Digital Commons Network^™

Maturity-Onset Diabetes Of The Young: A Proposal For Updated Nomenclature, Mustafa Tosur

Faculty, Staff and Students Publications

Given the contemporary understanding of diabetes genetics, the term "maturity-onset diabetes of the young (MODY)" warrants renaming. I propose adopting the term "monogenic diabetes" in conjunction with the specific gene name.

Lenvatinib Plus Ifosfamide And Etoposide In Children And Young Adults With Relapsed Osteosarcoma: A Phase 2 Randomized Clinical Trial, Nathalie Gaspar, Giun-Yi Hung, Sandra J Strauss, Quentin Campbell-Hewson, Filemon S Dela Cruz, Julia L Glade Bender, Kyung-Nam Koh, Sarah B Whittle, Godfrey Chi-Fung Chan, Nicolas U Gerber, Sauli Palmu, Daniel A Morgenstern, Alessandra Longhi, Fredrik Baecklund, Jun Ah Lee, Franco Locatelli, Catalina Márquez Vega, Katherine A Janeway, Geoffrey Mccowage, Martin G Mccabe, Behzad Bidadi, Jie Huang, Jodi Mckenzie, Chinyere E Okpara, Francisco Bautista, Olie Study Investigators

Faculty, Staff and Students Publications

IMPORTANCE: The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines.

OBJECTIVE: To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma.

DESIGN, SETTING, AND PARTICIPANTS: The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in …

Veno-Arterial Partial Pressure Of Carbon Dioxide Difference As A Metric Of Systemic Oxygen Delivery: Insights From A Correlative Meta-Analysis, Rohit S Loomba, Juan S Farias, Fabio Savorgnan, Sebastian Acosta, Saul Flores, Enrique G Villarreal

Faculty, Staff and Students Publications

The assessment of cardiac output and adequacy of systemic oxygen delivery in children after cardiac surgery require the use of an aggregate of hemodynamic monitors and blood tests. There are previously published data regarding the utility of the veno-arterial partial pressure of carbon dioxide difference (AVDco2) to help with this. This study pooled data on the correlation of AVDco2 with other metrics of cardiac output and systemic oxygen delivery such as arteriovenous oxygen saturation difference, venous saturation, and serum lactate. A systematic review of the literature was done to identify studies analyzing the correlation of AVDco2 with other hemodynamic and …

Systemic Sirolimus Therapy Is Associated With Reduced Intervention Frequency In Pulmonary Vein Stenosis, Alyssa B Kalustian, Joseph L Hagan, Paige E Brlecic, Ionela Iacobas, Rachel D Vanderlaan, Joseph Burns, Thao T Wu, Ravi Birla, Sharada Gowda, Manish Bansal, Srinath T Gowda, Lindsay F Eilers, Asra Khan, Juan Pablo Sandoval-Jones, Michiaki Imamura, Yishay Orr, Christopher A Caldarone, Athar M Qureshi

Faculty, Staff and Students Publications

BACKGROUND: Early clinical outcomes data for adjunctive systemic sirolimus therapy (SST) for moderate to severe pediatric pulmonary vein stenosis (PVS) are promising but limited.

OBJECTIVES: The authors aimed to characterize a cohort of patients treated with SST to determine if SST was associated with a reduction in frequency of PVS interventions.

METHODS: Medical records of 45 patients with PVS treated with SST for ≥1 month from 2015 to 2022 were retrospectively reviewed. PVS intervention rates pre-SST and on-SST were compared using generalized Poisson mixed models, accounting for paired intervals within each patient. In addition to an unadjusted model, an adjusted …

Evaluation Of Stress Ulcer Prophylaxis In Pediatric General Medicine Patients After Transfer From The Intensive Care Unit And At Discharge, Lamees Loubani, Jenna W Bartlett, Brent Mothner, Rathi Asaithambi, Surin Lee

Faculty, Staff and Students Publications

OBJECTIVES: The primary aim of this study was to determine continuation rates of stress ulcer prophylaxis (SUP) upon transfer from a pediatric intensive care unit (PICU) to a general medicine unit and upon hospital discharge. The secondary aim was to identify patient characteristics or concomitant medications that were associated with continuation of SUP at transfer from the PICU.

METHODS: This retrospective chart review included patients who were initiated on acid suppression for SUP in the PICU between June 2021 and May 2022 and subsequently transferred to a general medicine unit prior to discharge. Patients were excluded if they were receiving …

10 Practical Priorities To Prevent And Manage Serious Allergic Reactions: Ga2len Anacare And Efa Anaphylaxis Manifesto, Antonella Muraro, Debra De Silva, Marcia Podesta, Aikaterini Anagnostou, Victoria Cardona, Susanne Halken, Pete Smith, Luciana Kase Tanno, Paul Turner, Margitta Worm, Montserrat Alvaro-Lozano, Stefania Arasi, Anna Asarnoj, Simona Barni, Kirsten Beyer, Lucy A Bilaver, Andrew Bird, Roberta Bonaguro, Helen A Brough, R Sharon Chinthrajah, Emma E Cook, Céline Demoulin, Antoine Deschildre, Timothy E Dribin, Motohiro Ebisawa, Montserrat Fernandez-Rivas, Alessandro Fiocchi, David M Fleischer, Eleanor Garrow, Jennifer Gerdts, Mattia Giovannini, Kirsi M Järvinen, Mary Kelly, Edward F Knol, Gideon Lack, Francesca Lazzarotto, Thuy-My Le, Stephanie Leonard, Jay Lieberman, Michael Makris, Lianne Mandelbaum, Mary Jane Marchisotto, Gustavo Andres Marino, Francesca Mori, Caroline Nilsson, Anna Nowak-Wegrzyn, Mikaela Odemyr, H N G Oude Elberink, Kati Palosuo, Nandinee Patel, Jennifer Pier, Sung Poblete, Rima Rachid, Pablo Rodríguez Del Río, Maria Said, Hugh A Sampson, Angel Sánchez Sanz, Sabine Schnadt, Fallon Schultz, Alice Toniolo, Julia E M Upton, Carina Venter, Brian P Vickery, Berber Vlieg-Boerstra, Julie Wang, Graham Roberts, Torsten Zuberbier, Ga2len Anacare Centres And Efa

Faculty, Staff and Students Publications

This Anaphylaxis Manifesto calls on communities to prioritise 10 practical actions to improve the lives of people at risk of serious allergic reactions. The Global Allergy and Asthma European Network and the European Federation of Allergy and Airways Diseases Patients' Associations (EFA) compiled patient-centric priorities. We used qualitative consensus methods, research evidence and feedback from over 200 patient groups, stakeholder organisations and healthcare professionals. We encourage healthcare, education and food organisations to collaborate with people at risk of serious allergic reactions to tackle safety, anxiety and financial burdens for individuals and societies. Key priorities for prevention include awareness-raising campaigns for …

Responding To The Workforce Crisis: Consensus Recommendations From The Second Workforce Summit Of The American Society Of Pediatric Nephrology, Danielle E Soranno, Sandra Amaral, Isa Ashoor, Meredith A Atkinson, Gina-Marie Barletta, Michael C Braun, Joann Carlson, Caitlin Carter, Annabelle Chua, Vikas R Dharnidharka, Keri Drake, Elif Erkan, Dan Feig, Stuart L Goldstein, David Hains, Lyndsay A Harshman, Elizabeth Ingulli, Alexander J Kula, Mary Leonard, Sudha Mannemuddhu, Shina Menon, Zubin J Modi, Marva Moxey-Mims, Arwa Nada, Victoria Norwood, Michelle C Starr, Priya S Verghese, Darcy Weidemann, Adam Weinstein, Jodi Smith

Faculty, Staff and Students Publications

IMPORTANCE: Pediatric patients with complex medical problems benefit from pediatric sub-specialty care; however, a significant proportion of children live greater than 80 mi. away from pediatric sub-specialty care.

OBJECTIVE: To identify current knowledge gaps and outline concrete next steps to make progress on issues that have persistently challenged the pediatric nephrology workforce.

EVIDENCE REVIEW: Workforce Summit 2.0 employed the round table format and methodology for consensus building using adapted Delphi principles. Content domains were identified via input from the ASPN Workforce Committee, the ASPN's 2023 Strategic Plan survey, the ASPN's Pediatric Nephrology Division Directors survey, and ongoing feedback from ASPN …

Machine Learning-Based Prediction Model For Icu Mortality After Continuous Renal Replacement Therapy Initiation In Children, Sameer Thadani, Tzu-Chun Wu, Danny T Y Wu, Aadil Kakajiwala, Danielle E Soranno, Gerard Cortina, Rachana Srivastava, Katja M Gist, Shina Menon, Worldwide Exploration Of Renal Replacement Outcomes Collaborative In Kidney Diseases (We-Rock) Collaborators

Faculty, Staff and Students Publications

BACKGROUND: Continuous renal replacement therapy (CRRT) is the favored renal replacement therapy in critically ill patients. Predicting clinical outcomes for CRRT patients is difficult due to population heterogeneity, varying clinical practices, and limited sample sizes.

OBJECTIVE: We aimed to predict survival to ICUs and hospital discharge in children and young adults receiving CRRT using machine learning (ML) techniques.

DERIVATION COHORT: Patients less than 25 years of age receiving CRRT for acute kidney injury and/or volume overload from 2015 to 2021 (80%).

VALIDATION COHORT: Internal validation occurred in a testing group of patients from the dataset (20%).

PREDICTION MODEL: Retrospective international …

Fournier's Gangrene Severity Index And Charlson Comorbidity Index Predict Mortality, Intensive Care Unit Admission, And Length Of Hospital Stay In Patients With Fournier's Gangrene: An Analysis Of 264 Consecutive Patients, Nicholas Hauser, Chenlin Huang, Girija Vaidya, Timothy Chrusciel, Krithika Narayana Kumarasan, John Culhane, Sameer Siddiqui

Faculty, Staff and Students Publications

Introduction

Fournier’s gangrene (FG) is a rapidly progressing necrotizing fasciitis. The Fournier's Gangrene Severity Index (FGSI), in conjunction with the Charlson Comorbidity Index (CCI), has been used as a mortality predictor during hospitalization. Patients with diabetes have also been shown to be at an increased risk for the development of FG. This study explores the potential of using FGSI, CCI, and patient diabetes status in predicting more extensive patient outcomes, including intensive care unit (ICU) admission and length of hospital stay.

Methods

From 2013 to 2023, inpatient admissions with the diagnosis of FG were selected from the EPIC Clarity database …

Comparison Of Predicted And Actual Dermatitis Generated From Computed Tomography Images And Dose Distribution Maps, Yasuhide Miyabe, Saori Oshiro, Hiroto Seki, Yusuke Muroi, Eriko Kawashima, Megumi Hosoda, Kento Ohashi, Hiromu Yamanaka, Mingliang Shao, Hiromi Sugawara, Jyunetsu Mizoe, Ritsuko Komaki

Faculty, Staff and Students Publications

Anticipating the onset, location and severity of radiation dermatitis before radiotherapy can aid in dermatological care. This study developed a method for creation of a prediction diagram for dermatitis and conducted a comparative verification between the prediction diagram and actual patient condition. The prediction diagram involved converting skin doses into 2 Gy fractionated equivalent doses using α/β of 10.0, defining regions of interest (ROIs) from 20-50 Gy at 10 Gy intervals. Overlaps between these ROIs at each dose level and the skin (external) was sequentially color-coded as blue, yellow, red, and purple. The study included four patients: two underwent head …

Predicting Operative Mortality In Patients Who Undergo Elective Open Thoracoabdominal Aortic Aneurysm Repair, Kyle W Blackburn, Susan Y Green, Allen Kuncheria, Meng Li, Adel M Hassan, Brittany Rhoades, Scott A Weldon, Subhasis Chatterjee, Marc R Moon, Scott A Lemaire, Joseph S Coselli

Faculty, Staff and Students Publications

Background

We have developed a model aimed at identifying preoperative predictors of operative mortality in patients who undergo elective, open thoracoabdominal aortic aneurysm (TAAA) repair. We converted this model into an intuitive nomogram to aid preoperative counseling.

Methods

We retrospectively analyzed data from 2884 elective, open TAAA repairs performed between 1986 and 2023 in a single practice. Using clinical and selected operative variables, we built 4 predictive models: multivariable logistic regression (MLR), random forest, support vector machine, and gradient boosting machine. Each model’s predictive effectiveness was evaluated with the C-statistic. Test C-statistics were computed using an 80:20 cross-validation scheme with …

Substance Use And Outcomes Of Left-Sided Valve Replacement In Patients With Infective Endocarditis, Katie J Hogan, Christopher B Sylvester, Travis J Miles, Matthew Wall, Todd K Rosengart, Marc R Moon, Joseph S Coselli, Subhasis Chatterjee, Ravi K Ghanta

Faculty, Staff and Students Publications

BACKGROUND: Rising rates of substance use (SU) have resulted in an increasing need for left-sided valve surgery for SU-associated infective endocarditis (SU-IE). We compared outcomes, readmissions, and costs between IE patients with and without SU-IE in a national cohort.

METHODS: Using the Nationwide Readmissions Database (2016-2018), we identified 10,098 patients with infective endocarditis (IE) who underwent isolated aortic or mitral valve replacement. Outcomes within the same calendar year as the index operation were compared between patients with and without SU-IE. Multivariable logistic regressions were used to identify factors associated with in-hospital mortality and 30-day and 90-day readmissions. Kaplan-Meier analysis and …

Template-Assisted Covalent Modification Underlies Activity Of Covalent Molecular Glues, Yen-Der Li, Michelle W Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C Rutter, Ryan J Lumpkin, Brittany Sandoval, Cyrus Y Jin, Anna M Schmoker, Scott B Ficarro, Hakyung Cheong, Rebecca J Metivier, Michelle Y Wang, Shawn Xu, Woong Sub Byun, Brian J Groendyke, Inchul You, Logan H Sigua, Isidoro Tavares, Charles Zou, Jonathan M Tsai, Paul M C Park, Hojong Yoon, Felix C Majewski, Haniya T Sperling, Jarrod A Marto, Jun Qi, Radosław P Nowak, Katherine A Donovan, Mikołaj Słabicki, Nathanael S Gray, Eric S Fischer, Benjamin L Ebert

Faculty, Staff and Students Publications

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes …

Veterans' Experiences Of And Preferences For Patient-Centered, Measurement-Based Ptsd Care, Marcela C Weber, Ashlyn M Jendro, Ellen P Fischer, Karen L Drummond, Trenton M Haltom, Natalie E Hundt, Michael A Cucciare, Jeffrey M Pyne

Faculty, Staff and Students Publications

Background: Up to 50% of veterans drop out of trauma-focused evidence-based psychotherapies (TF-EBP) without completing treatment or recovering; evidence suggests this is in part because their posttraumatic stress disorder (PTSD) care is insufficiently patient-centered. There is also evidence that measurement-based care (MBC) for mental health should be personalized to the patient, yet this is not common practice in VA PTSD care.

Objectives: To explore veterans' experiences and preferences for aligning measurement-based PTSD care with their own treatment goals.

Method: Qualitative interviews were conducted with veterans (n=15) with PTSD who had received at least 2 sessions of a TF-EBP.

Measures: Survey …

Cardiovascular Disease Risk In South Asians In The Baylor Scott And White Health Dilwale Registry, Anandita Agarwala, Priyanka Satish, Tsung-Wei Ma, Preethi Ravindranathan, Aashna Vajramani, Noah Balarbar, Charles Brumley, Abhishek Gami, Khurram Nasir, Vijay Nambi, Javed Butler, Jaideep Patel

Faculty, Staff and Students Publications

Background: Despite implementation of preventive interventions targeting cardiovascular disease (CVD), atherosclerotic CVD (ASCVD) remains a major public health concern in the South Asian (SA) population.

Objectives: The purpose of this study was to assess the risk factor prevalence and ASCVD outcomes in SA population in the United States.

Methods: The DIL Wellness and Arterial health Longitudinal Evaluation registry collected data retrospectively on SA adult patients receiving care in the Baylor Scott & White Healthcare system. Overall and sex stratified analyses were performed to assess the prevalence of traditional CVD risk factors and adverse ASCVD events.

Results: A total of 31,781 …

Health Implications Of Racial Differences In Serum Growth Differentiation Factor Levels Among Men With Obesity, Siresha Bathina, Virginia Fuenmayor Lopez, Mia Prado, Elliot Ballato, Georgia Colleluori, Maryam Tetlay, Dennis Tan Villareal, Sanjay Mediwala, Rui Chen, Clifford Qualls, Reina Armamento-Villareal

Faculty, Staff and Students Publications

Growth differentiation factor (GDF15) has been considered a biomarker and recently a hormonal driver for diseases in different populations. However, the role of GDF15 as a biomarker of health outcomes in obese men from different racial/ethnic background has not been evaluated. The objective of this study was to investigate the racial/ethnic differences on the relationship between GDF15 and markers of glucometabolic status, hormonal profile, body composition and bone mineral density (BMD) in obese men. One hundred ninety-three obese men from diverse racial/ethnic backgrounds were enrolled. BMD and body composition were measured by dual energy X-ray absorptiometry. Serum GDF15, osteocalcin, C-terminal …

Temporal Trends In Mortality Related To Stroke And Atrial Fibrillation In The United States: A 21-Year Retrospective Analysis Of Cdc-Wonder Database, Owais Ahmad, Hanzala Ahmed Farooqi, Isra Ahmed, Adeena Jamil, Rayyan Nabi, Irfan Ullah, Abdul Wali Khan, Raheel Ahmed, Mahboob Alam, Bernardo Cortese, Mamas A Mamas

Faculty, Staff and Students Publications

Aims: Atrial Fibrillation (AF) is one of the most strongly associated risk factors for stroke. Our study aims to analyze changes in mortality from 1999 to 2020 in patients with AF and stroke.

Methods: Using the Centre for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC-WONDER), we retrospectively analyzed annual age-adjusted mortality rates (AAMR) per million from 1999 to 2020 in stroke patients with AF. Temporal trends were analyzed, and Annual Percentage Change (APC) was calculated using the JoinPoint regression model across variations in demographics (sex, race) and regional subgroups.

Results: Around 490 000 deaths were reported …

Acute Decompensated Valvular Disease In The Intensive Care Unit, P Elliott Miller, Balimkiz C Senman, Ann Gage, Anthony P Carnicelli, Mark Jacobs, Aniket S Rali, Mourad H Senussi, Ankeet S Bhatt, Steven M Hollenberg, Annapoorna Kini, Venu Menon, Kendra J Grubb, David A Morrow, American College Of Cardiology Critical Care Cardiology Section

Faculty, Staff and Students Publications

Acute decompensated valvular disease encompasses a group of complex and challenging conditions, which are often the primary reason for admission to the cardiac intensive care unit and can also complicate the management of other primary cardiac disorders. Critically ill patients with valvular disease also present unique diagnostic and management challenges. Historically, medical and percutaneous interventional therapies have been limited and surgery was the only definitive treatment; however, surgical risk can at times be prohibitive. High-quality evidence to direct management of acute valvular disorders in this population is lacking and societal guidelines largely do not address treatment options for critically ill …

The Clinical Efficacy And Safety Of Bempedoic Acid In Patients At Elevated Risk Of Cardiovascular Disease: A Meta-Analysis Of Randomized Clinical Trials, Ahmed Sayed, Omar Shazly, Leandro Slipczuk, Chayakrit Krittanawong, Farhala Baloch, Salim S Virani

Faculty, Staff and Students Publications

Purpose: Statins are first-line agents to reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, however, they are insufficient and/or intolerable in many patients. To that end, we conducted a meta-analysis of Bempedoic Acid (BA), a novel LDL-C lowering agent.

Methods: We retrieved randomized clinical trials (RCTs) of BA by searching Pubmed, the Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov. We used the Mantel-Haenszel method to pool estimates. The I2 measure was used to quantify heterogeneity. Treatment effects are provided as relative risks (RR), absolute risk differences (ARD), and number needed to treat/harm (NNTB/H). Analyses were conducted using R, version …

Genetics Of Cerebral Palsy: Diagnosis, Differential Diagnosis, And Beyond, Dae-Hyun Jang, Jaewon Kim, Aloysia Leisanne Schwabe, Timothy Edward Lotze

Faculty, Staff and Students Publications

Cerebral palsy (CP) is the most common motor disability in children, characterized by diverse clinical manifestations and often uncertain etiology, which has spurred increasing interest in genetic diagnostics. This review synthesizes findings from various studies to enhance understanding of CP's genetic underpinnings. The discussion is structured around five key areas: monogenic causes and copy number variants directly linked to CP, differential genetic disorders including atypical CP and mimics, ambiguous genetic influences, co-occurrence with other neurodevelopmental disorders, and polygenic risk factors. Case studies illustrate the clinical application of these genetic insights, underscoring the complexity of diagnosing CP due to the phenotypic …

Chronic Β3-Ar Stimulation Activates Distinct Thermogenic Mechanisms In Brown And White Adipose Tissue And Improves Systemic Metabolism In Aged Mice, Duraipandy Natarajan, Bhuvana Plakkot, Kritika Tiwari, Shoba Ekambaram, Weidong Wang, Michael Rudolph, Mahmoud A Mohammad, Shaji K Chacko, Madhan Subramanian, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar, Priya Balasubramanian

Faculty, Staff and Students Publications

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a …

Development Of A New Peyronie’S Disease Self-Assessment Screening App, Gregory A Broderick, Jesse N Mills, Lisa Bathish, Christopher Davis, Mohit Khera

Faculty, Staff and Students Publications

Peyronie's disease (PD) is an underdiagnosed and undertreated fibroproliferative disorder associated with the formation of plaques that results in penile curvature and discourages some men from seeking medical consultation. The PD self-assessment app, a digital application (app), was developed to increase PD awareness, provide men with a self-screening and educational tool for PD, and help eliminate barriers to seeking consultation with a physician. Prior to deployment, 4 board-certified urologists provided qualitative reviews on the app's usability and utility as a screening tool. The PD self-assessment app features a questionnaire that addresses penile curvature, challenges with penetration, partner distress, and the …

A Tetramer Of Bcl11a Is Required For Stable Protein Production And Fetal Hemoglobin Silencing, Ge Zheng, Maolu Yin, Stuti Mehta, I-Te Chu, Stacy Wang, Alia Alshaye, Kirstin Drainville, Altantsetseg Buyanbat, Frédérique Bienfait, Karin Tenglin, Qian Zhu, Stuart H Orkin

Faculty, Staff and Students Publications

Down-regulation of BCL11A protein reverses the fetal (HbF, α2γ2) to adult (HbA, α2β2) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Due to reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop novel small molecule approaches, we interrogated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc-finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for γ-globin gene repression, as an engineered monomer fails to engage a critical corepressor …

A Virtual Scalable Model Of The Hepatic Lobule For Acetaminophen Hepatotoxicity Prediction, Stelian Camara Dit Pinto, Jalal Cherkaoui, Debarshi Ghosh, Valentine Cazaubon, Kenza E Benzeroual, Steven M Levine, Mohammed Cherkaoui, Gagan K Sood, Sharmila Anandasabapathy, Sadhna Dhingra, John M Vierling, Nicolas R Gallo

Faculty, Staff and Students Publications

Addressing drug-induced liver injury is crucial in drug development, often causing Phase III trial failures and market withdrawals. Traditional animal models fail to predict human liver toxicity accurately. Virtual twins of human organs present a promising solution. We introduce the Virtual Hepatic Lobule, a foundational element of the Living Liver, a multi-scale liver virtual twin. This model integrates blood flow dynamics and an acetaminophen-induced injury model to predict hepatocyte injury patterns specific to patients. By incorporating metabolic zonation, our predictions align with clinical zonal hepatotoxicity observations. This methodology advances the development of a human liver virtual twin, aiding in the …

Host Dna Depletion On Frozen Human Respiratory Samples Enables Successful Metagenomic Sequencing For Microbiome Studies, Minsik Kim, Raymond C Parrish, Michael J Tisza, Viral S Shah, Thi Tran, Matthew Ross, Juwan Cormier, Aribah Baig, Ching-Ying Huang, Laura Brenner, Isabel Neuringer, Katrine Whiteson, J Kirk Harris, Amy D Willis, Peggy S Lai

Faculty, Staff and Students Publications

Most respiratory microbiome studies use amplicon sequencing due to high host DNA. Metagenomics sequencing offers finer taxonomic resolution, phage assessment, and functional characterization. We evaluated five host DNA depletion methods on frozen nasal swabs from healthy adults, sputum from people with cystic fibrosis (pwCF), and bronchoalveolar lavage (BAL) from critically ill patients. Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum, and BAL had 94.1%, 99.2%, and 99.7% host reads, respectively. Host depletion effects varied by sample type, generally increasing microbial reads, species and functional richness; this was mediated by higher effective sequencing depth. Rarefaction curves showed …

Strategies To Enhance Diagnostic Capabilities For The New Drug-Resistant Tuberculosis (Dr-Tb) Drugs, Antonia Morita Iswari Saktiawati, Anca Vasiliu, Francesca Saluzzo, Onno W Akkerman

Faculty, Staff and Students Publications

The global burden of drug-resistant tuberculosis (DR-TB) continues to challenge healthcare systems worldwide. There is a critical need to tackle DR-TB by enhancing diagnostics and drug susceptibility testing (DST) capabilities, particularly for emerging DR-TB drugs. This endeavor is crucial to optimize the efficacy of new therapeutic regimens and prevent the resistance and overuse of these invaluable weapons. Despite this urgency, there remains a lack of comprehensive review of public health measures aimed at improving the diagnostics and DST capabilities. In this review, we outline strategies to enhance the capabilities, especially tailored to address the challenges posed by resistance to new …

An Annotated Biobank Of Triple Negative Breast Cancer Patient-Derived Xenografts Featuring Treatment-Naïve And Longitudinal Samples Throughout Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Hancock, Sabrina Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Students Publications

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial ( NCT02276443 ) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models …

Targeted Variant Assessments Of Human Endogenous Retroviral Regions In Whole Genome Sequencing Data Reveal Retroviral Variants Associated With Papillary Thyroid Cancer, Erik Stricker, Erin C Peckham-Gregory, Stephen Y Lai, Vlad C Sandulache, Michael E Scheurer

Faculty, Staff and Students Publications

Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients …

The Brain Initiative Data-Sharing Ecosystem: Characteristics, Challenges, Benefits, And Opportunities, Sudhanvan Iyer, Kathryn Maxson Jones, Jill O Robinson, Nicole R Provenza, Dominique Duncan, Gabriel Lázaro-Muñoz, Amy L Mcguire, Sameer A Sheth, Mary A Majumder

Faculty, Staff and Students Publications

In this paper, we provide an overview and analysis of the BRAIN Initiative data-sharing ecosystem. First, we compare and contrast the characteristics of the seven BRAIN Initiative data archives germane to data sharing and reuse, namely data submission and access procedures and aspects of interoperability. Second, we discuss challenges, benefits, and future opportunities, focusing on issues largely specific to sharing human data and drawing on N = 34 interviews with diverse stakeholders. The BRAIN Initiative-funded archive ecosystem faces interoperability and data stewardship challenges, such as achieving and maintaining interoperability of data and archives and harmonizing research participants’ informed consents for …

Mechanisms Of Memory-Supporting Neuronal Dynamics In Hippocampal Area Ca3, Yiding Li, John J Briguglio, Sandro Romani, Jeffrey C Magee

Faculty, Staff and Students Publications

Hippocampal CA3 is central to memory formation and retrieval. Although various network mechanisms have been proposed, direct evidence is lacking. Using intracellular Vm recordings and optogenetic manipulations in behaving mice, we found that CA3 place-field activity is produced by a symmetric form of behavioral timescale synaptic plasticity (BTSP) at recurrent synapses among CA3 pyramidal neurons but not at synapses from the dentate gyrus (DG). Additional manipulations revealed that excitatory input from the entorhinal cortex (EC) but not the DG was required to update place cell activity based on the animal’s movement. These data were captured by a computational model that …