Digital Commons Network^™

The Role Of Vitamin D In Patients With Inflammatory Bowel Disease Treated With Vedolizumab, Bincy P Abraham, Christopher Fan, Theresa Thurston, Joshua Moskow, Hoda M Malaty

Faculty, Staff and Students Publications

BACKGROUND: Many clinical factors can contribute to the efficacy of medical therapy in Inflammatory Bowel Disease (IBD). We assessed their effects on the efficacy of vedolizumab therapy in a cohort of patients with IBD.

METHODS: We conducted a retrospective study on patients between 18 and 80 years of age with ulcerative colitis (UC) or Crohn's disease (CD) who were seen in the IBD program at Houston Methodist in Houston, TX and treated with vedolizumab for at least 6 months from 2018 to 2022. We investigated factors prior to the initiation of therapy that best predicted treatment response, with an emphasis …

Vaginal Microbial Dynamics And Pathogen Colonization In A Humanized Microbiota Mouse Model, Marlyd E Mejia, Vicki Mercado-Evans, Jacob J Zulk, Samantha Ottinger, Korinna Ruiz, Mallory B Ballard, Stephanie W Fowler, Robert A Britton, Kathryn A Patras

Faculty, Staff and Students Publications

Vaginal microbial composition is associated with differential risk of urogenital infection. Although Lactobacillus spp. are thought to confer protection against infection, the lack of in vivo models resembling the human vaginal microbiota remains a prominent barrier to mechanistic discovery. Using 16S rRNA amplicon sequencing of C57BL/6J female mice, we found that vaginal microbial composition varies within and between colonies across three vivaria. Noting vaginal microbial plasticity in conventional mice, we assessed the vaginal microbiome of humanized microbiota mice (

A Network Pharmacology And Molecular-Docking-Based Approach To Identify The Probable Targets Of Short-Chain Fatty-Acid-Producing Microbial Metabolites Against Kidney Cancer And Inflammation, Md Rezaul Karim, Md Niaj Morshed, Safia Iqbal, Shahnawaz Mohammad, Ramya Mathiyalagan, Deok Chun Yang, Yeon Ju Kim, Joon Hyun Song, Dong Uk Yang

Faculty, Staff and Student Publications

(1) Background: A large and diverse microbial population exists in the human intestinal tract, which supports gut homeostasis and the health of the host. Short-chain fatty acid (SCFA)-secreting microbes also generate several metabolites with favorable regulatory effects on various malignancies and immunological inflammations. The involvement of intestinal SCFAs in kidney diseases, such as various kidney malignancies and inflammations, has emerged as a fascinating area of study in recent years. However, the mechanisms of SCFAs and other metabolites produced by SCFA-producing bacteria against kidney cancer and inflammation have not yet been investigated. (2) Methods: We considered 177 different SCFA-producing microbial species …

Eicosanoid And Eicosanoid-Related Inflammatory Mediators And Exercise Intolerance In Heart Failure With Preserved Ejection Fraction, Emily S Lau, Athar Roshandelpoor, Shahrooz Zarbafian, Dongyu Wang, James S Guseh, Norrina Allen, Vinithra Varadarajan, Matthew Nayor, Ravi V Shah, Joao A C Lima, Sanjiv J Shah, Bing Yu, Mona Alotaibi, Susan Cheng, Mohit Jain, Gregory D Lewis, Jennifer E Ho

Faculty, Staff and Student Publications

Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.

Prediagnostic Selenium Status, Selenoprotein Gene Variants And Association With Breast Cancer Risk In A European Cohort Study, David J Hughes, Lutz Schomburg, Mazda Jenab, Carine Biessy, Catherine Méplan, Aurelie Moskal, Qian Sun, Kamil Demircan, Veronika Fedirko, Elisabete Weiderpass, Maryam Mukhtar, Anja Olsen, Anne Tjønneland, Kim Overvad, Matthias Schulze, Therese Haugdahl Nøst, Guri Skeie, Karina Standahl Olsen, Fulvio Ricceri, Sara Grioni, Domenico Palli, Giovanna Masala, Rosario Tumino, Fabrizio Pasanisi, Pilar Amiano, Sandra M Colorado Yohar, Antonio Agudo, Maria-Jose Sánchez, Eva Ardanaz, Malin Sund, Anne Andersson, Aurora Perez-Cornago, Ruth Travis, Alicia K Heath, Laure Dossus

Faculty, Staff and Student Publications

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional …

Mechanism Of Stepwise Electron Transfer In Six-Transmembrane Epithelial Antigen Of The Prostate (Steap) 1 And 2, Kehan Chen, Lie Wang, Jiemin Shen, Ah-Lim Tsai, Ming Zhou, Gang Wu

Faculty, Staff and Student Publications

Six transmembrane epithelial antigen of the prostate (STEAP) 1-4 are membrane-embedded hemoproteins that chelate a heme prosthetic group in a transmembrane domain (TMD). STEAP2-4, but not STEAP1, have an intracellular oxidoreductase domain (OxRD) and can mediate cross-membrane electron transfer from NADPH via FAD and heme. However, it is unknown whether STEAP1 can establish a physiologically relevant electron transfer chain. Here, we show that STEAP1 can be reduced by reduced FAD or soluble cytochrome b5 reductase that serves as a surrogate OxRD, providing the first evidence that STEAP1 can support a cross-membrane electron transfer chain. It is not clear whether …

Association Between Microbiome And The Development Of Adverse Posttraumatic Neuropsychiatric Sequelae After Traumatic Stress Exposure, Abigail L. Zeamer, Marie-Claire Salive, Xinming An, Francesca L. Beaudoin, Stacey L. House, Jennifer S. Stevens, Donglin Zeng, Thomas C. Neylan, Gari D. Clifford, Sarah D. Linnstaedt, Scott L. Rauch, Alan B. Storrow, Christopher Lewandowski, Paul I. Musey, Phyllis L. Hendry, Sophia Sheikh, Christopher W. Jones, Brittany E. Punches, Robert A. Swor, Lauren A. Hudak, Jose L. Pascual, Mark J. Seamon, Erica Harris, Claire Pearson, David A. Peak, Roland C. Merchant, Robert M. Domeier, Niels K. Rathlev, Brian J. O'Neil, Paulina Sergot, Leon D. Sanchez, Steven E. Bruce, Ronald C. Kessler, Karestan C. Koenen, Samuel A. Mclean, Vanni Bucci, John P. Haran

Einstein Health Papers

Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biological mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition after trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether the gut microbiomes of trauma-exposed emergency department patients who develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. We performed metagenomic analysis on stool samples (n = 51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA …

Efficacy Of Futibatinib, An Irreversible Fibroblast Growth Factor Receptor Inhibitor, In Fgfr-Altered Breast Cancer, Turcin Saridogan, Argun Akcakanat, Ming Zhao, Kurt W Evans, Erkan Yuca, Stephen Scott, Bryce P Kirby, Xiaofeng Zheng, Min Jin Ha, Huiqin Chen, Patrick K S Ng, Timothy P Diperi, Gordon B Mills, Jordi Rodon Ahnert, Senthil Damodaran, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and …

Association Between Microbiome And The Development Of Adverse Posttraumatic Neuropsychiatric Sequelae After Traumatic Stress Exposure, Abigail L Zeamer, Stacey L House, Et Al.

2020-Current year OA Pubs

Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biological mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition after trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether the gut microbiomes of trauma-exposed emergency department patients who develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. We performed metagenomic analysis on stool samples (n = 51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA …

Mutation Of Key Signaling Regulators Of Cerebrovascular Development In Vein Of Galen Malformations, Shujuan Zhao, Po-Ying Fu, Yung-Chun Wang, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10

Revisiting The Use Of Normal Saline For Peritoneal Washing In Ovarian Cancer, Hironari Akasaka, Honami Naora

Faculty, Staff and Student Publications

The omentum is the predominant site of ovarian cancer metastasis, but it is difficult to remove the omentum in its entirety. There is a critical need for effective approaches that minimize the risk of colonization of preserved omental tissues by occult cancer cells. Normal saline (0.9% sodium chloride) is commonly used to wash the peritoneal cavity during ovarian cancer surgery. The omentum has a prodigious ability to absorb fluid in the peritoneal cavity, but the impact of normal saline on the omentum is poorly understood. In this review article, we discuss why normal saline is not a biocompatible solution, drawing …

Blood-Based Proteomic Signatures Associated With Men1-Related Duodenopancreatic Neuroendocrine Tumor Progression, Johannes F Fahrmann, Amanda R Wasylishen, Carolina R C Pieterman, Ehsan Irajizad, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Christine B Peterson, Hua Zhao, Kim-Anh Do, Daniel M Halperin, Sunita K Agarwal, Jenny E Blau, Smita Jha, Jaydira Del Rivero, Naris Nilubol, Mary F Walter, James M Welch, Lee S Weinstein, Menno R Vriens, Rachel S Van Leeuwaarde, Mark J C Van Treijen, Gerlof D Valk, Nancy D Perrier, Samir M Hanash, Hiroyuki Katayama

Faculty, Staff and Student Publications

PURPOSE: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression.

EXPERIMENTAL DESIGN: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from …

Allogeneic Hematopoietic Cell Transplantation For Blastic Plasmacytoid Dendritic Cell Neoplasm: A Cibmtr Analysis, Hemant S. Murthy, Mei-Jie Zhang, Karen Chen, Sairah Ahmed, Uday Deotare, Siddhartha Ganguly, Ankit Kansagra, Fotios V. Michelis, Taiga Nishihori, Mrinal Patnaik, Muhammad Bilal Abid, Mahmoud Aljurf, Yasuyuki Arai, Ulrike Bacher, Talha Badar, Sherif M. Badawy, Karen Ballen, Minoo Battiwalla, Amer Beitinjaneh, Nelli Bejanyan, Vijaya Raj Bhatt, Valerie I. Brown, Rodrigo Martino, Jean-Yves Cahn, Paul Castillo, Jan Cerny, Saurabh Chhabra, Edward Copelan, Andrew Daly, Bhagirathbhai Dholaria, Miguel Angel Diaz Perez, César O. Freytes, Michael R. Grunwald, Shahrukh Hashmi, Gerhard C. Hildebrandt, Omer Jamy, Jacinth Joseph, Christopher G. Kanakry, Nandita Khera, Maxwell M. Krem, Yachiyo Kuwatsuka, Hillard M. Lazarus, Lazaros J. Lekakis, Hongtao Liu, Dipenkumar Modi, Pashna N. Munshi, Alberto Mussetti, Neil D. Palmisiano, Sagar S. Patel, David A. Rizzieri, Sachiko Seo, Mithun Vinod Shah, Akshay Sharma, Melhm Sohl, Scott R. Solomon, Matthew Ulrickson, Celalettin Ustun, Marjolein Van Der Poel, Leo F. Verdonck, John L. Wagner, Trent Wang, Baldeep Wirk, Amer Zeidan, Mark Litzow, Partow Kebriaei, Christopher S. Hourigan, Daniel J. Weisdorf, Wael Saber, Mohamed A. Kharfan-Dabaja

Department of Medical Oncology Faculty Papers

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), …

An Open Natural Language Processing (Nlp) Framework For Ehr-Based Clinical Research: A Case Demonstration Using The National Covid Cohort Collaborative (N3c), Sijia Liu, Andrew Wen, Liwei Wang, Huan He, Sunyang Fu, Robert Miller, Andrew Williams, Daniel Harris, Ramakanth Kavuluru, Mei Liu, Noor Abu-El-Rub, Dalton Schutte, Rui Zhang, Masoud Rouhizadeh, John D Osborne, Yongqun He, Umit Topaloglu, Stephanie S Hong, Joel H Saltz, Thomas Schaffter, Emily Pfaff, Christopher G Chute, Tim Duong, Melissa A Haendel, Rafael Fuentes, Peter Szolovits, Hua Xu, Hongfang Liu

Faculty, Staff and Student Publications

Despite recent methodology advancements in clinical natural language processing (NLP), the adoption of clinical NLP models within the translational research community remains hindered by process heterogeneity and human factor variations. Concurrently, these factors also dramatically increase the difficulty in developing NLP models in multi-site settings, which is necessary for algorithm robustness and generalizability. Here, we reported on our experience developing an NLP solution for Coronavirus Disease 2019 (COVID-19) signs and symptom extraction in an open NLP framework from a subset of sites participating in the National COVID Cohort (N3C). We then empirically highlight the benefits of multi-site data for both …

Mechanisms Of Endothelial Cell Membrane Repair: Progress And Perspectives., Duoduo Zha, Shizhen Wang, Paula Monaghan-Nichols, Yisong Qian, Venkatesh Sampath, Mingui Fu

Manuscripts, Articles, Book Chapters and Other Papers

Endothelial cells are the crucial inner lining of blood vessels, which are pivotal in vascular homeostasis and integrity. However, these cells are perpetually subjected to a myriad of mechanical, chemical, and biological stresses that can compromise their plasma membranes. A sophisticated repair system involving key molecules, such as calcium, annexins, dysferlin, and MG53, is essential for maintaining endothelial viability. These components orchestrate complex mechanisms, including exocytosis and endocytosis, to repair membrane disruptions. Dysfunctions in this repair machinery, often exacerbated by aging, are linked to endothelial cell death, subsequently contributing to the onset of atherosclerosis and the progression of cardiovascular diseases …

Identification Of Cdk1, Pbk, And Chek1 As An Oncogenic Signature In Glioblastoma: A Bioinformatics Approach To Repurpose Dapagliflozin As A Therapeutic Agent, Harold A Chinyama, Li Wei, Ntlotlang Mokgautsi, Bashir Lawal, Alexander T H Wu, Hsu-Shan Huang

Faculty, Staff and Student Publications

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells' presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle's main regulatory proteins. Herein, we identified and validated the …

Two Phase 3 Trials Of Gantenerumab In Early Alzheimer's Disease, Randall J Bateman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease.

METHODS: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab …

Nad+ Rescues Aging-Induced Blood-Brain Barrier Damage Via The Cx43-Parp1 Axis, Rui Zhan, Xia Meng, Dongping Tian, Jie Xu, Hongtu Cui, Jialei Yang, Yangkai Xu, Mingming Shi, Jing Xue, Weiwei Yu, Gaofei Hu, Ke Li, Xiaoxiao Ge, Qi Zhang, Mingming Zhao, Jianyong Du, Xin Guo, Wenli Xu, Yang Gao, Changyu Yao, Fan Chen, Yue Chen, Wenxin Shan, Yujie Zhu, Liang Ji, Bing Pan, Yan Yu, Wenguang Li, Xuyang Zhao, Qihua He, Xiaohui Liu, Yue Huang, Shengyou Liao, Bin Zhou, Dehua Chui, Y Eugene Chen, Zheng Sun, Erdan Dong, Yongjun Wang, Lemin Zheng

Faculty, Staff and Students Publications

Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5

Associations Between Birth Defects With Neural Crest Cell Origins And Pediatric Embryonal Tumors, Eugene C Wong, Philip J Lupo, Tania A Desrosiers, Hazel B Nichols, Susan M Smith, Charles Poole, Mark Canfield, Charles Shumate, Tiffany M Chambers, Jeremy M Schraw, Wendy N Nembhard, Mahsa M Yazdy, Eirini Nestoridi, Amanda E Janitz, Andrew F Olshan

Faculty, Staff and Students Publications

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins.

METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal …

Pharmacokinetics And Safety Of A Single Dose Of Telavancin In Pediatric Subjects 2-17 Years Of Age., John S. Bradley, Jennifer Goldman, Laura P. James, Byron Kaelin, Breanne H Y Gibson, Antonio Arrieta

Manuscripts, Articles, Book Chapters and Other Papers

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of …

A Multi-Institutional Phase 2 Trial Of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy For Borderline Resectable And Locally Advanced Pancreatic Cancer, Parag Jitendra Parikh, Hyun Kim, Lauren E Henke, Alex T Price, Et Al.

2020-Current year OA Pubs

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).

METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to …

A Paracrine Circuit Of Il-1Β/Il-1r1 Between Myeloid And Tumor Cells Drives Genotype-Dependent Glioblastoma Progression, Zhihong Chen, David H. Gutmann, Et Al.

2020-Current year OA Pubs

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast …

Circulating Tumor Dna Monitoring On Chemo-Immunotherapy For Risk Stratification In Advanced Non-Small Cell Lung Cancer, Bruna Pellini, Russell W Madison, Merrida A Childress, Shoshana T Miller, Ole Gjoerup, Jason Cheng, Richard S P Huang, Michael Krainock, Pratyush Gupta, Wei Zou, David S Shames, Solomon Moshkevich, Marcus Ballinger, Minetta C Liu, Amanda Young, Minu K Srivastava, Geoffrey R Oxnard, Mark A Socinski

Faculty, Staff and Student Publications

PURPOSE: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO.

EXPERIMENTAL DESIGN: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor …

Dietary L-Tryptophan Consumption Determines The Number Of Colonic Regulatory T Cells And Susceptibility To Colitis Via Gpr15, Nguyen Van, Karen Zhang, Rachel Wigmore, Anne Kennedy, Carolina Dasilva, Jialing Huang, Manju Ambelil, Jose Villagomez, Gerald O'Connor, Randy Longman, Miao Cao, Adam Snook, Michael Platten, Gerard Kasenty, Luis Sigal, George C Prendergast, Sangwon Kim

Department of Microbiology and Immunology Faculty Papers

Environmental factors are the major contributor to the onset of immunological disorders such as ulcerative colitis. However, their identities remain unclear. Here, we discover that the amount of consumed L-Tryptophan (L-Trp), a ubiquitous dietary component, determines the transcription level of the colonic T cell homing receptor, GPR15, hence affecting the number of colonic FOXP3⁺ regulatory T (Treg) cells and local immune homeostasis. Ingested L-Trp is converted by host IDO1/2 enzymes, but not by gut microbiota, to compounds that induce GPR15 transcription preferentially in Treg cells via the aryl hydrocarbon receptor. Consequently, two weeks of dietary L-Trp supplementation nearly double …

Targeted Suppression Of Mtorc2 Reduces Seizures Across Models Of Epilepsy, James Okoh, Jacqunae Mays, Alexandre Bacq, Juan A Oses-Prieto, Stefka Tyanova, Chien-Ju Chen, Khalel Imanbeyev, Marion Doladilhe, Hongyi Zhou, Paymaan Jafar-Nejad, Alma Burlingame, Jeffrey Noebels, Stephanie Baulac, Mauro Costa-Mattioli

Faculty, Staff and Students Publications

Epilepsy is a neurological disorder that poses a major threat to public health. Hyperactivation of mTOR complex 1 (mTORC1) is believed to lead to abnormal network rhythmicity associated with epilepsy, and its inhibition is proposed to provide some therapeutic benefit. However, mTOR complex 2 (mTORC2) is also activated in the epileptic brain, and little is known about its role in seizures. Here we discover that genetic deletion of mTORC2 from forebrain neurons is protective against kainic acid-induced behavioral and EEG seizures. Furthermore, inhibition of mTORC2 with a specific antisense oligonucleotide robustly suppresses seizures in several pharmacological and genetic mouse models …

Novel Clinical Trial Designs With Dose Optimization To Improve Long-Term Outcomes, Peter F Thall, Yong Zang, Andrew G Chapple, Ying Yuan, Ruitao Lin, David Marin, Pavlos Msaouel

Faculty, Staff and Student Publications

Conventional designs for choosing a dose for a new therapy may select doses that are unsafe or ineffective and fail to optimize progression-free survival time, overall survival time, or response/remission duration. We explain and illustrate limitations of conventional dose-finding designs and make four recommendations to address these problems. When feasible, a dose-finding design should account for long-term outcomes, include screening rules that drop unsafe or ineffective doses, enroll an adequate sample size, and randomize patients among doses. As illustrations, we review three designs that include one or more of these features. The first illustration is a trial that randomized patients …

Dhodh: A Promising Target In The Treatment Of T-Cell Acute Lymphoblastic Leukemia, Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David B Sykes

Faculty, Staff and Student Publications

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, …

The Landscape Of Alterations From 1407 Ultra-Rare Sarcomas From The Aacr Genie Database: Clinical Implications, Ryan A Denu, Justin T Moyers, Mohamed A Gouda, Anthony P Conley, Alexander J Lazar, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS.

Experimental design: Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data.

Results: Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most …

Missense Mutations In Crx Homeodomain Cause Dominant Retinopathies Through Two Distinct Mechanisms, Yiqiao Zheng, Chi Sun, Xiaodong Zhang, Philip A Ruzycki, Shiming Chen

2020-Current year OA Pubs

Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here, we use

Wire Snare Close Loop: A Novel Technique To Retrieve Embolized Devices, Manish Bansal, Gary E Stapleton, Srinath T Gowda, Athar M Qureshi

Faculty, Staff and Students Publications

No abstract provided.