Medicine and Health Sciences Commons^™

Global, Regional, And National Burden Of Cardiovascular Diseases And Risk Factors In 204 Countries And Territories, 1990-2023, Global Burden Of Cardiovascular Diseases And Risks 2023 Collaborators, Mohammadreza Abbasian

Department of Orthopaedic Surgery Faculty Papers

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of mortality and are among the foremost causes of disability globally. CVD burden has continued to increase in most countries since 1990, with trends driven by changing exposures to harmful risk factors, population growth, and population aging.

OBJECTIVES: We report estimates of global, national, and subnational CVD burden, including 18 subdiseases and 12 associated modifiable risk factors. We analyzed change in CVD burden from 1990 to 2023 and identified drivers of change including population growth, population aging, and risk factor exposure.

METHODS: The Global Burden of Disease (GBD) 2023 study, a multinational …

Refractory Cutaneous Symptoms In Systemic Mastocytosis, Laura Gleason, Safiyyah Bhatti, Molly Wallace, Jason B. Lee, Onder Alpdogan, Neda Nikbakht

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Association Of Genetic Scores Related To Insulin Resistance With Neurological Outcomes In Ancestrally Diverse Cohorts From The Trans-Omics For Precision Medicine (Topmed) Program, Chloé Sarnowski, Yixin Zhang, Farah Ammous, Lincoln M P Shade, Daniel Dicorpo, Xueqiu Jian, Donna K Arnett, Thomas R Austin, Alexa Beiser, Joshua C Bis, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Charles S Decarli, Harsha Doddapaneni, Josée Dupuis, David W Fardo, Jose C Florez, Stacey Gabriel, Richard A Gibbs, David C Glahn, Namrata Gupta, Hector M González, Kevin A González, Konstantinos Hatzikotoulas, Kathleen M Hayden, Susan R Heckbert, Bertha Hidalgo, Alicia Huerta-Chagoya, Timothy M Hughes, Sharon L R Kardia, Charles L Kooperberg, Lenore J Launer, W T Longstreth, Ravi Mandla, Rasika A Mathias, Andrew P Morris, Thomas H Mosley, Ilya M Nasrallah, Paul Nyquist, Bruce M Psaty, Qibin Qi, Laura M Raffield, Nigel W Rayner, Alexander P Reiner, Claudia L Satizabal, Elizabeth Selvin, Magdalena D R Sevilla-Gonzalez, Albert V Smith, Jennifer A Smith, Kirk Smith, Beverly M Snively, Lorraine Southam, Tamar Sofer, Ken Suzuki, Henry J Taylor, Miriam S Udler, Karine A Viaud-Martinez, Sylvia Wassertheil-Smoller, Alexis C Wood, Lisa R Yanek, Xianyong Yin, Alisa K Manning, Jerome I Rotter, Stephen S Rich, James B Meigs, Myriam Fornage, Sudha Seshadri, Alanna C Morrison, Topmed Neurocognitive Working Group, Topmed Diabetes Working Group

The Brown Foundation: Institute of Molecular Medicine

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P <  0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P <  0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.

Poziotinib For Egfr Exon 20-Insertion Nsclc: Clinical Efficacy Of The Phase 2 Zenith Trial And Differential Impact Of Egfr Exon 20 Insertion Location On Sensitivity, Xiuning Le, Jacqulyne P Robichaux, Monique Nilsson, R S K Vijayan, Ashwin Ravichandran, Jia Wu, Yasir Y Elamin, Lingzhi Hong, Jun Pei, Jun He, Sonia Patel, Hibiki Udagawa, Sriramvignesh Mani, Chang Woon Jang, Jeffrey M Clarke, Nishan Tchekmedyian, Jonathan W Goldman, Mark Socinski, Gajanan Bhat, Sharon Leu, Veronica Bunn, Zhenqiang Su, Sylvie Vincent, John W Lawson, Jason B Cross, John V Heymach

Faculty, Staff and Student Publications

EGFRex20 insertions (EGFRex20ins) can be classified as near- and far-loop based on the insertion location, however, the impact of location on responses to various EGFR tyrosine kinase inhibitors (TKIs) is poorly understood. In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. Molecular dynamics simulations reveal that near-loop insertions have multiple conformational states and lower transitional energy than far-loop insertions. ZENITH20 trial cohort 1 (NCT03318939) evaluates poziotinib in EGFRex20 NSCLC patients (n = 115) and demonstrates an objective response rate of 14.8% (95% Confidence …

Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells In The Aging Kidney: Secondary Results Of A Parkinson’S Disease Clinical Trial, Juan D Martinez-Lemus, Donald A Molony, Jessika Suescun, Emily Tharp, Tia S Thomas, Charles Green, Chiamaka Onuigbo, Robert Ritter, Mya C Schiess

Faculty, Staff and Student Publications

Background: Kidney function declines with age, largely due to chronic low-grade inflammation. Mesenchymal stem cells (MSCs) have demonstrated immunomodulatory effects in certain immune-mediated kidney diseases, but their role in preserving renal function in aging individuals without chronic kidney disease (CKD) remains unclear. This study presents secondary outcome findings from a randomized clinical trial in Parkinson's disease (PD), evaluating the impact of allogeneic human bone marrow-derived MSCs (allo-hMSCs) on kidney function in an aging population with PD with preserved renal function.

Methods: Subjects with PD aged 50-79 years with baseline estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 were randomized to …

Associations Between Adhering To 24-Hour Movement Guidelines And Anxiety Among Adolescents Across Intersectional Identities: Kyrbs 2020-2022., Suryeon Ryu, Eun Young Lee, Zan Gao

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Identifying preventive measures for adolescent mental health is a global public health priority, as poor mental health heightens the risk of early death from related issues, including suicide. This study examined the associations between adherence to the 24-Hour Movement Guidelines and anxiety among a nationally representative sample of South Korean adolescents, using an intersectional identity framework.

METHODS: Data from the 2020-2022 Korea Youth Risk Behavior Surveys were analyzed. Adolescents aged 12-17 years were grouped based on adherence to guidelines: none, physical activity (PA), sedentary behavior (SB), sleep, two guideline combinations, and all three. Anxiety was the mental health outcome. …

Fetal Congenital Complete Heart Block: 2 Success Stories Through Multidisciplinary Care., Mohamed Aashiq Abdul Ghayum, Jenna Schermerhorn, Hayley S. Hancock, Lindsey Malloy-Walton, Steven Olsen, Laura Vricella, Kelsey Brattrud, Melanie Kathol, Rita France, Maria Kiaffas

Manuscripts, Articles, Book Chapters and Other Papers

Congenital complete heart block (CCHB) is a rare condition associated with significant fetal and neonatal mortality. It may present as an isolated conduction abnormality in association with autoimmune disease, or in conjunction with congenital heart defects including heterotaxy-polysplenia syndrome. Early prenatal diagnosis and coordinated perinatal care are critical for improving outcomes. We present 2 cases of prenatally diagnosed CCHB. The first occurred in a fetus with heterotaxy-polysplenia syndrome, and the second in the setting of maternal anti-SSA antibody exposure. Both fetuses developed progressive bradycardia, with heart rates declining to < 50 beats/min, necessitating close fetal surveillance and individualized perinatal management. Preterm delivery and prompt placement of temporary pacing wires allowed initial stabilization before eventual definitive management, resulting in survival. The successful outcomes in these neonates highlight the critical role of multidisciplinary prenatal care, timely delivery planning, and early postnatal intervention in improving survival in fetuses diagnosed with CCHB.

Association Of Genetic Scores Related To Insulin Resistance With Neurological Outcomes In Ancestrally Diverse Cohorts From The Trans-Omics For Precision Medicine (Topmed) Program, Chloé Sarnowski, Yixin Zhang, Farah Ammous, Lincoln M. P. Shade, Daniel Dicorpo, Xueqiu Jian, Donna K. Arnett, Thomas R. Austin, John Blangero, Joanne E. Curran

School of Medicine Publications

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P <  0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P <  0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.

Site-1 Protease Is A Negative Regulator Of Sarcolipin Promoter Activity, Isha Sharma, Meredith O Kelly, Katelyn Hanners, Ella S Shin, Muhammad G Mousa, Shelby Ek, Gretchen A Meyer, Rita T Brookheart

2020-Current year OA Pubs

The timed contraction and relaxation of myofibers in tissues such as the heart and skeletal muscle occur via the tightly regulated movement of calcium ions into and out of the sarcoplasmic reticulum (SR). In skeletal muscle, this phenomenon enables humans to exercise, perform day-to-day tasks, and to breathe. Sarcolipin, a small regulatory protein, prevents calcium ions from entering the SR by binding to and inhibiting SERCA, contributing to myofiber contraction. Disruptions in sarcolipin (SLN) expression are implicated in the pathophysiology of obesity and musculoskeletal disease. However, the mechanisms regulating sarcolipin expression are not clearly understood. We recently showed that site-1 …

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 …

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 …

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 …

The Microenvironment Of Ocular Surface In Keratoconus: A Systematic Review, Sana Niazi, Farideh Doroodgar, Stephen Pflugfelder, Kia Bayat, Seyed-Farzad Mohammadi, Maedeh Mazloomi, Jorge L Alió Del Barrio, Majid Moshirfar, Jorge L Alió

Faculty, Staff and Students Publications

Purpose: Keratoconus is a progressive corneal ectatic disorder characterized by thinning and irregularity of the cornea, significantly impairing visual acuity. Recent studies have explored how non-ectatic conditions, such as dry eye and tear film instability and alteration of the ocular surface microenvironment, contribute to the development and progression of keratoconus. This comprehensive review aims to investigate the complex relationship between keratoconus and ocular surface diseases by examining the microenvironmental changes that occur on the ocular surface throughout the course of keratoconus, as well as the related clinical implications.

Methods: In this PROSPERO-registered study (ID: CRD42025643808), PubMed, Scopus, Cochrane, Embase, Web …

Monitoring The Hematologic Markers In Patients Undergoing Single-Stage Exchange Arthroplasty For Periprosthetic Joint Infection, Wenbo Mu, Juan D. Lizcano, Boyong Xu, Wentao Guo, Abudousaimi Aimaiti, Xiaogang Zhang, Javad Parvizi, Li Cao

Rothman Institute Papers

BACKGROUND: Periprosthetic joint infection (PJI) is a serious complication that necessitates a complex treatment strategy. Single-stage exchange arthroplasty, combined with intravenous and intra-articular antibiotic infusions, has shown high efficacy in treating complex PJIs. However, the impact of this approach on hematologic parameters remains underexplored. This study aims to evaluate the postoperative trends in blood platelet count, white blood cell (WBC) count, and neutrophil count in patients undergoing single-stage exchange arthroplasty.

METHODS: A retrospective analysis was conducted on 313 patients who underwent single-stage revision for PJI between June 2010 and October 2022. Hematologic parameters were monitored for the first seven postoperative …

Low Unintended Dural Puncture Rate Using A Flush-Measure-Check-Advance Technique To Perform Combined Spinal-Epidural Anesthesia In Parturients: A Quality Improvement Clinical Series, James Riopelle, Julie Gayle, Zubaer Anwar, Jeff Burton

School of Medicine Faculty Publications

Background: Reported rates of unintended dural puncture during performance of continuous epidural anesthesia (CEA) or combined spinal-epidural anesthesia (CSEA) have remained steady at approximately 0.5% to 1% since the 1970s. Methods: A modified method of inserting the Tuohy epidural catheterization needle was used during performance of CSEA in 393 parturients. A single staff/faculty anesthesiologist performed or supervised resident use of a flush-measure-check-advance Tuohy needle insertion algorithm. Results: The rate of evident Tuohy needle dural puncture during the series was 0%. One parturient experienced a post-dural puncture headache possibly because of intentional subarachnoid puncture with a very small diameter (25 gauge) …

Practice Patterns In Management Of Low- To Intermediate-Grade Salivary Gland Carcinoma: A Multi-Institutional Study, Mirabelle Sajisevi, Kenny Nguyen, Peter Callas, Andrew Holcomb, Emre Vural, Kyle Davis, Carissa Thomas, John Stein, Ameya Asarkar, Ricardo Aulet, Rebecca Bell, Michael Blasco, Vanessa Bowmaster, Clayton Burruss, Jeffson Chung, Kimberly Chan, Brent Chang, Charles Coffey, David Cognetti, Dylan Cooper, Joehassin Cordero, John Donovan, Yue Jennifer Du, Yusuf Dundar, Rogerio Dedivitis, Heather Edwards, Boban Erovic, Antoine Eskander, Philip Feinberg, Emily Garvey, David Goldstein, Joseph Goodman, Rafael Goulart, Neerav Goyal, Stefan Grasl, Jonathan Giurintano, Nikita Gupta, Andy Habib, Trevor Hackman, Jared Hara, Christina Henson, Michael Hinni, Nadia Hua, Stephanie Johnson-Obaseki, Aditya Juloori, Noah Kalman, Alexandra Kejner, Sobia Khaja, Jamie Ku, Arnaud Lambert, Bao Luu, Kelly Magliocca, Luiz Medina Dos Santos, Cara Michael, Brett Miles, Giulianno De Melo, Michael Moore, Gregoire Morand, Kauê Moura, Hesameddin Noroozi, Rusha Patel, Joseph Paydarfar, Karolina Plonowska-Hirschfeld, Nader Sadeghi, Fabrice Savaria, Nicole Schmitt, Justin Shapiro, Timothy Shaver, Sandro Stoeckli, William Stokes, Anita Sulibhavi, Jason Tasoulas, Varun Vendra, Daniel Vinh, Celina Virgen, Neil Woody, Geoffrey Young, Kiran Kakarala, Danny Enepekides, Michael Hier, Louise Davies, William Ryan

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVES: To characterize practice patterns and outcomes in the management of low- and intermediate-grade salivary gland carcinoma prior to the existence of treatment guidelines.

METHODS: Analysis of a registry of patients who underwent parotid and submandibular gland resections for low-and intermediate-grade carcinomas between 2010 and 2019.

RESULTS: Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial (n = 384, 53%) or total (n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was …

Mt1-Mmp Inhibition Rejuvenates Ageing Brain And Rescues Cognitive Deficits In Obesity, Pallavi Asthana, Liguo Li, Lin Lu, Jiayan Wu, Shuo Zhang, Ningning Li, Sheung Kin Ken Wong, Susma Gurung, Yijing Zhang, Yuwan Lin, Yufeng Peng, Zongtang Xu, Kui Ming Chan, Lixiang Zhai, Aiping Lyu, Zhao-Xiang Bian, Xin Ge, Ashok Iyaswamy, Min Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong

The Brown Foundation: Institute of Molecular Medicine

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the …

Complete Genome Sequence Of Rothia Mucilaginosa D1, A Genetically Amenable Strain, Hemendra P. Dhaked, Isabella Andonie, Bo Yang, Vinayka M. Joshi, Zezhang T. Wen

School of Dentistry Faculty Publications

Here, we report the complete genome sequence of Rothia mucilaginosa D1. Unlike many other strains that have been sequenced, R. mucilaginosa D1, a clinical isolate, is genetically amenable. The complete sequencing of the genome provides potential for further studies on the genetics and pathophysiology of this emerging pathobiont.

Synthetic Electrospun Fiber Matrix In The Management Of Acute Wounds Following Excision Of Hidradenitis Suppurativa Lesions: A Prospective Pilot Study, Michael Madueke, Frank Lau

School of Medicine Faculty Publications

Hurley Stage II or III hidradenitis suppurativa (HS) may necessitate surgical excision of diseased skin and subcutaneous fat for symptom control and disease management. These excisions result in open wounds in topographically challenging regions and typically cannot be primarily closed. This study evaluates the use of a synthetic electrospun fiber matrix (SEFM) as a post-resection regeneration template to accelerate re-granulation and improve subsequent skin graft incorporation. This prospective pilot study enrolled Hurley Stage II or III patients undergoing surgical resection of HS lesions. SEFM was applied to the resulting wounds in conjunction with negative pressure wound therapy (NPWT). Patients were …

“Not Today”: Overcoming Prep Hesitancy, Stigma, And Adherence Barriers With Lenacapavir, Margaret Conrad, Meredith Clement

School of Medicine Faculty Publications

No abstract provided.

Occupational Health Equity: A Call To Consider Social-Structural Factors In Injury Prevention Research, Shannon Guillot-Wright, Elizabeth S Mcclure, Marizen R Ramirez, Alexis Grimes Trotter, David B Richardson

Faculty, Staff and Student Publications

Occupational health equity scholarship has been growing over the past decade, including social-structural determinants of health research that centres the voices and experiences of historically marginalised communities. In our commentary, we focus on the intersection of work-related and non-work-related factors and how they impact the health of workers, their families and their communities through community-engaged research. Case studies include the implementation of mobile clinics that are developed alongside communities, community organising to examine and reduce health disparities among racially segregated workers, the development of research instruments and measures to study racism and discrimination, and a focus on how the distribution …

Identifying Independent Predictors Of Malignancy In Indeterminate Thyroid Nodules: A Systematic Review, Tirath Patel, Jabez David John, Arnesh Shukla, Ayesha Salma, Dev Patel, Anaya Noor, Gayatri Misra, Pragnesh Kalyandrug, Harshitha Nookala, Nikhilesh Anand

School of Medicine Publications

Introduction: Considering the importance of differentiating between benign and malignant thyroid nodules, this study explores the individual predictors of malignancy. Recent research has focused on individual predictors of isolation, but a comprehensive assessment of these predictors is essential to improve diagnostic accuracy and patient outcomes.

Methods: This comprehensive systematic review included seven articles after a rigorous screening of PubMed, PubMed Central, and MEDLINE databases and thus analyzed 1419 patients with indeterminate thyroid nodules using different determinants, such as genetic, biochemical, clinical, radiological, and cytological.

Results: Numerous independent indicators, such as a history of Hashimoto's thyroiditis, multinodular goiter, and past malignant …

Adsl Deficiency Is A Secondary Mitochondrial Disease Affecting Organelle Homeostasis And Erk2/Akt Signaling In A Linear Genotype-Phenotype Relation, Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi

Duncan NRI Faculty and Staff Publications

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and …

Humanization Of Cd47 Enables Development Of Functional Human Neutrophils Via Postirradiation Remodeling Of The Bone Marrow, Esen Sefik, Liang Shan, Et Al.

2020-Current year OA Pubs

Murine and human immune systems differ significantly, particularly within the myeloid lineage. Humanized mice, generated by transplanting human hematopoietic stem, progenitor cells into genetically modified mice, are invaluable to study human immune development and function in vivo. However, a major limitation of current models is suboptimal myelopoiesis, particularly lack of functional human neutrophils, hampering the modeling of human immune responses and chronic diseases. Here, we describe a humanized mouse model, named MaGIC for genes replaced, in the

Stable Cas9 Expression Regulates Cell Growth By Facilitating Mtorc2 Activation, Le Yu, Yi Jin, Jianfeng Chen, Zhichuan Zhu, Siyuan Su, Emily M Wilkerson, Joanna Gongora, Erica W Cloer, Michael B Major, Pengda Liu

2020-Current year OA Pubs

Clustered regularly interspaced short palindromic repeats (CRISPR), widely used for gene editing, relies on bacterial endonucleases like Cas9 to study gene functions and develop therapies. However, its potential effects on mammalian cellular behavior remain unclear. Here, we systematically profiled effects of stable Cas9 expression on growth of 32 cell lines spanning 9 cancer types and non-cancerous cells, finding growth alterations in a subset. To investigate mechanisms, we established the SpCas9 interactome in DU145 and MDA-MB-231 cells, both showing Cas9-enhanced growth, and identified ribosomal proteins as the top shared interactors. RNA-seq analysis revealed that Cas9 expression in DU145 cells activated PI3K …

Gata2 Mutation Is Associated With Immune Dysfunction And Increased Mycobacterium Haemophilum Susceptibility In Immunocompromised Individuals, Ananya Gupta, Shail B. Mehta, Abhimanyu, Bruce A. Rosa, John Martin, Mushtaq Ahmed, Shyamala Thirunavukkarasu, Farheen Fatma, Gaya K. Amarasinghe, Makedonka Mitreva, Thomas C. Bailey, David B. Clifford, Shabaana A. Khader

2020-Current year OA Pubs

Infections with nontuberculous mycobacterium (NTM) are on the rise. Here, we investigated an uncommon NTM infection, by M. haemophilum (Mh, n = 4), from a shared geographic location in the United States. All patients had underlying immunosuppressive conditions or treatments. We identified that all these individuals had a nonsynonymous mutation in GATA2 gene, which was absent in healthy controls (HCs, n = 4) from the same geographic area (Missouri, USA). Whole blood from these individuals had attenuated cytokine responses to Mh stimulation for IL-1β, IL-6, IL-8, MIP-1α and MIP-1β, but not to phytohemagglutinin (PHA) or another NTM, M. abscessus. Impaired …

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

Department of Medical Oncology Faculty Papers

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 …

Next-Gen Tools In Cancer Neuroscience, Vera Thiel, Debpali Sur, Caroline C Picoli, Tamara Mcerlain, Katalina Couto, David J Simon, Yuan Pan, Karen Olivia Dixon, Rajan P Kulkarni, Sebastien Talbot, Alexander Birbrair

Faculty, Staff and Student Publications

The emerging field of cancer neuroscience is rapidly evolving, driven by novel technologies and tools. These include advances in single-cell and spatial transcriptomics; genetic mouse models paired with automated high-throughput; and innovative optical electrophysiological approaches, optogenetics, chemogenetics, engineered viruses, and new methods for visualizing neuronal activity. Collectively, these technologies are revolutionizing how we investigate, manipulate, and characterize distinct components that contribute to the nervous system-cancer interface. In the present review, we discuss the key technologies that are closing the gap between oncology and neuroscience, highlighting the innovations that are propelling the cancer neuroscience field forward.

Rna/Dna-Binding Protein Tdp43 Regulates Dna Mismatch Repair Genes With Implications For Genome Stability, Vincent E Provasek, Albino Bacolla, Suganya Rangaswamy, Manohar Kodavati, Joy Mitra, Issa O Yusuf, Vikas H Malojirao, Velmarini Vasquez, Gavin W Britz, Guo-Min Li, Zuoshang Xu, Sankar Mitra, Ralph M Garruto, John A Tainer, Muralidhar L Hegde

Faculty, Staff and Student Publications

TDP43 is an RNA/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression …

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 …