Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.
We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, ...NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.
Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.
Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA ...germline mutation and for somatic mutations in luminal (
negative) breast cancer. Thirteen of 79 unselected very young patients were
1/2 germline mutation carriers. Of the non-
tumors, eight with luminal subtype (
negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were
and
. Potential cancer drivers affected in the present non-
tumors include
,
,
,
and
Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as
,
,
, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.
MultiS: A Context-Server for Pervasive Computing Fehlberg, Felipe Weber; Rolim, Carlos O.; Leithardt, Valderi R.Q. ...
Electronic notes in theoretical computer science,
03/2013, Letnik:
292
Journal Article
Odprti dostop
Context-aware applications are capable of recognizing environmental changes and adapting their behavior to the new context. This process can be divided into three stages: monitoring, context ...recognition and adaptation. On the monitoring layer, raw information about the environment is collected from sensors. The context recognition layer processes the data acquired from the context and transforms it into information which can be useful for the adaptation process. With this information, the adaptation system can determine what behavior is correct for the application in each different context. This paper proposes a context server called MultiS, which has the goal of solving the problems arising from the context recognition layer, and which includes the following advantages: a) the production of new context data based on the information of several sensors and an ability to react to changes in the environment; b) definition of a composed language for the context data called CD-XML; c) support for mobility.
The latest technological advances, which introduced innovative and more affordable devices, have contributed to boost the practical application of research in the field of ubiquitous computing ...(ubicomp). For the development of applications in this area, we need an adequate software infrastructure. In order to do so, we have proposed Continuum, an infrastructure based on service-oriented architecture (SOA), making use of framework and middleware, and employing a redefinition of follow-me semantics. In this redefined vision, users can go anywhere carrying the data and application they want, which they can use in a seamlessly integrated fashion with the real world. In this article, we focus on the description of the service-based architecture proposed for Continuum. The proposal widens the Web services standards to support the mobility of services, allowing them to be deployed, copied, or moved. Besides, the abstraction provided enables the adaptation of legacy applications as Continuum pluggable services.
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