This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with ...melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.
We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival.
The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval CI, 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively).
Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).
Ferredoxin‐NADP+ reductases (FNRs) are ubiquitous flavoenzymes involved in redox metabolisms. FNRs catalyze the reversible electron transfer between NADP(H) and ferredoxin or flavodoxin. They are ...classified as plant‐ and mitochondrial‐type FNR. Plant‐type FNRs are divided into plastidic and bacterial classes. The plastidic FNRs show turnover numbers between 20 and 100 times higher than bacterial enzymes and these differences have been related to their physiological functions. We demonstrated that purified Escherichia coli FPR (EcFPR) contains tightly bound NADP+, which does not occur in plastidic type FNRs. The three‐dimensional structure of EcFPR evidenced that NADP+ interacts with three arginines (R144, R174, and R184) which could generate a very high affinity and structured site. These arginines are conserved in other bacterial FNRs but not in the plastidic enzymes. We have cross‐substituted EcFPR arginines with residues present in analogous positions in the Pisum sativum FNR (PsFNR) and replaced these amino acids by arginines in PsFNR. We analyzed all proteins by structural, kinetic, and stability studies. We found that EcFPR mutants do not contain bound NADP+ and showed increased Km for this nucleotide. The EcFPR activity was inhibited by NADP+ but this behavior disappeared as arginines were removed. A NADP+ analog of the nicotinamide portion produced an activating effect on EcFPR and promoted the NADP+ release. Our results give evidence for a new model of NADP+ binding and catalysis in bacterial FNRs.We propose that this tight NADP+ binding constitutes an essential catalytic and regulatory mechanism of bacterial FNRs involved in redox homeostasis.
For survivors of severe COVID-19 disease, having defeated the virus is just the beginning of an uncharted recovery path. What follows after the acute phase of SARS-CoV-2 infection depends on the ...extension and severity of viral attacks in different cell types and organs. Despite the ridiculously large number of papers that have flooded scientific journals and preprint-hosting websites, a clear clinical picture of COVID-19 aftermath is vague at best. Without larger prospective observational studies that are only now being started, clinicians can retrieve information just from case reports and or small studies. This is the time to understand how COVID-19 goes forward and what consequences survivors may expect to experience. To this aim, a multidisciplinary post-acute care service involving several specialists has been established at the Fondazione Policlinico Universitario A. Gemelli IRCSS (Rome, Italy). Although COVID-19 is an infectious disease primarily affecting the lung, its multi-organ involvement requires an interdisciplinary approach encompassing virtually all branches of internal medicine and geriatrics. In particular, during the post-acute phase, the geriatrician may serve as the case manager of a multidisciplinary team. The aim of this article is to describe the importance of the interdisciplinary approach––coordinated by geriatrician––to cope the potential post-acute care needs of recovered COVID-19 patients.
The aim of this paper is to investigate the fluid dynamic behaviour of a commercial hydraulic proportional valve in order to evaluate and justify its global performances and, in particular, to ...analyze the effects of some additional design features on the reduction of the force required to maintain the valve open. The proposed analysis has been performed by applying the commercial computational fluid dynamics (CFD) code, Fluent, to the solution of the three dimensional turbulent flow field through a circumferential sector of the entire valve for different spool strokes. The reliability of the employed modelization is demonstrated by the comparison between the computed flow rate curve and the corresponding experimental data provided by the manufacturer. With regard to the metering edge design, it is shown that the cylindrical hole provided on the top of the hemi-spherical notch to improve metering at small valve openings has no influence on the flow force balance. The presented results also demonstrate that compensation techniques based on an adequate spool profiling are effective in balancing the flow forces mainly at medium and large valve openings, thanks to the pressure difference on the compensation profile; which also results in an increased axial momentum at the inlet of the high pressure chamber. The benefits of its presence are amplified by the adoption of two grooves machined on the valve body, which modify the flow field so as both to increase the axial momentum at the inlet of the high pressure chamber and to reduce it at the outlet.
IntroductionSubstance use disorders (SUDs) take an enormous toll on US Veterans and civilians alike. Existing empirically supported interventions vary by substance and demonstrate only moderate ...efficacy. Non-invasive brain stimulation represents an innovative treatment for SUDs, yet aspects of traditional neurostimulation may hinder its implementation in SUD populations. Synchronised transcranial magnetic stimulation (sTMS) uses rotating rare earth magnets to deliver low-field stimulation synchronised to an individual’s alpha peak frequency that is safe for at-home administration. The current trial aims to assess the acceptability and feasibility of sTMS, as well as the safety of at-home sTMS administration for substance-disordered Veterans.Methods and analysisSixty Veterans in substance treatment at the Providence Veterans Affairs will be randomised to receive 6 weeks of active or sham sTMS treatment. Eligibility will be confirmed by meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for an alcohol, cocaine or opioid use disorder. Daily supervised sTMS treatment will occur either in clinic or at home through video monitoring. Clinical and self-report assessments will be completed at baseline, end of treatment and 1-month follow-up. Urine drug screening will occur once per week during the treatment phase. Primary outcomes include treatment adherence/retention and satisfaction to evaluate sTMS feasibility and acceptability in Veterans with SUDs. The safety of at-home sTMS administration will be assessed via adverse event monitoring.Ethics and disseminationThe sTMS device received a significant risk determination for at-home use by the Food and Drug Administration in July 2021. Ethics approval was obtained in August 2021 from the Providence Veterans Affairs institutional review board and research and development committee. Data collection began in September 2021 and is planned to continue through December 2023. Findings will be disseminated at national conferences and in peer-reviewed journals. Results will serve to inform the development of large-scale clinical trials of sTMS efficacy for substance-disordered Veterans.Trial registration numberClinicalTrials.gov Registry (NCT04336293).
Xanthomonas citri subsp. citri (Xcc), the causal agent of citrus canker is maintained as an epiphyte on citrus leaves until entering the plant tissue. During epiphytic survival, bacteria may ...encounter low water availability that challenges the infection process. Proteomics analyses of Xcc under saline stress, mimicking the conditions found during epiphytic survival, showed increased abundance of a putative NAD(P)H dehydrogenase encoded by XAC2229.
Expression levels of XAC2229 and a Xcc mutant in XAC2229 were analyzed in salt and oxidative stress and during plant-pathogen interaction. An Escherichia coli expressing XAC2229 was obtained, and the role of this protein in oxidative stress resistance and in reactive oxygen species production was studied. Finally, Xac2229 protein was purified, spectrophotometric and cofactor analyses were done and enzymatic activities determined.
XAC2229 was expressed under salt stress and during plant-pathogen interaction. ΔXAC2229 mutant showed less number of cankers and impaired epiphytic survival than the wild type strain. ΔXAC2229 survived less in the presence of H2O2 and produced more reactive oxygen species and thiobarbituric acid-reactive substances than the wild type strain. Similar results were observed for E. coli expressing XAC2229. Xac2229 is a FAD containing flavoprotein, displays diaphorase activity with an optimum at pH 6.0 and has quinone reductase activity using NADPH as an electron donor.
A FAD containing flavoprotein from Xcc is a new NADPH quinone reductase required for bacterial virulence, particularly in Xcc epiphytic survival on citrus leaves.
A novel protein involved in the worldwide disease citrus canker was characterized.
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•Xanthomonas citri XAC2229 gene is required for bacterial epiphytic survival.•Xac2229 is a FAD-containing enzyme that preferentially uses NADPH as electron donor.•Xac2229 is a dehydrogenase with quinone reductase activity.
Heme oxygenase from Leptospira interrogans is an important virulence factor. During catalysis, redox equivalents are provided to this enzyme by the plastidic-type ferredoxin-NADP+ reductase also ...found in L. interrogans. This process may have evolved to aid this bacterial pathogen to obtain heme-iron from their host and enable successful colonization. Herein we report the crystal structure of the heme oxygenase-heme complex at 1.73 Å resolution. The structure reveals several distinctive features related to its function. A hydrogen bonded network of structural water molecules that extends from the catalytic site to the protein surface was cleared observed. A depression on the surface appears to be the H+ network entrance from the aqueous environment to the catalytic site for O2 activation, a key step in the heme oxygenase reaction. We have performed a mutational analysis of the F157, located at the above-mentioned depression. The mutant enzymes were unable to carry out the complete degradation of heme to biliverdin since the reaction was arrested at the verdoheme stage. We also observed that the stability of the oxyferrous complex, the efficiency of heme hydroxylation and the subsequent conversion to verdoheme was adversely affected. These findings underscore a long-range communication between the outer fringes of the hydrogen-bonded network of structural waters and the heme active site during catalysis. Finally, by analyzing the crystal structures of ferredoxin-NADP+ reductase and heme oxygenase, we propose a model for the productive association of these proteins.
A novel class of superfluorinated and NIR-luminescent gold nanoclusters were obtained starting from a branched thiol, bearing 27 equivalent
F atoms per molecule. These unprecedented clusters combine ...in a unique nanosystem both NIR photoluminescence and
F NMR properties, thus representing a promising multimodal platform for bioimaging applications.
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