Medicine and Health Sciences Commons^™

Just How Many Holes…?, Gyorgy Csordas, Stephen Hurst

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Commentary on the following article: https://doi.org/10.1085/jgp.202012631

Computational Modeling Analysis Of Generation Of Reactive Oxygen Species By Mitochondrial Assembled And Disintegrated Complex Ii., Nikolay I. Markevich, Lubov N. Markevich, Jan B. Hoek

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Reactive oxygen species (ROS) function as critical mediators in a broad range of cellular signaling processes. The mitochondrial electron transport chain is one of the major contributors to ROS formation in most cells. Increasing evidence indicates that the respiratory Complex II (CII) can be the predominant ROS generator under certain conditions. A computational, mechanistic model of electron transfer and ROS formation in CII was developed in the present study to facilitate quantitative analysis of mitochondrial ROS production. The model was calibrated by fitting the computer simulated results to experimental data obtained on submitochondrial particles (SMP) prepared from bovine and rat …

Credible Practice Of Modeling And Simulation In Healthcare: Ten Rules From A Multidisciplinary Perspective, Ahmet Erdemir, Lealem Mulugeta, Joy P Ku, Andrew Drach, Marc Horner, Tina M Morrison, Grace C Y Peng, Rajanikanth Vadigepalli, William W Lytton, Jerry G Myers

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The complexities of modern biomedicine are rapidly increasing. Thus, modeling and simulation have become increasingly important as a strategy to understand and predict the trajectory of pathophysiology, disease genesis, and disease spread in support of clinical and policy decisions. In such cases, inappropriate or ill-placed trust in the model and simulation outcomes may result in negative outcomes, and hence illustrate the need to formalize the execution and communication of modeling and simulation practices. Although verification and validation have been generally accepted as significant components of a model's credibility, they cannot be assumed to equate to a holistic credible practice, which …

Hepatic Lipocalin 2 Promotes Liver Fibrosis And Portal Hypertension, Jiegen Chen, Josepmaria Argemi, Gemma Odena, Ming-Jiang Xu, Yan Cai, Veronica Massey, Austin Parrish, Rajanikanth Vadigepalli, Jose Altamirano, Joaquin Cabezas, Pere Gines, Juan Caballeria, Natasha Snider, Pau Sancho-Bru, Shizuo Akira, Ivan Rusyn, Bin Gao, Ramon Bataller

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2−/− mice were protected from liver …

Educational Case: A Case Of Transfusion-Transmitted Babesiosis: Diagnostic Perspectives Across The Clinical Laboratory., Kaitlyn Dykes, Alexis R. Peedin

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology.

Regulation Of Microrna-497-Targeting Akt2 Influences Tumor Growth And Chemoresistance To Cisplatin In Lung Cancer., Lin Wang, Xiang-Bo Ji, Li-Hong Wang, Jian-Ge Qiu, Feng-Mei Zhou, Wen-Jing Liu, Di-Di Wan, Marie Chai-Mi Lin, Ling-Zhi Liu, Jian-Ying Zhang, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: MicroRNA-497 (miR-497) has been implicated in several cancers. Increasing studies demonstrate the role of AKT2 in cancers as an oncogene which is closely associated with tumor aggressiveness by enhancing cancer cell survival, migration and invasion However, miR-497/AKT2 axis in non-small cell lung cancer (NSCLC) remains unclear.

Methods: Quantitative real-time PCR (qRT-PCR) was used to quantify the expression of miR-497 and its target gene. The function of miR-497 in lung cancer was investigated through in vitro and in vivo assays (cell proliferation assay, cell migration assay, colony formation assay, flow cytometry assay, immunoblotting and tumorigenesis assay). Luciferase reporter assay was …

Quantification Of Lactoyl-Coa (Lactyl-Coa) By Liquid Chromatography Mass Spectrometry In Mammalian Cells And Tissues., Erika L Varner, Sophie Trefely, David Bartee, Eliana Von Krusenstiern, Luke Izzo, Carmen Bekeova, Roddy S O'Connor, Erin L Seifert, Kathryn E Wellen, Jordan L Meier, Nathaniel W Snyder

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Lysine lactoylation is a recently described protein post-translational modification (PTM). However, the biochemical pathways responsible for this acylation remain unclear. Two metabolite-dependent mechanisms have been proposed: enzymatic histone lysine lactoylation derived from lactoyl-coenzyme A (lactoyl-CoA, also termed lactyl-CoA), and non-enzymatic lysine lactoylation resulting from acyl-transfer via lactoyl-glutathione. While the former has precedent in the form of enzyme-catalysed lysine acylation, the lactoyl-CoA metabolite has not been previously quantified in mammalian systems. Here, we use liquid chromatography-high-resolution mass spectrometry (LC-HRMS) together with a synthetic standard to detect and validate the presence of lactoyl-CoA in cell and tissue samples. Conducting a retrospective analysis …

Dysregulation Of Ryr Calcium Channel Causes The Onset Of Mitochondrial Retrograde Signaling, Anindya Roy Chowdhury, Satish Srinivasan, György Csordás, György Hajnóczky, Narayan G Avadhani

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

This study shows that multiple modes of mitochondrial stress generated by partial mtDNA depletion or cytochrome c oxidase disruption cause ryanodine receptor channel (RyR) dysregulation, which instigates the release of Ca2+ in the cytoplasm of C2C12 myoblasts and HCT116 carcinoma cells. We also observed a reciprocal downregulation of IP3R channel activity and reduced mitochondrial uptake of Ca2+. Ryanodine, an RyR antagonist, abrogated the mitochondrial stress-mediated increase in [Ca2+]c and the entire downstream signaling cascades of mitochondrial retrograde signaling. Interestingly, ryanodine also inhibited mitochondrial stress-induced invasive behavior in mtDNA-depleted C2C12 cells and HCT116 carcinoma cells. In addition, co-immunoprecipitation shows reduced FKBP12 …

Genomic Characterization Of Malignant Progression In Neoplastic Pancreatic Cysts, Michaël Noë, Noushin Niknafs, Catherine G Fischer, Wenzel M Hackeng, Violeta Beleva Guthrie, Waki Hosoda, Marija Debeljak, Eniko Papp, Vilmos Adleff, James R White, Claudio Luchini, Antonio Pea, Aldo Scarpa, Giovanni Butturini, Giuseppe Zamboni, Paola Castelli, Seung-Mo Hong, Shinichi Yachida, Nobuyoshi Hiraoka, Anthony J Gill, Jaswinder S Samra, G Johan A Offerhaus, Anne Hoorens, Joanne Verheij, Casper Jansen, N Volkan Adsay, Wei Jiang, Jordan Winter, Jorge Albores-Saavedra, Benoit Terris, Elizabeth D Thompson, Nicholas J Roberts, Ralph H Hruban, Rachel Karchin, Robert B Scharpf, Lodewijk A A Brosens, Victor E Velculescu, Laura D Wood

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three …

Insulin-Like Growth Factor 2 Mrna-Binding Protein 3 Modulates Aggressiveness Of Ewing Sarcoma By Regulating The Cd164-Cxcr4 Axis, Caterina Mancarella, Giulia Caldoni, Irene Ribolsi, Alessandro Parra, Maria Cristina Manara, Arthur M Mercurio, Andrea Morrione, Katia Scotlandi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ewing sarcoma (EWS) is the second most common bone and soft tissue-associated malignancy in children and young adults. It is driven by the fusion oncogene EWS/FLI1 and characterized by rapid growth and early metastasis. We have previously discovered that the mRNA binding protein IGF2BP3 constitutes an important biomarker for EWS as high expression of IGF2BP3 in primary tumors predicts poor prognosis of EWS patients. We additionally demonstrated that IGF2BP3 enhances anchorage-independent growth and migration of EWS cells suggesting that IGF2BP3 might work as molecular driver and predictor of EWS progression. The aim of this study was to further define the …

Cd4 Deficiency Causes Poliomyelitis And Axonal Blebbing In Murine Coronavirus-Induced Neuroinflammation., Debanjana Chakravarty, Fareeha Saadi, Soumya Kundu, Abhishek Bose, Reas Khan, Kimberly Dine, Lawrence C Kenyon, Kenneth S Shindler, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, …

Diurnal Patterns Of Gene Expression In The Dorsal Vagal Complex And The Central Nucleus Of The Amygdala - Non-Rhythm-Generating Brain Regions, Mary M Staehle, Sean O'Sullivan, Rajanikanth Vadigepalli, Kate F Kernan, Gregory E Gonye, Babatunde A Ogunnaike, James S. Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Genes that establish the circadian clock have differential expression with respect to solar time in central and peripheral tissues. Here, we find circadian-time-induced differential expression in a large number of genes not associated with circadian rhythms in two brain regions lacking overt circadian function: the dorsal vagal complex (DVC) and the central nucleus of the amygdala (CeA). These regions primarily engage in autonomic, homeostatic, and emotional regulation. However, we find striking diurnal shifts in gene expression in these regions of male Sprague Dawley rats with no obvious patterns that could be attributed to function or region. These findings have implications …

Endorepellin Evokes An Angiostatic Stress Signaling Cascade In Endothelial Cells., Aastha Kapoor, Carolyn G Chen, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980 Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex …

Catabolic Degradation Of Endothelial Vegfa Via Autophagy, Thomas Neill, Carolyn Chen, Simone Buraschi, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion …

Discoidin Domain Receptor 1 Functionally Interacts With The Igf-I System In Bladder Cancer, Simone Buraschi, Alaide Morcavallo, Thomas Neill, Manuela Stefanello, Chiara Palladino, Shi-Qiong Xu, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

No abstract provided.

Abrogation Of Esophageal Carcinoma Development In Mir-31 Knockout Rats., Louise Y Fong, Cristian Taccioli, Alexey Palamarchuk, Guidantonio Malagoli Tagliazucchi, Ruiyan Jing, Karl J Smalley, Sili Fan, Joseph Altemus, Oliver Fiehn, Kay Huebner, John L Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear …

Investigating The Effects Of Brainstem Neuronal Adaptation On Cardiovascular Homeostasis., James H Park, Jonathan Gorky, Babatunde Ogunnaike, Rajanikanth Vadigepalli, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Central coordination of cardiovascular function is accomplished, in part, by the baroreceptor reflex, a multi-input multi-output physiological control system that regulates the activity of the parasympathetic and sympathetic nervous systems via interactions among multiple brainstem nuclei. Recent single-cell analyses within the brain revealed that individual neurons within and across brain nuclei exhibit distinct transcriptional states contributing to neuronal function. Such transcriptional heterogeneity complicates the task of understanding how neurons within and across brain nuclei organize and function to process multiple inputs and coordinate cardiovascular functions within the larger context of the baroreceptor reflex. However, prior analysis of brainstem neurons revealed …