Digital Commons Network^™

Systematic Targeting Of Gd2-Positive Neuroblastoma Tumors With A Photooncolytic Phage Nanovector Platform, Suleman Khan Zadran, Nicola Facchinello, Piergiuseppe De Rosa, Roberto Saporetti, Paolo Emidio Costantini, Luca Ulfo, Michela Nigro, Annapaola Petrosino, Lucia Pappagallo, Sara Aloisi, Giorgio Milazzo, Zainul Abe Din, Alberto Rigamonti, Leonardo Flora, Martina Santulli, Leonardo Cimadom, Giampaolo Zuccheri, Mattia Zangoli, Manuele Di Sante, Matteo Di Giosia, Francesca Di Maria, Roberto Bernardoni, Eveline Barbieri, Matteo Calvaresi, Alberto Danielli, Giovanni Perini

Faculty, Staff and Students Publications

Disialoganglioside-GD2 is a key molecular target for Neuroblastoma (NB) immunotherapy based on the employment of GD2-targeting antibodies. However, about 50% of treated patients can experience tumor relapse due to limited immune-mediated cytotoxicity and poor antibody penetration into tumors. To address this problem, a tumor-penetrating photo-oncolytic phage nanovector platform is genetically and chemically developed that selectively targets GD2-expressing NB cells. The phage bioconjugates, functionalized with different photosensitizers, result in specific and selective oncolysis of GD2-positive NB cells upon light irradiation, without affecting GD2-negative ones. The photo-oncolytic phage vectors are shown to deeply penetrate into GD2-positive tumor spheroids in vitro, and to …

Tigit Affects Car Nk-Cell Effector Function In The Solid Tumor Microenvironment By Modulating Immune Synapse Strength, Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar

Faculty, Staff and Students Publications

Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune …

Pfas Exposure And Postoperative Weight Regain In Adolescents After Bariatric Surgery: Findings From The Teen-Labs Study, Brittney O Baumert, Elizabeth Costello, Zhenjiang Li, Justin R Ryder, Thomas Inge, Todd Jenkins, Stephanie Sisley, Stavra A Xanthakos, Douglas I Walker, Nikos Stratakis, Damaskini Valvi, Scott M Bartell, Angela L Slitt, Rohit Kohli, Sarah Rock, Michele A La Merrill, Sandrah P Eckel, Max T Aung, Rob Mcconnell, David V Conti, Lida Chatzi

Faculty, Staff and Students Publications

Objective: Weight regain following bariatric surgery remains a clinical challenge, with limited understanding of contributing environmental factors. Per- and polyfluoroalkyl substances (PFAS), persistent chemicals linked to metabolic dysfunction, may influence long-term weight trajectories. This study aimed to evaluate associations between PFAS exposure and changes in BMI, percent weight loss, and waist circumference among adolescents after bariatric surgery.

Methods: We included 186 adolescents (mean age: 17.1 years; 76.3% female; 72.0% White) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort who underwent surgery between 2007 and 2012. Anthropometric measurements were collected at baseline and 6, 12, 36, and 60 months post …

From Assistance To Autonomy: Evaluating Procedural Competency In Pediatric Emergency Medicine, Richard Barber, Marideth Rus, Elizabeth Moran, Esther M Sampayo, Deborah Hsu, Corrie E Chumpitazi, Elizabeth A Camp, Nidhi V Singh

Faculty, Staff and Students Publications

Objective: Pediatric emergency medicine (PEM) physicians require expertise in numerous procedural skills to manage emergencies in children. Fellows require hands-on experience, expert supervision, and standardized feedback to build procedural competency. Our objective was to develop and gather validity evidence for an evaluation tool to assess PEM fellows' ability to perform procedures.

Methods: We conducted a retrospective study of PEM fellows' procedural performance within a children's hospital system. Faculty evaluated fellows using a one-item, five-point entrustment/level of supervision scale. We focused on three frequently performed procedures: laceration repair, intubation, and procedural sedation. To assess changes in supervision scores by training year, …

A Narrative Review Of The Ileal Pouch In Pediatric Inflammatory Bowel Disease And Familial Adenomatous Polyposis, Anitta Philip, Allyson Wyatt, Jose R Rodriguez, Brad Pasternak, Lisa Mcmahon, Kalyani Patel, Richard Kellermayer

Faculty, Staff and Students Publications

Ileal pouch-anal anastomosis is a surgical intervention in patients with medically refractory inflammatory bowel disease and familial adenomatous polyposis syndrome. Reported outcomes in children have been limited by both the retrospective nature and sample size of the investigations. In addition, there is a lack of consensus on surveillance guidelines in this patient population. Delay or lack of surveillance may increase the risk of complications (pouchitis, Crohn's disease-like inflammation, dysplasia, etc.). This narrative review aims to summarize the most recent literature (2013-2023) on short-term, long-term, and quality of life (QoL) outcomes in pediatric ileal pouch (J-pouch) patients. A proposed surveillance guidance …

Aging Affects Lipid Homeostasis In Lacrimal Glands By Upregulating Lipogenesis And Changing Its Specificity, Seher Yuksel, Prashant Kumar, Sydney E Krenz, Kaitlin K Scholand, Zhiyuan Yu, Anastasiia Ivanova, Helen P Makarenkova, Sarah F Hamm-Alvarez, Igor A Butovich, Cintia S De Paiva

Faculty, Staff and Students Publications

Purpose: The lacrimal gland (LG) develops age-related alterations. This study investigated the lipid content of the accumulated secretions within the murine aged LG.

Methods: C57BL/6J animals of different ages (3 months, 12 months, and 20-26 months) were used. Published data of bulk RNA sequencing of aged LGs were used to investigate lipid pathways. Exorbital LGs were excised for histology or PCR. Histologic sections were stained with standard histochemical stains or immunostained using anti-adiponectin, anti-perilipin 2 antibodies, and BODIPY dye. LG lipidomes were investigated using unbiased, untargeted high-resolution liquid chromatography/mass spectrometry (LC/MS), and the data were processed using unbiased, untargeted principal …

Critical Care Of The Adult With Congenital Heart Disease, Christopher W Valle, Amanda C Garfinkel, Jonathan Buber, Anitra W Romfh, Andrea M Elliott, Jonathan N Menachem, Jennifer Nelson, Peter C Laussen, Jane Heggie, Cameron Dezfulian, David Morrow, Anne Marie Valente, American College Of Cardiology Critical Care Cardiology Section And Adult Congenital And Pediatric Cardiology Section

Faculty, Staff and Students Publications

Advances in the treatment of congenital heart disease (CHD) have led to dramatic improvements in survival for individuals with CHD. While adults with CHD represent a small percentage of admissions to the intensive care unit (ICU), the critical care needs of this population will grow as this population ages and develops increasingly complex cardiac and noncardiac conditions. Adults with CHD require special care in the ICU because of both their unique cardiovascular conditions and the multi-organ dysfunction that often accompanies their cardiac pathophysiology. This review aims to summarize the current epidemiology of critical care for adults with CHD, describe key …

Protein Kinase Rock1 Activates Mitochondrial Fission Linking To Oxidative Stress And Muscle Atrophy, Meijun Si, Jihong Chen, Rizhen Yu, Hongchun Lin, Feng Li, Sungyun Jung, Sandhya S Thomas, Farhard R Danesh, Yanlin Wang, Hui Peng, Zhaoyong Hu

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is associated with protein-energy wasting, characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of muscle wasting, underlying mechanisms remain unclear.

Methods: Here, we used transcriptomic analysis, metabolomics analyses, and mouse gene manipulation to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting the subtotal nephrectomy mouse models of CKD. The mice with CKD were age- and sex-matched to sham-operated controls.

Results: Through these approaches, Rho-associated kinase ROCK1 emerged as a key molecule responsible for the observed mitochondrial fission and oxidative …

Lac-Phe Induces Hypophagia By Inhibiting Agrp Neurons In Mice, Hailan Liu, Veronica L Li, Qingzhuo Liu, Yao Liu, Cunjin Su, Hueyxian Wong, Na Yin, Hesong Liu, Xing Fang, Kristine M Mcdermott, Hueyzhong Wong, Meng Yu, Longlong Tu, Jonathan C Bean, Yongxiang Li, Mengjie Wang, Yue Deng, Yuhan Shi, Olivia Z Ginnard, Yuxue Yang, Junying Han, Megan E Burt, Sanika V Jossy, Chunmei Wang, Yongjie Yang, Benjamin R Arenkiel, Dong Kong, Yang He, Jonathan Z Long, Yong Xu

Faculty, Staff and Students Publications

Lactate-derived N-lactoyl-phenylalanine (Lac-Phe) was recently identified as an lactate-derived circulating metabolite that reduces feeding and obesity, but mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we demonstrated that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH). We also found that both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Further, we show that Lac-Phe inhibits AgRP neurons via activating the ATP-sensitive potassium (KATP) channel, and inhibition of the KATP channel blunts effects of Lac-Phe to suppress …

High Prevalence Of Abnormal Baseline Lung Function In Pediatric And Young Adult Hematopoietic Stem Cell Transplant Recipients: A Report From The Transpire Study, Jane Koo, Richard Cooper, Stephanie L Edwards, Adam Lane, Sara Katherine Loveless, Lauren Strecker, Kelly E Lake, Kasiani C Myers, Christopher Towe, Jessica Patti, Laura L Walkup, Kathryn A Wikenheiser-Brokamp, Margaret L Macmillan, Philip Lacher, Tamara Griffin, Merve Tekman, Gabriel Salinas Cisneros, Kevin Wu, Matthew S Zinter, Fernando A Urrego, K Scott Baker, Matthew F Abts, Sheri Ballard, Jason L Freedman, Alexander Caraballo, Lisa R Young, Maureen B Josephson, Julian L Allen, Devaney M Camburn, Erin E Doherty, Mashid Sababi Azamian, Martha Arredondo, Manuel Silva-Carmona, Leslie E Lehmann, Wai Wong, Jonathan M Gaffin, William Mcalpine, Mona Li, Samuel B Goldfarb, Jason C Woods, Stella M Davies

Faculty, Staff and Students Publications

Background: Pulmonary complications are a major cause of morbidity and mortality in pediatric and young adult hematopoietic stem cell transplant (HSCT) recipients. The impact of preexisting lung dysfunction on posttransplant outcomes remains understudied.

Methods: In a multi-institutional prospective cohort of 444 patients (≤24 years) undergoing allogeneic HSCT at eight centers, baseline lung function was categorized as normal or abnormal using clinical history, imaging, pulmonary function tests (PFTs), and pulmonologist review. Spirometry and diffusion capacity were assessed at baseline, Day 100, 1 year, and 2 years post-HSCT.

Results: Baseline pulmonary dysfunction was present in 224 patients (50.4%), including impaired spirometry (46.4%), …

Effects Of The Kcnq (Kv7) Channel Opener Ezogabine On Resting-State Functional Connectivity Of Striatal Brain Reward Regions, Depression, And Anhedonia In Major Depressive Disorder: Results From A Randomized Controlled Trial, Avijit Chowdhury, Sarah Boukezzi, Sara Costi, Sara Hameed, Yael Jacob, Ramiro Salas, Dan V Iosifescu, Ming-Hu Han, Alan Swann, Sanjay J Mathew, Laurel Morris, James W Murrough

Faculty, Staff and Students Publications

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests that targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state functional connectivity (RSFC) of the brain's reward circuitry and alleviate depressive symptoms, including anhedonia, a core feature of MDD.

Methods: A double-blind, randomized, placebo-controlled clinical trial in individuals with MDD ages 18 to 65 years compared daily dosing with ezogabine (n= 19) with placebo (n …

Exploring The Transformative Effects Of Calorie Restriction On The Lacrimal Gland In Adult Mice, Olivier Mauduit, Prashant Kumar, Kaitlin K Scholand, Emre Aksan, Laura Schaefer, Anmar Abu-Romman, Vanessa Delcroix, Zhiyuan Yu, Aude I Sindikubwabo, Ron Korstanje, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Advanced age is one of the most recognizable risk factors for dry eye. Dry eye disease affects millions worldwide and can result from age-related lacrimal gland dysfunction, which correlates with a decline in lacrimal gland secretory cell function and chronic inflammation. This study investigated the potential of calorie restriction to maintain lacrimal gland and ocular surface health. Adult female C57BL/6 J mice were subjected to a 40% calorie restriction for 4 months, starting at 6-7 months and continuing until 10-11 months. These mice were compared to controls fed ad libitum. Bulk RNA sequencing of lacrimal glands, conjunctiva, and cornea subjected …

Plasma Proteome Correlations With Liver Stiffness In Pediatric Cholestasis Implicate Epithelial To Mesenchymal Transition, Benjamin L Shneider, Rupa S Kanchi, Sandra L Grimm, Sridevi Devaraj, Juliet Emamaullee, Jeremy Schraw, Philip J Lupo, Jorge A Bezerra, Kathleen M Loomes, John C Magee, Ronald J Sokol, Kasper S Wang, Alyssa Kriegmeier, Evelyn Hsu, Jean P Molleston, Philip Rosenthal, Rohit Kohli, Saul J Karpen, Simon P Horslen, M Kyle Jensen, Arianna Barbetta, Cristian Coarfa

Faculty, Staff and Students Publications

Background: Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM).

Methods: Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken.

Results: There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was …

Cookie-Pro: Covalent Inhibitor Binding Kinetics Profiling On The Proteome Scale, Hanfeng Lin, Bin Yang, Lang Ding, Yen-Yu Yang, Matthew V Holt, Sung Yun Jung, Bing Zhang, Meng C Wang, Jin Wang

Faculty, Staff and Students Publications

Covalent inhibitors are an emerging class of therapeutics, but methods to comprehensively profile their binding kinetics and selectivity across the proteome have been limited. Here we introduce COOKIE-Pro (COvalent Occupancy KInetic Enrichment via Proteomics), an unbiased method for quantifying irreversible covalent inhibitor binding kinetics on a proteome-wide scale. COOKIE-Pro uses a two-step incubation process with mass spectrometry-based proteomics to determine kinact and KI values for covalent inhibitors against both on-target and off-target proteins. We validated COOKIE-Pro using BTK inhibitors spebrutinib and ibrutinib, accurately reproducing known kinetic parameters and identifying both expected and unreported off-targets. The method revealed that …

Observational Activation Of Anterior Cingulate Cortical Neurons Coordinates Hippocampal Replay In Social Learning, Xiang Mou, Daoyun Ji

Faculty, Staff and Students Publications

Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are reactivated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during …

Cyp1b1 Mediates Cigarette Smoke-Induced Lipid Accumulation In Alveolar Type 2 Cells, Yin Zhu, Siddhika Gamare, Francesca Polverino, Caroline A Owen, Payaningal R Somanath, Xiaoyun Wang, Duo Zhang

Faculty, Staff and Students Publications

Alterations in lipid profiles have been shown in patients with chronic obstructive pulmonary disease (COPD), but the underlying molecular mechanisms remain unclear. In this study, we aimed to investigate the role of cytochrome P450 family-1 subfamily B member 1 (CYP1B1) in cigarette smoke (CS)-induced lipid accumulation in alveolar type II epithelial (AT2) cells. We observed a steady increase in CYP1B1 protein levels in AT2 cells from COPD patients. Additionally, CS exposure induced CYP1B1 expression in AT2 cells of murine lungs. In vitro, treatment with cigarette smoke extract (CSE) not only upregulated CYP1B1 expression but also triggered lipid accumulation in AT2-like …

Engineered Exosomes With Krasg12d Specific Sirna In Pancreatic Cancer: A Phase I Study With Immunological Correlates, Valerie S Kalluri, Brandon G Smaglo, Krishnan K Mahadevan, Michelle L Kirtley, Kathleen M Mcandrews, Mayela Mendt, Sujuan Yang, Ana S Maldonado, Hikaru Sugimoto, Maria E Salvatierra, Luisa M Solis Soto, Cara Haymaker, Rick Finch, Mihai Gagea, Adam C Fluty, Steven J Ludtke, J Jack Lee, Abhinav K Jain, Gauri Varadhachary, Rachna T Shroff, Anirban Maitra, Elizabeth Shpall, Shubham Pant, Raghu Kalluri

Faculty, Staff and Students Publications

Oncogenic KRAS is amongst the key genetic drivers for initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) reveal a biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKrasG12D in the iEXPLORE (iExoKrasG12D in Pancreatic Cancer) Phase I study employed a non-randomized single-arm classical 3 + 3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (NCT03608631). The primary outcomes included safety, tolerability and target engagement, and the secondary outcomes aimed to assess disease control. …

Clinically Significant Neuroimaging Findings Among Pediatric Patients Presenting To The Emergency Department With Symptoms Of Psychosis: A Multicenter Retrospective Study, Jennifer A Hoffmann, Tapan K Parikh, Doug Lorenz, Michael P Goldman, Emily M Powers, Shilpa J Patel, Ilana S Lavina, Theodore W Heyming, Jasmin T England, Mohsen Saidinejad, Ilene Claudius, Pallavi Ghosh, Daniel J Shapiro, Tricia B Swan, Kamali L Bouvay, Eileen Murtagh Kurowski, Nadine M Smith, Justin R Davis, Alexander B Moxam, Eli J Muhrer, Rohit P Shenoi, Elyse N Portillo, Ron L Kaplan, Neil G Uspal, Robert M Lapus, Andrea T Vo, Daniel B Fenster, Danielle B Barrocas, Deborah R Liu, Pradip P Chaudhari, Rachel Cafferty, Stephen B Freedman, Jerri A Rose, Megan F Evers, Ashley M Metcalf, Fareed Saleh, Jennifer Dunnick, Raymond D Pitetti, Yashas R Nathani, Muhammad Waseem, Todd A Florin

Faculty, Staff and Students Publications

Background: The clinical utility of diagnostic neuroimaging for pediatric patients presenting to the emergency department (ED) for psychosis remains unclear. We sought to estimate the prevalence of and characteristics associated with clinically significant neuroimaging findings among pediatric patients presenting to the ED with symptoms of psychosis who had neuroimaging performed.

Methods: This retrospective cross-sectional study included visits by patients 5 to < 18 years old presenting with symptoms of psychosis to 28 EDs affiliated with the Pediatric Emergency Medicine Collaborative Research Committee from 2016 to 2019 and had neuroimaging performed. We estimated the rate of clinically significant neuroimaging findings, defined as those resulting in further testing, treatment, or medical admission, overall and by imaging modality. Multivariable logistic regression models examined presenting features associated with clinically significant findings.

Results: Clinically significant neuroimaging findings were identified in 5.4% (95% CI 4.2%, 6.9%) of 1118 ED visits (54% male, median [IQR] 14 [11-16] years old). Clinically significant findings occurred in 4.9% (34/699) of head computed tomography scans and 7.5% …

Distinct Intrinsic And Extrinsic Factors Differentially Regulate Skeletal Stem Cells In Calvaria Versus Long Bones During Bone Regeneration, Jea Solidum, Kohei Yamasaki, Youngjae Jeong, Laura Ortinau, Francisco Heralde, Dongsu Park

Faculty, Staff and Students Publications

Calvarial suture skeletal stem cells (Su-SSCs) are a distinct stem cell population for craniofacial bone formation by intramembranous ossification, compared to long bone periosteal SSCs (LB-PSSCs) with endochondral (osteochondrogenic) ossification. However, whether SSC intrinsic or extrinsic factors affect their differentiation process has not been well elucidated. Here, using an inducible Prx1-CreER-EGFP+/−;Rosa26-tdTomato mouse model, we observed that endogenous Prx1+ Su-SSCs and their orthotopic transplantation into calvarial injury do not form cartilage intermediates at the injury sites, while the transplantation of Prx1+ LB-PSSCs into LB injury induces osteochondrogenic differentiation, respectively. However, the heterotopic transplantation of Prx1+ Su-SSCs (Su-SSCs …

A Novel Self-Inhaled Nicotine Exposure System In Murine Models Reveals Age-Dependent Metabolic Effects Of Nicotine, Xu Xu, Hailan Liu, Meng Yu, Qingzhuo Liu, Yongxiang Li, Yue Deng, Yuxue Yang, Jingjing Cheng, Yutian Liu, Mengjie Wang, Xing Fang, Longlong Tu, Olivia Z Ginnard, Kristine M Mcdermott, Darah Threat, Fuhui Wang, Meixin Sun, Xinming Liu, Jiamin Qiu, Xi Wu, Jinjing Jian, Tong Zhou, Megan E Burt, Sanika V Jossy, Junying Han, Chunmei Wang, Yongjie Yang, Yong Xu, Yuhan Shi

Faculty, Staff and Students Publications

Background: Nicotine is known to influence metabolism and body weight, yet existing murine models of nicotine exposure often fail to replicate human smoking behaviors accurately. To address this gap, we designed a cost-effective, self-administered nicotine inhalation system that allows mice to voluntarily inhale nicotine vapor generated from e-liquid.

Results: Using this system, we investigated the metabolic effects of nicotine exposure in adult and adolescent mice. Adult mice exposed to nicotine vapor for 10 days exhibited significant weight loss, which was rapidly regained upon cessation, paralleling human smoking patterns. In contrast, adolescent mice did not lose weight during nicotine exposure but …

Smarcal1 Is A New Osteosarcoma Predisposition Gene, Maryam Rafati, Lillian M Guenther, Laura E Egolf, D Matthew Gianferante, Jung Kim, Kevin Wang, Bin Zhu, Logan G Spector, Nathan Anderson, Katherine A Janeway, Donald A Barkauskas, Douglas S Hawkins, Ana Patiño-Garcia, Philip J Lupo, Michael E Scheurer, Lindsay Morton, Gregory T Armstrong, Yadav Sapkota, M Monica Gramatges, Massimo Serra, Claudia Hattinger, Katia Scotlandi, Irene L Andrulis, Jay S Wunder, Mandy L Ballinger, David M Thomas, Meredith Yeager, Michael Dean, Douglas R Stewart, Aurelie Vogt, Jia Liu, Belynda D Hicks, Wen-Yi Huang, Maria Teresa Landi, Adriana Lori, W Ryan Diver, Sharon A Savage, Stephen J Chanock, Lisa Mirabello

Faculty, Staff and Students Publications

Osteosarcoma, the most common childhood bone tumor, can occur in rare cancer predisposition syndromes; however, most cases are sporadic with no known predisposing factors. We investigated the frequency of SMARCAL1 putative pathogenic variants in our large ongoing study of 2,119 osteosarcoma cases, their relation to patient characteristics, and the population prevalence. Our analysis uncovered a higher frequency of SMARCAL1 pathogenic variants across three osteosarcoma case sets (1.8%, n = 2,119) than in 2,625 comparably sequenced cancer-free controls (0.3%; P <  .001). Cases with SMARCAL1 pathogenic variants had significantly improved overall survival compared to cases without these variants (hazard ratio 0.36, 95% CI 0.14-0.96, P = .034). In the UK Biobank (469,557 exomes), there was a 33-fold increased risk of osteosarcoma in individuals with SMARCAL1 pathogenic variants. These results identify SMARCAL1 as a new osteosarcoma predisposition gene and thus warrant follow-up to identify the mechanisms by which SMARCAL1 contributes to the etiology of osteosarcoma.

Lysosomes Signal Through The Epigenome To Regulate Longevity Across Generations, Qinghao Zhang, Weiwei Dang, Meng C Wang

Faculty, Staff and Students Publications

The epigenome is sensitive to metabolic inputs and crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We find that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic-target-of-rapamycin (mTOR) signaling increased expression of a histone H3.3 variant and increased its methylation on K79, leading to lifespan extension across multiple generations. This transgenerational pro-longevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase, and was recapitulated by …

Pediatric Heart Failure: A Practical Guide For Primary Care Providers Supporting Families Across The Care Continuum, Shahnawaz Amdani, Kriti Puri, Julie Glickstein, Joseph A Spinner, Jonathan N Johnson, Ashraf S Harahsheh, Majd Makhoul, Susan Denfield

Faculty, Staff and Students Publications

Background/Objectives: Pediatric heart failure (HF) is a complex clinical syndrome with diverse etiologies and presentations. Primary care providers (PCPs) are critical in early recognition, family education, and coordination of ongoing care in collaboration with pediatric cardiologists. This review provides a comprehensive guide for PCPs to understand the causes, symptoms, treatments, and longitudinal considerations for children with HF.

Methods: We conducted a narrative review synthesizing published evidence and expert consensus guidelines, focusing on the clinical presentation, treatment options, and longitudinal care strategies in children with HF.

Results: HF in children most commonly results from congenital heart disease and …

Lung Nr3c1+ And Cxcr6high T Cells Distinguish Immunopathogenesis Of Human Emphysema, Yun Zhang, Maor Sauler, David B Corry, Scott A Ochsner, Sarah Perusich, Li-Zhen Song, Joshua Malo, Raul San Jose Estepar, Francesca Polverino, Farrah Kheradmand

Faculty, Staff and Students Publications

There is a significant knowledge gap in how T cells promote emphysema in smokers with chronic obstructive pulmonary disease (COPD). Single-cell RNA sequencing (scRNA seq) analysis of human samples and relevant clinical data can provide new mechanistic insights into disease pathogenesis. We generated a human lung scRNA seq dataset with extensive disease characteristic annotation and analyzed a second independent scRNA seq dataset to examine the pathophysiological role of T cells in emphysema. Comparisons of pulmonary immune landscapes in emphysematous (E)-COPD, non-emphysematous (NE)-COPD, and control showed positive enrichment of T cells in E-COPD. Pathway analyses identified upregulated inflammatory states in CD4 …

Biologic Management In Severe Asthma For Adults: An American College Of Chest Physicians Clinical Practice Guideline, Amber J Oberle, Farrukh Abbas, Muhammad Adrish, Ioana Agache, Megan Conroy, Angel Coz, Frederic F Little, Manoj J Mammen, Mahesh Padukudru Anand, Raju Reddy, Neha Solanki, Fernando Holguin

Faculty, Staff and Students Publications

Background: Severe asthma affects 5% to 10% of asthma patients but constitutes close to one-half of the medical costs related to asthma due to higher morbidity and health care utilization. Biologic agents have become a standard of care in those unresponsive to standard treatments yet the choice of biologic agent is complex due to the varying mechanisms of action, efficacies, and lack of head-to-head comparisons. Therefore, clinicians need further clinical guidance to optimize their use.

Study design and methods: Panelists developed key clinical questions utilizing the PICO (population, intervention, comparator, and outcome) format to address choice of a biologic agent …

Sars-Cov-2 Nsp13 Interacts With Tead To Suppress Hippo-Yap Signaling, Fansen Meng, Jong Hwan Kim, Chang-Ru Tsai, Jeffrey D Steimle, Jun Wang, Yufeng Shi, Rich G Li, Bing Xie, Vaibhav Deshmukh, Shijie Liu, Xiao Li, James F Martin

Faculty, Staff and Students Publications

The Hippo pathway controls organ development, homeostasis, and regeneration primarily by modulating YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it is largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and SARS-CoV-2-infected human lung samples, and observed a decrease in YAP target gene expression. In screening SARS-CoV-2 nonstructural proteins, we found that nonstructural protein 13 (NSP13), a conserved coronavirus helicase, inhibits YAP transcriptional activity independent of the upstream Hippo kinases LATS1/2. Consistently, introducing NSP13 into mouse cardiomyocytes suppresses …

Understanding Cancer Survivorship Care Needs Using Amazon Reviews: Content Analysis, Algorithm Development, And Validation Study, Liwei Wang, Qiuhao Lu, Rui Li, Taylor B Harrison, Heling Jia, Ming Huang, Heidi Dowst, Rui Zhang, Hoda Badr, Jungwei W Fan, Hongfang Liu

Faculty, Staff and Students Publications

Background: Complementary therapies are being increasingly used by cancer survivors. As a channel for customers to share their feelings, outcomes, and perceived knowledge about the products purchased from e-commerce platforms, Amazon consumer reviews are a valuable real-world data source for understanding cancer survivorship care needs.

Objective: In this study, we aimed to highlight the potential of using Amazon consumer reviews as a novel source for identifying cancer survivorship care needs, particularly related to symptom self-management. Specifically, we present a publicly available, manually annotated corpus derived from Amazon reviews of health-related products and develop baseline natural language processing models using deep …

Disparities In Liver Transplantation For Metabolic Dysfunction-Associated Steatohepatitis-Associated Hepatocellular Carcinoma, David W Victor, Sudha Kodali, Mazen Noureddin, Elizabeth W Brombosz, Analisa Lopez, Tamneet Basra, Edward A Graviss, Duc T Nguyen, Ashish Saharia, Ashton A Connor, Maen Abdelrahim, Yee Lee Cheah, Caroline J Simon, Mark J Hobeika, Constance M Mobley, R Mark Ghobrial

Faculty, Staff and Students Publications

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly common, as is hepatocellular carcinoma (HCC) in the background of MASH. Liver transplantation (LT) provides superior long-term survival for patients with unresectable MASH-HCC, but not all patients have equal access to transplant. MASH-HCC disproportionately affects Hispanic patients, but minorities are less likely to undergo LT for HCC. Additionally, females also undergo LT at lower rates than males.

Aim: To investigate whether race/ethnicity and sex affect LT waitlist outcomes.

Methods: Records of adults with MASH-HCC in the United States Organ Procurement and Transplantation Network database listed for LT between 1/2015 and 12/2021 were analyzed. …

Galntl5 Binds Galnac And Is Required For Migration Through The Uterotubal Junction And Sperm-Zona Pellucida Binding, Taichi Noda, Reika Uriu, Daisuke Mashiko, Hina Shinohara, Yongcun Qu, Ayumu Taira, Ryan M Matzuk, Duri Tahala, Motochika Nakano, Kimi Araki, Zhifeng Yu, Ying Zhang, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Objective: To review the global impact of the COVID-19 pandemic on stroke care-metrics and report data from a health system in Houston.

Methods: We performed a meta-analysis of the published literature reporting stroke admissions, intracerebral hemorrhage (ICH) cases, number of thrombolysis (tPA) and thrombectomy (MT) cases, and time metrics (door to needle, DTN; and door to groin time, DTG) during the pandemic compared to prepandemic period. Within our hospital system, between January-June 2019 and January-June 2020, we compared the proportion of stroke admissions and door to tPA and MT times.

Results: A total of 32,640 stroke admissions from 29 studies …

Galntl5 Binds Galnac And Is Required For Migration Through The Uterotubal Junction And Sperm-Zona Pellucida Binding, Taichi Noda, Reika Uriu, Daisuke Mashiko, Hina Shinohara, Yongcun Qu, Ayumu Taira, Ryan M Matzuk, Duri Tahala, Motochika Nakano, Kimi Araki, Zhifeng Yu, Ying Zhang, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

More than 20 genes expressed in the male reproductive tract have been identified as essential factors for sperm migration to and through the utero-tubal junction (UTJ), and they are divided into ADAM3-dependent and ADAM3-independent pathways. In parallel, sperm having UTJ migration defects also show impaired binding to the zona pellucida (ZP). Herein, we demonstrate that knockout of Galntl5, encoding a sperm surface protein, causes impaired sperm binding with the UTJ and ZP, and null males have severe infertility. GALNTL5 appreciably disappears in sperm lacking Adam3 or Lypd4, required for ADAM3-dependent and ADAM3-independent pathways, and GALNTL5 binds to N …