Digital Commons Network^™

Kaempferol Nanoparticles Achieve Strong And Selective Inhibition Of Ovarian Cancer Cell Viability., Haitao Luo, Bingbing Jiang, Bingyun Li, Zhaoliang Li, Bing-Hua Jiang, Yi Charlie Chen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ovarian cancer is one of the leading causes of cancer death for women throughout the Western world. Kaempferol, a natural flavonoid, has shown promise in the chemoprevention of ovarian cancer. A common concern about using dietary supplements for chemoprevention is their bioavailability. Nanoparticles have shown promise in increasing the bioavailability of some chemicals. Here we developed five different types of nanoparticles incorporating kaempferol and tested their efficacy in the inhibition of viability of cancerous and normal ovarian cells. We found that positively charged nanoparticle formulations did not lead to a significant reduction in cancer cell viability, whereas nonionic polymeric nanoparticles …

Emergence Of Bimodal Cell Population Responses From The Interplay Between Analog Single-Cell Signaling And Protein Expression Noise., Marc R Birtwistle, Jens Rauch, Anatoly Kiyatkin, Edita Aksamitiene, Maciej Dobrzyński, Jan B. Hoek, Walter Kolch, Babatunde A Ogunnaike, Boris N Kholodenko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses.

RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally …

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, Alex R. Vaccaro, Jefferson R Wilson, Anoushka Singh, David W Cadotte, James Harrop, Bizhan Aarabi, Christopher Shaffrey, Marcel Dvorak, Charles Fisher, Paul Arnold, Eric M Massicotte, Stephen Lewis, Raja Rampersaud

Department of Orthopaedic Surgery 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 (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 ordinal change …

The Formin Fmnl3 Is A Cytoskeletal Regulator Of Angiogenesis, Clare Hetheridge, Alice N. Scott, Rajeeb K. Swain, John W. Copeland, Henry N. Higgs

Dartmouth Scholarship

The process of angiogenesis requires endothelial cells (ECs) to undergo profound changes in shape and polarity. Although this must involve remodelling of the EC cytoskeleton, little is known about this process or the proteins that control it. We used a co-culture assay of angiogenesis to examine the cytoskeleton of ECs actively undergoing angiogenic morphogenesis. We found that elongation of ECs during angiogenesis is accompanied by stabilisation of microtubules and their alignment into parallel arrays directed at the growing tip. In other systems, similar microtubule alignments are mediated by the formin family of cytoskeletal regulators. We screened a library of human …

Rituximab Therapy In Pulmonary Alveolar Proteinosis Improves Alveolar Macrophage Lipid Homeostasis., Anagha Malur, Mani Kavuru, Irene Marshall, Barbara P Barna, Isham Huizar, Reema Karnekar, Mary Jane Thomassen

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

RATIONALE: Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the PPARγ-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients …

Macrophage Imbalance (M1 Vs. M2) And Upregulation Of Mast Cells In Wall Of Ruptured Human Cerebral Aneurysms: Preliminary Results., David Hasan, Nohra Chalouhi, Pascal Jabbour, Tomoki Hashimoto

Department of Neurosurgery Faculty Papers

BACKGROUND: M1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture.

METHODS: Ten patients with cerebral aneurysms (five ruptured and five unruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR), M2 cells (anti-CD 163), and mast cells (anti-tryptase clone AA). A segment of the superficial temporal artery (STA) was also removed and …

Is There A Role For The Quantification Of Rrm1 And Ercc1 Expression In Pancreatic Ductal Adenocarcinoma?, Matias E Valsecchi, Thomas Holdbrook, Benjamin E Leiby, Edward Pequignot, Susan J Littman, Charles Yeo, Jonathan Brody, Angieszka Witkiewicz

Department of Medical Oncology Faculty Papers

BACKGROUND: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.

METHODS: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).

RESULTS: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data …

Hypoplastic Right-Heart Syndrome Presenting As Multiple Miscarriages, Chadi Dib, Philip A Araoz, Norman P Davies, Joseph A Dearani, Naser M Ammash

The Texas Heart Institute Journal

Reversible causes of miscarriage are many, but they affect only 1% of women who are trying to conceive. Herein, we describe the case of a 23-year-old woman who presented for evaluation of repeated miscarriages and was found to have hypoxemia and erythrocytosis. Further evaluation revealed hypoplastic right-heart syndrome with an intracardiac shunt. She underwent hybrid repair with pulmonary valve balloon valvuloplasty, followed by surgery to perform atrial septal defect closure and a Glenn anastomosis. The erythrocytosis and hypoxemia resolved, and she was able to conceive and deliver a healthy baby at term 2 years later.

This is a unique case …

Coronary Arteriovenous Fistulae: The Complexity Of Coronary Artery-To-Coronary Sinus Connections, Todd L Kiefer, Anna Lisa Crowley, James Jaggers, J Kevin Harrison

The Texas Heart Institute Journal

Coronary artery fistulae are a rare cardiovascular anomaly. Even less common are multiple fistulae involving more than 1 coronary artery. Herein we report the case of a 47-year-old woman who had fistulae from both the right coronary and left circumflex coronary arteries draining into the coronary sinus. These lesions we attempted to close percutaneously but subsequently closed surgically. We discuss diagnostic imaging approaches, along with closure indications, closure options, and outcomes.

Medical Education On The Brink: 62 Years Of Front-Line Observations And Opinions, Herbert L Fred

The Texas Heart Institute Journal

No abstract provided.

Cellular Retrograde Cardiomyoplasty And Relaxin Therapy For Postischemic Myocardial Repair In A Rat Model, Gabriella Di Lascio, Guy Harmelin, Mattia Targetti, Cristina Nanni, Giacomo Bianchi, Tommaso Gasbarri, Sandro Gelsomino, Daniele Bani, Sandra Zecchi Orlandini, Massimo Bonacchi

The Texas Heart Institute Journal

We sought to determine whether skeletal myoblasts, wild-type or engineered to express relaxin, might improve myocardial viability and performance in a rat model of chronic myocardial infarction. Our purpose was to investigate a potential new therapy for heart failure.

From October 2005 through September 2009, we surgically induced acute myocardial infarction in 80 male Wistar rats. Thirty days after surgery, the rats underwent reoperation for the retrograde coronary venous infusion of skeletal myoblasts, relaxin, or both. The animals were randomly assigned to 4 experimental groups: R1 (the control group, which underwent saline-solution infusion), R2 (systemic relaxin therapy), R3 (myoblast infusion), …

Gene Expression Signatures Modulated By Epidermal Growth Factor Receptor Activation And Their Relationship To Cetuximab Resistance In Head And Neck Squamous Cell Carcinoma., Elana J Fertig, Qing Ren, Haixia Cheng, Hiromitsu Hatakeyama, Adam Dicker Md, Phd, Ulrich Rodeck, Michael Considine, Michael F Ochs, Christine H Chung

Department of Radiation Oncology Faculty Papers

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D.

RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity …

Testosterone Treatment Fails To Accelerate Disease In A Transgenic Mouse Model Of Spinal And Bulbar Muscular Atrophy., Erica S Chevalier-Larsen, Diane E Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA), a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR) that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice) reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone …

Genes Adopt Non-Optimal Codon Usage To Generate Cell Cycle-Dependent Oscillations In Protein Levels., Milana Frenkel-Morgenstern, Tamar Danon, Thomas Christian, Takao Igarashi, Lydia Cohen, Ya-Ming Hou, Lars Juhl Jensen

Department of Biochemistry and Molecular Biology Faculty Papers

The cell cycle is a temporal program that regulates DNA synthesis and cell division. When we compared the codon usage of cell cycle-regulated genes with that of other genes, we discovered that there is a significant preference for non-optimal codons. Moreover, genes encoding proteins that cycle at the protein level exhibit non-optimal codon preferences. Remarkably, cell cycle-regulated genes expressed in different phases display different codon preferences. Here, we show empirically that transfer RNA (tRNA) expression is indeed highest in the G2 phase of the cell cycle, consistent with the non-optimal codon usage of genes expressed at this time, and lowest …

Clinical And Biomarker Changes In Dominantly Inherited Alzheimer's Disease, R J Bateman, C Xiong, T L Benzinger, A M Fagan, A Goate, N C Fox, D S Marcus, N J Cairns, X Xie, T M Blazey, D M Holtzman, A Santacruz, V Buckles, A Oliver, K Moulder, P M Aisen, B Ghetti, W M Klunk, E Mcdade, Ralph Martins, C M Masters, R Mayeux, J M Ringman, M M Rossor, P M Schofield, R M Sperling, S Salloway, J M Morris

Research outputs 2012

Background: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.

Methods: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to …

Maternal Work Hours In Early To Middle Childhood Link To Later Adolescent Diet Quality, Jianghong Li, Therese O'Sullivan, Sarah Johnson, Fiona Stanley, Wendy H. Oddy

Research outputs 2012

Objective: Previous studies on maternal work hours and child diet quality have reported conflicting findings possibly due to differences in study design, lack of a comprehensive measure of diet quality and differing ages of the children under investigation. The present study aimed to prospectively examine the impact of parental work hours from age 1 year to age 14 years on adolescent diet quality.

Design: Multivariate linear regression models were used to examine independent associations between parents' work hours at each follow-up and across 14 years and adolescent diet quality at age 14 years. A diet quality index was based on …

Anxiety, Depression, And Comorbid Anxiety And Depression: Risk Factors And Outcome Over Two Years, O P Almeida, B Draper, J Pirkis, J Snowdon, N T Lautenschlager, G Byrne, Moira Sim, N Stocks, N Kerse, L Flicker, J J Pfaff

Research outputs 2012

Background: This study aimed to determine: (1) the prevalence of depression, anxiety, and depression associated with anxiety (DA); (2) the risk factor profile of depression, anxiety, and DA; (3) the course of depression, anxiety, and DA over 24 months. Methods: Two-year longitudinal study of 20,036 adults aged 60+ years. We used the Patient Health Questionnaire and the Hospital Anxiety and Depression Scale anxiety subscale to establish the presence of depression and anxiety, and standard procedures to collect demographic, lifestyle, psychosocial, and clinical data. Results: The prevalence of anxiety, depression, and DA was 4.7%, 1.4%, and 1.8%. About 57% of depression …

Predictors Of Rapid Cognitive Decline In Alzheimer's Disease: Results From The Australian Imaging, Biomarkers And Lifestyle (Aibl) Study Of Ageing, A Sona, P Zhang, D Ames, A I Bush, N T Lautenschlager, Ralph Martins, C L Masters, C C Rowe, C Szoeke, Kevin Taddei, Kathryn A Ellis

Research outputs 2012

Background: The AIBL study, which commenced in November 2006, is a two-center prospective study of a cohort of 1112 volunteers aged 60+. The cohort includes 211 patients meeting NINCDS-ADRDA criteria for Alzheimer's disease (AD) (180 probable and 31 possible). We aimed to identify factors associated with rapid cognitive decline over 18 months in this cohort of AD patients.

Methods: We defined rapid cognitive decline as a drop of 6 points or more on the Mini-Mental State Examination (MMSE) between baseline and 18-month follow-up. Analyses were also conducted with a threshold of 4, 5, 7 and 8 points, as well as …

Viability Of Healthcare Service Delivery Alternatives For The Australian Mining Sector, Patricia Williams, Margaret Giles

Research outputs 2012

The changing and demanding nature of the mining workforce in rural and remote Australia brings unique challenges to the delivery of healthcare services. In an attempt to control costs whilst delivering cost effective and quality healthcare, new models of delivery must be considered. For a workforce that is fly-in/fly-out, the provision of healthcare is problematic given the lack of consistency in location. A cost-benefit framework is analysed comparing three models of service provision using travel to a major location, locum services and remote health monitoring. Ultimately, new models of care must be considered to address the issues of increasing workforce …

Comparative Genomics Of Brachyspira Pilosicoli Strains: Genome Rearrangements, Reductions And Correlation Of Genetic Compliment With Phenotypic Diversity, Luke Mappley, Michael Black, Manal Abuoun, Alistair C. Darby, Martin J. Woodward, Julian Parkhill, A. Keith Turner, Matthew I. Bellgard, Tom La, Nyree D. Phillips, Roberto M. La Ragione, David J. Hampson

Research outputs 2012

Background: The anaerobic spirochaete Brachyspira pilosicoli causes enteric disease in avian, porcine and human hosts, amongst others. To date, the only available genome sequence of B. pilosicoli is that of strain 95/1000, a porcine isolate. In the first intra-species genome comparison within the Brachyspira genus, we report the whole genome sequence of B. pilosicoli B2904, an avian isolate, the incomplete genome sequence of B. pilosicoli WesB, a human isolate, and the comparisons with B. pilosicoli 95/1000. We also draw on incomplete genome sequences from three other Brachyspira species. Finally we report the first application of the high-throughput Biolog phenotype screening …

Chronic Low Back Pain Is Associated With Reduced Vertebral Bone Mineral Measures In Community-Dwelling Adults, Andrew Briggs, Leon Straker, Angus Burnett, John Wark

Research outputs 2012

Background: Chronic low back pain (CLBP) experienced in middle-age may have important implications for vertebral bone health, although this issue has not been investigated as a primary aim previously. This study investigated the associations between CLBP and dual energy X-ray absorptiometry (DXA)-derived vertebral bone mineral measures acquired from postero-anterior and lateral-projections, among community-dwelling, middle-aged adults. Methods. Twenty-nine adults with CLBP (11 male, 18 female) and 42 adults with no history of LBP in the preceding year (17 male, 25 female) were evaluated. Self-reported demographic and clinical data were collected via questionnaires. Areal bone mineral density (aBMD) was measured in the …

A Randomised Trial Of Robotic And Open Prostatectomy In Men With Localised Prostate Cancer, Robert Gardiner, J Yaxley, G Coughlin, N Dunglison, S Occhipinti, S Younie, R Carter, S Williams, R J Medcraft, Bennett Nigel, M F Lavin, Suzanne Chambers

Research outputs 2012

Background: Prostate cancer is the most common male cancer in the Western world however there is ongoing debate about the optimal treatment strategy for localised disease. While surgery remains the most commonly received treatment for localised disease in Australia more recently a robotic approach has emerged as an alternative to open and laparoscopic surgery. However, high level data is not yet available to support this as a superior approach or to guide treatment decision making between the alternatives. This paper presents the design of a randomised trial of Robotic and Open Prostatectomy for men newly diagnosed with localised prostate cancer …

Olfactory Discrimination Predicts Cognitive Decline Among Community-Dwelling Older Adults, Hamid Sohrabi, Kristyn Bates, Mg Weinborn, A N Johnston, A Bahramian, Kevin Taddei, Simon Laws, Mark Rodrigues, Michael Morici, Matthew Howard, Georgia Martins, A Mackay-Sim, Se Gandy, Ralph Martins

Research outputs 2012

The presence of olfactory dysfunction in individuals at higher risk of Alzheimer's disease has significant diagnostic and screening implications for preventive and ameliorative drug trials. Olfactory threshold, discrimination and identification can be reliably recorded in the early stages of neurodegenerative diseases. The current study has examined the ability of various olfactory functions in predicting cognitive decline in a community-dwelling sample. A group of 308 participants, aged 46-86 years old, were recruited for this study. After 3 years of follow-up, participants were divided into cognitively declined and non-declined groups based on their performance on a neuropsychological battery. Assessment of olfactory functions …

Structural Insight Into Mr1-Mediated Recognition Of The Mucosal Associated Invariant T Cell Receptor, Rangsima Reantragoon, Lars Kjer-Nielsen, Onisha Patel, Zhenjun Chen, Patricia T. Illing, Mugdha Bhati, Lyudmila Kostenko, Mandvi Bharadwaj, Bronwyn Meehan, Ted H. Hansen, Dale I. Godfrey, Jamie Rossjohn, James Mccluskey

Open Access Publications

Mucosal-associated invariant T (MAIT) cells express a semiinvariant αβ T cell receptor (TCR) that binds MHC class I-like molecule (MR1). However, the molecular basis for MAIT TCR recognition by MR1 is unknown. In this study, we present the crystal structure of a human Vα7.2Jα33-Vβ2 MAIT TCR. Mutagenesis revealed highly conserved requirements for the MAIT TCR-MR1 interaction across different human MAIT TCRs stimulated by distinct microbial sources. Individual residues within the MAIT TCR β chain were dispensable for the interaction with MR1, whereas the invariant MAIT TCR α chain controlled specificity through a small number of residues, which are conserved across …

Schistosome-Derived Omega-1 Drives Th2 Polarization By Suppressing Protein Synthesis Following Internalization By The Mannose Receptor, Bart Everts, Leonie Hussaarts, Nicole N. Driessen, Moniek H.J. Meevissen, Gabriele Schramm, Alwin J. Van Der Ham, Barbara Van Der Hoeven, Thomas Scholzen, Sven Burgdorf, Markus Mohrs, Edward J. Pearce, Cornelis H. Hokke, Helmut Haas, Hermelijn H. Smits, Maria Yazdanbakhsh

Open Access Publications

Omega-1, a glycosylated T2 ribonuclease (RNase) secreted by Schistosoma mansoni eggs and abundantly present in soluble egg antigen, has recently been shown to condition dendritic cells (DCs) to prime Th2 responses. However, the molecular mechanisms underlying this effect remain unknown. We show in this study by site-directed mutagenesis of omega-1 that both the glycosylation and the RNase activity are essential to condition DCs for Th2 polarization. Mechanistically, we demonstrate that omega-1 is bound and internalized via its glycans by the mannose receptor (MR) and subsequently impairs protein synthesis by degrading both ribosomal and messenger RNA. These experiments reveal an unrecognized …

Neurofibromatosis 2011: A Report Of The Children's Tumor Foundation Annual Meeting., Michel Kalamarides, Maria T. Acosta, Dusica Babovic-Vuksanovic, Olli Carpen, Karen Cichowski, Dg Evans, Filippo Giancotti, Co Hanemann, David Ingram, Alison C. Lloyd, Debra A. Mayes, Ludwine Messiaen, Helen Morrison, Kathryn North, Roger Packer, Duojia Pan, Anat Stemmer-Rachamimov, Meena Upadhyaya, David Viskochil, Margret R. Wallace, Kim Hunter-Schaedle, Nancy Ratner

Peninsula Medical School

The 2011 annual meeting of the Children's Tumor Foundation, the annual gathering of the neurofibromatosis (NF) research and clinical communities, was attended by 330 participants who discussed integration of new signaling pathways into NF research, the appreciation for NF mutations in sporadic cancers, and an expanding pre-clinical and clinical agenda. NF1, NF2, and schwannomatosis collectively affect approximately 100,000 persons in US, and result from mutations in different genes. Benign tumors of NF1 (neurofibroma and optic pathway glioma) and NF2 (schwannoma, ependymoma, and meningioma) and schwannomatosis (schwannoma) can cause significant morbidity, and there are no proven drug treatments for any form …

Guided Self-Help Concreteness Training As An Intervention For Major Depression In Primary Care: A Phase Ii Randomized Controlled Trial., E. R. Watkins, R. S. Taylor, R. Byng, C. Baeyens, R. Read, K. Pearson, L. Watson

Peninsula Medical School

BACKGROUND: The development of widely accessible, effective psychological interventions for depression is a priority. This randomized trial provides the first controlled data on an innovative cognitive bias modification (CBM) training guided self-help intervention for depression. METHOD: One hundred and twenty-one consecutively recruited participants meeting criteria for current major depression were randomly allocated to treatment as usual (TAU) or to TAU plus concreteness training (CNT) guided self-help or to TAU plus relaxation training (RT) guided self-help. CNT involved repeated practice at mental exercises designed to switch patients from an unhelpful abstract thinking habit to a helpful concrete thinking habit, thereby targeting …

Oral Health And Pathology: A Macrophage Account., Rebecca Merry, Louise Belfield, Paul Mcardle, Andrew Mclennan, Stjohn Crean, Andrew Foey

School of Biomedical Sciences

Macrophages are present in healthy oral mucosa and their numbers increase dramatically during disease. They can exhibit a diverse range of phenotypes characterised as a functional spectrum from pro-inflammatory to anti-inflammatory (regulatory) subsets. This review illustrates the role of these subsets in the oral inflammatory disease lichen planus, and the immunosuppressive disease oral squamous cell carcinoma (SCC). We conclude that the role of macrophages in driving progression in oral disease identifies them as potential therapeutic targets for a range of oral pathologies.

The Role Of Insulin-Like Growth Factors Signaling In Merlin-Deficient Human Schwannomas., Sylwia Ammoun, M. Caroline Schmid, Natalia Ristic, Lu Zhou, David Hilton, Emanuela Ercolano, Camille Carroll, C. Oliver Hanemann

Peninsula Medical School

Loss of the tumor suppressor merlin causes development of the tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas occurring spontaneously or as part of a hereditary disease Neurofibromatosis Type 2 (NF2). Current therapies, (radio) surgery, are not always effective. Therefore, there is a need for drug treatments for these tumors. Schwannomas are the most frequent of merlin-deficient tumors and are hallmark for NF2. Using our in vitro human schwannoma model, we demonstrated that merlin-deficiency leads to increased proliferation, cell-matrix adhesion, and survival. Increased proliferation due to strong activation of extracellular-signal-regulated kinase 1/2 (ERK1/2) is caused by overexpression/activation …

Control Of Interneuron Dendritic Growth Through Nrg1/Erbb4-Mediated Kalirin-7 Disinhibition., M. E. Cahill, K. A. Jones, I. Rafalovich, Z. Xie, C. S. Barros, U. Müller, P. Penzes

Peninsula Medical School

Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growth of dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies have shown associations of the KALRN gene with schizophrenia. Our data point to …