The importance for immunoregulation for long-term cancer control.

Immune checkpoint blockades have recently emerged as a breakthrough treatment for solid tumors showing high response rates and long durability. In melanoma, the combination of ipilimumab with nivolumab showed high efficacy. However, still half the patients do not respond to this treatment. In order to increase the therapeutic ratio in melanoma and other cancers, different approaches are under evaluation. Three relevant questions are at the moment driving the research community: how to maximize benefit while minimizing toxicity; how to better identify patients who are more likely to benefit from immunotherapy; how to convert nonresponders into responders. In this review we summarize the most recent findings and we outline the most likely future challenges

Effect of Pulsed or Continuous Delivery of Salt on Sensory Perception Over Short Time Intervals

Salt in the human diet is a major risk factor for hypertension and many countries have set targets to reduce salt consumption. Technological solutions are being sought to lower the salt content of processed foods without altering their taste. In this study, the approach was to deliver salt solutions in pulses of different concentrations to determine whether a pulsed delivery profile affected sensory perception of salt. Nine different salt profiles were delivered by a Dynataste device and a trained panel assessed their saltiness using time–intensity and single-score sensory techniques. The profile duration (15 s) was designed to match eating conditions and the effects of intensity and duration of the pulses on sensory perception were investigated. Sensory results from the profiles delivered in either water or in a bouillon base were not statistically different. Maximum perceived salt intensities and the area under the time– intensity curves correlated well with the overall perceived saltiness intensity despite the stimulus being delivered as several pulses. The overall saltiness scores for profiles delivering the same overall amount of sodium were statistically not different from one another suggesting that, in this system, pulsed delivery did not enhance salt perception but the overall amount of salt delivered in each profile did affect sensory perception

Complementary hydro-mechanical coupled finite/discrete element and microseismic modelling to predict hydraulic fracture propagation in tight shale reservoirs

This paper presents a novel approach to predict the propagation of hydraulic fractures in tight shale reservoirs. Many hydraulic fracture modelling schemes assume that the fracture direction is pre-seeded in the problem domain discretization. This is a severe limitation as the reservoir often contains large numbers of pre-existing fractures that strongly influence the direction of the propagating fracture. To circumvent these shortcomings a new fracture modelling treatment is proposed where the introduction of discrete fracture surfaces is based on new and dynamically updated geometrical entities rather than the topology of the underlying spatial discretization. Hydraulic fracturing is an inherently coupled engineering problem with interactions between fluid flow and fracturing when the stress state of the reservoir rock attains a failure criterion. This work follows a staggered hydro-mechanical coupled finite/discrete element approach to capture the key interplay between fluid pressure and fracture growth. In field practice the fracture growth is hidden from the design engineer and microseismicity is often used to infer hydraulic fracture lengths and directions. Microsesimic output can also be computed from changes of the effective stress in the geomechanical model and compared against field microseismicity. A number of hydraulic fracture numerical examples are presented to illustrate the new technology

Weakened magnetic braking as the origin of anomalously rapid rotation in old field stars

A knowledge of stellar ages is crucial for our understanding of many astrophysical phenomena, and yet ages can be difficult to determine. As they become older, stars lose mass and angular momentum, resulting in an observed slowdown in surface rotation. The technique of 'gyrochronology' uses the rotation period of a star to calculate its age. However, stars of known age must be used for calibration, and, until recently, the approach was untested for old stars (older than 1 gigayear, Gyr). Rotation periods are now known for stars in an open cluster of intermediate age (NGC 6819; 2.5 Gyr old), and for old field stars whose ages have been determined with asteroseismology. The data for the cluster agree with previous period-age relations, but these relations fail to describe the asteroseismic sample. Here we report stellar evolutionary modelling, and confirm the presence of unexpectedly rapid rotation in stars that are more evolved than the Sun. We demonstrate that models that incorporate dramatically weakened magnetic braking for old stars can---unlike existing models---reproduce both the asteroseismic and the cluster data. Our findings might suggest a fundamental change in the nature of ageing stellar dynamos, with the Sun being close to the critical transition to much weaker magnetized winds. This weakened braking limits the diagnostic power of gyrochronology for those stars that are more than halfway through their main-sequence lifetimes.Comment: 25 pages, 3 figures in main paper, 6 extended data figures, 1 table. Published in Nature, January 2016. Please see https://youtu.be/O6HzYgP5uyc for a video description of the resul

Amelioration of Acute Kidney Injury in Lipopolysaccharide-Induced Systemic Inflammatory Response Syndrome by an Aldose Reductase Inhibitor, Fidarestat

Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism.Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney.Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation.AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality

Eicosapentaenoic acid and docosahexaenoic acid reduce interleukin-1β-mediated cartilage degradation

Introduction: In inflammatory joint disease, such as osteoarthritis (OA), there is an increased level of proinflammatory cytokines, such as interleukin (IL)-1β. These cytokines stimulate the production of matrix metalloproteinases (MMPs), which leads to the degradation of the cartilage extracellular matrix and the loss of key structural components such as sulphated glycosaminoglycan (sGAG) and collagen II. The aim of this study was to examine the therapeutic potential of n-3 polyunsaturated fatty acids (PUFAs) in an in vitro model of cartilage inflammation. Methods: Two specific n-3 compounds were tested, namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), each at 0.1, 1 and 10 μM. Full thickness bovine cartilage explants, 5 mm in diameter, were cultured for 5 days with or without IL-1β and in the presence or absence of each n-3 compound. The media were replaced every 24 hours and assayed for sGAG content using the 1,9-dimethylmethylene blue (DMB) method. Chondrocyte viability was determined at the end of the culture period using fluorescence microscopy to visualise cells labelled with calcein AM and ethidium homodimer. Results: Treatment with IL-1β (10 ng.ml-1) produced a large increase in sGAG release compared to untreated controls, but with no effect on cell viability, which was maintained above 80% for all treatments. In the absence of IL-1β, both n-3 compounds induced a mild catabolic response with increased loss of sGAG, particularly at 10 μM. By contrast, in the presence of IL-1β, both EPA and DHA at 0.1 and 1 μM significantly reduced IL-1β-mediated sGAG loss. The efficacy of the EPA treatment was maintained at approximately 75% throughout the 5-day period. However, at the same concentrations, the efficacy of DHA, although initially greater, reduced to approximately half that of EPA after 5 days. For both EPA and DHA, the highest dose of 10 μM was less effective. Conclusions: The results support the hypothesis that n-3 compounds are anti-inflammatory through competitive inhibition of the arachidonic acid oxidation pathway. The efficacy of these compounds is likely to be even greater at more physiological levels of IL-1β. Thus we suggest that n-3 PUFAs, particularly EPA, have exciting therapeutic potential for preventing cartilage degradation associated with chronic inflammatory joint disease

suPAR as a prognostic biomarker in sepsis

Sepsis is the clinical syndrome derived from the host response to an infection and severe sepsis is the leading cause of death in critically ill patients. Several biomarkers have been tested for use in diagnosis and prognostication in patients with sepsis. Soluble urokinase-type plasminogen activator receptor (suPAR) levels are increased in various infectious diseases, in the blood and also in other tissues. However, the diagnostic value of suPAR in sepsis has not been well defined, especially compared to other more established biomarkers, such as C-reactive protein (CRP) and procalcitonin (PCT). On the other hand, suPAR levels have been shown to predict outcome in various kinds of bacteremia and recent data suggest they may have predictive value, similar to that of severity scores, in critically ill patients. This narrative review provides a descriptive overview of the clinical value of this biomarker in the diagnosis, prognosis and therapeutic guidance of sepsis

Transient Reversal of Episome Silencing Precedes VP16-Dependent Transcription during Reactivation of Latent HSV-1 in Neurons

Herpes simplex virus type-1 (HSV-1) establishes latency in peripheral neurons, creating a permanent source of recurrent infections. The latent genome is assembled into chromatin and lytic cycle genes are silenced. Processes that orchestrate reentry into productive replication (reactivation) remain poorly understood. We have used latently infected cultures of primary superior cervical ganglion (SCG) sympathetic neurons to profile viral gene expression following a defined reactivation stimulus. Lytic genes are transcribed in two distinct phases, differing in their reliance on protein synthesis, viral DNA replication and the essential initiator protein VP16. The first phase does not require viral proteins and has the appearance of a transient, widespread de-repression of the previously silent lytic genes. This allows synthesis of viral regulatory proteins including VP16, which accumulate in the cytoplasm of the host neuron. During the second phase, VP16 and its cellular cofactor HCF-1, which is also predominantly cytoplasmic, concentrate in the nucleus where they assemble an activator complex on viral promoters. The transactivation function supplied by VP16 promotes increased viral lytic gene transcription leading to the onset of genome amplification and the production of infectious viral particles. Thus regulated localization of de novo synthesized VP16 is likely to be a critical determinant of HSV-1 reactivation in sympathetic neurons