Medicine and Health Sciences Commons^™

The Effect Of Rare Variants In Trem2 And Pld3 On Longitudinal Cognitive Function In The Wisconsin Registry For Alzheimer's Prevention, Corinne D. Engelman, Burcu F. Darst, Murat Bilgel, Eva Vasiljevic, Rebecca L. Koscik, Bruno M. Jedynak, Sterling C. Johnson

Mathematics and Statistics Faculty Publications and Presentations

Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of initially asymptomatic adults, aged 36–73 years at baseline, enriched for a parental history of AD. A comprehensive cognitive test battery was performed at up to 5 visits. A factor analysis resulted in 6 cognitive factors that were standardized into z scores (∼N [0, 1]); the mean of these z scores was …

High-Resolution Physical Map For Chromosome 16q12.1-Q13, The Blau Syndrome Locus., Xiaoju Wang, Helena Kuivaniemi, Gina Bonavita, Charlene J Williams, Gerard Tromp

Charlene Williams

BACKGROUND: The Blau syndrome (MIM 186580), an autosomal dominant granulomatous disease, was previously mapped to chromosome 16p12-q21. However, inconsistent physical maps of the region and consequently an unknown order of microsatellite markers, hampered us from further refining the genetic locus for the Blau syndrome. To address this problem, we constructed our own high-resolution physical map for the Blau susceptibility region. RESULTS: We generated a high-resolution physical map that provides more than 90% coverage of a refined Blau susceptibility region. The map consists of four contigs of sequence tagged site-based bacterial artificial chromosomes with a total of 124 bacterial artificial chromosomes, …

Peripheral Blood Clinical Laboratory Variables Associated With Outcomes Following Combination Nivolumab And Ipilimumab Immunotherapy In Melanoma, Samuel Rosner, Erica Kwong, Alexander N. Shoushtari, Claire F. Friedman, Allison S. Betof, Mary Sue Brady, Daniel G. Coit, Margaret K. Callahan, Jedd D. Wolchok, Paul B. Chapman, Katherine S. Panageas, Michael A. Postow

Publications and Research

Both the combination of nivolumab + ipilimumab and single-agent anti-PD- 1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD- 1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab …

Cks1 Expression In Melanocytic Nevi And Melanoma, Anna A. Brożyna, Andrew Aplin, Cynthia Cohen, Grant Carlson, Andrew Joseph Page, Michael Murphy, Andrzej T. Slominski, J. Andrew Carlson

Department of Cancer Biology Faculty Papers

Cyclin-dependent kinase subunit 1 (Cks1) regulates the degradation of p27, an important G1-S inhibitor, which is up regulated by MAPK pathway activation. In this study, we sought to determine whether Cks1 expression is increased in melanocytic tumors and correlates with outcome and/or other clinicopathologic prognostic markers. Cks1 expression was assessed by immunohistochemistry in 298 melanocytic lesions. The frequency and intensity of cytoplasmic and nuclear expression was scored as a labeling index and correlated with clinico-pathological data. Nuclear Cks1 protein was found in 63% of melanocytic nevi, 89% primary and 90% metastatic melanomas with mean labeling index of 7 ± 16, …

Survival Advantage Of Both Human Hepatocyte Xenografts And Genome-Edited Hepatocytes For Treatment Of Alpha-1 Antitrypsin Deficiency, Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A. Kay, Leonard D. Shultz, Dale L. Greiner, Terence R. Flotte, Michael A. Brehm, Christian Mueller

Christian Mueller

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create …

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

Gary O. Rankin

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 …

Myricetin Inhibits Proliferation Of Cisplatin-Resistant Cancer Cells Through A P53-Dependent Apoptotic Pathway, Haizhi Huang, Allen Y. Chen, Xingqian Ye, Bingyun Li, Yon Rojanasakul, Gary O. Rankin, Yi Charlie Chen

Gary O. Rankin

Cisplatin is a commonly used drug for cancer treatment by crosslinking DNA, leading to apoptosis of cancer cells, resistance to cisplatin treatment often occurs, leading to relapse. Therefore, there is a need for the development of more effective treatment strategies that can overcome chemoresistance. Myricetin is a flavonoid from fruits and vegetables, showing anticancer activity in various cancer cells. In this study, we found myricetin exhibited greater cytotoxicity than cisplatin in two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and it was less cytotoxic to the normal ovarian cell line IOSE-364. Myricetin selectively induced apoptosis in both cisplatin-resistant cancer …

Cerium Oxide Nanoparticle Treatment Ameliorates Peritonitis-Induced Diaphragm Dysfunction, Shinichi Asano, Ravikumar Arvapalli, Nandini D. Manne, Mani Maheshwari, Bing Ma, Kevin M. Rice, Vellaisamy Selvaraj, Eric Blough

Nandini Manne

The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO₂) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO₂ nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO₂ nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in …

Cerium Oxide Nanoparticle Treatment Ameliorates Peritonitis-Induced Diaphragm Dysfunction, Shinichi Asano, Ravikumar Arvapalli, Nandini D. Manne, Mani Maheshwari, Bing Ma, Kevin M. Rice, Vellaisamy Selvaraj, Eric Blough

Kevin M Rice

The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO2) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile (Po) function …

Cerium Oxide Nanoparticle Treatment Ameliorates Peritonitis-Induced Diaphragm Dysfunction, Shinichi Asano, Ravikumar Arvapalli, Nandini D. Manne, Mani Maheshwari, Bing Ma, Kevin M. Rice, Vellaisamy Selvaraj, Eric Blough

Eric Blough

The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO₂) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO₂ nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO₂ nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in …

Possible Breakdown Of Dopamine Receptor Synergism In A Mouse Model Of Huntington's Disease, Samantha F. Kennedy

University of New Orleans Theses and Dissertations

The model of basal ganglia function proposed by Albin, Young and Penney (1989) describes two anatomically independent motor pathways, the direct and indirect. However, under normal conditions striatal dopamine (DA) is required for the expression of motor behavior, and DAergic control of the two pathways (via D1 and D2 receptors, respectively) is dependent on co-activation. We tested for a possible breakdown of D1/D2 synergism using transgenic R6/1 mice bearing the human huntingtin allele (Htt). Motor stereotypy, observed prior to the onset of HD-related symptoms, was rated on a 5-point scale following activation of: A) D1 receptors alone, B) D2 receptors …

Virtual Reality As A Training Tool To Treat Physical Inactivity In Children, Adam W. Kiefer, David Pincus, Michael J. Richardson, Gregory D. Myer

Psychology Faculty Articles and Research

Lack of adequate physical activity in children is an epidemic that can result in obesity and other poor health outcomes across the lifespan. Physical activity interventions focused on motor skill competence continue to be developed, but some interventions, such as neuromuscular training (NMT), may be limited in how early they can be implemented due to dependence on the child’s level of cognitive and perceptual-motor development. Early implementation of motor-rich activities that support motor skill development in children is critical for the development of healthy levels of physical activity that carry through into adulthood. Virtual reality (VR) training may be beneficial …

Comparison Between Listeria Sensu Stricto And Listeria Sensu Lato Strains Identifies Novel Determinants Involved In Infection, Jakob Schardt, Grant Jones, Stefanie Müller-Herbst, Kristina Schauer, Sarah E. F. D'Orazio, Thilo M. Fuchs

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The human pathogen L. monocytogenes and the animal pathogen L. ivanovii, together with four other species isolated from symptom-free animals, form the "Listeria sensu stricto" clade. The members of the second clade, "Listeria sensu lato", are believed to be solely environmental bacteria without the ability to colonize mammalian hosts. To identify novel determinants that contribute to infection by L. monocytogenes, the causative agent of the foodborne disease listeriosis, we performed a genome comparison of the two clades and found 151 candidate genes that are conserved in the Listeria sensu stricto species. Two factors were …

Week Of December 18, 2017, New York Medical College

InTouch

• Prominent Trauma Surgeon Addresses 14th Annual Louis R.M. DelGuercio Professorship and Research Day
• GSA Organizes Successful Second Annual Snowman Project
• SOM P2P Committee Recognizes Role Models at NYMC

Metabolic Dysregulation And Cancer Mortality In A National Cohort Of Blacks And Whites, Tomi Akinyemiju, Justin Xavier Moore, Suzanne Judd, Susan Lakoski, Michael Goodman, Monika M. Safford, Maria Pisu

Epidemiology and Environmental Health Faculty Publications

Background: We examined the association between metabolic dysregulation and cancer mortality in a prospective cohort of Black and White adults.

Methods: A total of 25,038 Black and White adults were included in the analysis. Metabolic dysregulation was defined in two ways: 1) using the joint harmonized criteria for metabolic syndrome (MetS) and 2) based on factor analysis of 15 variables characterizing metabolic dysregulation. We estimated hazards ratios (HRs) and 95% confidence intervals (CIs) for the association of MetS and metabolic dysregulation with cancer mortality during follow-up using Cox proportional hazards models.

Results: About 46% of Black and 39% of White …

Medical Sciences 4300: London-Middlesex Suicide Prevention Council, Harshith Bhaskar, Adnan Husein, Ramin Javaheri-Poya, Sabrina Jetly, Christopher Nguyen, Serena Tejpar

Community Engaged Learning Final Projects

Suicide is an issue that affects people of all backgrounds, and takes the lives of many individuals every year. The London-Middlesex Suicide Prevention Council (LMSPC), an organization established in 1990, seeks to provide suicide prevention training to members of the community. They seek to engage community members in prevention and intervention by recognizing warning signs that may exist among the London-Middlesex region. The three main programs that strive to deliver these skills are ASIST, ASK, and safeTALK, each with a slightly different focus. LMSPC’s current goal is to increase access to these services through external grants and potential partnerships. Our …

The Future Of Nuclear Security: A Medical Physicist’S Perspective, Katharine E. Thomson

International Journal of Nuclear Security

Planning for the future of nuclear security is a vital and complex task, requiring cooperation and contribution from many disciplines and industries. This diversity of expertise should include the medical sector, which faces many of the same challenges as the nuclear industry: controlling access to dangerous material, creating a strong security culture, cooperating with the wider world and engaging the public.

Medical physicists, of which the author is one, oversee all aspects of small-scale radiation use. This paper discusses three key areas increasingly important to both medical and nuclear uses of radioactive materials: public engagement, prevention of nuclear and radiological …

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity …

Novel Therapeutic Approaches For Juvenile Neuronal Ceroid Lipofuscinosis (Cln3), Megan Elizabeth Bosch

Theses & Dissertations

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in CLN3. Neuronal loss is thought to occur via glutamate excitotoxicity; however, little is known about neuron-astrocyte glutamate regulation in JNCL. We discovered that Cln3^Δex7/8 astrocytes have significantly lower basal spontaneous Ca²⁺ oscillations and decreased responses to glutamate, indicating a disrupted signaling network. Cln3^Δex7/8 astrocytes also displayed significantly lower basal mitochondrial respiration and ATP production, suggesting impaired metabolic functions. Concurrent with diminished astrocyte metabolism and Ca²⁺ signaling, Cln3^Δex7/8 neurons were hyper-responsive to glutamate stimulation. These studies suggest that CLN3 …

Mechanistic Insights Into The Regulation Of Mitochondrial Fission By Cyclin C, Vidyaramanan Ganesan, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Cyclin C is a component of the mediator complex of RNA polymerase II that localizes to the nucleus under normal conditions. In response to stress, cyclin C translocates to the cytosol and mitochondria and mediates stress‐induced mitochondrial fission and apoptosis. The molecular mechanisms by which cyclin C induces mitochondrial fission are unknown. Using in vitro experimental approaches, we sought to investigate the mechanistic basis of cyclin C mediated mitochondrial fission.

Translocation Of Cyclin C During Oxidative Stress Is Regulated By Interactions With Multiple Trafficking Proteins, Daniel G J Smethurst, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Eukaryotic cells take cues from their environment and interpret them to enact a response. External stresses can produce a decision between adjusting to behaviors which promote surviving the stress, or enacting a cell death program. The decision to undergo programmed cell death (PCD) is controlled by a complex interaction between nuclear and mitochondrial signals. The mitochondria are highly dynamic organelles that constantly undergo fission and fusion. However, a dramatic shift in mitochondrial morphology toward fission occurs early in the PCD process. We have identified the transcription factor cyclin C as the biochemical trigger for stress‐induced mitochondrial hyper‐fragmentation in yeast (Cooper …

The Role Of Mapk And Scf In The Destruction Of Med13 In Cyclin C Mediated Cell Death, David C Stieg, Stephen D Willis, Joseph Scuorzo, Mia Song, Vidyaramanan Ganesan, Randy Strich, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

In response to stress, the yeast¹ and mammalian² cyclin C translocate from the nucleus to the cytoplasm, where it associates with the GTPase Drp1/Dnm1 to drive mitochondrial fragmentation and apoptosis. Therefore, the decision to release cyclin C represents a key life or death decision. In unstressed cells, the cyclin C‐Cdk8 kinase regulates transcription by associating with the Mediator of RNA polymerase II. We previously reported that the Mediator component Med13 anchors cyclin C in the nucleus³. Loss of Med13 function leads to constitutive cytoplasmic localization of cyclin C, resulting in fragmented mitochondria, hypersensitivity to stress and …

Snf1 Dependent Destruction Of Med13 Is Required For Programmed Cell Death Following Oxidative Stress In Yeast, Stephen D Willis, David C Stieg, R. Shah, Randy Strich, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

All eukaryotic cells, when faced with unfavorable environmental conditions, have to decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In S. cerevisiae, oxidative stress triggers Med13 destruction¹, which thereafter releases cyclin Ci nto the cytoplasm. Cytoplasmic cyclin C associates with mitochondria where it induces hyper-fragmentation and programmed cell death². This suggests a model in …

Targeting Ribosome Assembly Factors Selectively Protects P53 Positive Cells From Chemotherapeutic Agents, Russell T. Sapio, Anastasiya Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J. Manna, N. Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Many chemotherapeutic agents act in a nondiscriminatory fashion, targeting both cancerous and noncancerous cells in Sphase and Mphase. One approach to reduce the toxic side effects in normal tissue is to exploit the differences in p53 functionality between cancerous and noncancerous cells. For example, activating p53 signaling by nongenotoxic means can transiently arrest noncancerous p53 positive cells in G1 phase and protect them from the cytotoxic effects of chemotherapeutic drugs. However, since most cancerous cells have faulty p53 signaling, they will proceed to cycle, and continue to be affected by the drug. In this study we asked if this G1‐phase …

Novel Therapeutic Strategies For Treatment Of Castration-Resistant Prostate Cancer, Matthew A. Ingersoll

Theses & Dissertations

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, …

Prostate Cancer Microparticles In Men Undergoing Radical Prostatectomy, Malcolm James Dewar

Electronic Thesis and Dissertation Repository

Objectives: To determine changes in prostate microparticle (PMP) concentrations in men with prostate cancer (PCa) after digital rectal examination (DRE), after radical prostatectomy (RP), and at follow-up.

Materials and Methods: 22 men were recruited before RP. Four blood specimens were collected – baseline (specimen 1), post-DRE (specimen 2), immediately post-RP (specimen 3), and follow-up (specimen 4). Pre- and post-DRE urine was collected (Specimen A and B respectively). Flow cytometric analysis of biofluids was performed with fluorescent-labeled antibodies against prostate-specific membrane antigen (PSMA) and polysialic acid. Total MP (TMP) and dual positive (PMP) events per µl of plasma or urine were …

Hepcidin-Mediated Iron Regulation In P19 Cells Is Detectable By Mri, Kobra Alizadeh Pourbouyeh

Electronic Thesis and Dissertation Repository

Magnetic resonance imaging (MRI) can be used to track cellular activities in the body using iron-based contrast agents. However, intrinsic cellular iron handling mechanisms may also influence the detection of magnetic resonance (MR) contrast. For instance, inflammation involves downregulation of iron export in macrophages by the hormone hepcidin, due to degradation of the iron export protein, ferroportin (Fpn). We examined the effect of hepcidin on iron regulation and MR transverse relaxation rates in multi-potent P19 cells, which display high iron export activity, similar to macrophages. In response to varying conditions of iron supplementation, our results showed similar Fpn expression in …

Proteomic Characterization Of Human Multipotent Stromal Cells Secreted Proteins With Therapeutic Potential For Β-Cell Regeneration, Miljan Kuljanin

Electronic Thesis and Dissertation Repository

Novel strategies to stimulate the expansion of β-cell mass in situ are warranted for diabetes therapy. Cell-replacement therapies for the treatment of diabetes have become a focal point in recent years. Endogenous regeneration of β-cell mass has been demonstrated using human multipotent stromal cells (hMSC). However, the secretory factors responsible for initiating endogenous regeneration remain unknown. Successful large-scale proteomic applications to address these questions have been limited in part by difficulties in correctly selecting the appropriate methodologies. Thus, the goal of this thesis was a combination of assessing different proteomic workflows to facilitate investigation into hMSC biology, applying these methods …

Crispr Screen For Identification Of Kinases That Mediate Prostate Cancer Cell Invasion, Hamad Aldhafeeri

Electronic Thesis and Dissertation Repository

Metastasis is the primary cause of mortality in cancer patients. Inhibition of proteins that are involved in the regulation of metastasis are expected to suppress metastasis and represent treatment targets. Our focus is on prostate cancer metastasis and we have developed a novel high-throughput means of performing in vitro screens for regulators of prostate cancer metastasis. We propose to use a focused CRISPR library screen that will “knock out” all human kinases to determine which ones are responsible for prostate cancer metastasis. CRISPR is a potent genetic editing tool and was used to silence all kinases in prostate cells (BPH …

Neuronal Correlates For Neuroendocrine Habituation To Repeated Stress, Sara Matovic

Electronic Thesis and Dissertation Repository

One way that the body actively responds to an impending stressor is by increasing systemic glucocorticoids through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. While it is essential for short-term adaptation to stress, the sustained activation of the HPA axis during chronic stress can be detrimental and is linked to stress-related psychiatric conditions such as anxiety and depression. Therefore, it is important that the HPA axis adapts, or habituates, during chronic stress to minimize the negative consequences. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) function to assimilate incoming information from the stress circuitry and …