Cell Senescence and the Genetics of Melanoma Development.

Cutaneous malignant melanoma is an aggressive skin cancer with an approximate lifetime risk of 1 in 38 in the UK. While exposure to ultraviolet radiation is a key environmental risk factor for melanoma, up to ~10% of patients report a family history of melanoma, and ~1% have a strong family history. The understanding of causal mutations in melanoma has been critical to the development of novel targeted therapies that have contributed to improved outcomes for late-stage patients. Here, we review current knowledge of the genes affected by familial melanoma mutations and their partial overlap with driver genes commonly mutated in sporadic melanoma development. One theme linking a set of susceptibility loci/genes is the regulation of skin pigmentation and suntanning. The largest functional set of susceptibility variants, typically with high penetrance, includes CDKN2A, RB1, and telomerase reverse transcriptase (TERT) mutations, associated with attenuation of cell senescence. We discuss the mechanisms of action of these gene sets in the biology and progression of nevi and melanoma

Fatigue in celiac disease: A review of the literature

Fatigue is increasingly recognized as a significant problem in patients with chronic inflammatory and autoimmune diseases. In celiac disease, a chronic immune‐mediated disease triggered by dietary gluten, conflicting opinions exist regarding both the size of the problem and the effect of a gluten‐free diet (GFD) on fatigue. We reviewed the existing literature regarding fatigue in celiac disease. We conducted a systematic search in the Embase, Ovid Medline, and Cochrane databases using subject terms from controlled vocabularies. Articles were reviewed based on language, type of article, title, and abstract or full text. Eighteen articles were finally selected for review. Fatigue was significantly greater in patients with celiac disease compared to healthy control subjects. Fatigue prevalence ranged from 8 to 100%. Fatigue severity was assessed in six studies. The fatigue visual analogue scale was the most frequently used fatigue instrument with scores from 57 to 79 prior to starting a GFD and from 39 to 59 in patients on a GFD. Seven studies investigated the effect of a GFD on fatigue, including five studies that reported less fatigue while on the diet and two studies that showed no significant difference. This review concludes that fatigue is a substantial complaint in patients with celiac disease. A GFD seems to reduce fatigue, but existing data are limited.publishedVersio

Managing Pain in People with Cancer—a Systematic Review of the Attitudes and Knowledge of Professionals, Patients, Caregivers and Public

Cancer pain is a common symptom experienced by patients, caused either by the disease or its treatment. Morphine remains the most effective and recommended treatment for cancer pain. However, cancer patients still do not receive appropriate management for their pain, and under-treatment is common. Lack of knowledge and negative attitudes towards cancer pain and analgesia among professionals, patients and family caregivers are reported as one of the most common barriers to effective cancer pain management (CPM). To systematically review research on the nature and impact of attitudes and knowledge towards CPM, a systematic literature search of 6 databases (the Cochrane library, MEDLINE, PsycINFO, CINAHL, Web of Science and EMBASE) was undertaken in July 2018. Additionally, hand-searching of Google, Google Scholar and reference lists was conducted. The inclusion criteria were adult (18–65 years of age), studies which included attitudes and knowledge towards CPM, studies written in English, published literature only and cross-sectional design. Included studies were critically appraised by two researchers independently using the Joanna Briggs Institute Analytical Cross Sectional Studies Assessment (JBI-ACSSA). A total of 36 studies met the inclusion criteria. The main finding was that among professionals, patients, caregivers and the public there were similar attitudinal barriers to effective CPM. The most commonly cited barriers were fear of drug addiction, tolerance of medication and side effects of opioids. We also found differences between professional groups (physicians versus nurses) and between different countries based on their potential exposure to palliative care training and services. There are still barriers to effective CPM, which might result in unrelieved cancer pain. Therefore, more educational programmes and training for professionals on CPM are needed. Furthermore, patients, caregivers, and the public need more general awareness and adequate level of knowledge about CPM

Building the Field of Health Policy and Systems Research: An Agenda for Action

In the final article in a series addressing the current challenges and opportunities for the development of Health Policy and Systems Research (HPSR), Sara Bennett and colleagues lay out an agenda for action moving forward

Study protocol: evaluation of a parenting and stress management programme: a randomised controlled trial of Triple P discussion groups and stress control

<br>Background: Children displaying psychosocial problems are at an increased risk of negative developmental outcomes. Parenting practices are closely linked with child development and behaviour, and parenting programmes have been recommended in the treatment of child psychosocial problems. However, parental mental health also needs to be addressed when delivering parenting programmes as it is linked with parenting practices, child outcomes, and treatment outcomes of parenting programmes. This paper describes the protocol of a study examining the effects of a combined intervention of a parenting programme and a cognitive behavioural intervention for mental health problems.</br> <br>Methods: The effects of a combined intervention of Triple P Discussion Groups and Stress Control will be examined using a randomised controlled trial design. Parents with a child aged 3?8?years will be recruited to take part in the study. After obtaining informed consent and pre-intervention measures, participants will be randomly assigned to either an intervention or a waitlist condition. The two primary outcomes for this study are change in dysfunctional/ineffective parenting practices and change in symptoms of depression, anxiety, and stress. Secondary outcomes are child behaviour problems, parenting experiences, parental self-efficacy, family relationships, and positive parental mental health. Demographic information, participant satisfaction with the intervention, and treatment fidelity data will also be collected. Data will be collected at pre-intervention, mid-intervention, post-intervention, and 3-month follow-up.</br> <br>Discussion: The aim of this paper is to describe the study protocol of a randomised controlled trial evaluating the effects of a combined intervention of Triple P Discussion Groups and Stress Control in comparison to a waitlist condition. This study is important because it will provide evidence about the effects of this combined intervention for parents with 3?8?year old children. The results of the study could be used to inform policy about parenting support and support for parents with mental health problems. Trial registration ClinicalTrial.gov: NCT01777724, UTN: U1111-1137-1053.</br&gt

Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies1 in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease2. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function3,4. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases

Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer

OBJECTIVES: There is an increasing number of driver fusions in NSCLC which are amenable to targeted therapy. Panel testing for fusions is increasingly appropriate but can be costly and requires adequate good quality biopsy material. In light of the typical mutual exclusivity of driver events in NSCLC, the objective of this study was to trial a novel testing pathway, supported by industrial collaboration, in which only patients negative for driver mutations on DNA-NGS were submitted for fusion panel analysis. MATERIALS AND METHODS: Over 18 months, all patients from a single centre with non-squamous NSCLC were submitted for DNA-NGS, plus ALK and ROS1 immunohistochemistry +/− FISH. Those which were negative for a driver mutation were then recalled for RNA panel testing. RESULTS: 307 samples were referred for DNA-NGS mutation analysis, of which, 10% of cases were unsuitable for or failed DNA-NGS analysis. Driver mutations were detected in 61% (167/275) of all those successfully tested. Of those without a driver mutation and with some remaining tissue available, 28% had insufficient tissue/extracted RNA or failed RNA-NGS. Of those successfully tested, 24% (17/72) had a fusion gene detected involving either ALK, ROS, MET, RET, FGFR or EGFR. Overall, 66% (184/277) of patients had a driver event detected through the combination of DNA and RNA panels. CONCLUSION: Sequential DNA and RNA based molecular profiling increased the efficacy of detecting fusion driven NSCLCs. Continued optimisation of tissue procurement, handling and the diagnostic pathways for gene fusion analysis is necessary to reduce analysis failure rates and improve detection rate for treatment with the next generation of small molecule inhibitors

Exoanal ultrasound of the anal sphincter: normal anatomy and sphincter defects

To describe the sonographic appearance of normal anal sphincter anatomy and sphincter defects evaluated with a conventional 5 MHz convex transducer placed on the perineum. Design Prospective, single-blind study. Setting Department of Obstetrics and Gynecology, University of Michigan Medical Center, USA. Population Twenty-five women with symptoms of faecal incontinence, 11 asymptomatic nulliparous women, and 32 asymptomatic parous women. Methods A convex scanner was placed on the perineum with the woman in lithotomy position. Images were taken at three levels of the sphincter canal. Pictures were evaluated by two examiners who were blinded to the case history of the women and to the results of each other for the presence or absence of sphincter defects. Main outcome measures Description of anal sphincter appearance on endoanal ultrasound. Reproducibilty of the evaluation of sphincter defects. Results The internal anal sphincter is visible as a hypoechoic circle; the external anal sphincter shows a hyperechoic pattern. Proximally the sling of the puborectalis muscle is visible. Sphincter defects were detected in 20 women. In all five women who subsequently underwent surgery, the presence and location of the defect was confirmed at the time of surgery. Examiners were in agreement 100% of the time on the presence or absence of internal defects. They disagreed in one patient on the presence of an external defect. Conclusion Exoanal ultrasound provides information on normal anatomy and on defects of the anal sphincter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75125/1/j.1471-0528.1997.tb12056.x.pd

High glucose up-regulates ENaC and SGK1 expression in HCD-cells

Background/Aim: Diabetic nephropathy is associated with progressive renal damage, leading to impaired function and end-stage renal failure. Secondary hypertension stems from a deranged ability of cells within the kidney to resolve and appropriately regulate sodium resorption in response to hyperglycaemia. However, the mechanisms by which glucose alters sodium re-uptake have not been fully characterised. Methods: Here we present RT-PCR, western blot and immunocytochemistry data confirming mRNA and protein expression of the serum and glucocorticoid inducible kinase (SGK1) and the a conducting subunit of the epithelial sodium channel (ENaC) in a model in vitro system of the human cortical collecting duct (HCD). We examined changes in expression of these elements in response to glucose challenge, designed to mimic hyperglycaemia associated with type 2 diabetes mellitus. Changes in Na+ concentration were assessed using single-cell microfluorimetry. Results: Incubation with glucose, the Ca2+-ionophore ionomycin and the cytokine TGF-beta 1 were all found to evoke significant and time-dependent increases in both SGK1 and alpha ENaC protein expression. These molecular changes were correlated to an increase in Na+-uptake at the single-cell level. Conclusion: Together these data offer a potential explanation for glucose-evoked Na+-resorption and a potential contributory role of SGK1 and ENaCs in development of secondary hypertension, commonly linked to diabetic nephropathy