Digital Commons Network^™

Met Pathway Inhibition Increases Chemo-Immunotherapy Efficacy In Small Cell Lung Cancer, Raúl Del Rey-Vergara, Miguel Alejandro Galindo-Campos, Pedro Rocha, Marina Carpes, Carlos Martínez, Laura Masfarré, Silvia Menéndez, Fabricio Quimis, Adrià Rossell, Albert Iñañez, Sandra Pérez-Buira, Federico Rojo, Ramon Gimeno, Dolores Isla, Jon Zugazagoitia, Cristina Martí Blanco, Rosario García-Campelo, Alberto Moreno-Vega, Luis León-Mateos, Ángel Callejo Mellén, Kwon-Sik Park, Simon Heeke, John V Heymach, Álvaro Taus, Luis Paz-Ares, Ana Rovira, Edurne Arriola

Faculty, Staff and Student Publications

The introduction of immunotherapy as a first-line treatment for advanced small cell lung cancer (SCLC) represents significant progress, yet there remains an opportunity to further improve patient outcomes. Hepatocyte growth factor (HGF) receptor (MET) pathway activation promotes epithelial-mesenchymal transition, driving chemoresistance and potentially impairing the efficacy of immunotherapy. In SCLC mouse models, adding MET inhibition to chemo-immunotherapy (anti-PD-L1) reduces tumor growth, extends survival, and reshapes the tumor microenvironment by decreasing suppressive myeloid cell infiltration and enhancing the immune response. Analysis of pretreatment human SCLC tumor samples reveals that myeloid-enriched immune infiltrates may contribute to chemo-immunotherapy resistance. Elevated serum HGF levels …

Synergistic Activity Of Combined Flt3-Itd And Mdm2 Inhibition With Quizartinib And Milademetan In Flt3-Itd Mutant/Tp53 Wild-Type Acute Myeloid Leukemias, Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff

Faculty, Staff and Student Publications

Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.

Experimental design: Preclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, …

Targeting The Cd40 Costimulatory Receptor To Improve Virotherapy Efficacy In Diffuse Midline Gliomas, Sara Labiano, Javier Marco-Sanz, Iker Ausejo-Mauleon, Virginia Laspidea, Reyes Hernández-Osuna, Marc Garcia-Moure, Daniel De La Nava, Sara Nuin, Marisol Gonzalez-Huarriz, Timothy N Phoenix, Ibon Tamayo, Marta Zalacain, Andrea Lacalle, Lucía Marrodan, Montserrat Puigdelloses, Irati Hervás-Corpión, Maria C Ochoa, Noelia Casares, Oren J Becher, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gallego Perez-Larraya, Ana Patiño-Garcia, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and …

Antitumor Efficacy Of Intermittent Low-Dose Erlotinib Plus Sulindac Via Mhc Upregulation And Remodeling Of The Immune Cell Niche, Chakrapani Tripathi, Jorge E Tovar Perez, Sabeeta Kapoor, Ahmed Muhsin, Wan Mohaiza Dashwood, Yunus Demirhan, Melek Demirhan, Alessandro Shapiro, Altaf Mohammed, Shizuko Sei, Jacklyn Thompson, Mahira Zaheer, Krishna M Sinha, Powel H Brown, Michelle I Savage, Eduardo Vilar, Praveen Rajendran, Roderick H Dashwood

Faculty, Staff and Student Publications

A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-γ signaling as a key pathway. In this study, we combine intermittent low-dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL ± SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor-associated Cd4+ T cells by ~2.6-fold (p < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-γ signaling may benefit FAP patients at drug doses below the clinical standard of care.

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Nana A Goode, Feni K Kadakia, Laura A Maile, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …

Fgfr3-Induced Y158 Parp1 Phosphorylation Promotes Parp Inhibitor Resistance Via Brg1/Mre11-Mediated Dna Repair In Breast Cancer Models, Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T Chang, Yu-Chun Hsiao, Tewodros W Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively …

Serum Metabolomic Profiling Of Incident Type 2 Diabetes Mellitus In The Multi-Ethnic Study Of Atherosclerosis And Rotterdam Study, Xuanwei Jiang, Fang Zhu, Gonçalo Graça, Xihao Du, Jinjun Ran, Fariba Ahmadizar, Alexis C Wood, Yanqiu Zhou, Denise M Scholtens, Ali Farzaneh, M Arfan Ikram, Alan Kuang, Carel W Le Roux, Meghana D Gadgil, Marilyn C Cornelis, Kent D Taylor, Xiuqing Guo, Mohsen Ghanbari, Laura J Rasmussen-Torvik, Russell P Tracy, Alain G Bertoni, Jerome I Rotter, David M Herrington, Philip Greenland, Maryam Kavousi, Victor W Zhong

Children’s Nutrition Research Center Staff Publications

Objective: This study aimed to investigate serum metabolomic biomarkers associated with incident type 2 diabetes mellitus (T2DM) and evaluate their performance in improving T2DM risk prediction.

Methods: Untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 3460; discovery cohort) and The Rotterdam Study (RS; n = 1556; replication cohort). Multivariable cause-specific hazards models were used to analyze the associations between 23 571 serum metabolomic spectral variables and incident T2DM. Replicated metabolites required an false discovery rate-adjusted P < .01 in MESA, P < .05 in RS, and consistent direction of association. Pathway and network analyses were conducted to elucidate biological mechanisms underlying T2DM development. The utility of the replicated metabolites in improving T2DM risk prediction was assessed based on the Framingham Diabetes Risk Score. A 2-sample Mendelian randomization was conducted to assess causal associations.

Results: Nineteen metabolites were significantly associated with incident T2DM. Pathway analyses …

Resilience And Traumatic Stress Among Latinx English Language Learners: A Cross-Sectional Study Of Students From An Urban School District, Roya Ijadi-Maghsoodi, Sara Rahmanian Koushkaki, Alexandra Klomhaus, Hilary Aralis, Angela Venegas-Murillo, Lauren Marlotte, Sameera Siddiqi, Kungeun Lee, Shirley A De La Cruz, Sheryl Kataoka

Staff and Researcher Publications

Background: Latinx students in the United States can face stressors and structural inequities that can lead to poor academic and mental health outcomes. They comprise 76% of the English Language Learner (ELL) population, yet little is known about the relationship between ELL status and traumatic stress and resilience outcomes among these Latinx students. We sought to see if resilience differs between ELL vs. non-ELL Latinx students, and if traumatic stress risk modifies the association between ELL designation and resilience among Latinx students to inform culturally relevant school resilience interventions and school-wide approaches for this population.

Methods: We analyzed deidentified school …

Parietal Cortex Is Recruited By Frontal And Cingulate Areas To Support Action Monitoring And Updating During Stopping, Jung Uk Kang, Layth Mattar, José Vergara, Victoria E Gobo, Hernan G Rey, Sarah R Heilbronner, Andrew J Watrous, Benjamin Y Hayden, Sameer A Sheth, Eleonora Bartoli

Faculty, Staff and Students Publications

Recent evidence indicates that the intraparietal sulcus (IPS) may play a causal role in action stopping, potentially representing a novel neuromodulation target for inhibitory control dysfunctions. Here, we leverage intracranial recordings in human subjects to establish the timing and directionality of information flow between IPS and prefrontal and cingulate regions during action stopping. Prior to successful inhibition, information flows primarily from the inferior frontal gyrus (IFG), a critical inhibitory control node, to IPS. In contrast, during stopping errors the communication between IPS and IFG is lacking, and IPS is engaged by posterior cingulate cortex, an area outside of the classical …

Role Of Lipoprotein(A) In Atherosclerotic Cardiovascular Disease In South Asian Individuals, Darshan Patel, Marlys L Koschinsky, Anandita Agarwala, Pradeep Natarajan, Harpreet S Bhatia, Anurag Mehta, Jaideep Patel, Matthew Peters, Shreya Pandya, Usman Sagheer, Raman Puri, Salim S Virani, Dinesh K Kalra

Faculty, Staff and Students Publications

South Asian individuals (SA), representing approximately one quarter of the global population, experience a disproportionately high burden of cardiovascular disease. Some of this increased susceptibility is accounted for by traditional risk factors such as diabetes, hypertension, carbohydrate-rich diets, and rising rates of obesity and metabolic syndrome. However, other previously underappreciated risk factors may also play a crucial role. These include environmental pollution, genetic factors, and Lp(a) (lipoprotein(a)). Various epidemiological and genetic studies support the role of Lp(a) as a causal and independent risk factor for atherosclerotic cardiovascular disease. SA have a higher prevalence of elevated Lp(a) levels (25% have levels …

Epha4 Signaling Dysregulation Links Abnormal Locomotion And The Development Of Idiopathic Scoliosis, Lianlei Wang, Xinyu Yang, Sen Zhao, Pengfei Zheng, Wen Wen, Kexin Xu, Xi Cheng, Qing Li, Anas M Khanshour, Yoshinao Koike, Junjun Liu, Xin Fan, Nao Otomo, Zefu Chen, Yaqi Li, Lulu Li, Haibo Xie, Panpan Zhu, Xiaoxin Li, Yuchen Niu, Shengru Wang, Sen Liu, Suomao Yuan, Chikashi Terao, Ziquan Li, Shaoke Chen, Xiuli Zhao, Pengfei Liu, Jennifer E Posey, Zhihong Wu, Guixing Qiu, Disco Study Group (Deciphering Disorders Involving Scoliosis & Comorbidities), Shiro Ikegawa, James R Lupski, Jonathan J Rios, Carol A Wise, Jianguo T Zhang, Chengtian Zhao, Nan Wu

Faculty, Staff and Students Publications

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited …

X-Linked Hypophosphatemia Management In Adults: An International Working Group Clinical Practice Guideline., Aliya A. Khan, Dalal S. Ali, Natasha M. Appelman-Dijkstra, Thomas O. Carpenter, Catherine Chaussain, Erik A. Imel, Suzanne M. Jan De Beur, Pablo Florenzano, Hajar Abu Alrob, Rana Aldabagh, R Todd Alexander, Farah Alsarraf, Signe Sparre Beck-Nielsen, Martin Biosse-Duplan, Martine Cohen-Solal, Rachel K. Crowley, Karel Dandurand, Guido Filler, Lisa Friedlander, Seiji Fukumoto, Claudia Gagnon, Paul Goodyer, Corinna Grasemann, Chelsey Grimbly, Salma Hussein, Muhammad K Javaid, Sarah Khan, Aneal Khan, Anna Lehman, Willem F. Lems, E Michael Lewiecki, Ciara Mcdonnell, Reza D. Mirza, Emmett Morgante, Archibald Morrison, Anthony A. Portale, Yumie Rhee, Eric T. Rush, Heide Siggelkow, Sotirios Tetradis, Laura Tosi, Leanne M. Ward, Gordon Guyatt, Maria Luisa Brandi

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: An international working group (IWG) consisting of experts in X-linked hypophosphatemia (XLH) developed global guidelines providing a comprehensive, evidence-based approach to XLH diagnosis, management, and monitoring.

METHODS: The IWG, consisting of 43 members as well as methodologists and a patient partner, conducted 2 systematic reviews (SRs) and narrative reviews to address key areas. The SRs addressed the impact of burosumab compared to conventional therapy (phosphate and active vitamin D) or no therapy on patient-important outcomes in adults. They also evaluated conventional therapy compared to no therapy. GRADE methodology was applied to evaluate the certainty of evidence. Non-GRADED recommendations were …

A Christian Imagination For Ai: Scripture, Screens, And The Shape Of Our Souls, David J. Mulder

Faculty Work Comprehensive List

No abstract provided.

Self-Other Generalisation Shapes Social Interaction And Is Disrupted In Borderline Personality Disorder, Joseph M Barnby, Jen Nguyen, Julia Griem, Magdalena Wloszek, Henry Burgess, Linda J Richards, Jessica Kingston, Gavin Cooper, P Read Montague, Peter Dayan, Tobias Nolte, Peter Fonagy, London Personality And Mood Disorders Consortium

2020-Current year OA Pubs

Generalising information from ourselves to others, and others to ourselves allows for both a dependable source of navigation and adaptability in interpersonal exchange. Disturbances to social development in sensitive periods can cause enduring and distressing damage to lasting healthy relationships. However, identifying the mechanisms of healthy exchange has been difficult. We introduce a theory of self-other generalisation tested with data from a three-phase social value orientation task - the Intentions Game. We involved humans with (

The Overlooked Impact Of Background Diet And Adherence In Nutrition Trials, Javier I Ottaviani, Hagen Schroeter, Dennis M Bier, John W Erdman, Howard D Sesso, Joann E Manson, Gunter G C Kuhnle

Children’s Nutrition Research Center Staff Publications

Randomised controlled trials in nutrition (RCTN) face unique challenges, including the considerable influence of the background diet and the challenge of assuring intervention adherence by participants. The impact of these factors on the outcome of RCTNs has been difficult to quantify, but nutritional biomarkers represent a valuable tool to address these challenges. Using flavanols as a model dietary intervention and a set of recently validated flavanol biomarkers, we here investigated the impact of background diet and adherence on the outcomes of a subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS, NCT 02422745). We found that 20% of participants …

Large B Cell Lymphoma Microenvironment Archetype Profiles, Xubin Li, Kartik Singhal, Qing Deng, Dai Chihara, David Russler-Germain, R Andrew Harkins, Jared Henderson, Kotaro Arita, Atish Kizhakeyil, Ryan Sun, Priya Lakra, Usama Hussein, Jennifer A Foltz, Ashley Wilson, Evelyn Schmidt, Imran Nizamuddin, Tommy Dinh, Akhil Kesaraju, Mark P Hamilton, Carl Allen, Maher K Gandhi, Joshua Tobin, Aixiang Jiang, Laura Hilton, David W Scott, Francisco Vega, Christopher R Flowers, Jason R Westin, Obi L Griffith, Todd A Fehniger, Malachi Griffith, Michael R Green

Faculty, Staff and Student Publications

Large B cell lymphomas (LBCL) are clinically and biologically heterogeneous lymphoid malignancies with complex microenvironments that are central to disease etiology. Here we have employed single-nucleus multiome profiling of 232 tumor and control biopsies to characterize diverse cell types and subsets that are present in LBCL tumors, effectively capturing the lymphoid, myeloid, and non-hematopoietic cell compartments. Cell subsets co-occurred in stereotypical Lymphoma Microenvironment Archetype Profiles (LymphoMAPs) defined by; (i) a sparsity of T cells and high frequencies of cancer-associated fibroblasts and tumor-associated macrophages [FMAC]; (ii) lymph node architectural cell types with naïve and memory T cells [LN]; or (iii) activated …

Gene Expression In Tumor And Adjacent Normal Tissues In Lung Adenocarcinoma Subtypes, Olga Y Gorlova, Ivan P Gorlov, R Taylor Ripley, Chao Cheng, Yafang Li, Bo Peng, Yanhong Liu, Hee-Jin Jang, Sung Wook Kang, Claire Lee, Priyanka Ranchod, Bryan M Burt, Hyun-Sung Lee, Christopher I Amos

Faculty, Staff and Students Publications

Background: Lung adenocarcinoma (LUAD) has several histologically distinct subtypes that differ by a number of clinical features including patient survival. Molecular mechanisms underlying histological and clinical differences between subtypes remain poorly understood.

Methods: We conducted a comparative analyses of gene expression in acinar, lepidic, papillary and solid subtypes, as well as mucinous adenocarcinoma. We used a novel, more efficient approach to identify subtype-specific genes. We compared the mean gene expression level separately for tumors and adjacent normal tissue with pure or a highly represented (≥ 75%) subtype of interest to the mean expression in tumors where the subtype of interest …

Mbiochemical Identification And Clinical Description Of Edetomidine Exposure In People Who Use Fentanyl In Philadelphia, Pa, Phil Durney, Jennifer L. Kahoud, Tareva Warrick-Stone, Maeve Montesi, Meg Carter, Sabrina Butt, Alberto Martinez Mencia, Louisa Omoregie, Monali Shah, Mariah Bloomfield, Nicholas Tomasko, Rebecca C. Jaffe, Allison Herens, Warren R. Korn, Karen Alexander, Douglas F. Stickle, Dennis Goodstein, Lara Weinstein, Kory S. London

Department of Emergency Medicine Faculty Papers

Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography-tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 …

Comparative Analysis Of Hiv Data Completeness In Haiti's Isanté Plus Electronic Medical Record System Across Children, Adolescents And Adults: A Cross-Sectional Evaluation Of 2016-2022 Data, Beryne Odeny, Jean Guy Honoré, Jean Gabriel Balan, James P Hughes, Bradley Wagenaar, Stephen Gloyd, Kemar Célestin, Marinho Elisma, Kesner Francois, Nancy Puttkammer

2020-Current year OA Pubs

OBJECTIVE: To evaluate and compare documentation completeness of HIV-related data by age group (children, adolescents and adults) in Haiti's Electronic Medical Record (EMR) system.

DESIGN: Cross-sectional evaluation.

SETTING: EMR data for 36 965 enrolment visits, and 123 608 return visits from 58 facilities in Haiti (from 2016 to 2022).

PARTICIPANTS: Children, adolescents and adults accessing HIV care and treatment services in Haiti.

MAIN EXPOSURE MEASURE: Health facility attendance for HIV-related healthcare.

MAIN OUTCOME MEASURE: Level of data completeness, as a measure of data quality. We developed Composite Completeness Scores (CCS scores) to measure data completeness. Lower scores meant lower completeness. …

A Combined Naturalistic Driving, Clinical, And Neurobehavioral Data Set For Investigating Aging And Dementia, Matthew Blake, David C Brown, Chen Chen, Noor Al-Hammadi, Ramon Casanova, Yiqi Zhu, Ganesh M Babulal

2020-Current year OA Pubs

Alzheimer's disease and related dementia (ADRD) are becoming increasingly prevalent and are predicted to affect up to 153 million globally by 2050. Outside of biomarkers that measure pathology, there is a lack of methods to quantify and study complex behaviors such as driving and managing finances that precede cognitive decline among older adults. The DRIVES Project at Washington University School of Medicine has developed a pipeline to measure naturalistic driving behavior of older adult drivers enrolled in longitudinal studies of aging and ADRD. This driving behavior is captured in the form of tabular data for each trip a participant takes …

Establishment Of A Reverse Genetics System For Studying Human Immune Functions In Mice, Priya Pal, Shuai Gao, Hongbo Gao, Xiwen Qin, Marina Cella, Qiankun Wang, Liang Shan

2020-Current year OA Pubs

Reverse genetics approaches in mice are widely used to understand gene functions and their aberrations in diseases. However, limitations exist in translating findings from animal models to human physiology. Humanized mice provide a powerful bridge to understanding human physiology and mechanisms of disease pathogenesis while maintaining the feasibility of working with small animals. Methods for generating humanized mouse models that allow scientists to probe contributions of particular genes have been rudimentary. Here, we established an efficient method for generating genetically modified human cord blood-derived CD34

Molecular Epidemiology And Clinical Characterization Of Carbapenemase-Producing Enterobacter Species From An International Cohort, Jianping Jiang, Lauren Komarow, Carol Hill, Angelique E Boutzoukas, Blake Hanson, Cesar A Arias, Robert A Bonomo, Scott Evans, Yohei Doi, Michael J Satlin, Gregory Weston, Eric Cober, Sandra Liliana Valderrama-Beltran, Soraya Salcedo Mendoza, Zhengyin Liu, Bettina C Fries, Paul Ananth Tambyah, Henry F Chambers, Vance G Fowler, David Van Duin, Barry N Kreiswirth, Liang Chen

Faculty, Staff and Student Publications

Background: Despite the global public health threat posed by carbapenem-resistant Enterobacter spp, clinical and molecular epidemiological studies on international isolates remain scarce. Historically, the taxonomy of Enterobacter has been challenging, limiting our understanding of the clinical characteristics and outcomes of carbapenemase-producing Enterobacter spp infections.

Methods: Hospitalized patients enrolled in the CRACKLE-2 study (ClinicalTrials.gov, NCT03646227) from 2016 to 2018 with cultures positive for carbapenemase-producing Enterobacter spp were included. Clinical and microbiologic data were collected from health records. Whole genome sequencing was performed, and the population structures of selected predominant clones were analyzed.

Results: We enrolled 136 hospitalized patients with carbapenemase-producing …

Hepatitis Patients Undergoing Cardiac Surgery: A Single-Center Retrospective Study, Jin-Long Ju, Yun-Tai Yao, Jun Li, Zhi Cheng, Ling-Ling Fan, Yu-Long Zhong

Faculty, Staff and Student Publications

This study aimed to investigate whether there is difference among various clinical variables, especially blood loss and total drainage volume, among patients with different types of hepatitis undergoing cardiac surgery. A retrospective study was performed on 150 hepatitis patients (127 hepatitis B and 23 hepatitis C) who underwent cardiac surgery at a single cardiovascular center in 2020. Data on their preoperative, intraoperative, and postoperative variables were collected and statistically analyzed to assess the inter-group differences in the following variables: intraoperative blood loss, postoperative drainage volume, proportion of patients treated with blood transfusion, proportion of patients treated with vasoactive drugs, and …

Rapid High-Sensitivity Detection Of Antibodies To Trypanosoma Cruzi With A Recombinant Tc24 Antigen-Based Magneto-Immunoassay: A Pilot Study, Kavya L Singampalli, Bin Zhan, Rojelio Mejia, Peter B Lillehoj

Faculty, Staff and Students Publications

The diagnosis of chronic Chagas disease is challenging due to the wide genetic diversity of Trypanosoma cruzi, the causative agent of Chagas disease, and low levels of parasitemia, resulting in low sensitivity and accuracy with existing diagnostics. We report a magneto-immunoassay that employs dually labeled magnetic beads incorporating a recombinant Tc24 antigen, which is homologous across multiple discrete typing units of T cruzi. In this pilot study, 102 serum samples from 7 endemic countries were tested by this magneto-immunoassay, revealing its ability to distinguish Chagas-positive from Chagas-negative cases more accurately and faster than a standard Tc24-based immunoassay.

Impact Of Sanitation System Types On Residential And Environmental Presence Of Human Waste And Parasites In Alabama, Brandon Hunter, Catherine Coleman Flowers, Rojelio Mejia, Marc Arnold Deshusses

Faculty, Staff and Students Publications

Lowndes County is a predominantly Black rural county in Alabama, in the United States, which has a historical and current legacy of racial discrimination, creating inequitable infrastructure access and adverse health impacts. Over 80% rely on on-site sanitation infrastructure and most are failing. A community assessment of exposure to untreated sewage was conducted using samples from residential drinking water, surface swabs, and soil combined with environmental water and soil samples using culture-based and quantitative polymerase chain reaction (qPCR) methods. Testing varied slightly across samples, due to difficulty of access or availability. Of 43 households, 68% and 55% of houses had …

Oral Dosing Of The Nucleoside Analog Obeldesivir Is Efficacious Against Rsv Infection In African Green Monkeys, Jared Pitts, J Lizbeth Reyes Zamora, Savrina Manhas, Thomas Aeschbacher, Josolyn Chan, Vincent Cutillas, Varsha Nair, Nicholas C Riola, Arya Vijjapurapu, Meghan S Vermillion, Stacey Eng, Christopher Richards, Dong Han, Jason K Perry, Subhra Chaudhuri, Szu-Wen Liu, Clarissa Martinez, Nadine Peinovich, Kai-Hui Sun, Arthur Cai, Ross Martin, Jasmine Moshiri, Charlotte Hedskog, Darius Babusis, Dustin S Siegel, Rao Kalla, Vasanthi Avadhanula, Pedro A Piedra, Kim Stobbelaar, Peter L Delputte, Caleb Marceau, Roberto Mateo, Evguenia Maiorova, Hongmei Mo, Raju Subramanian, Richard L Mackman, Tomas Cihlar, Simon P Fletcher, John P Bilello

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20–0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identify a single amino acid substitution, I777L, in the L polymerase with …

The Current And Future Burden Of Long Covid In The United States, Sarah M Bartsch, Kevin L Chin, Ulrich Strych, Danielle C John, Tej D Shah, Maria Elena Bottazzi, Kelly J O'Shea, Mckaylee Robertson, Colleen Weatherwax, Jessie Heneghan, Marie F Martinez, Allan Ciciriello, Sarah Kulkarni, Kavya Velmurugan, Alexis Dibbs, Sheryl A Scannell, Yanhan Shen, Denis Nash, Peter J Hotez, Bruce Y Lee

Faculty, Staff and Students Publications

Background: Long coronavirus disease (COVID), which affects an estimated 44.69-48.04 million people in the United States, is an ongoing public health concern that will persist as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread.

Methods: We developed a computational simulation model representing the clinical course, health effects, and associated costs of a person with long COVID.

Results: Simulations show that the average total cost of a long COVID case can range from $5084-$11 646 (assuming symptoms only last 1 year) with 92.5%-95.2% of these costs being productivity losses. Therefore, the current number of long COVID cases could cost …

Src/Fn1 Pathway Activation Drives Tumor Cell Cluster Formation And Metastasis In Lung Cancer: A Promising Therapeutic Target, Zujun Que, Zhichao Xi, Dan Qi, Rongchen Dai, Yang Li, Mengfan Liu, Bin Luo, Jiajun Liu, Pan Yu, Yun Yang, Erxi Wu, Hongxi Xu, Jianhui Tian

Children’s Nutrition Research Center Staff Publications

Lung cancer remains the leading cause of cancer-related death globally, with metastasis driven by circulating tumor cells (CTCs)-particularly clusters-being a major treatment challenge. Despite their critical role, the biological differences between single CTCs and CTC clusters remain unclear. Here, we comprehensively compared their behavioral, transcriptomic, and proteomic profiles in lung cancer models. Compared with single cells, CTC clusters present enhanced metastatic potential, greater survival in the bloodstream and increased resistance to microenvironment. Mechanistically, the Src/FN1 pathway is centrally activated in clusters, promoting intercellular cohesion and protecting against immune clearance and stress in circulation. Pharmacological inhibition of Src with the clinical …

Savings Associated With Bundled Payments For Outpatient Spine Surgery Among Medicare Beneficiaries, Austin S. Kilaru, Grace Y. Ng, Erkuan Wang, Erin Huang, Aidan P. Crowley, Jingsan Zhu, Joshua M. Liao, Said A. Ibrahim, Torrey Shirk, Deborah S. Cousins, Neil R. Malhotra, Amol S. Navathe

Department of Medicine Faculty Papers

IMPORTANCE: Few value-based payment programs have targeted outpatient surgery, although these procedures comprise most surgeries performed in hospitals. In 2018, the Centers for Medicare and Medicaid Services introduced Bundled Payments for Care Improvement Advanced (BPCI Advanced), the first episode-based payment model to include an outpatient surgical condition-spine surgery. It is not known whether bundled payments reduce spending or improve quality for outpatient surgery, despite plans to expand outpatient episodes in future models.

OBJECTIVE: To determine whether hospital participation in the first year of BPCI Advanced for outpatient and inpatient spine surgery (back and neck except spinal fusion procedures [BNESF]) was …

Molecular Landscape Of Respiratory Infection: A Large-Scale, Multi-Centre Blood Transcriptome Dataset., Tracy Chew, Tiana M Pelaia, Amy L Phu, Sally Teoh, Ya Wang, Nandan Deshpande, Karan Kim, Velma Herwanto, Gunawan, Thomas Karvunidis, Yoann Zerbib, Kirsty R Short, Stephen Macdonald, Irani Thevarajan, Darawan Rinchai, Win Sen Kuan, Ben Knippenberg, Jonathan Iredell, Philip N Britton, Owen Hutchings, Warwick J Britton, John-Sebastian Eden, Sam Orde, Benjamin Tang, Anthony Mclean, Damien Chaussabel, Klaus Schughart, Maryam Shojaei

Faculty Research 2025

Respiratory infections pose significant challenges to global health, impacting millions of individuals annually. Understanding the molecular mechanisms underlying the pathogenicity of these infections is crucial for developing effective interventions. RNA sequencing provides insights into a patient's global transcriptome changes, facilitating the identification of host gene signatures in response to infection and potential therapeutic targets. Here we present an extensive whole blood transcriptome dataset from a demographically diverse cohort of 502 patients with infections including COVID-19, seasonal coronavirus, influenza A or influenza B, sepsis, septic shock, and co-infections (Viral/Viral, Bacterial/Viral, Bacterial/Viral/Fungal, Viral/Fungal, Viral/ Viral/Fungal). The cohort size and depth of data …