Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial dysfunction in adult human skin fibroblasts, which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and adenosine triphosphate (ATP)-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance, which is associated with the molecular pathophysiology of MDD. The observed alterations in the oxidative phosphorylation system (OXPHOS) and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.

Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin with a poor prognosis. The factors driving this cancer must be better understood in order to discover novel targets for more effective therapies. In the search for targets, we followed our interest in citrate as a central and critical metabolite linked to fatty acid synthesis in cancer development. A key to citrate uptake in cancer cells is the high expression of the plasma membrane citrate transporter (pmCiC), which is upregulated in the different adenocarcinoma types tested so far. In this study, we show that the pmCiC is also highly expressed in Merkel cell carcinoma cell lines by western blot and human tissues by immunohistochemistry staining. In the presence of extracellular citrate, MCC cells show an increased proliferation rate in vitro; a specific pmCiC inhibitor (Na⁺-gluconate) blocks this citrate-induced proliferation. Furthermore, the 3D in vivo Chick Chorioallantoic Membrane (CAM) model showed that the application of Na⁺-gluconate also decreases Merkel cell carcinoma growth. Based on our results, we conclude that pmCiC and extracellular citrate uptake should be considered further as a potential novel target for the treatment of Merkel cell carcinoma.

Introduction Malignant melanoma is an aggressive skin tumor with a good prognosis when treated in an early tumor stage, but has a poor prognosis with distant metastases. The incidence of malignant melanoma has increased continuously over the last decades, with little change in mortality. One explanation for this is that melanomas are increasingly detected in early stages, especially after the establishment of statutory skin cancer screening in 2008, which allows a free skin examination every 2 years for people older than 35 years. Methods In this study incidence and mortality of malignant melanoma were correlated with the dermatologist density in Bavarian administrative regions. In addition, the incidence data were compared before and after the introduction of statutory skin cancer screening. Results There was a significant correlation between the incidence of malignant melanoma and dermatologist density (r = 0.258, p = 0.044), but no correlation between mortality and dermatologist density (r = 0.201, p = 0.121). Similarly, the increase of malignant melanoma incidence following the introduction of statutory skin cancer screening in 2008 was independent of dermatologist density (r = 0.021, p = 0.873). Conclusion The dermatologist density in Bavaria correlates positively with the incidence of malignant melanoma. Despite an increased incidence, mortality was not elevated in the respective administrative regions.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Background: Patients with BRAF wildtype metastatic melanoma who exhibit primary resistance to immune checkpoint inhibitors (ICIs) have a poor prognosis. Chemotherapy has been shown to induce genetic mutations, modify the tumour microenvironment and microbiome, and influence immune system activity. Objectives: To investigate in a prospective multicentre phase II trial whether two applications of an alkylating agent (dacarbazine) can sensitize patients with metastatic melanoma who are nonresponsive to ICIs to the same checkpoint inhibitor regime. Methods: The PROMIT trial (NCT04225390) enrolled patients with histologically confirmed BRAF wildtype metastatic melanoma who exhibited primary resistance to ICI therapy. Following radiological evidence of primary resistance to ICI (ipilimumab + nivolumab or pembrolizumab) upon the first staging after initiation, patients received two doses of dacarbazine at 850 mg m–2 intravenously on days 1 and 21. Subsequently, 1 week after application of the second dose of dacarbazine, patients were rechallenged with the same ICI therapy to which they had previously shown progressive disease. Results: In total, 53 patients were enrolled across four German skin cancer centres. Of these patients, 38 were evaluable for efficacy, having received at least one dose of ICI re-exposure. The overall objective response rate was 18% (95% confidence interval 0.08–0.34), with 7 of 38 patients achieving a partial response. The disease control rate was 37%. Therapy was well tolerated, with treatment-related ≥ grade 3 CTCAE adverse events occurring in 10% of patients. No new safety signals were observed. Conclusions: The study indicates that short-term chemotherapy followed by ICI rechallenge can overcome primary ICI resistance in patients with melanoma, supporting its potential as a new therapeutic option in clinical practice.

(1) Background: Ultraviolet (UV) radiation and sunburns are associated with an increased incidence of acquired nevi and melanomas. However, the data are controversial as to whether chronic UV exposure or high intermittent UV exposure is the major carcinogenic factor in melanocytic tumors. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure in nevi and different clinical melanoma subtypes (i.e., superficial spreading melanoma (SSM), nodular malignant melanoma (NMM), acral lentiginous melanoma (ALM), and lentigo maligna melanoma (LMM)) with respect to clinical variables (age, sex, and body site). (2) Methods: We defined a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 595 melanocytic lesions from 559 patients with their clinical variables. (3) Results: The TEG was correlated with age and UV-exposed body sites. Furthermore, the TEG was significantly higher in LMM than in all other types of melanomas and the TEG in NMM was higher than in SSM, irrespective of patient age and tumor site. (4) Conclusions: High cumulative UV exposure is more strongly associated with LMM and NMM than with other melanoma subtypes.