Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance

Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patient

Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML:a randomized, placebo-controlled study by the ALLG.

Sorafenib maintenance improves outcome after hematopoietic cell transplant (HCT) for patients with FLT3-ITD acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients 18-65 years (2:1) to sorafenib vs placebo (days 4-10) combined with intensive induction; idarubicin 12mg/m2 days 1-3 plus cytarabine 1.5g/m2 twice daily on days 1,3,5,7 (18-55 years) or 100mg/m2 days 1-7 (56-65 years), consolidation therapy, followed by maintenance treatment for 12 months (post-HCT excluded) in newly diagnosed FLT3-ITD AML. Four patients were excluded from modified intention-to-treat final analysis (3 not dosed and 1 later found to be FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery (CR/CRi) were high in both arms (sorafenib 78%/9%, placebo 70%/24%). With 49.1 months median follow-up, the primary endpoint of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%)(hazard ratio [HR] 0.87;95% confidence interval [CI] 0.51-1.51, p=0.61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR 0.76; 95% CI 0.42-1.39). For patients transplanted in first remission, 2-year OS was 84% and 67% in the sorafenib and placebo arms, respectively (HR 0.45;95% CI 0.18-1.12, p=0.08). In exploratory analyses, FLT3-ITD measurable residual disease negative status (<0.001%) post-induction was associated with improved 2-year OS (83% vs 60%) (HR 0.4;95% CI 0.17-0.93, p=0.028). In conclusion, routine use of pre-transplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study

Responses of grape berry anthocyanin and tritratable acidity to the projected climate change across the Western Australian wine regions

More than a century of observations has established that climate influences grape berry composition. Accordingly, the projected global climate change is expected to impact on grape berry composition although the magnitude and direction of impact at regional and subregional scales are not fully known. The aim of this study was to assess potential impacts of climate change on levels of berry anthocyanin and titratable acidity (TA) of the major grapevine varieties grown across all of the Western Australian (WA) wine regions. Grape berry anthocyanin and TA responses across all WA wine regions were projected for 2030, 2050 and 2070 by utilising empirical models that link these berry attributes and climate data downscaled (to ∼5 km resolution) from the csiro_mk3_5 and miroc3_2_medres global climate model outputs under IPCC SRES A2 emissions scenario. Due to the dependence of berry composition on maturity, climate impacts on anthocyanin and TA levels were assessed at a common maturity of 22 °Brix total soluble solids (TSS), which necessitated the determination of when this maturity will be reached for each variety, region and warming scenario, and future period.The results indicate that both anthocyanin and TA levels will be affected negatively by a warming climate, but the magnitude of the impacts will differ between varieties and wine regions. Compared to 1990 levels, median anthocyanins concentrations are projected to decrease, depending on global climate model, by up to 3–12 % and 9–33 % for the northern wine regions by 2030 and 2070, respectively while 2–18 % reductions are projected in the southern wine regions for the same time periods. Patterns of reductions in the median Shiraz berry anthocyanin concentrations are similar to that of Cabernet Sauvignon; however, the magnitude is lower (up to 9–18 % in southern and northern wine regions respectively by 2070). Similarly, uneven declines in TA levels are projected across the study regions. The largest reductions in median TA are likely to occur in the present day warmer wine regions, up to 40 % for Chardonnay followed by 15 % and 12 % for Shiraz and Cabernet Sauvignon, respectively, by 2070 under the high warming projection (csiro_mk3_5). It is concluded that, under existing management practices, some of the key grape attributes that are integral to premium wine production will be affected negatively by a warming climate, but the magnitudes of the impacts vary across the established wine regions, varieties, the magnitude of warming and future periods considered

Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death

Survival within macrophages is a central feature of Mycobacterium tuberculosis pathogenesis. Despite significant advances in identifying new immunological parameters associated with mycobacterial disease, some basic questions on the intracellular fate of the causative agent of human tuberculosis in antigen-presenting cells are still under debate. To get novel insights into this matter, we used a single-cell fluorescence resonance energy transfer (FRET)-based method to investigate the potential cytosolic access of M. tuberculosis and the resulting cellular consequences in an unbiased, quantitative way. Analysis of thousands of THP-1 macrophages infected with selected wild-type or mutant strains of the M. tuberculosis complex unambiguously showed that M. tuberculosis induced a change in the FRET signal after 3 to 4 days of infection, indicating phagolysosomal rupture and cytosolic access. These effects were not seen for the strains M. tuberculosisΔRD1 or BCG, both lacking the ESX-1 secreted protein ESAT-6, which reportedly shows membrane-lysing properties. Complementation of these strains with the ESX-1 secretion system of M. tuberculosis restored the ability to cause phagolysosomal rupture. In addition, control experiments with the fish pathogen Mycobacterium marinum showed phagolysosomal translocation only for ESX-1 intact strains, further validating our experimental approach. Most importantly, for M. tuberculosis as well as for M. marinum we observed that phagolysosomal rupture was followed by necrotic cell death of the infected macrophages, whereas ESX-1 deletion- or truncation-mutants that remained enclosed within phagolysosomal compartments did not induce such cytotoxicity. Hence, we provide a novel mechanism how ESX-1 competent, virulent M. tuberculosis and M. marinum strains induce host cell death and thereby escape innate host defenses and favor their spread to new cells. In this respect, our results also open new research directions in relation with the extracellular localization of M. tuberculosis inside necrotic lesions that can now be tackled from a completely new perspective

Parâmetros fitotécnicos e condições microclimáticas para videira vinífera conduzida sob dupla poda sequencial

A qualidade do vinho depende da qualidade da uva produzida. As condições microclimáticas incidentes no período de crescimento e desenvolvimento da videira, especialmente na fase do estabelecimento do fruto até a colheita, afetam a qualidade do fruto. A dinâmica da água no solo tem papel importante sobre a qualidade do mosto produzido à vinificação. Em São Paulo, nas bacias de maior concentração atual da vitivinicultura ocorre um período chuvoso que se estende de novembro a fevereiro, que alcança grande parte das variedades da região em fase de crescimento e maturação da baga, o que afeta negativamente a qualidade da uva e do vinho, na maioria das safras. Por outro lado, nas mesmas regiões ocorre um período mais favorável, que é o outono/inverno com potencial de soma térmica promissor para o crescimento da videira e com incidência de um longo período de baixa pluviometria, que vai de abril a outubro. Um experimento foi conduzido, objetivando estudar o cultivo da videira nas duas estações microclimáticas descritas. Avaliou-se a composição físico-química do fruto e a condições microclimáticas para maturação da baga da videira, de 2008 a 2010. Os resultados mostraram que as variedades de videira estudas desenvolveram maior potencial de qualidade da baga, quando cultivada no período de outono-inverno, sendo o efeito mais marcante sobre Vitis vinifera.The wine quality depends on the quality grapes produced. Actual micrometeorological conditions occurring in the time frame of grapevine growth and development will impact berry quality, especially from berry set to the harvest. Soil-water dynamics plays an important role on the quality grape must achieved at the vinification. In the São Paulo State (Brasil) in the regions of greatest clustering of vintners, there is a marked rainy time-frame from November to February, which matches with the vine time-cycle when the majority of grape varieties are in the berry set to berry maturation bracket, which negatively affects the grape and wine quality in most of the harvests. In contrast, for the same region there is more favorable condition in the autumn/winter time, which has a promise heat summation for proper grape growing, characterized by a long time-frame of low pluviometric rate (April to October). An experiment was conducted aiming at study the cultivation o grapevines in both described ''climatic windows''�. Physico-chemical composition of and microclimatic conditions for berry maturation during 2008 to 2010 were analysed. Results showed that the studied grape varieties developed better berry quality potential when cultivated in the autumn/winter time and this effect was more pronounced for Vitis vinifera

Composição quali-quantitativa da produção de 'Syrah' cultivada sob estresse hídrico transiente

A produção de vinho de qualidade requer o cultivo de uvas de padrão superior, com características químicas e físicas favoráveis, resultantes das condições micrometeorológicas locais, da variedade e do manejo do solo e da cultura. A composição quantitativa e qualitativa do rendimento da videira pode ser responsiva à variação na lâmina de irrigação e ao sistema de poda utilizado. Doravante, a interação entre os dois fatores citados e o meio físico circundante foi mostrada ser influente na qualidade do vinho. Um experimento foi conduzido com uva vinífera nas estações de crescimento de 2003 a 2005; cujo objetivo foi determinar a melhor combinação entre sistemas de poda (manual e mecânica) e manejo da água, para a produção de vinho de 'Syrah' (Vitis vinifera L.) cultivada em condições de microclima quente e seco. Os resultados mostraram que a composição do rendimento foi consistentemente afetada pelo sistema de poda, enquanto o melhor perfil aromático foi observado para 'Syrah', cultivada sob poda mecânica e estresse hídrico baixo a moderado.The production of a quality wine depends on the cultivation of high quality grapes with favorable chemical and physical characteristics, which result from the submitted micrometeorological regime, variety and soil-plant management. Grape yield and quality performance can be responsive to varying levels of water depth and the pruning system. The interaction between these two factors and the surrounding environment has been proved to be influential upon the wine quality. An experiment was carried out with wine grapes through the growing seasons of 2003 to 2005. The objective was to determine the best combination of pruning (manual and mechanized) and irrigation practices on 'Syrah' (Vitis vinifera L.) envisaging wine quality achievement, under a hot and dry microclimate. Results showed that the grape composition was consistently affected by the pruning system whereas the best aroma profile was observed in mechanically pruned plots cultivated under low to moderate water stress