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The present study was designed to develop a novel method for identifying significant pathways associated with human hypertrophic cardiomyopathy (HCM), based on gene co-expression analysis. The microarray dataset associated with HCM (E-GEOD-36961) was obtained from the European Molecular Biology Laboratory-European Bioinformatics Institute database. Informative pathways were selected based on the Reactome pathway database and screening treatments. An empirical Bayes method was utilized to construct co-expression networks for informative pathways, and a weight value was assigned to each pathway. Differential pathways were extracted based on weight threshold, which was calculated using a random model. In order to assess whether the co-expression method was feasible, it was compared with traditional pathway enrichment analysis of differentially expressed genes, which were identified using the significance analysis of microarrays package. A total of 1,074 informative pathways were screened out for subsequent investigations and their weight values were also obtained. According to the threshold of weight value of 0.01057, 447 differential pathways, including folding of actin by chaperonin containing T-complex protein 1 (CCT)/T-complex protein 1 ring complex (TRiC), purine ribonucleoside monophosphate biosynthesis and ubiquinol biosynthesis, were obtained. Compared with traditional pathway enrichment analysis, the number of pathways obtained from the co-expression approach was increased. The results of the present study demonstrated that this method may be useful to predict marker pathways for HCM. The pathways of folding of actin by CCT/TRiC and purine ribonucleoside monophosphate biosynthesis may provide evidence of the underlying molecular mechanisms of HCM, and offer novel therapeutic directions for HCM. [ABSTRACT FROM AUTHOR]

Purpose: Urapidil is putatively effective for patients with hypertension and acute heart failure, although randomized controlled trials thereon are lacking. We investigated the efficacy and safety of intravenous urapidil relative to that of nitroglycerin in older patients with hypertension and heart failure in a randomized controlled trial. Materials and Methods: Patients (>60 y) with hypertension and heart failure were randomly assigned to receive intravenous urapidil (n=89) or nitroglycerin (n=91) for 7 days. Hemodynamic parameters, cardiac function, and safety outcomes were compared. Results: Patients in the urapidil group had significantly lower mean systolic blood pressure (110.1±6.5 mm Hg) than those given nitroglycerin (126.4±8.1 mm Hg, p=0.022), without changes in heart rate. Urapidil was associated with improved cardiac function as reflected by lower N terminal-pro B type natriuretic peptide after 7 days (3311.4±546.1 ng/mL vs. 4879.1±325.7 ng/mL, p=0.027) and improved left ventricular ejection fraction (62.2±3.4% vs. 51.0±2.4%, p=0.032). Patients given urapidil had fewer associated adverse events, specifically headache (p=0.025) and tachycardia (p=0.004). The one-month rehospitalization and allcause mortality rates were similar. Conclusion: Intravenous administration of urapidil, compared with nitroglycerin, was associated with better control of blood pressure and preserved cardiac function, as well as fewer adverse events, for elderly patients with hypertension and acute heart failure. [ABSTRACT FROM AUTHOR]

The flow softening behaviors of a nickel-based superalloy with δ phase are investigated by hot compression tests over wide ranges of deformation temperature and strain rate. Electron backscattered diffraction (EBSD), optical microscopy (OM), and scanning electron microscopy (SEM) are employed to study the flow softening mechanisms of the studied superalloy. It is found that the flow softening behaviors of the studied superalloy are sensitive to deformation temperature and strain rate. At high strain rate and low deformation temperature, the obvious flow softening behaviors occur. With the increase of deformation temperature or decrease of strain rate, the flow softening degree becomes weaken. At high strain rate (1s-1), the flow softening is mostly induced by the plastic deformation heating and flow localization. However, at low strain rate domains (0.001-0.01s-1), the effects of deformation heating on flow softening are slight. Moreover, the flow softening at low strain rates is mainly induced by the discontinuous dynamic recrystallization and the dissolution of δ phase (Ni3Nb). [ABSTRACT FROM AUTHOR]

Urapidil has been proposed to be an effective vasodilator for the treatment of acute decompensated heart failure (ADHF); however, its effect on cardiac function, as compared with that of nitroglycerin, in elderly patients with hypertension and ADHF has yet to be determined. In the present study, a multicenter, open-label clinical trial was performed, in which 120 elderly patients with hypertension and ADHF were randomly assigned to the treatment (50-400 μg/min intravenous urapidil) or control group (5-40 μg/min intravenous nitroglycerin). The dosages of the medications were adjusted according to the blood pressure of the patients. The systolic and diastolic blood pressure, heart rate and serum level of N-terminal pro B-type natriuretic peptide (NT-proBNP) were evaluated at hospital admission and at days 1, 2, 3 and 7 after treatment. In addition, the left ventricular function was assessed by measuring the left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume at hospital admission and at days 2 and 7 after treatment. The results indicated that intravenous administration of urapidil and nitroglycerin were effective in lowering the blood pressure and heart rate within 7 days, with no significant differences observed between the two groups (P>0.05). By contrast, greater reduction in the serum NT-proBNP level (2,410.4±546.1 vs. 4,234.1±876.4 pg/ml; P<0.05) and greater improvement in the LVEF (55.3±3.4 vs. 45.2±2.4%; P<0.05) were observed in the urapidil-treated group, as compared with the nitroglycerin-treated group. No adverse events were reported during the treatment period in the two groups. The clinical outcomes at 6 months following discharge were evaluated and were not found to be significantly different between the two groups. In conclusion, the present results of the present study suggested that urapidil was as effective as nitroglycerin in controlling blood pressure and heart rate and was more effective in improving cardiac systolic function in elderly patients with hypertension and ADHF. [ABSTRACT FROM AUTHOR]

Scinderin is a Ca2+-dependent filamentous actin (F-actin) severing and capping protein, which has a key role in regulated secretion. However, little is known regarding the function and mechanism of scinderin in human carcinoma development and progression. In the present study, the biological function of scinderin was investigated using a cell proliferation assay, flow cytometric analysis and a Transwell assay in highly tumorigenic and the metastatic human gastric cancer cell line SGC-7901 transfected with scinderin-small hairpin RNA lentivirus. The changes in the expression of epithelial-mesenchymal transition (EMT) markers were also investigated. The results indicated that scinderin knockdown effectively suppressed proliferation, reduced migration and arrested the cell cycle of the SGC-7901 cells at G2/M phase. Furthermore, scinderin knockdown altered the expression of EMT markers; the expression of E-cadherin was significantly upregulated, along with an evident decrease in N-cadherin and β-catenin expression. In conclusion, the present study suggested that suppression of scinderin impaired proliferation and migration of gastric cancer SGC-7901 cells and attenuates its EMT process. Scinderin may therefore be a potential target for tumor EMT and therapy against gastric cancer. [ABSTRACT FROM AUTHOR]

For the first two equations of the Volterra lattice hierarchy and the first two equations of its non-autonomous (non-isospectral) extension, we present Riccati systems for functions cj(t), , such that an expression in terms of Hankel determinants built from them solves these equations on the right half of the lattice. This actually achieves a complete linearization of these equations of the extended Volterra lattice hierarchy. [ABSTRACT FROM AUTHOR]

In this paper, we present a generalized Toeplitz determinant solution for the generalized Schur flow and propose a mixed form of the two known relativistic Toda chains together with its generalized Toeplitz determinant solution. In addition, we also give a Hankel type determinant solution for a nonisospectral Toda lattice. All these results are obtained by technical determinant operations. As a bonus, we finally obtain some new combinatorial numbers based on the moment relations with respect to these semi-discrete integrable systems and give the corresponding combinatorial interpretations by means of the lattice paths. [ABSTRACT FROM AUTHOR]

By introducing some special bi-orthogonal polynomials, we derive the so-called discrete hungry quotient-difference (dhQD) algorithm and a system related to the QD-type discrete hungry Lotka–Volterra (QD-type dhLV) system, together with their Lax pairs. These two known equations can be regarded as extensions of the QD algorithm. When this idea is applied to a higher analogue of the discrete-time Toda (HADT) equation and the quotient–quotient-difference (QQD) scheme proposed by Spicer, Nijhoff and van der Kamp, two extended systems are constructed. We call these systems the hungry forms of the higher analogue discrete-time Toda (hHADT) equation and the quotient-quotient-difference (hQQD) scheme, respectively. In addition, the corresponding Lax pairs are provided. [ABSTRACT FROM AUTHOR]

Abstract To evaluate the effect of SGLT2 inhibitor (SGLT2i) on albuminuria, nephrin (NPH) and transforming-growth-factor-beta1 (TGF-β1) levels in urine and low-grade inflammation in type 2 diabetes (T2D) patients. A randomized, blank-controlled clinical trial included 68 T2D patients and 10 controls. Based on the urinary albumin-to-creatinine ratio (UACR), 68 diabetic patients were stratified into three levels, UACR

Abstract Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.