Detecting Clusters of Mutations

Positive selection for protein function can lead to multiple mutations within a small stretch of DNA, i.e., to a cluster of mutations. Recently, Wagner proposed a method to detect such mutation clusters. His method, however, did not take into account that residues with high solvent accessibility are inherently more variable than residues with low solvent accessibility. Here, we propose a new algorithm to detect clustered evolution. Our algorithm controls for different substitution probabilities at buried and exposed sites in the tertiary protein structure, and uses random permutations to calculate accurate P values for inferred clusters. We apply the algorithm to genomes of bacteria, fly, and mammals, and find several clusters of mutations in functionally important regions of proteins. Surprisingly, clustered evolution is a relatively rare phenomenon. Only between 2% and 10% of the genes we analyze contain a statistically significant mutation cluster. We also find that not controlling for solvent accessibility leads to an excess of clusters in terminal and solvent-exposed regions of proteins. Our algorithm provides a novel method to identify functionally relevant divergence between groups of species. Moreover, it could also be useful to detect artifacts in automatically assembled genomes

Low-dose integrated chemoimmuno-hormonotherapy with cisplatin, subcutaneous interleukin-2, alpha-interferon and tamoxifen for advanced metastatic melanoma--a pilot study.

Recently, Khayat et al. reported that high-dose recombinant interleukin-2 (rIL-2) i.v. may induce tumour regressions in metastatic melanoma patients through an association with cisplatin (CDDP) and alpha-interferon (alpha-IFN). Treatment-related toxicities are, however, important. Previous studies have demonstrated that rIL-2 toxicity may be reduced through a subcutaneous injection. In order to evaluate the effectiveness of low subcutaneous rIL-2 doses in a chemoimmuno-hormonotherapeutic combination, 36 metastatic melanoma patients were treated with CDDP, rIL-2, alpha-IFN and tamoxifen (TAM). The overall response rate was 47.2%: five patients had complete response (14%), 12 partial response (33%) and 13 stable disease (36%). Median response duration was 6.4 months (range: 2-29+). Median overall survival was 10 months (range: 3-36+). The CDDP/rIL-2/alpha-IFN/TAM regimen was effective both on soft tissue and visceral metastases. Toxicity was low and patient management did not require an intensive care unit. A statistically significant increase in both percentage and absolute values of lymphocytes, eosinophils, CD3+/CD4+, CD25+, CD16/56+ and HLA-DR+ cells was found in all patients after two treatment courses. This study shows that lower doses of subcutaneous rIL-2, as well as CDDP and alpha-IFN, associated with TAM, may have similar anticancer efficacy with respect to Khayat's schedule but lower toxicity

Use of Subcutaneous ICD after transvenous ICD extraction: an analysis of Italian clinical practice

Background: The subcutaneous implantable cardioverter defibrillator (S-ICD) is a relatively novel alternative to the transvenous ICD (T-ICD) for the treatment of life-threatening ventricular arrhythmias and is currently adopted in the clinical practice of several centers. Patients undergoing T-ICD explantation may be eligible for reimplantation with an S-ICD. Purpose: The aim of this analysis was to describe current Italian practice associated with S-ICD use after T-ICD explantation. Methods: We analyzed all consecutive patients who underwent transvenous extraction of a T-ICD and subsequent reimplantation of an S-ICD or a single-chamber T-ICD at 13 Italian centers from 2011 to 2017. Results: Data from 219 patients were analyzed. 83 patients received an S-ICD and 136 a single-chamber T-ICD. The utilization of S-ICD increased from 9% in 2011 to 83% in 2017 (p<0.001). S-ICD patients were younger than patients who received T-ICD (54±13 vs. 60±18 years, p=0.011), more frequently were male (90% vs. 74%, p=0.006) and showed a trend toward higher BMI (26±4 vs. 25±4, p=0.088). However, the underlying cardiomyopathy, the systolic function and the rate of comorbidities (diabetes, chronic renal disease) were comparable between groups. Venous thrombosis or obstruction was the reason for previous T-ICD extraction only in 4% of patients reimplanted with S-ICD. While, the reason was infection in 76% of patients reimplanted with S-ICD and in 53% of patients who received a new T-ICD (p<0.001). The proportion of patients previously implanted with a multi-lead (dual-chamber or biventricular) T-ICD and reimplanted with S-ICD or single-chamber T-ICD increased from 16% in 2011 to 71% in 2017 (p<0.001). Overall, a multi-lead T-ICD was previously implanted in 50% of patients reimplanted with S-ICD and 35% of those who received a single-chamber T-ICD (p=0.025). Conclusions: Our analysis demonstrated a trend to wider use of S-ICD after T-ICD explantation over the years. Also in this group of patients, the S-ICD is preferably adopted for specific patients (younger, male). The S-ICD is used not only in case of limited vascular access, but became the preferred option in case of infection. Increased consideration seemed to be given to the reappraisal of the actual need for pacing therapies, since multi-lead T-ICDs were not reimplanted in many patients, and an S-ICD was more frequently preferred

Enzymatic catalysis on conducting graphite particles.

A new concept for enzyme-catalyzed redox transformations features pairs of electron donor and acceptor enzymes attached to conducting particles. Electrons furnished by oxidation at one enzyme are used at the other. Graphite microparticles modified with hydrogenase and nitrate reductase or fumarate reductase catalyze reductions of nitrate or fumarate by H2