Digital Commons Network^™

Oxidative Stress In Hpv-Driven Viral Carcinogenesis: Redox Proteomics Analysis Of Hpv-16 Dysplastic And Neoplastic Tissues, Federico De Marco, Elona Bucaj, Cesira Foppoli, Ada Fiorini, Carla Blarzino, Kozeta Filipi, Alessandra Giorgi, Maria Eugenia Schininà, Fabio Di Domenico, Raffaella Coccia, D. Allan Butterfield, Marzia Perluigi

Chemistry Faculty Publications

Genital infection by high risk Human Papillomavirus (HR-HPV), although recognized as the main etio-pathogenetic factor of cervical cancer, is not per se sufficient to induce tumour development. Oxidative stress (OS) represents an interesting and under-explored candidate as a promoting factor in HPV-initiated carcinogenesis. To gain insight into the role of OS in cervical cancer, HPV-16 positive tissues were collected from patients with invasive squamous cervical carcinoma, from patients with High Grade dysplastic HPV lesions and from patients with no clinical evidence of HPV lesions. After virological characterization, modulation of proteins involved in the redox status regulation was investigated. ERp57 and …

Hyccin, The Molecule Mutated In The Leukodystrophy Hypomyelination And Congenital Cataract (Hcc), Is A Neuronal Protein., Elisabetta Gazzerro, Simona Baldassari, Caterina Giacomini, Veronica Musante, Floriana Fruscione, Veronica La Padula, Roberta Biancheri, Sonia Scarfì, Valeria Prada, Federica Sotgia, Ian D Duncan, Federico Zara, Hauke B Werner, Michael P Lisanti, Lucilla Nobbio, Anna Corradi, Carlo Minetti

Kimmel Cancer Center Faculty Papers

"Hypomyelination and Congenital Cataract", HCC (MIM #610532), is an autosomal recessive disorder characterized by congenital cataract and diffuse cerebral and peripheral hypomyelination. HCC is caused by deficiency of Hyccin, a protein whose biological role has not been clarified yet. Since the identification of the cell types expressing a protein of unknown function can contribute to define the physiological context in which the molecule is explicating its function, we analyzed the pattern of Hyccin expression in the central and peripheral nervous system (CNS and PNS). Using heterozygous mice expressing the b-galactosidase (LacZ) gene under control of the Hyccin gene regulatory elements, …

Motor Neuron Apoptosis And Neuromuscular Junction Perturbation Are Prominent Features In A Drosophila Model Of Fus-Mediated Als, Ruohan Xia, Yajuan Liu, Liuqing Yang, Jozsef Gal, Haining Zhu, Jianhang Jia

Markey Cancer Center Faculty Publications

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants.

RESULTS: Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the …

Reactive Oxygen Species And Mitochondrial Sensitivity To Oxidative Stress Determine Induction Of Cancer Cell Death By P21, Ionica Masgras, Samantha Carrera, Petra J. De Verdier, Paul Brennan, Aneela Majid, Wan Makhtar, Eugene Tulchinsky, George D. Jones, Igor Roninson, Salvador Macip

Faculty Publications

p21(Waf1/Cip1/Sdi1) is a cyclin-dependent kinase inhibitor that mediates cell cycle arrest. Prolonged p21 up-regulation induces a senescent phenotype in normal and cancer cells, accompanied by an increase in intracellular reactive oxygen species (ROS). However, it has been shown recently that p21 expression can also lead to cell death in certain models. The mechanisms involved in this process are not fully understood. Here, we describe an induction of apoptosis by p21 in sarcoma cell lines that is p53-independent and can be ameliorated with antioxidants. Similar levels of p21 and ROS caused senescence in the absence of significant death in other cancer …

Developing An Online Learning Community For Mental Health Professionals And Service Users: A Discursive Analysis., Janet Smithson, Ray B. Jones, Emily Ashurst

School of Nursing and Midwifery

BACKGROUND: There is increasing interest in online collaborative learning tools in health education, to reduce costs, and to offer alternative communication opportunities. Patients and students often have extensive experience of using the Internet for health information and support, and many health organisations are increasingly trying out online tools, while many healthcare professionals are unused to, and have reservations about, online interaction. METHODS: We ran three week-long collaborative learning courses, in which 19 mental health professionals (MHPs) and 12 mental health service users (MHSUs) participated. Data were analysed using a discursive approach to consider the ways in which participants interacted, and …

The Graded Redefined Assessment Of Strength Sensibility And Prehension: Reliability And Validity., Sukhvinder Kalsi-Ryan, Dorcas Beaton, Armin Curt, Susan Duff, Milos R Popovic, Claudia Rudhe, Michael G Fehlings, Mary C Verrier

Department of Physical Therapy Faculty Papers

Abstract With the advent of new interventions targeted at both acute and chronic spinal cord injury (SCI), it is critical that techniques and protocols are developed that reliably evaluate changes in upper limb impairment/function. The Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP) protocol, which includes five subtests, is a quantitative clinical upper limb impairment measure designed for use in acute and chronic cervical SCI. The objectives of this study were to: (1) establish the inter-rater and test-retest reliability, and (2) establish the construct and concurrent validity with the International Standards of Neurological Classification of Spinal Cord Injury (ISNCSCI), …

Variable Effect Of Co-Infection On The Hiv Infectivity: Within-Host Dynamics And Epidemiological Significance, Diego F. Cuadros, Gisela García-Ramos

Biology Faculty Publications

BACKGROUND: Recent studies have implicated viral characteristics in accounting for the variation in the HIV set-point viral load (spVL) observed among individuals. These studies have suggested that the spVL might be a heritable factor. The spVL, however, is not in an absolute equilibrium state; it is frequently perturbed by immune activations generated by co-infections, resulting in a significant amplification of the HIV viral load (VL). Here, we postulated that if the HIV replication capacity were an important determinant of the spVL, it would also determine the effect of co-infection on the VL. Then, we hypothesized that viral factors contribute to …

Inhibition Of Fatty Acid Synthase Attenuates Cd44-Associated Signaling And Reduces Metastasis In Colorectal Cancer, Yekaterina Y. Zaytseva, Piotr G. Rychahou, Pat Gulhati, Victoria Allison Elliott, William Conan Mustain, Kathleen O'Connor, Andrew J. Morris, Manjula Sunkara, Heidi L. Weiss, Eun Young Lee, B. Mark Evers

Markey Cancer Center Faculty Publications

Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of …

Development And Functional Analysis Of Novel Genetic Promoters Using Dna Shuffling, Hybridization And A Combination Thereof, Rajiv Ranjan, Sunita Patro, Bhubaneswar Pradhan, Alok Kumar, Indu B. Maiti, Nrisingha Dey

Kentucky Tobacco Research and Development Center Faculty Publications

BACKGROUND: Development of novel synthetic promoters with enhanced regulatory activity is of great value for a diverse range of plant biotechnology applications.

METHODOLOGY: Using the Figwort mosaic virus full-length transcript promoter (F) and the sub-genomic transcript promoter (FS) sequences, we generated two single shuffled promoter libraries (LssF and LssFS), two multiple shuffled promoter libraries (LmsFS-F and LmsF-FS), two hybrid promoters (FuasFScp and FSuasFcp) and two hybrid-shuffled promoter libraries (LhsFuasFScp and LhsFSuasFcp). Transient expression activities of approximately 50 shuffled promoter clones from each of these libraries were assayed in tobacco (Nicotiana tabacum cv. Xanthi) protoplasts. It was observed that most …

Pf19 Encodes The P60 Catalytic Subunit Of Katanin And Is Required For Assembly Of The Flagellar Central Apparatus In Chlamydomonas, Erin E. Dymek, Elizabeth F. Smith

Dartmouth Scholarship

For all eukaryotic cilia the basal bodies provide a template for the assembly of the doublet microtubules, and intraflagellar transport provides a mechanism for transport of axonemal components into the growing cilium. What is not known is how the central pair of microtubules is nucleated or how their associated polypeptides are assembled. Here we report that the Chlamydomonas pf19 mutation results in a single amino acid change within the p60 catalytic subunit of katanin, and that this mutation prevents microtubule severing activity. The pf19 mutant has paralyzed flagella that lack the central apparatus. Using a combination of mutant analysis, RNAi-mediated …

Gender-Sensitive Reporting In Medical Research., Shirin Heidari, Quarraisha Abdool Karim, Judith D Auerbach, Simone E Buitendijk, Pedro Cahn, Mirjam J Curno, Catherine Hankins, Elly Katabira, Susan Kippax, Richard Marlink, Joan Marsh, Ana Marusic, Heidi M Nass, Julio Montaner, Elizabeth Pollitzer, Maria Teresa Ruiz-Cantero, Lorraine Sherr, Papa Salif Sow, Kathleen Squires, Mark A Wainberg

Department of Medicine Faculty Papers

Sex and gender differences influence the health and wellbeing of men and women. Although studies have drawn attention to observed differences between women and men across diseases, remarkably little research has been pursued to systematically investigate these underlying sex differences. Women continue to be underrepresented in clinical trials, and even in studies in which both men and women participate, systematic analysis of data to identify potential sex-based differences is lacking. Standards for reporting of clinical trials have been established to ensure provision of complete, transparent and critical information. An important step in addressing the gender imbalance would be inclusion of …

Fibrinogen, Chronic Obstructive Pulmonary Disease (Copd) And Outcomes In Two United States Cohorts, Deepa Valvi, David M. Mannino, Hana Müllerova, Ruth Tal-Singer

Preventive Medicine and Environmental Health Faculty Publications

BACKGROUND: Fibrinogen is a marker of systemic inflammation and may be important in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD).

METHODS: We used baseline data from Atherosclerosis Risk in Communities and Cardiovascular Health Studies to determine the relation between fibrinogen levels and COPD and to examine how fibrinogen levels at baseline affected outcomes of death, development of COPD, lung function decline, and COPD-hospitalizations.

RESULTS: Our study sample included 20,192 subjects, of whom 2995 died during the follow-up period. The mean fibrinogen level was 307.6 mg/dL and 10% of the sample had levels >393.0 mg/dL. Subjects with Stage …

Age Before Stage: Insulin Resistance Rises Before The Onset Of Puberty: A 9-Year Longitudinal Study (Earlybird 26)., An Jeffery, Bs Metcalf, J Hosking, Aj Streeter, Ld Voss, Tj Wilkin

Peninsula Medical School

OBJECTIVE: Insulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1. RESEARCH DESIGN AND METHODS: The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5-14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity …

Rapid Perceptual Learning Of Noise-Vocoded Speech Requires Attention, Julia Jones Huyck, Ingrid Johnsrude

Brain and Mind Institute Researchers' Publications

Humans are able to adapt to unfamiliar forms of speech (such as accented, time-compressed, or noise-vocoded speech) quite rapidly. Can such perceptual learning occur when attention is directed away from the speech signal? Here, participants were simultaneously exposed to noise-vocoded sentences, auditory distractors, and visual distractors. One group attended to the speech, listening to each sentence and reporting what they heard. Two other groups attended to either the auditory or visual distractors, performing a target-detection task. Only the attend-speech group benefited from the exposure when subsequently reporting noise-vocoded sentences. Thus, attention to noise-vocoded speech appears necessary for learning.

Cyclin D1 Induces Chromosomal Instability., Mathew C Casimiro, Richard Pestell

Department of Cancer Biology Faculty Papers

We developed mouse model systems to investigate the potential for cyclin D1 to induce CIN in vivo. In a mammary gland specific Tet-inducible model the acute expression profile regulated by cyclin D1 after 7 days was enriched in genes that rank highly with CIN. We also used a mammary gland targeted model (MMTV) to continuously express cyclin D1. The mice started to develop mammary gland tumors at 400 days and the tumor-free incidence was 40% in MMTV-cyclin D1. The gene expression profile of the tumors showed enrichment for the CIN signature. We next compared cyclin D1 expression and the highest …

Small Non-Coding Rnas Govern Mammary Gland Tumorigenesis., Zuoren Yu, Richard Pestell

Department of Cancer Biology Faculty Papers

Small non-coding RNAs include siRNA, miRNA, piRNA and snoRNA. The involvement of miRNAs in the regulation of mammary gland tumorigenesis has been widely studied while the role for other small non-coding RNAs remains unclear. Here we summarize the involvement of miRNA in breast cancer onset and progression through regulating the cell cycle and cellular proliferation. The regulation of breast cancer stem cells and tumor regeneration by miRNA is reviewed. In addition, the emerging evidence demonstrating the involvement of piRNA and snoRNA in breast cancer is briefly described.

Robotic Surgery Training With Commercially Available Simulation Systems In 2011: A Current Review And Practice Pattern Survey From The Society Of Urologic Robotic Surgeons., Costas D Lallas, John W Davis And Members Of The Society Of Urologic Robotic Surgeons

Department of Urology Faculty Papers

Abstract Objectives: Virtual reality (VR) simulation has the potential to standardize surgical training for robotic surgery. We sought to evaluate all commercially available VR robotic simulators. Materials and Methods: A MEDLINE(®) literature search was performed of all applicable keywords. Available VR simulators were evaluated with regard to face, content, and construct validation. Additionally, a survey was e-mailed to all members of the Endourological Society, querying the pervasiveness of VR simulators in robotic surgical training. Finally, each company was e-mailed to ask for a price quote for their respective system. Results: There are four VR robotic surgical simulators currently available: RoSS™, …

The Economic, Institutional, And Political Determinants Of Public Health Delivery System Structures, Richard C. Ingram, F. Douglas Scutchfield, Glen P. Mays, Michelyn W. Bhandari

Preventive Medicine and Environmental Health Faculty Publications

OBJECTIVES: A typology of local public health systems was recently introduced, and a large degree of structural transformation over time was discovered in the systems analyzed. We present a qualitative exploration of the factors that determine variation and change in the seven structural configurations that comprise the local public health delivery system typology.

METHODS: We applied a 10-item semistructured telephone interview protocol to representatives from the local health agency in two randomly selected systems from each configuration--one that had maintained configuration over time and one that had changed configuration over time. We assessed the interviews for patterns of variation between …

Effect Of Level Of Farm Mechanization Early In Life On Bone Later In Life, Lacey A. Mccormack, Teresa L. Binkley, Bonny Specker

Health and Nutritional Sciences Faculty Publications

OBJECTIVE: To determine whether an active rural lifestyle during childhood and adolescence, defined as low farm mechanization, was associated with bone measures later in life.
METHODS: DXA bone data from total body, hip and spine, and pQCT data from 4% and 20% distal radius were obtained on 330 individuals (157 women) aged 20-66 years who farmed at least 75% of their lives. Primary bone outcomes included areal bone mineral density (aBMD), aBMD Z-scores, cortical and trabecular volumetric BMD, cortical thickness and periosteal circumference. Relationship between bone and recall of level of farm mechanization as a child was determined after stratifying …

Interactions Between Antiepileptics And Second-Generation Antipsychotics, Jose De Leon, Vincenza Santoro, Concetta D'Arrigo, Edoardo Spina

Psychiatry Faculty Publications

INTRODUCTION: Pharmacokinetic and pharmacodynamic drug interactions (DIs) can occur between antiepileptics (AEDs) and second-generation antipsychotics (SGAPs). Some AED and SGAP pharmacodynamic mechanisms are poorly understood. AED-SGAP combinations are used for treating comorbid illnesses or increasing efficacy, particularly in bipolar disorder.

AREAS COVERED: This article provides a comprehensive review of the interactions between antiepileptics and second-generation antipsychotics. The authors cover pharmacokinetic AED-SGAP DI studies, the newest drug pharmacokinetics in addition to the limited pharmacodynamic DI studies.

EXPERT OPINION: Dosing correction factors and measuring SGAP levels can help to compensate for the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone. Further studies …

Invited Commentary On: Orthotopic Heart Transplantation In Patients With Metabolic Risk Factors, Nicholas C. Cavarocchi, Paul Mather

Department of Surgery Faculty Papers

This is invited commentary to the following article:

Kilic, A., Conte, J. V., Shah, A. S., & Yuh, D. D. (2012). Orthotopic heart transplantation in patients with metabolic risk factors. Annals of Thoracic Surgery, 93(3), 718-724.

Integrating An Automated Diabetes Management System Into The Family Management Of Children With Type 1 Diabetes: Results From A 12-Month Randomized Controlled Technology Trial., Tammy Toscos Phd, Stephen W Ponder, Barbara J Anderson, Mayer B Davidson, Martin L Lee, Elaine Montemayor-Gonzalez, Patricia Reyes, Eric Link, Kevin L Mcmahon

Health Services and Informatics Research

OBJECTIVE: The study objective was to evaluate how the use of a pervasive blood glucose monitoring (BGM) technology relates to glycemic control, report of self-care behavior, and emotional response to BGM of children with type 1 diabetes and their parents.

RESEARCH DESIGN AND METHODS: Forty-eight children aged less than 12 years (mean 8.8 years) with type 1 diabetes were randomly assigned to one of two study groups, a control group (conventional care without technology) or an experimental group (conventional care with technology), and followed for 12 months. Families in the experimental group were given the Automated Diabetes Management System (ADMS), …

Evaluation Of Lay Support In Pregnant Women With Social Risk (Elsips): A Randomised Controlled Trial, Sara Kenyon, Kate Jolly, Karla Hemming, Lucy Annang Ingram Phd, Nicola Gale, Sophie-Anna Dann, Jacky Chambers, Christine Macarthur

Faculty Publications

BACKGROUND: Maternal, neonatal and child health outcomes are worse in families from black and ethnic minority groups and disadvantaged backgrounds. There is little evidence on whether lay support improves maternal and infant outcomes among women with complex social needs within a disadvantaged multi-ethnic population in the United Kingdom (UK). METHOD/DESIGN: The aim of this study is to evaluate a lay Pregnancy Outreach Worker (POW) service for nulliparous women identified as having social risk within a maternity service that is systematically assessing social risks alongside the usual obstetric and medical risks. The study design is a randomised controlled trial (RCT) in …

Vitamin D And Brain Imaging In The Elderly: Should We Expect Some Lesions Specifically Related To Hypovitaminosis D?, Cédric Annweiler, Manuel Montero-Odasso, Susan W Muir, Olivier Beauchet

Physical Therapy Publications

Hypovitaminosis D is associated with cognitive decline in the elderly, but the issue of causality remains unresolved. Definitive evidence would include the visualization of brain lesions resulting from hypovitaminosis D. The aim of the present article is to determine, through a literature review, the location and nature of possible brain disorders in hypovitaminosis D. We found limited brain-imaging data, which reported ischemic infarcts and white matter hyperintensities in hypovitaminosis D, though did not provide their specific location or report any focal atrophy. Based on the finding of executive dysfunctions (i.e., mental shifting and information updating impairments) in the presence of …

Krüppel-Like Factor 4 Regulates Intestinal Epithelial Cell Morphology And Polarity, Tianxin Yu, Xi Chen, Wen Zhang, Juan Li, Ren Xu, Timothy C Wang, Walden Ai, Chunming Liu

Markey Cancer Center Faculty Publications

Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays a vital role in regulating cell lineage differentiation during development and maintaining epithelial homeostasis in the intestine. In normal intestine, KLF4 is predominantly expressed in the differentiated epithelial cells. It has been identified as a tumor suppressor in colorectal cancer. KLF4 knockout mice demonstrated a decrease in number of goblet cells in the colon, and conditional ablation of KLF4 from the intestinal epithelium led to altered epithelial homeostasis. However, the role of KLF4 in differentiated intestinal cells and colon cancer cells, as well as the mechanism by which …

Active Site Mutations Change The Cleavage Specificity Of Neprilysin., Travis Sexton, Lisa J. Hitchcook, David W. Rodgers, Luke H. Bradley, Louis B. Hersh

Molecular and Cellular Biochemistry Faculty Publications

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe⁵⁶³ and Ser⁵⁴⁶. Among the mutants studied in detail we observed changes in their activity towards leucine⁵-enkephalin, insulin B chain, and amyloid β_1-40. For example, NEP^F563I displayed an increase in preference towards cleaving leucine⁵-enkephalin relative to insulin B chain, while mutant NEP^S546E was less discriminating …

Early Versus Delayed Decompression For Traumatic Cervical Spinal Cord Injury: Results Of The Surgical Timing In Acute Spinal Cord Injury Study (Stascis), Michael G. Fehlings, Alexander Vaccaro, Jefferson R. Wilson, Anoushka Singh, David W. Cadotte, James S. Harrop, Bizhan Aarabi, Christopher Shaffrey, Marcel Dvorak, Charles Fisher, Paul Arnold, Eric M. Massicotte, Stephen Lewis, Raja Rampersaud

Department of Neurosurgery Faculty Papers

Background: There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (,24 hours after injury) versus late ($24 hours after injury) decompressive surgery after traumatic cervical SCI.

Methods: We performed a multicenter, international, prospective cohort study (Surgical Timing in Acute Spinal Cord Injury Study: STASCIS) in adults aged 16–80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was …

Pathobiological Implications Of The Expression Of Egfr, Pakt, Nf-Κb And Mic-1 In Prostate Cancer Stem Cells And Their Progenies., Murielle Mimeault, Sonny L. Johansson, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser(473)-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of …

Gucy2c Opposes Systemic Genotoxic Tumorigenesis By Regulating Akt-Dependent Intestinal Barrier Integrity, Jieru Egeria Lin, Adam Eugene Snook, Peng Li, Brian Arthur Stoecker, Gilbert Won Kim, Michael Sullivan Magee, Alex Vladimir Mejia Garcia, Michael Anthony Valentino, Terry Hyslop, Stephanie Schulz, Scott Arthur Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c^−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated …

Ovarian Cancer Progression Is Controlled By Phenotypic Changes In Dendritic Cells, Uciane K. Scarlett, Melanie R. Rutkowski, Adam M. Rauwerdink, Jennifer Fields, Ximena Escovar-Fadul, Jason Baird, Juan R. Cubillos-Ruiz, Ana C. Jacobs, Jorge L. Gonzalez, John Weaver, Steven Fiering, Jose R. Conejo-Garcia

Dartmouth Scholarship

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable antitumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but …