Digital Commons Network^™

Survodutide For Treatment Of Obesity: Baseline Characteristics Of Participants In A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial (Synchronize™-1), Carel W Le Roux, Sean Wharton, Biykem Bozkurt, Elke Platz, Gabriele Bleckert, Samina Ajaz Hussain, Martina Brueckmann, Elena Startseva, Isabel M Kloer, Lee M Kaplan

Faculty, Staff and Students Publications

Aims: Survodutide, a novel glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor dual agonist, elicited significant weight loss in a phase 2 trial in individuals with obesity without type 2 diabetes (T2D). Two multinational phase 3 trials are investigating survodutide for obesity management in individuals with or without T2D. We report the baseline characteristics of participants in the SYNCHRONIZE-1 trial in adults with obesity without T2D (ClinicalTrials.gov: NCT06066515).

Materials and methods: Participants aged ≥18 years with BMI ≥30 or ≥27 kg/m2 with ≥1 obesity complication without T2D were randomized 1:1:1 to double-blind, once-weekly, subcutaneous injections of survodutide (up-titrated to 3.6 …

Unraveling Posttranslational Modification Complexity: Advances In Quantitative Histone Proteoform Mass Spectrometry, Karl F Poncha, Alyssa T Paparella, Nicolas L Young

Faculty, Staff and Students Publications

Histone proteins and their posttranslational modifications are central to chromatin structure and function. These modifications often occur in combinations, generating a diverse array of histone proteoforms that contribute to the dynamic regulation of chromatin architecture. Advancements in mass spectrometry-based proteomics, particularly top-down and middle-down approaches, have significantly enhanced our ability to characterize these proteoforms and elucidate PTM crosstalk. This review provides an analysis of the epigenetic machinery involved in the addition, recognition, and removal of histone PTMs, emphasizing the complexity introduced by histone variants and combinatorial PTM patterns. We examine the challenges and limitations of traditional antibody-based methods for PTM …

Mindful Diagnostics In Culture-Negative Endocarditis: Early Noninvasive Diagnosis Of Tropheryma Whipplei By Plasma Microbial Cell-Free Dna, Ashita Jain, Sarwat Khalil, Muhammad R Sohail, Laura C Lelenwa, Enrique Garcia-Sayan, Kenneth K Liao, Ahmed Hamdi, Todd Lasco, Mayar Al Mohajer

Faculty, Staff and Students Publications

Tropheryma whipplei was identified by plasma microbial cell-free DNA sequencing within 4 days in severe culture-negative endocarditis after antibiotics had already been started. The result supported earlier diagnostic clarification and antimicrobial de-escalation before valve pathology was available, illustrating a practical diagnostic-stewardship role for noninvasive sequencing in high-acuity endocarditis.

Modulation Of Corneal Sensory Processing And Pain Responses By Dry Eye And Corneal Wounding, Ebru Yaman, Yangluowa Qu, Kaylin C Arpaia, Fairouz Elsaeidi, Uma Lakshmi Balakrishnan, Lance He, Henry Skrehot, Jehan Alam, Rui Chen, Mary Ann Stepp, Cintia S De Paiva, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Background: Dry eye disease (DED) is a multifactorial disorder of the ocular surface in which tear film instability, epithelial barrier disruption, and neurosensory dysfunction contribute to symptom generation. Although several contributing factors have been identified, how different forms of ocular surface stress affect sensory pathways and behavioral responses remains unclear.

Purpose: This study aimed to evaluate corneal barrier function, sensory responses, and pain-related behaviors across acute and chronic dry eye and corneal injury models, and to assess stimulus-specific responses associated with TRPV1 and TRPM8 mediated pathways.

Methods: Female C57BL/6 J wild type and Mmp9KO mice were evaluated in acute desiccating …

Strategies And Challenges For The Recruitment Of Young Healthy Participants In The Dietary Approaches To Longevity And Health (Dial Health) Pilot Trial, Hannah E Cabre, Courtney M Peterson, Gareth R Dutton, Kimberly L Drews, Stephanie T Broyles, Robert Dubin, Laura Q Rogers, Catherine Champagne, Dennis T Villareal, Daniel S Hsia, Leanne M Redman, Corby K Martin

Faculty, Staff and Students Publications

Background: Understanding the impact of nutrition on human aging requires long-term trials in young, healthy, unmedicated adults. As part of the Dietary Approaches for Longevity and Health (DiAL Health) pilot project, we evaluated strategies for recruiting this population for aging-related dietary intervention studies.

Methods: We analyzed recruitment costs to enroll 70 participants (ages 25-49, BMI 22.0-29.9 kg/m2) across two DiAL Health sites and used NHANES data (2017-March 2020) to estimate the proportion of U.S. adults meeting partial trial eligibility. Additionally, a formative study surveyed 492 U.S. adults (≥18 years) to assess interest in aging-focused dietary trials.

Results: Of 2049 applicants …

Sewers To Solutions: A Guide To Wastewater Pathogen Monitoring, Justin R Clark, Anthony W Maresso

Faculty, Staff and Students Publications

Wastewater-based epidemiology (WBE) is the analysis of wastewater to detect pathogen levels or activity for public health awareness or action. Pioneered in the 1940s, WBE underwent a resurgence during the COVID-19 pandemic, providing important information about number of cases, outbreaks, and seasonal impact. With advancements in detection technologies and growing interest in environmental surveillance, WBE is poised to become a standard practice in public health monitoring. Here, we provide an overview of the current state of the art of pathogen WBE, including methods of molecular detection, analysis of wastewater data, real-world applications and programs, public health interventions, and benefits and …

Correction: Establishing Standardized Transthoracic Echocardiography Reference Ranges For Mouse Models: Insights Into The Impact Of Anesthesia, Sex, And Age, Manuela A Oestereicher, Christopher S Ward, Elida Schneltzer, Susan Marschall, Helmut Fuchs, Valerie Gailus-Durner, Ghina Bou About, Mohammed Selloum, Hamid Meziane, Michelle Stewart, Lydia Teboul, Clare Norris, Dale Pimm, Marina Kan, Federico López Gómez, Robert Wilson, Mayra Monroy, Sheraz Pasha, Eva Zabrodska, Jan Prochazka, David Pajuelo Reguera, Zuzana Nichtova, Yann Herault, Sara Wells, Helen Parkinson, Jason D Heaney, Radislav Sedlacek, Xiang Gao, Martin Hrabe De Angelis, Nadine Spielmann

Faculty, Staff and Students Publications

This corrects the article "Establishing standardized transthoracic echocardiography reference ranges for mouse models: insights into the impact of anesthesia, sex, and age" in volume 12, 1695034.

Noradrenergic Innervation Across Brain Regions Is Altered By Aging And By Disease Progression In A Mouse Model Of Alzheimer’S Disease Neuropathology, Nicole M Hernandez, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Norepinephrine plays critical roles in modulating arousal and attention, is highly dynamic in awake, behaving individuals, and has anti-inflammatory and neuroprotective actions. Notably, the locus coeruleus (LC), the primary source of norepinephrine in the central nervous system, is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease (AD). LC neuronal loss and associated reductions in norepinephrine in the brain have therefore been postulated to play a key role in AD pathophysiology. LC neurons and their axons have been studied in several mouse models of AD-related neuropathology to investigate their contribution to brain dysfunction in …

Cultured Ex Vivo Human Brain Tissue Maintains Cell-Type Transcriptional Identities, J P Mcginnis, Sai Mallannagari, Maria Camila Guevara, Joshua Ortiz-Guzman, Benjamin D W Belfort, Suyang Bao, Snigdha Srivastava, Maria Morkas, Emily Ji, Kalman A Katlowitz, Angela Addison, Evelyne K Tantry, Carrie A Mohila, Melissa M Blessing, Nisha Gadgil, Samuel G Mcclugage, David F Bauer, William E Whitehead, Guillermo Aldave, Omar Tanweer, Naser Jaleel, Ali Jalali, Akash J Patel, Sameer A Sheth, Howard L Weiner, Shankar Gopinath, Ganesh Rao, Akdes Serin Harmanci, Daniel Curry, Benjamin R Arenkiel

Faculty, Staff and Students Publications

There is growing recognition of the need for human-based models of the nervous system and its diseases. Studies have investigated the electrophysiological properties of neurons in ex vivo human brain tissue, but the maintenance of other cell types remains unclear. We therefore used single-nucleus RNA sequencing of six patient samples to determine how well various cell types maintain their transcriptional identities over two weeks in organotypic slice culture (day 0, with 83 501 nuclei, and day 14, with 45 738). For each patient sample (two pediatric temporal lobectomies, one adult frontal cortex, two glioblastomas, and one medulloblastoma), we generated correlations …

Astrocytic Sox9 Overexpression In Alzheimer’S Disease Mouse Models Promotes Aβ Plaque Phagocytosis And Preserves Cognitive Function, Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes …

Old Lesions And New Targets: Seeg-Identified Onsets In Traditionally Inoperable Epilepsy Lesions And Associated Surgical Outcomes, Yosef M Dastagirzada, Spencer Frome, Daniel J Curry, Howard L Weiner

Faculty, Staff and Students Publications

Background: Patients with epilepsy who do not respond to pharmacotherapy are often offered a noninvasive diagnostic workup to localize an epileptogenic focus that might be treated with resection, neuromodulation, or ablation. Yet in many cases, this evaluation fails to identify surgical candidates.

Summary: Patients with tuberous sclerosis, periventricular nodular heterotopia, or polymicrogyria may have clearly visible lesions on MRI, but the resulting epileptogenic onset zones/networks are often too complex for scalp electroencephalography to decode. Similarly, seizures arising from the cingulate gyrus originate in deep structures that are inaccessible to noninvasive techniques. In post-traumatic epilepsy without a dominant lesion such as …

Surgical Outcomes And Learning Curve Of Robotic Single-Port Vaginal Natural Orifice Transluminal Endoscopic Surgery (Vnotes) Hysterectomy Using The Da Vinci Single-Port System, Qiannan Yang, Daniel Y Lovell, Xiaoming Guan

Faculty, Staff and Students Publications

Objective: This study aims to assess the surgical outcomes and learning curve of robotic single-port vaginal natural orifice transluminal endoscopic surgery (RSP-vNOTES) for hysterectomy in benign gynecologic conditions.

Materials and methods: A retrospective observational analysis was conducted of 97 consecutively enrolled patients who underwent RSP-vNOTES hysterectomy using the da Vinci (single-port) SP system between December 2023 and July 2025 at a single tertiary care center.

Results: Median procedural durations included a total operative time of 151 minutes, a port placement time of five minutes, a docking time of two minutes, a robotic console time of 78 minutes, and a hysterectomy …

Dynamic Progression Of Ectopic Lymphoid Structure Formation In Lacrimal Glands Of A Sjögren’S Disease Murine Model, Sara Abdelhamid, Alison V Ramirez, Emre Aksan, Elizaveta A Demianova, Cintia S De Paiva, Maria C Edman, J Andrew Mackay, Sarah F Hamm-Alvarez

Faculty, Staff and Students Publications

Background: Sjögren's Disease (SjD) is a chronic autoimmune condition characterized by lymphocytic infiltration of lacrimal glands (LG) and salivary glands (SG). In SG, these immune structures have properties of ectopic lymphoid structures (ELS) and appear to play a critical role in disease pathology. While the presence of ELS in patients' SG biopsies is linked to disease severity, their presence and composition in LG has not been well characterized.

Methods: The properties and time course of apparent ELS development in LG from the male non-obese diabetes free (NOR) sub-strain of the Non-Obese Diabetic (NOD) mice was investigated at stages encompassing early …

Using Lotilaner Ophthalmic Solution, 0.25% To Treat Demodex Blepharitis In Patients Who Were Initially Misdiagnosed: A Case Series, Laura M Periman, Richard Lindstrom, Paul Karpecki, Brandon Ayres, Eric Donnenfeld, Marjan Farid, Ian Benjamin Gaddie, Preeya K Gupta, Selina Mcgee, Kelly K Nichols, Stephen Pflugfelder, Christopher E Starr, Nandini Venkateswaran, Elizabeth Yeu, Cecelia Koetting

Faculty, Staff and Students Publications

Introduction: Demodex blepharitis (DB) is a chronic ocular inflammation caused by Demodex mite infestation of the eyelid. DB is often misdiagnosed, as some of its clinical findings and patient-reported outcomes overlap with those of other ocular surface diseases. The Demodex Expert Panel on Treatment and Eyelid Health (DEPTH) has reached consensus on the symptomatology, diagnosis, and treatment of DB. Consensus findings from the DEPTH group include that collarettes are pathognomonic for DB and that lotilaner ophthalmic solution, 0.25%, the first and only FDA-approved treatment for DB, should be the first-line treatment for the disease. This case series highlights two instances …

Utilizing A Culture System For Horizontal Cells To Study Neural Circuit Assembly In The Developing Mouse Retina, Ross M Perez, Yong H Park, Ajeet Singh, Collin Todora, Marlon F Mattos, Daniela Becerril, Rajashree Venkatraman, Arlene A Hirano, Nicholas C Brecha, Rinki Ratnapriya, Benjamin J Frankfort, Elizabeth Zuniga-Sanchez

Faculty, Staff and Students Publications

The precise wiring of the nervous system relies on neurons extending their processes at the right time and place to find their appropriate synaptic partner. The mechanisms that determine when and where neurons extend their neurites during synaptogenesis remains a central question in the field. In the present study, we used a cell culture system coupled with live imaging to investigate the wiring mechanisms in the developing mouse retina. We focused on horizontal cells which are a class of interneurons in the outer mouse retina known to synapse selectively to the distinct types of photoreceptors. Previous research has shown horizontal …

Common And Recurrent Dysregulated Molecular Network Of Placental Hypoxia And Associated Vasculogenesis And Angiogenesis In Fetal Growth Restriction, Wei Li, Xiaoyi Bai, Oi Ka Chan, Maran Bo Wah Leung, So Ling Lau, Chi Chiu Wang, Tak Yeung Leung

Faculty, Staff and Students Publications

Fetuses with fetal growth restriction (FGR) and selective FGR (sFGR) face elevated health risks both before and after birth. Although the underlying pathomechanisms remain unclear, placental dysfunction is recognized as a major contributing factor. By integrating untargeted transcriptomic data from FGR/sFGR placentae, this study identified 69 differentially expressed mRNAs (DEmRs) and eight differentially expressed miRNAs (DEmiRs). Functional enrichment analysis demonstrated significant enrichment in the angiogenesis and vasculogenesis pathways, with the hypoxia-related genes

Functional Analysis Of Genes Enriched In Male Reproductive Organs: Validation Via Fertility Assessment Of 14 Knockout Mouse Lines, Kazumasa Takemoto, Katarzyna Kent, Kaori Nozawa, Shingo Tonai, Ahn H Pham, Terumi Fujimoto, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa, Keizo Tokuhiro

Faculty, Staff and Students Publications

Tissue-restricted gene expression serves as a key indicator of functional importance within specific organs. Despite advances in high-throughput sequencing and genome editing over the past decade, this principle remains the gold standard for identifying candidate genes for functional studies. In reproductive biology, testis-restricted expression is anticipated to indicate genes crucial for gametogenesis, given the conserved features shared between spermatogenesis and oogenesis. Concurrently, rapid evolution of spermatogenesis-related genes is well documented and thought to arise through duplication and subsequent mutation of ubiquitously expressed genes. In this study, we established 14 knockout (KO) mouse lines for male reproductive organ-enriched genes, all of …

Host- And Pathogen-Related Determinants Of Pulmonary Versus Extrapulmonary Tuberculosis, Begna Tulu, Thomas Theo Brehm, Reinout Van Crevel, Tobias Dallenga, Andrew R Dinardo, Keertan Dheda, Johanna Eggeling, Wendemagegn Enbiale, Matthias I Gröschel, Jialun Hao, Vinod Kumar, Arjan Van Laarhoven, Rolanda Londt, Gareth Prosser, Philippa Randall, Norbert Reiling, Jan Rybniker, Ulrich E Schaible, Erwin Schurr, Isabelle Suarez, Sebastian J Theobald, Robert J Wilkinson, Christoph Lange

Faculty, Staff and Students Publications

Tuberculosis (TB) primarily manifests as pulmonary TB (PTB), but extrapulmonary TB (EPTB) remains a major clinical challenge. Distinct diagnostic and therapeutic difficulties arise from differences in immune responses, pathogen behaviour and host susceptibility. However, the factors driving disease localisation are still incompletely understood. We conducted a comprehensive narrative review of studies examining differences between PTB and EPTB in terms of epidemiology, mycobacterial factors, genetic and epigenetic determinants, host immune responses, transcriptomic profiles, cytokine and chemokine patterns, and immunophenotypes. EPTB is more common among females, children, older adults and immunocompromised individuals with deficient granuloma formation. This review is intended to provide …

Gender-Specific Behavior Reductions In Spontaneous Locomotive And Rearing In A Rat Model Of Paclitaxel-Induced Peripheral Neuropathy: A Pilot Study, Serena Jiyeon Kim, Kevin Cao, Patrick M Dougherty, Kathleen E Mcdonough, Saba Javed

Faculty, Staff and Students Publications

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) from agents like paclitaxel causes sensory loss and functional impairment, with limited treatment options. To better model patient-relevant outcomes, we used open field video tracking in rodents to assess gait, anxiety, and exploratory behavior. This approach provides a more comprehensive assessment of CIPN-related deficits beyond pain responses.

Methods and materials: Adult male and female Sprague Dawley rats were given paclitaxel (Taxol; 24 mg/kg cumulative dose) or a vehicle over 8 days. Their distance traveled, time spent in the center and outer zones of the OF test, and rearing behaviors were recorded using a PhenoTyper 4500 …

Netrin-1 Promotes Pancreatic Tumorigenesis And Innervation Through Neo1, Hiroki Kobayashi, Yosuke Ochiai, Junya Arai, Masahiro Hata, Feijing Wu, Masaki Sunagawa, Tadashi Iida, Taisuke Baba, Ermanno Malagola, Takayuki Tanaka, Zhengyu Jiang, Ruth A White, Xiaofei Zhi, Jin Qian, Quin T Waterbury, Ruhong Tu, Biyun Zheng, Yi Zeng, Hualong Zheng, Puran Zhang, Shuang Li, Leah B Zamechek, Jonathan S Labella, Takahiro Sugie, Atsushi Enomoto, Holger K Eltzschig, Carmine F Palermo, Iok In Christine Chio, Kenneth P Olive, Timothy C Wang

Faculty, Staff and Student Publications

Nerves can regulate tumorigenesis and cancer progression. However, clarification of the role of axon guidance molecules in tumorigenesis, innervation, and metastasis is required to better understand the tumor-promoting functions of nerves. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules and identified netrin-1 upregulation. Netrin-1 was also upregulated in vivo during pancreatic tumorigenesis in humans and mice. Mutant KRAS and β-adrenergic signaling upregulated netrin-1 and its receptor NEO1 in epithelial cells in part through the MAPK pathway. Ex vivo culture of celiac ganglia showed that netrin-1 promoted the axonogenesis of sympathetic neurons through nerve NEO1. In the Pdx1-Cre;LSL-KrasG12D/+ model, …

Gut Microbiome Metagenomics In Clinical Practice: Bridging The Gap Between Research And Precision Medicine, Henok Ayalew Tegegne, Tor C Savidge

Faculty, Staff and Students Publications

Gut microbiome metagenomics is emerging as a cornerstone of precision medicine, offering exceptional opportunities for improved diagnostics, risk stratification, and therapeutic development. Advances in high-throughput sequencing have uncovered robust microbial signatures linked to infectious, inflammatory, metabolic, and neoplastic diseases. Clinical applications now include pathogen detection, antimicrobial resistance profiling, microbiota-based therapies, and enterotype-guided patient stratification. However, translation into routine care is hindered by significant barriers including methodological variability, limited functional annotation, lack of bioinformatics standardization, and underrepresentation of global populations. This review synthesizes current translational strategies, emphasizing the need for hypothesis-driven designs, multi-omic integration, longitudinal and multi-center cohorts, and mechanistic validation. …

Novel Physical And Biological Applications Of Carbon Ion Radiotherapy, Danushka Seneviratne, Prapannajeet Biswal, Sunil Krishnan

The Brown Foundation: Institute of Molecular Medicine

Carbon ion radiation therapy (CIRT) is a high-LET radiotherapy, which distinguishes itself from traditional low-LET radiation, such as photons and protons, through its unique physical aspects, biological attributes, and the dramatically increased damage it causes within cellular DNA. Given its distinctive characteristics, it is expected to improve the therapeutic ratio of radiation treatments and enhance treatment outcomes in traditionally radiation-resistant tumor histologies. Despite these unique properties, much remains to be understood regarding the clinical use of CIRT before its full potential can be realized. In this review, we summarize the distinct advantages of CIRT with regard to its physical and …

Invasive Candidiasis In Critically Ill Patients: Fundamental Concepts And Future Directions, María Alejandra Pérez, Wesley J Hoffmann, J Christian Pérez, Max W Adelman

Faculty, Staff and Student Publications

Topic importance: Invasive candidiasis (IC) is a common complication in patients in ICUs. IC can be divided into bloodstream infections (candidemia) and deep-seated infections. Candida infections are associated with high mortality and longer hospital stays. Moreover, the emergence of Candida auris and other species prone to cause ICU outbreaks highlights the importance of this pathogen.

Review findings: Candidemia represents about 20% of bloodstream infections in ICU patients, whereas intraabdominal candidiasis, the most common form of deep-seated infection, predominantly affects surgical ICU patients. Regarding species distribution, Candida albicans is the most common species; however, non-albicans species have become more prevalent in …

Dcpr: A Deep Learning Framework For Circadian Phase Reconstruction, Xiao Han, Xiaochen Cen, Zhijin Li, Xiaobo Zhou, Zhiwei Ji

Faculty, Staff and Student Publications

Background: The circadian clock is an evolutionarily conserved system that orchestrates 24-h physiological rhythms through transcriptional and translational feedback loops. Mounting evidence suggests a bidirectional relationship between circadian rhythm alteration and disease progression, positioning the circadian clock as a potential therapeutic target. Due to the scarcity of high-resolution temporal omics data, it remains very challenging to elucidate the underlying regulatory mechanisms of the circadian system. As a practical alternative, public untimed transcriptomic datasets offer the potential to infer gene expression oscillations retrospectively. However, existing computational approaches for circadian phase estimation often suffer from limited predictive accuracy, reducing their ability to …

Sex Differences In Bile Acid Homeostasis And Excretion Underlie The Disparity In Liver Cancer Incidence Between Males And Females, Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate …

Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for …

Loss Of The Maternal Effect Gene Nlrp2 Impairs Embryonic And Extra-Embryonic Development, Revealing A Novel Genetic Cause Of Congenital Anomalies†, Momal Sharif, Zahra Anvar, Imen Chakchouk, Sara H El-Dessouky, Roni Zemet, Eric C Kao, Wessam E Sharaf-Eldin, Ying-Wooi Wan, Zhandong Liu, Pengfei Liu, Michael Jochum, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Maternal-effect genes (MEGs) play a crucial role in early mammalian development, and their dysfunction can lead to severe embryonic and extra-embryonic abnormalities. NLRP2, a MEG that encodes a subcortical maternal complex (SCMC) protein, has been implicated in preimplantation development, but its role after implantation remains underexplored. In this study, we investigated the developmental consequences of maternal Nlrp2 loss-of-function in a maternal knockout (KO) mouse model at embryonic day 11.5. Embryos derived from Nlrp2-KO females have abnormal yolk sac vasculature, increased embryonic resorption, craniofacial abnormalities, neural tube defects, and congenital heart defects. Placental architecture is disrupted with an altered junctional zone …

Amino Acid Signaling In Skeletal Muscle Is Blunted By Prematurity In A Piglet Model, Antonio C Ramos Dos Santos, Agus Suryawan, Ki Beom Jang, Rosemarie D Parada, Mahmoud A Mohammad, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

Background: Preterm (PT) infants are at increased risk for reduced postnatal lean mass accretion. We established that the feeding-induced stimulation of protein synthesis in skeletal muscle is blunted in piglets born PT compared with those born at term.

Objectives: We evaluated the extent to which key components of the amino acid-sensing pathways that regulate mechanistic target of rapamycin complex 1 (mTORC1) activation contribute to anabolic resistance in skeletal muscle of piglets born PT compared with those born term.

Methods: Piglets delivered by cesarean section 10 d PT (n = 23) or at term (n = 22) were administered total parenteral …

A Spatiotemporal Model Of Cxcl10 As A Master Regulator Of Immune Evasion And Metastasis In Osteosarcoma, Benjamin B Gyau, Tsz-Kwong Man

Faculty, Staff and Students Publications

The C-X-C motif chemokine ligand 10 (CXCL10) is implicated in the progression of osteosarcoma (OS), the most aggressive pediatric bone malignancy. However, its role often presents a profound clinical paradox: although high circulating levels are strongly linked to poor prognosis, its canonical function is to recruit anti-tumor immune cells. This review unravels these contrasting roles by proposing a novel spatiotemporal model. We argue that in the early stages, immune-evading OS cells initiate the formation of a pre-metastatic niche (PMN) in the lungs, creating a localized inflammatory environment that becomes the primary source of elevated circulating CXCL10. As the disease progresses, …

Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed …