Project description:Cysteine cathepsins are a group of proteases involved in many physiological and pathological processes. Yet, the selective detection and inhibition of individual cathepsins is still challenging. This editorial is discussing the context of a recent work introducing a designed ankyrin repeat protein (DARPin) as novel approach for selective targeting of the protease cathepsin B.
Project description:Rationale: Tissue Doppler imaging (TDI) is an echocardiographic method that measures the velocity of moving tissue.Objectives: We applied this technique to the diaphragm to assess the velocity of diaphragmatic muscle motion during contraction and relaxation.Methods: In 20 healthy volunteers, diaphragmatic TDI was performed to assess the pattern of diaphragmatic motion velocity, measure its normal values, and determine the intra- and interobserver variability of measurements. In 116 consecutive ICU patients, diaphragmatic excursion, thickening, and TDI parameters of peak contraction velocity, peak relaxation velocity, velocity-time integral, and TDI-derived maximal relaxation rate were assessed during weaning. In a subgroup of 18 patients, transdiaphragmatic pressure (Pdi)-derived parameters (peak Pdi, pressure-time product, and diaphragmatic maximal relaxation rate) were recorded simultaneously with TDI.Measurements and Main Results: In terms of reproducibility, the intercorrelation coefficients were >0.89 for all TDI parameters (P < 0.001). Healthy volunteers and weaning success patients exhibited lower values for all TDI parameters compared with weaning failure patients, except for velocity-time integral, as follows: peak contraction velocity, 1.35 ± 0.34 versus 1.50 ± 0.59 versus 2.66 ± 2.14 cm/s (P < 0.001); peak relaxation velocity, 1.19 ± 0.39 versus 1.53 ± 0.73 versus 3.36 ± 2.40 cm/s (P < 0.001); and TDI-maximal relaxation rate, 3.64 ± 2.02 versus 10.25 ± 5.88 versus 29.47 ± 23.95 cm/s2 (P < 0.001), respectively. Peak contraction velocity was strongly correlated with peak transdiaphragmatic pressure and pressure-time product, whereas Pdi-maximal relaxation rate was significantly correlated with TDI-maximal relaxation rate.Conclusions: Diaphragmatic tissue Doppler allows real-time assessment of the diaphragmatic tissue motion velocity. Diaphragmatic TDI-derived parameters differentiate patients who fail a weaning trial from those who succeed and correlate well with Pdi-derived parameters.
Project description:Vitamin D is an essential steroid hormone, with well established effects on mineral metabolism, skeletal health, and recently established effects on the cardiovascular and immune systems. Vitamin D deficiency is highly prevalent and evidence is mounting that it contributes to the morbidity and mortality of multiple chronic diseases, including systemic lupus erythematosus (SLE). Patients with SLE avoid the sun because of photosensitive rashes and potential for disease fare, so adequate oral supplementation is critical. This review will describe the prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency, and review current vitamin D recommendations for patients with rheumatic diseases.
Project description:The discovery of the Ten-Eleven-Translocation (TET) oxygenases that catalyze the hydroxylation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) has triggered an avalanche of studies aiming to resolve the role of 5hmC in gene regulation if any. Hitherto, TET1 is reported to bind to CpG-island (CGI) and bivalent promoters in mouse embryonic stem cells, whereas binding at DNAseI hypersensitive sites (HS) had escaped previous analysis. Significant enrichment/accumulation of 5hmC but not 5mC can indeed be detected at bivalent promoters and at DNaseI-HS. Surprisingly, however, 5hmC is not detected or present at very low levels at CGI promoters notwithstanding the presence of TET1. Our meta-analysis of DNA methylation profiling points to potential issues with regard to the various methodologies that are part of the toolbox used to detect 5mC and 5hmC. Discrepancies between published studies and technical limitations prevent an unambiguous assignment of 5hmC as a 'true' epigenetic mark, that is, read and interpreted by other factors and/or as a transiently accumulating intermediary product of the conversion of 5mC to unmodified cytosines.
Project description:Androgen-deprivation therapy (ADT) is the cornerstone of metastatic prostate cancer treatment. ADT can be achieved through surgical castration, or it may be induced either by gonadotrophin-releasing hormone (GnRH) agonists or GnRH antagonists. GnRH antagonists provide a more rapid castration alongside with a safer profile regarding adverse events. Degarelix is the sole GnRH antagonist used in clinical practice. Injection site reactions are the commonest adverse events related to the use of degarelix. Relugolix, a novel molecule, represents the first orally administered United States Food and Drug Administration approved GnRH antagonist, with clinical efficacy equal to that of the established ADT regimens. The main advantages of relugolix are the avoidance of the injection site reactions of GnRH antagonists such as degarelix alongside its patient-friendly oral administration. The aim of the present review article is to present novel data regarding the role of relugolix as ADT for the treatment of prostate cancer. Abbreviations: ADT: androgen-deprivation therapy; FDA: United States Food and Drug Administration.
Project description:Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1-7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9-63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.