To evaluate whether cardiomyocyte membrane structure and cell/extracellular matrix adhesion alterations perturb the cadherin/catenin complex in the hypertrophic cardiomyopathy (HCM).
Hypertrophic ...cardiomyopathic hamster (UM-X7.1 strain) and human hearts were studied by light and electron microscopy, Northern and Western blot analyses and immunohistochemistry.
Intercalated disks are disorganized in both hamster and human cardiomyopathic hearts; beta-catenin is increased and accumulated in intercalated disks depriving cardiomyocyte nuclei of fundamental signals. The accumulation of beta-catenin is post-translationally regulated by an increased Wnt expression, a simultaneous decrease in glycogen synthase kinase 3beta (GSK3beta) expression and a different expression pattern of adenomatous polyposis coli (APC) isoforms.
The reorganization of cell/cell adhesion in cardiomyopathic hearts is mainly contributed by the cadherin/catenin system, which is differently regulated to sustain cell structural rather than signalling needs causing considerable consequences in the determination of cardiomyocyte phenotype and clinical outcome. The accumulation of beta-catenin in intercalated disks could concur to increase myocardial wall stiffness and left ventricular end-diastolic pressure (LVEDP) in hypertrophic cardiomyopathic hamster and human hearts.
The aim of this study was to evaluate the safety profile of s.c. administered recombinant human interleukin 12 (rHuIL-12). Pharmacokinetics and pharmacodynamics of rHuIL-12 and any evidence of ...antitumor effect were also considered. Ten pretreated patients with progressive metastatic melanoma were enrolled in this pilot study. Patients received a fixed dose of rHuIL-12 (0.5 microgram/kg) for two identical 28-day cycles, with injections given on days 1, 8, and 15 of each cycle. In case of any evidence of response or disease stabilization, the treatment was continued for two further 28-day cycles. Toxicity mainly consisted of a flu-like syndrome. Transient increases in transaminasemia (6 of 10 patients) and triglyceridemia (8 of 10 patients) were observed. Peak serum IL-12 levels were reached 8-12 h after the first injection in all patients; no serum IL-12 was detectable in 6 of 9 evaluable patients after the last injection of the second cycle. No antibody response to rHuIL-12 could be detected in any of the patients. A marked, transient reduction in circulating CD8+ and CD16+ lymphocytes and neutrophils was observed after the first administration and high levels of serum IFN-gamma and IL-10 were detected in all patients within 24-48 h. Tumor shrinkage, not reaching partial or complete remission, involved the regression of s.c. nodules (2 of 3 patients), superficial adenopathies (1 of 3 patients), and hepatic metastases (1 of 3 patients); regressions were detected after the first cycle of treatment and were maintained in spite of progression at different sites. s.c. rHuIL-12 treatment was well tolerated and had marked effects on immune parameters and potential antitumor activity.
Summary
Recent studies suggest that the prosurvival signal transduction pathway involving phosphoinositide 3‐kinase (PI3K)/Akt can confer an aggressive, apoptosis‐resistant phenotype to acute ...leukaemia cells. We have investigated the effect of modulating this signalling pathway on the sensitivity of leukaemic cell lines (NB‐4, CEM, Jurkat, MOLT‐4) and acute promyelocytic primary blasts to apoptosis induced by 1 μmol/l As2O3. Whereas parental NB‐4 cells did not display any phosphorylated (active) Akt, CEM, Jurkat and MOLT‐4 cells exhibited high levels of Akt activation. Consistently, treatment of NB‐4 cells with pharmacological inhibitors of the PI3K/Akt pathway (LY294002, wortmannin) did not increase sensitivity of these cells to arsenic trioxide (As2O3), whereas siRNA knock‐down of Akt enhanced As2O3‐induced apoptosis of CEM, Jurkat and MOLT‐4 cells. Overexpression of a constitutively active Akt cDNA rendered NB‐4 cells less susceptible to As2O3. Upon prolonged exposure to As2O3, we isolated a NB‐4 cell clone that was resistant to As2O3 and displayed high levels of active Akt. LY294002 treatment of acute promyelocytic primary blasts with elevated Akt phosphorylation levels resulted in an increased sensitivity to As2O3. These results may provide a rationale for the development of combined or sequential treatment with PI3K/Akt inhibitors to improve the efficacy of As2O3 on acute leukaemias and also to overcome As2O3 resistance.
As an extension of previous investigations (Tetrahedron 1999, 55, 5433-5440; J. Heterocycl. Chem. 2000, 37, 875-878), a series of 21 1,4thiazino3,4-c1,2,4oxadiazolones, which has already been ...synthesized (except for compounds 5a, 5b, 6), was evaluated as calcium entry blockers by functional studies, namely, in isolated guinea-pig left and right atria and K(+)-depolarized aortic strips. With the aim of investigating the effect of a condensed benzene ring on the molecular structure and the influence of substituents on the 8-phenyl ring of 4a, ab initio computations (RHF/3-21G) were performed on compounds 3, 4a-d, 4f, and 4k. The results obtained show that many of the compounds studied are potent and selective negative inotropic agents; in particular, compounds 4e and 4f are about 3- and 2-fold more potent than diltiazem, respectively.
The CUBES Science Case Evans, Chris; Cristiani, Stefano; Opitom, Cyrielle ...
arXiv.org,
09/2022
Paper, Journal Article
Odprti dostop
We introduce the scientific motivations for the development of the Cassegrain U-Band Efficient Spectrograph (CUBES) that is now in construction for the Very Large Telescope. The assembled cases span ...a broad range of contemporary topics across Solar System, Galactic and extragalactic astronomy, where observations are limited by the performance of current ground-based spectrographs shortwards of 400nm. A brief background to each case is presented and specific technical requirements on the instrument design that flow-down from each case are identified. These were used as inputs to the CUBES design, that will provide a factor of ten gain in efficiency for astronomical spectroscopy over 300-405nm, at resolving powers of R~24,000 and ~7,000. We include performance estimates that demonstrate the ability of CUBES to observe sources that are up to three magnitudes fainter than currently possible at ground-ultraviolet wavelengths, and we place its predicted performance in the context of existing facillities.
PDF
