Medical Cell Biology Commons^™

Prognostic Significance Of High-Grade Dysplasia In Colorectal Adenomas., A D Toll, D Fabius, T Hyslop, E Pequignot, A J Dimarino, A Infantolino, J P Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Aim  Colonoscopy to detect and remove polyps has contributed to a reduction in colorectal carcinoma. Three-year follow up is recommended for patients considered to be at high risk (at least three adenomas, adenoma ≥ 1 cm, villous or high-grade features). Our study focused on patients diagnosed with high-grade dysplasia with regard to initial management and follow up. Method  A search of patients who had had endoscopic removal of a high-grade adenoma was carried out. Patients with the following were excluded: follow up of < 1 year, polyposis syndromes, prior colon cancer and a diagnosis of adenocarcinoma within 6 months following initial diagnosis. Results  Eighty-three patients treated between 1999 and 2007 for high-grade dysplasia (HGD) in a colorectal adenoma were identified. Over a median follow-up period of 4 years, 53 (64%) developed further adenomatous polyps. Among these, 7% had an adenoma with HGD or an adenocarcinoma. In all these patients, the initial high-grade adenoma was > 1 cm in diameter. Initial follow-up colonoscopy was performed on average 7 months following the initial diagnosis. …

Mir-21 Induced Angiogenesis Through Akt And Erk Activation And Hif-1Α Expression., Ling-Zhi Liu, Chongyong Li, Qi Chen, Yi Jing, Richard Carpenter, Yue Jiang, Hsiang-Fu Kung, Lihui Lai, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1α and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated …

Effects Of Influenza Viral Infection On The Cellular Sumoylation System, Joshua Ortiz^, Jason Chacon, German Rosas- Acosta*

COURI Symposium Abstracts, Spring 2011

The tendency of influenza strains to mutate rapidly, changing their antigenic makeup between consecutive seasons and allowing them to jump over the genetic barriers that limit their host range, imposes the risk for the influx of highly pathogenic viral strains into humans. Current available anti-influenza drugs target structural components of the virus and consequently, resistant viral strains arise due to point mutations that render the drugs ineffective. SUMOylation, the reversible post-translational attachment of a SUMO (Small Ubiquitin-like MOdifier) molecule to its target proteins, regulates numerous biological processes. Our studies have shown that some influenza viral proteins are SUMOylated during infection, …

Aging Enhances Serum Cytokine Response But Not Task-Induced Grip Strength Declines In A Rat Model Of Work-Related Musculoskeletal Disorders., Dong L Xin, Michelle Y Harris, Christine K Wade, Mamta Amin, Ann E Barr, Mary F Barbe

Department of Physical Therapy Faculty Papers

BACKGROUND: We previously reported early tissue injury, increased serum and tissue inflammatory cytokines and decreased grip in young rats performing a moderate demand repetitive task. The tissue cytokine response was transient, the serum response and decreased grip were still evident by 8 weeks. Thus, here, we examined their levels at 12 weeks in young rats. Since aging is known to enhance serum cytokine levels, we also examined aged rats.

METHODS: Aged and young rats, 14 mo and 2.5 mo of age at onset, respectfully, were trained 15 min/day for 4 weeks, and then performed a high repetition, low force (HRLF) …

Chloroquine Treatment Of Arpe-19 Cells Leads To Lysosome Dilation And Intracellular Lipid Accumulation: Possible Implications Of Lysosomal Dysfunction In Macular Degeneration, Patrick M. Chen, Zoë J. Gombart, Jeff W. Chen

Dartmouth Scholarship

Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly people over 60. The pathogenesis is still unclear. It has been suggested that lysosomal stress may lead to drusen formation, a biomarker of AMD. In this study, ARPE-19 cells were treated with chloroquine to inhibit lysosomal function. Chloroquine-treated ARPE-19 cells demonstrate a marked increase in vacuolation and dense intracellular debris. These are identified as chloroquine-dilated lysosomes and lipid bodies with LAMP-2 and LipidTOX co-localization, respectively. Dilation is an indicator of lysosomal dysfunction. Chloroquine disrupts uptake of exogenously applied rhodamine-labeled dextran by these cells. This suggests a disruption …

Activation Of The Basolateral Membrane Cl- Conductance Essential For Electrogenic K+ Secretion Suppresses Electrogenic Cl- Secretion, Quanhua He, Susan T. Halm, Jin Zhang, Dan R. Halm

Neuroscience, Cell Biology & Physiology Faculty Publications

Adrenaline activates transient Cl^--secretion and sustained K⁺-secretion across isolated distal colonic mucosa of guinea pig. The Ca⁺⁺-activated Cl^- channel inhibitor CaCCinh-A01 [30μM] significantly reduced electrogenic K⁺-secretion, detected as short-circuit current (I_sc). This inhibition supported the cell model for K⁺-secretion in which basolateral membrane Cl^- channels provide an exit pathway for Cl^- entering the cell via Na⁺/K⁺/2Cl^--cotransporters. CaCCinh-A01 inhibited both I_sc and transepithelial conductance in a concentration dependent manner, IC₅₀ = 6.3 μM. GlyH-101, another Cl^- channel …

Expression Of Aldehyde Dehydrogenase In Dysplastic Lesions Arising From Inflammatory Bowel Disease, Adam D. Toll, Bruce M. Boman, Juan P. Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusion: Our study demonstrates ALDH1 is significantly expressed in dysplatic lesions arising from IBD. ALDH1-expression in cancer stem cells suggest an important causative role in the progression to cancer in IBD. Although we found high sensitivity for dysplasia, the specificity was poor. In addition to neoplasia, ALDH1-expressing stem cells proliferate in response to chronic inflammation, accounting for the cases of inflammatory atypia with positive ALDHI1 expression.

Fus Transgenic Rats Develop The Phenotypes Of Amyotrophic Lateral Sclerosis And Frontotemporal Lobar Degeneration., Cao Huang, Hongxia Zhou, Jianbin Tong, Han Chen, Yong-Jian Liu, Dian Wang, Xiaotao Wei, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and …

Correlation Of P16ink4a Expression And Hpv Copy Number With Cellular Ftir Spectroscopic Signatures Of Cervical Cancer Cells, Kamila Ostrowska, Amaya Garcia, Aidan Meade, Alison Malkin, Ifeoluwapo Okewumi, John O’Leary, Cara Martin, Hugh Byrne, Fiona Lyng

Articles

Cervical cancer, a potentially preventable disease, has its main aetiology in infection by high risk human papillomavirus (HR-HPV). Approaches to improving cervical cancer screening and diagnostic methodologies include molecular biological analysis, targeting of biomarker proteins, but also exploration and implementation of new techniques such as vibrational spectroscopy. This study correlates the biomarker protein p16^INK4A expression levels dependent on HPV copy number with the infrared absorption spectral signatures of the cervical cancer cell lines, HPV negative C33A, HPV-16 positive SiHa and CaSki and HPV-18 positive HeLa. Confocal fluorescence microscopy demonstrated that p16^INK4A is expressed in all investigated cell lines …

Prolactin-Induced Mouse Mammary Carcinomas Model Estrogen Resistant Luminal Breast Cancer., Lisa M Arendt, Debra E Rugowski, Tara A Grafwallner-Huseth, Maria Jose Garcia-Barchino, Hallgeir Rui, Linda A Schuler

Kimmel Cancer Center Faculty Papers

INTRODUCTION: Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To …

Evidence-Based Genomic Diagnosis Characterized Chromosomal And Cryptic Imbalances In 30 Elderly Patients With Myelodysplastic Syndrome And Acute Myeloid Leukemia., Renu Bajaj, Fang Xu, Bixia Xiang, Katherine Wilcox, Autumn J Diadamo, Rachana Kumar, Alexandra Pietraszkiewicz, Stephanie Halene, Peining Li

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: To evaluate the clinical validity of genome-wide oligonucleotide array comparative genomic hybridization (aCGH) for detecting somatic abnormalities, we have applied this genomic analysis to 30 cases (13 MDS and 17 AML) with clonal chromosomal abnormalities detected in more than 50% of analyzed metaphase cells.

RESULTS: The aCGH detected all numerical chromosomal gains and losses from the mainline clones and 113 copy number alterations (CNAs) ranging from 0.257 to 102.519 megabases (Mb). Clinically significant recurrent deletions of 5q (involving the RPS14 gene), 12p12.3 (ETV6 gene), 17p13 (TP53 gene), 17q11.2 (NF1 gene) and 20q, double minutes containing the MYC gene and …

Effect Of Aging On Cellular Mechanotransduction, Miaozong Wu, Jacqueline Fannin, Kevin M. Rice, Bin Wang, Eric R. Blough

MIIR Faculty Research

Aging is becoming a critical heath care issue and a burgeoning economic burden on society. Mechanotransduction is the ability of the cell to sense, process, and respond to mechanical stimuli and is an important regulator of physiologic function that has been found to play a role in regulating gene expression, protein synthesis, cell differentiation, tissue growth, and most recently, the pathophysiology of disease. Here we will review some of the recent findings of this field and attempt, where possible, to present changes in mechanotransduction that are associated with the aging process in several selected physiological systems, including musculoskeletal, cardiovascular, neuronal, …

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 …

Identification Of Genes Involved In Hematopoietic Stem Cell Differentiation And Leukemia Differentiation And Leukemia, Jasjeet Bhullar

Theses, Dissertations and Capstones

Hematopoiesis is maintained by a proper balance between self renewal and multipotent differentiation of the hematopoietic stem cells (HSC). Acute myelogenous leukemia (AML) is characterized by the blockage in the differentiation of HSC, while self renewal and proliferation is preserved. It is important to understand the mechanisms involved in the inhibition of hematopoietic differentiation and maintenance of the HSC state in order to develop better therapies for AML. In these studies I have explored the role of Hsp90, omega-3 fatty acids and YB-1 in hematopoietic differentiation. EML, a hematopoietic precursor cell line, was used as a model for the hematopoietic …