Two new species of Arcuphantes (Araneae: Linyphiidae: Micronetinae) from Owase, Kii Peninsula, Japan

Two new linyphiid species, Arcuphantes shiozakii sp. nov. and A. yakiyama sp. nov., from Owase, eastern Kii Peninsula, Japan, are described based on both sexes. Given the fact that the two new species share almost identical mitochondrial cytochrome c oxidase subunit I sequences, they may represent closely related sister species, but nonetheless, they are clearly distinguishable from each other by the genital characters. Additionally, the new species are closely related to A. osugiensis (Oi 1960) and A. yamakawai (Oi 1960), but they are also distinguished by the morphology of genitalia

Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations

LC-SCRUM-Japanで構築した日本最大のがん臨床ゲノムデータを活用しスーパーコンピュータで治療薬の効き目を予測 --がんゲノム医療における新たなツールの開発--. 京都大学プレスリリース. 2019-05-13.Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of EGFR mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot EGFR mutations (n = 3, 779) revealed that the majority (>90%) of cases with rare EGFR mutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI (R2 = 0.72, P = 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rare EGFR mutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer

Thyroid hormone receptor β mutants: Dominant negative regulators of peroxisome proliferator-activated receptor γ action

Thyroid hormone (T3) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis. Their actions are mediated by their respective receptors: thyroid hormone receptors (TR) and peroxisome proliferator-activated receptors (PPAR). We recently found that a dominantly negative TRβ mutant (PV) that causes a genetic disease, resistance to thyroid hormone, acts to repress the ligand (troglitazone)-mediated transcriptional activity of PPARγ in cultured thyroid cells. This finding suggests that TRβ mutants could crosstalk with PPARγ-signaling pathways. The present study explored the molecular mechanisms by which PV represses the PPARγ transcriptional activity. Gel-shift assays show that the PV, similar to wild-type TRβ, bound to the peroxisome proliferator response element (PPRE) as homodimers and heterodimers with PPARγ or the retinoid X receptor (RXR), thereby competing with PPARγ for binding to PPRE and for sequestering RXR. Association of PPRE-bound PV with corepressors [e.g., nuclear receptor corepressor (NCoR)] that led to transcriptional repression was independent of T3 and troglitazone. Chromatin immunoprecipitation assay further demonstrated that, despite the presence of ligands, NCoR was recruited to PPRE-bound PV on a PPARγ-target gene, the lipoprotein lipase, in vivo, suggesting the dominant action of PV on PPARγ-mediated transcriptional activity. Thus, the dominant negative action of PV is not limited on the wild-type TRs. The findings that TRβ mutants affect PPARγ functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPARγ-target genes involved in metabolic pathways, lipid homeostasis, and carcinogenesis

Determinant factors on differences in survival for gastric cancer between the US and Japan using nationwide databases.

BackgroundAlthough the incidence and mortality have decreased, gastric cancer (GC) is still a public health issue globally. An international study reported higher survival in Korea and Japan than other countries, including the US. We examined the determinant factors of the high survival in Japan, compared with the US.MethodsWe analysed data on 78,648 cases from the nationwide GC registration project, the Japanese Gastric Cancer Association (JGCA), from 2004-2007 and compared them with 16,722 cases from the Surveillance, Epidemiology, and End Results Program (SEER), a US population-based cancer registry data from 2004-2010. We estimated five-year relative survival and applied a multivariate excess hazard model to compare the two countries, considering the effect of number of lymph nodes (LNs) examined.ResultsFive-year relative survival in Japan was 81.0%, compared with 45.0% in the US. After controlling for confounding factors, we still observed significantly higher survival in Japan. Among N2 patients, a higher number of LNs examined showed better survival in both countries. Among N3 patients, the relationship between number of LNs examined and differences in survival between the two countries disappeared.ConclusionAlthough the wide differences in GC survival between Japan and US can be largely explained by differences in the stage at diagnosis, the number of LNs examined may also help to explain the gaps between two countries, which is related to stage migration

Regulation of the muscarinic K(+) channel by extracellular ATP through membrane phosphatidylinositol 4,5-bisphosphate in guinea-pig atrial myocytes

1. The present study was designed to examine the functional role of membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) in the regulation of the muscarinic K(+) channel (I(K,ACh)) by extracellular ATP and adenosine in guinea-pig atrial myocytes, using the whole-cell patch-clamp method. 2. Bath application of ATP in micromolar concentrations typically evoked a transient activation of I(K,ACh); a rapid activation phase was consistently followed by a progressive decline even to the baseline level despite the continued presence of ATP. This progressive decline of I(K,ACh) was significantly attenuated either by blockade of phospholipase C (PLC) with compound 48/80 (100 μM) or by addition of PtdIns(4,5)P(2) (50 μM) to the cell inside, suggesting that depletion of membrane PtdIns(4,5)P(2) via PLC activation is mainly, if not totally, responsible for the progressive decline of I(K,ACh) during the presence of ATP. 3. When atrial myocytes were exposed to wortmannin (50 μM) following ATP (50 μM) application to impair the resynthesis of PtdIns(4,5)P(2), the activation of I(K,ACh) evoked by subsequently applied ATP (50 μM) was greatly reduced. Activation of I(K,ACh) by adenosine (100 μM) was partially reduced by pretreatment of atrial myocytes with ATP (100 μM) and was largely abolished by a further addition of wortmannin (50 μM) in the presence of ATP (100 μM). These results support the view that the activation of I(K,ACh) by ATP and adenosine depends on membrane PtdIns(4,5)P(2) that is subject to reduction by extracellular ATP. 4. The present study thus provides functional evidence to suggest that extracellular ATP activates PLC and thereby depletes membrane PtdIns(4,5)P(2) that is critically involved in the activation process of I(K,ACh) by its agonists ATP and adenosine in guinea-pig atrial myocytes