Medicine and Health Sciences Commons^™

Gliopathy Of Demyelinating And Non-Demyelinating Strains Of Mouse Hepatitis Virus., Lawrence C. Kenyon, Kaushiki Biswas, Kenneth S Shindler, Manasi Nabar, Marjorie Stout, Susan T Hingley, Judith B Grinspan, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white …

T(3;8)(Q26;Q24) With Myc Rearrangement In Acute Myeloid Leukemia: A Case Report, Vandi Ly, Md, Renu Bajaj, Phd, Jerald Z. Gong, Md, Zi-Xuan Wang, Phd, Stephen C Peiper, Md, Guldeep Uppal, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Rearrangements of 3q26 have been described in 5% of de novo or therapy related acute myeloid leukemia, myelodysplastic syndrome (MDS), and blast phase of chronic myeloid leukemia. The most common translocations involving 3q26 are t(3;12)(q26;p13), t(3;21)(q26;q22), t(3;3)(q21;q26), t(2;3)(p15∼23;q26∼27) and rarely t(3;7)(q26;q21). However, t(3;8)(q26;q24) with or without monosomy 7 is a rare phenomenon and has been reported in only 10 patients so far. Hereby, we describe a 58 year old patient who was diagnosed with refractory anemia with multilineage dysplasia. Cytogenetic studies revealed monosomy 7. He was then lost to follow-up. A year later he was found to have worsening cytopenias …

Intracellular Information Processing Through Encoding And Decoding Of Dynamic Signaling Features., Hirenkumar K Makadia, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cell signaling dynamics and transcriptional regulatory activities are variable within specific cell types responding to an identical stimulus. In addition to studying the network interactions, there is much interest in utilizing single cell scale data to elucidate the non-random aspects of the variability involved in cellular decision making. Previous studies have considered the information transfer between the signaling and transcriptional domains based on an instantaneous relationship between the molecular activities. These studies predict a limited binary on/off encoding mechanism which underestimates the complexity of biological information processing, and hence the utility of single cell resolution data. Here we pursue a …

Gsk-3Β Regulates Tumor Growth And Angiogenesis In Human Glioma Cells., Peng Zhao, Qi Li, Zhumei Shi, Charlie Li, Lin Wang, Xue Liu, Chengfei Jiang, Xu Qian, Yongping You, Ning Liu, Ling-Zhi Liu, Lianshu Ding, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Glioma accounts for the majority of primary malignant brain tumors in adults.

METHODS: Glioma specimens and normal brain tissues were analyzed for the expression levels of GSK-3β and p-GSK-3β (Ser9) by tissue microarray analysis (TMA) and Western blotting. Glioma cells over-expressing GSK-3β were used to analyze biological functions both in vitro and in vivo.

RESULTS: The levels of p-GSK-3β (Ser9), but not total GSK-3β, are significantly up-regulated in glioma tissues compared to normal tissues, and are significantly correlated with the glioma grades. Ectopic expression of GSK-3β decreased the phosphorylation levels of mTOR and p70S6K1; and inhibited β-catenin, HIF-1α and …

Mir-497 Decreases Cisplatin Resistance In Ovarian Cancer Cells By Targeting Mtor/P70s6k1., Shaohua Xu, Guang-Bo Fu, Zhen Tao, Jun Ouyang, Fanfei Kong, Bing-Hua Jiang, Xiaoping Wan, Ke Chen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The mechanism of cisplatin resistance in ovarian cancer is not clearly understood. In the present investigation, we found that the expression levels of miR-497 were reduced in chemotherapy-resistant ovarian cancer cells and tumor tissues due to hypermethylation of miR-497 promoter. Low miR-497 expression levels were associated with chemo-resistant phonotype of ovarian cancer. By analyzing the expression levels of miR-497, mTOR and p70S6K1 in a clinical gene-expression array dataset, we found that mTOR and p70S6K1, two proteins correlated to chemotherapy-resistance in multiple types of human cancers, were inversely correlated with miR-497 levels in ovarian cancer tissues. By using an orthotopic ovarian …

The Role Of Perlecan And Endorepellin In The Control Of Tumor Angiogenesis And Endothelial Cell Autophagy., Stephen Douglass, Atul Goyal, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

During tumor growth and angiogenesis there is a dynamic remodeling of tissue architecture often accompanied by the release of extracellular matrix constituents full of biological activity. One of the key constituents of the tumor microenvironment is the large heparan sulfate proteoglycan perlecan. This proteoglycan, strategically located at cell surfaces and within basement membranes, is a well-defined pro-angiogenic molecule when intact. However, when partially processed by proteases released during cancer remodeling and invasion, the C-terminal fragment of perlecan, known as endorepellin, has opposite effects than its parent molecule. Endorepellin is a potent inhibitor of angiogenesis by exerting a dual receptor antagonism …

Disseminated Histiocytoses Biomarkers Beyond Brafv600e: Frequent Expression Of Pd-L1., Nurija Bilalovic, Juan P. Palazzo, Ryan P Bender, Jeffrey Swensen, Sherri Z Millis, Semir Vranic, Daniel Von Hoff, Robert J Arceci, Zoran Gatalica

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF …

Low Level Lead Exposure Impairs Attentional Set Shifting Task Performance Depending Upon Sex And Developmental Periods Of Exposure, L.S. Neuwirth, D.W. Anderson, J. S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Introduction

Exposure to low levels of lead (Pb) impairs a variety of cognitive processes. Although children exposed to Pb developmentally present with a variety of cognitive impairments that include deficits in learning, memory, language, and executive functioning, experimental work on Pb toxicity in rats has focused mostly on learning and memory deficits and less on executive functions. However, detrimental effects on executive functioning could lead to or even underlie a variety of other cognitive problems attributed to Pb exposure. In this study, we examined the ability of Long Evans rats (control and Pb-exposed: 150ppm Pb-acetate in food given perinatally (gestation …

Strategic Distribution Of The Mitochondrial Ca2+ Uniporter In Cardiac Mitochondria, Sergio De La Fuente, Caitlin Vail, Elorm J. Agra, Kira Holmstrom, Junhui Sun, Jyotsna Mishra, Toren Finkel, Elizabeth Murphy, Shey-Shing Sheu, György Csordás

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background:

1) Control of the mitochondrial ATP production by SR-derived Ca²⁺ signals includes local, nanodomain Ca²⁺ transfer from ryanodine receptors (RyR2) to the mitochondrial matrix (excitation-bioenergetics coupling).

2) Ca²⁺ crosses the inner mitochondrial membrane (IMM) via the mtCU, a low-affinity Ca²⁺-activated Ca²⁺ channel complex.

3) The surface area of cardiac IMM is extensively enhanced by cristae folding; however, mitoplast patch clamp studies showed mtCU current density the lowest amongst a range of tissues (Fieni 2012. Nat Commun).

Desmin Common Mutation Is Associated With Multi-Systemic Disease Manifestations And Depletion Of Mitochondria And Mitochondrial Dna., Elizabeth M. Mccormick, Lawrence C. Kenyon, Marni J. Falk

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Desmin (DES) is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for citrate synthase …

Compensatory Fetal Membrane Mechanisms Between Biglycan And Decorin In Inflammation., Luciana Batalha De Miranda De Araujo, Casie E Horgan, Abraham Aron, Renato V. Iozzo, Beatrice E Lechner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Preterm premature rupture of fetal membranes (PPROM) is associated with infection, and is one of the most common causes of preterm birth. Abnormal expression of biglycan and decorin, two extracellular matrix proteoglycans, leads to preterm birth and aberrant fetal membrane morphology and signaling in the mouse. In humans and mice, decorin dysregulation is associated with inflammation in PPROM. We therefore investigated the link between biglycan and decorin and inflammation in fetal membranes using mouse models of intraperitoneal Escherichia coli injections superimposed on genetic biglycan and decorin deficiencies. We assessed outcomes in vivo as well as in vitro using quantitative PCR, …

Relationship Between Motor Symptoms, Cognition, And Demographic Characteristics In Treated Mild/Moderate Parkinson's Disease., Jay S Schneider, Stephanie Sendek, Chengwu Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Although Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized primarily by motor symptoms, PD patients, at all stages of the disease, can experience cognitive dysfunction. However, the relationships between cognitive and motor symptoms and specific demographic characteristics are not well defined, particularly for patients who have progressed to requiring dopaminergic medication.

OBJECTIVE: To examine relationships between motor and cognitive symptoms and various demographic factors in mild to moderate, PD patients requiring anti-PD medication.

METHODS: Cognitive function was assessed in 94 subjects with a variety of neuropsychological tests during baseline evaluations as part of an experimental treatment study. Data …

An Assessment Of The Reliability Of Platelet-Associated Flags Generated By The Sysmex Xe-5000 Automated Hematology Analyzer In Detecting Platelet Clumps, Jennifer M. Hawkins, Do, Gene Gulati, Ph.D, Guldeep Uppal, Md, Jerald Z. Gong, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background

XE-5000 is an automated hematology analyzer utilized by clinical laboratories worldwide to perform CBC and differential leukocyte counts on EDTA-anticoagulated blood specimens. The overall reliability of the results generated by this analyzer has been assessed and found acceptable for clinical use. The CBC results generated on some of the blood specimens are, however, flagged by the analyzer for verification of the result of the flagged parameter by other means. One such parameter of clinical significance is the automated platelet count, which is often unreliable if the blood specimen contains platelet clumps.

Loss Of Expression Of Swi/Snf Chromatin Remodeling Complex Components And Setd2 Are Heterogeneous, Widespread, And Co-Occur In Clear Cell Renal Cell Carcinoma, Wei Jiang, Md, Phd, Essel Dulaimi, Theodore Parsons, Qiong Wang, Karthik Devarajan, Raymond O'Neill, Charalambos C. Solomides, Md, Stephen C Peiper, Phd, Jospeh R. Testa, Robert Uzzo, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background

The subunits of the SWI/SNF chromatin remodeling complex have one of the highest mutation rate in human cancers (see Figure 1). Polybromo-1 (PBRM1), a subunit of the SWI/SNF complex, is the second most mutated gene (40%) in clear cell Renal Cell Carcinoma (ccRCC). ARID1A, another subunit that competes with PBRM1 for binding to the complex, was infrequently mutated. The protein expressions of BRG1 and BRM (two catalytic subunits of the complex), and SETD2, a histone modifier (10-15% mutation rate), are not known in ccRCC. In this study we examined their protein expressions by immunohistochemistry (IHC) in tissue microarrays (TMAs), …

Phylogenetic Tree Construction And “Truncal Loss” Analysis Reveal Hidden Associations Between Loss Of Protein Expression In Swi/Snf Complex Components And Tumor Stage And Survival In Clear Cell Renal Cell Carcinoma (Ccrcc), Wei Jiang, Md, Phd, Essel Dulaimi, Karthik Devarajan, Qiong Wang, Raymond O'Neill, Charalambos C. Solomides, Md, Stephen C Peiper, Phd, Robert Uzzo, Joseph R. Testa, Haifeng Yang, Phd

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background

Polybromo-1 (PBRM1), a targeting subunit of the SWI/SNF chromatin remodeling complex, is mutated at a rate of ~40% in clear cell Renal Cell Carcinoma (ccRCC), second only to VHL. Whether its mutation is correlated with tumor stage is controversial. As other components of the SWI/SNF complex were also reported to be mutated in ccRCC, we aim to examine the protein expression patterns of PBRM1, ARID1A, BRG1, and BRM in ccRCC, and to investigate possible association between their loss of expression and tumor stage, as well as survival. We also included a histone modifier, SETD2, which is recently discovered to …

Assessment For Risk Factors Associated With Local Recurrence In Chordoma, John A. Abraham, Md, Wei Jiang, Md, Phd

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background

Chordoma is a rare but locally aggressive malignant neoplasm showing notochordal differentiation. The clinical differential diagnoses can be extensive, and definitive diagnosis often relies on histopathologic evaluation. Histologically, chordoma shows dual epithelial and mesenchymal differentiation, with various morphologies. Despite surgical resection and use of adjuvant radiation therapy, the local recurrence rate of chordoma remains high. We aim to establish factors associated with the increased risk of recurrence and help guide treatment decisions.

Age-Related Ebv-Associated Lymphoproliferative Disorder With Widespread Gastrointestinal Involvement And Subsequent Development Of T-Cell Lymphoma, Guldeep Uppal, Md, Alaina Chodoff, Msii, Zi-Xuan Wang, Phd, Jeffrey P. Baliff Md, Jerald Z. Gong, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background

Age-related EBV-associated lymphoproliferative disorder (AR-EBVLPD) has emerged as a new subset of B-cell lymphoproliferative disorders. We report a unique case of AR-EBVLPD with a widespread gastrointestinal presentation and subsequent transformation to EBV-associated T-cell lymphoma. To our knowledge, this is the first report of a generalized polymorphic extranodal AR-EBVLPD with subsequent transformation to EBV-induced T-cell lymphoma.

Pathology Encountered During Cadaver Dissection Provides An Opportunity For Integrated Learning And Critical Thinking, Guiyan Zhang, Bruce Fenderson

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Abstract

Cadaver dissection engages medical students in active learning, critical thinking, and problem solving. During dissection, students at SKMC are encouraged to document pathologic findings in their cadavers and discuss the findings with their peers. Here, we describe two cases that provided opportunities for integrating anatomy with pathology and clinical medicine. The first case was a benign ovarian neoplasm. This large pelvic mass displaced the urinary bladder and uterus, and compressed the ureters and rectum. Students discussed clinical complications of this pelvic mass and reviewed pathologic findings that differentiate benign from malignant neoplasms. The second case was breast cancer with …

Mitochondrial Ca(2+) Uptake By The Voltage-Dependent Anion Channel 2 Regulates Cardiac Rhythmicity., Hirohito Shimizu, Johann Schredelseker, Jie Huang, Kui Lu, Shamim Naghdi, Fei Lu, Sarah Franklin, Hannah Dg Fiji, Kevin Wang, Huanqi Zhu, Cheng Tian, Billy Lin, Haruko Nakano, Amy Ehrlich, Junichi Nakai, Adam Z Stieg, James K Gimzewski, Atsushi Nakano, Joshua I. Goldhaber, Thomas M. Vondriska, György Hajnóczky, Ohyun Kwon, Jau-Nian Chen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression …