Medical Specialties Commons^™

Race And Ethnicity And Overall Survival In Pediatric Acute Myeloid Leukemia, Daniel J. Zheng, Long Khuong, Catherine Aftandilian, Kira Bona, Emi H. Caywood, Caitlin W. Elgarten, Brian T. Fisher, Cody-Aaron L. Gathers, Taumoha Ghosh, M. Monica Gramatges, Gary Hettinger, Meret R. Henry, Yuan-Shung V Huang, Yimei Li, Kelly Maloney, Amir Mian, Tamara P Miller, Arunkumar Modi, Rajen Mody, Regina M. Myers, Haley Newman, Jose Ortiz, Alix E. Seif, Caroline Smith, Jamie Stokke, Naomi Winick, Jennifer J. Wilkes, Victor Wong, Richard Aplenc, Kelly D. Getz

Department of Pediatrics Faculty Papers

IMPORTANCE: Hispanic and non-Hispanic Black (hereafter, Black) children with acute myeloid leukemia (AML) have historically experienced worse survival outcomes compared with non-Hispanic White (hereafter, White) children. Understanding specific intermediate pathways underlying these outcome disparities is a critical step to directing interventional efforts and resources.

OBJECTIVE: To compare survival outcomes by race and ethnicity in a large contemporary cohort of pediatric patients with AML and to examine presentation acuity, frontline organ toxic effects, and relapse as potential mediators of any observed outcome disparities.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was analyzed from April 2025 to January 2026 and included …

Large-Scale Admixture Mapping In The All Of Us Research Program Improves The Characterization Of Cross-Population Phenotypic Differences, Ying Wang, Georgia Mies, Alan J Aw, Sinead Cullina, Penn Medicine Biobank, Eimear Kenny, Iain Mathieson, Elizabeth G Atkinson, Alicia R Martin, Bogdan Pasaniuc

Faculty, Staff and Students Publications

Admixed individuals have been understudied in medical research largely due to their complex genetic ancestries. However, the consideration of admixture can identify ancestry-enriched genetic associations, delineating genetic underpinnings of cross-population phenotypic variation. Here, we performed admixture mapping in individuals with inferred admixture from African and European populations (N = 48,921). Across 22 traits, we identified 71 ancestry-trait associations, including loci where ancestral haplotypes explained phenotypic variation yet were missed by single-variant association testing due to their stricter multiple testing burden. One such locus where inferred local AFR ancestries are associated with increased hemoglobin A1c (HbA1c) was 12q14.3, highlighting its potential …

A Clinical Accuracy Study Protocol For A Saliva-Based Point-Of-Care Lateral Flow Test To Assess Protective Immunity To Tetanus (Tetanus Study), H F Kwok, R Agarwal, Y Takwoingi, Semukunzi H, C Umuhoza, A Richter, J Nyombayire, C M Muvunyi, J Heaney, C A Green

Faculty, Staff and Students Publications

Introduction: Despite the availability of a safe and effective vaccine, 2000-3000 neonates die of tetanus yearly, predominantly in low- to middle-income countries (LMICs). Inaccurate coverage estimates and vaccination records, together with variability in vaccine response, make identifying individuals who lack protective immunity and may benefit from vaccination difficult. A more direct measure of protective immunity is widely accepted as anti-tetanus IgG concentration at or above 0.1 IU/mL. This study aims to evaluate the performance of a novel saliva-based point-of-care lateral flow test (CIS-IMMUNE Tet) for the binary classification of tetanus protective immune status (protected/unprotected) against WHO threshold-based classification of IgG …

Ultrasound-Guided Renal Artery Administration Of Angiopoietin-1 Rna Therapy Slows The Progression Of Preclinical Wt1 Glomerular Disease, Maria Kolatsi-Joannou, William J Mason, Lauren G Russell, Shunping Han, Yanis Harfouche, Daniyal J Jafree, Emily A E Moore, Hanna Gautier, Christina Katsiva, Reem Al-Saadi, Kathy Pritchard-Jones, Daniel J Stuckey, Andrew V Benest, David O Bates, Paul J Winyard, Aoife M Waters, Luigi Gnudi, Stephen L Hart, Tammy L Kalber, David A Long

Faculty, Staff and Students Publications

Mutations in the transcription factor gene Wilms Tumor 1 (WT1) are one of the leading causes of congenital glomerular disease, characterized by severe urinary protein loss and glomerular scarring. No disease-modifying therapies exist for WT1 glomerulopathies, and affected children rely on dialysis or kidney transplantation. We evaluated a previously uncharacterized treatment in a mouse model with an orthologous human mutation in Wt1 (Wt1+/R394W) that replicates the pathology of WT1 glomerulopathy. Lipid nanocomplexes were engineered to target integrin αvβ3 for efficient delivery of mRNA to primary podocytes and glomerular endothelial cells in vitro. A minimally …

Th17 Effector Cytokines Induce Shared And Distinct Microglial And Endothelial Cell Responses In A Mouse Model For Post-Streptococcal Encephalitis, Charlotte Wayne, Uğur Akcan, Travis Faust, Violeta Durán-Laforet, Danny Jamoul, Luca Bremner, Nicole Ampatey, Büşra Akcan, Sarah Ho, Bogoljub Ciric, Shannon Delaney, Wendy Vargas, Susan Swedo, Vilas Menon, Dorothy Schafer, Tyler Cutforth, Dritan Agalliu

Department of Neurology Faculty Papers

Group A Streptococcus (GAS) infections cause neuropsychiatric complications in children, but the mechanisms linking peripheral infection to brain dysfunction remain unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory transcriptional programs in microglia and brain endothelial cells (BECs), accompanied by loss of blood-brain barrier (BBB) gene expression in female mice. Spatial transcriptomic analyses reveal that GAS-responsive microglia localize near infiltrating CD4+ T cells. Several microglial chemokines induced in mice are elevated in sera from affected patients. Deletion of GM-CSF in CD4⁺ T cells partially reduces microglial chemokine gene expression, without restoring BBB …

Malt1 Protease Inhibition Restrains Glioblastoma Progression By Reversing Tumor-Associated Macrophage-Dependent Immunosuppression In Mice, Juliana Hofstätter Azambuja, Saigopalakrishna Yerneni, Lisa Maurer, Hannah Crentsil, Gabriela Debom, Linda Klei, Mei Smyers, Chaim Sneiderman, Kristina Schwab, Rajesh Acharya, Aivi Nguyen, Josie Emery, John Little, Jeffrey Meridew, Yijen Lin Wu, Prasanna Ekambaram, Dong Hu, Pete Gough, John Bertin, Ari Melnick, Gary Kohanbash, Riyue Bao, Peter Lucas, Linda Mcallister-Lucas

College of Life Sciences Faculty Papers

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive ('M2-like') phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor 'M1-like' phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages …

A Case Report Of Myocardial Infarction Complicated With Blood Pressure Fluctuations Caused By Pheochromocytoma, Huiping Li, Wei Yang, Yu Feng, You Zhang, Gan-Xin Yan, Chuanyu Gao

Department of Medicine Faculty Papers

Pheochromocytoma typically presents with sustained or paroxysmal hypertension, but initial manifestation as acute non-ST-segment elevation myocardial infarction (NSTEMI) is rare. Peri-procedural hemodynamic fluctuations are often dramatic, making diagnosis and management challenging. We report a 51-year-old male admitted with chest tightness for 17 days. Elevated troponin and coronary angiography showing multivessel disease with total occlusion of the mid-left anterior descending artery (LAD) led to a preliminary diagnosis of NSTEMI. During percutaneous coronary intervention, blood pressure surged to 240/130 mmHg; intravenous nitroprusside caused an instantaneous drop to 95/55 mmHg, with rapid rebound to >200 mmHg upon withdrawal, showing no clear temporal relationship …

Cigarette Smoke Induces Fasn-Dependent Fatty Acid Metabolic Rewiring To Drive Bladder Cancer Progression, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, Minjae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri

Faculty, Staff and Students Publications

Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via …

Translational Reading Frame Predicts The Pathogenicity Of C-Terminal Frameshift Deletions In Mecp2, Jacky Guy, Elena Hein, Beatrice Alexander-Howden, Timur Von Bock Und Polach, Tricia Mathieson, Benjamin P Kleinstiver, Huda Y Zoghbi, Adrian Bird

Duncan NRI Faculty and Staff Publications

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline …

Surgical Outcomes Of Hidradenitis Suppurativa Excision: Factors Impacting Wound Healing Time, Christina Huang, Scott H. Koeneman, Sherry Yang, Sami Tannour

Department of Surgery Faculty Papers

Hidradenitis suppurativa (HS) can be treated surgically to excise recurrent and recalcitrant regions of disease activity. However, surgical outcomes are highly variable depending on closure method, concomitant medical management and area of excision. In this study, we aim to characterise the healing courses from HS excision in a case series. To reduce operator variability, we opted to conduct a case series from a single surgeon. Surgeries conducted from June 2024-December 2025 by surgeon S.T. were included, and the postoperative course was followed until February 2026. Surgical details and postoperative course for 34 sites of HS across 20 patients were analysed. …

Development Of A Structurally Distinct Topbp1 Inhibitor That Enhances Parp Blockade And Reverses Osimertinib Resistance, Yang Xiao, Lidija A Wilhelms Garan, Helena Folly-Kossi, Weei-Chin Lin

Faculty, Staff and Students Publications

Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship–driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, …

The Impact Of Structural Variation On Alzheimer’S Disease In The Alzheimer’S Disease Sequencing Project, Songmi Lee, Adam C English, Gina M Peloso, Joshua C Bis, Eric Boerwinkle, Seung Hoan Choi, Nancy L Heard-Costa, Honghuang Lin, Rui Xia, Sudha Seshadri, Anita L Destefano, Myriam Fornage, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Introduction: Structural variants (SV), genomic alterations spanning more than 50 base pairs, can significantly impact gene expression and protein function. However, their contribution to Alzheimer's disease (AD) remains poorly understood. Leveraging a novel SV calling pipeline, we identified SVs with high accuracy in a diverse sample of the Alzheimer's Disease Sequencing Project (ADSP) and investigated the role of SVs in AD.

Results: We analyze SVs in 16,841 individuals from ADSP whole genome sequencing data using BioGraph, a semi-assembly-based method that employs graph-based representation for accurate SV detection. We identify 456,644 high-quality SVs, 65% of which were novel. Of these, 272,728 …

Intravenous Thrombolysis Beyond The Conventional Time Window For Acute Ischemic Stroke: A Systematic Review And Meta-Analysis, Shaan Patel, Shiva A. Nischal, Kush M. Kale, Michael R. Gooch, Stavropoula I. Tjoumakaris, Pascal Jabbour

Department of Neurosurgery Faculty Papers

IMPORTANCE: Intravenous thrombolysis (IVT) is an established therapy for acute ischemic stroke when administered within 4.5 hours of symptom onset. However, many patients present beyond this window or with unknown onset, and recent randomized clinical trials (RCTs) have evaluated whether imaging-selected patients may benefit from thrombolysis in the extended window.

OBJECTIVE: To evaluate the functional and safety outcomes associated with IVT administered 4.5 hours or more after stroke onset.

DATA SOURCES: PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from database inception through March 3, 2026.

STUDY SELECTION: RCTs enrolling adults with acute ischemic stroke treated …

Young-Onset Stroke In The Uae: A Single-Centre Retrospective Analysis Of Risk Factors And Outcomes, Sobia Siddiq, Saryia Adra, Kamel A. Samara, Batool Aldaher, Mohamad Emad Aldeen Mahfouz, Nour Sakan, Fathima Musfira, Roomiyah Riyaz Assadi, Ahlam Mohamed Almarzooqi, Hiba Jawdat Barqawi, Eman Abu-Gharbieh

Abington Jefferson Health Papers

BACKGROUND: Young-onset stroke represents a growing public health concern, yet data from the United Arab Emirates (UAE) remain limited. This study aimed to examine the risk factors and clinical outcomes associated with young-onset stroke in the UAE.

METHODS: A retrospective chart review was conducted on 419 patients aged below 50 years who were admitted at Al Qassimi Hospital, Sharjah, UAE, with a diagnosis of stroke between 2016 and 2022. Data on demographics, comorbidities, stroke subtype, management, and outcomes were collected and analyzed using Python-based statistical libraries.

RESULTS: The study population comprised predominantly of male individuals (78.28%), with most patients originating …

Dose-Expansion Study Of Obi-999, A Globo H-Targeting Antibody-Drug Conjugate, In Patients With Advanced Solid Tumors, Apostolia Maria Tsimberidou, Darren Sigal, Anna Varghese, Daniel Vaena, Li-Yuan Bai, Ming-Huang Chen, Chun-Nan Yeh, Chia-Jui Yen, Mehmet A Baysal, Abhijit Chakraborty, Ingly Lee, Chi-Sheng Shia, Konul Ristoski, Dong Xu

Children’s Nutrition Research Center Staff Publications

Background: OBI-999 is an antibody-drug conjugate consisting of the Globo H-targeting antibody OBI-888 linked to the cytotoxic payload monomethyl auristatin E. In a dose-escalation study, the OBI-999 recommended phase 2 dose (RP2D) was 1.2 mg/kg every 3 weeks. This dose-expansion study evaluated the efficacy and safety of OBI-999 in patients with pancreatic cancer, colorectal cancer (CRC), or other tumor types ("basket cohort") and tumoral Globo H H-scores ≥100 (NCT04084366).

Patients and methods: Patients were treated at RP2D of OBI-999. We assessed response, progression-free survival (PFS), treatment-emergent adverse events (TEAEs), and pharmacokinetics of OBI-999.

Results: Of 29 patients treated, …

Interpreting Continuous Glucose Monitoring Through Metabolic Physiology: A Framework For Precision Nutrition In Type 2 Diabetes, Jitendra D. Belani

College of Pharmacy Faculty Papers

Background: Type 2 diabetes is characterized by substantial interindividual variability in postprandial glucose responses, yet continuous glucose monitoring (CGM)-derived glucose patterns are commonly described using quantitative metrics without sufficient consideration of the physiological mechanisms that generate them. Objective: To develop a physiology-based framework for interpreting CGM-derived glycemic phenotypes in relation to dietary exposures and individual metabolic characteristics, thereby supporting precision nutrition in adults with type 2 diabetes. Methods: A structured narrative review of the literature was conducted using PubMed to identify studies examining CGM, postprandial glucose regulation, dietary exposures, metabolic physiology, and precision nutrition. Evidence was synthesized within a predefined …

Shared Neural Geometries For Bilingual Semantic Representations In Human Hippocampal Neurons, Xinyuan Yan, Ana G Chavez, Melissa Franch, Kalman A Katlowitz, Ivy Gautam, Brian Kim, Aaditya Krishna, Aadit Shrivastava, Katie Van Arsdel, James Belanger, Assia Chericoni, Taha Ismail, Elizabeth A Mickiewicz, Danika Paulo, Hanlin Zhu, Alica M Goldman, Vaishnav Krishnan, Atul Maheshwari, Eleonora Bartoli, Nicole R Provenza, Seng Bum Michael Yoo, Benjamin Y Hayden, Sameer A Sheth

Duncan NRI Faculty and Staff Publications

The human brain has the remarkable ability to comprehend and express similar concepts in multiple languages. To understand how it does so, we examined responses of hippocampal neurons during passive listening, directed speaking, and spontaneous conversation in both English and Spanish in a small group of balanced bilinguals. We found a small number of putative "cross-language neurons," whose responses to equivalent words (e.g., "tierra" and "earth") are correlated. However, neurons' semantic tunings differed substantially by language, suggesting language-specific neural implementations. Instead, the crucial driver of translation was a preserved geometric organization of neural responses between the two languages, one that …

Endometrial Cells With High Aldh Activity Contribute To Uterine Development And Regeneration, Sydney E Parks, Genesis J Herrera, Ting Geng, Linda Alpuing Radilla, Brooke A Thigpen, Xiaoming Guan, Diana Monsivais

Faculty, Staff and Students Publications

Adult stem cells are thought to drive the regenerative potential of the endometrium and contribute to the pathogenesis of endometriosis; however, their identity and defining features remain to be characterized. Here, we used in vivo and in vitro approaches to demonstrate that cells with high aldehyde dehydrogenase 1 activity (ALDHHI cells) were long-lived progenitors in the endometrium with a higher organoid formation capacity, long-term passaging potential, and stemness gene signatures. Using lineage tracing with an Aldh1a1creERT2/+; Rosa26LSL-tdTomato reporter mouse, Aldh1a1+ epithelial cells expanded during postnatal development, Aldh1a1+ stromal cells expanded during estrous cycling, and both populations of Aldh1a1 …

A Complete Diploid Human Genome Benchmark For Personalized Genomics, Nancy F Hansen, Nathan Dwarshuis, Hyun Joo Ji, Arang Rhie, Hailey Loucks, Glennis A Logsdon, Mitchell R Vollger, Jessica M Storer, Juhyun Kim, Eleni Adam, Nicolas Altemose, Dmitry Antipov, Mobin Asri, Sofia Barreira, Stephanie C Bohaczuk, Andrey V Bzikadze, Sara A Carioscia, Andrew Carroll, Kuan-Hao Chao, Yanan Chu, Arun Das, Peter Ebert, Adam English, Mark Fleharty, Laura E Fleming, Giulio Formenti, Andrea Guarracino, Gabrielle A Hartley, Katharine Jenike, Jenna Kalleberg, Yu Kang, Robert King, Josipa Lipovac, Mira Mastoras, Matthew W Mitchell, Shloka Negi, Nathan D Olson, Keisuke K Oshima, Luis F Paulin, Brandon D Pickett, David Porubsky, Jane Ranchalis, Desh Ranjan, Mikko Rautiainen, Harold Riethman, Robert D Schnabel, Fritz J Sedlazeck, Kishwar Shafin, Mile Sikic, Steven J Solar, Alexander P Sweeten, Winston Timp, Justin Wagner, Dongahn Yoo, Ying Zhou, Erik Garrison, Evan E Eichler, Michael C Schatz, Andrew B Stergachis, Rachel J O'Neill, Karen H Miga, Steven L Salzberg, Sergey Koren, Justin M Zook, Adam M Phillippy

Faculty, Staff and Students Publications

Human genome sequencing typically relies on mapping reads to a reference genome to call variants, but this approach introduces technical biases, excluding duplicated and structurally polymorphic regions of the genome. To overcome this, we present a telomere-to-telomere genome benchmark with near-perfect accuracy across 99.4% of the diploid HG002 genome. This benchmark adds 701.4 Mb of autosomal sequence and both sex chromosomes (216.8 Mb), which were absent from prior benchmarks. We annotated genes and repeats on both haplotypes, including 19,956 protein-coding genes on the maternal haplotype and 19,190 on the paternal haplotype, and developed new methods to measure the accuracy of …

Endoscopic Versus Catheter-Based Minimally Invasive Evacuation Of Spontaneous Supratentorial Intracerebral Hemorrhage: A Systematic Review And Meta-Analysis, Shaan Patel, Shiva A Nischal, Kush M Kale, Angelette Mendonca, Keenan Piper, Pious D. Patel, Michael R. Gooch, Stavropoula Tjoumakaris, Pascal M. Jabbour

Department of Neurosurgery Faculty Papers

Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral hemorrhage (sICH) includes endoscopic evacuation and catheter-based evacuation (aspiration or drainage ± thrombolysis), but comparative performance remains uncertain. We performed a systematic review and meta-analysis comparing MIS approaches. PubMed, Embase, and CENTRAL were searched (December 2025) for studies in adults undergoing endoscopic or catheter-based MIS for supratentorial sICH. Random-effects meta-analysis was conducted. Prespecified subgroup analyses stratified catheter-based techniques by thrombolysis use. Risk of bias and certainty of evidence was assessed. Twenty-nine studies (8221 patients; 5041 endoscopic; 3180 catheter-based) were included. Endoscopic evacuation was associated with lower mortality (RR 0.64; 95% CI: 0.47–0.87; …

Larotrectinib In Trk Fusion Differentiated Thyroid Carcinoma: Updated Trial Data, Steven Waguespack, Marcia Brose, Jessica J Lin, Ray Mcdermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Shivaani Kummar, Se-Hoon Lee, Damian Rieke, Do-Youn Oh, Changsong Qi, Natascha Neu, Domnita-Ileana Burcoveanu, Chiara Mussi, Alexander Drilon, David Hong, Maria Cabanillas

Department of Medical Oncology Faculty Papers

Larotrectinib is a first-in-class, highly selective, central nervous system-active tropomyosin receptor kinase (TRK) inhibitor approved for tumour-agnostic use in TRK fusion cancer. It has previously demonstrated rapid and durable disease control and favourable safety in patients with advanced TRK fusion thyroid carcinoma (TC). After an additional 4 years of follow-up with the inclusion of two additional patients, and utilising an independent review committee (IRC) to assess overall response rate (ORR), we report updated pooled analyses from three phase 1-2 larotrectinib clinical trials, focusing only on patients with TRK fusion differentiated TC (DTC). The primary endpoint was the IRC-determined ORR per …

Molecular Mechanisms, Therapeutic Strategies, And Inter-Organ Fibrosis Crosstalk Of Gla Proteins In Cardiovascular Disease, Shuai Zhao, Siena Bush, Ivan O Rosas, Svetlana Reilly, Xander H T Wehrens

Faculty, Staff and Students Publications

Gla proteins are a vitamin K-dependent family long studied for their roles in blood clotting and vascular calcification. This review examines their broader involvement in cardiovascular disease, particularly cardiac fibrosis. We highlight that their functions are context-dependent, varying with disease stage and cellular environment, and that several occur independently of γ-carboxylation, challenging the view that this modification is universally required for their function. By comparing fibrosis across the heart, lung, liver, and kidney, we distinguish shared from organ-specific mechanisms. Finally, we discuss prospective therapies, from vitamin K supplementation to receptor-targeted approaches, and the questions that remain before clinical translation.

Childhood Cancer Predisposition Study: A Prospective Registry And Biorepository Protocol, Jennie Vagher, Junne Kamihara, Surya Rednam, Philip J Lupo, Garrett M Brodeur, Joshua Schiffman, Lisa Diller, Lauren Desrosiers-Battu, Sharon E Plon, Kim E Nichols, Samuel L Volchenboum, David Malkin, Anita Villani, Christopher C Porter

Faculty, Staff and Students Publications

Introduction: Cancer is the most common cause of disease-related mortality in children, highlighting the urgent need for improved care in this population. It is estimated that >15% of children diagnosed with cancer harbour a germline pathogenic variant in a cancer predisposition gene which confers an increased risk to develop cancer. There are over 100 genes associated with cancer predisposition syndromes (CPSs) and greater availability and acceptability of genetic testing in the last decade has facilitated their recognition in childhood. However, individually, each of these CPSs is rare, impeding robust research and advancement of clinical care. Once a specific CPS is …

Unfolded Protein Response As A Therapeutic Target: 4-(Heptyloxy)Phenol Induces Programmed Cell Death In Ewing Sarcoma, Terzah M Horton, Scott R Gilbertson, Debananda Pati

Faculty, Staff and Students Publications

Ewing sarcoma is a rare and aggressive pediatric malignancy with limited therapeutic options, particularly for relapsed or refractory cases, highlighting the urgent need for innovative treatment strategies. In this study, we identify endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as critical therapeutic vulnerabilities in Ewing sarcoma and introduce 4-(heptyloxy)phenol (AC-45594) as a novel small-molecule agent that exploits these stress pathways. AC-45594 selectively inhibited the growth of Ewing sarcoma cells among 13 cancer and 6 noncancerous cell lines, demonstrating marked tumor specificity. Structure-activity relationship studies revealed that both the phenolic hydroxyl group and an optimal alkoxy chain length …

Non-Enzymatic Hepatic Abhd6 Interacts With Akt-Foxo1 Axis To Regulate Metabolic Health, Guannan Li, Laurence T Maeyens, Jiyuan Yin, Jan-Bernd Funcke, Chanmin Joung, Ruizhen Li, Ziying Xu, Ting Wu, Xin Li, Nisi Jiang, Mbolle Ekane, Maria Paula Lopez, Pengju Cao, Sijia He, Adam B Salmon, S R Murthy Madiraju, Marc Prentki, Juli Bai, James F Nelson, Xianlin Han, Yi Zhu, Shangang Zhao

Children’s Nutrition Research Center Staff Publications

The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin …

Defining The Value Of Elective Lumbar Fusion: A Systematic Review Of Existing Methodologies And Framework For The Operative Value Index, Advith Sarikonda, Anthony Chen, Theo S. Biddle, Danyal A. Quraishi, Preston Carey, Arbaz A. Momin, Matthews Lan, Dwight Mitchell Self, Ashmal S. Kabani, Ahilan Sivaganesan

Department of Neurosurgery Faculty Papers

BACKGROUND: Despite wide variation in the outcomes and costs of lumbar fusion, few studies have integrated these domains together within a single metric to assess "value" (outcomes achieved per dollar spent). In this review, we sought to 1) characterize existing metrics of cost-effectiveness for lumbar fusion, 2) evaluate all applications of time-driven activity-based costing (TDABC) in spine surgery, and 3) outline the conceptual foundation for a standardized Operative Value Index (OVI).

METHODS: Two PRISMA-concordant systematic reviews were performed on PubMed and Scopus databases. The first review examined all studies which reported a cost-effectiveness metric for lumbar fusion. The second review …

Ecmo Use In Infants With Bronchopulmonary Dysplasia: A Literature Review., John Ibrahim, Nicholas Carr, Franscesca Miquel Verges, Natalie Rintoul, Robert Digeronimo, John M. Daniel Iv, Sarah Keene, Burhan Mahmood

Manuscripts, Articles, Book Chapters and Other Papers

Bronchopulmonary dysplasia (BPD) is a leading cause of chronic respiratory failure in infants. Severe BPD is associated with prolonged mechanical ventilation, pulmonary hypertension, and high morbidity and mortality. As disease severity increases, extracorporeal membrane oxygenation (ECMO) is being reconsidered as a potential rescue therapy. Historically, ECMO has been reserved for neonates with reversible respiratory failure and those who required mechanical ventilation for less than 14 days, while infants with BPD were excluded. However, advancements in ECMO technology, anticoagulation strategies, and ventilatory management have led to a reassessment of its role in this population. Emerging reports suggest ECMO may serve as …

Hippo Signaling Regulates Cuticle Pigmentation And Dopamine Metabolism In Drosophila, Shelley B Gibson, Samantha L Deal, Ye-Jin Park, Bo Sun, Yanyan Qi, Jung-Wan Mok, Hyung-Lok Chung, Hongjie Li, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Pigmentation plays multiple important roles in development, physiology and evolution. Melanization of the insect cuticle requires dopamine as a precursor of melanin and involves key enzymes in dopamine biosynthesis including Tyrosine hydroxylase (TH) and Dopa decarboxylase (Ddc). Some studies have hinted that disruption of the evolutionarily conserved Hippo signaling pathway, which has been primarily studied in the context of tissue growth, may lead to changes in cuticle pigmentation in the fruit fly Drosophila melanogaster. However, to our knowledge, there have not been any systematic investigations into their potential mechanistic links. In this study, we identified that all genes that comprise …

Impact Of Trisomy 21 On Post Pull-Through Enterocolitis And Bowel Function In Children With Hirschsprung Disease: A Pcplc Analysis., Marshall W. Wallace, Scott S. Short, Rachel C. Crady, Ron W. Reeder, Hira Ahmad, Kelly Austin, Andrea Badillo, Casey M. Calkins, Megan M. Durham, Julie R. Fuchs, Christopher Gayer, Julia E. Grabowski, Jamie C. Harris, Charles R. Hong, Ankur Rana, Rebecca M. Rentea, Nelson Rosen, Payam Saadai, Caitlin A. Smith, K Elizabeth Speck, Cristine S. Velazco, Richard J. Wood, Michael D. Rollins

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: We evaluated whether Trisomy 21 (T21) affected bowel management use, ability to toilet train for stool, and rates of Hirschsprung-Associated Enterocolitis (HAEC) in children with Hirschsprung disease (HD). We hypothesized that T21 would be associated with increased rates of HAEC, bowel management program (BMP) use, and delayed toilet training for stool.

METHODS: Children with HD in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) database who underwent primary pull-through were included and stratified by T21 status: HD only versus HD + T21. Children requiring a redo pull-through, initially managed with a stoma, or those who had inadequate follow-up were …

All-Cause And Cause-Specific Mortality In Gambling Disorder: Evidence From A Nation-Wide Matched And Sibling Cohort Study In Taiwan, Yang-Chieh Brian Chen, Chih-Wei Hsu, Liang-Jen Wang, Mu-Hong Chen, Yao-Hsu Yang, Chih-Sung Liang, Edward Chia-Cheng Lai

Children’s Nutrition Research Center Staff Publications

Background and aims: Gambling disorder (GD) has been linked to suicidal ideation and suicide deaths; however, evidence on all-cause and cause-specific mortality-particularly in Asian populations-remains limited. Using a retrospective cohort study based on nationwide matched and sibling cohort, we investigated all-cause and cause-specific mortality risk in patients with GD.

Design, setting and participants: A retrospective cohort study was conducted using 2000-2022 data from Taiwan's National Health Insurance Research Database. A cohort of 961 individuals diagnosed with GD was identified. An age- and sex-matched control cohort (n = 3,844) and an unaffected sibling cohort (n = 675) were constructed. Cumulative survival …