An investigation of the associations between stigma, self-compassion, and pain outcomes during treatment based on Acceptance and Commitment Therapy for chronic pain.

Introduction: Stigma adversely affects people with chronic pain. The qualities within self-compassion may be particularly useful for buffering the impact of stigma on people with pain. In the context of an Acceptance and Commitment Therapy-based (ACT) treatment for chronic pain, this study investigated the association between changes in stigma and self-compassion and pain outcomes, and the potential moderating role of self-compassion on the association between stigma and pain outcomes. Materials and methods: Five-hundred and nineteen patients completed standardized self-report questionnaires of stigma, self-compassion, psychological flexibility, pain intensity and interference, work and social adjustment, and depression symptoms at the start of an interdisciplinary ACT-based treatment for chronic pain. The same measures were completed at post-treatment (n = 431). Results: The results indicated that key pain outcomes and self-compassion significantly improved during treatment, but stigma did not. Changes in stigma and self-compassion were significantly negatively correlated and changes in these variables were associated with improvements in treatment outcomes. There were significant main effects of stigma and self-compassion for many of the pre- and post-treatment regression models when psychological flexibility was not controlled for, but self-compassion did not moderate the association between stigma and pain outcomes. Stigma remained significant when psychological flexibility variables were controlled for, while self-compassion did not. Discussion: The findings add to our conceptual understanding of the inter-relationships between stigma, self-compassion, and psychological flexibility and can contribute to treatment advancements to optimally target these variables.

MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1.

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in oxidation of MITF itself. This newly discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage.

The role of thioredoxin reductase 1 in melanoma metabolism and metastasis.

Although significant progress has been made in targeted and immunologic therapeutics for melanoma, many tumors fail to respond, and most eventually progress when treated with the most efficacious targeted combination therapies thus far identified. Therefore, alternative approaches that exploit distinct melanoma phenotypes are necessary to develop new approaches for therapeutic intervention. Tissue microarrays containing human nevi and melanomas were used to evaluate levels of the antioxidant protein thioredoxin reductase 1 (TR1), which was found to increase as a function of disease progression. Melanoma cell lines revealed metabolic differences that correlated with TR1 levels. We used this new insight to design a model treatment strategy that creates a synthetic lethal interaction wherein targeting TR1 sensitizes melanoma to inhibition of glycolytic metabolism, resulting in a decrease in metastases in vivo. This approach holds the promise of a new clinical therapeutic strategy, distinct from oncoprotein inhibition.