Preponderance of the oncogenic V599E and V599K mutations in B-raf kinase domain is enhanced in melanoma cutaneous/subcutaneous metastases

BACKGROUND: Downstream of Ras, the serine/threonine kinase B-raf has been reported to be mutated, among other carcinomas, in a substantial subset of primary melanomas with a preponderance of mutations within the kinase domain including the activating V599E and V599K transitions. METHODS: We here investigated a representative series of 60 resection specimens of cutaneous and subcutaneous melanoma metastases for the presence of mutations within the activation segment (exon 15) of the B-raf kinase domain by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) gel electrophoresis. RESULTS: Sequencing of cloned PCR-SSCP amplicons resulted in 24 (40%) samples harbouring somatic mutations which is not exceeding the mutation frequency in recently investigated primary melanomas. The activating mutation T1796A was present in 24/60 (40%) resection specimens, followed in frequency by the oncogenic g1795A mutation in 8/60 (13%) cases. As to the B-raf protein sequence, the acidic amino acid transitions V599E and V599K were predicted in 19/60 (32%) and 6/60 (10%) cases, resepectively, but were not associated with enhanced risk for subsequent metastasis in patients' follow up. In comparison to the primary melanomas that we recently investigated, the spectrum of predicted B-raf protein mutations narrowed significantly in the cutaneous/subcutaneous metastases. Unexpectedly, V599 and V599E mutations were absent in cutaneous/subcutaneous metastases derived from acrolentiginous melanomas as preceding primary tumours. CONCLUSION: During transition from primary melanomas towards cutaneous/subcutaneous metastases, the spectrum of predicted B-raf mutations narrows significantly. Focusing on the V599E and V599K, these oncogenic mutations are likely to affect melanocyte-specific pathways controlling proliferation and differentiation

Active Externalism, Virtue Reliabilism and Scientific Knowledge

Combining active externalism in the form of the extended and distributed cognition hypotheses with virtue reliabilism can provide the long sought after link between mainstream epistemology and philosophy of science. Specifically, by reading virtue reliabilism along the lines suggested by the hypothesis of extended cognition, we can account for scientific knowledge produced on the basis of both hardware and software scientific artifacts (i.e., scientific instruments and theories). Additionally, by bringing the distributed cognition hypothesis within the picture, we can introduce the notion of epistemic group agents, in order to further account for collective knowledge produced on the basis of scientific research teams

B-raf Alternative Splicing Is Dispensable for Development but Required for Learning and Memory Associated with the Hippocampus in the Adult Mouse

The B-raf proto-oncogene exerts essential functions during development and adulthood. It is required for various processes, such as placental development, postnatal nervous system myelination and adult learning and memory. The mouse B-raf gene encodes several isoforms resulting from alternative splicing of exons 8b and 9b located in the hinge region upstream of the kinase domain. These alternative sequences modulate the biochemical and biological properties of B-Raf proteins. To gain insight into the physiological importance of B-raf alternative splicing, we generated two conditional knockout mice of exons 8b and 9b. Homozygous animals with a constitutive deletion of either exon are healthy and fertile, and survive up to 18 months without any visible abnormalities, demonstrating that alternative splicing is not essential for embryonic development and brain myelination. However, behavioural analyses revealed that expression of exon 9b-containing isoforms is required for B-Raf function in hippocampal-dependent learning and memory. In contrast, mice mutated on exon 8b are not impaired in this function. Interestingly, our results suggest that exon 8b is present only in eutherians and its splicing is differentially regulated among species

Impact of intra-daily SST variability on ENSO characteristics in a coupled model

This paper explores the impact of intra-daily Sea Surface Temperature (SST) variability on the tropical large-scale climate variability and differentiates it from the response of the system to the forcing of the solar diurnal cycle. Our methodology is based on a set of numerical experiments based on a fully global coupled ocean–atmosphere general circulation in which we alter (1) the frequency at which the atmosphere sees the SST variations and (2) the amplitude of the SST diurnal cycle. Our results highlight the complexity of the scale interactions existing between the intra-daily and inter-annual variability of the tropical climate system. Neglecting the SST intra-daily variability results, in our CGCM, to a systematic decrease of 15% of El Niño—Southern Oscillation (ENSO) amplitude. Furthermore, ENSO frequency and skewness are also significantly modified and are in better agreement with observations when SST intra-daily variability is directly taken into account in the coupling interface of our CGCM. These significant modifications of the SST interannual variability are not associated with any remarkable changes in the mean state or the seasonal variability. They can therefore not be explained by a rectification of the mean state as usually advocated in recent studies focusing on the diurnal cycle and its impact. Furthermore, we demonstrate that SST high frequency coupling is systematically associated with a strengthening of the air-sea feedbacks involved in ENSO physics: SST/sea level pressure (or Bjerknes) feedback, zonal wind/heat content (or Wyrtki) feedback, but also negative surface heat flux feedbacks. In our model, nearly all these results (excepted for SST skewness) are independent of the amplitude of the SST diurnal cycle suggesting that the systematic deterioration of the air-sea coupling by a daily exchange of SST information is cascading toward the major mode of tropical variability, i.e. ENSO