Pigment Cell & Melanoma Research最新文献

Vitiligo pathogenesis is complex. There is some evidence in support of the neurohormonal pathways involved. Although considered a nonpruritic condition, some patients may experience itching, which can occur ahead of the appearance of the patches. We aimed to assess sensory symptoms in active and stable vitiligo patients and to measure 3 neuropeptide expressions in their lesional skin (neuropeptide Y [NPY], calcitonin gene–related peptide [CGRP], and nerve growth factors [NGF]) to correlate neuropeptide levels and sensory symptoms, with vitiligo activity. This case–control study included 85 patients, aged 18 years and older, analyzed into active or stable vitiligo groups. Patients were screened for itching or other abnormal neurological sensations such as paresthesia and numbness. The Vitiligo Disease Activity Score, Vitiligo Signs of Activity Score, and dermoscopic score were performed to assess disease activity. Three neuropeptides were quantified by enzyme-linked immunosorbent assay in skin biopsies from the edge of vitiligo lesions. A normal control group was also included. Results showed that 24.7% of patients had sensory symptoms: itching (18.8%), paresthesia (2.4%), and numbness (3.5%). The NGF, CGRP, and NPY levels were significantly higher in skin of normal controls compared to stable and active vitiligo patients. They were lowest in active vitiligo skin (p = 0.001, 0.016, and 0.01, respectively). NGF was the most relevant neuropeptide to vitiligo activity and sensory manifestations. In conclusion, almost one-third of the patients with active vitiligo reported sensory symptoms, predominantly itching, thus sensory manifestations may suggest a prodroma of activity and could be included in the screening tools for vitiligo activity.

Trial Registration: www.clinicaltrials.gov (NCT05390164).

Epidermal melanocytes form synaptic-like contacts with cutaneous nerve fibers, but the functional outcome of these connections remains elusive. In this pilot study we used our fully humanized re-innervated skin organ culture model to investigate melanocyte-nerve fiber interactions in UV-B-induced melanogenesis. UV-B-irradiation significantly enhanced melanin content and tyrosinase activity in re-innervated skin compared to non-innervated controls, indicating that neuronal presence is essential for exacerbating pigmentation upon UV-B irradiation in long-term culture. Comparative transcriptomic analysis between laser-capture-microdissected melanocytes from freshly embedded human skin and published microarray data on in vitro primary melanocytes identified Semaphorin-4A (SEMA4A) as possible mediator of melanocyte-nerve fibers interactions. SEMA4A protein levels in Gp100⁺-epidermal melanocytes were significantly higher in re-innervated skin, and reduced by UV-B treatment. Analysis of melanocytes in vitro showed reduced SEMA4A protein expression 24 h after UV-B-irradiation while SEMA4A secretion into the medium was increased. Beta-tubulin expression and axon growth in sensory neurons were stimulated by conditioned media (CM) from UV-B irradiated melanocytes. When this neuronal-conditioned medium was transferred to fresh melanocytes, melanin content increased, but only if neurons had been treated with CM from UV-B irradiated melanocytes. These findings highlight the importance of melanocyte-neuron interactions for UV-B-induced melanogenesis and suggest that secreted proteins (e.g., SEMA4A) can function as a novel target to treat hypo- and hyperpigmentation disorders.

Beta-blockers have generated an exciting discourse for their potential as a cheap, safe, and effective adjunctive therapy for cutaneous melanoma patients, but the field remains murky. This systematic review investigates the association between beta-blocker use and survival outcomes in cutaneous melanoma patients. We reviewed 12 studies with 21,582 patients in a network meta-analysis and found a benefit between beta-blocker use and disease-free survival but no other significant association for melanoma-specific or overall survival. However, some evidence suggests that pan-selective beta-blockers, rather than cardio-selective ones, may have a protective effect. We conclude that the current evidence is insufficient to recommend beta-blockers for melanoma treatment but suggest further research focusing on pan-selective beta-blockers to clarify their potential benefits.

In solar lentigo, a typical age-related pigmentary disorder of the skin, abundant melanin is deposited in the basal layer of keratinocytes and not spontaneously eliminated. The reason for the prolonged melanin accumulation in keratinocytes is not fully understood. Therefore, we focused on the energy metabolism of keratinocytes that incorporate melanosomes, specialized organelles where melanin pigment is synthesized, and investigated the mechanism of melanin accumulation in keratinocytes. Energy metabolism in keratinocytes after the addition of melanosomes was assessed by measuring ATP levels, lactate production, and oxygen consumption rate. Energy limitations after melanosome addition were evaluated by microscopy. Cells with incorporated melanosomes were stained for senescence and proliferation markers. The results showed that keratinocytes upregulated their energy metabolism after melanosome incorporation and energy limitations increased the amount of melanin per cell. Keratinocytes positive for senescence-associated β-galactosidase, a cellular senescence marker, accumulated large amounts of melanin, while keratinocytes positive for 5-ethynyl-2′-deoxyuridine, a proliferation marker, contained little melanin. These findings indicate that senescent keratinocytes tend to accumulate melanin, which may be due to their impaired energy metabolism and thus inability to activate energy metabolism after melanosome incorporation. Our results suggest that melanosome incorporation by senescent keratinocytes causes the persistent melanin deposition in solar lentigo.

Metabolic syndrome (MetS) remains a significant global public health concern. However, the relationship between MetS, its individual components and melanoma metastasis remains unexplored. We analysed the clinical data of 258 Chinese melanoma patients who had not undergo systemic therapy. Binary logistic regression, adjusted for sex and age, was employed to evaluate the connection between MetS and its components and melanoma metastasis. Of the 258 melanoma patients, 92 met the MetS criteria upon diagnosis. No direct association between MetS and melanoma metastasis was identified. However, specific components of MetS, namely low HDL-cholesterol levels (OR = 2.85, 95% CI:1.50–5.41, p < 0.05) and dysglycaemia (OR = 4.23, 95% CI:1.80–8.96, p < 0.05), were associated with melanoma metastasis. In subgroup analysis, hypertriglyceridemia correlated with melanoma metastasis in non-elderly patients (< 65 years) (OR = 2.69, 95% CI: 1.14–6.33, p < 0.05). Central obesity and hypertension showed no association. A dose–response analysis further indicated that melanoma metastasis risk escalated with increasing fasting blood glucose and blood triglyceride concentrations, and with decreasing blood HDL concentration. Our results suggest that monitoring and managing individual components of the MetS, particularly HDL-cholesterol levels, fasting glucose and triglyceride levels, may have potential prognostic benefits for melanoma in the Chinese population.

Oculocutaneous albinism type 2 (OCA-2, OMIM: 203200) is associated with variants in the OCA2 gene. In this study, we aimed to re-classify variants of uncertain significance (VUS) in OCA2 by evaluating subcellular localization and channel activity through multiplex assays of variant effect (MAVEs). Following the ClinGen guidelines for PS3 evidence, we selected 13 OCA2 variants from ClinVar (6 benign/likely benign [B/LB] and 7 pathogenic/likely pathogenic [P/LP]) for OddsPath analysis. The P/LP variants exhibited abnormal functions, while the B/LB variants demonstrated normal functions, supporting the application of “PS3_moderate” evidence for VUS re-classification. In our functional evaluation of 30 VUS identified in 38 individuals with suspected OCA-2 by trio whole-exome sequencing, we observed 6 VUS with abnormal localization and 11 with abnormal channel activity. Based on PS3_moderate evidence, 8 VUS were re-classified as LP, while 22 remained VUS. Consequently, 7 out of 38 previously undiagnosed patients received a molecular diagnosis of OCA-2. These MAVEs offer a robust approach for curating OCA2 VUS, enhancing diagnostic accuracy, and informing genetic counseling. Additionally, this variant cohort is a valuable resource for public databases.

Current NICE guidelines state that in high-risk melanoma patients, imaging should not be offered before SLNB unless lymph node or distant metastases are suspected. Our experience has been that in patients with pT3b, pT4a and pT4b melanomas, the rate of management-changing findings on axial imaging prior to SLNB was high and that ‘stage before operating’ is a better approach. We now offer full axial imaging as staging to all high-risk melanoma patients prior to SLNB and advise other skin cancer MDTs to follow this approach.