Neural regulation of cancer: from mechanobiology to inflammation.

Despite recent progress in cancer research, the exact nature of malignant transformation and its progression is still not fully understood. Particularly metastasis, which accounts for most cancer death, is a very complex process, and new treatment strategies require a more comprehensive understanding of underlying regulatory mechanisms. Recently, the sympathetic nervous system (SNS) has been implicated in cancer progression and beta-blockers have been identified as a novel strategy to limit metastasis. This review discusses evidence that SNS signaling regulates metastasis by modulating the physical characteristics of tumor cells, tumor-associated immune cells and the extracellular matrix (ECM). Altered mechanotype is an emerging hallmark of cancer cells that is linked to invasive phenotype and treatment resistance. Mechanotype also influences crosstalk between tumor cells and their environment, and may thus have a critical role in cancer progression. First, we discuss how neural signaling regulates metastasis and how SNS signaling regulates both biochemical and mechanical properties of tumor cells, immune cells and the ECM. We then review our current knowledge of the mechanobiology of cancer with a focus on metastasis. Next, we discuss links between SNS activity and tumor-associated inflammation, the mechanical properties of immune cells, and how the physical properties of the ECM regulate cancer and metastasis. Finally, we discuss the potential for clinical translation of our knowledge of cancer mechanobiology to improve diagnosis and treatment

Counterion density profiles at charged flexible membranes

Counterion distributions at charged soft membranes are studied using perturbative analytical and simulation methods in both weak coupling (mean-field or Poisson-Boltzmann) and strong coupling limits. The softer the membrane, the more smeared out the counterion density profile becomes and counterions pentrate through the mean-membrane surface location, in agreement with anomalous scattering results. Membrane-charge repulsion leads to a short-scale roughening of the membrane.Comment: 4 pages, 4 figure

Joint Shapley Values: a measure of joint feature importance

The Shapley value is one of the most widely used measures of feature importance partly as it measures a feature's average effect on a model's prediction. We introduce joint Shapley values, which directly extend Shapley's axioms and intuitions: joint Shapley values measure a set of features' average effect on a model's prediction. We prove the uniqueness of joint Shapley values, for any order of explanation. Results for games show that joint Shapley values present different insights from existing interaction indices, which assess the effect of a feature within a set of features. The joint Shapley values seem to provide sensible results in ML attribution problems. With binary features, we present a presence-adjusted global value that is more consistent with local intuitions than the usual approach

A voice for change? Trust relationships between ombudsmen, individuals and public service providers

There has been a debate for years about what the role of the ombudsman is. This article examines a key component of the role, to promote trust in public services and government. To be able to do this, however, an ombudsman needs to be perceived as legitimate and be trusted by a range of stakeholders, including the user. This article argues that three key relationships in a person’s complaint journey can build trust in an institution, and must therefore be understood as a system. The restorative justice framework is adapted to conceptualize this trust model as a novel approach to understanding the institution from the perspective of its users. Taking two public sector ombudsmen as examples, the article finds that voice and trust need to be reinforced through the relationships in a consumer journey to manage individual expectations, prevent disengagement, and thereby promote trust in the institution, in public service providers, and in government

The stroke oxygen pilot study: a randomized control trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months

Introduction: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. Methods: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p#0.05. Results: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p= 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p= 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. Conclusions: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. Trial Registration: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-4

Nuclear Envelope Composition Determines The Ability Of Neutrophil-Type Cells To Passage Through Micron-Scale Constrictions

Neutrophils are characterized by their distinct nuclear shape, which is thought to facilitate the transit of these cells through pore spaces less than one-fifth of their diameter. We used human promyelocytic leukemia (HL-60) cells as a model system to investigate the effect of nuclear shape in whole cell deformability. We probed neutrophil-differentiated HL-60 cells lacking expression of lamin B receptor, which fail to develop lobulated nuclei during granulopoiesis and present an in vitro model for Pelger-Huët anomaly; despite the circular morphology of their nuclei, the cells passed through micron-scale constrictions on similar timescales as scrambled controls. We then investigated the unique nuclear envelope composition of neutrophil-differentiated HL-60 cells, which may also impact their deformability; although lamin A is typically down-regulated during granulopoiesis, we genetically modified HL-60 cells to generate a subpopulation of cells with well defined levels of ectopic lamin A. The lamin A-overexpressing neutrophil-type cells showed similar functional characteristics as the mock controls, but they had an impaired ability to pass through micron-scale constrictions. Our results suggest that levels of lamin A have a marked effect on the ability of neutrophils to passage through micron-scale constrictions, whereas the unusual multilobed shape of the neutrophil nucleus is less essential

The SOS Pilot Study: a RCT of routine oxygen supplementation early after acute stroke—effect on recovery of neurological function at one week

Mild hypoxia is common after stroke and associated with poor long-term outcome. Oxygen supplementation could prevent hypoxia and improve recovery. A previous study of routine oxygen supplementation showed no significant benefit at 7 and 12 months. This pilot study reports the effects of routine oxygen supplementation for 72 hours on oxygen saturation and neurological outcomes at 1 week after a stroke