Significance of myocardial tenascin-C expression in left ventricular remodelling and long-term outcome in patients with dilated cardiomyopathy

Aim Dilated cardiomyopathy (DCM) has a variety of causes, and no useful approach to predict left ventricular (LV) remodelling and long-term outcome has yet been established. Myocardial tenascin-C (TNC) is known to appear under pathological conditions, possibly to regulate cardiac remodelling. The aim of this study was to clarify the significance of myocardial TNC expression in LV remodelling and the long-term outcome in DCM. Methods and results One hundred and twenty-three consecutive DCM patients who underwent endomyocardial biopsy for initial diagnosis were studied. Expression of TNC in biopsy sections was analysed immunohistochemically to quantify the ratio of the TNC-positive area to the whole myocardial tissue area (TNC area). Clinical parameters associated with TNC area were investigated. The patients were divided into two groups based on receiver operating characteristic analysis of TNC area to predict death: high TNC group with TNC area ≥2.3% (22 patients) and low TNC group with TNC area <2.3% (101 patients). High TNC was associated with diabetes mellitus. Comparing echocardiographic findings between before and 9 months after endomyocardial biopsy, the low TNC group was associated with decreased LV end-diastolic diameter and increased LV ejection fraction, whereas the high TNC group was not. Survival analysis revealed a worse outcome in the high TNC group than in the low TNC group (P < 0.001). Multivariable Cox regression analysis revealed that TNC area was independently associated with poor outcome (HR = 1.347, P = 0.032). Conclusions Increased myocardial TNC expression was associated with worse LV remodeling and long-term outcome in DCM

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35).Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV

Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid

The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA

Upregulated EMMPRIN/CD147 might contribute to growth and angiogenesis of gastric carcinoma: a good marker for local invasion and prognosis

Tumour growth depends on angiogenesis, which is closely associated with vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Extracellular MMP inducer (EMMPRIN) was reported to involve in the progression of malignancies by regulating expression of VEGF and MMPs in stromal cells. To clarify the role of EMMPRIN in progression and angiogenesis of gastric carcinoma, expression of EMMPRIN, ki-67, MMP-2, MMP-9 and VEGF was examined on tissue microarray containing gastric carcinomas (n=234) and non-cancerous mucosa adjacent to carcinoma (n=85) by immunohistochemistry. Additionally, microvessel density (MVD) was assessed after labelling with anti-CD34 antibody. Extracellular MMP inducer expression was compared with clinicopathological parameters of tumours, including levels of ki-67, MMP-2, MMP-9 and vascular endothelial growth factor (VEGF), MVD as well as survival time of carcinoma patients. Gastric carcinoma cell lines (HGC-27, MKN28 and MKN45) were studied for EMMPRIN expression by immunohistochemistry and Western blot. Extracellular MMP inducer expression was gradually increased from normal mucosa to carcinomas through hyperplastic or metaplastic mucosa of the stomach (P<0.05). There was strong EMMPRIN expression in all gastric carcinoma cell lines despite different levels of glycosylation. Extracellular MMP inducer expression was positively correlated with tumour size, depth of invasion, lymphatic invasion, expression of ki-67, MMP-2, MMP-9 and VEGF of tumours (P<0.05), but not with lymph node metastasis, UICC staging or differentiation (P>0.05). Interestingly, there was a significantly positive relationship between EMMPRIN expression and MVD in gastric carcinomas (P<0.05). Survival analysis indicated EMMPRIN expression to be negatively linked to favourable prognosis (P<0.05), but not be independent factor for prognosis (P>0.05). Further analysis showed three independent prognostic factors, depth of invasion, lymphatic and venous invasion, to influence the relationship between EMMPRIN expression and prognosis. Upregulated expression of EMMPRIN possibly contributes to genesis, growth and local invasion of gastric carcinomas. Altered EMMPRIN expression might enhance growth, invasion and angiogenesis of gastric carcinoma via upregulating MMP expression of both stromal fibroblasts and gastric cancer cells and could be considered as an objective and effective marker to predict invasion and prognosis

Hitomi Constraints on the 3.5 keV Line in the Perseus Galaxy Cluster

High-resolution X-ray spectroscopy with Hitomi was expected to resolve the origin of the faint unidentified E=3.5 keV emission line reported in several low-resolution studies of various massive systems, such as galaxies and clusters, including the Perseus cluster. We have analyzed the Hitomi first-light observation of the Perseus cluster. The emission line expected for Perseus based on the XMM-Newton signal from the large cluster sample under the dark matter decay scenario is too faint to be detectable in the Hitomi data. However, the previously reported 3.5 keV flux from Perseus was anomalously high compared to the sample-based prediction. We find no unidentified line at the reported high flux level. Taking into account the XMM measurement uncertainties for this region, the inconsistency with Hitomi is at a 99% significance for a broad dark-matter line and at 99.7% for a narrow line from the gas. We do not find anomalously high fluxes of the nearby faint K line or the Ar satellite line that were proposed as explanations for the earlier 3.5 keV detections. We do find a hint of a broad excess near the energies of high-n transitions of Sxvi (E=3.44 keV rest-frame) -- a possible signature of charge exchange in the molecular nebula and another proposed explanation for the unidentified line. While its energy is consistent with XMM pn detections, it is unlikely to explain the MOS signal. A confirmation of this interesting feature has to wait for a more sensitive observation with a future calorimeter experiment

Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells

Background Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. Results Here, we report ARID1A, a DNA-binding subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) through distinct mechanisms. Knockout-of-ARID1A (ARID1A−/−) leads to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A −/− hESCs is prominently suppressed, whereas neural differentiation is significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses reveal that ARID1A is required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes is dependent on ARID1A, which can interact with a known neural restrictive silencer factor REST/NRSF. Conclusions We uncover the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction

Survey of period variations of superhumps in SU UMa-type dwarf novae. VII. the seventh year (2014-2015)

© The Author 2015. Published by Oxford University Press on behalf of the Astronomical Society of Japan. All rights reserved. Continuing the project described by Kato et al. (2009, PASJ, 61, S395), we collected times of superhump maxima for 102 SU UMa-type dwarf novae, observed mainly during the 2014-2015 season, and characterized these objects. Our project has greatly improved the statistics of the distribution of orbital periods, which is a good approximation of the distribution of cataclysmic variables at the terminal evolutionary stage, and has confirmed the presence of a period minimum at a period of 0.053 d and a period spike just above this period. The number density monotonically decreased toward the longer period and there was no strong indication of a period gap. We detected possible negative superhumps in Z Cha. It is possible that normal outbursts are also suppressed by the presence of a disk tilt in this system. There was no indication of enhanced orbital humps just preceding the superoutburst, and this result favors the thermal-tidal disk instability as the origin of superoutbursts. We detected superhumps in three AM CVn-type dwarf novae. Our observations and recent other detections suggest that 8% of objects showing dwarf nova-type outbursts are AM CVn-type objects. AM CVn-type objects and EI Psc-type objects may be more abundant than previously recognized. OT J213806, a WZ Sge-type object, exhibited remarkably different features between the 2010 and 2014 superoutbursts. Although the 2014 superoutburst was much fainter, the plateau phase was shorter than the 2010 one, and the course of the rebrightening phase was similar. This object indicates that the O - C diagrams of superhumps can indeed be variable, at least in WZ Sge-type objects. Four deeply eclipsing SU UMa-type dwarf novae (ASASSN-13cx, ASASSN-14ag, ASASSN-15bu, and NSV 4618) were identified. We studied long-term trends in supercycles in MM Hya and CY UMa and found systematic variations of supercycles of ∼20%