Cardiovascular (CV) toxicity is a potential short- or long-term complication of various anticancer therapies. Some drugs, such as anthracyclines or other biological agents, have been implicated in ...causing potentially irreversible clinically important cardiac dysfunction. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare but serious complications have been described, and longer follow-up is needed to determine the exact profile and outcomes of related cardiac side-effects. Some of these side-effects are irreversible, leading to progressive CV disease, and some others induce reversible dysfunction with no long-term cardiac damage to the patient. Assessment of the prevalence, type and severity of cardiac toxicity caused by various cancer treatments is a breakthrough topic for patient management. Guidelines for preventing, monitoring and treating cardiac side-effects are a major medical need. Efforts are needed to promote strategies for cardiac risk prevention, detection and management, avoiding unintended consequences that can impede development, regulatory approval and patient access to novel therapy. These new ESMO Clinical Practice Guidelines are the result of a multidisciplinary cardio-oncology review of current evidence with the ultimate goal of providing strict criteria-based recommendations on CV risk prevention, assessment, monitoring and management during anticancer treatment.
Aging is usually accompanied by a significant reduction in muscle mass and force. To determine the relative contribution of inactivity and aging per se to this decay, we compared muscle function and ...structure in (a) male participants belonging to a group of well-trained seniors (average of 70 years) who exercised regularly in their previous 30 years and (b) age-matched healthy sedentary seniors with (c) active young men (average of 27 years). The results collected show that relative to their sedentary cohorts, muscle from senior sportsmen have: (a) greater maximal isometric force and function, (b) better preserved fiber morphology and ultrastructure of intracellular organelles involved in Ca(2+) handling and ATP production, (c) preserved muscle fibers size resulting from fiber rescue by reinnervation, and (d) lowered expression of genes related to autophagy and reactive oxygen species detoxification. All together, our results indicate that: (a) skeletal muscle of senior sportsmen is actually more similar to that of adults than to that of age-matched sedentaries and (b) signaling pathways controlling muscle mass and metabolism are differently modulated in senior sportsmen to guarantee maintenance of skeletal muscle structure, function, bioenergetic characteristics, and phenotype. Thus, regular physical activity is a good strategy to attenuate age-related general decay of muscle structure and function (ClinicalTrials.gov: NCT01679977).
Background. Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. Methods. ...Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography—tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. Results. Twenty-four patients aged 21–87 years received intravenous polymyxin B (0.45–3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10–143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r2 = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. Conclusions. Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.
Herpes simplex virus type 1 (HSV-1) protein ICP27 is a multifunctional regulator of gene expression that assumes different roles during the course of infection. Early in infection, ICP27 mediates the ...inhibition of cellular splicing, whereas, later it helps to recruit cellular RNA polymerase II (RNAP II) to viral replication sites and to facilitate viral RNA export. ICP27 has also been shown to stimulate translation of viral transcripts. ICP27 performs its activities by interacting with RNA and with an assortment of proteins. ICP27 binds viral RNAs in its role as an export adaptor. An ever increasing number of cellular proteins have been shown to interact with ICP27, including splicing factors, export proteins and RNAP II. A number of protein motifs within ICP27 have been predicted based upon sequence comparisons; however, detailed structural information is not yet available. Although much has been learned about the mechanisms by which ICP27 performs its roles, relatively little is known about how its activities are regulated. The roles and activities of ICP27 are the subject of this review.
Viral tracers are important tools for neuroanatomical mapping and genetic payload delivery. Genetically modified viruses allow for cell-type-specific targeting and overcome many limitations of ...non-viral tracers. Here, we summarize the viruses that have been developed for neural circuit mapping, and we provide a primer on currently applied anterograde and retrograde viral tracers with practical guidance on experimental uses. We also discuss and highlight key technical and conceptual considerations for developing new safer and more effective anterograde trans-synaptic viral vectors for neural circuit analysis in multiple species.
Xu et al. review the viruses that have been used for neural circuit mapping and provide a primer on currently applied anterograde and retrograde viral tracers with practical guidance on experimental uses.
In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, ...the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial.
In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke.
At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval CI, 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups.
Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).
A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional ...organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a model of the disease, with accumulation of damaged organelles. The defect in autophagy was accompanied by persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR) and of the autophagy-inhibiting pathways dependent on them, including the translation-initiation factor 4E-binding protein 1 and the ribosomal protein S6, and downregulation of the autophagy-inducing genes LC3, Atg12, Gabarapl1 and Bnip3. The defective autophagy was rescued in mdx mice by long-term exposure to a low-protein diet. The treatment led to normalisation of Akt and mTOR signalling; it also reduced significantly muscle inflammation, fibrosis and myofibre damage, leading to recovery of muscle function. This study highlights novel pathogenic aspects of DMD and suggests autophagy as a new effective therapeutic target. The treatment we propose can be safely applied and immediately tested for efficacy in humans.
•Mitochondria and redox homeostasis are intimately correlated in ageing process.•Mitochondria can be both source and target of ROS.•ROS can exert both beneficial and deleterious biological effects in ...the cell.•Antioxidant enzymes represent a first line defence for tightly regulating ROS.•Visual data mining can aid in visualizing their connection from ageing to AD.
Several theories have been postulated, trying to explain why and how living organisms age. Despite some controversies and still huge open questions, a growing body of evidence suggest alterations of mitochondrial functionality and redox-homeostasis occur during the ageing process. Oxidative damage and mitochondrial dysfunction do not represent the cause of ageing per se but they have to be analyzed within the complexity of those series of processes occurring during lifespan. The establishment of a crosstalk among them is a shared common feature of many chronic age-related diseases, including neurodegenerative disorders, for which ageing is a major risk factor. The challenge is to understand when and how the interplay between these two systems move towards from normal ageing process to a pathological phenotype. Here in this review, we discuss the crosstalk between mitochondria and cytosolic-ROS. Furthermore, through a visual data mining approach, we attempt to describe the dynamic interplay between mitochondria and cellular redox state on the route from ageing to an AD phenotype.
The long-term use of Cu-containing fungicides contaminates vineyards soils, which can induce Cu toxicity and nutrient imbalances in several plant species. The aim of this work was to evaluate the ...effect of Cu toxicity on two grapevine rootstocks, Fercal and 196.17, and to elucidate if intercropping with oat can alleviate grapevine Cu toxicity. Plants were hydroponically-cultivated and treated with different Cu concentrations. At harvest the biomass accumulation, the SPAD index and the symplastic and apoplastic root and leaves ionome were measured to evaluate possible synergistic and/or antagonistic effects on other micro- and macronutrients. The root exudation analysis was correlated with genes expression (VvPEZ-like), whereas PCA analysis performed on the grapevine and oat ionome revealed that both mono- and intercropped 196.17 rootstock display a positive effect on Zn and Mn in the root tissues at high Cu concentrations. An increase of Zn and Mn in roots was also reported for the intercropped Fercal rootstock at high Cu concentrations while an antagonistic relation was reported for root Zn concentration in the monocropped Fercal rootstock. Our results showed that grapevine and oat compete for nutrient uptake and that this phenomenon can possibly alleviate grapevine Cu toxicity. However, Fercal rootstock is able to take advantage from oat, while 196.17 is disadvantaged by the intercropping system. Even though intercropping system seems to be a valuable tool to counteract grapevine Cu toxicity, the application of this agricultural practice has shown to be species dependent and should be evaluated for each rootstock.
•196.17 performs better than Fercal in monocropping systems in Cu toxicity.•Phenolic compounds are involved in alleviating Cu toxicity.•The grapevine exudation pattern was influenced by the intercropping with oat.•Ionomic analysis of intercropped plants reveals a competition between plant species.•The effectiveness of intercropping is rootstock dependent.
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