The influence of microstructure on the fatigue crack growth rate in marine steels in the Paris Region

This paper presents a study on the effect of microstructure on the fatigue crack growth (FCG) rate in advanced S355 marine steels in the Paris Region of the da/dN versus ΔK log–log plot. The environments of study were air and seawater (SW), under constant amplitude sinewave fatigue loading. Fundamentally, three phenomena (crack tip diversion, crack front bifurcation and metal crumb formation) were observed to influence the rate of FCG. These phenomena appear to be a function of the material microstructure, environment and crack tip loading conditions. The three factors retarded the crack growth by reducing or redistributing the effective driving force at the main active crack tip. A crack path containing extensively the three phenomena was observed to offer strong resistance to FCG. In SW, the degree of the electrochemical dissolution of the microplastic zone appears to be an additional primary factor influencing FCG in the steel

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Pro-apoptotic synergistic interactions between ERK1/2 and Bcl-2 inhibitors in acute myeloid leukemia cells.

We previously reported that activation of the Ras/MEK/ERK signaling pathway alone or in combination with high levels of Bcl-2 confers poor prognosis in patients with acute myeloid leukemias (AML). In this study, we investigated whether the simultaneous disruption of these two pathways by pharmacological inhibition of ERK1/2 and Bcl-2 utilizing novel small molecule inhibitors would induce pro-apoptotic activity in myeloid leukemic cells. For inhibition of ERK1/2 signaling, we utilized the MEK inhibitor CI-1040 (Pfizer Global Research and Development). Functional Bcl-2 inhibition was achieved by the novel BH3 peptide binding domain inhibitor A438744.7 (Abbott Laboratories). A dose-dependent increase in apoptosis as assessed by an increase in phosphatidylserine externalization was observed in OCI-AML3 cells after 24h incubation with CI-1040 or A438744.7 (both in a range between 0.25 and 2 µM). When these agents were used in combination at a fixed 1:1 ratio, a dramatic enhancement of cell killing was observed especially at lower concentrations (70.63%±9.95 Annexin V+ cells at 0.25 µM of each compound). Isobologram analysis (Chou and Talalay method) revealed a Combination Index (CI) < 1 (CI=0.114 and 0.436 at 0.25 µM and 2 µM, respectively) suggesting the strongly synergistic nature of these interactions. In addition, combined treatment with CI-1040 and A438744.7 resulted in a substantial increase of mitochondrial damage and caspase cleavage. Pre-incubation (1-hour) with a pan-caspase inhibitor (IDN-1965) was able to completely abrogate sensitivity to the inhibitors. We further demonstrated that bcl-2 overexpression prevented induction of apoptosis by low doses of both, MEK and BH3 inhibitors, whereas enforced Bcl-XL expression essentially abrogated the lethal effects of A438744.7, but not of CI-1040. Finally, to evaluate whether the combined strategy of ERK1/2 and Bcl-2 inhibition would be potentially applicable to leukemia patients, primary cells were isolated from AML samples and exposed to CI-1040 and A438744.7, as single agents or in combination at a 1:1 ratio for up to 96 hours. In each sample, drugs administrated individually were minimally toxic. Co-administration of CI-1040 and BH3 inhibitors displayed strong synergistic lethal effects toward primary cells from AML patients (CI=0.45±0.42 at 0.25 µM and CI=0.20±0.22 at 0.5 µM after 48h incubation). In conclusion, simultaneous exposure to nanomolar concentrations of MEK and bcl-2 inhibitors induced mitochondrial dysfunction, caspases activation and striking synergistic pro-apoptotic activity in myeloid leukemic cells. Similar synergistic interactions occured in primary AML samples. Together, these data strongly suggest that therapeutic strategies combining MEK and Bcl-2 inhibitors warrant further examination in AML