Controlling secretion to limit chemoresistance

The tumor microenvironment influences cancer progression and therapy outcome by mechanisms not yet fully understood. In this issue, Bent et al. (2016) show how chemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells do not mount a typical senescence-associated secretory phenotype but instead acutely secrete IL-6, promoting chemoresistance. This study unveils a physiological switch involving PI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit the detrimental consequences of persistent inflammation

Effect of Solvent on the Self-Assembly of Dialanine and Diphenylalanine Peptides

Diphenylalanine (FF) is a very common peptide with many potential applications, both biological and technological, due to a large number of different nanostructures which it attains. The current work concerns a detailed study of the self assembled structures of FF in two different solvents, an aqueous (H2O) and an organic (CH3OH) through simulations and experiments. Detailed atomistic Molecular Dynamics (MD) simulations of FF in both solvents have been performed, using an explicit solvent model. The self assembling propensity of FF in water is obvious while in methanol a very weak self assembling propensity is observed. We studied and compared structural properties of FF in the two different solvents and a comparison with a system of dialanine (AA) in the corresponding solvents was also performed. In addition, temperature dependence studies were carried out. Finally, the simulation predictions were compared to new experimental data, which were produced in the framework of the present work. A very good qualitative agreement between simulation and experimental observations was found

mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses

Post-stroke infection: A systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p><b>s</b>troke is the main cause of disability in high-income countries, and ranks second as a cause of death worldwide. Patients with acute stroke are at risk for infections, but reported post-stroke infection rates vary considerably. We performed a systematic review and meta-analysis to estimate the pooled post-stroke infection rate and its effect on outcome.</p> <p>Methods</p> <p>MEDLINE and EMBASE were searched for studies on post-stroke infection. Cohort studies and randomized clinical trials were included when post-stroke infection rate was reported. Rates of infection were pooled after assessment of heterogeneity. Associations between population- and study characteristics and infection rates were quantified. Finally, we reviewed the association between infection and outcome.</p> <p>Results</p> <p>87 studies were included involving 137817 patients. 8 studies were restricted to patients admitted on the intensive care unit (ICU). There was significant heterogeneity between studies (P < 0.001, I²= 97%). The overall pooled infection rate was 30% (24-36%); rates of pneumonia and urinary tract infection were 10% (95% confidence interval [CI] 9-10%) and 10% (95%CI 9-12%). For ICU studies, these rates were substantially higher with 45% (95% CI 38-52%), 28% (95%CI 18-38%) and 20% (95%CI 0-40%). Rates of pneumonia were higher in studies that specifically evaluated infections and in consecutive studies. Studies including older patients or more females reported higher rates of urinary tract infection. Pneumonia was significantly associated with death (odds ratio 3.62 (95%CI 2.80-4.68).</p> <p>Conclusions</p> <p>Infection complicated acute stroke in 30% of patients. Rates of pneumonia and urinary tract infection after stroke were 10%. Pneumonia was associated with death. Our study stresses the need to prevent infections in patients with stroke.</p

A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15INK4b and p21CIP1. Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo

Aetiology of fever in patients with acute stroke

Objective. Fever in patients with acute stroke is usually related to infectious complications. In some cases, a focus of infection cannot be identified, fever does not respond to empirical antibiotic treatment: and is thought to be due to the central nervous system lesion. The aim of this study was to determine the frequency and origin of fever in patients with acute stroke and the characteristics associated with the presence of fever. Design. A retrospective study of 36 months’ duration. Setting. The study was carried out at ‘Alexandra’ Hospital, a tertiary care teaching centre in Athens, Greece. Subjects. A total of 330 patients hospitalized for acute stroke from June 1992 until July 1994. Results. In 37.6% of 330 patients, fever was noted; 22.7% had a documented infection and 14.8% had fever without a documented infection. In univariate analysis, older age was associated with the presence of fever (P = 0.001). The development of fever was associated with intracerebral haemorrhage versus ischaemic infarct (P &lt; 0.001) and with the presence of mass effect (P &lt; 0.001), transtentorial herniation (P &lt; 0.001), intraventricular blood (P &lt; 0.001), and larger size of ischaemic infarct (P = 0.0001) and of haemorrhage (P = 0.0002). Patients with fever had lower scores on admission on the Glasgow Coma Scale (P = 0.0001) and the Scandinavian Stroke Scale (P = 0.0001). The development of fever was associated with prior use of an invasive technique (P &lt; 0.001) and more specifically with urinary catheterization (P &lt; 0.001), but not with the presence of risk factors for infection. Patients with fever had a worse outcome assessed by the Modified Rankin Scale (P = 0.0001) and the Barthel Index (P = 0.0001). In multivariate analysis, age, Scandinavian Stroke Scale score and mass effect were found to be significantly associated with fever (P = 0.035, P = 0.0001 and P = 0.0004, respectively). Patients with fever without documented infection had an earlier onset of fever than those with infection (P = 0.0061). In a logistic regression analysis, tl-le only factor predictive of fever without documented infection versus infection was earlier onset of fever (P = 0.029). Conclusion. Patients with acute stroke who develop fever are older, suffer severe stroke, their fever is associated with the use of invasive techniques, and they have a poor outcome. In patients with fever without a focus of infection, the only characteristic that is different from patients with known infection is earlier onset of fever