Digital Commons Network^™

Inflammation In The Tumor-Adjacent Lung As A Predictor Of Clinical Outcome In Lung Adenocarcinoma, Igor Dolgalev, Hua Zhou, Nina Murrell, Hortense Le, Theodore Sakellaropoulos, Nicolas Coudray, Kelsey Zhu, Varshini Vasudevaraja, Anna Yeaton, Chandra Goparaju, Yonghua Li, Imran Sulaiman, Jun-Chieh J Tsay, Peter Meyn, Hussein Mohamed, Iris Sydney, Tomoe Shiomi, Sitharam Ramaswami, Navneet Narula, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw A Smolen, Wei-Yi Cheng, James Cai, Salman Punekar, Vamsidhar Velcheti, Daniel H Sterman, J T Poirier, Ben Neel, Kwok-Kin Wong, Luis Chiriboga, Adriana Heguy, Thales Papagiannakopoulos, Bettina Nadorp, Matija Snuderl, Leopoldo N Segal, Andre L Moreira, Harvey I Pass, Aristotelis Tsirigos

Faculty, Staff and Student Publications

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell …

Pericentrin Deficiency In Smooth Muscle Cells Augments Atherosclerosis Through Hsf1-Driven Cholesterol Biosynthesis And Perk Activation, Suravi Majumder, Abhijnan Chattopadhyay, Jamie M Wright, Pujun Guan, L Maximilian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme …

Voltage- And Calcium-Gated Membrane Currents Tune The Plateau Potential Properties Of Multiple Neuron Types, Curtis L Neveu, Paul Smolen, Douglas A Baxter, John H Byrne

Faculty, Staff and Student Publications

Many neurons exhibit regular firing that is limited to the duration and intensity of depolarizing stimuli. However, some neurons exhibit all-or-nothing plateau potentials that, once elicited, can lead to prolonged activity that is independent of stimulus intensity or duration. To better understand this diversity of information processing, we compared the voltage-gated and Ca²⁺-gated currents of three identified neurons from hermaphroditic Aplysia californica. Two of these neurons, B51 and B64, generated plateau potentials and a third neuron, B8, exhibited regular firing and was incapable of generating a plateau potential. With the exception of the Ca²⁺-gated potassium …

Counts, Incidence Rates, And Trends Of Pediatric Cancer In The United States, 2003–2019, David A Siegel, Jessica B King, Philip J Lupo, Eric B Durbin, Eric Tai, Kathi Mills, Elizabeth Van Dyne, Natasha Buchanan Lunsford, S Jane Henley, Reda J Wilson

Faculty, Staff and Students Publications

BACKGROUND: Cancer is a leading cause of death by disease among children and adolescents in the United States. This study updates cancer incidence rates and trends using the most recent and comprehensive US cancer registry data available.

METHODS: We used data from US Cancer Statistics to evaluate counts, age-adjusted incidence rates, and trends among children and adolescents younger than 20 years of age diagnosed with malignant tumors between 2003 and 2019. We calculated the average annual percent change (APC) and APC using joinpoint regression. Rates and trends were stratified by demographic and geographic characteristics and by cancer type.

RESULTS: With …

A Single Cell Genomics Atlas Of The Drosophila Larval Eye Reveals Distinct Photoreceptor Developmental Timelines, Komal Kumar Bollepogu Raja, Kelvin Yeung, Yoon-Kyung Shim, Yumei Li, Rui Chen, Graeme Mardon

Faculty, Staff and Students Publications

The Drosophila eye is a powerful model system to study the dynamics of cell differentiation, cell state transitions, cell maturation, and pattern formation. However, a high-resolution single cell genomics resource that accurately profiles all major cell types of the larval eye disc and their spatiotemporal relationships is lacking. Here, we report transcriptomic and chromatin accessibility data for all known cell types in the developing eye. Photoreceptors appear as strands of cells that represent their dynamic developmental timelines. As photoreceptor subtypes mature, they appear to assume a common transcriptomic profile that is dominated by genes involved in axon function. We identify …

Pharmacotherapies Targeting Gaba-Glutamate Neurotransmission For Treatment-Resistant Depression, Courtney M Vecera, Alan C Courtes, Gregory Jones, Jair C Soares, Rodrigo Machado-Vieira

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this …

The Functions Of Oligodendrocyte Lineage-Derived Laminins Under Homeostatic And Intracerebral Hemorrhagic Stroke Conditions, Minkyung Kang

USF Tampa Graduate Theses and Dissertations

Oligodendrocyte lineage is a glial cell population in the central nervous system. The lineage starts with oligodendrocyte precursor cells, which differentiate and mature into mature oligodendrocytes. Myelination, the major function of mature oligodendrocytes, plays a significant role for normal function of the central nervous system, and its dysfunction leads to many demyelinating diseases, such as multiple sclerosis. During the lineage progression, an extracellular matrix protein, laminin, actively regulates the cells' biology, including cell proliferation, differentiation, and myelination. However, the cellular sources of the laminin that controls oligodendrocyte lineage cells remain largely unknown. Interestingly, previous studies have shown that oligodendrocyte lineage …

Traumatic Stress-Induced Increases In Anxiety-Like Behavior And Alcohol Self-Administration Are Mediated By Central Amygdala Crf1 Neurons That Project To The Lateral Hypothalamus, Marcus M. Weera, Daniel A. Webster, Rosetta S. Shackett, Federica Benvenuti, Jason W. Middleton, Nicholas W. Gilpin

School of Graduate Studies Faculty Publications

Avoidance stress coping, defined as persistent internal and/or external avoidance of stress-related stimuli, is a key feature of anxiety- and stress-related disorders, and contributes to increases in alcohol misuse after stress exposure. Previous work using a rat model of predator odor stress avoidance identified corticotropin-releasing factor (CRF) signaling via CRF type-1 receptors (CRF1) in the central amygdala (CeA), as well as CeA projections to the lateral hypothalamus (LH) as key mediators of conditioned avoidance of stress-paired contexts and/or increased alcohol drinking after stress. Here, we report that CRF1-expressing CeA cells that project to the LH are preferentially activated in male …

Intouch Week Of November 6, 2023, New York Medical College

InTouch

• Dr. Victor Garcia Empowers the Next Generation of Scientists
• SOM Student Thomas Gagliardi Awarded AMA Physician of Tomorrow Scholarship
• NYMC Shines at the International Winter Eicosanoid Conference
• NYMC and TU Hosts “Ninety Minutes: The Medical Magazine of the Web”
• Student Accolade: NYMC Research | Eva Chorna, SOM Class of 2024

The Deubiquitinase Zranb1 Is An E3 Ubiquitin Ligase For Slc7a11 And Regulates Ferroptotic Resistance, Shan Huang, Qimin Zhang, Manyu Zhao, Xing Wang, Yilei Zhang, Boyi Gan, Peijing Zhang

Faculty, Staff and Student Publications

The dependency of cancer cells on iron increases their susceptibility to ferroptosis, thus providing new opportunities for patients with treatment-resistant tumors. However, we show that lipid peroxidation, a hallmark of ferroptosis, was found in various areas of patient samples, indicating the potential resistance of ferroptosis. Using whole deubiquitinases (DUBs) sgRNA screening, we found that loss of ZRANB1 confers cancer cell resistance to ferroptosis. Intriguingly, functional studies revealed that ZRANB1 ubiquitinates and represses SLC7A11 expression as an E3 ubiquitin ligase and that ZRANB1 inhibits glutathione (GSH) synthesis through SLC7A11 degradation, leading to elevated lipid peroxidation and ferroptosis. Deletion of the region …

Aptamers As Potential Therapeutic Tools For Ovarian Cancer: Advancements And Challenges, Wojciech Szymanowski, Anna Szymanowska, Anna Bielawska, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, Paola Amero

Faculty, Staff and Student Publications

Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of effective diagnostic methods, and relapses. Aptamers, synthetic, short single-stranded oligonucleotides, have emerged as promising anticancer therapeutics. Their ability to selectively bind to target molecules, including cancer-related proteins and receptors, has revolutionized drug discovery and biomarker identification. Aptamers offer unique insights into the molecular pathways involved in cancer development and progression. Moreover, they show immense potential as drug …

Molecular Mechanisms Of Twist1-Regulated Transcription In Emt And Cancer Metastasis, Xiaobin Yu, Tao He, Zhangwei Tong, Lan Liao, Shixia Huang, Walid D Fakhouri, Dean P Edwards, Jianming Xu

Faculty, Staff and Students Publications

TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to …

Mechanistic Toxicology In Light Of Genetic Compensation, Mary Jane Elizalde, Daniel A Gorelick

Faculty, Staff and Students Publications

Mechanistic toxicology seeks to identify the molecular and cellular mechanisms by which toxicants exert their deleterious effects. One powerful approach is to generate mutations in genes that respond to a particular toxicant, and then test how such mutations change the effects of the toxicant. CRISPR is a rapid and versatile approach to generate mutations in cultured cells and in animal models. Many studies use CRISPR to generate short insertions or deletions in a target gene and then assume that the resulting mutation, such as a premature termination codon, causes a loss of functional protein. However, recent studies demonstrate that this …

Machine Learning Methods For Endocrine Disrupting Potential Identification Based On Single-Cell Data, Zahir Aghayev, Adam T Szafran, Anh Tran, Hari S Ganesh, Fabio Stossi, Lan Zhou, Michael A Mancini, Efstratios N Pistikopoulos, Burcu Beykal

Faculty, Staff and Students Publications

Humans are continuously exposed to a variety of toxicants and chemicals which is exacerbated during and after environmental catastrophes such as floods, earthquakes, and hurricanes. The hazardous chemical mixtures generated during these events threaten the health and safety of humans and other living organisms. This necessitates the development of rapid decision-making tools to facilitate mitigating the adverse effects of exposure on the key modulators of the endocrine system, such as the estrogen receptor alpha (ERα), for example. The mechanistic stages of the estrogenic transcriptional activity can be measured with high content/high throughput microscopy-based biosensor assays at the single-cell level, which …

Plasma Metabolomics And Quantitative Interstitial Abnormalities In Ever-Smokers, Bina Choi, Raúl San José Estépar, Suneeta Godbole, Jeffrey L Curtis, Jennifer M Wang, Rubén San José Estépar, Ivan O Rosas, Jared R Mayers, Brian D Hobbs, Craig P Hersh, Samuel Y Ash, Meilan K Han, Russell P Bowler, Kathleen A Stringer, George R Washko, Wassim W Labaki

Faculty, Staff and Students Publications

BACKGROUND: Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality.

METHODS: In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles …

Comparative Analysis Of Swine Antibody Responses Following Vaccination With Live-Attenuated And Killed African Swine Fever Virus Vaccines, Hung Q. Luong, Huong T. L. Lai, Lam Q. Truong, The N. Nguyen, Hanh D. Vu, Hoa T. Nguyen, Lan T. Nguyen, Trang H. Pham, David Scott Mcvey, Hiep Vu

Nebraska Center for Virology: Faculty Publications

African swine fever virus (ASFV) is circulating in many swine-producing countries, causing significant economic losses. It is observed that pigs experimentally vaccinated with a live-attenuated virus (LAV) but not a killed virus (KV) vaccine develop solid homologous protective immunity. The objective of this study was to comparatively analyze antibody profiles between pigs vaccinated with an LAV vaccine and those vaccinated with a KV vaccine to identify potential markers of vaccineinduced protection. Thirty ASFV seronegative pigs were divided into three groups: Group 1 received a single dose of an experimental LAV, Group 2 received two doses of an experimental KV vaccine, …

Identification Of Blood Protein Biomarkers Associated With Prostate Cancer Risk Using Genetic Prediction Models: Analysis Of Over 140,000 Subjects, Hua Zhong, Jingjing Zhu, Shuai Liu, Dalia H Ghoneim, Praveen Surendran, Tao Liu, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Hong-Wen Deng, Herbert Yu, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant …

Repurposing Egfr Inhibitors For Oral Cancer Pain And Opioid Tolerance, Maria Daniela Santi, Morgan Zhang, Naijiang Liu, Chi T Viet, Tongxin Xie, Dane D Jensen, Moran Amit, Huilin Pan, Yi Ye

Faculty, Staff and Student Publications

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how …

Discovery, Structure-Activity Relationship And In Vitro Anticancer Activity Of Small-Molecule Inhibitors Of The Protein-Protein Interactions Between Af9/Enl And Af4 Or Dot1l, Xin Li, Xiaowei Wu, Shenyou Nie, Jidong Zhao, Yuan Yao, Fangrui Wu, Chandra Bhushan Mishra, Md Ashraf-Uz-Zaman, Bala Krishna Moku, Yongcheng Song

Faculty, Staff and Students Publications

Simple Summary

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene generate potent fusion oncogenes and cause acute myeloid leukemia or lymphocytic leukemia, which account for ~75% infant and 5–10% child/adult acute leukemia cases with a poor prognosis (5-year survival rates < 45%). Protein–protein interactions between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are critical to malignant gene expression and are therefore a potential drug target for cancer. Compound screening followed by medicinal chemistry studies identified several novel small-molecule inhibitors showing strong inhibition of these protein–protein interactions, significant suppression of characteristic gene expression, and robust cellular anticancer activities with negligible cytotoxicity. These compounds are useful chemical probes for biological studies of these protein–protein interactions, as well as pharmacological leads for further drug development against MLL-rearranged and other leukemias.

Abstract

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC₅₀ values as …

In Situ Profiling Reveals Metabolic Alterations In The Tumor Microenvironment Of Ovarian Cancer After Chemotherapy, Sara Corvigno, Sunil Badal, Meredith L Spradlin, Michael Keating, Igor Pereira, Elaine Stur, Emine Bayraktar, Katherine I Foster, Nicholas W Bateman, Waleed Barakat, Kathleen M Darcy, Thomas P Conrads, G Larry Maxwell, Philip L Lorenzi, Susan K Lutgendorf, Yunfei Wen, Li Zhao, Premal H Thaker, Michael J Goodheart, Jinsong Liu, Nicole Fleming, Sanghoon Lee, Livia S Eberlin, Anil K Sood

Faculty, Staff and Student Publications

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline …

Management Of Chronic Pain And Ptsd In Veterans With Tdcs+Prolonged Exposure: A Pilot Study, Melba A Hernandez-Tejada, Kathryn E Cherry, Sheila A M Rauch, Ron Acierno, Gabriel R Fries, Wendy Muzzy, Ellen J Teng, Bethany Wangelin, Hyochol Ahn

Faculty, Staff and Student Publications

Introduction: Chronic pain and posttraumatic stress disorder (PTSD) are prevalent comorbid conditions, particularly in Veterans; however, there are few integrated treatments for chronic pain and PTSD. Instead, interventions are typically implemented separately and may involve addictive opioids. Although there are highly effective, non-pharmacological treatments for PTSD, they are plagued by high dropout, which may be exacerbated by comorbid pain, as these PTSD treatments typically require increased activity. Importantly, a noninvasive pain treatment, tDCS (transcranial direct current stimulation) shows indications of effectiveness and may be integrated with psychological treatments, even when delivered via telehealth. This study examines the feasibility and initial …

How Irish Medical Scientists Can Assist In The Improved Diagnosis Of Disease - Infectious Mononucleosis (Im) A Case In Point, Patrick Naughton

ORBioM (Open Research BioSciences Meeting)

The Epstein-Barr Virus (EBV) or human herpesvirus 4 (HHV-4) is the sole etiologic agent of the acute illness in humans described either as infectious mononucleosis (IM), or glandular fever. IM is a self-limiting disease with various but transient symptoms which include fever, fatigue, malaise, sore throat, swollen lymph glands (particularly of the neck), swollen liver and spleen. Diagnosis relies on clear, timely and informative laboratory test results. Patients with primary IM infection often present on investigation with a well-documented population of atypical/plasmacytoid lymphocytes. The qualitative detection of heterophile antibodies (HAs) is also a useful aid in the diagnosis of primary …

Racial Disparities In Mit Family Translocation Renal Cell Carcinoma, Xiaofan Lu, Nassim Tawanaie Pour Sedehi, Xiaoping Su, Fangrong Yan, Omar Alhalabi, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Racial disparities have been documented in the biology and outcome of certain renal cell carcinomas (RCCs) among Black patients. However, little is known about racial differences in MiT family translocation RCC (TRCC). To investigate this issue, we performed a case-control study using data from The Cancer Genome Atlas (TCGA) and the Chinese OrigiMed2020 cohort. A total of 676 patients with RCC (14 Asian, 113 Black, and 525 White) were identified in TCGA, and TRCC was defined as RCC with TFE3/TFEB translocation or TFEB amplification, leading to 21 patients with TRCC (2 Asian, 8 Black, 10 White, and 1 unknown). Asian …

Conformational Ensemble-Dependent Lipid Recognition And Segregation By Prenylated Intrinsically Disordered Regions In Small Gtpases, Mussie K Araya, Alemayehu A Gorfe

Faculty, Staff and Student Publications

We studied diverse prenylated intrinsically disordered regions (PIDRs) of Ras and Rho family small GTPases using long timescale atomistic molecular dynamics simulations in an asymmetric model membrane of phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. Here we show that conformational plasticity is a key determinant of lipid sorting by polybasic PIDRs and provide evidence for lipid sorting based on both headgroup and acyl chain structures. We further show that conformational ensemble-based lipid recognition is generalizable to all polybasic PIDRs, and that the sequence outside the polybasic domain (PBD) modulates the conformational plasticity, bilayer adsorption, and interactions of PIDRs with membrane lipids. …

Srcap Mutations Drive Clonal Hematopoiesis Through Epigenetic And Dna Repair Dysregulation, Chun-Wei Chen, Linda Zhang, Ravi Dutta, Abhishek Niroula, Peter G Miller, Christopher J Gibson, Alexander G Bick, Jaime M Reyes, Yi-Tang Lee, Ayala Tovy, Tianpeng Gu, Sarah Waldvogel, Yi-Hung Chen, Bryan J Venters, Pierre-Olivier Estève, Sriharsa Pradhan, Michael-Christopher Keogh, Pradeep Natarajan, Koichi Takahashi, Adam S Sperling, Margaret A Goodell

Faculty, Staff and Students Publications

Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead …

Rare De Novo Gain-Of-Function Missense Variants In Dot1l Are Associated With Developmental Delay And Congenital Anomalies, Zelha Nil, Ashish R Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Siddharth Banka, Alexandra Afenjar, Cyril Mignot, Florence Robin-Renaldo, Boris Keren, Oguz Kanca, Xiao Mao, Daniel J Wegner, Kathleen Sisco, Marwan Shinawi, Undiagnosed Disease Network, Michael F Wangler, Rosanna Weksberg, Shinya Yamamoto, Gregory Costain, Hugo J Bellen

Faculty, Staff and Students Publications

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L …

Prognostic Value Of Integrative Genomic Approaches For Idh-Mutant Gliomas, Marco Gallo

Faculty, Staff and Students Publications

No abstract provided.

Tfeb And Tfe3 Control Glucose Homeostasis By Regulating Insulin Gene Expression, Adrien Pasquier, Nunzia Pastore, Luca D'Orsi, Rita Colonna, Alessandra Esposito, Veronica Maffia, Rossella De Cegli, Margherita Mutarelli, Susanna Ambrosio, Gennaro Tufano, Antonio Grimaldi, Marcella Cesana, Davide Cacchiarelli, Nathalie Delalleau, Gennaro Napolitano, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

To fulfill their function, pancreatic beta cells require precise nutrient-sensing mechanisms that control insulin production. Transcription factor EB (TFEB) and its homolog TFE3 have emerged as crucial regulators of the adaptive response of cell metabolism to environmental cues. Here, we show that TFEB and TFE3 regulate beta-cell function and insulin gene expression in response to variations in nutrient availability. We found that nutrient deprivation in beta cells promoted TFEB/TFE3 activation, which resulted in suppression of insulin gene expression. TFEB overexpression was sufficient to inhibit insulin transcription, whereas beta cells depleted of both TFEB and TFE3 failed to suppress insulin gene …

The Persistence Of Blue Ash In The Aftermath Of Emerald Ash Borer May Be Due To Adult Oviposition Preferences And Reduced Larval Performance, Don Cipollini, Emily Morton

Biological Sciences Faculty Publications

1. We examined the health of mature blue ash, Fraxinus quadrangulata, in two forests in southwestern Ohio in relation to that of mature white ash, F. americana, and examined the potential importance of oviposition preferences and larval resistance in the persistence of blue ash.
2. Both blue ash and white ash were largely unaffected by emerald ash borer in 2012. By 2018, nearly 90% of the blue ash trees observed in these forests had full or nearly full canopies, as opposed to less than 20% of the white ash encountered in our studies. In 2021, blue ash maintained a …

Microfluidic Coaxial 3d Bioprinting Of Cell-Laden Microfibers And Microtubes For Salivary Gland Tissue Engineering, Yu Yin, Ephraim J Vázquez-Rosado, Danielle Wu, Vignesh Viswananthan, Andrew Farach, Mary C Farach-Carson, Daniel A Harrington

Faculty, Staff and Student Publications

Replacement therapy for the salivary gland (SG) remains an unmet clinical need. Xerostomia ("dry mouth") due to hyposalivation can result from injury or disease to the SG, such as salivary acinar death caused by radiation therapy (RT) for head and neck squamous cell carcinoma (HNSCC). Currently, only palliative treatments exist for xerostomia, and many patients endure deteriorated oral health and poor quality of life. Tissue engineering could offer a permanent solution for SG replacement by isolating healthy SG tissues prior to RT, expanding its cells in vitro, and recreating a functional salivary neogland for implantation post-RT. 3D bioprinting methods potentiate …