The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To ...identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy.
•Whole exome sequencing reveals novel mutations in ARAF that activate the kinase and are inhibitable by vemurafenib in a patient with LCH.•Requiring the presence of BRAF V600E in LCH to qualify for rat fibrosarcoma inhibitor treatment may be overly exclusionary.
High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin ...is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.
Background: EGFR and VEGFR2 protein expressions are hallmarks of clear cell renal cancer (RCC) with questionable prognostic
impact. The skeletal system is one of the most common metastatic sites of ...RCC. Unfortunately, there are no data for EGFR and
VEGFR2 protein expression in such lesions. Materials and Methods: Twenty cases of bone metastatic clear cell RCC were analyzed.
EGFR and VEGFR2 proteins were detected by immunohistochemistry and analyzed by morphometry scoring both % positivity and the
intensity. Results: EGFR protein scores were significantly reduced in bone metastases of RCC due to the reduction of EGFR
protein expression in about one third of the cases (7/20). The VEGFR2 protein-positive phenotype of clear cell RCC was relatively
frequent (7/20, 35%), but was lost in bone metastases (2/20, 10%). Conclusion: These data suggest a phenotypic/genotypic change
of clear cell RCC during the progression to bones and warrant further investigation.
Obsidian was widely used by our ancestors for tool making. In the Trans-Caucasian region, obsidian-bearing volcanic deposits are distributed over wide areas. Forty three obsidian occurrences were ...analysed using the fission-track (FT) dating method to better constrain the history of Plio-Pleistocene volcanism of this region. The determined formation ages cluster into restricted groups: 0.042–0.120, 0.25–0.40, 0.43–0.56, 1.17–1.38, 1.53, 2.34–2.63 and 4.26–4.56 Ma. The FT data-set on geological samples was used for provenance studies of 112 artefacts from Armenian prehistoric sites or of pebbles from river banks. All artefacts originated from Armenian sources or from sources located in adjacent regions of Turkey and Georgia.
In the Mediterranean and adjacent regions, the Caucasus is one of the less studied areas in relation to provenance studies of prehistoric obsidian artefacts. In the frame of an international INTAS ...research project, an extensive surveying and sampling campaign was carried out in the numerous obsidian bearing volcanic complexes of Armenia. 33 obsidian samples were analysed using the fission-track dating method in order to characterise the potential sources of the numerous artefacts found in prehistoric sites. Ages cluster into five groups—Upper Neopleistocene Q
III, Middle Neopleistocene Q
II, Lower Neopleistocene Q
I, Lower Eopleistocene Q
EI and Lower Pliocene N
3
1 groups. This research represents a significant contribution to a better knowledge of chronology of Armenian volcanism for which only few data were available. The resulting data-set appears to be a solid base for future provenance studies.
Using heterocyclic-
N-oxide chemistry, various substituted quinoline and isoquinoline compounds were synthesized on the solid support in excellent purity and good to excellent yield.
Using ...heterocyclic-
N-oxide chemistry, various substituted quinoline and isoquinoline compounds were synthesized on the solid support in excellent purity and good to excellent yield.
Phys.Rev. D57 (1998) 4367-4375 An analysis procedure is proposed to measure the antiquark distributions in
the proton over the region 0.01 < x < 0.1. The procedure involves the
measurement of high ...p_t asymmetric direct photon and jet final states in pp
interactions. This measurement can be made at the RHIC collider running in pp
mode at an energy of sqrt(s)=500 GeV/c. This analysis identifies a region of
phase space where the contribution from quark-antiquark annihilation
uncharacteristically approaches the magnitude of the contribution from the
leading process, quark-gluon Compton scattering. The forward-backward angular
asymmetry in the parton center of mass is sensitive to the antiquark content of
the proton and the ubar parton density function can be extracted.
An analysis procedure is proposed to measure the antiquark distributions in the proton over the region 0.01 < x < 0.1. The procedure involves the measurement of high p_t asymmetric direct photon and ...jet final states in pp interactions. This measurement can be made at the RHIC collider running in pp mode at an energy of sqrt(s)=500 GeV/c. This analysis identifies a region of phase space where the contribution from quark-antiquark annihilation uncharacteristically approaches the magnitude of the contribution from the leading process, quark-gluon Compton scattering. The forward-backward angular asymmetry in the parton center of mass is sensitive to the antiquark content of the proton and the ubar parton density function can be extracted.
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