Medical Pathology Commons^™

Ip3 Receptor Isoforms Differently Regulate Er-Mitochondrial Contacts And Local Calcium Transfer, Adam Bartok, David Weaver, Tünde Golenár, Zuzana Nichtova, Máté Katona, Száva Bánsághi, Kamil J. Alzayady, V. Kaye Thomas, Hideaki Ando, Katsuhiko Mikoshiba, Suresh K. Joseph, David I. Yule, György Csordás, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP₃ receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts. This role is independent of calcium fluxes. We also show that, while each isoform can support contacts, type …

A Proline Insertion-Deletion In The Spike Glycoprotein Fusion Peptide Of Mouse Hepatitis Virus Strongly Alters Neuropathology., Manmeet Singh, Abhinoy Kishore, Dibyajyoti Maity, Punnepalli Sunanda, Bankala Krishnarjuna, Sreeparna Vappala, Srinivasarao Raghothama, Lawrence C. Kenyon, Debnath Pal, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fusion peptides (FPs) in spike proteins are key players mediating early events in cell-to-cell fusion, vital for intercellular viral spread. A proline residue located at the central FP region has often been suggested to have a distinctive role in this fusion event. The spike glycoprotein from strain RSA59 (PP) of mouse hepatitis virus (MHV) contains two central, consecutive prolines in the FP. Here, we report that deletion of one of these proline residues, resulting in RSA59 (P), significantly affected neural cell syncytia formation and viral titers postinfection in vitro. Transcranial inoculation of C57Bl/6 mice with RSA59 (PP) or RSA59 (P) …

Probable Donor-Derived Human Adenovirus Type 34 Infection In 2 Kidney Transplant Recipients From The Same Donor., Matthew A. Pettengill, Tara M. Babu, Paritosh Prasad, Sally Chuang, Michael G. Drage, Marilyn Menegus, Daryl M. Lamson, Xiaoyan Lu, Dean Erdman, Nicole Pecora

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Human adenovirus type 34 (HAdV-34) infection is a recognized cause of transplant-associated hemorrhagic cystitis and, in rare cases, tubulointerstitial nephritis. The source of such infections is often difficult to assess, that is, whether acquired as a primary infection, exposure to a pathogen in the transplanted organ, or reactivation of an endogenous latent infection. We present here 2 cases of likely transplant-acquired HAdV-34 infection from the same organ donor, manifesting as tubulointerstitial nephritis in 1.

High Affinity Binding Of H3k14ac Through Collaboration Of Bromodomains 2, 4 And 5 Is Critical For The Molecular And Tumor Suppressor Functions Of Pbrm1., Lili Liao, Nilda L. Alicea-Velázquez, Lauren Langbein, Xiaohua Niu, Weijia Cai, Eun-Ah Cho, Meiling Zhang, Celeste B. Greer, Qin Yan, Michael S. Cosgrove, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative …

Altered Expression Of Genes Involved In Ganglioside Biosynthesis In Substantia Nigra Neurons In Parkinson's Disease., Jay S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Reduced expression of GM1 and other major brain gangliosides GD1a, GD1b and GT1b have been reported in Parkinson's disease (PD) brain. Mechanisms underlying these changes are unclear but may be due to a deficit in the ganglioside biosynthetic process. The present study examined the extent to which deficits in gene expression of key biosynthetic enzymes involved in synthesis of GM1 and GD1b (B3galt4) and GD1a and GT1b (St3gal2) exist in neuromelanin-containing neurons in the PD substantia nigra (SN). In situ hybridization histochemistry was used to examine gene expression of B3GALT4 and ST3GAL2 in neuromelanin-containing neurons in the SN in 8 …

Credibility, Replicability, And Reproducibility In Simulation For Biomedicine And Clinical Applications In Neuroscience., Lealem Mulugeta, Andrew Drach, Ahmet Erdemir, C A Hunt, Marc Horner, Joy P. Ku, Jerry G Myers, Rajanikanth Vadigepalli, William W. Lytton

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical …

Induction Of Immune Surveillance Of The Dysmorphogenic Lens., Caitlin M. Logan, Caitlin J. Bowen, A. Sue Menko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The lens has been considered to be an immune privileged site not susceptible to the immune processes normally associated with tissue injury and wound repair. However, as greater insight into the immune surveillance process is gained, we have reevaluated the concept of immune privilege. Our studies using an N-cadherin lens-specific conditional knockout mouse, N-cadΔlens, show that loss of this cell-cell junctional protein leads to lens degeneration, necrosis and fibrotic change, postnatally. The degeneration of this tissue induces an immune response resulting in immune cells populating the lens that contribute to the development of fibrosis. Additionally, we demonstrate that the lens …

Ros Control Mitochondrial Motility Through P38 And The Motor Adaptor Miro/Trak., Valentina Debattisti, Akos A. Gerencser, Masao Saotome, Sudipto Das, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondrial distribution and motility are recognized as central to many cellular functions, but their regulation by signaling mechanisms remains to be elucidated. Here, we report that reactive oxygen species (ROS), either derived from an extracellular source or intracellularly generated, control mitochondrial distribution and function by dose-dependently, specifically, and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca2+], mitochondrial membrane potential, or permeability transition pore opening, known effectors of oxidative stress. However, multiple lines of genetic and pharmacological evidence support that a ROS-activated mitogen-activated protein kinase (MAPK), p38α, is …

Integration Of Metabolomics, Transcriptomics, And Microrna Expression Profiling Reveals A Mir-143-Hk2-Glucose Network Underlying Zinc-Deficiency-Associated Esophageal Neoplasia, Louise Y. Fong, Ruiyan Jing, Karl Smalley, Cristian Taccioli, Johannes Fahrmann, Dinesh K. Barupal, Hansjuerg Alder, John L. Farber, Oliver Fiehn, Carlo M. Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of-flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P < 0.0001), indicating aerobic glycolysis (the "Warburg effect"), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor-suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn-deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zndeficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention. © Fong et al.

Microrna Dysregulation And Esophageal Cancer Development Depend On The Extent Of Zinc Dietary Deficiency., Louise Fong, Cristian Taccioli, Ruiyan Jing, Karl Smalley, Hansjuerg Alder, Yubao Jiang, Paolo Fadda, John Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC), and marginal ZD is prevalent in humans. In rats, marked-ZD (3 mg Zn/kg diet) induces a proliferative esophagus with a 5-microRNA signature (miR-31, -223, -21, -146b, -146a) and promotes ESCC. Here we report that moderate and mild-ZD (6 and 12 mg Zn/kg diet) also induced esophageal hyperplasia, albeit less pronounced than induced by marked-ZD, with a 2-microRNA signature (miR-31, -146a). On exposure to an environmental carcinogen, ~16% of moderate/mild-ZD rats developed ESCC, a cancer incidence significantly greater than for Zn-sufficient rats (0%) (P ≤ 0.05), but lower than …

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 …

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 …

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).

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 …

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 …

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 …

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.

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), …

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.

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.

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 …

Seeing Is Believing: Optical Computed Tomography (Oct) And Histologic Analysis To Define Pathophysiology Of “Very”, Very Late Stent Thrombosis Occurring More Than 7 Years After Drug Eluting Stent Implantation, Antony G. Kaliyadan, Md, Alec Vishnevsky, Md, Henry Siu, Md, David Fishman, Md, John Farber, Md, Nicholas Ruggiero Ii, Md, Michael P. Savage, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Case Presentation

• 58-year-old male with prior non-ST elevation MI with PCI performed using a sirolimus eluting stent placed in a large OM1 branch 86 months prior presented with five hours chest pain similar to prior MI >7 years earlier.
• Additional history of hypertension, hyperlipidemia, non-compliance with antiplatelet therapy and active tobacco abuse at time of presentation.
• Patient reported self-discontinuation of medications (aspirin (time unknown), statin, beta blocker) and resumed smoking.
• Clopidogrel was discontinued by his primary physician 97 days prior to presentation
• Initial electrocardiogram revealed a lateral ST elevation MI and the patient was taken to the cardiac catheterization lab …

A Comparison Of The Who 2004 And 2010 Classification Systems In Pancreatic Neuroendocrine Tumors (Pancreatic Net), James P. Casey, Md, Aakanksha Asija, Md, Anthony J. Prestipino, M.D., Jocelyn A. Sendecki, Md, Jonathan Brody, Md, Harish Lavu, Md, Jordan M. Winter, Md, Charles Yeo, Md, Ashwin R. Sama, Md, Madhaven V. Pillai, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pancreatic NETs are rare tumors with multiple classification systems. Previous classification systems included tumor size, histologic grade, mitoses, Ki67, and metastases. The current WHO 2010 system utilizes mitotic rate and Ki67% to assign a grade. We compared the WHO 2004 and 2010 classification systems in predicting mortality and metastasis.

Pathologic parameters were used to classify 50 cases of Pancreatic NET according to the WHO 2004 and WHO 2010 systems. The relationship between the WHO 2004 and WHO 2010 grading was investigated using an exact Chi squared test. WHO grade categorization was next explored by vital status, by the exact method, …

Differentiation State-Specific Mitochondrial Dynamic Regulatory Networks Are Revealed By Global Transcriptional Analysis Of The Developing Chicken Lens., Daniel Chauss, Subhasree Basu, Suren Rajakaruna, Zhiwei Ma, Victoria Gau, Sara Anastas, Lisa A. Brennan, J. Fielding Hejtmancik, A. Sue Menko, Marc Kantorow

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The mature eye lens contains a surface layer of epithelial cells called the lens epithelium that requires a functional mitochondrial population to maintain the homeostasis and transparency of the entire lens. The lens epithelium overlies a core of terminally differentiated fiber cells that must degrade their mitochondria to achieve lens transparency. These distinct mitochondrial populations make the lens a useful model system to identify those genes that regulate the balance between mitochondrial homeostasis and elimination. Here we used an RNA sequencing and bioinformatics approach to identify the transcript levels of all genes expressed by distinct regions of the lens epithelium …

Burkitt Lymphoma In A Pediatric Patient With Hereditary Multiple Exostose, Sara D. Prince, Portia A. Krieger, Md, Andrew W. Walter, Ms, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Introduction

Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by the growth of multiple bony tumors. These tumors include benign osteochondromas and less commonly, malignant tumors that arise from transformation of exostoses into secondary osteosarcomas and chondrosarcomas [1,3]. There have been no reported cases of lymphoma in the pediatric HME population. We report a case of a 10 year old boy with HME who developed Burkitt lymphoma of the abdomen.

Inputs Drive Cell Phenotype Variability., James Park, Anthony Brureau, Kate Kernan, Alexandria Starks, Sonali Gulati, Babatunde Ogunnaike, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

What is the significance of the extensive variability observed in individual members of a single-cell phenotype? This question is particularly relevant to the highly differentiated organization of the brain. In this study, for the first time, we analyze the in vivo variability within a neuronal phenotype in terms of input type. We developed a large-scale gene-expression data set from several hundred single brainstem neurons selected on the basis of their specific synaptic input types. The results show a surprising organizational structure in which neuronal variability aligned with input type along a continuum of sub-phenotypes and corresponding gene regulatory modules. Correlations …

Chronic Arsenic Exposure And Angiogenesis In Human Bronchial Epithelial Cells Via The Ros/Mir-199a-5p/Hif-1Α/Cox-2 Pathway., Jun He, Min Wang, Yue Jiang, Qiudan Chen, Shaohua Xu, Qing Xu, Bing-Hua Jiang, Ling-Zhi Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.Objectives: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.Methods: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.Results: We …

Targeting Fibroblast Activation Protein In Tumor Stroma With Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth And Augment Host Immunity Without Severe Toxicity., Liang-Chuan S. Wang, Albert Lo, John Scholler, Jing Sun, Rajrupa S. Majumdar, Veena Kapoor, Michael Antzis, Cody E. Cotner, Laura A. Johnson, Amy C. Durham, Charalambos C. Solomides, Md, Carl H. June, Ellen Puré, Steven M. Albelda

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the …