hoke, John D Heiss, Lawrence Charnas, Jody E Hooper, Thomas W Bouldin, Elizabeth M Kang, Denis Rybin, Steven J Gray, Carsten G Bönnemann

Faculty, Staff and Student Publications

Background: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin.

Methods: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope.

Results: One of …

Case 9-2024: An 84-Year-Old Man With A Fall, Zaven Sargsyan, Sunita D Srivastava, Virginia A Triant, Brian B Ghoshhajra

Faculty, Staff and Students Publications

No abstract provided.

A Journey In Science: Molecular Vaccines For Global Child Health In Troubled Times Of Anti-Science, Peter J Hotez

Faculty, Staff and Students Publications

My scientific life in translational medicine runs in two parallel, yet often converging paths. The first, is four-decade-long commitment to develop new vaccines for parasitic and neglected tropical diseases, as well as pandemic threats. This includes a vaccine for human hookworm infection that I began as an MD-PhD student in New York City in the 1980s, and a new low-cost COVID vaccine that reached almost 100 million people in low- and middle-income countries. Alongside this life in scientific research, is one in public engagement for vaccine and neglected disease diplomacy to ensure that people who live in extreme poverty can …

Tissue-Resident Memory T Cell Signatures From Single-Cell Analysis Associated With Better Melanoma Prognosis, Chongming Jiang, Cheng-Chi Chao, Jianrong Li, Xin Ge, Aidan Shen, Vadim Jucaud, Chao Cheng, Xiling Shen

Faculty, Staff and Students Publications

Tissue-resident memory T cells (TRM) are a specialized T cell population residing in peripheral tissues. The presence and potential impact of TRM in the tumor immune microenvironment (TIME) remain to be elucidated. Here, we systematically investigated the relationship between TRM and melanoma TIME based on multiple clinical single-cell RNA-seq datasets and developed signatures indicative of TRM infiltration. TRM infiltration is associated with longer overall survival and abundance of T cells, NK cells, M1 macrophages, and memory B cells in the TIME. A 22-gene TRM–derived risk score was further developed to effectively classify patients into low- and high-risk categories, distinguishing overall …

Effect Of Neutralizing Monoclonal Antibody Treatment On Early Trajectories Of Virologic And Immunologic Biomarkers In Patients Hospitalized With Covid-19, Tomas O Jensen, Greg A Grandits, Mamta K Jain, Thomas A Murray, Birgit Grund, Kathryn Shaw-Saliba, Michael A Matthay, Mahsa Abassi, Magdalena Ardelt, Jason V Baker, Peter Chen, Robin L Dewar, Anna L Goodman, Timothy J Hatlen, Helene C Highbarger, Mark Holodniy, Perrine Lallemand, Sylvain Laverdure, Bradley G Leshnower, David Looney, Charalampos D Moschopoulos, Henry Mugerwa, Daniel D Murray, Eleftherios Mylonakis, Stephanie Nagy-Agren, M Tauseef Rehman, Adam Rupert, Randy A Stevens, Stuart Turville, Amy Weintrob, Katherine Wick, Jens Lundgren, Emily R Ko, Activ-3/Tico Study Group

Faculty, Staff and Student Publications

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.

METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.

RESULTS: Analysis included 2149 participants enrolled between …

Btn1a1 Is A Novel Immune Checkpoint Mutually Exclusive To Pd-L1, Young-Seung Kim, Seung-Hoon Lee, Andrew H Park, Chunai Wu, Bong-Ki Hong, Hyunjin Jung, Steven H Lin, Stephen S Yoo

Faculty, Staff and Student Publications

BACKGROUND: While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized.

METHODS: BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. …

Effect Of Neutralizing Monoclonal Antibody Treatment On Early Trajectories Of Virologic And Immunologic Biomarkers In Patients Hospitalized With Covid-19, Tomas O Jensen, Greg A Grandits, Mamta K Jain, Thomas A Murray, Birgit Grund, Kathryn Shaw-Saliba, Michael A Matthay, Mahsa Abassi, Magdalena Ardelt, Jason V Baker, Peter Chen, Robin L Dewar, Anna L Goodman, Timothy J Hatlen, Helene C Highbarger, Mark Holodniy, Perrine Lallemand, Sylvain Laverdure, Bradley G Leshnower, David Looney, Charalampos D Moschopoulos, Henry Mugerwa, Daniel D Murray, Eleftherios Mylonakis, Stephanie Nagy-Agren, M Tauseef Rehman, Adam Rupert, Randy A Stevens, Stuart Turville, Amy Weintrob, Katherine Wick, Jens Lundgren, Emily R Ko

Faculty, Staff and Student Publications

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.

METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.

RESULTS: Analysis included 2149 participants enrolled between …