Digital Commons Network^™

N-Terminal Α-Amino Sumoylation Of Cofilin-1 Is Critical For Its Regulation Of Actin Depolymerization, Weiji Weng, Xiaokun Gu, Yang Yang, Qiao Zhang, Qi Deng, Jie Zhou, Jinke Cheng, Michael X Zhu, Junfeng Feng, Ou Huang, Yong Li

Faculty, Staff and Student Publications

Small ubiquitin-like modifier (SUMO) typically conjugates to target proteins through isopeptide linkage to the ε-amino group of lysine residues. This posttranslational modification (PTM) plays pivotal roles in modulating protein function. Cofilins are key regulators of actin cytoskeleton dynamics and are well-known to undergo several different PTMs. Here, we show that cofilin-1 is conjugated by SUMO1 both in vitro and in vivo. Using mass spectrometry and biochemical and genetic approaches, we identify the N-terminal α-amino group as the SUMO-conjugation site of cofilin-1. Common to conventional SUMOylation is that the N-α-SUMOylation of cofilin-1 is also mediated by SUMO activating (E1), conjugating (E2), …

Cardiovascular Disease And Stroke In Immune Ttp-Challenges And Opportunities, Senthil Sukumar, Marshall A Mazepa, Shruti Chaturvedi

Faculty, Staff and Students Publications

Advances in the management of immune thrombotic thrombocytopenic purpura (iTTP) have dramatically improved outcomes of acute TTP episodes, and TTP is now treated as a chronic, relapsing disorder. It is now recognized that iTTP survivors are at high risk for vascular disease, with stroke and myocardial infarction occurring at younger ages than in the general population, and cardiovascular disease is the leading cause of premature death in this population. iTTP appears to have a phenotype of accelerated vascular aging with a particular predilection for cerebral circulation, and stroke is much more common than myocardial infarction. In addition to traditional cardiovascular …

Speg Interactions That Regulate The Stability Of Excitation-Contraction Coupling Protein Complexes In Triads And Dyads, Chang Seok Lee, Sung Yun Jung, Rachel Sue Zhen Yee, Nadia H Agha, Jin Hong, Ting Chang, Lyle W Babcock, Jorie D Fleischman, Benjamin Clayton, Amy D Hanna, Christopher S Ward, Denise Lanza, Ayrea E Hurley, Pumin Zhang, Xander H T Wehrens, William R Lagor, George G Rodney, Susan L Hamilton

Faculty, Staff and Students Publications

Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) …

The Impact Of Home Confinement By Covid-19 On Mood State And Adaptive Behaviors In Spanish Swimmers, Jose Carlos Jaenes, David Alarcon Rubio, María José Arenilla-Villalba, Dominika Wilczyńska

Baltic Journal of Health and Physical Activity

Introduction: This study aimed to assess the mental condition of aquatic athletes during COVID-19 lockdowns and identify factors that could predict changes in their emotions and mood disturbances. Materials and Methods: The sample was composed of 506 competitive swimmers (ages 15-36) in four aquatic specializations, with 82.4% competing at the national level. Data was collected through questionnaires between April 10th and May 1st, 2020. Results: Female athletes had higher levels of unpleasant mood states and were generally more vulnerable to the lockdown's harmful effects. Team athletes had higher levels of friendliness, which may be a coping strategy for difficult situations. …

Quality Of Cardiopulmonary Resuscitation Performed Over Hockey Shoulder Pads: A Simulation Study, Jennifer Longo, Katie J. Lyman, Thomas A. Hanson, Adam G. Estabrooks

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Purpose: Athletic trainers (ATs) must be prepared to manage cardiac arrest events in all athletes, including those participating in equipment-intensive sports. The goal of this study was to determine if first responders, specifically ATs, were able to perform high-quality cardiopulmonary resuscitation (CPR) over hockey shoulder pads. Methods: A sample of 50 ATs completed a one-minute, compression-only CPR proficiency test on a medium-fidelity manikin (Resusci Anne QCPR). Once deemed proficient, each participant completed CPR according to 2020 AHA guidelines on the manikin fitted with hockey shoulder pads for 8 minutes and 59 seconds. The primary measures of interest were the percentage …

Anti-Inflammatory And Antioxidant Effects Of Sea Urchin Spine Extract, Dina Magdy El Gamal

The Undergraduate Research Journal

Diadema savignyi spine extract in an experimental setup using L929 cell line in vitro. The cell metabolic activity of L929 cells is tested through an MTT assay. The sea urchin spine extract is applied to the cells in two concentrations: 100 μg/ml (136% viability) and 200 μg/ml (95% viability). The bioactive components of the sea urchin spine are identified via GC-MS, and the antioxidant and anti-inflammatory activities are evaluated using catalase assay (CAT), glutathione (GSH), and nitric oxide (NO) tests. Results show that the GC-MS identified bioactive components including the anti-inflammatory and anti-irritant bisabolol oxide and the pro-inflammatory oleic acid. …

The Effectiveness Of Disinfection Protocols In Osteopathic Family Medicine Offices, Riley Phyu, Harrison A Patrizio, Thomas Boyle, Todd Schachter

Rowan-Virtua School of Osteopathic Medicine Departmental Research

CONTEXT: Healthcare-associated infections (HAIs) pose a substantial public health threat. Despite significant strides to curb HAIs in hospital environments, outpatient settings have not received the same degree of attention. Given their emphasis on holistic, patient-centered care, osteopathic family medicine offices are pivotal in both disease prevention and comprehensive patient treatment. The importance of simple yet effective disinfection protocols, such as thorough cleaning between patient appointments, cannot be overstated in these settings because they are integral to minimizing disease transmission.

OBJECTIVES: This study aims to assess the effectiveness of the current disinfection protocols in osteopathic family medicine offices.

METHODS: A cross-sectional …

Radio-Pathomic Approaches In Pediatric Neurooncology: Opportunities And Challenges, Ariana M. Familiar, Aria Mahtabfar, Anahita Fathi Kazerooni, Mahsa Kiani, Arastoo Vossough, Angela Viaene, Philip B. Storm, Adam C. Resnick, Ali Nabavizadeh

Department of Neurosurgery Faculty Papers

With medical software platforms moving to cloud environments with scalable storage and computing, the translation of predictive artificial intelligence (AI) models to aid in clinical decision-making and facilitate personalized medicine for cancer patients is becoming a reality. Medical imaging, namely radiologic and histologic images, has immense analytical potential in neuro-oncology, and models utilizing integrated radiomic and pathomic data may yield a synergistic effect and provide a new modality for precision medicine. At the same time, the ability to harness multi-modal data is met with challenges in aggregating data across medical departments and institutions, as well as significant complexity in modeling …

Examining Pi3k-Signaling-Dependent Regulation Of Lens Organelle Free Zone Formation Via Immunolocalization And Immunoblotting In Chick Embryos, Rifah Gheyas, A. Sue Menko

Computational Medicine Center Faculty Papers

The elimination of lens organelles during development, required for mature lens function, is an autophagy-dependent mechanism induced through suppression of PI3K signaling. Here, we present a protocol for investigating the signaling pathways responsible for induction of the formation of this lens organelle free zone. We describe steps for preparation of lens organ culture and use of signaling pathway inhibitors. We then detail procedures for analyzing their impact using both confocal microscopy imaging of immunolabeled lens cryosections and immunoblot approaches. For complete details on the use and execution of this protocol, please refer to Gheyas et al. (2022).

Dosimetry Of A Novel 111indium-Labeled Anti-P-Cadherin Monoclonal Antibody (Ff-21101) In Non-Human Primates, Gregory Ravizzini, William Erwin, Louis De Palatis, Lucia Martiniova, Vivek Subbiah, Vincenzo Paolillo, Jennifer Mitchell, Asa P Mccoy, Jose Gonzalez, Osama Mawlawi

Faculty, Staff and Student Publications

P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human-mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were …

A Real-Time Contouring Feedback Tool For Consensus-Based Contour Training, Christopher L Nelson, Callistus Nguyen, Raymond Fang, Laurence E Court, Carlos E Cardenas, Dong Joo Rhee, Tucker J Netherton, Raymond P Mumme, Skylar Gay, Casey Gay, Barbara Marquez, Mohammad D El Basha, Yao Zhao, Mary Gronberg, Soleil Hernandez, Kelly A Nealon, Mary K Martel, Jinzhong Yang

Faculty, Staff and Student Publications

PURPOSE: Variability in contouring structures of interest for radiotherapy continues to be challenging. Although training can reduce such variability, having radiation oncologists provide feedback can be impractical. We developed a contour training tool to provide real-time feedback to trainees, thereby reducing variability in contouring.

METHODS: We developed a novel metric termed localized signed square distance (LSSD) to provide feedback to the trainee on how their contour compares with a reference contour, which is generated real-time by combining trainee contour and multiple expert radiation oncologist contours. Nine trainees performed contour training by using six randomly assigned training cases that included one …

Gut Barrier Defects, Intestinal Immune Hyperactivation And Enhanced Lipid Catabolism Drive Lethality In Ngly1-Deficient Drosophila, Ashutosh Pandey, Antonio Galeone, Seung Yeop Han, Benjamin A Story, Gaia Consonni, William F Mueller, Lars M Steinmetz, Thomas Vaccari, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of Pngl in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of Pngl mutants rescued their developmental delay but not …

Global Impact Of Somatic Structural Variation On The Cancer Proteome, Fengju Chen, Yiqun Zhang, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels …

Shp2 Promotes Sarcoidosis Severity By Inhibiting Skp2-Targeted Ubiquitination Of Tbet In Cd8+ T Cells, Sherly I Celada, Clarice X Lim, Alexandre F Carisey, Scott A Ochsner, Carlos F Arce Deza, Praveen Rexie, Fernando Poli De Frias, Rafael Cardenas-Castillo, Francesca Polverino, Markus Hengstschläger, Konstantin Tsoyi, Neil J Mckenna, Farrah Kheradmand, Thomas Weichhart, Ivan O Rosas, Luc Van Kaer, Lindsay J Celada

Faculty, Staff and Students Publications

Sarcoidosis is an interstitial lung disease (ILD) characterized by IFNγ and TBET dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we report that pharmacological inhibition of phosphorylated SH2 containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFNγ levels, decreases large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8+ T cells. Mechanistically, our findings identified a previously unknown post-translational modification (PTM) pathway in which the E3 F-box …

The Use Of Prognostic Markers To Predict Disease Progression And Clinical Outcome In Monoclonal Gammopathy Of Undetermined Significance, Smouldering Multiple Myeloma And Multiple Myeloma., Róisín C. Mcmonagle

International Undergraduate Journal of Health Sciences

Multiple Myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM) precede MM, with variable risks and rates of disease progression. The continuing high relapse and death rate in MM cases has prompted research into more accurate prognostic markers to predict progression from MGUS and SMM to MM, as well as identify MM cases with aggressive disease, in order to begin early, targeted and effective therapeutic intervention. Many studies have focused on utilising current markers more effectively, including M-protein, serum-free light chain ratio, …

Biosafety And Biohazard Considerations Of Hsv-1-Based Oncolytic Viral Immunotherapy., Elizabeth Robilotti, Nathalie C Zeitouni, Marlana Orloff

Department of Medical Oncology Faculty Papers

Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with …

The Endosomal Escape Vehicle Platform Enhances Delivery Of Oligonucleotides In Preclinical Models Of Neuromuscular Disorders, Xiang Li, Mahboubeh Kheirabadi, Patrick G Dougherty, Kimberli J Kamer, Xiulong Shen, Nelsa L Estrella, Suresh Peddigari, Anushree Pathak, Sara L Blake, Emmanuelle Sizensky, Carmen Del Genio, Arti B Gaur, Mohanraj Dhanabal, Mahasweta Girgenrath, Natarajan Sethuraman, Ziqing Qian

Faculty, Staff and Student Publications

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of …

Interaction Between Myelodysplasia-Related Gene Mutations And Ontogeny In Acute Myeloid Leukemia, Joseph G W Mccarter, David Nemirovsky, Christopher A Famulare, Noushin Farnoud, Abhinita S Mohanty, Zoe S Stone-Molloy, Jordan Chervin, Brian J Ball, Zachary D Epstein-Peterson, Maria E Arcila, Aaron J Stonestrom, Andrew Dunbar, Sheng F Cai, Jacob L Glass, Mark B Geyer, Raajit K Rampal, Ellin Berman, Omar I Abdel-Wahab, Eytan M Stein, Martin S Tallman, Ross L Levine, Aaron D Goldberg, Elli Papaemmanuil, Yanming Zhang, Mikhail Roshal, Andriy Derkach, Wenbin Xiao

Faculty, Staff and Student Publications

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort …

Cell-Type-Specific Alternative Polyadenylation Promotes Oncogenic Gene Expression In Non-Small Cell Lung Cancer Progression, Kexin Huang, Yun Zhang, Xiaorui Shi, Zhiqin Yin, Weiling Zhao, Liyu Huang, Fu Wang, Xiaobo Zhou

Faculty, Staff and Student Publications

Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and …

Description Of A New Pavlovskyella Species (Acari: Argasidae) From Chile, Sebastián Muñoz-Leal, José M Venzal, Alexander R Kneubehl, Job E Lopez, Thiago F Martins, Marcelo B Labruna

Faculty, Staff and Students Publications

Soft ticks (Argasidae) of the Pavlovskyella Pospelova-Shtrom subgenus are important vectors of relapsing fever spirochetes, which are agents of disease globally. South American representatives of the Pavlovskyella subgenus include 3 species: Ornithodoros (Pavlovskyella) brasiliensis Aragão, Ornithodoros (Pavlovskyella) furcosus Neumann, and Ornithodoros (Pavlovskyella) rostratus Aragão. Here, we describe a fourth species based on morphological and mitogenomic evidence of ticks collected in burrows of unknown hosts in central Chile. The larva of the new species separates from other South American soft ticks by the following combination of characters: 13 pairs of dorsolateral setae, dorsal plate hexagonal, hypostome blunt with denticles from apex …

Disease Modeling And Gene Correction Of Lgmdr21 Ipscs Elucidates The Role Of Poglut1 In Skeletal Muscle Maintenance, Regeneration, And The Satellite Cell Niche, Jose L Ortiz-Vitali, Jianbo Wu, Nasa Xu, Annie W Shieh, Nima Niknejad, Megumi Takeuchi, Carmen Paradas, Chunru Lin, Hamed Jafar-Nejad, Robert S Haltiwanger, Sidney H Wang, Radbod Darabi

Faculty, Staff and Student Publications

Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro …

Treatment Of Older Adults With Flt3-Mutated Aml: Emerging Paradigms And The Role Of Frontline Flt3 Inhibitors, Nicholas J Short, Daniel Nguyen, Farhad Ravandi

Faculty, Staff and Student Publications

FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable …

Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows …

Unfolding The Secrets Of Small Cell Lung Cancer Progression: Novel Approaches And Insights Through Rapid Autopsies, Zsolt Megyesfalvi, Simon Heeke, Benjamin J Drapkin, Anna Solta, Ildiko Kovacs, Kristiina Boettiger, Lilla Horvath, Busra Ernhofer, Janos Fillinger, Ferenc Renyi-Vamos, Clemens Aigner, Karin Schelch, Christian Lang, Gyorgy Marko-Varga, Carl M Gay, Lauren A Byers, Benjamin B Morris, John V Heymach, Peter Van Loo, Fred R Hirsch, Balazs Dome

Faculty, Staff and Student Publications

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.

Early Onset Horizontal Gaze Palsy And Progressive Scoliosis Due To A Noncanonical Splicing-Site Variant And A Missense Variant In The Robo3 Gene, Sheng Yi, Zailong Qin, Xunzhao Zhou, Junjie Chen, Shang Yi, Qiuli Chen, Limei Huang, Qinle Zhang, Biyan Chen, Jingsi Luo

Faculty, Staff and Student Publications

BACKGROUND: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.

METHODS: We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.

RESULTS: We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention …

Reduced Maternal Immunity And Vertical Transfer Of Immunity Against Sars-Cov-2 Variants Of Concern With Covid-19 Exposure Or Initial Vaccination In Pregnancy., Rupsa Boelig, Sidhartha Chaudhury, Gregory D Gromowski, Sandra Mayer, Jocelyn King, Zubair H Aghai, Elke Bergmann-Leitner

Department of Obstetrics and Gynecology Faculty Papers

INTRODUCTION: As the SARS-CoV-2 pandemic continues to evolve, we face new variants of concern with a concurrent decline in vaccine booster uptake. We aimed to evaluate the difference in immunity gained from the original SARS-CoV-2 mRNA vaccine series in pregnancy versus SARS-CoV-2 exposure during pregnancy against recent variants of concern.

STUDY DESIGN: This is a retrospective analysis of previously collected samples from 192 patients who delivered between February 2021 and August 2021. Participants were categorized as 1) COVID vaccine: mRNA vaccine in pregnancy, 2) COVID-exposed, and 3) controls. The primary outcome was neutralizing capacity against wild-type, Delta, and Omicron-B1 between …

Preface: Causes Of Obesity, Theories, Conjectures And Evidence, David B Allison, Thorkild I A Sørensen, Kevin D Hall, John R Speakman

Children’s Nutrition Research Center Staff Publications

No abstract provided.

Integrative Multi-Omic Cancer Profiling Reveals Dna Methylation Patterns Associated With Therapeutic Vulnerability And Cell-Of-Origin, Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G Jayasinghe, Steven M Foltz, Eduard Porta-Pardo, Yifat Geffen, Michael C Wendl, Rossana Lazcano, Iga Kolodziejczak, Yizhe Song, Akshay Govindan, Elizabeth G Demicco, Xiang Li, Yize Li, Sunantha Sethuraman, Samuel H Payne, David Fenyö, Henry Rodriguez, Maciej Wiznerowicz, Hui Shen, D R Mani, Karin D Rodland, Alexander J Lazar, Ana I Robles, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A …

Krasg12d Inhibition Reprograms The Tumor Microenvironment Of Early And Advanced Pancreatic Cancer To Promote Fas-Mediated Killing By Cd8+ T Cells, Krishnan K Mahadevan, Kathleen M Mcandrews, Valerie S Lebleu, Sujuan Yang, Hengyu Lyu, Bingrui Li, Amari M Sockwell, Michelle L Kirtley, Sami J Morse, Barbara A Moreno Diaz, Michael P Kim, Ningping Feng, Anastasia M Lopez, Paola A Guerrero, Francesca Paradiso, Hikaru Sugimoto, Kent A Arian, Haoqiang Ying, Yasaman Barekatain, Lakshmi Kavitha Sthanam, Patience J Kelly, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri

Faculty, Staff and Student Publications

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 …