The aspartic protease cathepsin D, a poor prognostic indicator of breast cancer, is abundantly secreted as procathepsin D by human breast cancer cells and self-activates at low pH in vitro, giving ...rise to catalytically active cathepsin D. Due to a lower extracellular pH in tumor microenvironments compared to normal tissues, cathepsin D may cleave pathophysiological substrates contributing to cancer progression. Here, we show by yeast 2-hybrid and degradomics analyses that cystatin C, the most potent natural secreted inhibitor of cysteine cathepsins, both binds to and is a substrate of extracellular procathepsin D. The amount of cystatin C in the extracellular environment is reduced in the secretome of mouse embryonic fibroblasts stably transfected with human cathepsin D. Cathepsin D extensively cleaved cystatin C in vitro at low pH. Cathepsin D secreted by breast cancer cells also processed cystatin C at the pericellular pH of tumors and so enhancing extracellular proteolytic activity of cysteine cathepsins. Thus, tumor derived cathepsin D assists breast cancer progression by reducing cystatin C activity, which, in turn, enhances cysteine cathepsin proteolytic activity, revealing a new link between protease classes in the protease web.
Aims
Syncope in Wolff-Parkinson-White (WPW) syndrome may reveal an arrhythmic event or is not WPW syndrome related. The aim of the study is to evaluate the results of electrophysiological study in ...WPW syndrome according to the presence or not of syncope and the possible causes of syncope.
Methods and results
Among 518 consecutive patients with diagnosis of WPW syndrome, 71 patients, mean age 34.5 ± 17, presented syncope. Transoesophageal electrophysiological study in control state and after isoproterenol infusion was performed in the out-patient clinic. Atrioventricular re-entrant tachycardia (AVRT) was more frequently induced than in asymptomatic patients (n = 38, 53.5%, P < 0.01), less frequently than in those with tachycardia; atrial fibrillation (AF) and/or antidromic tachycardia (ATD) was induced in 28 patients (39%) more frequently (P < 0.05) than in asymptomatic patients or those with tachycardia. The incidence of high-risk form rapid conduction over accessory pathway (AP) and AF or ATD induction was higher in syncope group (n = 18, 25%, P < 0.001) than in asymptomatic subjects (8%) or those with tachycardias (7.5%). Maximal rate conducted over AP was similar in patients with and without syncope, and higher in patients with spontaneous AF, but without syncope. Results were not age-related.
Conclusion
Tachycardia inducibility was higher in patients with syncope than in the asymptomatic group. The incidence of malignant WPW syndrome was higher in patients with syncope than in asymptomatic or symptomatic population, but the maximal rate conducted over AP was not higher and another mechanism could be also implicated in the mechanism of syncope.
Intravenous (IV) alteplase is not currently recommended in octogenarian patients, and the benefit/risk ratio of endovascular (intra-arterial, IA) therapy remains to be determined. The aim of this ...study was to determine the impact of a combined IV-IA approach in octogenarians.
From a single-centre interventional study, we report age-specific outcomes of patients treated by a combined IV-IA thrombolytic approach. Patients ≥80 years with documented arterial occlusion treated by conventional IV thrombolysis constituted the control group.
Among 84 patients treated by the IV-IA approach, those ≥80 years (n = 25) had a similar rate of early neurological improvement to that of patients <80 years, whereas the 90-day favourable outcome rate was lower in octogenarians (adjusted odds ratio, OR, 0.21; 95% confidence interval, CI, 0.06-0.75). No difference in symptomatic intracranial haemorrhage was observed whereas a higher rate of 90-day mortality (adjusted OR, 3.27; 95% CI, 0.76-14.14) and asymptomatic intracranial haemorrhage (adjusted OR, 6.39; 95% CI, 1.54-26.63) were found in patients ≥80 years old. Among octogenarians, and compared to IV-thrombolysis-treated patients (n = 24), patients treated by the IV-IA approach had a higher rate of recanalization (76 vs. 33%, p = 0.003) associated with increased early neurological improvement (32 vs. 8%, p = 0.07). Although there was a higher rate of asymptomatic intracranial haemorrhage (44 vs. 8%, p = 0.005) observed in the IV-IA group, no difference existed in symptomatic intracranial haemorrhage rates and 90-day favourable outcome.
The IV-IA approach in octogenarians was associated with lower efficacy at 3 months and higher mortality and asymptomatic haemorrhagic complications than in patients <80 years old. Definite recommendations cannot be given, but an endovascular approach may cause more harm than positive effects in patients over 80 years and should not be considered outside an approved protocol.
Under microwave irradiation, a series of 2-aminomorpholines were readily produced in a straightforward four-component process from commercially available 1,2-aminoalcohols, glyoxal, boronic acids and ...aliphatic or aromatic amines. Further reduction furnished the corresponding diaminoalcohols.
Background.Fungal aneurysms of the carotid artery are rare. We report here a case of Aspergillus fumigatus invasive sphenoidal sinusitis complicated by carotid artery aneurysms in a severely ...neutropenic patient who was successfully treated with a combination of antifungal therapy and embolization of all aneurysms. Methods and results.Carotid aneurysms were suspected when severe epistaxis occurred during follow-up for sinusitis. MRI angiograph and cerebral angiograph revealed 5 aneurysms involving the right intracavernous carotid artery. Coil endovascular embolization was successfully used for the first time in this context, and the patient is alive 2 years later. We also reviewed the literature and identified 10 cases of fungal carotid artery aneurysms. Aspergillus species was the most common fungal organism. All patients were immunocompromised and had to be treated surgically. Conclusions.Internal carotid arterial involvement is a rare but life-threatening complication of invasive fungal sinusitis. Fungal aneurysms should be diagnosed early, so that the embolization procedure can be performed before the occurrence of severe bleeding.
In crop species, the impact of temperature on plant development is classically modelled using thermal time. We examined whether this method could be used in a non-crop species, Arabidopsis thaliana, ...to analyse the response to temperature of leaf initiation rate and of the development of two leaves of the rosette. The results confirmed the large plant-to-plant variability in the studied isogenic line of the Columbia ecotype: 100-fold differences in leaf area among plants sown on the same date were commonly observed at a given date. These differences disappeared in mature leaves, suggesting that they were due to a variability in plant developmental stage. The whole population could therefore be represented by any group of synchronous plants labelled at the two-leaf stage and followed during their development. Leaf initiation rate, duration of leaf expansion and maximal relative leaf expansion rate varied considerably among experiments performed at different temperatures (from 6 to 26 degrees C) but they were linearly related to temperature in the range 6-26 degrees C, with a common x-intercept of 3 degrees C. Expressing time in thermal time with a threshold temperature of 3 degrees C unified the time courses of leaf initiation and of individual leaf development for plants grown at different temperatures and experimental conditions. The two leaves studied (leaf 2 and leaf 6) had a two-phase development, with an exponential phase followed by a phase with decreasing relative elongation rate. Both phases had constant durations for a given leaf position if expressed in thermal time. Changes in temperature caused changes in both the rate of development and in the expansion rate which mutually compensated such that they had no consequence on leaf area at a given thermal time. The resulting model of leaf development was applied to ten experiments carried out in a glasshouse or in a growth chamber, with plants grown in soil or hydroponically. Because it predicts accurately the stage of development and the relative expansion rate of any leaf of the rosette, this model facilitates precise planning of sampling procedures and the comparison of treatments in growth analyses.
Pneumatic actuators have inherent compliance and hence they are very interesting for applications involving interaction with environment or human. But controlling such kind of actuators is not ...trivial. The paper presents an implementation of iterative Linear Quadratic regulator (iLQR) based optimal control framework to control an anthropomorphic arm with each joint actuated by an agonist-antagonistic pair of Mckibben artificial muscles. The method is applied to positioning tasks and generation of explosive movements by maximizing the link speed. It is then compared to traditional control strategies to justify that optimal control is effective in controlling the position in highly non-linear pneumatic systems. Also the importance of varying compliance is highlighted by repeating the tasks at different compliance level. The algorithm validation is reported here by several simulations and hardware experiments in which the shoulder and elbow flexion are controlled simultaneously.
Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate ...melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp)=0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp)=0.006) and secretion of suppressive factors (p(emp)=0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.
Intracranial haemorrhage (ICH) is known to be a severe although uncommon complication of haemophilia. A national survey has been conducted in France in order to collect information about ICHs which ...occurred in haemophiliacs between 1991 and 2001 and to propose recommendations for the diagnostic and treatment of ICH. Within this period, 123 episodes of ICH were recorded from 106 patients. Two‐thirds of ICH concerned patients with severe haemophilia. Half of the cases occurred in patients under 15 years of age, 67.2% of which were post‐traumatic. Ten cases occurred in neonates with three fatal outcomes. Overall mortality was high (21.9%) suggesting that availability of clotting factor concentrates has not improved the prognosis of this event. Morbidity was also high with 60% of long‐term sequelae. The following parameters have been identified as prognostic factors for death: thrombocytopenia, HCV infection, intraventricular or intraparenchymatous haemorrhage. A delay in diagnosis was mentioned in 43.3% of cases, often related to the lack of recognition of the initial symptoms, which may be very common (apathy, tearfulness in young children and headache in elder patients). Delayed replacement therapy was recorded in 37.2% of cases. Emergency units initially dealt with half of these patients. Information concerning recognition and management of these episodes, not only in severe haemophilia, but also in moderate and mild forms, should be regularly supplied to paediatricians in maternity and physicians from emergency units, as well as to patients and their relatives.
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