Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity

Pré-melhoramento do sabiá (Mimosa caesalpiniifolia Benth): indução precoce do florescimento.

Resumo: A presença de acúleos em sabiá é uma característica dominante na espécie, que dificulta sua exploração. Torna-se necessário aplicar técnicas de melhoramento genético, para selecionar plantas que não apresentem essa característica indesejável. Para acelerar o melhoramento, a utilização de biorreguladores pode ser uma alternativa, como o paclobutrazol (PBZ), cujo objetivo é induzir o florescimento, o que diminuirá o tempo para seleção dos genótipos desejados. Foram testadas quatro doses: 0,5 mL, 1,0 mL, 1,5 mL e 2,0 mL de PBZ, diluídos em 1000 mL de água, aplicado mensalmente durante cinco meses a partir do quarto mês após o plantio. Quatro plantas floresceram precocemente aos onze meses, esses resultados foram obtidos nas épocas de aplicação aos 5 e 6 meses de idade com doses de 1 mL e 2 mL de PBZ. Existem evidências que o PBZ contribuiu para o florescimento precoce, uma vez que as testemunhas não apresentaram resultado similar. A ausência de acúleos no Sabiá é um caráter recessivo, pois muitas plantas após a germinação exibiram a presença de acúleos, mesmo sendo coletadas de uma população sem acúleo. E a indução do florescimento aos onze meses de idade, está relacionada com a utilização do PBZ. [Pre-breeding the sabiá (Mimosa caesalpiniifolia Benth) - Early induction of flowering]. Abstract: The presence of thorns dominant character in sabiá, makes it difficult their exploitation which makes it necessary to apply genetic improvement techniques, to select plants that do not show this trait. To expedite the improvement, the use of biorreguladores may be an alternative, as the paclobutrazol (PBZ), to induce flowering, aiming to reduce the time for selection. Were tested four doses of PBZ that was applied for five months from the fourth month after sowing. Four plants early flowering at eleven months, these results were obtained in seasons 5 and 6 with doses of 1 mL and 2 mL of PBZ. There is evidence that the PBZ contributed to the early flowering, since the check did not show similar results. We conclude that the absence of thorns on Sabia is a recessive character, because many plants after germination exhibited the presence of thorns, even collected from a population without thorns. The induction of flowering at eleven months of age is related to the use of PBZ

Comportamento de híbridos e variedades de milho em região semiárida no ano agrícola 2013.

Resumo: A produção de milho no Brasil é bastante difundida, uma vez que o País apresenta áreas consideradas propensas para a implantação de tal cultura. No entanto, em algumas regiões como o Semiárido brasileiro as condições ambientais são variáveis e o que prevalece são as variedades de polinização aberta na produção do pequeno e médio produtor. Pretendendo compensar o déficit de conhecimento técnico sobre os tipos de milho mais adaptados às características climáticas da nossa região o presente trabalho tem como objetivo a realização de um estudo comparativo do comportamento e potencial produtivo do milho no Semiárido brasileiro, relevando justamente a análise do desempenho dos grãos de híbridos e variedades de polinização aberta. Na presente pesquisa, foram avaliados 72 genótipos, sendo 30 variedades de polinização aberta e 33 híbridos elites, ambos oriundos de programas de melhoramento genético. O delineamento utilizado foi o de blocos ao acaso com duas repetições, sendo cada parcela constituída de duas linhas de quatro metros com espaçamento de 0,75 m entre linha e 0,20 m entre plantas. Pretendeu-se aqui identificar a variação de produtividade presente nos híbridos e variedades em relação aos tratamentos bem como a viabilidade do uso destes na região do experimento, conforme apresentado no decorrer do trabalho. [Behavior of hybrids and varieties of maize semiarid region in the agricultural year 2013]. Abstract: The maize production in Brazil is widespread, since the country has areas considered appropriate to implantation such culture. However, in some regions such as the Brazilian semiarid, the environmental conditions are variable and prevailing open pollinated varieties in the production of small and medium growers. Intending to make up the little knowledge about the maize types best adapted to the climatic characteristics from this region, this study aimed compare the behavior and yield potential of maize in Brazilian semi-arid, revealing the performance analysis of maize hybrids and open pollinated varieties. In the present study, it was evaluated 72 genotypes, being 30 open-pollinated varieties and 33 hybrids, both derived from breeding programs. The experimental design was a randomized block design with two replications, each plot consisted of two rows with four length meters, spacing 0.75 m between row and 0.20 m between plants. The intention here is to identify the variation in productivity present in hybrids and varieties in relation to treatment as well as viability of their use in the region, as presented in this work

Teores de clorofila e índice SPAD em folhas de mudas de gliricídia em função da aplicação de diferentes doses de composto orgânico oriundo de resíduos de pequenos ruminantes.

Resumo: Objetivou-se avaliar os teores de clorofila através de medidas diretas e indiretas em folhas de gliricídia em função da aplicação de diferentes doses de composto orgânico oriundo de resíduos da produção de pequenos ruminantes. Em delineamento inteiramente casualizado foram testados cinco tratamentos (doses) com cinco repetições, realizou-se o plantio sendo a parcela composta por três mudas. As doses seguiram as seguintes proporções de composto: 0, 10, 20, 30 e 40% mais solo (v/v). Aos 90 dias foram coletadas folhas para mensuração de medidas diretas e indiretas de clorofila (a, b e total) e índice SPAD. O incremento das quantidades de composto orgânico proveniente de resíduos da produção e abate de pequenos ruminantes no substrato proporcionou diminuição nos teores de clorofila em mudas de gliricídia. [Chlorophyll content and SPAD index gliricidia seedlings with the application of different doses of compost derived from waste from small ruminants] Abstract: With the aimed to evaluate the contents of chlorophyll through direct and indirect measures in gliricidia seedlings due to the application of different doses of compost derived from waste from the production of small ruminants. A completely randomized design were tested five treatments (doses) with five replications, planting took place and the portion composed of three seedlings. The doses applied it was: 0, 10, 20, 30 and 40% over the soil (v / v). At day 90 leaves were collected for measurement of direct and indirect measurements of chlorophyll (a, b and total) and SPAD index. The increase in the quantities of organic compost from waste production and slaughter of small ruminants in the substrate caused reduction in chlorophyll content in gliricídia seedlings

Parâmetros biométricos e biomassa de milho adubado com composto orgânico oriundo de resíduos da produção e abate de caprinos e ovinos.

Resumo: Objetivou-se determinar os efeitos da aplicação de composto orgânico oriundos de resíduos da produção e abate de caprinos e ovinos na produção da cultura do milho. O delineamento utilizado foi em blocos casualizados com 5 doses de composto + 1 tratamento adicional (adubos minerais) com 4 repetições, totalizando 24 parcelas. As doses aplicadas foram (t ha-1): 3, 6, 9, 12 e 24. Os dados biométricos das plantas de milho mensurados foram: altura; altura de inserção da espiga ; número de folhas; diâmetro do colmo e biomassa produzida (colmo, folhas, espigas e total). Quando se compara as doses de composto com o tratamento adicional verifica-se que não houve diferença entre a aplicação da adubação orgânica ou mineral. Na avaliação das doses do composto houve incremento nas variáveis diâmetro de colmo, massa seca de folhas e de colmo. A dose de 16,6 t ha-1 proporcionou maior biomassa seca total em plantas de milho. [Biometrics parameters and biomass corn fertilized with compound organic derived of production and slaughter of sheeps and goats]. Abstract: This study aimed to determine the effects of applying of doses of compost derived from production and slaughter of sheep and goats in the production of corn. The experimental design was a randomized block with five doses of compost + 1 additional treatment (mineral fertilizers), with four replications, totaling 24 plots. The doses were applied (t ha-1): 3, 6, 9, 12 and 24. The biometric data of maize plants measured were: height, ear insertion height, number of leaves, stem diameter of culm in mm and produced biomass (stem, leaves, cobs and total). For contrast analysis, we verified that there were no significant results when compared with doses of mineral fertilizer applied. The application of organic compost provided an increase in the variables such as stem diameter, dry weight of leaf and stem in maize plants. The dose of 16.6 t ha-1 provided the higher total dry biomass in maize plants

Paraoxonase 2 protein is spatially expressed in the human placenta and selectively reduced in labour

Humans parturition involves interaction of hormonal, neurological, mechanical stretch and inflammatory pathways and the placenta plays a crucial role. The paraoxonases (PONs 1–3) protect against oxidative damage and lipid peroxidation, modulation of endoplasmic reticulum stress and regulation of apoptosis. Nothing is known about the role of PON2 in the placenta and labour. Since PON2 plays a role in oxidative stress and inflammation, both features of labour, we hypothesised that placental PON2 expression would alter during labour. PON2 was examined in placentas obtained from women who delivered by cesarean section and were not in labour and compared to the equivalent zone of placentas obtained from women who delivered vaginally following an uncomplicated labour. Samples were obtained from 12 sites within each placenta: 4 equally spaced apart pieces were sampled from the inner, middle and outer placental regions. PON2 expression was investigated by Western blotting and real time PCR. Two PON2 forms, one at 62 kDa and one at 43 kDa were found in all samples. No difference in protein expression of either isoform was found between the three sites in either the labour or non-labour group. At the middle site there was a highly significant decrease in PON2 expression in the labour group when compared to the non-labour group for both the 62 kDa form (p = 0.02) and the 43 kDa form (p = 0.006). No spatial differences were found within placentas at the mRNA level in either labour or non-labour. There was, paradoxically, an increase in PON2 mRNA in the labour group at the middle site only. This is the first report to describe changes in PON2 in the placenta in labour. The physiological and pathological significance of these remains to be elucidated but since PON2 is anti-inflammatory further studies are warranted to understand its role

Protein-Protein Interactions in Crystals of the Human Receptor-Type Protein Tyrosine Phosphatase ICA512 Ectodomain

ICA512 (or IA-2) is a transmembrane protein-tyrosine phosphatase located in secretory granules of neuroendocrine cells. Initially, it was identified as one of the main antigens of autoimmune diabetes. Later, it was found that during insulin secretion, the cytoplasmic domain of ICA512 is cleaved and relocated to the nucleus, where it stimulates the transcription of the insulin gene. The role of the other parts of the receptor in insulin secretion is yet to be unveiled. The structures of the intracellular pseudocatalytic and mature extracellular domains are known, but the transmembrane domain and several intracellular and extracellular parts of the receptor are poorly characterized. Moreover the overall structure of the receptor remains to be established. We started to address this issue studying by X-ray crystallography the structure of the mature ectodomain of ICA512 (ME ICA512) and variants thereof. The variants and crystallization conditions were chosen with the purpose of exploring putative association interfaces, metal binding sites and all other structural details that might help, in subsequent works, to build a model of the entire receptor. Several structural features were clarified and three main different association modes of ME ICA512 were identified. The results provide essential pieces of information for the design of new experiments aimed to assess the structure in vivo

Efeitos do composto orgânico proveniente de resíduos da produção e abate de pequenos ruminantes em plantas de milho.

Resumo: Os resíduos da produção de caprinos e ovinos podem ser aplicados como fertilizantes orgânicos por meio da compostagem e utilizados na adubação de culturas. Objetivou-se neste trabalho avaliar os efeitos da aplicação de composto orgânico em parâmetros biométricos de plantas de milho. As doses foram (t ha-1): 3, 6, 9, 12, 24, sendo o delineamento utilizado em blocos ao acaso com as 5 doses de composto e 4 blocos. Os dados biométricos das plantas de milho mensurados foram: altura; altura de inserção da espiga; número de folhas; diâmetro do colmo e biomassa produzida (colmo, folhas, espigas e total). As doses de composto orgânico influenciaram significativamente o aumento da massa da matéria seca da espiga e massa de matéria seca total na cultura do milho