Medicine and Health Sciences Commons^™

Comparing The Effects Of Ect And Intravenous Ketamine In Psychiatric Patients With Major Depressive Episodes, Julia Myerson, Katrina A Rufino, Sanjay J Mathew, Marie Fletcher, Neil Puri, Hyuntaek Oh

Faculty, Staff and Students Publications

Background: Electroconvulsive therapy (ECT) and intravenous (IV) ketamine are treatments used for severe depression and/or treatment-resistant depression (TRD). ECT is considered one of the most effective treatments for severe depression, although there is debate within the field regarding the effectiveness between ECT and IV ketamine in comparable TRD patient groups.

Methods: This retrospective chart review of open-label, nonrandomized treatment from a psychiatric hospital compared the effects of up to three weeks of ECT and IV ketamine in patients with major depressive episodes (MDEs). Our cohort included 146 inpatients and outpatients aged 18 to 74 years old. 94 patients received subanesthetic …

First-Line Met Tyrosine Kinase Inhibitors Versus Immunotherapy ± Chemotherapy For Patients With Met Exon 14 Skipping Mutant Metastatic Nsclc, Federica Pecci, Hui Li, Alessandro Di Federico, Jia Wu, Hong Chen, Eleonora Gariazzo, Francesco Mantuano, Edoardo Garbo, Mihaela Aldea, Valentina Santo, Don Gibbons, Hai Tran, Francesco Paoloni, Guilherme Rossato De Almeida, Giulio Metro, Andrea De Giglio, Francesco Gelsomino, Xinan Wang, Marcello Tiseo, Julia Rotow, Andrea Ardizzoni, J Jack Lee, Mark M Awad, Alfredo Addeo, Lingzhi Hong, Marcelo V Negrao, Pasi A Jänne, John V Heymach, Jianjun Zhang, Biagio Ricciuti, Xiuning Le

Faculty, Staff and Student Publications

Purpose: First-line treatment options for MET exon 14 skipping-mutant metastatic non-small cell lung cancer vary because of differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI) ± chemotherapy.

Experimental design: Clinicopathologic data were collected from patients with metastatic MET exon 14 skipping-mutant non-small cell lung cancer treated with first-line MET TKI or ICI ± chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI ± chemotherapy. Subgroup analyses by clinical and tumor characteristics …

Oligomeric Cystatin C Supports The Immunosuppressive Activity Of Myeloid Cells Through Interaction With Inhibitory Receptors, Chengcheng Zhang, Yubo He, Xiaoye Liu, Jingjing Xie, Meng Fang, Xing Yang, Ryan Huang, Qi Lou, Bufan Li, Ankit Gupta, Cheryl Lewis, Marc I Diamond, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes …

Vitamin D Is Glucoprotective In Aging Males But Not Females, Olivia Z B Ginnard, Maria Morales, Ji Youn Youn, Yong Xu, Stephanie R Sisley

Faculty, Staff and Students Publications

Vitamin D supplementation is linked to many beneficial health outcomes in the geriatric population, such as decreased mortality, epigenetic aging, and fracture risk. Conversely, type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in …

A Role For Gut Mycobiome And Altered Fungal-Bacterial Interactions In Women With Endometriosis†, Chandni Talwar, Ashirbad Guria, Kristi Hoffman, Scott Biest, Patricia Jimenez, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Endometriosis is a gynecological pathology prevalent in reproductive age women in which the inner uterine wall (endometrium) grows outside as ectopic lesions. The inflammation resulting from these growing implants closely associates with disease severity, causing chronic pain and infertility. Emerging studies have found altered bacterial communities in endometriosis and a causal role for gut bacteria in endometriosis. However, the role of the gut mycobiome, i.e., the fungal component of the microbiome in endometriosis is a current knowledge gap that needs to be addressed. In this study, utilizing the stool samples from women with endometriosis, we found that the gut fungal …

Efficacy Of Medical-Legal Partnerships To Address Health-Harming Legal Needs: A Systematic Review Of Experimental Studies In The Field, Jemima John, Thomas Murphy, Emily Zientek, Winston Liaw, Odinakachukwu Dimgba, Thien-An Nguyen, Catherine Burnett, Mary Aitken, Shreela Sharma

Faculty, Staff and Student Publications

Background: Despite the documented success of medical-legal partnerships (MLPs), there is a dearth of robust experimental-based research on their efficacy. This review synthesizes the findings of MLP interventions and identifies opportunities for MLP expansion in vulnerable communities.

Methods: Articles were eligible if they tested the experimental effects of an MLP intervention on health-harming legal needs (HHLNs) and had full text for review. Two reviewers independently screened articles for inclusion and assessed the quality (risk of bias) of each study.

Results: Seven studies were eligible. Populations were largely women, of color, and of lower socioeconomic status. All studies demonstrated positive effects …

Developing A General Ai Model For Integrating Diverse Genomic Modalities And Comprehensive Genomic Knowledge, Zhenhao Zhang, Xinyu Bao, Linghua Jiang, Xin Luo, Zheyu Zhang, Jing Yin, Meiqi Zhao, Yichun Wang, Annelise Comai, Joerg Waldhaus, Anders S Hansen, Wenbo Li, Jie Liu

Faculty, Staff and Student Publications

Advances in next-generation sequencing technologies have vastly expanded the availability of diverse genomic, epigenomic, and transcriptomic data, presenting the opportunity to develop a general AI model that integrates comprehensive genomic knowledge into a unified model. Unlike previous predictive models, which are typically specialized to certain tasks, our general AI model unifies a wide range of genomic modalities, such as nascent RNA and ultra-high-resolution chromatin organization, within a multi-task architecture. Using ATAC-seq and DNA sequences as inputs, we incorporated diverse genomic modalities as output, and the model exhibits strong generalizability across different cell types and tissues in all tasks we trained. …

The Unfolded Protein Response-Novel Mechanisms, Challenges, And Key Considerations For Therapeutic Intervention, P M Quan Mai, Tam-Anh Truong, Sai Kumar Samala, Bhoomika Muruvekere Lakshmisha, Prapannajeet Biswal, Khadijeh Koushki, Prudhvi Chand Mallepaddi, Geraldine Vijay, Sunil Krishnan

Faculty, Staff and Student Publications

Background: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER's capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood.

Objectives: Here, we critically …

Primary Intramedullary Spinal Melanocytomas: Case Report And Review Of Clinical Features, Diagnosis, And Management, Gil Kimchi, Samantha Varela, Juan Pablo Zuluaga-Garcia, Francisco Call-Orellana, Esteban Ramirez Ferrer, Romulo Augusto Andrade De Almeida, Maria A Gubbiotti, Isabella C Glitza, Andrew J Bishop, Jonathan D Grant, Robert Y North, Christopher A Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Objective: Intramedullary melanocytomas are extremely rare spinal cord tumors with distinct histopathological and imaging characteristics. This report reviews the literature on this pathology and presents a representative case study, highlighting aspects of diagnosis and management.

Methods: A scoping review of PubMed, Web of Science, and Embase databases was conducted to identify reports on intramedullary melanocytomas, focusing on clinical presentation, imaging features, histopathology, treatment, and outcomes. Case reports and case series were included due to the rarity of these tumors.

Results: Twelve manuscripts met the inclusion criteria, including 15 patients. In the majority of patients, intramedullary melanocytomas present with progressive myelopathy …

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …

A Practical Primer On How To Detect And Treat Depression In Ckd, L Parker Gregg, Lynnel Goodman, Ella Q Carroll, S Susan Hedayati

Faculty, Staff and Students Publications

Detection and management of depression have special considerations in people with kidney disease. Screening should be done every 6-12 months using a self-reported questionnaire. Clinicians should rule out symptoms from medical conditions such as dialysis inadequacy or hypothyroidism and confirm the presence of sadness or anhedonia. Sertraline has shown limited efficacy and an increased risk for adverse effects such as gastrointestinal symptoms, so cautious, gradual dose titration is warranted. Cognitive behavioral therapy has potential benefit for depressive symptoms in people with kidney disease. Current trials are evaluating behavioral activation therapy. Physical activity has many benefits and likely improves depression.

Design, Optimization, And Development Of Ripk1 Degraders With Improved Pharmacokinetic And Pharmacodynamic Properties, Dong Lu, Xin Yu, Hanfeng Lin, Ran Cheng, Bin Yang, Min Zhang, Jingjing Chen, Feng Li, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Pharmacological degradation of receptor-interacting protein kinase 1 (RIPK1) offers a compelling therapeutic strategy to overcome its scaffolding role in tumor resistance and to enhance the efficacy of immune checkpoint blockade (ICB) therapies. In this study, we report the discovery of a novel RIPK1 degrader, LD5097(24b), developed through systematic optimization of its precursor compound, LD4172—specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. LD5097(24b) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated apoptosis in Jurkat cells. Compared to LD4172, LD5097(24b) demonstrates markedly improved metabolic stability and pharmacokinetic properties. In …

Genetic And Embryonic Transcriptome Analyses Reveal The Molecular And Developmental Basis Of Mayer-Rokitansky-Küster-Hauser Syndrome, Na Chen, Xi Cheng, Sen Zhao, Hengqiang Zhao, Chenglu Qin, Yaru Zhang, Xijuan Lin, Qing Li, Yuan Wang, Jia Kang, Jing Yu, Jianbin Guo, Qianqian Gao, Jiali Duan, Yuchen Niu, Jianzhong Su, Zhihong Wu, Terry Jianguo Zhang, Wanlu Liu, Pengfei Liu, Shan Deng, Nan Wu, Lan Zhu

Faculty, Staff and Students Publications

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterised by aplasia of the uterus, cervix and upper part of the vagina. The genetic aetiology remains incompletely understood.

Methods: We performed gene-level and gene set-level burden analyses based on exome sequencing/genome sequencing data from 727 probands with MRKHS and 2504 female control individuals. Single-cell RNA sequencing (scRNA-seq) was performed on human and mouse embryonic metanephros at different developmental stages. Genetic and transcriptomic data were integrated to prioritise suboptimal genetic signals, identify relevant cell types and determine key developmental stages. Potential digenic inheritance was assessed and prioritised using coexpression patterns from scRNA-seq data.

Results: We …

Implementing Pst In Older Adults Facing Major Surgery: A Randomised Controlled Pilot Study, Victoria Tang, Lejla Pepic, Erika Higuchi, Christina Keny, Elizabeth Macias Lopez, Ezenwa C Onyema, Harleen Sandhu, Veronica Yank, Patrick J Raue

Faculty, Staff and Student Publications

Introduction: Depressive symptoms are common in the growing geriatric surgical population and are associated with important patient-centred surgical outcomes, including postoperative delirium, discharge to postacute care facility and decline in functional status. Few interventions have been developed to address depressive symptoms in the perioperative setting.

Methods and analysis: We designed a feasibility and acceptability study of a nine-session problem-solving therapy (PST) telehealth perioperative intervention aimed at reducing postoperative functional decline and depressive symptoms among at-risk older adults undergoing major surgical procedures. Acceptability will be evaluated using a patient-centred five-question survey, assessing participant satisfaction and perceived usefulness of the perioperative intervention. …

Genome-Wide Discovery Of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity, Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan

Faculty, Staff and Students Publications

Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use Massively Parallel Reporter Assays to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our …

Low Mutation Rate But High Male-Bias In The Germline Of A Short-Lived Opossum, Yadira Peña-García, Richard J Wang, Muthuswamy Raveendran, R Alan Harris, Paul B Samollow, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

Age and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than 6 mo of age. Whole-genome sequencing of 22 trios reveals one of the lowest mutation rates per generation …

Discovery Of A Novel Small Molecule Degrader Of Wild Type And Mutant Estrogen Receptors Using Dna Encoded Libraries, Anil Kumar Devakrishnan, Chandrashekhar Madasu, Yong Wang, Ramkumar Modukuri, Kurt M Bohren, Kevin R Mackenzie, Damian W Young, Suzanne A W Fuqua, Martin M Matzuk, Murugesan Palaniappan

Faculty, Staff and Students Publications

Estrogen receptor α (ERα) variants with mutations in the ligand binding domain (LBD) are less sensitive than wild type to standard-of-care drugs that bind ERα directly. To identify novel small-molecule drugs that target ERα mutants, we screened our multibillion-compound DNA-encoded libraries against ERα LBD variants. CDD-1274, which was highly enriched with all three variants, blocked spontaneous coactivator peptide recruitment to mutant ERα LBDs and inhibited estradiol-driven proliferative markers in several ER-positive breast cancer cell lines, but not in ER-negative breast cancer cells. We demonstrated that CDD-1274 induced proteasomal degradation of ERα variants in breast cancer cell lines and caused Y537S …

Stereotactic Body Radiation Therapy Utilization Trends For Stage I Non-Small Cell Lung Cancer, Sara Sakowitz, Haley I Tupper, Lawrence N Benjamin, Scott Oh, Tao He, Reza Ronaghi, Colleen L Channick, Brian J Rosenberg, Ramin Salehi-Rad, Malcolm I Smith, Joanne M Bando, Timothy J Young, Igor Barjaktarvic, Maria A Velez Velez, Arjan Gower, Amy L Cummings, Jonathan Goldman, Aaron E Lisberg, Edward B Garon, Jane Yanagawa, Emily A Cameron, Bryan M Burt, Sha'shonda L Revels, Paul Toste, Jay M Lee, Alan Lee, Jie Deng, Hanjoo Lee, Peyman Benharash, Drew Moghanaki

Faculty, Staff and Students Publications

No abstract provided.

Slc35g3 Is A Udp-N-Acetylglucosamine Transporter For Sperm Glycoprotein Formation And Underpins Male Fertility In Mice, Daisuke Mashiko, Shingo Tonai, Haruhiko Miyata, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Despite the recognized importance of glycans in biological phenomena, their complex roles in spermatogenesis and sperm function remain unclear. SLC35G3, a 10-transmembrane protein specifically found in early round spermatids, belongs to the sugar-nucleotide transporter family, indicating its involvement in glycan formation. In this study, we found that Slc35g3 knockout male mice were sterile due to impaired sperm functions in uterotubal junction passage, zona pellucida binding, and oocyte fusion. Mouse SLC35G3 has UDP-GlcNAc transporter activity, and its ablation caused abnormal processing of the sperm plasma membrane and acrosome membrane proteins. Reported human SLC35G3 mutations (F267L and T179HfsTer27) diminished the UDP-GlcNAc transporter …

Reducing Moral Distress Through Interdisciplinary Collaboration: The Impact Of A Weekly Palliative Care And Neonatology Conference, Kirthi Devireddy, Riddhi Shukla, Rachel Boren, James E Slaven, Rebecca A Baker, Jayme D Allen, Karen M Moody

Faculty, Staff and Student Publications

Background: Moral distress is the experience of knowing what ethically right action to take, but being unable to act accordingly, due to external factors. It is an experience common to providers working in the neonatal intensive care unit (NICU) where care for infants, often born at the edges of viability or with other life-limiting diagnoses, includes life and death medical decision-making in the context of uncertain prognoses. Palliative care, which aims to reduce suffering, can assist with staff moral distress by providing space for conversations regarding goals-of-care and end-of-life decision making.

Methods: The palliative care and NICU teams co-developed a …

Hepatic Ischemia-Reperfusion Injury: Underlying Mechanisms And Concepts In Liver Surgery And Liver Transplantation, Jie Zhao, Lidan Hou, Kenneth J Dery, Xiaoyi Yuan, Kang Ho Kim, Jerzy W Kupiec-Weglinski, David R Hall, Caitlin J Thornley, Mark J Hobeika, Holger K Eltzschig, Cynthia Ju

Faculty, Staff and Student Publications

Hepatic ischemia-reperfusion injury (H-IRI) is a critical complication in liver surgery and liver transplantation, contributing to graft dysfunction and poor clinical outcomes. When hepatocyte protective mechanisms are insufficient to counteract energy depletion and oxidative stress during ischemia, cell death occurs. Tissue damage during H-IRI leads to the release of damage-associated molecular patterns (DAMPs), which recruit and activate immune cells such as neutrophils and monocytes, orchestrating the initiation, progression, and eventual resolution of sterile inflammation. Extended criteria donor (ECD) livers, particularly steatotic ones, are more vulnerable to H-IRI, leading to poorer outcomes and limiting expansion of the donor pool. However, the …

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

Real-World Outcomes Of Infections Following Tisagenlecleucel In Patients With B-Cell All: A Cibmtr Analysis, Hemalatha G Rangarajan, Prakash Satwani, Megan M Herr, Min Chen, Michael J Martens, Kitsada Wudhikarn, Samuel John, Vanessa A Fabrizio, Emily M Hsieh, Amar H Kelkar, Erin Doherty, David I Marks, Olle Ringden, Brian Friend, Matthew S Kelly, Nosha Farhadfar, Tim Prestidge, Nasheed M Hossain, Hongtao Liu, Shahrukh Hashmi, Dipenkumar Modi, Lena E Winestone, Zeinab El Boghdadly, Hemant S Murthy, Miguel-Angel Perales, Roy F Chemaly, Christopher E Dandoy, Joshua A Hill, Anna Huppler, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. …

Infection After Cd19 Chimeric Antigen Receptor T-Cell Therapy For Large B-Cell Lymphoma: Real-World Analysis From Cibmtr, Kitsada Wudhikarn, Megan M Herr, Min Chen, Michael J Martens, John H Baird, Lohith Gowda, Hemalatha G Rangarajan, Muhammad Bilal Abid, Mohamed A Kharfan-Dabaja, Kirsten M Williams, Siddhartha Ganguly, Jo-Anne H Young, Akshay Sharma, Giancarlo Fatobene, Tania Jain, Christopher G Kanakry, Dipenkumar Modi, Natalie S Grover, Baheyeldin Salem, Marjorie Vieira Batista, Paschalis Vergidis, Dwight E Yin, Amer M Beitinjaneh, Amar H Kelkar, Taiga Nishihori, Jennifer Holter Chakrabarty, Usama Gergis, Melody Smith, Zeinab El Boghdadly, Christopher E Dandoy, Hemant S Murthy, Anna R Huppler, Miguel-Angel Perales, Roy F Chemaly, Joshua A Hill, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, …

Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla

Faculty, Staff and Students Publications

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD …

‘In Texas, Everybody Wants Antibiotics’: Reducing Inappropriate Antibiotic Expectations And Use With A Provider-Patient Communication Tool In Primary Care, Ashley Collazo, Paige Wermuth, Johanan Luna Rodriguez, Kiara Olmeda, Azalia Mancera, Fabrizia Faustinella, Michael K Paasche-Orlow, Roger Zoorob, Barbara Wells Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Background/objective: Patients often expect antibiotics for self-limiting diseases, pressuring providers to prescribe antibiotics unnecessarily. These expectations also contribute to the unsafe practice of taking antibiotics without a prescription (non-prescription use), such as pills retained from prior prescriptions or antibiotics from non-medical sources. Previous work shows that non-prescription use is due to strong, widely held misconceptions regarding the curative power of antibiotics. To reduce unnecessary use of antibiotics, we developed and pilot-tested a patient-focused, bilingual (English and Spanish) educational tool with patient and provider stakeholder input. The tool, a trifold brochure, included information on safe antibiotic use, potential antibiotic harms and …

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Whole-Exome Sequencing-Based Linkage Analysis Of Multiple Myeloma (Mm) And Monoclonal Gammopathy Of Undetermined Significance (Mgus) Pedigrees, Alyssa I Clay-Gilmour, Nicola J Camp, Xiaomu Wei, Angel Earle, Aaron Norman, Jason Sinnwell, Delphine Demangel, Rosalie Griffin, Charles Dumontet, James Mckay, Ken Offit, Vijai Joseph, Siwei Chen, Daniel O'Brien, Vincent Rajkumar, Robert Klein, Shaji Kumar, Steve Lipkin, Celine M Vachon

Faculty, Staff and Student Publications

Background/objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis.

Methods: Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander-Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, …

Peripheral Microvascular And Cerebral White Matter Dysfunction In Schizophrenia: Implications Of A Body-Brain Endothelial Pathophysiology, Eric L Goldwaser, Alexa Yuen, Wyatt Marshall, Bhim M Adhikari, Joshua Chiappelli, Andrew Van Der Vaart, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Heather Bruce, Patrick Donnelly, Braxton Mitchell, Charles Hong, Danny J J Wang, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

Background and hypothesis: Schizophrenia spectrum disorder (SSD) is a chronic neuropsychiatric illness accompanied by significant brain structural and functional abnormalities and higher rate of cardio- and cerebrovascular comorbidities. We hypothesized that genetic and environmental risk factors that led to SSD act throughout the body and demonstrated the association between lower integrity of peripheral vascular endothelium and white matter (WM) microstructure.

Study design: Microvascular endothelial function was evaluated using brachial artery post-occlusive reactive hyperemia (PORH), in which endothelial responses are measured under reduced blood flow and after blood flow is restored. White matter microstructure was assessed by multi-shell diffusion tensor imaging …