Exploring the utility of human DNA methylation arrays for profiling mouse genomic DNA

AbstractIllumina Infinium Human Methylation (HM) BeadChips are widely used for measuring genome-scale DNA methylation, particularly in relation to epigenome-wide association studies (EWAS) studies. The methylation profile of human samples can be assessed accurately and reproducibly using the HM27 BeadChip (27,578 CpG sites) or its successor, the HM450 BeadChip (482,421 CpG sites). To date no mouse equivalent has been developed, greatly hindering the application of this methodology to the wide range of valuable murine models of disease and development currently in existence. We found 1308 and 13,715 probes from HM27 and HM450 BeadChip respectively, uniquely matched the bisulfite converted reference mouse genome (mm9). We demonstrate reproducible measurements of DNA methylation at these probes in a range of mouse tissue samples and in a murine cell line model of acute myeloid leukaemia. In the absence of a mouse counterpart, the Infinium Human Methylation BeadChip arrays have utility for methylation profiling in non-human species

Avaliação técnico-econômica de suínos machos imuno e cirurgicamente castrados

Realizou-se este estudo com o objetivo de avaliar o desempenho técnico-econômico e determinar a lucratividade, por meio da análise de sensibilidade econômica, de suínos machos imuno (IM) e cirurgicamente castrados (MC). Foram realizados dois experimentos, em delineamento inteiramente casualizado, composto por dois tratamentos (IM e MC), com oito repetições de 10 animais cada, totalizando 160 suínos por experimento. Verificou-se que suínos IM apresentam menor consumo de ração e melhor conversão alimentar nas fases de crescimento em relação aos MC. Na fase de terminação, suínos IM apresentam melhor ganho de peso, conversão alimentar, rendimento de carcaça e porcentagem de carne em relação aos MC. A utilização de IM aumenta a lucratividade na produção de suínos. A análise de lucratividade entre suínos IM e MC deve considerar todas as fases de criação, uma vez que o desempenho diferencial dos suínos não castrados na fase de crescimento influencia economicamente os resultados da produção.This study was conducted to evaluate the technical and economic performance and determine profitability through the economic sensitivity analysis of immune (IM) and male pigs surgically castrated (SC). Two experiments were conducted in a completely randomized design, consisting of two treatments (IM and SC) with eight replicates of 10 animals each, totaling 160 pigs per experiment. It was found that IM pigs have lower feed intake and feed conversion during the growth phases in relation to SC. In the finishing phases, IM have better weight gain, feed conversion, carcass yield and lean meat percentage in relation to SC. The use of IM increases the profitability in pig production. The analysis of profitability differential between IM and SC should consider all stages of creation, since the differential performance of not castrated pigs during growth influences economic results of production

Fyn Mediates Leptin Actions in the Thymus of Rodents

BACKGROUND:Several effects of leptin in the immune system rely on its capacity to modulate cytokine expression and apoptosis in the thymus. Surprisingly, some of these effects are dependent on signal transduction through the IRS1/PI3-kinase, but not on the activation of JAK2. Since all the well known effects of leptin in different cell types and tissues seem to be dependent on JAK2 activation, we hypothesized that, at least for the control of thymic function, another, unknown kinase could mediate the transduction of the leptin signal from the ObR towards the IRS1/PI3-kinase signaling cascade. METHODOLOGY/PRINCIPAL FINDINGS:Here, by employing immunoblot, real-time PCR and flow citometry we show that the tyrosine kinase, Fyn, is constitutively associated with the ObR in thymic cells. Following a leptin stimulus, Fyn undergoes an activating tyrosine phosphorylation and a transient association with IRS1. All these effects are independent of JAK2 activation and, upon Fyn inhibition, the signal transduction towards IRS1/PI3-kinase is abolished. In addition, the inhibition of Fyn significantly modifies the effects of leptin on thymic cytokine expression. CONCLUSION/SIGNIFICANCE:Therefore, in the thymus, Fyn acts as a tyrosine kinase that transduces the leptin signal independently of JAK2 activation, and mediates some of the immunomodulatory effects of leptin in this tissue

Future Therapeutic Directions for Smac-Mimetics

It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy

BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia

The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies