Germline genetic variants of the renin-angiotensin system, hypoxia and angiogenesis in non-small cell lung cancer progression: Discovery and validation studies

Introduction: The renin–angiotensin system (RAS) is involved in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. Our aim was to study the association of putatively functional genetic polymorphisms in genes coding for proteins involved in RAS, hypoxia and angiogenesis with non-small cell lung cancer (NSCLC) prognosis. Methods: Genotyping of 52 germline variants from genes of the RAS and hypoxic/angiogenic factors/receptors was performed using MassARRAY iPLEX Gold in a retrospective cohort (n = 167) of advanced NSCLC patients. Validation of the resulting genetic markers was conducted in an independent group (n = 190), matched by clinicopathological characteristics. Results: Multivariate analysis on the discovery set revealed that MME rs701109 C carriers were protected from disease progression in comparison with homozygous T (hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.2–0.8, p = 0.010). Homozygous A and T genotypes for KDR rs1870377 were at increased risk for disease progression and death compared to heterozygous (HR = 1.7, 95% CI = 1.2–2.5, p = 0.005 and HR = 2.1, 95% CI = 1.2–3.4, p = 0.006, respectively). Carriers of homozygous genotypes for ACE2 rs908004 presented increased risk for disease progression, only in the subgroup of patients without tumour actionable driver mutations (HR = 2.9, 95% CI = 1.3–6.3, p = 0.010). Importantly, the association of homozygous genotypes in MME rs701109 with risk for disease progression was confirmed after multivariate analysis in the validation set. Conclusion: This study provides evidence that MME polymorphism, which encodes neprilysin, may modulate progression-free survival in advanced NSCLC. Present genetic variation findings will foster basic, translational, and clinical research on their role in NSCLC.M.J.C. was supported by the Associação de Estudos Respiratórios and the Portuguese Pulmonology Society

Quantized Nambu-Poisson Manifolds in a 3-Lie Algebra Reduced Model

We consider dimensional reduction of the Bagger-Lambert-Gustavsson theory to a zero-dimensional 3-Lie algebra model and construct various stable solutions corresponding to quantized Nambu-Poisson manifolds. A recently proposed Higgs mechanism reduces this model to the IKKT matrix model. We find that in the strong coupling limit, our solutions correspond to ordinary noncommutative spaces arising as stable solutions in the IKKT model with D-brane backgrounds. In particular, this happens for S^3, R^3 and five-dimensional Neveu-Schwarz Hpp-waves. We expand our model around these backgrounds and find effective noncommutative field theories with complicated interactions involving higher-derivative terms. We also describe the relation of our reduced model to a cubic supermatrix model based on an osp(1|32) supersymmetry algebra.Comment: 22 page

INTERPRETANDO O LÍQUOR – COMO DADOS EPIDEMIOLÓGICOS PODEM AJUDAR NO RACIOCÍNIO CLÍNICO

Introdução: A meningite bacteriana sofreu grandes mudanças epidemiológicas após a introdução dos antibióticos e vacinas, passando de uma condição letal para tratável e prevenível. Compreender essas mudanças no perfil epidemiológico em nível local permitem planejar estratégias de terapia empírica. As alterações de líquor possuem papel fundamental nessa avaliação. Metodologia: Foi realizado um estudo transversal dos casos notificados de meningite entre janeiro de 2010 e junho de 2015 no Complexo Hospital de Clínicas – Universidade Federal do Paraná. Foram analisados a celularidade e citologia do líquor e os agentes etiológicos. Para as etiologias bacterianas, foi avaliado dados epidemiológicos. Resultados: Foram notificados 504 casos de meningite no período avaliado. A meningite asséptica foi a classificação epidemiológica mais comum. As meningites bacterianas com confirmação etiológica causadas por Neisseria meningitidis, Streptococcus pneumoniae ou Haemophilus influenzae ocorreram em 8,7% dos casos notificados, sendo que 30% delas ocorreram em menores de 1 ano. A N. meningitidis correspondeu a 61% desses casos, enquanto que S. pneumoniae a 34%. As meningites neutrofílicas com mais de 75% de neutrófilos são causadas por tais bactérias em mais da metade (53%). A meningite asséptica é a segunda principal etiologia (20%) seguida de perto pela meningite tuberculosa (17%). Os casos de meningite meningocócica se concentram em crianças até 1 ano (56% dos casos), a meningite pneumocócica se concentra nos adultos entre 18 e 50 anos (46%) e idosos (27%). Conclusões: O conhecimento da epidemiologia local através da interpretação do líquor, somada à avaliação da faixa etária são importantes aliados da avaliação clínica para determinação do agente etiológico mais provável e podem ajudar na decisão terapêutica

Investigação de um sistema de alimentação em recém-nascidos prematuros a partir de estimulação gustativa

Objetivo: investigar a existência do sistema de alimentação em recém-nascidos prematuros a partir da estimulação gustativa. Métodos: estudo experimental, analítico, duplo-cego. Participaram 90 recém-nascidos prematuros, de uma maternidade pública de Sergipe. O teste foi filmado, constituindo-se por três momentos de cinco minutos. O primeiro e último momento sem realizar estímulo, o segundo momento com estimulação gustativa, sendo que os recém-nascidos foram divididos em dois grupos (água ou sacarose). Foram estudados os comportamentos específicos sucção de mão direita e esquerda, protrusão de língua e movimentos de sucção nos estados comportamentais sono profundo, sono leve, sonolento, agitado/irritado e choro. Para caracterizar a população foram utilizadas média, desvio-padrão e prevalências. Foi utilizado o teste não paramétrico Mann-Whitney para comparação de médias. O teste de Spearman verificou correlação entre estados comportamentais e comportamentos específicos em cada momento do teste. O valor de p foi significante quando menor que 0,05. Resultados: independente do estímulo administrado, a correlação aumentou em todos os comportamentos específicos. Comparando os grupos separadamente, após a estimulação, observou-se aumento de correlação em sucção de mão direita e protrusão de língua para ambos os grupos. O mesmo aconteceu em sucção, com exceção do estado agitado/irritado. Após a estimulação, houve maior correlação para o comportamento de sucção de mão esquerda no grupo sacarose quando comparado ao grupo água. Os resultados evidenciam que estímulos gustativos podem contribuir na prontidão para alimentação nesta população. Conclusões: evidenciou-se nos recém-nascidos prematuros aumento de correlação para os comportamentos específicos relacionados ao sistema de alimentação, após estimulação oral, o que vislumbra a possibilidade da estimulação gustativa ser utilizada para ativação de um sistema de alimentação em recém-nascidos prematuros. _________________________________________________________________________________________ ABSTRACT: Purpose: to investigate the existence of the alimentation system in premature newborns in response to gustatory stimulation. Methods: experimental, analytical, double-blind study. 90 premature newborns of a public maternity in Sergipe took part in the test which was filmed and divided into three parts of five minutes. In the first and last, there was no stimulus; in the second, the gustatory stimulation was applied and the newborn children were divided into two groups (water or sucrose). We studied the specific behaviors suction right and left hands, tongue protrusion and suction movements in behavioral states deep sleep, light sleep, drowsy, restless / irritable and crying. In the statistical analysis of the population, average, standard deviation and prevalence studies were performed. We used the non-parametric Mann-Whitney test to compare averages. The Spearman test observed correlation between behavioral states at each time of the test. The p value was significant when less than 0.05. Results: independent of the given stimulus, the correlation increased in all specific behaviors. Comparing the groups separately, after stimulation, we observed an increase in correlation in right hand suction and tongue protrusion for both. The same happened in suction, except for the agitated/irritated state. After stimulation, there was a higher correlation to the behavior of left hand suction in the sucrose group when compared to water. The results show that gustatory stimuli may contribute to the readiness to feed this population. Conclusions: it was found in premature newborns an increased in correlation for the specific behaviors related to the alimentation system after oral stimulation, which envisions the possibility of gustatory stimulation be used for activating a alimentation system in premature newborns

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions