Inhibitors of oncogenic B-RAF(V600E) and MKK1/2 have yielded remarkable responses in B-RAF(V600E)-positive melanoma patients. However, the efficacy of these inhibitors is limited by the inevitable onset of resistance. Despite the fact that these inhibitors target the same pathway, combination treatment with B-RAF(V600E) and MKK1/2 inhibitors has been shown to improve both response rates and progression-free survival in B-RAF(V600E) melanoma patients. To provide insight into the molecular nature of the combinatorial response, we used quantitative mass spectrometry to characterize the inhibitor-dependent phosphoproteome of human melanoma cells treated with the B-RAF(V600E) inhibitor PLX4032 (vemurafenib) or the MKK1/2 inhibitor AZD6244 (selumetinib). In three replicate experiments, we quantified changes at a total of 23,986 phosphosites on 4784 proteins. This included 1317 phosphosites that reproducibly decreased in response to at least one inhibitor. Phosphosites that responded to both inhibitors grouped into networks that included the nuclear pore complex, growth factor signaling, and transcriptional regulators. Although the majority of phosphosites were responsive to both inhibitors, we identified 16 sites that decreased only in response to PLX4032, suggesting rare instances where oncogenic B-RAF signaling occurs in an MKK1/2-independent manner. Only two phosphosites were identified that appeared to be uniquely responsive to AZD6244. When cells were treated with the combination of AZD6244 and PLX4032 at subsaturating concentrations (30 nm), responses at nearly all phosphosites were additive. We conclude that AZD6244 does not substantially widen the range of phosphosites inhibited by PLX4032 and that the benefit of the drug combination is best explained by their additive effects on suppressing ERK1/2 signaling. Comparison of our results to another recent ERK1/2 phosphoproteomics study revealed a surprising degree of variability in the sensitivity of phosphosites to
mcnp5 free 93
The chemistry of the carbonate-free clay-size fraction of Owens Lake sediments supports the use of total organic carbon and magnetic susceptibility as indicators of stadial-interstadial oscillations. Owens Lake records of total organic carbon, magnetic susceptibility, and chemical composition of the carbonate-free, clay-size fraction indicate that Tioga glaciation began 24,500 and ended by 13,600 14C yr B.P. Many of the components of glacial rock flour (e.g., TiO2, MnO, BaO) found in Owens Lake sediments achieved maximum values during the Tioga glaciation when valley glaciers reached their greatest extent. Total organic carbon and SiO2 (amorphous) concentrations reached minimum values during Tioga glaciation, resulting from decreases in productivity that accompanied the introduction of rock flour into the surface waters of Owens Lake. At least 20 stadial-interstadial oscillations occurred in the Sierra Nevada between 52,600 and 14,000 14C yr B.P. Total organic carbon data from a Pyramid Lake sediment core also indicate oscillations in glacier activity between >39,500 and 13,600 14C yr B.P. Alpine glacier oscillations occurred on a frequency of ???1900 yr in both basins, suggesting that millennial-scale oscillations occurred in California and Nevada during most of the past 52,600 yr.
... 10 Energy 4 2010-01-01 2010-01-01 false Competition. 600.143 Section 600.143 Energy DEPARTMENT OF... Nonprofit Organizations Post-Award Requirements 600.143 Competition. All procurement transactions shall be conducted in a manner to provide, to the maximum extent practical, open and free competition. The recipient...
... labels are required to bear range values as required by paragraph (b) of this section, or determined by... requested which has a combined unadjusted fuel economy value at or below the minimum tax-free value, the... manufacturer shall include the current range of fuel economy of comparable automobiles (as described in 600...
Elucidation of the molecular targets and pathways regulated by the tumour-suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR-188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy. PMID:25714029
Elucidation of the molecular targets and pathways regulated by the tumour-suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR-188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy.
The BRAF V600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAF V600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAF V600E -mutated LCH were investigated to detect ccf BRAF V600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAF V600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P
In this work, Bsub 4C particulate-reinforced Al composite was fabricated by a pressureless infiltration technique, and its interfacial microstructure was studied in detail by X-ray diffraction as well as by scanning and transmission electron microscopy. The Bsub 4C phase was unstable in Al melt during the infiltration process, forming AlBsub 10-type AlBsub 24Csub 4 or Alsub 2.1Bsub 51Csub 8 as a major reactant phase. The Al matrix was large grains (over 10 microm), which had no definite orientation relationships (ORs) with the randomly orientated Bsub 4C or its reactant particles, except for possible nucleation sites with l_brace011r_bracesub Bsub 4C almostmore parallel to l_brace111r_bracesub Al at a deviation angle of 1.5 deg. Both Bsub 4C-Al and reactant-Al interfaces are semicoherent and free of other phases. A comparison was made with the SiC/Al composite fabricated similarly by the pressureless infiltration. It was suggested that the lack of ORs between the Al matrix and reinforced particles, except for possible nucleation sites, is the common feature of the composites prepared by the infiltration method. less
Abdullah, Mohd. Jaya and Mohd. Supa'at, Abu Sahmah and Mudin, Taisah and Shahida Syafiqah, Shahida Syafiqah (2012)10 Mbs ethernet via free space optic during rainy weather. Trends in Opto Electro and Optical Communications, 2 (2). pp. 1-7. ISSN 2231-0401
Shamsuri, Nur Afiqah Ahmad and Mohidem, Nur Atikah and Mansor, Azmi Fadziyana and Mat, Hanapi (2012)Biodegradation of dye using free laccase and sol-gel laccase. Jurnal Teknologi (Sciences and Engineering), 59 . pp. 39-42. ISSN 0127-9696
Mohidem, Nur Atikah and Mat, Hanapi (2012)The catalytic activity enhancement and biodegradation potential of free laccase and novel sol-gel laccase in non-conventional solvents. Bioresource Technology, 114 . pp. 472-477. ISSN 0960-8524
Anwar, Muhammad Imran and Shafie, Sharidan and Khan, Ilyas and Salleh, Mohd. Zuki (2012)Conjugate effects of radiation flux on double diffusive MHD free convection flow of a nanofluid over a power law stretching sheet. International Scholarly Research Network (ISRN) Thermodynamics, 2012 . pp. 1-7. ISSN 2090-5211
Phama, Thi Thanh Thuy and See, Hong Heng and Morand, Réjane and Krähenbühld, Stephan and Hausera, Peter C. (2012)Determination of free and total valproic acid in human plasma by capillary electrophoresis with contactless conductivity detection. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 907 . pp. 74-78. ISSN 1570-0232 2ff7e9595c
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