Klebsiella pneumoniae is a Gram-negative pathogen associated with numerous infections. Like all Gram-negative bacteria, K. pneumoniae naturally release outer membrane vesicles (OMVs) during all stages of cellular growth. OMVs are composed of the outer membrane components such as lipopolysaccharide (LPS) and outer membrane proteins and contain cytosolic and periplasmic proteins in the lumen. K. pneumoniae is often found to lack an O antigen. The absence of the O antigen has been reported to alter the protein content of the membrane which may further alter the immune response elicited by K. pneumoniae. Therefore the purpose of this study was to analyze the protein content and inflammatory responses of the cellular outer membrane (OM) and the secreted OMVs. A secondary goal of this study was to evaluate any changes to the membrane protein content due to O antigen loss and determine if the loss of the O antigen influences the inflammatory response. This study demonstrated that the cellular OM and OMVs have distinct protein profiles as well as inflammatory responses. OMVs were highly enriched in outer membrane proteins compared to the cellular OM and had a significantly stronger inflammatory response. The protein content of the OM and OMVs were further modified by the absence of the O antigen from the outer membrane. Although there were no significant differences seen in the wild type and O antigen deficient OM inflammatory responses, the loss of the O antigen resulted in OMVs that produced a significantly stronger IL-6 response.

Orientadores: Andrei Carvalho Sposito, Valéria Nasser Figueiredo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T20:27:16Z (GMT). No. of bitstreams: 1 Carvalho_LuizSergioFernandesde_D.pdf: 19288751 bytes, checksum: ea3c4fda36c00d542fbe2d8c4f4242e8 (MD5) Previous issue date: 2015 / Resumo: Introdução: A resposta de fase aguda (RFA) transforma a lipoproteína de alta densidade (HDL) em uma partícula disfuncional que pode favorecer o estresse oxidativo/inflamatório e disfunção da enzima óxido nítrico sintase endotelial (eNOS). Ao mesmo tempo, a modulação do metabolismo da HDL pela proteína de transferência de colesteril ester (CETP) parece estar associada a um potencial efeito anti-inflamatório durante a RFA relacionada a sepse. Embora esses mecanismos possam estar envolvidos na disfunção endotelial que se segue ao infarto do miocárdio com supra de ST (IMCSST), essas hipóteses nunca foram testadas em humanos. Método: Plasma foi obtido de pacientes consecutivos com IMCSST (n=116 a 180) nas primeiras 24 horas após o início dos sintomas (D1) e no 5o dia (D5), sendo utilizado para medir: proteína C reativa (PCR), nitrato/nitrito (NOx) e atividade de CETP. As lipoproteínas foram isoladas por ultracentrifugação de gradiente. A oxidabilidade de LDL co-incubada com HDL (HDLaoxLDL) e auto-oxidabilidade da HDL (HDLautox) foram medidas após a incubação com CuSO4. A atividade anti-inflamatória da HDL foi estimada pela secreção de VCAM-1 por células endoteliais da veia umbilical humana, após a incubação com TNF-?. Dilatação mediada por fluxo (FMD) foi avaliada no 30o dia (D30). Resultados: Entre os pacientes no 1o tercil de HDL-colesterol no D1 (<33mg/dL), o incremento de NOx entre D1 e D5 e a FMD ajustada para várias co-variáveis foram maiores do que naqueles no 2o (33- 42mg/dL) e 3o (>42mg/dL) tercis. Do D1 ao D5 houve redução no tamanho e no número de partículas de HDL, bem como aumento da HDLaoxLDL e HDLautox. A secreção de VCAM-1 após estímulo com TNF-? foi reduzida após co-incubação com HDL de voluntários saudáveis, de doentes com IM no D1 e D30, mas não para a HDL do D5. A oxidação da HDL foi medida pela concentração de TBARS em partículas de HDL isoladas, sendo observado aumento entre D1 e D5, e permanecendo elevado no D30. O aumento no conteúdo de TBARS na HDL foi associado com a atividade de CETP (r=0,72; p=0,014), FMD (r =-0,61; p=0,046) e HDL-C (r=0,83; p=0,004). Em paralelo, elevada atividade de CETP na admissão foi associado a menor FMD, menor biodisponibilidade de NOx e a maior incidência de morte súbita e infarto recorrente após 30 (OR=12,8; p=0,032) e 180 dias (OR=3,3; p=0,044). Conclusão: O IMCSST induz mudanças na composição química e função do HDL, bem como alterações na atividade enzimática da CETP que paralelamente contribuem para o aumento da oxidação de partículas de HDL, que se traduz em disfunção endotelial / Abstract: Introduction: Acute phase response (APR) turns high-density lipoprotein (HDL) into a dysfunctional particle that may favor oxidative/inflammatory stress and endothelial nitric oxide (NO) synthase (eNOS) dysfunction. Moreover, modulation of HDL intravascular metabolism by cholesteryl ester transfer protein (CETP) action has also been implicated as a potentially anti-inflammatory and thrombotic mechanism during APR. Although these mechanisms may be involved into endothelial dysfunction that follows acute ST-elevation myocardial infarction (STEMI), these assumptions have never been in investigated in humans. Method: Plasma was obtained in the first 24-hours after STEMI symptoms onset (D1) and after 5 days (D5) in consecutive patients (n=116 to 180), and then used to measure C-reactive protein (CRP), nitrate/nitrite (NOx) and CETP activity. Lipoproteins were isolated by gradient ultracentrifugation. The oxidizability of low-density lipoprotein incubated with HDL (HDLaoxLDL) and the HDL self-oxidizability (HDLautox) were measured after CuSO4 co-incubation. Anti-inflammatory activity of HDL was estimated by VCAM-1 secretion by human umbilical vein endothelial cells after incubation with TNF-?. Flowmediated dilation (FMD) was assessed at the 30th day (D30) after STEMI. Results: Among patients in the first tertile of admission HDL-Cholesterol (<33mg/dL), the increment of NOx from D1 to D5 and the FMD adjusted for multiple covariates were higher than in those in the second (33-42mg/dL) or third (>42mg/dL) tertiles, respectively. From D1 to D5, there was a decrease in HDL size and particle number and increase in both HDLaoxLDL and HDLautox. VCAM-1 secretion after TNF-a stimulation was reduced after co-incubation with HDL from healthy volunteers, from MI patients at D1 and D30 but not from D5. Oxidized HDL was measured by TBARS in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r=0.72;p=0.014), FMD (r=-0.61;p=0.046) and HDL-C (r=0,83,p=0,004). High CETP activity at admission was associated lower FMD, lower NOx bioavailability and with the incidence of sudden death and recurrent MI at 30 days (OR 12.8;p=0.032) and 180 days (OR 3.3;p=0.044). Conclusion: STEMI induces changes in the chemical composition and function of HDL as well as changes in the enzymatic activity of CETP that in parallel contribute to increased oxidation of HDL particles, and thus inducing endothelial dysfunction / Doutorado / Patologia Clinica / Doutor em Ciências Médicas

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This study investigated the effects of abomasal infusion of essential fatty acids, especially alpha-linolenic acid, and conjugated linoleic acid on their distribution in milk fat and blood plasma and on the plasma inflammatory response in dairy cows from late to early lactation. The most important essential fatty acids for ruminants are alpha-linolenic acid and linoleic acid. They are abundant in pasture which is nowadays reduced in the ration of dairy cows due to the replacement of fresh feeds by preserved diets. Conjugated linoleic acid is formed as a by-product during ruminal biohydrogenation of essential fatty acids and has been associated with positive effects on the energy metabolism and immune system. Forty rumen-cannulated Holstein Friesian cows were assigned to four treatment groups in their late second lactation. Prior to supplementation, cows were fed a total mixed rations with a low-fat content. In late gestation cows were abomasally treated with coconut oil, linseed and safflower oil, conjugated linoleic acid, or both. Performance data, milk composition and fatty acid pattern in milk and plasma as well as inflammatory response parameters in plasma were measured regularly. Furthermore, liver tissue was tested for the abundance of genes related to the inflammatory response.:TABLE OF CONTENTS ABBREVIATIONS 1. INTRODUCTION 2. LITERATURE OVERVIEW 2.1 Essential Fatty Acids and Conjugated Linoleic Acid 2.1.1 Essential Fatty Acids (EFA) 2.1.2 Conjugated Linoleic Acid (CLA) 2.1.3 EFA in Dairy Cow Nutrition 2.2 Fatty Acid Distribution in Blood, Erythrocyte Membranes, and Milk Fat 2.2.1 Plasma Lipids 2.2.2 EFA and CLA in Plasma Lipids 2.2.3 EFA and CLA in Erythrocyte Membranes 2.2.4 EFA and CLA in Milk Fat 2.3 Effects of EFA and CLA on Inflammatory Processes during the Transition Period 2.3.1 Metabolic and Immunological Challenges during the Transition Period 2.3.2 Effects of EFA on the Metabolism, Inflammatory- and Immune Response 2.3.3 Effects of CLA on the Metabolism, Inflammatory- and Immune Response 2.4 Scope of the Thesis 3. PUBLICATION 4. GENERAL DISCUSSION 4.1 Abomasal Infusion 4.2 Animal Performance 4.3 Distribution of EFA and CLA in Blood and Milk Fat 4.4 Effects of EFA and CLA on Plasma and Hepatic Acute Phase and Inflammatory Response 4.5 Conclusion and Practical Considerations 4.5.1 Summary of EFA effects 4.5.2 Summary of CLA effects 4.5.3 Summary of synergistic effects of EFA and CLA 4.5.4 Summary of Observations apart from Treatments and Practical Considerations 5. SUMMARY 6. ZUSAMMENFASSUNG 7. REFERENCES APPENDIX

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L’apparition de plusieurs maladies, telles que le cancer, le diabète, l'hypertension artérielle et la propagation d'infections de type virus mutagènes peuvent être liées à la qualité et au mode de vie que nous menons aujourd’hui. En effet, plusieurs études sur les facteurs déclenchant ces maladies dites "morbides" à long ou à court terme, sont liées au stress et à la qualité des aliments consommés, qu'ils soient d'origine végétale ou animale. Ces maladies deviennent un phénomène courant, elles touchent différentes races et toutes les catégories de la société. D'après les recherches ethnobotaniques, les substances d’origine naturelle, ont permis à des civilisations de survivre à des maladies mortelles. A titre d'exemple, on retrouve ainsi des références à des périodes de fièvre paludique en Chine et à des symptômes de cette maladie dans le «Huangdi Neijiang» Le Canon de Médecine datant des environs du premier siècle avant notre ère, plus de 2000 ans, qui relate de l'emploi de plantes médicinales, pour soulager les fièvres (Desgrouas et al., 2014).Vers 186 avant J.-C. apparaît, dans certaines régions de Chine, l'utilisation en tisane, du Qing hao su, appelé plus tard artémisinine en Occident et extrait d'une plante médicinale utilisée comme antipyrétique appelée "Qing hao", Artemisia annua ou Armoise annuelle. L'artemisinine bloque une enzyme qui permet au parasite de pomper le calcium et l'empêche ainsi de se développer. Au jour d'aujourd'hui l’Artemisinin-based combination therapy, en français Thérapie combinée à base d'artémisinine et en sigle ACT, est une thérapie et une prévention tertiaire dans les cas de paludisme simple.Dans cette optique notre étude vient s'ajouter à une longue série d'études menées sur les plantes médicinales et les substances naturelles extraites. Elle a pour objectif de révéler de nouvelles biomolécules, de mettre en évidence leurs activités biologiques grâce à des techniques de biotechnologies d'une part. D'autre part ces investigations permettront de valoriser les ressources naturelles qui se distinguent par leur endémicité.Pour se faire, notre choix s'est porté sur deux plantes médicinales endémiques à l'Algérie Cyclamen africanum Boiss. & Reuter et Zygophyllum cornutum Coss. , après une recherche ethnobotanique sur la pharmacopée traditionnelle du Nord de l'Afrique, et qui a révélé l’efficacité de ces plantes dans les problèmes inflammatoires minimes chez les autochtones, nous avons entrepris des investigations pharmaco- biochimiques.Ces dernières nous ont permis d'isoler : cinq composés à partir de l'extrait méthanolique des racines de l'espèce Cyclamen africanum Boiss. & Reuter, deux nouvelles saponines triterpéniques de type Oleanane, Afrocyclamin A et B (1, 2), ainsi que trois saponines triterpénoïdes connus sous le nom de lysikokianoside (3), deglucocyclamin I (4) et de son dérivé d'acide dicrotalique (5); et Sept saponosides connus à partir de l'extrait méthanolique de la plante entière de Zygophyllum cornutum Coss., ces saponosides sont de type ursane, ce type de triterpène est rapporté dans cette espèce pour la première fois et peuvent être considérés comme un marqueur chimio-taxonomique (chemotype) du genre Zygophyllum. Les structures ont été élucidées, sur la base de l'analyse des spectres de l'expérience RMN-1D et RMN- 2D (COSY, TOCSY, NOESY, HMBC et HSQC) et spectrométrie de masse en source FAB mode ion négatif. Des activités biologiques, des fractions saponosidiques Fr.1 et Fr.2, ont été testées sur des lignées de Rats mâles et femelles, de la race Winstar pour évaluer l'activité anti inflammatoire.La fraction saponosidique Fr.1 de Cyclamen africanum à la dose 5 mg, a montré un effet significatif sur l'inflammation causé par la carragénine, en réduisant l'oedème et la réponse immunitaire, qui s'est traduite par la concentration des protéines de la réponse inflammatoire (PRI) à travers leurs action sur les pro-médiateurs de l'inflammation (COX-2, PGE2, TNF -α, iNOS). / The appearance of several diseases, such as cancer, diabetes, high blood pressure and spread of infections mutagenic virus type can be linked to the quality and lifestyle that we lead today. Indeed, several studies on the factors triggering these so-called "morbid" long-or short-term illnesses are related to stress and quality of food consumed, whether of plant and animal origin. These diseases are becoming a common occurrence, they affect different races and all classes of society. According ethnobotanical research, naturally occurring substances, allowed civilizations to survive deadly diseases. For example, we thus find references to periods of malarial fever in China and one of the symptoms of this disease in the "Huangdi Neijiang" The Canon of Medicine dating from around the first century BC, more than 2000 years, which relates to the use of herbal medicines to relieve fevers (Desgrouas et al., 2014).Around 186 BC appears, in some parts of China, the use in herbal tea, Qing hao su, later known as artemisinin in the West and extracted from a medicinal plant used as antipyretic called "Qing hao" Artemisia annua or annual wormwood. Artemisinin blocks an enzyme which enables the parasite to pump calcium and prevents it from developing. As of today the Artemisinin-based combination therapy in French Combination therapy of artemisinin and ACT acronym, is a therapy and tertiary prevention in cases of uncomplicated malaria.From this perspective our study adds to a long series of studies on medicinal plants and natural substances extracted. It aims to reveal new biomolecules, highlighting their biological activities through techniques of biotechnology on the one hand. Moreover, these investigations will develop natural resources that are characterized by endemic.To do this, our choice is focused on two endemic medicinal plants in Algeria Cyclamen africanum Boiss. & Reuter and Zygophyllum cornutum Coss. After an ethnobotanical research on traditional medicine in Northern Africa, which showed the effectiveness of these plants in minimal inflammatory problems among Aboriginal, we undertook biochemical pharmacological investigations.The latter allowed us to isolate, five compounds from the methanol extract of the roots of the species Cyclamen africanum Boiss. Reuter & two new oleanane triterpene saponins type, Afrocyclamin A and B (1, 2) and three triterpenoid saponins known lysikokianoside of (3), deglucocyclamin I (4) and its derivative dicrotalique acid (5) September and known from the methanol extract saponins from the whole plant of Zygophyllum cornutum Coss. these saponins are ursane type, type triterpenes are reported in this species for the first time and can be considered a chemotherapy marker Taxonomic (chemotype) of Zygophyllum kind. The structures were elucidated on the basis of the analysis of NMR spectra of the experience-1D and 2D-NMR (COSY, TOCSY, NOESY, HSQC and HMBC) and mass spectrometry method negative ion FAB source. The biological activities of saponosidiques FR.1 and Fr.2 fractions were tested on lines of male and female rats of the Winstar rats to evaluate the anti-inflammatory activity. The saponosidique fraction FR.1 Cyclamen africanum the 5 mg dose, showed a significant effect on inflammation caused by carrageenan, reducing edema and immune response, which resulted in the concentration of protein the inflammatory response (PRI) through their action on the pro-inflammatory mediators (COX-2, PGE2, TNF -α, iNOS). The fraction of Fr.2 saponosidique Zygophyllum dose 20 mg did not show a significant effect on inflammation in general.

Fragestellung: Es wird untersucht, ob die isolierte hypertherme Extremitätenperfusion (ILP) mit TNF-alpha und Melphalan eine akute systemische inflammatorische Reaktion (SIRS) auslöst. Weiterhin soll der Einfluß von zwei verschiedenen total intravenösen Narkoseverfahren sowie der Zusammenhang der unabhängig voneinander bestimmten Meßgrößen Herzindex/Sauerstoffverbrauchsindex (HI/VO2I) und Sauerstoffverbrauchsindex/Sauerstoffangebotsindex (VO2I/DO2I) beim Entstehen eines SIRS analysiert werden. Methodik: 73 Patienten, die sich einer ILP mit TNF-alpha und Melphalan in Allgemeinanästhesie unterzogen, wurden in diese klinische, retrospektive Untersuchung eingeschlossen. Ein erweitertes kardiopulmonales Monitoring, bestehend aus kontinuierlicher Thermodilution, kontinuierlicher indirekter Kalorimetrie, invasiver Blutdruckmessung sowie arterieller und gemischtvenöser Blutgasanalysen ermöglichte die Analyse von hämodynamischen, metabolischen und gasanalytischen Parametern an 8 definierten Zeitpunkten im Verlauf der ILP mit TNF-alpha und Melphalan. 21 Patienten erhielten eine Narkose mit Etomidate/Midazolam/Sufentanil/Pancuroniumbromid (N1), und bei 52 Patienten wurde die Narkose mit Propofol/Remifentanil/Cis-Atracurium (N2) durchgeführt. Ergebnisse: Während der ILP mit TNF-alpha und Melphalan kam es bei folgenden Parametern zu signifikanten Veränderungen in der systemischen Reperfusionsphase gegenüber den Ausgangswerten vor der extrakorporalen Zirkulation: Herzfrequenz, Herzindex, Temperatur, Gesamtsauerstoffaufnahme, pulmonale Sauerstoffaufnahme, Sauerstoffangebot, systemischer Gefäßwiderstand, pulmonalarterieller Mitteldruck, kardiale Füllungsdrücke, gemischtvenöser Kohlendioxid- und Sauerstoffpartialdruck, arterieller Kohlendioxid- und Sauerstoffpartialdruck, gemischtvenöse Sauerstoffsättigung, arterieller und gemischtvenöser Sauerstoffgehalt sowie arterieller pH- und Laktatwert. Bezüglich der Narkoseverfahren zeigte die Narkose N2 versus N1 signifikant geringere Herzfrequenzen und Herzindices, sowie signifikant erhöhte pulmonalarterielle Mitteldrücke, pulmonale und systemische Gefäßwiderstände. Die Korrelationen von HI/VO2I und VO2I/DO2I sind in der prä-Bypass-Phase gering, nehmen im Verlauf der ILP zu und erreichen zum Zeitpunkt der systemischen Reperfusion jeweils ihren Maximalwert. Schlußfolgerungen: Die ILP mit TNF-alpha und Melphalan kann als dynamisches in-vivo Modell für das Entstehen einer SIRS-Reaktion aufgefaßt werden. Die inflammatorische Antwort ist in ihrem Ausmaß eher gering und erreicht nach Aufhebung der extrakorporalen Zirkulation mit systemischer Reperfusion der behandelten Extremität ihr Maximum. Die Überwachung der Teilkreisläufe, ein erweitertes hämodynamisches Monitoring sowie forcierte intravenöse Volumentherapie in der Reperfusionsphase lassen dieses Behandlungsverfahren für die Patienten in Allgemeinanästhesie sicher erscheinen. Beide beschriebenen Narkoseverfahren sind für diese operative Therapie geeignet. Der Zusammenhang von HI/VO2I sowie VO2I/DO2I ist im Verlauf der ILP gering, kann sich aber mit Zunahme der inflammatorischen Reaktion verstärken. / objective: To determine whether the isolated hyperthermic limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha) and melphalan causes an acute systemic inflammatory response syndrome (SIRS)? Also analysed will be the influence of two total intravenous anaesthesias and the correlation of independent measured values cardiac index/oxygen consumption index (HI/VO2I) and oxygen consumption index/oxygen delivery index (VO2I/DO2I). design: Retrospective review of hemodynamic, metabolic and blood gas values from 73 patients, undervented isolated hyperthermic limb perfusion of leg with TNF-alpha and Melphalan in general anaesthesia. methods: Cardiopulmonary monitoring consisted of continuous thermodilution, continuous calorimetry, arterial pressure and arterial as well as admixed blood-gas analyses. Values were measured on 8 time points in the course of ILP. In 21 patients anaesthesia was carried out with drug-combination of Etomidate/Midazolam/Sufentanil/Pancuroniumbromid (N1), and 52 patients were given anaesthesia with Propofol/Remifentanil/Cis-atracurium (N2). results: The following values changed significantly after limb-reperfusion compared with the baseline: heart rate, cardiac index, temperature, oxygen consumption, pulmonary oxygen consumption, oxygen delivery, systemic vascular resistance, mean pulmonary arterial pressure, precardial pressures, admixed carbon dioxide pressure, admixed oxygen pressure, arterial carbon dioxide pressure, arterial oxygen pressure, admixed oxygen saturation, arterial and admixed oxygen content as well as arterial pH- and lactat. conclusions: The isolated hyperthermic limb perfusion with TNF-alpha and melphalan may be used as a dynamic in-vivo model for the development of an SIRS. The inflammatory response is slight and reached the maximum after reperfusion of treated limb. Monitoring of the two circulations, extended cardiopulmonary monitoring and intravenous volumetherapie in the reperfusion time makes this cancer treatment in general anaesthesia safe. Both anaesthesia are suitable. The correlations of HI/VO2I as well as VO2I/DO2I are low in the beginning and rise with the increase of the inflammatory response.

Introdução: Os linfomas não-Hodgkin de células T periféricas (LCTP) são neoplasias raras caracterizadas pela proliferação monoclonal de linfócitos T maduros. Correspondem a 15% das malignidades linfoides e têm distribuição geográfica peculiar. Compreendem 22 entidades clínico-patológicas distintas, heterogêneas do ponto de vista clínico-epidemiológico, morfológico, fenotípico e molecular. O grupo de apresentação predominantemente nodal compreende as variantes histológicas LGCA/ALK+, LGCA/ALK-, LCTA e LCTP/SOE. Sua terapêutica se baseia em poliquimioterápicos à base de antraciclina e consolidação com transplante de células tronco hematopoiéticas autólogas (TCTH). Com exceção do LGCA/ALK+, apresentam sobrevida global em cinco anos de 30% a 40%. Devido aos desfechos desfavoráveis, estudos de perfil de expressão gênica e de metilação de genes supressores tumorais têm emergido nos últimos anos para refinar o diagnóstico destas neoplasias, melhorar o conhecimento fisiopatológico e o prognóstico e estabelecer possíveis alvos terapêuticos. Estudos preliminares com LCTP nodais indicam valor prognóstico favorável da hiperexpressão de genes de padrão inflamatório NFkB1 e IKBkB e desfavorável nos casos de supraregulação de genes de padrão proliferativo como CCNA2, TOP2A e CHEK1 e do fenótipo metilado de p15INK4b e p16INK4a. Objetivo:Avaliar o impacto da expressão relativa dos genes CCNA2, TOP2A, CHEK1, NFkB1, IKBkB e VEGF1 e da metilação dos genes p15 e p16 em população brasileira com LCTP nodais tratados com quimioterapia CHOP-símile para os desfechos de sobrevida global, sobrevida livre de progressão e sobrevida livre de doença. Métodos: A expressão gênica foi avaliada por qtPCR de amostras fixadas em formol e incluídas em parafina de 63 pacientes. A mediana de expressão dos genes foi comparada com variáveis clínicas e desfechos. PCR qualitativa metilação-específico foi usada avaliar a metilação de p15 e p16. Resultados: Com mediana de seguimento de vinte meses, as SG, SLP e SLD foram, respectivamente, 45,6%, 34,3% e 63,0% e a resposta completa de 46,0%. Em análise multivariada, ECOG >= 2 e a hiperexpressão do gene CCNA2 foram associadas à pior SG em cinco anos, nos LCTP nodais (p=0,008 e p=0,002). Em análise univariada os genes CCNA2, TOP2A e CHEK1 foram associados ao pior prognóstico nos LCTP/SOE e melhor nos LGCA/ALK-. A hiperexpressão do gene VEGF1 se associou ao pior prognóstico no LGCA/ALK- e LCTA. Metilação de p15INK4b não foi encontrada nos LGCA/ALK+ e em análise multivariada foi associada a pior SLP em 5 anos nos LCTP não-ALK+ (HR: 9,88; p=0,03). O painel gênico testado não apresentou poder para discriminar as diferentes variantes histopatólogicas de LCTP nodais, porém demonstrou-se associação direta entre a intensidade de mediana de expressão desses genes e agressividade biológica nesse grupo heterogêneo de neoplasias. O significado prognóstico de imunoexpressão da proteína ALK sofreu influência das variáveis constituintes do IPI nessa coorte. Conclusão: A hiperexpressao dos genes CCNA2, TOP2A e CHEK1 foram associadas a prognóstico desfavorável nos LCTP/SOE e favorável nos LGCA/ALK-. Fenótipo hipermetilado de p15INK4b não foi evento observado em LGCA/ALK+, porém foi associado a pior prognóstico nos LCTP nodais não-ALK+ / Background: Peripheral T-cell non-Hodgkin\'s lymphomas (PTCL) are rare tumors characterized by monoclonal proliferation of mature T lymphocytes; they correspond to 15% of lymphoid malignancies and have specific geographic distribution. PTCL comprise 22 distinct clinicopathologic entities, heterogeneous from the clinical and epidemiological perspective, as well as morphologic, phenotypic and molecular. The group of presentation predominantly nodal comprises the histological variants ALCL/ALK+, ALCL/ALK-, AITL and PTCL/NOS. Its treatment is based on polychemotherapy with anthracycline and consolidation with autologous hematopoietic stem cell transplantation (ASCT). With the exception of ALCL/ALK+, these tumors show overall survival at 5 years from 30% to 40%. Due to unfavorable outcomes, gene expression profile studies, as well as studies of methylation of tumor suppressor genes, have emerged in recent years in order to refine the pathological diagnosis of these cancers, improve the pathophysiological knowledge and prognosis, and establish possible therapeutic targets. Preliminary studies with nodal PTCLs indicate favorable prognostic value of overexpression of inflammatory pattern genes like NFkB1 e IKBkB, and unfavorable in the case of proliferative genes as CCNA2, TOP2A, CHEK1 and the methylated phenotype of suppressor genes p15INK4b e p16INK4a. Objectives: Assess the impact of relative expression of genes CCNA2, TOP2A, CHEK1, NFkB, IKBkB and VEGF1 and the methylation of the genes p15 and p16 in Brazilian population with nodal PTCLs treated with CHOP-like chemotherapy for the outcomes of overall survival, progression-free survival and disease-free survival. Methods: Gene expression was assessed by qtPCR of paraffin samples of 63 patients. The median gene expression was compared with clinical variables and outcomes. Qualitative methylation-specific PCR was used to assess the methylation of p15 and p16. Results: With a segment median of 20 months, the OS, PFS and DFS were, respectively, 45,6%, 34,3% and 63,0% and the complete response (CR) was 46,0%. In multivariate analysis, ECOG >= 2 and overexpression of the gene CCNA2 were associated with worse OS at 5 years in nodal PTCLs (p = 0,008 and p = 0,002). In univariate analysis, the genes CCNA2, TOP2A and CHEK1 were associated with worse prognosis in PTCL/NOS and better in ALCL/ALK negative. The overexpression of the gene VEGF1 was associated with worse prognosis in the variants AITL and ALCL/ALK negative. Methylation of the gene p15INK4b was not found in ALCL/ALK+ group, and in multivariate analysis was associated with worse 5-years PFS in the group of PTCL non-ALK+ (HR: 9,88 and p = 0,03). The gene panel tested showed no power to discriminate the different histopathology of nodal PTCL, but it showed a direct association between the median intensity of expression of these genes and biological aggressiveness in this heterogeneous group of neoplasms. The prognostic significance of immunostaining of ALK protein was influenced by IPI constituents variables in this cohort. Conclusion: The overexpression of genes CCNA2, TOP2A e CHEK1 were associated with poor prognosis in PTCL/NOS and favorable in ALCL/ALK negative. Hypermethylated phenotype of gene p15INK4b was not an observed event in ALCL/ALK+, but it was associated with poor prognosis in nodal PTCL non-ALK+

Homeostase do O2 é essencial para a sobrevivência e desenvolvimento fisiológico dos organismos. A falta de O2 nos tecidos é um fator subjacente comum na morbidade e mortalidade de situações clínicas como na Síndrome do Desconforto Respiratório Agudo (ARDS). Na retomada da homeostase as células mielóides exercem suas funções especializadas nas áreas de hipóxia. A adaptação destas células nesta condição depende dos produtos do gene HIF-1<font face=\"Symbol\">&#945, fator de transcrição que responde às mudanças de O2. Neste trabalho caracterizamos os mecanismos celulares e moleculares operantes no estado de hipóxia em resposta à reação inflamatória aguda no pulmão induzida pela I/R ateria mesentérica em duas linhagens de camundongos geneticamente selecionadas para máxima (AIRmax) ou mínima (AIRmin) Resposta Inflamatória Aguda (AIR). Observamos uma alta reação inflamatória aguda em resposta a I/R. Altos níveis de expressão dos genes envolvidos em situações de hipóxia Hif-1<font face=\"Symbol\">&#945, Vhl e das citocinas Il-1<font face=\"Symbol\">&#946 e Il-6 mostraram-se relacionados com a alta AIR nos camundongos AIRmax. / Oxygen homeostasis is essential for survival and physiologic development of organisms. Lack of O2 in tissues is a common underlying factor in morbidity and mortality for numerous serious medical conditions such as the Acute Respiratory Distress Syndrome (ARDS). For homeostasis recovery the myeloid cells exert their functions in specialized areas of hypoxia. The adaptation of myeloid cells in low O2 tissue depends on the HIF-1<font face=\"Symbol\">&#945 gene products. Hif-1<font face=\"Symbol\">&#945 is a transcription factor that responds to O2 levels change. In this study we characterize, in two lines of mice selected for maximal (AIRmax) or minimal (AIRmin) Acute Inflammatory response (AIR), the cellular and molecular mechanisms operating in the hypoxia state during an acute inflammatory reaction in the lung parenchyma produced by mesenteric artery Ischemia. We observed an acute inflammatory reaction with high levels of Hif-1<font face=\"Symbol\">&#945 and Vhl genes expression involved in hypoxia conditions and IL-1<font face=\"Symbol\">&#946 and IL-6 genes showed related to high AIR in AIRmax mice.

Pulmonary TNFa concentration and wall thickness after on- versus off pump cardiac surgery