The Dual RAF/MEK Inhibitor CH5126766/RO5126766 May Be a Potential Therapy for RAS-Mutated Tumor Cells

Although melanoma is the most aggressive skin cancer, recent advances in BRAF and/or MEK inhibitors against BRAF-mutated melanoma have improved survival rates. Despite these advances, a treatment strategy targeting NRAS-mutated melanoma has not yet been elucidated. We discovered CH5126766/RO5126766 as a potent and selective dual RAF/MEK inhibitor currently under early clinical trials. We examined the activity of CH5126766/RO5126766 in a panel of malignant tumor cell lines including melanoma with a BRAF or NRAS mutation. Eight cell lines including melanoma were assessed for their sensitivity to the BRAF, MEK, or RAF/MEK inhibitor using in vitro growth assays. CH5126766/RO5126766 induced G1 cell cycle arrest in two melanoma cell lines with the BRAF V600E or NRAS mutation. In these cells, the G1 cell cycle arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclinD1. CH5126766/RO5126766 was more effective at reducing colony formation than a MEK inhibitor in NRAS- or KRAS-mutated cells. In the RAS-mutated cells, CH5126766/RO5126766 suppressed the MEK reactivation caused by a MEK inhibitor. In addition, CH5126766/RO5126766 suppressed the tumor growth in SK-MEL-2 xenograft model. The present study indicates that CH5126766/RO5126766 is an attractive RAF/MEK inhibitor in RAS-mutated malignant tumor cells including melanoma.     

Self-aggregation of synthetic zinc methyl 20-substituted 3-hydroxymethyl-pyropheophorbides as models of bacteriochlorophyll-c

Photosynthesis Research - Zinc 3-hydroxymethyl-131-oxo-chlorins bearing a variety of primary alkyl groups at the 20-position were prepared as models of bacteriochlorophyll-c by chemical...     

Changes in plasma levels of testosterone during male-male interactions in the song sparrow,Melospiza melodia: time course and specificity of response

Summary Previous investigations have shown that malemale interactions over territory boundaries result in an increase in plasma levels of testosterone (T). In order to determine the time course of this increase following an agonistic challenge, male song sparrows, Zonotrichia (= Melospiza) melodia, were exposed to simulated territorial intrusions. Responding males were captured at intervals after onset of the intrusion for up to 60 min. Plasma levels of T were elevated by 10 min after onset of the challenge, and remained high in birds sampled 10–60 min after onset of the intrusion. In addition, plasma levels of luteinizing hormone (LH) increased and were significantly elevated after 10 min of stimulation. The results suggest that at least the prolonged elevation of T secretion precipitated by a male-male interaction was mediated via an increase in LH release. However, the initial surge of T levels in plasma may be LH independent. p Investigations of captive birds confirmed that circulating LH and T levels increased when male song sparrows were challenged by a conspecific male. Challenges involving a male house sparrow, Passer domesticus, had no effect suggesting that responses to male intrusions were species characteristic and not a result of general arousal. Further, auditory stimuli (vocalizations) alone, and visual stimuli (a devocalized male) alone were less effective in stimulating an increase in secretion of T than a combination of auditory and visual stimuli.Abbreviations DHT dihydrotestosterone - LH luteinizing hormon; - T testosterone     

Interactions between cytoskeletal components during myoplasm rearrangement in ascidian eggs

Ooplasmic segregation in ascidian eggs consists of two phases of cytoplasmic movement, the first phase is mediated by the microfilament system and the second is mediated by the microtubule system. Recently, two novel proteins, p58 and myoplasmin-C1, which are localized to the myoplasm, were suggested to have important roles in muscle differentiation. In order to analyze the molecular mechanisms underlying ooplasmic segregation, the interactions between actin, tubulin, p58 and myoplasmin-C1 were examined. During the first segregation, microtubule meshwork in the unfertilized egg disappeared. At the second segregation, a novel structure of the microtubules that extended from the sperm aster and localized in the cortical region of the myoplasm was found. Moreover, uniform distribution of the cortical actin filament was observed at the second segregation. During the course of myoplasm rearrangement, p58 and myoplasmin-C1 are colocalized and can form a molecular complex in vitro. This complex of p58 and myoplasmin-C1 is a good candidate for a cytoskeletal component of the myoplasm, and is likely to be involved in the correct distribution of cytoplasmic determinants.     

Barricade building in Ilyoplax pusillus (De Haan) (Crustacea : Brachyura)

Ilyoplax pusillus (De Haan, 1835) was sometimes found to build an earthen structure, termed a barricade, close to its neighbour's burrow. Most barricaders were males > 6.4 mm in carapace width. Either males or females were barricaded and almost all of them were smaller than their barricaders. Burrow to burrow distance between a barricader and its barricaded neighbour ranged from 1.6 to 7.2 cm. The home range of a barricaded crab was biased toward the areas devoid of the barricade, i.e. to other directions than the barricader's burrow, in either the presence or absence of the barricader. When a barricade was removed, the crab freed from it extended its home range towards the barricader's burrow. If the crab freed from a barricade moved towards the barricader, the former was frequently repelled by the latter. These findings suggest that barricades function as an aid to territorial defence by deterring invasion by a neighbour.     

Isolation of a Gene for a Metallothionein-Like Protein from Soybean

Using a synthetic oligonucleotide that corresponded to the consensusnucleotide sequence of the N-terminal region of mammalian metallothioneinas probe, we isolated a cDNA clone from a soybean library. Theclone had an ORF that encode a protein of 79 amino acids whichshowed significant homology to both N- and C-terminal regionsof mammalian and Neurospora crassa metallothioneins ⁴Present address: Department of Biosciences, Teikyo University,Toyosatodai, Utsunomiya, Tochigi, 320 Japan (Received March 13, 1991; Accepted June 17, 1991)     

Molecular genotyping of N-acetylation polymorphism to predict phenotype

Summary N-acetylation polymorphism is one of the representative pharmacogenetic traits that underlie interindividual and interethnic differences in response to xenobiotics. To develop a practical genotyping method to predict acetylator phenotype, we studied the conditions for accurate phenotyping, and identified the phenotype in 51 Japanese. Then we performed Southern blot analysis of genomic DNA from these subjects using ³²P-labeled cDNA for polymorphic N-acetyltransferase in the liver, and found that four N-acetyltransferase alleles generated six genotypes. The present genotyping method predicted the rapid, intermediate, and slow acetylators correctly in 48 of 51 overall subjects (96%) and in all of 4 slow acetylators.