Medical Cell Biology Commons^™

How Loss Of Neurofibromin In Oligodendrocytes Affects The Brain, Debra A. Mayes, Tilat A. Rizvi, Nathan T. Kolasinski, S. Miller, Nancy Ratner

Neuroscience, Cell Biology & Physiology Faculty Publications

Neurofibromatosis type 1 patients are predisposed to central nervous system (CNS) phenotypes including enlarged brains, delayed acquisition of motor skills, brain tumors, and cognitive deficits. Imaging and pathologic analysis suggest that changes in white matter myelination may underlie both the enlargement of white matter tracts that contributes to megancephaly, and/or hyper-intense signals visualized on MRI. To study the role(s) of Nf1 and HRasin oligodendrocytes, we examined the optic nerve and corpus callosum,myelinated fiber tracts.We studiedNf1heterozygous mice,tamoxifen-induced Nf1 loss in mature oligodendrocytes (Plp-CreERT), and a new transgenic model in which the CNPase promoter drives expression of HRasG12V. Activated HRas and loss …

Perinatal Or Adult Nf1 Inactivation Using Tamoxifen-Inducible Plpcre Each Cause Neurofibroma Formation, Debra A. Mayes, Tilat A. Rizvi, Jose A. Cancelas, Nathan T. Kolasinski, Georgianne M. Ciraolo, Anat O. Stemmer-Rachamimov, Nancy Ratner

Neuroscience, Cell Biology & Physiology Faculty Publications

OBJECTIVES

Neurofibromas are tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. One idea within the field suggests that Nf1loss must occur within progenitor cells present within a critical window during Schwann cell development in order for neurofibromas to form. To test this hypothesis and to examine whethermyelinating Schwann cells can serve as aneurofibroma cell of origin, Nf1 loss was induced at perinatal or adult timepoints using a tamoxifen-inducible Plp-CreERT driver.

RESULTS

Perinatal loss of Nf1 resulted in small neurofibromas late in life, while adult loss caused large neurofibromas and morbidity beginning …

Molecular Bases Of Cutaneous And Uveal Melanomas, Sudeep Gaudi, Jane L. Messina

Pathology and Cell Biology Faculty Publications

Intensive research in recent years has begun to unlock the mysteries surrounding the molecular pathogenesis of melanoma, the deadliest of skin cancers. The high-penetrance, low-frequency susceptibility gene CDKN2A produces tumor suppressor proteins that function in concert with p53 and retinoblastoma protein to thwart melanomagenesis. Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma. Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes. The proliferative effects of the MAPK pathway may be complemented by the …

Primary Colorectal Adenocarcinoma Metastatic To The Breast: Case Report And Review Of Nineteen Cases, Rodney E. Shackelford, Pushpa Allam-Nandyala, Marilyn M. Bui, John V. Kiluk, Nicole Nicosia Esposito

Pathology and Cell Biology Faculty Publications

Metastases to the breast from extramammary primaries are uncommon and account for 0.5–6% of all breast malignancies (Georgiannos et al., 2001, and Vizcaíno et al., 2001). Malignant melanoma, lymphoma, and lung and gastric carcinomas are the most frequently encountered nonmammary metastases to the breast in adults (Georgiannos et al., 2001, and Chaignaud et al., 1994). Primary colorectal adenocarcinoma (CRC) metastatic to the breast is extremely rare, with the medical literature having only 19 recorded cases. Typically CRC metastatic to the breast is indicative of widely disseminated disease and a poor prognosis. Here we present a case of poorly differentiated colon …

Pathology Of Breast Carcinoma: Diagnostic, Prognostic, And Therapeutic Issues And Challenges, Rohit Bhargava, Sunati Sahoo, Nicole Nicosia Esposito, Beiyun Chen

Pathology and Cell Biology Faculty Publications

No abstract provided.

Novel Molecular Markers Of Malignancy In Histologically Normal And Benign Breast, Aejaz Nasir, Dung-Tsa Chen, Mike Gruidl, Evita B. Henderson-Jackson, Chinnambally Venkataramu, Susan M. Mccarthy, Heyoung L. Mcbrid, Eleanor Harris, Nazanin Khakpour, Timothy J. Yeatman

Pathology and Cell Biology Faculty Publications

To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and “budding-uninhibited-by-benzimidazoles-1-homolog-beta” (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; ) and high-grade molecular abnormality (HNB-HGMA; ). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and …

Ovarian Epithelial-Stromal Interactions: Role Of Interleukins 1 And 6, Kamisha T. Woolery, Patricia A. Kruk

Pathology and Cell Biology Faculty Publications

Ovarian epithelial cancer is the most lethal gynecologic malignancy. The high mortality is attributed to the fact that most cases typically present in late stage when ovarian cancer (OC) has already spread beyond the ovary. Ovarian epithelial cancer cells are shed into intraperitoneal ascites and easily disseminate throughout the peritoneal cavity with preferential metastasis to the omentum, peritoneum, and local organs. Understanding how ovarian epithelial cells interact with and modulate their microenvironment can provide insight into the molecular mechanism(s) involved with malignant transformation and progression which may eventually identify novel diagnostic, prognostic, and therapeutic targets. The objective of this paper …

Serum Monocyte Chemoattractant Protein-1 In Pancreatic Cancer., Jennifer Sullivan, Qiaoke Gong, Terry Hyslop, Harish Lavu, Galina Chipitsyna, Charles Yeo, Hwyda A Arafat

Department of Surgery Faculty Papers

Background/Aims. Pancreatic ductal adenocarcinoma (PDA) has etiological association with chronic inflammation. Elevated circulating levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), are found in obese individuals. We hypothesized that serum MCP-1 levels are elevated in obese PDA patients. Methods. ELISA was used to analyze MCP-1 serum levels in PDA (n = 62) and intraductal papillary mucinous neoplasms (IPMN) (n = 27). Recursive partitioning statistical analysis investigated the relationship between log MCP-1 and clinicopathological parameters. Results. Log MCP-1 values were significantly (P < 0.05) elevated in patients with BMI ≥ 37.5. In patients with BMI < 37.5, average log MCP-1 values were significantly elevated in PDA patients when compared to IPMN patients. Within the IPMN group, higher log MCP-1 levels correlated with increased age. Recursive partitioning analysis of IPMN versus PDA revealed a strategy of predicting characteristics of patients who are more likely to have cancer. This strategy utilizes log MCP-1 as the primary factor and also utilizes smoking status, gender, and age. Conclusion. MCP-1 is a promising biomarker in pancreatic cancer. The potential of using MCP-1 to distinguish PDA from IPMN patients must be studied in larger populations to validate and demonstrate its eventual clinical utility.

Tdp-43 Potentiates Alpha-Synuclein Toxicity To Dopaminergic Neurons In Transgenic Mice., Tian Tian, Cao Huang, Jianbin Tong, Ming Yang, Hongxia Zhou, Xugang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

TDP-43 and α-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, α-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on α-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution) in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in …

Phosphorylation Meets Nuclear Import: A Review., Jonathan D Nardozzi, Kaylen Lott, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Phosphorylation is the most common and pleiotropic modification in biology, which plays a vital role in regulating and finely tuning a multitude of biological pathways. Transport across the nuclear envelope is also an essential cellular function and is intimately linked to many degeneration processes that lead to disease. It is therefore not surprising that phosphorylation of cargos trafficking between the cytoplasm and nucleus is emerging as an important step to regulate nuclear availability, which directly affects gene expression, cell growth and proliferation. However, the literature on phosphorylation of nucleocytoplasmic trafficking cargos is often confusing. Phosphorylation, and its mirror process dephosphorylation, …

Role Of Extracellular Signal-Regulated Kinase (Erk) In Regulation Of Intestinal Epithelial Tight Junctions, Sudhir Aggarwal

Theses and Dissertations (ETD)

Evidence indicates that MAP kinase (ERK1/2) is involved in regulation of epithelial tight junctions. There are different opinions expressed by investigators as to whether ERK disrupts the junctions or protects them. ERK has also been demonstrated to mediate the EGF-caused protection of the intestinal epithelial tight junctions (TJ) from hydrogen peroxide. Studies using pharmacological inhibitors have shown that EGF increases Thr-phosphorylation of occludin by a MAP kinase-dependent mechanism. This study aimed at looking at the role of ERK in regulation of tight junctions using pharmacological and molecular techniques.

Hypothesis: ERK protects tight junctions in differentiated Caco-2 cells, while it is …

D2r Dopamine Receptor Mediates Changes In Dual Specificity Phosphatase Expression In A Small Cell Lung Cancer Cell Line, Scott Lemar Lattimer

Theses and Dissertations (ETD)

Bromocriptine, a D2 dopamine receptor (D2R) agonist, is used clinically as a treatment for pituitary tumors of a lactotroph origin. Many questions remain unanswered about the mechanism of this effect. The antiproliferative effect has not been demonstrated in DMS 53 cell line, a Small Cell Lung Cancer (SCLC). In this thesis, we have shown that treatment with NPA (N‑propylnorapomorphine), a dopamine receptor agonist inhibits ERK phosphorylation and proliferation in DMS 53 cells. NPA treatment causes significant increases in DUSP‑1 (MKP‑1), DUSP‑4 (MKP‑2) and DUSP5 mRNA. NPA treatment also correlates with increases in DUSP5 (hVHR3) protein visualized using Western Blot. These …

Cd151 Reinforces Vascular Stability By Balancing Endothelial Cell Adhesion And Cytoskeletal Tension, Feng Zhang

Theses and Dissertations (ETD)

Tetraspanin CD151 is highly expressed in endothelial cells and regulates pathological angiogenesis. However, the mechanism by which CD151 promotes vascular morphogenesis and whether CD151 engages other vascular functions are unclear. We observed that CD151 is required for the maintenance of endothelial capillary-like structures formed in vitro and the integrity of lung endothelial cell-cell contacts in vivo. As a master regulator of endothelial cell-matrix and cell-cell adhesions, CD151 is needed for the optimal functions of various cell adhesion proteins such as integrin, cadherin, and CD44. The loss of CD151 elevates the cellular intrinsic contraction by upregulating RhoA signaling and downregulating of …

Acetate Causes Alcohol Hangover Headache In Rats., Christina R Maxwell, Rebecca Jay Spangenberg, Jan B Hoek, Stephen D Silberstein, Michael L Oshinsky

Department of Neurology Faculty Papers

BACKGROUND: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

METHODS: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

RESULTS: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate …

Biological Rationale For The Use Of Dna Methyltransferase Inhibitors As New Strategy For Modulation Of Tumor Response To Chemotherapy And Radiation., Giovanni L Gravina, Claudio Festuccia, Francesco Marampon, Vladimir M Popov, Richard G Pestell, Bianca M Zani, Vincenzo Tombolini

Kimmel Cancer Center Faculty Papers

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic …

Carhsp1 Is Required For Effective Tumor Necrosis Factor Alpha Mrna Stabilization And Localizes To Processing Bodies And Exosomes, Jason R. Pfeiffer, Bethany L. Mcavoy, Ryan E. Fecteau, Kristen M. Deleault, Seth A. Brooks

Dartmouth Scholarship

Tumor necrosis factor alpha (TNF-α) is a critical mediator of inflammation, and its production is tightly regulated, with control points operating at nearly every step of its biosynthesis. We sought to identify uncharacterized TNF-α 3' untranslated region (3'UTR)-interacting proteins utilizing a novel screen, termed the RNA capture assay. We identified CARHSP1, a cold-shock domain-containing protein. Knockdown of CARHSP1 inhibits TNF-α protein production in lipopolysaccharide (LPS)-stimulated cells and reduces the level of TNF-α mRNA in both resting and LPS-stimulated cells. mRNA stability assays demonstrate that CARHSP1 knockdown decreases TNF-α mRNA stability from a half-life (t(1/2)) of 49 min to a t(1/2) …

The Cyclin E Regulator Cullin 3 Prevents Mouse Hepatic Progenitor Cells From Becoming Tumor-Initiating Cells, Uta Kossatz, Kai Breuhahn, Benita Wolf, Matthias Hardtke-Wolenski, Ludwig Wilkens, Doris Steinemann, Stephan Singer, Felicitas Brass, Stefan Kubicka, Brigitte Schlegelberger, Peter Schirmacher, Michael P. Manns, Jeffrey D. Singer, Nisar P. Malek

Biology Faculty Publications and Presentations

Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent substantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of …

Proteoglycans In Health And Disease: Novel Regulatory Signaling Mechanisms Evoked By The Small Leucine-Rich Proteoglycans., Renato V. Iozzo, Liliana Schaefer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The small leucine-rich proteoglycans (SLRPs) are involved in many aspects of mammalian biology, both in health and disease. They are now being recognized as key signaling molecules with an expanding repertoire of molecular interactions affecting not only growth factors, but also various receptors involved in controlling cell growth, morphogenesis and immunity. The complexity of SLRP signaling and the multitude of affected signaling pathways can be reconciled with a hierarchical affinity-based interaction of various SLRPs in a cell- and tissue-specific context. Here, we review this interacting network, describe new relationships of the SLRPs with tyrosine kinase and Toll-like receptors and critically …

Sarcoidosis Cannot Be Reliably Distinguished From Other Causes Of Hepatic Granulomas In A Liver Biopsy Alone, Phililp A. Grieshaber, Md, Whitney Jackson, Md, John L. Farber, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Context:

Hepatic granulomas occur in a variety of circumstances. Sarcoidosis is a common cause with the liver following lymph nodes and the lung in frequency of involvement. The present study aimed to determine where granulomatous hepatisis caused by sarcoidosis can be distinguished in a liver biopsy from other etiologies.

Interesting Case Presentation: Placental Site Trophoblastic Tumor, Nicole Qualtieri, Ms, Pa (Ascp), Andrea Gadue, Mhs, Pa (Ascp)

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Case Study:

A 26 year-old female (G3P1) had a D&E in March, 2010 for a blighted ovum. The diagnosis on the uterine contents at an outside institution was placental site trophoblastic tumor. No follow up care was obtained. Four months later (July, 2010), the patient presented to her OB-GYN stating that she had missed a period and had a positive home pregnancy test. An ultrasound examination failed to identify a fetus, and the patient was referred to TJUH.

At Jefferson an MRI showed a poorly defined uterine mass that extended into the myometrium. The slides from the original D&E were …