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Factors Within the Endoneurial Microenvironment Act to Suppress Tumorigenesis of MPNST

Background: Deciphering avenues to adequately control malignancies in the peripheral nerve will reduce the need for current, largely-ineffective, standards of care which includes the use of invasive, nerve-damaging, resection surgery. By avoiding the need for en bloc resection surgery, the likelihood of retained function or efficient nerve regeneration following the control of tumor growth is greater, which has several implications for long-term health and well-being of cancer survivors. Nerve tumors can arise as malignant peripheral nerve sheath tumors (MPNST) that result in a highly-aggressive form of soft tissue sarcoma. Although the precise cause of MPNST remains unknown, studies suggest that dysregulation of Schwann cells, mediated by the microenvironment, plays a key role in tumor progression. This study aimed to further characterize the role of local microenvironment on tumor progression, with an emphasis on identifying factors within tumor suppressive environments that have potential for therapeutic application.Methods: We created GFP-tagged adult induced tumorigenic Schwann cell lines (iSCs) and transplanted them into various in vivo microenvironments. We used immunohistochemistry to document the response of iSCs and performed proteomics analysis to identify local factors that might modulate divergent iSC behaviors.Results: Following transplant into the skin, spinal cord or epineurial compartment of the nerve, iSCs formed tumors closely resembling MPNST. In contrast, transplantation into the endoneurial compartment of the nerve significantly suppressed iSC proliferation. Proteomics analysis revealed a battery of factors enriched within the endoneurial compartment, of which one growth factor of interest, ciliary neurotrophic factor (CNTF) was capable of preventing iSCs proliferation in vitro.Conclusions: This dataset describes a novel approach for identifying biologically relevant therapeutic targets, such as CNTF, and highlights the complex relationship that tumor cells have with their local microenvironment. This study has significant implications for the development of future therapeutic strategies to fight MPNSTs, and, consequently, improve peripheral nerve regeneration and nerve function

Stimulation of the tibial nerve: a protocol for a multicentred randomised controlled trial for urinary problems associated with Parkinson’s disease—STARTUP

Introduction Parkinson’s disease is the second most common chronic neurodegenerative condition with bladder dysfunction affecting up to 71%. Symptoms affect quality of life and include urgency, frequency, hesitancy, nocturia and incontinence. Addressing urinary dysfunction is one of the top 10 priority research areas identified by the James Lind Alliance and Parkinson’s UK. Objectives Conduct a randomised controlled trial (RCT) targeting people with Parkinson’s disease (PwP) who have self-reported problematic lower urinary tract symptoms, investigating the effectiveness of transcutaneous tibial nerve stimulation (TTNS) compared with sham TTNS. Implement a standardised training approach and package for the correct application of TTNS. Conduct a cost-effectiveness analysis of TTNS compared with sham TTNS. Methods and analysis An RCT of 6 weeks with twice weekly TTNS or sham TTNS. Participants will be recruited in 12 National Health Service neurology/movement disorder services, using a web-based randomisation system, and will be shown how to apply TTNS or sham TTNS. Participants will receive a weekly telephone call from the researchers during the intervention period. The trial has two coprimary outcome measures: International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and the International Prostate Symptom Score. Secondary outcomes include a 3-day bladder diary, quality of life, acceptability and fidelity and health economic evaluation. Outcomes will be measured at 0, 6 and 12 weeks. A sample size of 208 randomised in equal numbers to the two arms will provide 90% power to detect a clinically important difference of 2.52 points on the Internatioanl Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF) and of 3 points in the International Prostate Symptom Score total score at 12 weeks at 5% significance level, based on an SD of 4.7 in each arm and 20% attrition at 6 weeks. Analysis will be by intention to treat and pre defined in a statistical analysis plan Ethics and dissemination East of Scotland Research Ethics Service (EoSRES), 18/ES00042, obtained on 10 May 2018. The trial will allow us to determine effectiveness, safety, cost and acceptability of TTNS for bladder dysfunction in PWP. Results will be published in open access journals; lay reports will be posted to all participants and presented at conferences. Trial registration number ISRCTN12437878; Pre-results

Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted

The Effect of Body Size on Countermovement Jump Kinetics in Children aged 7 to 11 years

The purpose this study was to examine the effect of body size oncountermovement jump (CMJ)kinetics in children.Participants(n = 160) aged 7-11 years, divided equally by sex and into primary school year groups(years 3, 4, 5 and 6), each performedone CMJ on aforce platform. The variables bodyweight(BW), peak force (Fmax), in-jump minimum force (IMF), in-jump vertical force range (IFR) and basic rate of force development (BRFD)wereattained from the force-time history and then subsequently scaled to account for body size. A significant age, sex and interaction effect werefound for theabsolutevariables BW, IMF, Fmaxand IFR (P 0.05). No significant age or sex differences were observed for normalised or allometrically scaled values(P > 0.05). The results indicate thatgirls and boys can be grouped together but that body size must be accounted for to enable accurate conclusions to be drawn independent of growth.Bodysizesignificantlyeffects the representation of CMJ kinetic results and therefore, future studies should report both absolute and scaled values.Future research should developan age-appropriate criterion method for children in order to determine processed CMJ variables to further investigate neuromuscular performance of children

PREVIEW Behavior Modification Intervention Toolbox (PREMIT) : A Study Protocol for a Psychological Element of a Multicenter Project

Background: Losing excess body weight and preventing weight regain by changing lifestyle is a challenging but promising task to prevent the incidence of type-2 diabetes. To be successful, it is necessary to use evidence-based and theory-driven interventions, which also contribute to the science of behavior modification by providing a deeper understanding of successful intervention components. Objective: To develop a physical activity and dietary behavior modification intervention toolbox (PREMIT) that fulfills current requirements of being theory-driven and evidence-based, comprehensively described and feasible to evaluate. PREMIT is part of an intervention trial, which aims to prevent the onset of type-2 diabetes in pre-diabetics in eight clinical centers across the world by guiding them in changing their physical activity and dietary behavior through a group counseling approach. Methods: The program development took five progressive steps, in line with the Public Health Action Cycle: (1) Summing-up the intervention goal(s), target group and the setting, (2) uncovering the generative psychological mechanisms, (3) identifying behavior change techniques and tools, (4) preparing for evaluation and (5) implementing the intervention and assuring quality. Results: PREMIT is based on a trans -theoretical approach referring to valid behavior modification theories, models and approaches. A major "product" of PREMIT is a matrix, constructed for use by onsite-instructors. The matrix includes objectives, tasks and activities ordered by periods. PREMIT is constructed to help instructors guide participants' behavior change. To ensure high fidelity and adherence of program -implementation across the eight intervention centers standardized operational procedures were defined and "train-the-trainer" workshops were held. In summary PREMIT is a theory-driven, evidence-based program carefully developed to change physical activity and dietary behaviors in pre diabetic people.Peer reviewe

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Effect of a high protein/low glycaemic index diet on insulin resistance in adolescents with overweight/obesity-APREVIEWrandomized clinical trial

Background Pubertal insulin resistance (IR) is associated with increased risk of type 2 diabetes mellitus development in adolescents with overweight/obesity. Objectives The PREVIEW study was a randomized parallel trial assessing the change in IR, analyzed by Homeostatic Model Assessment of IR (HOMA-IR), at 2 years after randomization to a high protein vs a moderate protein diet in adolescents with overweight/obesity. It was hypothesized that a high protein/low glycaemic index diet would be superior in reducing IR compared to a medium protein/medium GI diet, in insulin resistant adolescents with overweight or obesity. Methods Adolescents with overweight/obesity and IR from the Netherlands, United Kingdom and Spain were randomized into a moderate protein/moderate GI (15/55/30En% protein/carbohydrate/fat, GI >= 56) or high protein/low GI (25/45/30En% protein/carbohydrate/fat, GI < 50) diet. Anthropometric and cardiometabolic parameters, puberty, dietary intake and physical activity (PA) were measured and effects on HOMA-IR were analyzed. Results 126 adolescents were included in this study (13.6 +/- 2.2 years, BMI z-score 3.04 +/- 0.66, HOMA-IR 3.48 +/- 2.28, HP n = 68, MP n = 58). At 2 years, changes in protein intake were not significantly different between timepoints or intervention groups and no effects of the intervention on IR were observed. The retention rate was 39%, while no compliance to the diets was observed. Conclusions The PREVIEW study observed no effect of a high protein/low GI diet on IR in adolescents with overweight/obesity and IR because of lack of feasibility, due to insufficient retention and dietary compliance after 2 years.Peer reviewe

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice

<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div

Objectively Measured Physical Activity and Sedentary Time Are Associated With Cardiometabolic Risk Factors in Adults With Prediabetes: The PREVIEW Study

OBJECTIVE The aim of the present cross-sectional study was to examine the association among physical activity (PA), sedentary time (ST), and cardiometabolic risk in adults with prediabetes.RESEARCH DESIGN AND METHODS Participants (n = 2,326; 25–70 years old, 67% female) from eight countries, with a BMI >25 kg ⋅ m−2 and impaired fasting glucose (5.6–6.9 mmol ⋅ L−1) or impaired glucose tolerance (7.8–11.0 mmol ⋅ L−1 at 2 h), participated. Seven-day accelerometry objectively assessed PA levels and ST.RESULTS Multiple linear regression revealed that moderate-to-vigorous PA (MVPA) was negatively associated with HOMA of insulin resistance (HOMA-IR) (standardized β = −0.078 [95% CI −0.128, −0.027]), waist circumference (WC) (β = −0.177 [−0.122, −0.134]), fasting insulin (β = −0.115 [−0.158, −0.072]), 2-h glucose (β = −0.069 [−0.112, −0.025]), triglycerides (β = −0.091 [−0.138, −0.044]), and CRP (β = −0.086 [−0.127, −0.045]). ST was positively associated with HOMA-IR (β = 0.175 [0.114, 0.236]), WC (β = 0.215 [0.026, 0.131]), fasting insulin (β = 0.155 [0.092, 0.219]), triglycerides (β = 0.106 [0.052, 0.16]), CRP (β = 0.106 [0.39, 0.172]), systolic blood pressure (BP) (β = 0.078 [0.026, 0.131]), and diastolic BP (β = 0.106 [0.39, −0.172]). Associations reported between total PA (counts ⋅ min−1) and all risk factors were comparable or stronger than for MVPA: HOMA-IR (β = −0.151 [−0.194, −0.107]), WC (β = −0.179 [−0.224, −0.134]), fasting insulin (β = −0.139 [−0.183, −0.096]), 2-h glucose (β = −0.088 [−0.131, −0.045]), triglycerides (β = −0.117 [−0.162, −0.071]), and CRP (β = −0.104 [−0.146, −0.062]).CONCLUSIONS In adults with prediabetes, objectively measured PA and ST were associated with cardiometabolic risk markers. Total PA was at least as strongly associated with cardiometabolic risk markers as MVPA, which may imply that the accumulation of total PA over the day is as important as achieving the intensity of MVPA