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

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

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

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

An informatics model for tissue banks – Lessons learned from the Cooperative Prostate Cancer Tissue Resource

BACKGROUND: Advances in molecular biology and growing requirements from biomarker validation studies have generated a need for tissue banks to provide quality-controlled tissue samples with standardized clinical annotation. The NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) is a distributed tissue bank that comprises four academic centers and provides thousands of clinically annotated prostate cancer specimens to researchers. Here we describe the CPCTR information management system architecture, common data element (CDE) development, query interfaces, data curation, and quality control. METHODS: Data managers review the medical records to collect and continuously update information for the 145 clinical, pathological and inventorial CDEs that the Resource maintains for each case. An Access-based data entry tool provides de-identification and a standard communication mechanism between each group and a central CPCTR database. Standardized automated quality control audits have been implemented. Centrally, an Oracle database has web interfaces allowing multiple user-types, including the general public, to mine de-identified information from all of the sites with three levels of specificity and granularity as well as to request tissues through a formal letter of intent. RESULTS: Since July 2003, CPCTR has offered over 6,000 cases (38,000 blocks) of highly characterized prostate cancer biospecimens, including several tissue microarrays (TMA). The Resource developed a website with interfaces for the general public as well as researchers and internal members. These user groups have utilized the web-tools for public query of summary data on the cases that were available, to prepare requests, and to receive tissues. As of December 2005, the Resource received over 130 tissue requests, of which 45 have been reviewed, approved and filled. Additionally, the Resource implemented the TMA Data Exchange Specification in its TMA program and created a computer program for calculating PSA recurrence. CONCLUSION: Building a biorepository infrastructure that meets today's research needs involves time and input of many individuals from diverse disciplines. The CPCTR can provide large volumes of carefully annotated prostate tissue for research initiatives such as Specialized Programs of Research Excellence (SPOREs) and for biomarker validation studies and its experience can help development of collaborative, large scale, virtual tissue banks in other organ systems

The CAP cancer protocols – a case study of caCORE based data standards implementation to integrate with the Cancer Biomedical Informatics Grid

BACKGROUND: The Cancer Biomedical Informatics Grid (caBIG™) is a network of individuals and institutions, creating a world wide web of cancer research. An important aspect of this informatics effort is the development of consistent practices for data standards development, using a multi-tier approach that facilitates semantic interoperability of systems. The semantic tiers include (1) information models, (2) common data elements, and (3) controlled terminologies and ontologies. The College of American Pathologists (CAP) cancer protocols and checklists are an important reporting standard in pathology, for which no complete electronic data standard is currently available. METHODS: In this manuscript, we provide a case study of Cancer Common Ontologic Representation Environment (caCORE) data standard implementation of the CAP cancer protocols and checklists model – an existing and complex paper based standard. We illustrate the basic principles, goals and methodology for developing caBIG™ models. RESULTS: Using this example, we describe the process required to develop the model, the technologies and data standards on which the process and models are based, and the results of the modeling effort. We address difficulties we encountered and modifications to caCORE that will address these problems. In addition, we describe four ongoing development projects that will use the emerging CAP data standards to achieve integration of tissue banking and laboratory information systems. CONCLUSION: The CAP cancer checklists can be used as the basis for an electronic data standard in pathology using the caBIG™ semantic modeling methodology

The development of common data elements for a multi-institute prostate cancer tissue bank: The Cooperative Prostate Cancer Tissue Resource (CPCTR) experience

BACKGROUND: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a consortium of four geographically dispersed institutions that are funded by the U.S. National Cancer Institute (NCI) to provide clinically annotated prostate cancer tissue samples to researchers. To facilitate this effort, it was critical to arrive at agreed upon common data elements (CDEs) that could be used to collect demographic, pathologic, treatment and clinical outcome data. METHODS: The CPCTR investigators convened a CDE curation subcommittee to develop and implement CDEs for the annotation of collected prostate tissues. The draft CDEs were refined and progressively annotated to make them ISO 11179 compliant. The CDEs were implemented in the CPCTR database and tested using software query tools developed by the investigators. RESULTS: By collaborative consensus the CPCTR CDE subcommittee developed 145 data elements to annotate the tissue samples collected. These included for each case: 1) demographic data, 2) clinical history, 3) pathology specimen level elements to describe the staging, grading and other characteristics of individual surgical pathology cases, 4) tissue block level annotation critical to managing a virtual inventory of cases and facilitating case selection, and 5) clinical outcome data including treatment, recurrence and vital status. These elements have been used successfully to respond to over 60 requests by end-users for tissue, including paraffin blocks from cases with 5 to 10 years of follow up, tissue microarrays (TMAs), as well as frozen tissue collected prospectively for genomic profiling and genetic studies. The CPCTR CDEs have been fully implemented in two major tissue banks and have been shared with dozens of other tissue banking efforts. CONCLUSION: The freely available CDEs developed by the CPCTR are robust, based on "best practices" for tissue resources, and are ISO 11179 compliant. The process for CDE development described in this manuscript provides a framework model for other organ sites and has been used as a model for breast and melanoma tissue banking efforts

The 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed