Pentraxin 3 (PTX3) is an acute phase protein which regulates peripheral inflammationand it has been suggested to have neuroprotective properties. Inflammation iscommonly associated with poor outcome during diverse central nervous system (CNS)disorders, but the role of PTX3 in brain inflammation is completely unknown. Westudied the role of PTX3 in brain inflammation and repair after stroke, a CNS disorderwhich is the third cause of death worldwide. To induce ischaemic stroke, we used themiddle cerebral artery occlusion (MCAo) model and found that the pro-inflammatorycytokine interleukin (IL)-1 was the inducer of PTX3 expression in the brain. Theanalysis of markers of inflammation and repair up to 14 days after MCAo in wild typeand PTX3 knockout (KO) mice revealed that, in general, lack of PTX3 has a negativeeffect on recovery after MCAo. PTX3 KO mice had delayed oedema resolution,defective glial scar, impaired microglial proliferation and reduced angiogenesis andneurogenesis. Therefore, PTX3 emerges as a target for stroke recovery and possiblyother CNS inflammatory diseases. PTX3 was, however, not involved in remoteneurodegeneration in the substantia nigra (SN) (an area of the brain remote butconnected with the area affected by the stroke), but we observed that remoteinflammation preceded remote neuronal death in the SN. Therefore, prevention ofremote inflammation may help prevent remote neurodegeneration in the SN afterstroke. This could have long term implications in SN neurodegeneration, which is akey pathological feature of Parkinson´s disease.

<p>Unga vuxna som överlevt barncancer i centrala nervsystemet (CNS) löper ökad risk för negativa neuropsykologiska, fysiska och psykologiska sena effekter. Låg självkänsla är en riskfaktor för psykisk ohälsa men tidigare forskning om hur barncancer i CNS och dess behandling påverkar självkänsla är begränsad. Med självrapporteringsformuäret Self Esteem Questionnaire (SEQ-42) undersöktes självkänsla hos en populationsbaserad rikstäckande kohort med 528 unga vuxna överlevare jämfört med 995 personer i en stratifierad kontrollgrupp. Patientgruppen hade signifikant lägre självkänsla än kontroller i fem av sex dimensioner i SEQ-42 (<em>p</em> <0,0001). Bland patienterna var den sammanfattande globala självkänslan positiv (skalvärde > 2,5) hos en majoritet, 78,2%, men risken för negativ självkänsla var i flera dimensioner dubbelt så stor för patientgruppen jämfört med kontrollgruppen. Kvinnor och personer med diagnoserna oligodendrogliom, medulloblastom/PNET, kraniala och spinala germinom eller kraniofaryngeom hade lägre självkänsla än andra undergrupper (<em>p</em> < 0,0001 – 0,037).</p><p> </p>

Unga vuxna som överlevt barncancer i centrala nervsystemet (CNS) löper ökad risk för negativa neuropsykologiska, fysiska och psykologiska sena effekter. Låg självkänsla är en riskfaktor för psykisk ohälsa men tidigare forskning om hur barncancer i CNS och dess behandling påverkar självkänsla är begränsad. Med självrapporteringsformuäret Self Esteem Questionnaire (SEQ-42) undersöktes självkänsla hos en populationsbaserad rikstäckande kohort med 528 unga vuxna överlevare jämfört med 995 personer i en stratifierad kontrollgrupp. Patientgruppen hade signifikant lägre självkänsla än kontroller i fem av sex dimensioner i SEQ-42 (p &lt;0,0001). Bland patienterna var den sammanfattande globala självkänslan positiv (skalvärde &gt; 2,5) hos en majoritet, 78,2%, men risken för negativ självkänsla var i flera dimensioner dubbelt så stor för patientgruppen jämfört med kontrollgruppen. Kvinnor och personer med diagnoserna oligodendrogliom, medulloblastom/PNET, kraniala och spinala germinom eller kraniofaryngeom hade lägre självkänsla än andra undergrupper (p &lt; 0,0001 – 0,037).

Multiple sclerosis is a chronic autoimmune neurological disease characterized by inflammatory cell infiltration and demyelination in the central nervous system (CNS). It is considered to be mediated by Th1 and Th17 immune responses. Experimental autoimmune encephalomyelitis (EAE) is widely used as a mouse model to study MS as it has features and histopathology similar to that of MS. Tolerogenic dendritic cells (DC) are reported to efficiently prevent sensitization for EAE. In this research, we induced tolerogenic DC (DC10) by differentiating them with IL-10. Compared to immature DC, DC10 did not show increased expression of MHC II or the co-stimulatory molecules CD40, CD80 and CD86, and produced low levels of pro-inflammatory cytokines IL-1â, IL-6, and IL-12 but higher levels of IL-10. This is consistent with their possessing a tolerogenic phenotype. We found that three intraperitoneal (i.p.) injections of DC10 successfully inhibited the signs of established, ongoing EAE: DC10 significantly reduced the clinical scores, demyelination and cell infiltration in the spinal cord, as well as the production of IL-4, IL-6, IL-10, IL-17 and IFN-ã by spleen and lymph node (LN) lymphocytes. DC10 treatments did not significantly affect inflammatory cytokine mRNA levels in the CNS. We found that there was higher FoxP3 expression in the CNS in response to DC10 treatments relative to PBS-treated animals. We also found that DC10 treatments significantly enhanced IgG1, IgG2a and IgG2b production and total spleen and LN lymphocyte proliferation following challenge with myelin oligodendrocyte glycoprotein (MOG) antigen. As far as we know, this is the first report showing the successful therapeutic treatment with tolerogenic DC10 of established EAE in mice.

Multiple sclerosis is a chronic autoimmune neurological disease characterized by inflammatory cell infiltration and demyelination in the central nervous system (CNS). It is considered to be mediated by Th1 and Th17 immune responses. Experimental autoimmune encephalomyelitis (EAE) is widely used as a mouse model to study MS as it has features and histopathology similar to that of MS. Tolerogenic dendritic cells (DC) are reported to efficiently prevent sensitization for EAE. In this research, we induced tolerogenic DC (DC10) by differentiating them with IL-10. Compared to immature DC, DC10 did not show increased expression of MHC II or the co-stimulatory molecules CD40, CD80 and CD86, and produced low levels of pro-inflammatory cytokines IL-1â, IL-6, and IL-12 but higher levels of IL-10. This is consistent with their possessing a tolerogenic phenotype. We found that three intraperitoneal (i.p.) injections of DC10 successfully inhibited the signs of established, ongoing EAE: DC10 significantly reduced the clinical scores, demyelination and cell infiltration in the spinal cord, as well as the production of IL-4, IL-6, IL-10, IL-17 and IFN-ã by spleen and lymph node (LN) lymphocytes. DC10 treatments did not significantly affect inflammatory cytokine mRNA levels in the CNS. We found that there was higher FoxP3 expression in the CNS in response to DC10 treatments relative to PBS-treated animals. We also found that DC10 treatments significantly enhanced IgG1, IgG2a and IgG2b production and total spleen and LN lymphocyte proliferation following challenge with myelin oligodendrocyte glycoprotein (MOG) antigen. As far as we know, this is the first report showing the successful therapeutic treatment with tolerogenic DC10 of established EAE in mice.

CNS-PNETs are rare, aggressive, paediatric embryonal brain tumours that are poorly studied. We recently identified an aggressive sub-group of CNS-PNETs characterized by the amplification of the C19MC microRNA cluster, however, little is known regarding the features of other CNS-PNET tumours. This study was designed to define additional molecular sub-groups of CNS-PNET by interrogating a large cohort of CNS-PNETs. To elucidate the features of CNS-PNET, we examined transcriptional and copy number profiles from primary hemispheric CNS-PNETs. We then validated and examined the clinical significance of novel sub-group markers in 123 primary CNS-PNETs. This thesis demonstrates that CNS-PNET can be categorized into three molecular sub-groups that are distinguished by distinct primitive neural, oligo-neural and mesenchymal lineage gene expression signatures and also correlated with distinct clinical features. Data from my thesis has generated a substantial body of knowledge to fuel both biological and clinical investigations of childhood CNS-PNETs.

CNS-PNETs are rare, aggressive, paediatric embryonal brain tumours that are poorly studied. We recently identified an aggressive sub-group of CNS-PNETs characterized by the amplification of the C19MC microRNA cluster, however, little is known regarding the features of other CNS-PNET tumours. This study was designed to define additional molecular sub-groups of CNS-PNET by interrogating a large cohort of CNS-PNETs. To elucidate the features of CNS-PNET, we examined transcriptional and copy number profiles from primary hemispheric CNS-PNETs. We then validated and examined the clinical significance of novel sub-group markers in 123 primary CNS-PNETs. This thesis demonstrates that CNS-PNET can be categorized into three molecular sub-groups that are distinguished by distinct primitive neural, oligo-neural and mesenchymal lineage gene expression signatures and also correlated with distinct clinical features. Data from my thesis has generated a substantial body of knowledge to fuel both biological and clinical investigations of childhood CNS-PNETs.

No description available.

OBJECTIVE: The aim of this study was to investigate the safety and tolerability of a novel anti-folate drug, pemetrexed, in the setting of a phase I clinical trial in patients with non-HIV related central nervous system lymphoma (CNSL). METHODS: In this multicenter, open-label, phase I dose finding clinical trial, pemetrexed was investigated as a single agent treatment for primary or secondary CNSL. RESULTS: A total of 18 patients were enrolled between January 2009 and November 2014. The mean age was 64.6 years old (range: 47-79). The ratio of male to female was 1:1. One out of six patients experienced a dose limiting toxicity (DLT) at dose level 1 (600mg/m2). There were no DLTs among the four patients enrolled at dose level 2 (900m/m2). Two of six patients experienced a DLT at dose level 3 (1200mg/m2). The MTD was therefore determined to be 900mg/m2. Overall, pemetrexed was well tolerated but toxicities were seen and need to be monitored. All patients experienced at least one type of toxicity of any grade. Most patients (92.9%) experienced at least one type of neurological toxicity. Grade-3 toxicities included confusion, speech impairment, and psychosis. Twelve patients (85.7%) experienced at least one bone marrow type of toxicity of any grade. These toxicities included anemia (78.6%), thrombocytopenia (57.1%), neutropenia (50%), leukocytopenia (42.9%), and lymphopenia (42.9%). Four patients experienced either grade-3 (14.3%) or grade-4 (14.3%) neutropenia. Three patients experienced grade-3 leukopenia (21.4%). One patient experienced grade-3 lymphopenia (7.1%) and two patients experienced grade-4 lymphopenia (14.3%). Twelve patients (85.7%) experienced at least one metabolic type of toxicity of any grade. A majority of these were also grade-1 or 2, with the exception of hypophosphatemia (grade-4), hyperglycemia (grade-3) and increased ALT (grade-3), increased AST (grade-3) and increased creatinine phosphokinase (CPK) (grade-4). Constitutional and gastrointestinal symptoms were seen in >60% of patients. These consisted mainly of fatigue, constipation, nausea, and anorexia. Musculoskeletal symptoms were seen in greater than 60% of patients. Less common adverse events included pain (<60%), infection (<40%), dermatologic, ocular/visual, and pulmonary/upper respiratory (<30%). The average number of cycles on treatment for all patients was 5.5 cycles. 14 patients were evaluated for response to treatment by neuroimaging (MRI) while on treatment. Of these, four patients (28.6%) showed a complete response (CR). Of those patients, 2 patients achieved this response after only 2 doses, and 2 patients after a total of 8 doses. 5 patients (35.7%) showed a partial response (PR) and four patients (28.6%) achieved stable disease (SD). The overall response rate (ORR) was determined at 92.9% (SD, PR and CR combined). CONCLUSIONS: Given this data, pemetrexed is a powerful drug and feasible alternative to existing treatment options; however, certain toxicities need to be closely monitored. Further studies are needed to assess the efficacy of pemetrexed in a larger cohort of patients with CNSL.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Economia, Administração e Contabilidade, Programa de Pós-Graduação em Administração, Mestrado Profissional em Administração, 2016. / Submitted by Camila Duarte (camiladias@bce.unb.br) on 2017-01-23T13:43:48Z No. of bitstreams: 1 2016_RodrigoFáveroClemente.pdf: 2075366 bytes, checksum: 0e0e111e007e78805c4718605f30d768 (MD5) / Approved for entry into archive by Ruthléa Nascimento(ruthleanascimento@bce.unb.br) on 2017-02-20T17:04:01Z (GMT) No. of bitstreams: 1 2016_RodrigoFáveroClemente.pdf: 2075366 bytes, checksum: 0e0e111e007e78805c4718605f30d768 (MD5) / Made available in DSpace on 2017-02-20T17:04:01Z (GMT). No. of bitstreams: 1 2016_RodrigoFáveroClemente.pdf: 2075366 bytes, checksum: 0e0e111e007e78805c4718605f30d768 (MD5) / A responsividade democrática pressupõe que, em regimes democráticos, governos constituídos devem buscar correspondência entre suas ações e as expectativas e preferências dos governados. Além das formas tradicionais de participação política, foram estabelecidos recentemente no Brasil espaços institucionais mediante os quais a população pode informar, diretamente ou por meio de representantes, expectativas ou preferências aos governantes. A efetividade desses espaços, chamados de instituições participativas, depende da correspondência entre preferências da sociedade e atos do governo. Nesse contexto, a presente dissertação teve por objetivo identificar a efetividade das Conferências Nacionais de Saúde (CNS), realizadas entre os anos de 1996 e 2011, mediante a análise da responsividade do governo federal diante das propostas aprovadas nessas CNS. Para esse fim, estabeleceu-se como premissa que as propostas constantes nas CNS representam a opinião da sociedade em relação à saúde, devendo ser consideradas pelo governo federal no estabelecimento das políticas públicas voltadas à saúde. Para realizar a pesquisa empírica, as propostas foram categorizadas por temas, mediante análise de conteúdo, e posteriormente pareadas com os atos administrativos do governo federal voltados à saúde. Dessa forma foi possível a realização de testes de congruência, método pelo qual a responsividade democrática pode ser mensurada. Com base no referencial teórico utilizado, foi testado empiricamente um conjunto de hipóteses a respeito da responsividade do governo federal e a efetividade das CNS. A análise do conteúdo das propostas revelou que as CNS variaram pouco em relação aos temas tratados. Em relação aos testes de congruência, percebeu-se que a efetividade das CNS variou de acordo com a atuação dos governos. Essa variação apresentou-se não apenas em relação ao número de propostas respondidas, mas sobretudo em relação aos temas que apresentaram congruência. Na parte final da presente dissertação são propostas possíveis explicações para os resultados encontrados, bem como uma agenda de estudos futuros a respeito do tema. / The democratic responsiveness assumes that, in democratic regimes, constituted governments should seek correspondence between their actions and the expectations and preferences of the governed. In addition to traditional forms of political participation, institutional spaces through which the public can inform, directly or through representatives, expectations or preferences to the rulers have been established recently in Brazil. The effectiveness of these spaces, called Participatory institutions, depends on the correspondence between preferences of society and governmental actions. In this context, the present work aimed to identify the effectiveness of the National Conferences of Health (CNS), made between the years 1996 and 2011, through the analysis of federal government’s responsiveness on the proposals approved by these CNS. To this end, it established the premise that the subjects contained in the CNS’s proposals represent the views of society in relation to health, and as so should be considered by the federal government in the establishment of public policies on health. To conduct this empirical research, proposals were categorized by themes, through content analysis, and then paired with the administrative acts of the federal government focused on health. Thus it was possible to perform matching tests, method by which democratic responsiveness can be measured. Based on the theoretical framework, was empirically tested a set of assumptions about the responsiveness of the federal government and the effectiveness of the CNS. The content analysis of the proposals revealed that CNS varied little in relation to the topics covered. Regarding the congruence tests, it was noted that the effectiveness of CNS varied according to the actions of governments. This variation presented not only in the number of answered proposals, but especially for those issues that presented congruence. In the final part of present work some possible explanations are proposed for the findings, as well as an agenda for future studies on the subject.