Medical Cell Biology Commons^™

Micu1 Regulation Of Mitochondrial Ca(2+) Uptake Dictates Survival And Tissue Regeneration., Anil Noronha Antony, Melanie Paillard, Cynthia Moffat, Egle Juskeviciute, Jason Correnti, Brad Bolon, Emanual Rubin, Md, György Csordás, Erin L Seifert, Jan B. Hoek, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondrial Ca(2+) uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis. …

Role Of Heme Oxygenase-1 In The Pathogenesis And Tumorigenicity Of Kaposi's Sarcoma-Associated Herpesvirus, Lu Dai, Jing Qiao, David Nguyen, Amanda P. Struckhoff, Lisa Doyle, Karlie Bonstaff, Luis Del Valle, Chris Parsons, Bryan P. Toole, Rolf Renne, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation and lack effective therapeutic options. Heme oxygenase-1 (HO-1) has been reported as an important regulator of endothelial cell cycle control, proliferation and angiogenesis. HO-1 has also been found to be highly expressed in KSHV-infected endothelial cells and oral AIDS-KS lesions. We previously demonstrate that the multifunctional glycoprotein CD147 is required for KSHV/LANA-induced endothelial cell invasiveness. During the identification of CD147 controlled downstream genes by microarray analysis, we found that the expression of HO-1 is significantly …

Structure-Activity Relationships Governing The Interaction Of Nanoparticles With Mammalian Cells- Predictive Models For Toxicology And Medical Appliances, Marcus A. Maher

Doctoral

Nanoscience is seen as one of the key enabling technologies of the 20th century and as its range of applications increases it is important to look at how nanomaterials interact with biological environments. Some of these interactions have given rise to toxic effects and thus, the creation of the field of nanotoxicology, it has also been noted that current methods of evaluating toxicity may not be sufficient to keep up with the rapidly emerging range of nanomaterials becoming available. It is clear that alternatives are necessary. In this thesis, a phenomenological rate equation model is constructed to simulate nanoparticle uptake …

Microcystic, Elongated, And Fragmented (Melf) Pattern Invasion In Ovarian Endometrioid Carcinoma: Immunohistochemical Profile And Prognostic Implications, Allison F. Goldberg, Md, Lauren Cooper, Md, D. De Cotiis, Norman G. Rosenblum, Md, Phd, Joanna Chan, Md

Department of Pathology, Anatomy, and Cell Biology Resident's Posters

BACKGROUND

•Microcystic, Elongated and Fragmented (MELF) is a well-recognized pattern of uterine endometrioid carcinoma (UEC) associated with lymphovascular space invasion and occult lymph node metastasis

•MELF in UEC may be seen with Lynch Syndrome

•MELF in UEC is hypothesized to be histologic evidence of an epithelial mesenchymal transition

•MELF pattern invasion in ovarian endometrioid carcinoma (OEC) was first described at USCAP 2015 •

Current study evaluates MELF in OEC for

•Prognostic implications

•Immunohistochemical (IHC) profile related to

•Lynch Syndrome

•Epithelial mesenchymal transition

DESIGN

•42 consecutive cases of OEC without concurrent UEC (1996-2014) evaluated by 2 pathologists

•MELF defined as at …

Two Separate Colorectal Granular Cell Tumors: A Case Report, Danica N. Giugliano, Md, Danielle Fortuna, Md, Scott D. Goldstein, Md, Benjamin Philllips, Md, Gerald A. Isenberg, Md

Department of Surgery Posters

Introduction, Case Report, Discussion, Conclusion and References.

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 …

Challenges Of Adoptive (T-)Cell Transfer Immunotherapy For Cancer, Aaron Volk

Biology: Student Scholarship & Creative Works

Background and significance: The rebirth of the theory of immunosurveillance in 2001 rejuvenated interest in anticancer immunotherapies. In particular, T-cell-based therapies have garnered substantial interest due to the robustness and tumor antigen-specific cytotoxicity of T-cell anticancer immune responses.

Hypothesis: The efficacy of adoptive cell transfer (ACT) T-cell immunotherapy could significantly improve and gain widespread approval if future innovations in ACT-based approaches account for the pro- and antitumoral properties of non-CD8⁺ lineages of effector T-cells, evasion of T-cell antitumor immunity, and tumor-induced suppression of antitumor immunity.

Problem Analysis: Despite numerous reports of highly successful ACT-based clinical trials, no such therapy …

Prevalence And Spectrum Of Brca Germline Variants In Mainland Chinese Familial Breast And Ovarian Cancer Patients., Yeong C. Kim, Linli Zhao, Hanwen Zhang, Ye Huang, Jian Cui, Fengxia Xiao, Bradley Downs, San Ming Wang

Journal Articles: Genetics, Cell Biology & Anatomy

Germline mutations in BRCA1 and BRCA2 are the most penetrating genetic predispositions for breast and ovarian cancer, and their presence is largely ethnic-specific. Comprehensive information about the prevalence and spectrum of BRCA mutations has been collected in European and North American populations. However, similar information is lacking in other populations, including the mainland Chinese population despite its large size of 1.4 billion accounting for one fifth of the world's population. Herein, we performed an extensive literature analysis to collect BRCA variants identified from mainland Chinese familial breast and ovarian cancer patients. We observed 137 distinct BRCA1 variants in 409 of …

Mitogenic Activation And Proliferation Of T Lymphocytes In Trpm7 Kinase-Dead Mutant Mice, Pavani Beesetty, Masayuki Matsushita, J. Ashot Kozak

Neuroscience, Cell Biology & Physiology Faculty Publications

Calcium and magnesium ions have been implicated in T lymphocyte proliferation in response to antigen recognition. Specifically, it is believed that calcium and magnesium elevations in the cytoplasm are necessary for efficient T cell proliferation. Research over the past two decades has focused on identifying the plasma membrane ion channels responsible for governing Ca2+ influx in lymphocytes and Orai-STIM, Kv1.3 and KCa3.1 channels were shown to be crucial for persistent calcium mobilization. Pharmacologic or genetic suppression of calcium influx gives rise to lymphoproliferative defects. In addition to Ca2+, several studies have demonstrated that Mg2+ influx positively regulates proliferation. TRPM7 is …

Cells Activated For Wound Repair Have The Potential To Direct Collective Invasion Of An Epithelium., Brigid M Bleaken, A Sue Menko, Janice Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mechanisms regulating how groups of cells are signaled to move collectively from their original site and invade surrounding matrix are poorly understood. Here we develop a clinically relevant ex vivo injury invasion model to determine whether cells involved in directing wound healing have invasive function and whether they can act as leader cells to direct movement of a wounded epithelium through a three-dimensional (3D) extracellular matrix (ECM) environment. Similar to cancer invasion, we found that the injured cells invade into the ECM as cords, involving heterotypical cell-cell interactions. Mesenchymal cells with properties of activated repair cells that typically locate to …

Cd147 And Downstream Adamtss Promote The Tumorigenicity Of Kaposi's Sarcoma-Associated Herpesvirus Infected Endothelial Cells, Lu Dai, Jimena Trillo-Tinoco, Yihan Chen, Karlie Bonstaff, Luis Del Valle, Chris Parsons, Augusto C. Ochoa, Jovanny Zabaleta, Bryan P. Toole, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS), which preferentially arise in immunocompromised patients and lack effective therapeutic options. We have previously shown that KSHV or viral protein LANA up-regulates the glycoprotein CD147, thereby inducing primary endothelial cell invasiveness. In the current study, we identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among downstream genes, two specific metalloproteases, ADAMTS1 and 9, are strongly expressed in AIDS-KS tissues and contribute to KSHV-infected endothelial cell invasiveness through up-regulation of IL-6 and VEGF. By using a KS-like nude …

Reversible Recruitment Of A Homeostatic Reserve Pool Of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity Of Quantal Content, Xueyong Wang, Martin J. Pinter, Mark M. Rich

Neuroscience, Cell Biology & Physiology Faculty Publications

Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregulation of release is due to Ca²⁺-dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization …

In-Silico Identification Of Prognostically Inversely Correlated Mirnas And Mrnas (Pic’S) In Multiple Cancers, Chirayu Pankaj Goswami, Zi-Xuan Wang

Department of Pathology, Anatomy, and Cell Biology Posters

Despite numerous methods available to identify potential mRNA targets for miRNAs, prognostic relationship of these molecules in diseases like cancers where deregulation of gene expression is a major pathogenic factor, has not yet been emphasized. We performed in-silico identification of prognostically inversely correlated miRNA - mRNA pairs (PIC’s) in multiple cancers using expression data from The Cancer Genome Atlas. Partners in a PIC show inverse correlation of expression and opposite hazard implication. Using a three step approach, we identified a total of 1,253,443 PIC’s from 23 cancer types, several of which have previously been shown to have a predicted or …

Exome Screening To Identify Loss-Of-Function Mutations In The Rhesus Macaque For Development Of Preclinical Models Of Human Disease, Adam Cornish, Robert M. Gibbs, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: Exome sequencing has been utilized to identify genetic variants associated with disease in humans. Identification of loss-of-function mutations with exome sequencing in rhesus macaques (Macaca mulatta) could lead to valuable animal models of genetic disease. Attempts have been made to identify variants in rhesus macaques by aligning exome data against the rheMac2 draft genome. However, such efforts have been impaired due to the incompleteness and annotation errors associated with rheMac2. We wished to determine whether aligning exome reads against our new, improved rhesus genome, MacaM, could be used to identify high impact, loss-of-function mutations in rhesus macaques that would …

Hexokinase Ii Localization Is Independent Of Ampk Activation In Hela Cells, Alyssa Brown

Graduate School of Biomedical Sciences Theses and Dissertations

In order for a cancer cell to thrive, it must alter its metabolism to produce the energy needed for rapid growth. Cells accomplish this by the Warburg Effect, or switching metabolism to aerobic glycolysis, where a cell can rapidly break down sugar into ATP, lactic acid and additional byproducts. Hexokinase 2, the enzyme that catalyzes the first committed step of glycolysis, may also be upregulated in cancer cells to increase glucose breakdown. Similar proteins for metabolism are found in both S. cerevisiae and mammalian cells. S. cerevisiae regulates metabolism through glucose repression, by Snf1 (mammalian homolog: AMPK) activation, which aids …

Delaying Chemotherapy In The Treatment Of Stage Iv Non-Small Cell Lung Cancer Does Not Adversely Affect Survival Outcome, Mohammad Mozayen Md, Mohamed Alsharedi, Inderjit Mehmi, Todd W. Gress Md, Maria Tria Tirona Md

Biochemistry and Microbiology

Background: Whether a delay in the initiation of chemotherapy for advanced non-small cell lung cancer (NSCLC) can affect overall survival is not well studied. We aim to evaluate the effect of the time interval between diagnosis and initiation of chemotherapy on overall survival in patients with stage IV NSCLC.

Methods: A retrospective review of newly diagnosed stage IV NSCLC patients who received chemotherapy between 1995 and 2012 was conducted. Demographics, histology and site(s) of metastases of patients were reviewed. Time interval between the date of diagnosis and the date of starting chemotherapy was calculated in days. Patients were divided in …

Gallic Acid, A Phenolic Compound, Exerts Anti-Angiogenic Effects Via The Pten/Akt/Hif-1Α/Vegf Signaling Pathway In Ovarian Cancer Cells, Zhiping He, Allen Y. Chen, Yon Rojanasakul, Gary O. Rankin, Yi Charlie Chen

Pharmacology, Physiology and Toxicology

Gallic acid (GA), a polyphenol, is widely found in numerous fruits and vegetables, particularly in hickory nuts. In the present study, we found that gallic acid, a natural phenolic compound isolated from fruits and vegetables, had a more potent growth inhibitory effect on two ovarian cancer cell lines, OVCAR-3 and A2780/CP70, than the effect on a normal ovarian cell line, IOSE-364. These results demonstrated that GA selectively inhibits the growth of cancer cells. Gene expression was examined by ELISA and western blot analysis, and gene pathways were examined by luciferase assay. It was found that GA inhibited VEGF secretion and …

Novel Role Of Cd47 In Obesity-Associated Metabolic Dysfunctions, Heather L. Norman-Burgdolf

Theses and Dissertations--Pharmacology and Nutritional Sciences

Obesity and its associated comorbidities are of global concern. These complications are largely driven by perturbations in energy homeostasis, inflammation, and oxidative stress within metabolic tissues. Although these underlying pathways have been established, molecular mechanisms augmenting metabolic dysfunction have not been fully defined. CD47, a ubiquitously expressed cell membrane receptor, has been previously implicated in the development of inflammation and oxidative stress in a number of disease conditions. Previous work from our lab and others has confirmed that the most potent ligand of CD47, TSP1, plays a critical role in facilitating inflammation and metabolic dysfunction in diet-induced obesity. Whether these …

Turn-Around-Time Improvements For Positive Blood Cultures From Incorporation Of Workflow Modifications, Brent Bobik, Allison F. Goldberg, Md, P. Prior, Amity L. Roberts, Phd, D(Abmm)

Department of Pathology, Anatomy, and Cell Biology Resident's Posters

Background:

Emergence of direct from positive blood culture bottle identification (ID) methods reveal opportunities for improving bacterial ID and select resistance marker detection turn-around-times. Each system has various advantages and disadvantages; each institution must select the method/s that best fit the laboratory and patient needs. Here we elucidate improvements in 24 hour workflow through incorporating multiple rapid technologies for positive blood culture ID into a 24 hour algorithm.

Methods:

MALDI-TOF (Bruker) analysis with sepsityper extraction (aerobic Gram-positive and anaerobic bacteria); MALDI-TOF analysis with serum separator tube concentration (Gram-negative bacteria); and a FilmArray Blood Culture Panel (Biofire) were utilized. MALDI was …

Il-15 Mediates Mitochondrial Activity Through A Ppar𝛿-Dependent-Ppar𝛼-Independent Mechanism In Skeletal Muscle Cells, Shantaé M. Thornton, James E. Krolopp, Marcia J. Abbott

Health Sciences and Kinesiology Faculty Articles

Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed “myokines,” has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPAR𝛼 and/or PPAR𝛿 as targets of IL-15 signaling. C2C12 SKM cells were differentiated for 6 days and treated every other day with IL-15 (100 ng/mL), a PPAR𝛼 inhibitor (GW-6471), a PPAR𝛿 …