Digital Commons Network^™

Polygenic Scores For Obstructive Sleep Apnoea Reveal Pathways Contributing To Cardiovascular Disease, Nuzulul Kurniansyah, Satu J Strausz, Geetha Chittoor, Shreyash Gupta, Anne E Justice, Yana Hrytsenko, Brendan T Keenan, Brian E Cade, Brian W Spitzer, Heming Wang, Jennifer Huffman, Matthew R Moll, Bernhard Haring, Su Yon Jung, Laura M Raffield, Robert Kaplan, Jerome I Rotter, Stephen S Rich, Sina A Gharib, Traci M Bartz, Peter Y Liu, Han Chen, Myriam Fornage, Lifang Hou, Daniel Levy, Alanna C Morrison, Heather M Ochs-Balcom, Bruce M Psaty, Peter W F Wilson, Kelly Cho, Allan I Pack, Hanna M Ollila, Susan Redline, Daniel J Gottlieb, Tamar Sofer

Faculty, Staff and Student Publications

Background: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors.

Methods: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger's MyCode, MGB Biobank, and the Human Phenotype Project, we …

Lmp7-Specific Inhibitor M3258 Modulates The Tumor Microenvironment Of Triple-Negative Breast Cancer And Inflammatory Breast Cancer, Xuemei Xie, Jangsoon Lee, Ganiraju C Manyam, Troy Pearson, Gina Walter-Bausch, Manja Friese-Hamim, Sheng Zhao, Julia Jabs, Angela A Manginelli, Nadine Piske, Thomas Mrowiec, Corinna M Wolf, Bharat S Kuntal, Debu Tripathy, Jing Wang, Michael P Sanderson, Naoto T Ueno

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8+ T …

Eph Receptors Activate Myeloid Checkpoint Receptor Lilrb5 To Support Tumor Development, Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Ryan Huang, Xing Yang, Jingjing Xie, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid …

Deep Learning Based Rapid X-Ray Fluorescence Signal Extraction And Image Reconstruction For Preclinical Benchtop X-Ray Fluorescence Computed Tomography Applications, Amrit Kaphle, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

Recent research advances have resulted in an experimental benchtop X-ray fluorescence computed tomography (XFCT) system that likely meets the imaging dose/scan time constraints for benchtop XFCT imaging of live mice injected with gold nanoparticles (GNPs). For routine in vivo benchtop XFCT imaging, however, additional challenges, most notably the need for rapid/near-real-time handling of X-ray fluorescence (XRF) signal extraction and XFCT image reconstruction, must be successfully addressed. Here we propose a novel end-to-end deep learning (DL) framework that integrates a one-dimensional convolutional neural network (1D CNN) for rapid XRF signal extraction with a U-Net model for XFCT image reconstruction. We trained …

Mesenchymal Stem Cells And Fibroblasts Contribute To Microvascular Proliferation In Glioblastoma And Are Correlated With Immunosuppression And Poor Outcome, Candice C Poon, Shelley M Herbrich, Yulong Chen, Anwar Hossain, Gregory N Fuller, Sonali Jindal, Sreyashi Basu, Daniel Ledbetter, Marc Macaluso, Lynnette M Phillips, Joy Gumin, Zhong He, Brittany C Parker Kerrigan, Sanjay K Singh, Pratishtha Singh, Mohammed Fayyad Zaman, Derek Ng Tang, Sangeeta Goswami, Frederick F Lang, Padmanee Sharma

Faculty, Staff and Student Publications

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45-CD105+ vascular/perivascular stromal cells (PVSC) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA …

Linking Dna Methylation In Brain Regions To Alzheimer’S Disease Risk: A Mendelian Randomization Study, Hua Zhong, Jingjing Zhu, Shuai Liu, Dan Zhou, Quan Long, Chong Wu, Bingxin Zhao, Chao Cheng, Yaohua Yang, Qing Wu, Yong Wu, Changwei Li, Zhaoming Wang, Jianyong Wu, Xingyi Guo, Degui Zhi, Youping Deng, Lang Wu

Faculty, Staff and Students Publications

Aim: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

Methods: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 …

Prediction Of Methotrexate Neurotoxicity Using Clinical, Sociodemographic, And Area-Based Information In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, Maria Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Center for Medical Ethics and Health Policy Staff Publications

Background: Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL.

Methods: We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 …

Oxygen Saturation Targeting In The Neonatal Intensive Care Unit, Faeq Almudares, Bheru Gandhi, Jonathan Davies, Xanthi Couroucli, Natalie Villafranco, Nidhy Paulose Varghese, Milenka Cuevas Guaman, Charleta Guillory, Binoy Shivanna

Faculty, Staff and Students Publications

Oxygen (O2) is vital for cellular development, function, proliferation, and repair, underscoring its critical role in organogenesis. Both hypoxia (reduced tissue O2) and hyperoxia (excess tissue O2), when prolonged, can trigger inflammation and oxidative stress, contributing to acute and long-term cardiopulmonary and neurodevelopmental morbidity. In sick neonates, immature defense mechanisms and coexisting morbidities demand nuanced and sometimes opposing strategies for O2 saturation targets and therapeutic titration. Most current neonatal O2 targeting guidelines are based on animal models or small clinical studies, resulting in recommendations with limited evidence. This narrative review aims to provide an updated overview of the physiological roles …

Assessment Of Water Quality Among Handwashing And Drinking Water Stations In Schools In Belize, 2022, Anh N Ly, Alexandra Kossik, Ary Sosa, Uriel Sosa, Dian Maheia, Yolanda Gongora, Russell Manzanero, Francis Morey, Melissa Diaz-Musa, Dennis Nichols, Adrianna Maliga, Kelsey Mcdavid, Christina Craig, Gerhaldine Morazan, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Water quality assessments are critical for ensuring timely responses to water-related concerns, particularly in low-resource areas with limited water, sanitation, and hygiene (WASH) infrastructure. In collaboration with the Belize Ministry of Health and Wellness and the Ministry of Education, Culture, Science and Technology, we conducted a survey on WASH infrastructure and resources among 221 schools. We identified 65 schools across all six districts of Belize for water quality testing. Among these 65 schools, 83% had at least one water sample that did not meet the WHO's recommended free chlorine residual level for drinking water. Additionally, coliforms and Escherichia coli were …

Tumor Microenvironment Governs The Prognostic Landscape Of Immunotherapy For Head And Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis, Priyan Bhattacharya, Alban J Linnenbach, Andrew P. South, Ubaldo E. Martinez-Outshoorn, Joseph M. Curry, Jennifer M. Johnson, Larry A. Harshyne, Mỹ G. Mahoney, Adam J. Luginbuhl, Rajanikanth Vadigepalli

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly …

Restoration Of The Tumor Suppressor Function Of Y220c-Mutant P53 By Rezatapopt, A Small-Molecule Reactivator, Anna M Puzio-Kuter, Lizhong Xu, Mary Kate Mcbrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky

Faculty, Staff and Student Publications

Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild-type p53 program. …

Maternal Loss Of Mouse Nlrp2 Alters The Transcriptome And Dna Methylome In Gv Oocytes And Impairs Zygotic Genome Activation In Embryos, Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van Den Veyver

Center for Medical Ethics and Health Policy Staff Publications

Background: NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.

Results: We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the …

Xbp1s-Edem2 Prevents The Onset And Development Of Hfpef By Ameliorating Cardiac Lipotoxicity, Oveena Fonseka, Rida Raja, Claire Ross, Sanskruti R Gare, Jiayan Zhang, Susanne S Hille, Katharine King, Andrea Ruiz-Velasco, Namrita Kaur, Xinyi Chen, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Zhiyong Zou, Xiangjun Zhao, Cristian Sotomayor-Flores, Derk Frank, Eileithyia Swanton, Martin R Pool, Sara Missaglia, Daniela Tavian, Gabriele G Schiattarella, Tao Wang, Luigi Venetucci, Christian Pinali, Martin K Rutter, Bernard D Keavney, Elizabeth J Cartwright, Tamer M A Mohamed, Oliver J Müller, Wei Liu

Center for Medical Ethics and Health Policy Staff Publications

Background: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing and treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying EDEM2 (endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2) regulation of cardiac lipid homeostasis and assess strategies that inhibit the incidence and progression of HFpEF.

Methods: Metabolic stress was induced in C57BL/6 male mice using a high-fat diet and Nω-nitro-L-arginine methyl ester. The recombinant adeno-associated virus 9 delivery system was used for loss- and gain-of-function studies. Palmitic acid and oleic acid …

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …

In Situ Structure And Assembly Of The Abc-Type Tripartite Pump Macab-Tolc, Tong Huo, Wenfang Zhang, Zhili Yu, Wei Zheng, Yaoming Wu, Qiuyu Ren, Zekai Wan, Junli Cao, Zhao Wang, Xiaodong Shi

Faculty, Staff and Students Publications

The MacAB-TolC tripartite efflux pump is widely distributed in Gram-negative bacteria, extruding antibiotics and virulence factors that lead to multidrug resistance and pathogenicity. However, the in situ structure and assembly mechanism of MacAB-TolC remain unclear. Here, we resolve the in situ structures of the MacAB-TolC efflux pump in Escherichia coli by electron cryo-tomography and subtomogram averaging. In the cells without antibiotic treatment, we observe a fully assembled MacAB-TolC pump. When Escherichia coli cells are treated with erythromycin, in addition to the tripartite pumps, we also discover the emergence of MacA-TolC subcomplexes without MacB, indicating flexible binding of MacB in the …

Correlations Within And Between Highly Multiplexed Proteomic Assays Of Human Plasma, Mary R Rooney, Jingsha Chen, Christie M Ballantyne, Ron C Hoogeveen, Eric Boerwinkle, Bing Yu, Keenan A Walker, Pascal Schlosser, Elizabeth Selvin, Nilanjan Chatterjee, David Couper, Morgan E Grams, Josef Coresh

Faculty, Staff and Students Publications

Introduction: The number of assays on proteomic platforms has grown rapidly. The leading platforms, SomaScan and Olink, have strengths and limitations. Comparisons of precision on the latest platforms-SomaScan 11k and Olink Explore HT-have not yet been established.

Methods: Among 102 participants in the Atherosclerosis Risk in Communities Study (mean age 74 years, 53% women, 47% Black), we used split plasma samples to measure platform precision. CV and Spearman correlations were calculated for each assay. Cross-platform agreement was assessed for overlapping proteins.

Results: SomaScan 11k demonstrated a median correlation of 0.85 for the 10 778 assays and a median CV of …

Oral Pcsk9 Inhibitors: Can Novel Therapies Overcome Barriers To Effective Ldl-Cholesterol Management?, Christie M Ballantyne, Alberico L Catapano, Khurram Nasir

Faculty, Staff and Students Publications

No abstract provided.

Beyond The Surface: Mapping Dde's Metabolic Footprint On Adolescent Obesity, Zhenjiang Li, Shudi Pan, Brittney O Baumert, Jiawen Carmen Chen, Jesse A Goodrich, Hongxu Wang, Sarah Rock, Justin Ryder, Damaskini Valvi, Todd Jenkins, Stephanie Sisley, Xiangping Lin, Scott M Bartell, Thomas H Inge, Stavra Xanthakos, Brooklynn Mcneil, Anna R Robuck, Catherine E Mullins, Sandrah P Eckel, Rob S Mcconnell, Michele A La Merrill, Douglas I Walker, David V Conti, Lida Chatzi

Faculty, Staff and Students Publications

Background: Bariatric surgery is an intervention for severe obesity, leading to significant weight loss and metabolic improvements. However, the release of lipophilic chemicals accumulated in adipose tissue during weight loss presents a unique clinical challenge and research opportunity. Dichlorodiphenyldichloroethylene (DDE) is a persistent organic pollutant increasingly recognized as obesogen, while the biological mechanisms through which DDE influences body mass index (BMI) and waist circumference remain underexplored.

Objectives: We aimed to identify metabolic signatures mediating the association between DDE exposure and weight loss by plasma and adipose tissue metabolomics.

Methods: We conducted a longitudinal study involving 60 adolescents with severe obesity …

Lipoprotein(A) And Heart Failure Among Black And White Participants In Atherosclerosis Risk In Communities Study, Framingham Offspring Study, And Multi-Ethnic Study Of Atherosclerosis: The Pooling Project, Sarah Nomura, Weihua Guan, Yixin Zhang, Geoffrey H Tison, Hiroaki Ikezaki, Margaret R Diffenderfer, Ching-Ti Liu, Ron C Hoogeveen, Christie M Ballantyne, Ernst J Schaefer, Michael Y Tsai

Faculty, Staff and Students Publications

Background: This study investigated Lp(a) (lipoprotein(a)) levels with heart failure (HF) incidence overall and ejection fraction (EF) subtypes among Black and White participants in a pooled analysis of MESA (Multi-Ethnic Study of Atherosclerosis), FOS (Framingham Offspring Study), and ARIC (Atherosclerosis Risk in Communities Study).

Methods: This study was conducted among 16 771 White and Black participants in ARIC (N=10 347), MESA (N=4150), and FOS (N=2274). Baseline was time of Lp(a) measurement (ARIC Visit 4: 1996-1998; MESA Visit 1: 2000-2002; FOS Cycle 6: 1995-1998). HF with reduced EF (HFrEF) was defined as EF < 50% and ≥50% as HF with preserved EF (HFpEF). Cox proportional hazards regression was used to evaluate associations between Lp(a) (log-transformed continuous, dichotomized at ≥30 mg/dL and ≥50 mg/dL, and quartiles) and HF (overall, HFpEF, HFrEF) in the overall population and stratified by race. Analyses were replicated excluding prior history of myocardial infarction.

Results: There were 2759 HF cases (HFpEF N=859; …

Phage-Induced Protection Against Lethal Bacterial Reinfection, Yikun Xing, Haroldo J Hernandez Santos, Ling Qiu, Samantha R Ritter, Jacob J Zulk, Rachel Lahowetz, Kathryn A Patras, Austen L Terwilliger, Anthony W Maresso

Faculty, Staff and Students Publications

Bacteriophages, or phages, are viruses that target and infect bacteria. Due to a worldwide rise in antimicrobial resistance (AMR), phages have been proposed as a promising alternative to antibiotics for the treatment of resistant bacterial infections. Up to this point in history, phage use in preclinical animal studies, clinical trials, and emergency-use compassionate care cases has centered around the original observation from 1915 showing phage as lytic agent, and thus a treatment that kills bacteria. Here, we describe an activity associated with phage therapy that extends beyond lytic activity that results in long-term protection against reinfection. This activity is potent, …

Mutant P53 Gain Of Function: Why Many See It, Why Some Do Not, Guillermina Lozano, Carol Prives, Kanaga Sabapathy

Faculty, Staff and Student Publications

Mutations in the TP53 tumor-suppressor gene in human cancer are unique in that 60% to 70% are of the missense variety, resulting in a full-length protein that is often highly expressed in patients' tumors. These missense mutant proteins often exhibit pro-oncogenic activities (referred to as gain of function) in mouse models and human cell lines and correlate with poor cancer prognosis in some cases.

Mutation Of Smarca4 Induces Cancer Cell-Intrinsic Defects In The Enhancer Landscape And Resistance To Immunotherapy, Yawen Wang, Ismail M Meraz, Md Qudratullah, Sasikumar Kotagiri, Yanyan Han, Yuanxin Xi, Jing Wang, Kadir C Akdemir, Jack A Roth, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent alterations in genes encoding components of the SWI/SNF chromatin remodeling complex, including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. In this study, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, models with SMARCA4 loss showed decreased response to anti-PD-1 immunotherapy associated with significantly reduced infiltration of dendritic cells and CD4+ T cells into the tumor microenvironment. SMARCA4 loss in tumor cells led to profound downregulation of STING1, IL1β, and …

Present And Future Of Microbiome-Targeting Therapeutics, Lauren E Lynch, Rachel Lahowetz, Christian Maresso, Austen Terwilliger, Jason Pizzini, Valeria Melendez Hebib, Robert A Britton, Anthony W Maresso, Geoffrey A Preidis

Children’s Nutrition Research Center Staff Publications

A large body of evidence suggests that single- and multiple-strain probiotics and synbiotics could have roles in the management of specific gastrointestinal disorders. However, ongoing concerns regarding the quality and heterogeneity of the clinical data, safety in vulnerable populations, and the lack of regulation of products containing live microbes are barriers to widespread clinical use. Safety and regulatory issues must be addressed and new technologies considered. One alternative future strategy is the use of synthetic bacterial communities, defined as manually assembled consortia of two or more bacteria originally derived from the human gastrointestinal tract. Synthetic bacterial communities can model functional, …

Intouch Week Of June 2, 2025, New York Medical College

InTouch

• NYMC Celebrates the Class of 2025 at 166th Commencement
• SOM Awards Ceremony Honors Excellence
• SHSP Dean’s Awards Recognize Rising Health Leaders
• GSBMS Honors Excellence in Biomedical Science at Annual Awards Ceremony
• TCDM Celebrates the Class of 2025
• Noninvasive Method for Early Intraventricular Hemorrhage Detection in Preemies Revealed

Suppression Of Brca1 Facilitates Kidney Regeneration, Kaira A Church, Xunian Zhou, Raghu Kalluri

Faculty, Staff and Student Publications

Maladaptive repair following kidney injury leads to the development of kidney disease. In this issue of JEM, Ajay et al. (https://doi.org/10.1084/jem.20231107) uncover the role of breast cancer susceptibility gene 1 (BRCA1) in cell cycle arrest, DNA damage, and cell senescence, preventing maladaptive repair.

Drosha: A New Tumor Suppressor In Pineoblastoma, Zhixuan Huang, Xueli Ren, Jian Hu

Faculty, Staff and Student Publications

In this Outlook, Huang et al. discuss a study in this issue of Genes & Development by Fraire et al. that shows that a deficiency in miRNA processors Drosha and Dicer and consequent cell cycle gene derepression promote pineoblastoma development. The authors highlight the heterogeneity of pineoblastoma's pathogenic mechanisms and its implications for therapeutic interventions in the clinic.

Hyaluronan Network Remodeling By Zeb1 And Itih2 Enhances The Motility And Invasiveness Of Cancer Cells, Sieun Lee, Jihye Park, Seongran Cho, Eun Ju Kim, Seonyeong Oh, Younseo Lee, Sungsoo Park, Keunsoo Kang, Dong Hoon Shin, Song Yi Ko, Jonathan M Kurie, Young-Ho Ahn

Faculty, Staff and Student Publications

Hyaluronan (HA) in the extracellular matrix promotes epithelial-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-α-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when cocultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and …

A Comprehensive, Multi-Center, Immunogenomic Analysis Of Melanoma Brain Metastases, Lucy Boyce Kennedy, Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Jeff Sheng, Dadong Zhang, Xiaodi Qin, Eric S Lipp, Swaminathan Kumar, Aron Joon, Pixu Shi, Michael A Davies, Kouros Owzar, Carey K Anders, April K S Salama

Faculty, Staff and Student Publications

Background: Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies.

Methods: We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. …

Harnessing Electrophiles In Vivo: A Pilot Study In Swine Using A Hydrophobic Radiopaque Formulation Of 2-Propylpentanoyl Chloride, Erik Cressman, Danielle Stolley, Natalie Fowlkes, Edd Felix, Waldemar Priebe, Steve Parrish, David Fuentes

Faculty, Staff and Student Publications

Manipulating biology through chemistry is older than the discipline of chemistry itself. Traditionally, selectivity of oral or intravenous drugs relied on preferential drug-receptor binding. A novel approach exploiting image-guided techniques to impart spatial selectivity opens up a wide range of new possibilities for study and manipulation of biology. Motivated initially by the poor prognosis for solid tumors such as liver cancer, we demonstrate the use of an extreme form of in vivo chemistry for targeted delivery of 2-propylpentanoyl chloride in a swine model. The ensuing reaction in tissue devitalizes it by multiple mechanisms with lasting effects and, critically, demonstrates very …

Ocular Phenotyping Of Knockout Mice Identifies Genes Associated With Late Adult Retinal Phenotypes, Abraham Hang, Andy Shao, Michael Shea, Michel J Roux, Denise M Imai-Leonard, David J Adams, Takanori Amano, Oana V Amarie, Zorana Berberovic, Raphaël Bour, Lynette Bower, Brian C Leonard, Steve D Brown, Soo Young Cho, Sharon Clementson-Mobbs, Abigail J D'Souza, Mary Dickinson, Mohammad Eskandarian, Ann M Flenniken, Helmut Fuchs, Valerie Gailus-Durner, Jason Heaney, Yann Hérault, Martin Hrabe De Angelis, Chih-Wei Hsu, Shundan Jin, Russell Joynson, Yeon Kyung Kang, Haerim Kim, Hiroshi Masuya, Ki-Hoan Nam, Hyuna Noh, Lauryl M J Nutter, Marcela Palkova, Jan Prochazka, Miles Joseph Raishbrook, Fabrice Riet, Jason Salazar, John Richard Seavitt, Radislav Sedlacek, Mohammed Selloum, Kyoung Yul Seo, Je Kyung Seong, Hae-Sol Shin, Toshihiko Shiroishi, Tania Sorg, Michelle Stewart, Masaru Tamura, Heather Tolentino, Uchechukwu Udensi, Sara Wells, Wolfgang Wurst, Atsushi Yoshiki, Hamid Meziane, Glenn Yiu, Paul A Sieving, Louise Lanoue, K C Kent Lloyd, Colin Mckerlie, Ala Moshiri, International Mouse Phenotyping Consortium (Impc)

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Analyze phenotypic data from knockout mice with late-adult retinal pathologic phenotypes to identify genes associated with development of adult-onset retinal diseases.

Methods: The International Mouse Phenotyping Consortium (IMPC) database was queried for genes associated with abnormal retinal phenotypes in the late-adult knockout mouse pipeline (49-80 weeks postnatal age). We identified human orthologs and performed protein-protein analysis and biological pathways analysis with known inherited retinal disease (IRD) and age-related macular degeneration (AMD) genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), PLatform for Analysis of single cell Eye in a Disk (PLAE), Protein Analysis Through Evolutionary Relationships (PANTHER), …