Scopolamine induces deficits in spontaneous object-location recognition and fear-learning in marmoset monkeys

The non-selective muscarinic receptor antagonist scopolamine (SCP) induces memory deficits in both animals and humans. However, few studies have assessed the effects of amnesic agents on memory functions of marmosets – a small-bodied neotropical primate that is becoming increasingly used as a translational model for several neuropathologies. Here we assessed the effects of an acute SCP administration (0.03 mg/kg, sc) on the behavior of adult marmoset monkeys in two tasks. In the spontaneous object-location (SOL) recognition task, two identical neutral stimuli were explored on the sample trial, after which preferential exploration of the displaced versus the stationary object was analyzed on the test trial. In the fear-motivated behavior (FMB) procedure, the same subjects were submitted to an initial baseline trial, followed by an exposure period to a snake model and lastly a post-exposure trial. All trials and inter-trial intervals lasted 10 min for both tests. Results showed that on the SOL test trial, the saline group explored the displaced object significantly longer than its identical stationary counterpart, whereas SCP-treated marmosets explored both objects equivalently. In the FMB test, the saline group – but not the SCP-treated animals – spent significantly less time where the stimulus had been specifically encountered and more time being vigilant of their surroundings, compared to pre-exposure levels. Drug-related effects on general activity, overall exploration (SOL task) and behavioral response to the aversive stimulus (FMB task) were not observed. SCP thus impaired the marmosets’ short-term ability to detect changes associated with the spatial location of ethologically irrelevant (SOL task) and relevant stimuli (FMB task). Similar results have been reported in other animal species. Marmosets may thus help reduce the translational gap between pre-clinical studies and memory-associated human pathologies

Papel do receptor taquicinérgico NK3, via agonista senktide, na sensitização comportamental induzida pela administração repetida de cocaína em micos-estrela

Dissertação (mestrado)—Universidade de Brasília, Programa de Pós-graduação em Ciências da Saúde, 2011.A exposição repetida ao psicoestimulante cocaína gera uma variedade de efeitos, incluindo a sensitização comportamental. Esta é o aumento da expressão de determinados comportamentos após um regime repetido de algumas drogas de abuso. Ainda, os neuropeptídeos da família das taquicininas parecem exercer um papel modulatório sobre os sistemas neurais envolvidos na adicção. No entanto, a maioria dos estudos tem avaliado esse efeito quando da administração aguda de ligantes dos receptores taquicinérigicos NK3 em roedores. Dessa forma, o presente estudo avaliou em uma espécie de primata não-humano (mico-estrela; Callithrix penicillata): 1) o desenvolvimento de uma sensitização comportamental após a administração repetida de cocaína; 2) o efeito da ativação repetida do receptor taquicinérgico NK3, com o agonista direto senktide, nas alterações comportamentais induzidas pela cocaína; e 3) os níveis de cortisol antes e depois da injeção repetida de cocaína e senktide. Para tanto, 15 micos foram divididos em três grupos (n=5) e submetidos a uma administração diária, durante sete dias consecutivos, com salina, cocaína (7 mg/kg) ou senktide (0,2 mg/kg). O comportamento dos animais foi observado por 20 min no campo aberto (CA) depois de cada injeção (sessões de tratamento; dias 1-7). Após sete dias sem nenhuma intervenção, todos os animais receberam uma única dose de 5 mg/kg de cocaína e foram novamente observados por 20 min no CA (sessão teste; dia 14). Uma amostra de sangue de cada mico foi obtida nos dias 0, 8, 15 e 30. Apenas nos animais tratados repetidamente com cocaína (7 mg/kg) foi observado um aumento significativo nos comportamentos de vigilância. Esse efeito foi mantido mesmo após a aplicação de uma dose menor da droga (5 mg/kg) depois de sete dias de retirada. Ainda, o tratamento prévio com senktide aumentou significativamente os níveis de glance e a velocidade média de locomoção quando 5 mg/kg de cocaína foi administrado. Por outro lado, os níveis de cortisol permaneceram inalterados ao longo de todo o estudo, independente do tratamento dado. Portanto, o tratamento repetido de cocaína induziu um efeito de hipervigilância nos micos, os quais foram sensitizados pelo presente regime de administração. Ainda, a ativação repetida do receptor NK3 com senktide potencializou alguns dos efeitos de 5 mg/kg de cocaína. Desta forma, o micoestrela parece ser um bom sujeito experimental, e o protocolo de doses fixas repetidas uma ferramenta ímpar, no estudo comparativo de aspectos da dependência por cocaína.Repeated exposure to the pyschostimulant cocaine induces a variety of effects, including behavioral sensitization. This is the increased expression of certain behaviors after the repeated administration of some drugs of abuse. In addition, the family of tachykinin neuropeptides seems to exert a modulatory role on the neural systems involved in addiction. Most studies, however, have analyzed this effect after the acute administration of NK3 receptor ligands in rodents. Thus, the present study evaluated in a non-human primate (black-tufted ear marmosets; Callithrix penicillata) the: 1) development of a behavioral sensitization effect after a repeated administration of cocaine; 2) effect of repeated activation of the NK3 receptor, with the direct agonist senktide, on behavioral changes induced by cocaine; and 3) cortisol levels before and after repeated injections of cocaine and senktide. Accordingly, 15 marmosets were divided into three groups (n=5) and subjected, during seven consecutive days, to a daily administration with saline, cocaine (7 mg/kg) or senktide (0.2 mg/kg). After each injection, behavioral observations were made during 20 min in an open field (OF) (treatment sessions, days 1-7). After seven days without any intervention, all animals received a single 5 mg/kg dose of cocaine and were again observed in the OF for 20 min (test session, day 14). A blood sample was obtained from each marmoset on days 0, 8, 15 and 30. A significant increase in vigilance behaviors was observed only in animals repeatedly treated with cocaine (7 mg/kg). This effect was maintained even after the administration of a lower dose of the drug (5 mg/kg) held after the seven-day withdrawal. Furthermore, treatment with senktide significantly increased glance levels and average speed when 5 mg/kg of cocaine was administered. On the other hand, cortisol levels remained unaltered throughout the study, regardless of the treatment given. Therefore, repeated treatment with cocaine induced a hypervigilance effect in the marmosets, which were sensitized by the present administration regimen. Also, repeated activation of the NK3 receptor with senktide potentiated some of the effects of 5 mg/kg of cocaine. Thus, the black-tufted ear marmoset seems to be a good experimental model, and the repeated and fixeddose protocol a unique tool, for comparative studies related to cocaine addiction. hypervigilance, cortisol

National Mesothelioma Virtual Bank: A standard based biospecimen and clinical data resource to enhance translational research

Background: Advances in translational research have led to the need for well characterized biospecimens for research. The National Mesothelioma Virtual Bank is an initiative which collects annotated datasets relevant to human mesothelioma to develop an enterprising biospecimen resource to fulfill researchers' need. Methods: The National Mesothelioma Virtual Bank architecture is based on three major components: (a) common data elements (based on College of American Pathologists protocol and National North American Association of Central Cancer Registries standards), (b) clinical and epidemiologic data annotation, and (c) data query tools. These tools work interoperably to standardize the entire process of annotation. The National Mesothelioma Virtual Bank tool is based upon the caTISSUE Clinical Annotation Engine, developed by the University of Pittsburgh in cooperation with the Cancer Biomedical Informatics Grid™ (caBIG™, see http://cabig.nci.nih.gov). This application provides a web-based system for annotating, importing and searching mesothelioma cases. The underlying information model is constructed utilizing Unified Modeling Language class diagrams, hierarchical relationships and Enterprise Architect software. Result: The database provides researchers real-time access to richly annotated specimens and integral information related to mesothelioma. The data disclosed is tightly regulated depending upon users' authorization and depending on the participating institute that is amenable to the local Institutional Review Board and regulation committee reviews. Conclusion: The National Mesothelioma Virtual Bank currently has over 600 annotated cases available for researchers that include paraffin embedded tissues, tissue microarrays, serum and genomic DNA. The National Mesothelioma Virtual Bank is a virtual biospecimen registry with robust translational biomedical informatics support to facilitate basic science, clinical, and translational research. Furthermore, it protects patient privacy by disclosing only de-identified datasets to assure that biospecimens can be made accessible to researchers. © 2008 Amin et al; licensee BioMed Central Ltd

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

The Essential Role for Laboratory Studies in Atmospheric Chemistry

Laboratory studies of atmospheric chemistry characterize the nature of atmospherically relevant processes down to the molecular level, providing fundamental information used to assess how human activities drive environmental phenomena such as climate change, urban air pollution, ecosystem health, indoor air quality, and stratospheric ozone depletion. Laboratory studies have a central role in addressing the incomplete fundamental knowledge of atmospheric chemistry. This article highlights the evolving science needs for this community and emphasizes how our knowledge is far from complete, hindering our ability to predict the future state of our atmosphere and to respond to emerging global environmental change issues. Laboratory studies provide rich opportunities to expand our understanding of the atmosphere via collaborative research with the modeling and field measurement communities, and with neighboring disciplines

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

The development and deployment of Common Data Elements for tissue banks for translational research in cancer – An emerging standard based approach for the Mesothelioma Virtual Tissue Bank

<p>Abstract</p> <p>Background</p> <p>Recent advances in genomics, proteomics, and the increasing demands for biomarker validation studies have catalyzed changes in the landscape of cancer research, fueling the development of tissue banks for translational research. A result of this transformation is the need for sufficient quantities of clinically annotated and well-characterized biospecimens to support the growing needs of the cancer research community. Clinical annotation allows samples to be better matched to the research question at hand and ensures that experimental results are better understood and can be verified. To facilitate and standardize such annotation in bio-repositories, we have combined three accepted and complementary sets of data standards: the College of American Pathologists (CAP) Cancer Checklists, the protocols recommended by the Association of Directors of Anatomic and Surgical Pathology (ADASP) for pathology data, and the North American Association of Central Cancer Registry (NAACCR) elements for epidemiology, therapy and follow-up data. Combining these approaches creates a set of International Standards Organization (ISO) – compliant Common Data Elements (CDEs) for the mesothelioma tissue banking initiative supported by the National Institute for Occupational Safety and Health (NIOSH) of the Center for Disease Control and Prevention (CDC).</p> <p>Methods</p> <p>The purpose of the project is to develop a core set of data elements for annotating mesothelioma specimens, following standards established by the CAP checklist, ADASP cancer protocols, and the NAACCR elements. We have associated these elements with modeling architecture to enhance both syntactic and semantic interoperability. The system has a Java-based multi-tiered architecture based on Unified Modeling Language (UML).</p> <p>Results</p> <p>Common Data Elements were developed using controlled vocabulary, ontology and semantic modeling methodology. The CDEs for each case are of different types: demographic, epidemiologic data, clinical history, pathology data including block level annotation, and follow-up data including treatment, recurrence and vital status. The end result of such an effort would eventually provide an increased sample set to the researchers, and makes the system interoperable between institutions.</p> <p>Conclusion</p> <p>The CAP, ADASP and the NAACCR elements represent widely established data elements that are utilized in many cancer centers. Herein, we have shown these representations can be combined and formalized to create a core set of annotations for banked mesothelioma specimens. Because these data elements are collected as part of the normal workflow of a medical center, data sets developed on the basis of these elements can be easily implemented and maintained.</p