Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program.

BACKGROUND: Antibody-based therapies blocking the programmed cell death-1/ligand-1 (PD-1/PD-L1) axis have provided unprecedent clinical success in cancer treatment. Acquired resistance, however, frequently occurs, commonly associated with the upregulation of additional inhibitory molecules. Diacylglycerol kinase (DGK) α limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGKα targeting restores cytotoxic function of chimeric antigen receptor and CD8+ T cells isolated from solid tumors, suggesting a mechanism to reverse T cell exhausted phenotypes. Nevertheless, the contribution of DGKα downstream of the PD-1/PD-L1 inhibitory axis in human T cells and the consequences of combining DGKα and anti-PD-1/PD-L1 inhibitors are still unresolved relevant issues. MATERIALS AND METHODS: We used a human triple parameter reporter cell line to investigate DGKα contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGKα expression in the growth dynamics and systemic tumor-derived effects of a PD-1-related tumor model, the MC38 colon adenocarcinoma. RESULTS: We identify DGKα as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGKα function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGKα inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation. CONCLUSIONS: Our results indicate that DGKα inhibition could provide an important mechanism to revert exhausted T lymphocyte phenotypes and thus favor proper anti-tumor T cell responses. The cooperative effect observed after PD-1/PD-L1 and DGKα blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS.

Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.

Single nucleotide polymorphisms V4 and T1 of the ADAM33 gene in Venezuelan patients with asthma or chronic obstructive pulmonary disease.

ADAM33 is a metalloproteinase important in the extracellular matrix for tissue remodeling, and, consequently, in asthma and chronic obstructive pulmonary disease (COPD). Several polymorphisms of the ADAM33 gene have been associated with enzyme activity. One of the most studied polymorphisms is V4, cytosine for guanine in the 3 'UTR region, and T1, adenine for guanine in the exon 19 of the gen. The aim of this study was to ascertain the possible association among single polymorphisms of ADAM33, V4 and T1, in Venezuelan patients with asthma or COPD. The polymorphisms V4 and T1 were analyzed in 303 individuals (103 asth- matic, 100 COPD and 100 controls) by PCR-RFLP (polymerase chain reaction and restriction fragment length polymorphisms). There was a significant difference (P<0.05) in the frequency of ADAM33 V4 polymorphism in both, asthmatic and COPD patients groups, as compared to controls. No significant differences (P=0.4) were found for T1 polymorphism. However, there were significant differences (P

The classification of Spanish adolescents based on substance consumption patterns and the analysis of the relationships within their social developmental contexts

This research is part of the 2006 edition of the Health Behavior in School-aged Children (HBSC) study. The data presented were composed of a sample of 15942 Spanish adolescents ranging from 13 to 18 years of age. The instruments used included a variety of questions related to substance consumption among adolescents, their bio-psycho-social adjustment and developmental contexts, all of which are part of the HBSC study instrument bank. Through classification analysis, as well as significance and effect size tests, we obtained relevant information about the current epidemiology of substance consumption among Spanish adolescents. These results are representative of the Spanish adolescent population which allows the typical risk profile attributed to young people to be clarified. A gradual adjustment can be seen in terms of substance consumption levels in youth and that same level in their friends. Likewise, the analysis of the developmental context (family, friends and school) provides important information when it comes to preventing substance consumption, thus showing the advantages that coherence and connection have between the different environments where youth live, grow up and develop (AU)

Esta investigación forma parte de la edición 2006 del estudio Health Behavior in School-aged Children (HBSC). Los datos que se presentan constituyen una muestra de 15942 adolescentes españoles de 13 a 18 años. Los instrumentos utilizados han sido diversas preguntas relacionadas con el consumo de sustancias, el ajuste biopsicosocial de los adolescentes y sus contextos de desarrollo, que forman parte del banco de instrumentos del estudio HBSC. Realizando análisis de clasificación, pruebas de significación y tamaños de efecto, se obtiene información relevante acerca de la epidemiología actual del consumo de sustancias en los adolescentes españoles. Se trata de resultados representativos de la población española que permiten matizar con detalle el perfil de riesgo típicamente atribuido a los jóvenes. Se demuestra una graduación en la relación entre el nivel de consumo de sustancias de los jóvenes y el nivel de consumo de sus amistades. Así mismo, el análisis de los contextos de desarrollo (familia, amistades y escuela) aporta información relevante a la hora de prevenir el consumo de sustancias, demostrando las ventajas que supone la coherencia y conexión entre los diferentes ámbitos donde los jóvenes viven, crecen y se desarrollan (AU)

Letter: Recurrence of periumbilical Paget disease after fresh Mohs treated with slow Mohs with CK-7.

Extrammamary Paget disease (EMPD) is an uncommon neoplasm that often involves the skin of the genital or perianal regions. There are no clearly established guidelines for treatment, but surgical excision with wide margins (3-5 cm) or Mohs micrographic surgery (MMS) are the techniques of choice when there is no association with an underlying neoplasm. We present a case of EMPD in an unusual location (periumbilical skin). This was treated with fresh MMS, but reappeared, necessitating a second MMS (slow).

[Behavior of immatures Aedes aegypti in the coast State of São Paulo, Brazil]. / Comportamento de formas imaturas de Aedes aegypti, no litoral do Estado de São Paulo.

INTRODUCTION: In a region of high dengue incidence, on the coast of the State of São Paulo, 9 areas were selected to evaluate the behavior of immature Aedes aegypti. METHODS: The 9 areas were grouped into 4 strata according to soil use and occupation. Larvae and pupas were collected in a sample of approximately 500 buildings in each area. RESULTS: Although tires and canvas presented the highest positive rates for Aedes aegypti, drains and other containers fixed to the buildings were highly predominant among positive containers; 32 to 76% of the positive containers in the 4 study strata. Public areas of apartment buildings and large non-residential premises presented the highest positive rates for Aedes Aegypti, while apartments presented the lowest. Infestation levels were greater in residential areas with predominance of apartment buildings, where 76% of the breeding sites detected were containers fixed to the buildings. CONCLUSIONS: This knowledge is an important tool in the control strategy, since it reinforces the need for special attention regarding certain types of buildings and the adjustment of technical norms for pluvial water drains and improvement of building maintenance. Moreover, systematic observations are required to follow-up the occupancy dynamic of different buildings and containers by Aedes aegypti and the incorporation of this knowledge in the control of vectors in the region.

Comportamento de formas imaturas de Aedes aegypti, no litoral do Estado de São Paulo / Behavior of immatures Aedes aegypti in the coast State of São Paulo, Brazil

INTRODUÇÃO: Em região de alta incidência de dengue, no litoral do Estado de São Paulo, selecionaram-se 9 áreas, com objetivo de avaliar o comportamento de formas imaturas de Aedes aegypti. MÉTODOS: As 9 áreas foram agrupadas em 4 estratos, diferenciados pelo uso e ocupação do solo. Foram coletadas larvas e pupas numa amostra de cerca de 500 imóveis em cada área. RESULTADOS: Apesar do pneu e lona apresentarem as maiores taxas de positividade para Aedes aegypti, o ralo, juntamente com outros recipientes fixos nas edificações foram altamente predominantes entre os recipientes positivos (32 a 76 por cento dos recipientes positivos). As áreas coletivas de prédios e os imóveis não residenciais de grande porte apresentaram as maiores taxas de positividade para Aedes aegypti enquanto os apartamentos, as menores. Os níveis de infestação foram maiores na área residencial com predominância de prédios de apartamentos, onde 76 por cento dos criadouros detectados foram recipientes fixos nas edificações. CONCLUSÕES: Esses conhecimentos são importantes subsídios para a estratégia de controle, pois reforçam a necessidade de atenção especial para determinados tipos de imóveis, bem como da adequação da norma técnica de ralo de água pluvial e da melhoria de manutenção das edificações. Além disso, são necessárias observações sistemáticas que permitam acompanhar a dinâmica de ocupação de diferentes imóveis e recipientes por Aedes aegypti e a incorporação desses conhecimentos nas ações de controle do vetor na região.

INTRODUCTION: In a region of high dengue incidence, on the coast of the State of São Paulo, 9 areas were selected to evaluate the behavior of immature Aedes aegypti. METHODS: The 9 areas were grouped into 4 strata according to soil use and occupation. Larvae and pupas were collected in a sample of approximately 500 buildings in each area. RESULTS: Although tires and canvas presented the highest positive rates for Aedes aegypti, drains and other containers fixed to the buildings were highly predominant among positive containers; 32 to 76 percent of the positive containers in the 4 study strata. Public areas of apartment buildings and large non-residential premises presented the highest positive rates for Aedes Aegypti, while apartments presented the lowest. Infestation levels were greater in residential areas with predominance of apartment buildings, where 76 percent of the breeding sites detected were containers fixed to the buildings. CONCLUSIONS: This knowledge is an important tool in the control strategy, since it reinforces the need for special attention regarding certain types of buildings and the adjustment of technical norms for pluvial water drains and improvement of building maintenance. Moreover, systematic observations are required to follow-up the occupancy dynamic of different buildings and containers by Aedes aegypti and the incorporation of this knowledge in the control of vectors in the region.

Sarcoma de Kaposi gástrico asociado a infección por el virus de la inmunodeficiencia humana (variante epidémica) / Kaposis sarcoma of the stomach with concurrent HIV fection(epidemic form)

No disponible

No disponible

Manual de vigilância e controle da leishmaniose visceral americana do Estado de São Paulo / Leishmaniasis, cutaneous and visceral surveillance and control manual from São Paulo State

Este manual referente às atividades de vigilância e controle da leishmaniose visceral americana, incorporou todo conhecimento obtido com as revisões das atividades desenvolvidas deste 1999. Conforme já apresentamos anteriormente no II Informe Técnico: Leishmaniose Visceral Americana, entre outras alterações, modificou-se a classificação dos municípios, revisou-se o esquema de tratamento para casos humanos, o fluxo de notificação de casos humanos e caninos e a vigilância e o controle das populações canina e vetorial. Com este manual esperamos contribuir para uma melhor orientação dos técnicos da Secretaria Estadual da Saúde e dos municípios, para o desenvolvimento das atividades de vigilância e controle de doença.

Manual de vigilância e controle da leishmaniose visceral americana do Estado de São Paulo

Este manual referente às atividades de vigilância e controle da leishmaniose visceral americana, incorporou todo conhecimento obtido com as revisões das atividades desenvolvidas deste 1999. Conforme já apresentamos anteriormente no II Informe Técnico: Leishmaniose Visceral Americana, entre outras alterações, modificou-se a classificação dos municípios, revisou-se o esquema de tratamento para casos humanos, o fluxo de notificação de casos humanos e caninos e a vigilância e o controle das populações canina e vetorial. Com este manual esperamos contribuir para uma melhor orientação dos técnicos da Secretaria Estadual da Saúde e dos municípios, para o desenvolvimento das atividades de vigilância e controle de doença.

Vigilância entomológica e controle de vetores do dengue / Entomological surveillance and control of dengue fever vectors

Discorre sobre a ecologia do Aedes aegypti, apontando questöes relevantes para a transmissäo do dengue e para o seu controle. Indica temas a serem investigados na atual conjuntura epidemiológica da doença no Brasil, procurando apontar algumas lacunas da compreensäo da ecologia dos mosquitos, que poderiam contribuir para o aprimoramento e recisäo dos programas de controle desses vetores no país. Foi abordada a influência das condiçöes climáticas (temperatura, pluviosidade, altitude) no ciclo vital dos vetores, além da adaptaçäo das espécies a diferentes contextos ecológicos e sociais, de relevância para a vigilância entomológica. Também foram revistas as principais investigaçöes sobre a domiciliaçäo, dispersäo, repasto e reproduçäo dos vetores do dengue, além da competência e capacidade vetorial, chaves na compreensäo da disseminaçäo da doença e na organizaçäo das medidas de controle. Foi também abordada a resistência do Aedes aegypti, cujo tema tem sido pesquisado em várias partes do mundo. Ressaltou-se a importância do monitoramento sistemático do tratamento químico durante as açöes de campo. Foram apresentadas de forma resumida, as alternativas mais comumente utilizadas no controle físico, químico e biológico pelos programas de controle de Aedes aegypti no país