👤 M Eto

Advanced/metastatic urothelial cancer (a/m UC) still has a poor prognosis despite the recent medical advances. Recent studies demonstrated that fibroblast growth factor receptor (FGFR) gene alterations (GAs) may be driver genes for UC; however, the proportion of UC genetic panel testing in Japan remains low. We clarified the proportion of patients with FGFR2/3 GAs, treatment patterns, and clinical outcomes in a/m UC patients in Japan. This study was a descriptive epidemiological study using the MONSTAR-SCREEN database, and 138 patients with a/m UC were evaluated. The primary endpoint was the proportion of patients with FGFR2/3 GAs. The secondary endpoints included treatment patterns, clinical outcomes, genomic status before and after treatment, etc. The proportion of FGFR GA-positive patients in a/m UC was 11.9%. The most common FGFR mutation variant and fusion gene were S249C (4.4%) and FGFR3-TACC3 fusion (3.7%), respectively. Fifty-one patients were tested two or more times; a few changes were observed in the FGFR GA status, regardless of the treatment regimen. Co-occurrence association was observed in FGFR1 with TET2, and in FGFR3 with CHEK2 or MLL2. During the first-, second-, and third-line treatment, median progression-free survival (PFS) of GA-positive patients was 7.3, 2.9, and 6.2 months, while for GA-negative patients, 6.9, 3.1, and 6.9 months, respectively. This study revealed that one in eight a/m UC patients had FGFR2/3 GAs, and a few changes were observed in FGFR GA status before and after treatment. Genetic testing will be beneficial for the selection of appropriate treatments after a diagnosis of a/m UC. Show less

The prevalence of gestational diabetes mellitus (GDM) is significantly increasing. Hyperglycaemia and dyslipidaemia have been demonstrated to contribute to endothelial dysfunction linked to foetal-placental circulation. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) is crucial for the lipolytic processing of TG-rich lipoproteins through the anchoring of lipoprotein lipase (LPL). In this study, circulating GPIHBP1 levels during pregnancy were evaluated, and their associations with hypertriglyceridaemia and the perinatal outcomes of GDM were evaluated. This study included 12 pregnant women with GDM and 21 pregnant women with normal glucose tolerance (NGT). No significant differences in obstetrical outcomes were detected between the two groups. In participants with NGT, circulating GPIHBP1 levels were markedly lower in the 3rd trimester than in the 2nd trimester and at delivery. In women with GDM, circulating GPIHBP1 levels were unchanged during the 3rd trimester, and circulating GPIHBP1 levels throughout the 3 Our findings suggest a possible association between circulating GPIHBP1 levels and perinatal outcomes in patients with GDM. Show less

Platelet-rich plasma (PRP), which is prepared by concentrating platelets in autologous blood, shows efficacy in chronic skin wounds via multiple growth factors. However, it exhibits heterogeneity across patients, leading to unstable therapeutic efficacy. Human induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) are capable of providing a stable supply, holding promise as materials for novel platelet concentrate-based therapies. In this context, we evaluated the effect of iMPs on wound healing and validated lyophilization for clinical applications. The growth factors released by activated iMPs were measured. The effect of the administration of iMPs on human fibroblasts and human umbilical vein endothelial cells (HUVECs) was investigated in vitro. iMPs were applied to dorsal skin defects of diabetic mice to assess the wound closure rate and quantify collagen deposition and angiogenesis. Following the storage of freeze-dried iMPs (FD-iMPs) for three months, the stability of growth factors and their efficacy in animal models were determined. Multiple growth factors that promote wound healing were detected in activated iMPs. iMPs specifically released FGF2 and exhibited a superior enhancement of HUVEC proliferation compared to PRP. Moreover, an RNA-seq analysis revealed that iMPs induce polarization to stalk cells and enhance ANGPTL4 gene expression in HUVECs. Animal studies demonstrated that iMPs promoted wound closure and angiogenesis in chronic wounds caused by diabetes. We also confirmed the long-term stability of growth factors in FD-iMPs and their comparable effects to those of original iMPs in the animal model. Our study demonstrates that iMPs promote angiogenesis and wound healing through the activation of vascular endothelial cells. iMPs exhibited more effectiveness than PRP, an effect attributed to the exclusive presence of specific factors including FGF2. Lyophilization enabled the long-term maintenance of the composition of the growth factors and efficacy of the iMPs, therefore contributing to stable supply for clinical application. These findings suggest that iMPs provide a novel treatment for chronic wounds. Show less

To investigate differential gene expression profiles in the bladder of spontaneously hypertensive rat (SHR), as the underlying mechanisms involved in hypertension-associated bladder dysfunction remain to be clarified. SHR and normotensive Wistar-Kyoto (WKY) rats were distributed initially in three groups: group 1 received doxazosin (30 mg/kg/day); group 2 received nifedipine (30 mg/kg/day); and group 3 received the vehicle orally for 4 weeks. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential biological relevance were verified by real-time reverse transcription-polymerase chain reaction (RT-PCR). Voiding frequency was significantly higher, and mean voided volume was significantly lower in untreated SHRs than untreated WKY rats. Microarray analysis revealed that 25 of the differentially expressed genes in untreated SHRs compared to untreated WKY rats were related to G(s), G(i), G(q) and G(12/13) signalling, calcium handling, ion transport and smooth muscle-related genes. Furthermore, RT-PCR data, in accord with the microarray analysis, indicated that untreated SHRs had lower mRNA expression levels of Adcy2, Adcy3, Rgs2, Rgs3, Rgs4 and Arhgdia, and higher mRNA expression levels of Arhgef1, Arhgef11, Arhgef12, Geft, Rock1 and Rock2 than untreated WKY rats. The differential alterations in the micturition patterns and in the expression of several genes related to G-protein signalling pathway observed in SHRs were attenuated by treatment with doxazosin, but not nifedipine. Our data suggest that differential alterations in the expression of several genes related to G(s), G(q) and G(12/13) signalling pathways in the SHR bladder might be important in hypertension-associated bladder dysfunction. Show less

There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, heterochromatin protein 1beta (HP1beta), but not HP1alpha or HP1gamma was found to be an AR cofactor. HP1beta interacted with the AR, and enhanced the DNA-binding ability of AR to androgen-responsive element in the prostate-specific antigen enhancer and promoter regions, and to increase the transcription of AR target genes. In prostate cancer (PCa) tissues, HP1beta expressions correlated with Gleason score and tri-methylation levels of histone H3 lysine 9. Silencing of HP1beta suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, HP1beta was overexpressed in castration-resistant LNCaP derivative CxR cells, and HP1beta knockdown also suppressed the cell growth in CxR cells. These findings indicate that HP1beta is involved in the proliferation of AR-expressing PCa cells and progression to CRPC as an AR coactivator. Modulation of HP1beta expression or function might be a useful strategy for developing novel therapeutics for PCa, even in CRPC. Show less