Medical Specialties Commons^™

Gli1 Activates Pro-Fibrotic Pathways In Myelofibrosis Fibrocytes, Taghi Manshouri, Ivo Veletic, Ping Li, C Cameron Yin, Sean M Post, Srdan Verstovsek, Zeev Estrov

Faculty, Staff and Student Publications

Bone marrow (BM) fibrosis was thought to be induced exclusively by mesenchymal stromal cells (MSCs). However, we and others found that neoplastic fibrocytes induce BM fibrosis in myelofibrosis (MF). Because glioma-associated oncogene-1 (GLI1), an effector of the Hedgehog pathway, plays a role in the induction of BM fibrosis, we wondered whether GLI1 affects fibrocyte-induced BM fibrosis in MF. Multiplexed fluorescence immunohistochemistry analysis of MF patients' BM detected high levels of GLI1 in MF fibrocytes compared to MSCs or normal fibrocytes. Immunostaining, RNA in situ hybridization, gene expression analysis, and western immunoblotting detected high levels of GLI1 and GLI1-induced matrix metalloproteases …

Pirtobrutinib Inhibits Wild-Type And Mutant Bruton’S Tyrosine Kinase-Mediated Signaling In Chronic Lymphocytic Leukemia, Burcu Aslan, Gorkem Kismali, Lakesla R Iles, Ganiraju C Manyam, Mary L Ayres, Lisa S Chen, Mihai Gagea, Maria Teresa Sabrina Bertilaccio, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Pirtobrutinib (LOXO-305), a reversible inhibitor of Bruton's tyrosine kinase (BTK), was designed as an alternative strategy to treat ibrutinib-resistant disease that develops due to C481 kinase domain mutations. The clinical activity of pirtobrutinib has been demonstrated in CLL, but the mechanism of action has not been investigated. We evaluated pirtobrutinib in 4 model systems: first, MEC-1, a CLL cell line overexpressing BTKWT, BTKC481S, or BTKC481R; second, murine models driven by MEC-1 overexpressing BTKWT or BTKC481S; third, in vitro incubations of primary CLL cells; and finally, CLL patients during pirtobrutinib therapy (NCT03740529, ClinicalTrials.gov). Pirtobrutinib inhibited BTK activation as well …

Inhibition Of Mitochondrial Complex I Reverses Notch1-Driven Metabolic Reprogramming In T-Cell Acute Lymphoblastic Leukemia, Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva

Faculty, Staff and Student Publications

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with …

Rapid Molecular Diagnostics Of Tuberculosis Resistance By Targeted Stool Sequencing, Doctor B Sibandze, Alexander Kay, Viola Dreyer, Welile Sikhondze, Qiniso Dlamini, Andrew Dinardo, Godwin Mtetwa, Bhekumusa Lukhele, Debrah Vambe, Christoph Lange, Muyalo Glenn Dlamini, Tara Ness, Rojelio Mejia, Barbara Kalsdorf, Jan Heyckendorf, Martin Kuhns, Florian P Maurer, Sindisiwe Dlamini, Gugu Maphalala, Stefan Niemann, Anna Mandalakas

Faculty, Staff and Students Publications

BACKGROUND: Stool is an important diagnostic specimen for tuberculosis in populations who struggle to provide sputum, such as children or people living with HIV. However, the culture of Mycobacterium tuberculosis (M. tuberculosis) complex strains from stool perform poorly. This limits the opportunity for phenotypic drug resistance testing with this specimen. Therefore, reliable molecular methods are urgently needed for comprehensive drug resistance testing on stool specimens.

METHODS: We evaluated the performance of targeted next-generation sequencing (tNGS, Deeplex® Myc-TB) for the detection of mutations associated with M. tuberculosis complex drug resistance on DNA isolated from stool specimens provided by participants from a …

The Emotional Impact Of Urinary Tract Infections In Women: A Qualitative Analysis, Larissa Grigoryan, Aruni Mulgirigama, Marcy Powell, Guido Schmiemann

Faculty, Staff and Students Publications

BACKGROUND: While many studies address the clinical management of participants with uncomplicated urinary tract infection (uUTI), the emotional impact of uUTIs has been investigated less often. The aim of this qualitative study was to understand the emotional experience of women with uUTIs.

METHODS: This was a qualitative, exploratory, in-depth interview-based study conducted among women in the United States (US) and Germany. Women aged ≥ 18 years with at least one uUTI treated with antibiotics in the past year were recruited through a patient community panel and physician referrals. Participants were recruited using purposive sampling to include an equal split of …

Early Short Course Of Neuromuscular Blocking Agents In Patients With Covid-19 Ards: A Propensity Score Analysis., Gianluigi Li Bassi, Kristen Gibbons, Jacky Y Suen, Heidi J Dalton, Nicole White, Amanda Corley, Sally Shrapnel, Samuel Hinton, Simon Forsyth, John G Laffey, Eddy Fan, Jonathon P Fanning, Mauro Panigada, Robert Bartlett, Daniel Brodie, Aidan Burrell, Davide Chiumello, Alyaa Elhazmi, Mariano Esperatti, Giacomo Grasselli, Carol Hodgson, Shingo Ichiba, Carlos Luna, Eva Marwali, Laura Merson, Srinivas Murthy, Alistair Nichol, Mark Ogino, Paolo Pelosi, Antoni Torres, Pauline Yeung Ng, John F Fraser

Department of Anesthesiology Faculty Papers

BACKGROUND: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis.

METHODS: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 …

An Observational Retrospective Study Of Adverse Events And Behavioral Outcomes During Pediatric Dental Sedation, Kawtar Zouaidi, Gregory Olson, Helen H Lee, Elsbeth Kalenderian, Muhammad F Walji

Faculty, Staff and Student Publications

Purpose: The purpose of this study was to examine a university-based dental electronic health records (EHR) database to identify sedation-related adverse events (AEs) and assess patients' behavioral outcomes during routine pediatric dental sedations (PDSs) in a dental school clinic.

Methods: A database was screened for patients younger than 18 years old who had received dental sedation in 2019. The qualifying EHRs were then accessed and sedations were reviewed for AEs, which were categorized using a 12-point classification system and the Tracking and Reporting Outcomes of Procedural Sedation Tool. Patient behaviors were assessed using provider progress notes and categorized as presence/ …

Fibroblast Growth Factor 15/19 Expression, Regulation, And Function: An Overview, Greg Guthrie, Caitlin Vonderohe, Douglas Burrin

Children’s Nutrition Research Center Staff Publications

Since the discovery of fibroblast growth factor (FGF)-19 over 20 years ago, our understanding of the peptide and its role in human biology has moved forward significantly. A member of a superfamily of paracrine growth factors regulating embryonic development, FGF19 is unique in that it is a dietary-responsive endocrine hormone linked with bile acid homeostasis, glucose and lipid metabolism, energy expenditure, and protein synthesis during the fed to fasted state. FGF19 achieves this through targeting multiple tissues and signaling pathways within those tissues. The diverse functional capabilities of FGF19 is due to the unique structural characteristics of the protein and …

Global Community Of Practice: A Means For Capacity And Community Strengthening For Health Professionals In Low- And Middle-Income Countries, Allison Silverstein, Amy Benson, Catriona Gates, Diane Nguyen

Faculty, Staff and Students Publications

BACKGROUND: Low- and middle-income countries face distinct challenges in providing health care services and training. The community of practice (CoP) has been described as a method of facilitating much-needed connections and conversations on this topic and has been adapted over time to include virtual CoPs. We describe the development and evaluation of a global Clinical Lead Forum (CLF) using a CoP framework to structure informal continuing professional development (CPD) and enhance the capacity of health care professionals in low- and middle-income countries.

METHODS: Baylor College of Medicine International Pediatric AIDS Initiative (BIPAI) and its network of affiliated, independent non-governmental organizations …

Rapid Acceleration Of Kras-Mutant Pancreatic Carcinogenesis Via Remodeling Of Tumor Immune Microenvironment By Pparδ, Yi Liu, Yasunori Deguchi, Daoyan Wei, Fuyao Liu, Micheline J Moussalli, Eriko Deguchi, Donghui Li, Huamin Wang, Lovie Ann Valentin, Jennifer K Colby, Jing Wang, Xiaofeng Zheng, Haoqiang Ying, Mihai Gagea, Baoan Ji, Jiaqi Shi, James C Yao, Xiangsheng Zuo, Imad Shureiqi

Faculty, Staff and Student Publications

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This …

Treatment For Mild Chronic Hypertension During Pregnancy, Alan T Tita, Jeff M Szychowski, Kim Boggess, Lorraine Dugoff, Baha Sibai, Kirsten Lawrence, Brenna L Hughes, Joseph Bell, Kjersti Aagaard, Rodney K Edwards, Kelly Gibson, David M Haas, Lauren Plante, Torri Metz, Brian Casey, Sean Esplin, Sherri Longo, Matthew Hoffman, George R Saade, Kara K Hoppe, Janelle Foroutan, Methodius Tuuli, Michelle Y Owens, Hyagriv N Simhan, Heather Frey, Todd Rosen, Anna Palatnik, Susan Baker, Phyllis August, Uma M Reddy, Wendy Kinzler, Emily Su, Iris Krishna, Nicki Nguyen, Mary E Norton, Daniel Skupski, Yasser Y El-Sayed, Dotum Ogunyemi, Zorina S Galis, Lorie Harper, Namasivayam Ambalavanan, Nancy L Geller, Suzanne Oparil, Gary R Cutter, William W Andrews

Faculty, Staff and Students Publications

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth.

METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal …

Immunogenomic Intertumor Heterogeneity Across Primary And Metastatic Sites In A Patient With Lung Adenocarcinoma, Runzhe Chen, Jun Li, Junya Fujimoto, Lingzhi Hong, Xin Hu, Kelly Quek, Ming Tang, Akash Mitra, Carmen Behrens, Chi-Wan Chow, Peixin Jiang, Latasha D Little, Curtis Gumbs, Xingzhi Song, Jianhua Zhang, Dongfeng Tan, John V Heymach, Ignacio Wistuba, P Andrew Futreal, Don L Gibbons, Lauren A Byers, Jianjun Zhang, Alexandre Reuben

Faculty, Staff and Student Publications

Background: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy.

Methods: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. …

Ezh2 Engages Tgfβ Signaling To Promote Breast Cancer Bone Metastasis Via Integrin Β1-Fak Activation, Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu

Faculty, Staff and Student Publications

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type …

Mortality After Transcatheter Aortic Valve Replacement For Aortic Stenosis Among Patients With Malignancy: A Systematic Review And Meta-Analysis, Muhammad U Siddiqui, Omar Yacob, Joey Junarta, Ahmed K Pasha, Farouk Mookadam, Mamas A Mamas, D L Fischman

Division of Internal Medicine Faculty Papers & Presentations

Background: With advancements in cancer treatment, the life expectancy of oncology patients has improved. Thus, transcatheter aortic valve replacement (TAVR) may be considered as a feasible option for oncology patients with severe symptomatic aortic stenosis (AS). We aim to evaluate the difference in short- and long-term all-cause mortality in cancer and non-cancer patients treated with TAVR for severe AS.

Methods: Medline, PubMed, and Cochrane Central Register of Controlled Trials were searched for relevant studies. Patients with cancer who underwent treatment with TAVR for severe AS were included and compared to an identical population without cancer. The primary endpoints were short- …

Evaluation Of Heat Inactivation Of Human Norovirus In Freshwater Clams Using Human Intestinal Enteroids, Tsuyoshi Hayashi, Yoko Yamaoka, Atsushi Ito, Takashi Kamaishi, Ryuichi Sugiyama, Mary K Estes, Masamichi Muramatsu, Kosuke Murakami

Faculty, Staff and Students Publications

Foodborne disease attributed to the consumption of shellfish contaminated with human norovirus (HuNoV) is one of many global health concerns. Our study aimed to determine the conditions of the heat-inactivation of HuNoV in freshwater clams (Corbicula japonica) using a recently developed HuNoV cultivation system employing stem-cell derived human intestinal enteroids (HIEs). We first measured the internal temperature of the clam tissue in a water bath during boiling at 90 °C and found that approximately 2 min are required for the tissue to reach 90 °C. Next, GII.4 HuNoV was spiked into the center of the clam tissue, followed …

Racial And Ethnic Differences In Genomic Profiling Of Early Onset Colorectal Cancer, David M Hein, Weiye Deng, Marylena Bleile, Syed Ali Kazmi, Brooke Rhead, Francisco M De La Vega, Amy L Jones, Radhika Kainthla, Wen Jiang, Brandi Cantarel, Nina N Sanford

Faculty, Staff and Student Publications

The incidence and mortality of early onset colorectal cancer (EOCRC) is rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (non-Hispanic Asian, non-Hispanic Black, non-Hispanic White, White Hispanic) using data from the American Association for Cancer Research Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1752 EOCRC patients, non-Hispanic Black patients had higher rates of KRAS mutations (60.9%; P = .001, q = 0.015), and non-Hispanic White and non-Hispanic Black …

Pattern Differentiation And Tuning Shift In Human Sensory Cortex Underlie Long-Term Threat Memory, Yuqi You, Lucas R Novak, Kevin J Clancy, Wen Li

Faculty, Staff and Student Publications

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system 1, but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit 2-4. Through non-human research, the sensory cortex has emerged as a critical substrate for long-term threat memory 5-9, underpinned by sensory cortical pattern separation/completion 10,11 and tuning shift 12,13. In humans, research has begun to associate the human sensory cortex with long-term threat memory 14,15, but the lack of mechanistic insights obscures a direct linkage. Towards that end, …

Central Nervous System Immune Interactome Is A Function Of Cancer Lineage, Tumor Microenvironment, And Stat3 Expression, Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M Sonabend, Craig Horbinski, Roel Verhaak, Anand Shankar, Santhoshi N Krishnan, Frederick S Varn, Víctor A Arrieta, Pravesh Gupta, Sherise D Ferguson, Jason T Huse, Gregory N Fuller, James P Long, Daniel E Winkowski, Ben A Freiberg, Charles David James, Leonidas C Platanias, Maciej S Lesniak, Jared K Burks, Amy B Heimberger

Faculty, Staff and Student Publications

BACKGROUND

Immune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.

METHODS

En bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.

RESULTS

Within gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163⁺ macrophages were evident throughout the TME of metastatic …

Burden Of Cardiovascular Risk Factors And Disease In Five Asian Groups In Catalonia: A Disaggregated, Population-Based Analysis Of 121 000 First-Generation Asian Immigrants, Priyanka Satish, Emili Vela, Usama Bilal, Montse Cleries, Alka M Kanaya, Namratha Kandula, Salim S Virani, Nadia Islam, Javier Valero-Elizondo, Tamer Yahya, Josep Comin-Colet, Khurram Nasir, Josepa Mauri, Miguel Cainzos-Achirica

Faculty, Staff and Students Publications

AIMS: To evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese.

METHODS AND RESULTS: Retrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes …

The Ep300/Tp53 Pathway, A Suppressor Of The Hippo And Canonical Wnt Pathways, Is Activated In Human Hearts With Arrhythmogenic Cardiomyopathy In The Absence Of Overt Heart Failure, Leila Rouhi, Siyang Fan, Sirisha M Cheedipudi, Aitana Braza-Boïls, Maria Sabater Molina, Yan Yao, Matthew J Robertson, Cristian Coarfa, Juan R Gimeno, Pilar Molina, Priyatansh Gurha, Esther Zorio, Ali J Marian

Faculty, Staff and Students Publications

AIMS: Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiac arrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations in genes encoding desmosome proteins. Desmosomes are cell-cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure.

METHODS AND RESULTS: Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and five control samples were analysed by RNA-Seq (discovery group). These cases …

Evidence Supporting A Role For The Immune Checkpoint Protein B7-H3 In Nk Cell-Mediated Cytotoxicity Against Aml, Anudishi Tyagi, Stanley Ly, Fouad El-Dana, Bin Yuan, Appalaraju Jaggupilli, Sabrina Grimm, Marina Konopleva, Hans-Jörg Bühring, V Lokesh Battula

Faculty, Staff and Student Publications

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop …

Novel Fold Of Rotavirus Glycan-Binding Domain Predicted By Alphafold2 And Determined By X-Ray Crystallography, Liya Hu, Wilhelm Salmen, Banumathi Sankaran, Yi Lasanajak, David F Smith, Sue E Crawford, Mary K Estes, B V Venkataram Prasad

Faculty, Staff and Students Publications

The VP8* domain of spike protein VP4 in group A and C rotaviruses, which cause epidemic gastroenteritis in children, exhibits a conserved galectin-like fold for recognizing glycans during cell entry. In group B rotavirus, which causes significant diarrheal outbreaks in adults, the VP8* domain (VP8*B) surprisingly lacks sequence similarity with VP8* of group A or group C rotavirus. Here, by using the recently developed AlphaFold2 for ab initio structure prediction and validating the predicted model by determining a 1.3-Å crystal structure, we show that VP8*B exhibits a novel fold distinct from the galectin fold. This fold with a β-sheet clasping …

Assessing The Coverage Of Us Cancer Center Primary Catchment Areas., Amy E Leader, Christopher Mcnair, Christina Yurick, Matthew Huesser, Elizabeth Schade, Emily E Stimmel, Caryn Lerman, Karen E Knudsen

Kimmel Cancer Center Faculty Papers

Background: Cancer centers are expected to engage communities and reduce the burden of cancer in their catchment areas. However, the extent to which cancer centers adequately reach the entire US population is unknown. Methods: We surveyed all members of the Association of American Cancer Institutes (N ¼ 102 cancer centers) to document and map each cancer center’s primary catchment area. Catchment area descriptions were aggregated to the county level. Catchment area coverage scores were calculated for each county and choropleths generated representing coverage across the US. Similar analyses were used to overlay US population density, cancer incidence, and cancer-related mortality …

Elucidating Human Milk Oligosaccharide Biosynthetic Genes Through Network-Based Multi-Omics Integration, Benjamin P Kellman, Anne Richelle, Jeong-Yeh Yang, Digantkumar Chapla, Austin W T Chiang, Julia A Najera, Chenguang Liang, Annalee Fürst, Bokan Bao, Natalia Koga, Mahmoud A Mohammad, Anders Bech Bruntse, Morey W Haymond, Kelley W Moremen, Lars Bode, Nathan E Lewis

Children’s Nutrition Research Center Staff Publications

Human Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we use a systems biology framework that integrates glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we construct models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. Our …

A Bayesian Group Sequential Design For Randomized Biosimilar Clinical Trials With Adaptive Information Borrowing From Historical Data, Wen Zhang, Zhiying Pan, Ying Yuan

Faculty, Staff and Student Publications

At the time of developing a biosimilar, the reference product has been on market for years and thus ample data are available on its efficacy and characteristics. We develop a Bayesian adaptive design for randomized biosimilar clinical trials to leverage the rich historical data on the reference product. This design takes a group sequential approach. At each interim, we employ the elastic meta-analytic-predictive (EMAP) prior methodology to adaptively borrow information from the historical data of the reference product to make go/no-go decision based on Bayesian posterior probabilities. In addition, the randomization ratio between the test and reference arms is adaptively …

Bhlhe40 Regulates The T-Cell Effector Function Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery J Salmon, Alexander S Shavkunov, Qi Miao, Nicholas N Jarjour, Sunita Keshari, Ekaterina Esaulova, Charmelle D Williams, Jeffrey P Ward, Anna M Highsmith, Josué E Pineda, Reshma Taneja, Ken Chen, Brian T Edelson, Matthew M Gubin

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study., Lindsey Malloy-Walton, Nicholas H. Von Bergen, Seshadri Balaji, Peter S. Fischbach, Jason M. Garnreiter, S Yukiko Asaki, Jeffrey P. Moak, Luis A. Ochoa, Philip M. Chang, Hoang H. Nguyen, Akash R. Patel, Christa Kirk, Ashley K. Sherman, Jennifer N. Avari Silva, J Philip Saul

Manuscripts, Articles, Book Chapters and Other Papers

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study, Lindsey E Malloy-Walton, Nicholas H Von Bergen, Seshadri Balaji, Peter S Fischbach, Jason M Garnreiter, S Yukiko Asaki, Jeffrey P Moak, Luis A Ochoa, Philip M Chang, Hoang H Nguyen, Akash R Patel, Christa Kirk, Ashley K Sherman, Jennifer N Avari Silva, J Philip Saul

Faculty, Staff and Student Publications

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Systems Biology Approach To Functionally Assess The Clostridioides Difficile Pangenome Reveals Genetic Diversity With Discriminatory Power, Charles J Norsigian, Heather A Danhof, Colleen K Brand, Firas S Midani, Jared T Broddrick, Tor C Savidge, Robert A Britton, Bernhard O Palsson, Jennifer K Spinler, Jonathan M Monk

Faculty, Staff and Students Publications

Combatting Clostridioides difficile infections, a dominant cause of hospital-associated infections with incidence and resulting deaths increasing worldwide, is complicated by the frequent emergence of new virulent strains. Here, we employ whole-genome sequencing, high-throughput phenotypic screenings, and genome-scale models of metabolism to evaluate the genetic diversity of 451 strains of C. difficile. Constructing the C. difficile pangenome based on this set revealed 9,924 distinct gene clusters, of which 2,899 (29%) are defined as core, 2,968 (30%) are defined as unique, and the remaining 4,057 (41%) are defined as accessory. We develop a strain typing method, sequence typing by accessory genome (STAG), …

Diminished Immune Surveillance During Histologic Progression Of Intraductal Papillary Mucinous Neoplasms Offers A Therapeutic Opportunity For Cancer Interception, Sharia Hernandez, Edwin Roger Parra, Naohiro Uraoka, Ximing Tang, Yu Shen, Wei Qiao, Mei Jiang, Shanyu Zhang, Barbara Mino, Wei Lu, Renganayaki Pandurengan, Cara Haymaker, Kajsa Affolter, Courtney L Scaife, Michele Yip-Schneider, C Max Schmidt, Matthew A Firpo, Sean J Mulvihill, Eugene J Koay, Huamin Wang, Ignacio I Wistuba, Anirban Maitra, Luisa M Solis, Subrata Sen

Faculty, Staff and Student Publications

Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.

Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples …