Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Estudo de confiabilidade da aplicação da escala de Fugl-Meyer no Brasil / Reliability study on the application of the Fugl-Meyer scale in Brazil

OBJETIVOS: Os objetivos do estudo foram realizar uma versão brasileira da escala original de Fugl-Meyer e verificar a confiabilidade da aplicação inter e intra-observador desta versão em pacientes crônicos pós AVC. MÉTODO: Participaram do estudo 50 pacientes portadores de hemiparesia, os quais foram submetidos a duas avaliações (confiabilidade intra-observador), realizadas por três fisioterapeutas (confiabilidade interobservador), procedentes de três centros de reabilitação. RESULTADOS: Os resultados demonstraram alta confiabilidade inter e intra-observador da EFM total (IC = 0,99 e 0,98; respectivamente), assim como para todas as subescalas (interobservador IC = 0,99 a 0,94; intra-observador IC = 0,98 a 0,87). CONCLUSÃO: Conclui-se neste artigo que não foi verificado conflitos de interpretação na versão brasileira da escala de Fugl-Meyer. Obtivemos alto índice de confiabilidade, tanto intra como interobservador, permitindo assim seu uso como instrumento de avaliação clínica e de pesquisa no Brasil.

Bioinformatics of the Paracoccidioides brasiliensis EST Project

Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, an endemic mycosis of Latin America. This fungus presents a dimorphic character; it grows as a mycelium at room temperature, but it is isolated as yeast from infected individuals. It is believed that the transition from mycelium to yeast is important for the infective process. The Functional and Differential Genome of Paracoccidioides brasiliensis Project--PbGenome Project was developed to study the infection process by analyzing expressed sequence tags--ESTs, isolated from both mycelial and yeast forms. The PbGenome Project was executed by a consortium that included 70 researchers (professors and students) from two sequencing laboratories of the midwest region of Brazil; this project produced 25,741 ESTs, 19,718 of which with sufficient quality to be analyzed. We describe the computational procedures used to receive process, analyze these ESTs, and help with their functional annotations; we also detail the services that were used for sequence data exploration. Various programs were compared for filtering and grouping the sequences, and they were adapted to a user-friendly interface. This system made the analysis of the differential transcriptome of P. brasiliensis possible.

Defining 3D residue environment in protein structures using SCORPION and FORMIGA.

SUMMARY: Two web-based applications to analyze amino acids three-dimensional (3D) local environment within protein structures-SCORPION and FORMIGA-are presented. SCORPION and FORMIGA produce a graphical presentation for simple statistical data showing the frequency of residue occurrence within a given sphere (defined here as the 3D contacts). The center of that sphere is placed at the Calpha and at the last heavy atom in the side chain of the selected amino acid. Further depth of detail is given in terms of a secondary structure to which the profiled amino acid belongs. Results obtained with those two applications are relevant for estimating the importance of the amino acid 3D local environment for protein folding and stability. Effectively, SCORPION and FORMIGA construct knowledge-based force fields. The difference between SCORPION and FORMIGA is in that the latter operates on protein interfaces, while the former only functions for a single protein chain. Both applications are implemented as stand-alone components of STING Millennium Suite. AVAILABILITY: http://sms.cbi.cnptia.embrapa.br/SMS, http://trantor.bioc.columbia.edu/SMS, http://mirrors.rcsb.org/SMS, http://www.es.embnet.org/SMS and http://www.ar.embnet.org/SMS. [options: Scorpion, Formiga]

Transcriptome characterization of the dimorphic and pathogenic fungus Paracoccidioides brasiliensis by EST analysis.

Paracoccidioides brasiliensis is a pathogenic fungus that undergoes a temperature-dependent cell morphology change from mycelium (22 degrees C) to yeast (36 degrees C). It is assumed that this morphological transition correlates with the infection of the human host. Our goal was to identify genes expressed in the mycelium (M) and yeast (Y) forms by EST sequencing in order to generate a partial map of the fungus transcriptome. Individual EST sequences were clustered by the CAP3 program and annotated using Blastx similarity analysis and InterPro Scan. Three different databases, GenBank nr, COG (clusters of orthologous groups) and GO (gene ontology) were used for annotation. A total of 3,938 (Y = 1,654 and M = 2,274) ESTs were sequenced and clustered into 597 contigs and 1,563 singlets, making up a total of 2,160 genes, which possibly represent one-quarter of the complete gene repertoire in P. brasiliensis. From this total, 1,040 were successfully annotated and 894 could be classified in 18 functional COG categories as follows: cellular metabolism (44%); information storage and processing (25%); cellular processes-cell division, posttranslational modifications, among others (19%); and genes of unknown functions (12%). Computer analysis enabled us to identify some genes potentially involved in the dimorphic transition and drug resistance. Furthermore, computer subtraction analysis revealed several genes possibly expressed in stage-specific forms of P. brasiliensis. Further analysis of these genes may provide new insights into the pathology and differentiation of P. brasiliensis.

Helicobacter pylori seropositivity among 963 Japanese Brazilians according to sex, age, generation, and lifestyle factors.

Seropositivity of anti-Helicobacter pylori antibody (HP + ) was examined among Japanese Brazilians. The study was announced through 18 Japanese community culture associations in São Paulo, Curitiba, Mogi das Cruzes, and Mirandopolis in 2001. Among 969 participants, 963 individuals aged 33 - 69 years were analyzed. The overall HP + % was 48.1% (95% confidence interval, 44.9 - 51.3%). There was no difference in HP + % between 399 males and 564 females (49.6% and 47.0%, respectively). The HP + % increased with age; 35.3% for those aged 33 - 39 years, 46.2% for those aged 40 - 49 years, 46.5% for those aged 50 - 59 years, and 56.9% for those aged 60 - 69 years, but no differences were observed among the generations (Issei, Nisei, and Sansei) for each 10-year age group. Mogi das Cruzes, a rural area, showed a higher HP + %. Length of education was inversely associated with the positivity; the odds ratio (OR) relative to those with eight years or less of schooling was 0.61 (0.42 - 0.89) for those with 12 years or more. The associations with smoking and alcohol drinking were not significant. Fruit intake was associated with the HP + %; the OR relative to everyday intake was 1.38 (1.05 - 1.83) for less frequent intake, while intake frequencies of green tea, miso soup, and pickled vegetables (tsukemono) were not. Multivariate analysis including sex, 10-year age group, residence, education, and fruit intake showed that all factors except sex were significant. This is the largest study of HP infection among Japanese Brazilians, and the results indicated a similar pattern of age-specific infection rate to that for Japanese in Japan.

EFEITO DA TEMPERATURA NO PARASITISMO DE Trichogramma pretiosum Riley, 1879 SOBRE OVOS DE Sitotroga cerealella (Olivier, 1819)

The effect of temperature was evaluated on egg parasitization of the angoumois grain moth, Sitotroga cerealella (Olivier, 1819), by Trichogramma pretiosum Riley, 1879 as a basis for mass production of T. pretiosum or biological control of S. cerealella in stored corn T. pretiosum parasitization was studied under six constant temperatures (18, 20, 22, 25, 30, and 32°C) and was evaluated through the counting number of darkened eggs (parasitization characteristic) and the number of emerged parasitoids. The highest temperatures were the best for T. pretiosum parasitization. At 30°C, 97.6% of the females were effective on parasitization with an average of 18.8 S. cerealella eggs per female during the first 48 h period and a high parasitoid emergence (88.5%).

Avaliou-se o efeito da temperatura no parasitismo de Trichogramma pretiosum Riley, 1879 sobre ovos de Sitotroga cerealella (Olivier, 1819), para sua utilização em criações massais e/ou para o controle biológico desta traça de grãos armazenados. Os parasitóides foram mantidos sob as temperaturas de 18, 20, 22, 25, 30 e 32°C, durante 48 horas, com umidade relativa de 60±10% e fotofase de 14 horas, em todas as condições. O parasitismo foi avaliado pela contagem do número de ovos pretos (característica do parasitismo) e pelo número de parasitóides emergidos. As altas temperaturas foram favoráveis ao desempenho de T. pretiosum que, a 30°C teve 97,6% das fêmeas parasitando, com uma média de 18,8 ovos parasitados em 48 horas e com uma viabilidade de 88,5%.

EFEITO DA TEMPERATURA NO PARASITISMO DE Trichogramma pretiosum Riley, 1879 SOBRE OVOS DE Sitotroga cerealella (Olivier, 1819)

The effect of temperature was evaluated on egg parasitization of the angoumois grain moth, Sitotroga cerealella (Olivier, 1819), by Trichogramma pretiosum Riley, 1879 as a basis for mass production of T. pretiosum or biological control of S. cerealella in stored corn T. pretiosum parasitization was studied under six constant temperatures (18, 20, 22, 25, 30, and 32°C) and was evaluated through the counting number of darkened eggs (parasitization characteristic) and the number of emerged parasitoids. The highest temperatures were the best for T. pretiosum parasitization. At 30°C, 97.6% of the females were effective on parasitization with an average of 18.8 S. cerealella eggs per female during the first 48 h period and a high parasitoid emergence (88.5%).

Avaliou-se o efeito da temperatura no parasitismo de Trichogramma pretiosum Riley, 1879 sobre ovos de Sitotroga cerealella (Olivier, 1819), para sua utilização em criações massais e/ou para o controle biológico desta traça de grãos armazenados. Os parasitóides foram mantidos sob as temperaturas de 18, 20, 22, 25, 30 e 32°C, durante 48 horas, com umidade relativa de 60±10% e fotofase de 14 horas, em todas as condições. O parasitismo foi avaliado pela contagem do número de ovos pretos (característica do parasitismo) e pelo número de parasitóides emergidos. As altas temperaturas foram favoráveis ao desempenho de T. pretiosum que, a 30°C teve 97,6% das fêmeas parasitando, com uma média de 18,8 ovos parasitados em 48 horas e com uma viabilidade de 88,5%.

Mechanisms associated with the generation of biologically active human immunodeficiency virus type 1 particles from defective proviruses.

The human immunodeficiency virus (HIV) is the etiological agent of acquired immunodeficiency syndrome (AIDS). HIV exhibits extensive genetic diversity and it is apparent that an infected individual contains different populations of distinct viral strains, a large proportion of which has been found surprisingly to be defective for replication. A similar phenomenon has also been observed with some cell lines that are known to produce infectious viral particles but harbor defective proviral genomes. Here, we investigated the molecular basis of this phenomenon by cloning proviral genomes of HIV from a cell line that was capable of producing high titers of biologically active HIV particles that readily induced syncytia with CD4+ cell lines and peripheral blood lymphocytes. This cell line was found to contain five proviral genomes, all of which, when tested individually, failed to produce replication-competent viruses upon transfection into human cells. However, when a specific combination of two proviral genomes was used in such transfection studies, it was possible to obtain biologically active, replication-competent viral particles that infected and replicated in CD4+ cell lines and induced syncytia characteristic of HIV. Such a result may be due to homologous recombination between proviral DNAs occurring in cells after transfection and/or complementation of replication-defective proviral DNAs. The diploid nature of the viral RNA genome present in the viral particle may enable the persistence of defective HIV genomes.