Modulation of the β-Catenin Signaling Pathway by the Dishevelled-Associated Protein Hipk1

BACKGROUND:Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. METHODOLOGY:We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. CONCLUSIONS:These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene expression and cell movements that are essential for gastrulation

Childhood exposure to ultraviolet radiation and harmful skin effects: Epidemiological evidence

We review the general amount and patterns of exposure to solar ultraviolet (UV) radiation that children and teenagers experience and the spectrum of UV-related skin damage that can occur as a result. Data about the amount of solar UV received by children and teenagers are relatively few but suggest that around 40–50% of total UV to age 60 occurs before age 20. Among white children, those with the palest complexions suffer the most damage. Comparisons of prevalence and incidence of outcomes in children and teenagers sharing common ancestry, but living at different latitudes, show that prevalence rates of photoaging and melanocytic naevi are higher in Australian compared with British children, and similarly for melanoma. Genetic risk for the majority of the melanomas in teens is a function of genes controlling naevus propensity and pigmentation in the skin. High numbers of naevi and freckles, red hair, blue eyes, inability to tan, as well as a family history are the primary determinants of melanoma among adolescents. Beyond the signs of skin damage seen in children are the latent effects observed later in adulthood. Childhood is believed to be a susceptible window for long-term harmful effects of UV, as evidenced by clear differences in skin cancer risk between child and adult migrants from high to low latitudes. Effective UV radiation protection from childhood is necessary to control both immediate and long-term harmful effects on children’s skin

Psychotic disorder and cannabis use: Canadian hospitalization trends, 2006-2015.

INTRODUCTION: Given the recent and impending changes to the legal status of nonmedical cannabis use in Canada, understanding the effects of cannabis use on the health care system is important for evaluating the impact of policy change. The aim of this study was to examine pre-legalization trends in hospitalizations for mental and behavioural disorders due to the use of cannabis, according to demographics factors and clinical conditions. METHODS: We assessed the total number of inpatient hospitalizations for psychiatric conditions with a primary diagnosis of a mental or behavioural disorder due to cannabis use (ICD-10-CA code F12) from the Hospital Mental Health Database for ten years spanning 2006 to 2015, inclusive. We included hospitalizations from all provinces and territories except Quebec. Rates (per 100 000 persons) and relative proportions of hospitalizations by clinical condition, age group, sex and year are reported. RESULTS: Between 2006 and 2015, the rate of cannabis-related hospitalizations in Canada doubled. Of special note, however, is that hospitalizations during this time period for those with the clinical condition code "mental and behavioural disorders due to use of cannabinoids, psychotic disorder" (F12.5) tripled, accounting for almost half (48%) of all cannabis-related hospitalizations in 2015. CONCLUSION: Further research is required to investigate the reasons for the increase in hospitalizations for cannabis-related psychotic disorder. The introduction of high-potency cannabinoid products and synthetic cannabinoids into the illicit market are considered as possible factors

Skin cancer arising in scars: A systematic review

BACKGROUND: Despite numerous case reports, epidemiologic evidence regarding true rate of skin cancer in scars of any etiology is sparse. METHODS: Systematic literature review of all published epidemiologic studies on skin cancer in scar tissue from surgery, ulcers, or burns using citation databases and manual review. RESULTS: There were no epidemiologic data to quantify risk of skin cancer in surgical scars or chronic ulcers. Two eligible cohort studies were identified, from Denmark and Sweden, in which skin cancers in 16, 903 and 37,095 burn patients, respectively, were ascertained through cancer registry follow-up. Each reported standardized incidence ratios (SIRs) for skin cancer types on any site that were uniformly less than unity compared with the general population. Only the Danish cohort assessed skin cancers specifically on past burn injury sites and found a burn-site-specific SIR of 1.2 (95% confidence interval (CI) = 0.4–2.7) for squamous cell carcinoma (SCC), 0.7 (95% CI = 0.4–1.1) for basal cell carcinoma, and 0.3 (95% CI = 0.0–1.2) for melanoma. CONCLUSIONS: Available epidemiologic data suggest that burn patients are not at higher risk of skin cancers in general, although a modest excess of SCC in burn scars cannot be excluded, nor can excess risk with longer follow-up. Risk of skin cancer in scars other than burn scars has not been investigated epidemiologically

Plasma omega-3 and omega-6 concentrations and risk of cutaneous basal and squamous cell carcinomas in Australian adults

Laboratory-based evidence suggests that omega-3 and omega-6 polyunsaturated fatty acids may affect skin photocarcinogenesis, but epidemiologic evidence is inconsistent. In 1,191 White Australian adults, we prospectively investigated associations between baseline plasma concentrations of omega-3 and omega-6 fatty acids and cutaneous basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). Relative risks (RR) and 95% confidence intervals (CI) were estimated on the basis of number of histologically confirmed tumors diagnosed during follow-up (1997-2007). Plasma eicosapentaenoic acid (EPA) concentrations and omega-3/-6 ratio showed significant inverse associations with SCC tumors, comparing higher tertiles with the lowest, in age- and sex-adjusted models (Ptrend = 0.02 and 0.03, respectively) which weakened after adjustment for past sun exposure. Associations between EPA and SCC were stronger among participants with a history of skin cancer at baseline (n = 378; highest vs. lowest tertile: RR = 0.50; 95% CI, 0.28-0.92; Ptrend = 0.01). Total omega-6 was inversely associated withBCCtumors in multivariate models (P=0.04; highest vs. lowest tertile:RR=0.71; 95% CI, 0.51-0.99), and more strongly in the subgroup with past skin cancer. Linoleic and linolenic acids were also inversely associated with BCC occurrence in this subgroup. When fatty acids were analyzed as continuous variables, however, there was no evidence of any linear or nonlinear associations. This study provides some support for reduced skin cancer risk with high plasma concentrations of omega-3 and omega-6 fatty acids, but results depended on how fatty acid data were modeled. Further investigation of these associations in larger datasets is needed

Three-way assessment of long-chain n-3 PUFA nutrition: By questionnaire and matched blood and skin samples

The long-chain n-3 PUFA, EPA, is believed to be important for skin health, including roles in the modulation of inflammation and protection from photodamage. FFQ and blood levels are used as non-invasive proxies for assessing skin PUFA levels, but studies examining how well these proxies reflect target organ content are lacking. In seventy-eight healthy women (mean age 42·8, range 21–60 years) residing in Greater Manchester, we performed a quantitative analysis of long-chain n-3 PUFA nutrition estimated from a self-reported FFQ (n 75) and correlated this with n-3 PUFA concentrations in erythrocytes (n 72) and dermis (n 39). Linear associations between the three n-3 PUFA measurements were assessed by Spearman correlation coefficients and agreement between these measurements was estimated. Average total dietary content of the principal long-chain n-3 PUFA EPA and DHA was 171 (sd 168) and 236 (sd 248) mg/d, respectively. EPA showed significant correlations between FFQ assessments and both erythrocyte (r 0·57, P<0·0001) and dermal (r 0·33, P=0·05) levels, as well as between erythrocytes and dermis (r 0·45, P=0·008). FFQ intake of DHA and the sum of n-3 PUFA also correlated well with erythrocyte concentrations (r 0·50, P<0·0001; r 0·27, P=0·03). Agreement between ranked thirds of dietary intake, blood and dermis approached 50 % for EPA and DHA, though gross misclassification was lower for EPA. Thus, FFQ estimates and circulating levels of the dietary long-chain n-3 PUFA, EPA, may be utilised as well-correlated measures of its dermal bioavailability