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.

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

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).

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.

[Climate and the superimposed distribution of Aedes aegypti and Aedes albopictus on infestation of São Paulo State, Brazil]. / Clima e sobreposição da distribuição de Aedes aegypti e Aedes albopictus na infestação do Estado de São Paulo.

OBJECTIVE: To study the influence of climatic factors and superimposed distribution of Aedes aegypti and Aedes albopictus populations on their geographic dispersal in the state of São Paulo. METHODS: Data from government agencies on Ae. aegypti and Ae. albopictus foci and their distribution throughout counties of the state of São Paulo year by year, from 1985 to 1995, were obtained. Temperatures and rainfall data were also collected. Two indicators were used: infestation and rate. RESULTS AND CONCLUSIONS: The analysis indicated that the lower the temperature, the slower the geographic dispersal of Ae. aegypti population. This factor predominantly influenced the macro regional dispersal patterns of the species in the state of São Paulo. There was no clear influence of temperature on the dispersal of Ae. albopictus. The influence of rainfall on dispersal patterns was seen only for Ae. aegypti in a state area. No influence was detected on the prior presence of Ae. albopictus on the establishment of Ae. aegypti.

[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.

IgM-immunofluorescence test as a diagnostic tool for epidemiologic studies of Schistosomiasis in low endemic areas.

The high sensitivity and the ability to diagnose schistosomiasis in a very early phase after infection have indicated the detection of IgM antibodies to Schistosoma mansoni gut antigens by the immunofluorescence test (IgM-IFT) as a useful serological test for epidemiological studies in low endemic areas. When applied in a follow-up study for two years, higher rates of seroconversion from IFT negative to positive were observed during the summer months, suggesting seasonal transmission of schistosomiasis in the rural area of the municipality of Itariri (São Paulo, Brazil). In each survey, blood samples from about 600 schoolchildren were collected on filter paper and submitted to IgM-IFT. When the blood samples were classified for the IgM antibody levels, according to the intensity of fluorescent reaction observed at fluorescence microscopy, and correlated to the egg counts in the Kato-Katz positive patients, no association was observed. This observation might suggest that the intensity of fluorescence observed in the IgM-IFT, as an indicator of IgM antibody levels, could not be an useful seroepidemiological marker for classifying areas of low endemicity according to degrees of infection.

Control / Schistosomiasis control in the State of São Paulo

The program of schistosomiasis control for the State of São Paulo, where only low endemicity areas occur, is discussed in this paper. Inclusion of schistosomiasis among the diseases due to obligatory notification is considered as a measure of great importance. Accordingly the search for passive cases conducted by the public health system acquired major importance in the disease surveillance. As from 1981 to 1992 only 11 of the detected cases were considered as autochthonous. The main transmission areas are located at the Litoral and Paraiba Valley regions. In the period of time under analysis, the epidemiological surveillance data suggest a decrease in the morbidity and in the autochthony tendency in the State of São Paulo.

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

Infestaçäo do Estado de Säo Paulo por Aedes aegypti e Aedes albopictus / Infestation of S. Paulo State by Aedes aegypti e Aedes albopictus

Objetivo: Estudar a influência da distância entre áreas infestadas e näo infestadas na expansäo geográfica das populaçöes de Aedes aegypti e de Aedes albopictus no Estado de Säo Paulo e os padröes regionais observados, considerando os determinantes relacionados com a ocupaçäo do solo. Métodos: Foram utilizadas informaçöes sobre ocorrência de focos de Ae. aegypti e de Ae. albopictus em municípios do Estado de Säo Paulo, a cada ano, e sobre a infestaçäo em municípios deste e de Estados vizinhos, ao final de cada ano (1985 a 1995). Foram definidos quatro indicadores para a análise do processo de infestaçäo. Resultados/Conclusöes: A análise realizada indicou influência dos Estados do Mato Grosso do Sul e do Paraná no início da infestaçäo do Estado de Säo Paulo por Ae. aegypti e do Rio de Janeiro e de Minas Gerais naquela por Ae. albopictus. Dentre os municípios com ocorrência de focos dessas espécies, o estabelecimento das mesmas foi mais freqüente naqueles mais próximos de áreas infestadas. Dos municípios em que se verificou o estabelecimento de Ae. aegypti ou Ae. albopictus, 75 por cento distavam até 34 e 60 Km, respectivamente, do município infestado mais próximo. Pela análise da velocidade de expansäo geográfica de Ae. aegypti, identificaram-se três grandes áreas, com padröes diferentes, observando-se o contrário do esperado: a área com maior densidade demográfica (leste do Estado) foi aquela em que se observou a menor rapidez de expansäo geográfica da espécie, indicando a existência de outros fatores com influência preponderante nos padröes macro regionais. Para Ae. albopictus näo ficou evidenciada qualquer relaçäo entre seu padräo de expansäo geográfica e a densidade demográfica das regiöes

Clima e sobreposiçäo da distribuiçäo de Aedes aegypti e Aedes albopictus na infestaçäo do Estado de Säo Paulo / Climate and the superimposed distribution of Aedes aegypti and Aedes albopictus on infestation of Säo Paulo State, Brazil

OBJETIVO: Estudar a influência de fatores climáticos e da sobreposiçäo da distribuiçäo das populaçöes de Aedes aegypti e de Aedes albopictus na expansäo geográfica dessas espécies no Estado de Säo Paulo. MÉTODOS: Foram obtidas informaçöes de órgäos do governo sobre ocorrência de focos de Ae. aegypti e de Ae. albopictus e sobre o estabelecimento dessas espécies em municípios do Estado de Säo Paulo ano a ano, entre 1985 e 1995, além de informaçöes referentes a temperatura e índices pluviométricos. Dois indicadores foram utilizados: infestaçäo e velocidade. RESULTADOS E CONCLUSOES: Verificou-se que quanto menor a temperatura, mais lento foi o processo de expansäo geográfica da populaçäo de Ae. aegypti. Esse fator teve influência preponderante na determinaçäo dos diversos padröes macrorregionais de expansäo geográfica dessa espécie no Estado de Säo Paulo. Näo foram encontradas indicaçöes claras sobre a influência da temperatura na dispersäo de Ae. albopictus. A influência dos índices pluviométricos nos padröes de expansäo geográfica dessas espécies somente foi constatada para Ae. aegypti numa das áreas do Estado. Näo se verificou influência da presença anterior de Ae. albopictus para o estabelecimento de Ae. aegypti