Approach avoidance training versus Sham in veterans with alcohol use disorder: protocol for a randomized controlled trial.

BACKGROUND: Alcohol use disorder (AUD) is highly prevalent and commonly co-occurs with other psychiatric disorders among Veterans. Provisional evidence supports the use of Approach Avoidance Training (AAT) - a form of computer-delivered cognitive bias modification designed to target implicit approach bias for alcohol-related cues - as an adjunctive program to treat AUD. However, the extent to which AAT is effective for improving AUD recovery outcomes in outpatient Veteran samples and those with psychiatric comorbidities has been understudied to date. Here we describe a double-blind randomized controlled trial of AAT versus a comparison condition (Sham) being conducted in Veterans with comorbid psychiatric conditions completing outpatient standard care. METHODS: One hundred thirty-six Veterans currently receiving outpatient treatment for AUD will be recruited for this randomized controlled trial with parallel group assignment. Participants will be randomized to either 6 weeks of AAT (n = 68) or Sham (n = 68) training in conjunction with usual care. Assessments will occur at baseline and 6 weeks, 3 months, and 6 months post-baseline. Primary outcome variables will include functional consequences of drinking. Secondary outcome variables will include alcohol consumption, and behavioral indicators of alcohol approach bias. A subset of participants (n = 51) will also complete functional magnetic resonance imaging (fMRI) to assess neural response during an alcohol approach bias assessment. DISCUSSION: This study is the first randomized controlled trial of AAT administered as an adjunctive treatment to standard care in Veterans with AUD and comorbid psychiatric disorders. Additionally, behavioral and neuroimaging data will be used to determine the extent to which AAT targets approach bias for alcohol cues. If effective, AAT may be a promising low-cost adjunctive treatment option for individuals with AUD. REGISTRY NAME: AAT for Alcohol Use Disorder in Veterans. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05372029; Date of Registration: 5/9/2022.

G protein-coupled receptor 40 expression in human melanoma - correlation with tumour thickness, AJCC stage and survival.

BACKGROUND: In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein-coupled receptor GPR40, was identified in melanoma cells. OBJECTIVES: The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker. METHODS AND RESULTS: A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti-GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease-free survival (0.040). CONCLUSION: The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient's survival.

6-Tetrahydrobiopterin functions as a UVB-light switch for de novo melanogenesis.

(6R)-L-erythro 5,6,7,8-tetrahydrobiopterin (6-BH4) and its 7-isomer (7-BH4) function as uncompetitive inhibitors of human and mushroom tyrosinases. Stoichiometry for the binding of [3H]-labeled 6-BH4 to both tyrosinases has been established as 1:1. Stable complexation of 6-BH4 to tyrosinase appears to involve a hydrophilic conserved glutamic acid (Glu131) with a pKa = 4.7. Photo-oxidation by UVB-light and O2 reverses the inhibition of tyrosinase by 6-BH4 and 7-BH4 with the 6-BH4/tyrosinase complex being four-fold more photolabile than 7-BH4/tyrosinase. The photo-oxidation of 6-BH4 by UVB-light can be assessed spectrophotometrically with this reaction yielding 7,8-dihydroxanthopterin as the final product, 7,8-Dihydroxanthopterin neither binds to nor inhibits tyrosinase. By contrast, UVA light does not catalyze the photodegradation of 6-BH4. Taken together, our results indicate that the photo-oxidation of the tetrahydrobiopterins by UVB may represent a photo-switch in the regulation of tyrosinase activity to promote de novo melanogenesis.