Pigment Cell & Melanoma Research最新文献

The unique pharmacokinetics of BRAF and MEK inhibitors make patients vulnerable to drug–drug interactions (DDIs), which may compromise treatment efficacy in metastatic melanoma. This study evaluates the impact of DDIs on clinical outcomes in patients with metastatic melanoma treated with BRAF/MEK inhibitors. This multicenter, observational, retrospective study assessed DDIs using the Drug-PIN software. Associations between the Drug-PIN continuous score, Drug-PIN light, and treatment outscomes were analyzed along with the specific drugs involved in the DDIs. A total of 177 patients with BRAF-mutant metastatic melanoma undergoing BRAF/MEK inhibitor therapy were included. Of these, 94 patients (55.9%) were exposed to complex drug regimens related to comorbidities, supportive care, and symptom management. A significant change in Drug-PIN scores was observed before and after therapy initiation. Patients with low-grade DDIs demonstrated significantly longer median overall survival (OS) and progression-free survival (PFS) compared to those with high-grade DDIs (log-rank p = 0.0045 and p = 0.012, respectively); this observation was further validated by multiple regression analysis. By combining clinical and DDI data, we identified four patient subgroups with distinct prognoses, showing statistically significant differences in OS and PFS (log-rank p < 0.0001). The subgroup with the highest clinical risk and high DDI had markedly poorer outcomes (HR 2.87, 95% CI [1.7–4.8], p < 0.001). The drugs involved in high-level pharmacological interactions were analyzed. DDIs significantly contribute to poorer OS and PFS outcomes, independent of other clinical risk factors. Optimizing pharmacological regimens to minimize DDIs should be prioritized to enhance treatment efficacy in oncology. Prospective clinical trials are warranted to further validate the advantages of individualized, preemptive therapy optimization.

Acral lentiginous melanoma (ALM) is a rare and insufficiently understood subtype of melanoma lacking in effective treatment options. Recent work has demonstrated that the response of ALM to immune checkpoint blockade is inferior to that of cutaneous melanoma (CM). Here we performed bulk genomic and transcriptomic sequencing of tumor tissue from 28 ALM and 5692 CM cases. Similar to prior studies, ALM was associated with a significantly lower incidence of point mutations, including in the TERT promoter and BRAF, but increased numbers of gene amplifications, notably of CCND1, HMGA2, and MDM2. Reactome pathway analysis revealed enhancement of keratinization and PI3K/AKT signaling pathways. Overall immunogenicity was decreased in ALM, which possessed lower IFNγ (p < 0.001) and T-cell inflammatory (p = 0.03) pathway scores than CM. Despite higher computationally inferred levels of myeloid dendritic cells (p = 0.006), neoantigen load independent of predicted HLA binding affinity was lower (p < 0.01) in ALM versus CM. Assessment of classical and nonclassical HLA mRNA levels revealed upregulation of HLA-G, suggesting alternative ALM immune evasion pathways in the setting of lower PD-L1 expression (p = 0.005). Additional research is needed to better understand and therapeutically target signaling networks in the ALM tumor microenvironment.

Natural selection has rarely promoted the evolution of colour polymorphism in wild mammals. However, it is more common in domestic mammals due to artificial selection. For this reason, domestication could provide valuable insights into the mechanisms underlying the evolution of colour diversity. This raises the question of whether the associations between coat colour and other phenotypes in domestic animals are similar to those in free-living animals. Our literature review of cows, goats and sheep suggests that these associations can differ not only between species but also within and between breeds. This pattern holds for all the traits that we considered: morphology, behaviour, physiology, reproduction, milk production and parasitism. The only consistent association we found in the literature was the attraction of flies towards dark-coloured cows. The relationships between same colour morph, cortisol and thermoregulation varied across environments, suggesting a possible condition-dependent expression of multiple traits. We conclude that artificial selection may lead to a different integration of multiple phenotypes compared to animals living in the wild. Therefore, colour variation may not always serve the same functional roles in domestic animals as it does in wild ones.

We have identified a chemically induced mouse mutation which increases the eumelanic hair pigmentation. We identify a coding mutation, A3533G, resulting in an amino acid substitution Y1133C, in the Gnas gene encoding the G_αs subunit of the tripartite G-protein, consistent with an activation of signalling via MC1R. In addition heterozygous mutant females are significantly lighter than wild type littermates. In cultured melanocytes, derived from mutant mice crossed to C57BL6 mice carrying Cdkn2a^tm1Rdp, basal pigmentation is higher than wild type melanocytes derived from litter mates. However, the addition of exogenous NDP-MSH does not increase pigmentation in mutant melanocytes in contrast to the pigmentation response of non-mutant melanocytes. The mutant and wild type cells respond in the same way to agouti signalling protein (ASP), consistent with ASP signalling mediated through a pathway other than G_αs-protein.

Pigment cells not only are intrinsic factors to determine animal patterns, but also play vital roles in numerous behavioral and physiological processes as well as health, such as melanomas originating from melanocytes. Model organisms are commonly used to study pigment cell development and the mechanisms underlying related diseases, with zebrafish and mice, and Xenopus being well-established examples. Xenopus tropicalis, a diploid amphibian model, offers advantages such as high fecundity and easily observable pigment cell development. Recent advancements in gene-editing techniques have increased its prominence in research on pigment cell biology and melanoma pathogenesis. Here, we compare the skin pigment cell distribution as well as the skin structure in X. tropicalis, zebrafish, mice, and humans and point out the potential value of using X. tropicalis to model human skin diseases, such as melanoma.

Uveal melanoma (UM) is an aggressive intraocular malignancy. Despite effective control of primary tumors, ~50% of UM patients develop metastases, with the liver being the predominant secondary site. BAP1 deficiency, present in ~80% of metastatic UM cases, is strongly associated with increased metastatic risk and poor prognosis. In silico analysis of UM patient samples suggests that reduced BAP1 is linked to enhanced expression of genes involved in fatty acid processing; therefore, we hypothesize that BAP1 deficiency primes UM cells for survival in the hepatic microenvironment by enhancing lipid tolerance and oxidative stress responses. Our findings demonstrate BAP1-mutant UM resist lipotoxicity, whereas BAP1-competent UM exhibit sensitivity due to lipid peroxide accumulation—a hallmark of ferroptotic-like stress, and a response that can be mitigated by ferroptosis inhibition. Using an ex vivo liver slice model, we found that disrupting lipid metabolism with atorvastatin, an HMG-CoA reductase inhibitor, reduced tumor burden of BAP1-mutant UM. Moreover, we demonstrate a positive correlation between BAP1 and an epigenetic regulator of lipid homeostasis, ASXL2. Notably, ASXL2 depletion in BAP1-competent UM phenocopies the lipotoxicity resistance observed in BAP1-mutant UM—an effect that may be mediated by altered PPAR expression. This study reveals a novel mechanism linking BAP1 expression to lipid sensitivity via ASXL2, providing insights into liver tropism and potential therapeutic avenues for metastatic uveal melanoma.

Evaluating measurement properties (MPs) of Patient Reported Outcome Measures (PROMs) in vitiligo is essential for evidence-based recommendations and identifying research gaps. This study assesses the quality of PROMs used in vitiligo. A systematic search of PubMed, Embase, and the Cochrane Library (up to 20 February 2024) included studies on PROM analysis or development, excluding those validating other tools. Quality assessments followed the COSMIN guidelines. PROMs with the highest number MPs rated sufficient (supported by moderate/high Quality of Evidence [QoE]) were reported per construct category, and information related to content validity specifically was provided. Forty articles on 24 PROMs (=161 MP studies) were analyzed. In the QoL group, the VIT, VLQI, VIP-FS, and ViPPO had the highest number of MPs rated sufficient (n = 3). For severity-related constructs, the Self-Assessment Vitiligo Extent Score (SA-VES) had the most MPs rated sufficient (n = 3). For treatment-related PROMs, the BMQ had the highest number MPs rated sufficient (n = 2). Content validity was limitedly assessed in 12 different PROMs. Comprehensive MP assessment and further validation of vitiligo PROMs are necessary to make definitive conclusions. These systematic reviews are registered at PROSPERO (CRD42020216338). Only English publications were included, which may limit the scope. Additionally, systematic searches conducted by different reviewers in consecutive updates may introduce subjectivity.

Vitiligo is the most common skin depigmentation disease, affecting 0.1%–2% of people in the world. 3.5%–20.5% of segmental patients account for the total number of vitiligo patients. It has been clinically observed that segmental vitiligo patients are more likely to generate white hair, which may be related to neuroendocrine factors. The color of human skin and hair is affected by the number and functional status of melanocytes. Vitiligo affects patients' physical and mental health due to the shame it causes from the white patches and hair. This article reviews the underlying mechanisms of segmental vitiligo with white hair based on skin and hair follicle melanocytes. The article attempts to propose possible targets for the treatment of this disease.