Medical Pathology Commons^™

Codon Bias Can Determine Sorting Of A Potassium Channel Protein, Anja J. Engel, Marina Kithil, Markus Langhans, Oliver Rauh, Matea Cartolano, James L. Van Etten, Anna Moroni, Gerhard Thiel

Nebraska Center for Virology: Faculty Publications

Due to the redundancy of the genetic code most amino acids are encoded by multiple synonymous codons. It has been proposed that a biased frequency of synonymous codons can affect the function of proteins by modulating distinct steps in transcription, translation and folding. Here, we use two similar prototype K⁺ channels as model systems to examine whether codon choice has an impact on protein sorting. By monitoring transient expression of GFP-tagged channels in mammalian cells, we find that one of the two channels is sorted in a codon and cell cycle-dependent manner either to mitochondria or the secretory pathway. …

Hypercalcemia Of Malignancy Attributed To Cosecretion Of Pth And Pthrp In Lung Adenocarcinoma, Jeffrey Kroopnick, Ubaldo E. Martinez-Outshoorn, Madalina Tuluc, Caroline S Kim

Department of Medical Oncology Faculty Papers

Introduction: Hypercalcemia of malignancy (HCM) portends a very poor prognosis, and no established guidelines exist regarding its management. Most instances of HCM are due to local osteolysis or secretion of parathyroid hormone related-peptide, while less than 1% of all cases are due to ectopic secretion of parathyroid hormone.

Case report: We present an unusual case of HCM due to proposed cosecretion of both parathyroid hormone and parathyroid hormone-related protein in a 36-year-old man with a poorly differentiated lung adenocarcinoma. The patient's hypercalcemia was refractory to conventional measures, including intravenous bisphosphonate therapy (zoledronic acid), and was improved with administration of denosumab. …

Dabigatran Reduces Thrombin-Induced Neuroinflammation And Ad Markers In Vitro: Therapeutic Relevance For Alzheimer's Disease, Syed Waseem Bihaqi, Haripriya Vittal Rao, Abhik Sen, Paula Grammas

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y. Methods: SH-SY5Y cells exposed to thrombin concentrations (10–100 nM) +/- 250 nM dabigatran for 24 h were analyzed for protein and gene expression. Electrophoretic mobility shift assay (EMSA) was used to …

Imaging Based Prediction Of Pathology In Adult Diffuse Glioma With Applications To Therapy And Prognosis, Evan Gates

Dissertations and Theses (Open Access)

The overall aggressiveness of a glioma is measured by histologic and molecular analysis of tissue samples. However, the well-known spatial heterogeneity in gliomas limits the ability for clinicians to use that information to make spatially specific treatment decisions. Magnetic resonance imaging (MRI) visualizes and assesses the tumor. But, the exact degree to which MRI correlates with the actual underlying tissue characteristics is not known.

In this work, we derive quantitative relationships between imaging and underlying pathology. These relations increase the value of MRI by allowing it to be a better surrogate for underlying pathology and they allow evaluation of the …

Non-Selective Primary Human Tumor Cell Line Generation From Surgical Resections To Be Paired With Flash Frozen And Paraffin Embedded Tissue: Advancements In Democratizing Translational Research Materials To Rural Institutions, Jennifer Hawkins, Rebecca Russell, Logan M. Lawrence, Amrita Valluri, Jessica Wellman, Krista Denning

Marshall Journal of Medicine

Translational cancer research relies on the availability of human patient tissue demonstrating the specific disease process under investigation. Biobanks of human tissue have historically been and remain to date the primary access point for cancer research samples. Biorepositories routinely supply researchers with varying sample types for use in biomedical studies; most commonly formalin-fixed and paraffin-embedded (FFPE) tissue, or fresh snap-frozen tissue. In conjunction with preserved tissue samples, viable tumor cell lines derived from patient tissue have emerged to be a new gold standard in cancer research particularly in drug discovery and functional prognostic assays. Tissue banks providing these samples are …

Identification Of A Chlorovirus Pbcv-1 Protein Involved In Degrading The Host Cell Wall During Virus Infection, Irina V. Agarkova, Leslie C. Lane, David D. Dunigan, Cristian F. Quispe, Garry A. Duncan, Elad Milrot, Abraham Minsky, Ahmed Esmael, Jayadri S. Ghosh, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

Chloroviruses are unusual among viruses infecting eukaryotic organisms in that they must, like bacteriophages, penetrate a rigid cell wall to initiate infection. Chlorovirus PBCV-1 infects its host, Chlorella variabilis NC64A by specifically binding to and degrading the cell wall of the host at the point of contact by a virus-packaged enzyme(s). However, PBCV-1 does not use any of the five previously characterized virus-encoded polysaccharide degrading enzymes to digest the Chlorella host cell wall during virus entry because none of the enzymes are packaged in the virion. A search for another PBCV-1-encoded and virion-associated protein identified protein A561L. The fourth domain …

Impaired 26s Proteasome Assembly Precedes Neuronal Loss In Mutant Ubqln2 Rats., Wenjuan Zhang, Bo Huang, Limo Gao, Cao Huang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Proteasomal dysfunction is known to be associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). Our previous reports have shown that a mutant form of ubiquilin-2 (UBQLN2) linked to ALS/FTD leads to neurodegeneration accompanied by accumulations of the proteasome subunit Rpt1 in transgenic rats, but the precise pathogenic mechanisms of how this mutation impairs the proteasome remains to be elucidated. Here, we reveal that this UBQLN2 mutation in rats disrupted the proteasome integrity prior to neurodegeneration, that it dissociated the 26S proteasome in vitro, and that its depletion did not affect 26S proteasome assembly. During both disease progression and in …

D-Dimer Levels And Acute Pulmonary Embolism Development In Covid-19 Patients, Vural Ahmet, Kahraman Ahmet Nedim

Journal of Mind and Medical Sciences

Objective. To identify those who develop pulmonary embolism with Ddimer levels by evaluating pulmonary CT angiographies of patients who are followed up with suspicion of coronavirus disease 2019 (COVID-19). Methods. Patients who were followed up in a community hospital with suspicion of COVID-19 and underwent Pulmonary CT angiography examination were evaluated. Clinical and demographic parameters and DDimer values for patients with and without pulmonary embolism were evaluated in the pulmonary CT angiogram. Results. During the COVID-19 pandemic, Thorax CT examination was performed in our center for suspicion or follow-up of COVID-19 infection in 3396 patients. Pulmonary CT angiography was applied …

Characterization And Clinical Significance Of Eif1ax Mutations And Co-Mutations In Cytologically Indeterminate Thyroid Nodules: A 5-Year Retrospective Analysis., Stacey Gargano, Nitika Badjatia, Yanina Nikolaus, Stephen C Peiper, Zi-Xuan Wang, Phd

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

OBJECTIVE: Mutations in the EIF1AX gene have been recently detected in a small percentage of benign and malignant thyroid lesions. We sought to investigate the prevalence and clinical significance of EIF1AX mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution.

MATERIALS AND METHODS: A 5-year retrospective analysis was performed on thyroid nodules with a cytologic diagnosis of Bethesda category III or IV, which had undergone testing by our in-house next generation sequencing panel. Surgically resected nodules with EIF1AX mutations were identified, and mutation type and presence of co-mutations were correlated with histopathologic diagnosis.

RESULTS: 41/904 (4.5%) cases overall …

Resident Immune Cells Of The Avascular Lens: Mediators Of The Injury And Fibrotic Response Of The Lens., A. Menko, Jodirae Dedreu, Caitlin M. Logan, Heather Paulson, Alex V Levin, Janice L Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Tissues typically harbor subpopulations of resident immune cells that function as rapid responders to injury and whose activation leads to induction of an adaptive immune response, playing important roles in repair and protection. Since the lens is an avascular tissue, it was presumed that it was absent of resident immune cells. Our studies now show that resident immune cells are a shared feature of the human, mouse, and chicken lens epithelium. These resident immune cells function as immediate responders to injury and rapidly populate the wound edge following mock cataract surgery to function as leader cells. Many of these resident …

Sars-Cov-2 Infects Human Engineered Heart Tissues And Models Covid-19 Myocarditis, Adam L Bailey, Oleksandr Dmytrenko, Lina Greenberg, Andrea L Bredemeyer, Pan Ma, Jing Liu, Vinay Penna, Emma S Winkler, Sanja Sviben, Erin Brooks, Ajith P Nair, Kent A Heck, Aniket S Rali, Leo Simpson, Mehrdad Saririan, Dan Hobohm, W Tom Stump, James A Fitzpatrick, Xuping Xie, Xianwen Zhang, Pei-Yong Shi, J Travis Hinson, Weng-Tein Gi, Constanze Schmidt, Florian Leuschner, Chieh-Yu Lin, Michael S Diamond, Michael J Greenberg, Kory J Lavine

Faculty, Staff and Student Publications

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology …

Presence Of Antibody-Dependent Cellular Cytotoxicity (Adcc) Against Sars-Cov-2 In Covid-19 Plasma, For Yue Tso, Salum J. Lidenge, Lisa K. Poppe, Phoebe B. Pena, Sara R. Privatt, Sydney J. Bennett, John R. Ngowi, Julius Mwaiselage, Michael Belshan, Jacob A. Siedlik, Morgan A. Raine, Juan B. Ochoa, Julia Garcia-Diaz, Bobby Nossaman, Lyndsey Buckner, W Mark Roberts, Matthew J. Dean, Augusto C. Ochoa, John T. West, Charles Wood

Nebraska Center for Virology: Faculty Publications

Background Neutralizing-antibody (nAb) is the major focus of most ongoing COVID-19 vaccine trials. However, nAb response against SARS-CoV-2, when present, decays rapidly. Given the myriad roles of antibodies in immune responses, it is possible that antibodies could also mediate protection against SARS-CoV-2 via effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), which we sought to explore here. Methods Plasma of 3 uninfected controls and 20 subjects exposed to, or recovering from, SARS CoV-2 infection were collected from U.S. and sub-Saharan Africa. Immunofluorescence assay was used to detect the presence of SARS-CoV-2 specific IgG antibodies in the plasma samples. SARS-CoV-2 specific …

Inhibition Of Zika Virus Replication By G-Quadruplex-Binding Ligands, Indian Institute Of Technology Indore, Aryamav Pattnaik, Bikash R. Sahoo, Uma Shankar, Asit K. Pattnaik, Amit Kumar, Debasis Nayak

Nebraska Center for Virology: Faculty Publications

Zika virus (ZIKV), a mosquito-transmitted Flavivirus, emerged in the last decade causing serious diseases and affecting human health globally. Currently, no licensed vaccines or antivirals are available to combat ZIKV, although several vaccine candidates are in the pipeline. In recent years, the presence of non-canonical G-quadruplex (GQ) secondary structures in viral genomes has ignited significant attention as potential targets for antiviral strategy. In this study, we identified several novel conserved potential GQ structures by analyzing published ZIKV genome sequences using an in-house algorithm. Biophysical and biochemical analysis of the RNA sequences containing these potential GQ sequences suggested the existence of …

Methamphetamine Associated Cardiomyopathy In Pregnancy: The Distinctions And The Implications, Ashan Hatharasinghe, Hossein Akhondi

HCA Healthcare Journal of Medicine

Introduction

Methamphetamine associated cardiomyopathy (MAC) and peripartum cardiomyopathy (PPCM) are both rare obstetric conditions. Literature regarding methamphetamine associated cardiomyopathy in the obstetric population is limited, and it can be difficult to make the distinction between the two given the similarities in clinical presentation. However similar, there are significant distinctions in the pathophysiology of these two that can help clinicians with the management process.

Clinical Findings and Outcomes

This case involves a 35-year-old Hispanic G6P5005 at 37 weeks gestation presenting with acute respiratory failure secondary to acute decompensated heart failure with reduced ejection fraction and superimposed preeclampsia leading to urgent cesarean …

Esophageal Cancer Complicated By A Distal Acquired Esophagopulmonary Fistula, Alexander D. Lake, Yousef Almuzaini, Aaron Jaffe, Joseph Staffetti, Mukesh Patel

HCA Healthcare Journal of Medicine

Esophageal respiratory fistulas, commonly found as a tracheoesophageal fistula (TEF), are abnormal connections between the esophagus and trachea. These can be congenital (infants) or acquired (malignancy). A more rare form of an esophageal respiratory fistula is an abnormal connection between the esophagus and the lung parenchyma—also known as an esophagopulmonary fistula. In our case, we present a middle-aged male with a history of esophageal cancer undergoing chemotherapy and radiation presenting into the intensive care unit for increasing shortness of breath and vomiting after eating found to have a rare form of a TEF causing his symptoms.

Parameters Affecting Continuous In Vitro Culture Of Treponema Pallidum Strains, Diane G Edmondson, Bridget D Delay, Lindsay E Kowis, Steven J Norris

Faculty, Staff and Student Publications

The bacterium that causes syphilis, Treponema pallidum subsp. pallidum, has now been cultured in vitro continuously for periods exceeding 3 years using a system consisting of coculture with Sf1Ep rabbit epithelial cells in TpCM-2 medium and a low-oxygen environment. In addition, long-term culture of several other syphilis isolates (SS14, Mexico A, UW231B, and UW249B) and the T. pallidum subsp. endemicum Bosnia A strain has been achieved. During in vitro passage, T. pallidum subsp. pallidum exhibited a typical bacterial growth curve with logarithmic and stationary phases. Sf1Ep cells are required for sustained growth and motility; however, high initial Sf1Ep cell …

Primary Effusion Lymphoma: A Clinicopathological Study Of 70 Cases, Zhihong Hu, Zenggang Pan, Weina Chen, Yang Shi, Wei Wang, Ji Yuan, Endi Wang, Shanxiang Zhang, Habibe Kurt, Brenda Mai, Xiaohui Zhang, Hui Liu, Adan A Rios, Hilary Y Ma, Nghia D Nguyen, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Student Publications

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26–91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses …

Impaired Eif5a Function Causes A Mendelian Disorder That Is Partially Rescued In Model Systems By Spermidine., Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G L Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt, Siddharth Banka

Manuscripts, Articles, Book Chapters and Other Papers

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles …

Induction Of Brain Tumors By The Archetype Strain Of Human Neurotropic Jcpyv In A Transgenic Mouse Model, Luis Del Valle, Kamel Khalili

School of Medicine Faculty Publications

JC Virus (JCPyV), a member of the Polyomaviridiæ family, is a human neurotropic virus with world-wide distribution. JCPyV is the established opportunistic infectious agent of progressive multifocal leukoencephalopathy, a fatal demyelinating disease, which results from the cytolytic infection of oligodendrocytes. Mutations in the regulatory region of JCPyV determine the different viral strains. Mad-1 the strain associated with PML contains two 98 base pair repeats, whereas the archetype strain (CY), which is the transmissible form of JCPyV, contains only one 98 tandem with two insertions of 62 and 23 base pairs respectively. The oncogenicity of JCPyV has been suspected since direct …

High Prevalence Of Pre-Existing Serological Cross-Reactivity Against Severe Acute Respiratory Syndrome Coronavirus-2 (Sars-Cov-2) In Sub-Saharan Africa, For Yue Tso, Salum J. Lidenge, Phoebe B. Peña, Ashley A. Clegg, John R. Ngowi, Julius Mwaiselage, Owen Ngalamika, Peter Julius, John T. West, Charles Wood

Nebraska Center for Virology: Faculty Publications

Objective: Significant morbidity and mortality have occurred in the USA, Europe, and Asia due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), whereas the numbers of infections and deaths in sub-Saharan Africa (SSA) have remained comparatively low. It has been hypothesized that exposure of the population in SSA to other coronaviruses prior to the COVID-19 pandemic resulted in some degree of cross-protection against SARS-CoV-2 infection and pathogenesis. We evaluated this hypothesis by comparing SARS-CoV-2 cross-reactive antibodies in pre-pandemic plasma samples collected from SSA and the USA.

Method: Pre-COVID-19 pandemic plasma samples from SSA and the USA were collected and tested by …