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Background In clinical practice, the quality of images may vary depending on the imaging device, and the focus of the dermoscope is on the superficial layer of the lesion. Therefore, it is desirable to have a dermoscopy device that can easily focus on any lesion and clearly show the findings. Objectives We conducted a clinical study to compare dermoscopic images of the same skin tumours obtained using a prototype dermoscopy camera, DZ‐D100 (DD, Casio Computer Co., Ltd.), and three existing dermoscopy imaging devices (Derma9500S®‐GR or DG, Derma Medical Inc.; DELTA 20® T or DT, HEINE Optotechnik; and DermLite Foto II Pro® or DF, DermLite LLC). Methods Dermoscopic images of 117 skin tumours from 94 patients who visited Chiba University Hospital were evaluated by two experts in terms of the focus, and the clarity and presence or absence (the primary endpoint) of seven findings (pigmented lines, shiny white lines, dots/globules, blue‐grey structures, vascular structures, milia‐like cysts and comedo‐like openings). Results No significant differences in the number of cases with each of the seven findings (pigmented lines, shiny white lines, dots/globules, blue‐grey structures, vascular structures, milia‐like cysts and comedo‐like openings) among the four groups were observed. The clarity of focus was significantly better with the DD than with the other three devices (all, p < 0.05). Pigmented lines were significantly clearer with the DD than with the DF and DT (all, p < 0.05). A strong correlation was found between the focus and clarity of pigmented lines/globules, blue‐grey structures and vascular structures (all, p < 0.005). Conclusions DD was less affected by elevated lesions and was considered to be the easiest to focus and recognize brown to black lines and dots/globules. The well‐focused captured images are also expected to be applied to diagnosis by artificial intelligence.

Background: Paucity of literature and non consensus on clinicohistopathological features amongst the nonmelasma facial melanosis for example lichen planus pigmentosus (LPP), pigmented contact dermatitis (PCD), macular amyloidosis, acanthosis nigricans, pigmented demarcation line, post inflammatory hyperpigmentation, etc., make them difficult to diagnose and equally challenging to treat. Materials and Methods: It was a prospective, uncontrolled study, conducted at tertiary hospital at eastern India in 100 patients presenting with facial hyperpigmentation who agreed to undergo 3 mm skin biopsy during Jan 2014 to Jun 2015. Cases of melasma were excluded by clinical, Woods lamp examination and if required dermoscopy. Details of history, physical examination, histopathological examination, and Immunohistochemical studies were recorded. Melan A was used as melanocytic differentiation marker while CD4, CD8 were used as inflammatory markers. Mean ± SD, chi-square test or Fisher's exact test, degree of agreement by Cohen's Kappa were calculated. P-value was considered significant if ≤0.05. Results: 44 males and 56 females (56%) (M: F=1:1.24) with mean age of 45.98 years and median duration of illness of 28 months (5 months-13 years) were studied. Out of 43 confirmed cases of PCD, 16 had associated hypothyroidism (chi square 6.11, P-value 0.0134). Maximum patients belonged PCD (n = 47) followed by LPP (n = 27). Maximum concordance of clinical and histopathological diagnosis was present in PCD and LPP (Cohen kappa more than 0.9). Epidermal atrophy and band like inflammatory infiltrate were statistically significant features in LPP (P < 0.001). There was no histopathological and immunohistochemical correlation. Overall, clinical histopathological concordance rate was 77%. Conclusion: Subset of nonmelasma facial melanosis is difficult to diagnose clinically which require further confirmation by histopathological examination. Small number of patients in other groups apart from PCD and LPP and uncontrolled study were major limitations of this study.

Although autophagy plays a role in melanogenesis by regulating melanosome degradation and biogenesis in melanocytes, a detailed understanding of the regulatory functions of autophagy factors is lacking. Here, we report a mechanistic link between microtubule-associated protein light chain 3 (LC3) activation and melanogenesis. We observed high expression of LC3 in melanosome-associated pigment-rich melanocytic nevi of sun-exposed skin, as indicated by patterns of melanosomal protein MART1 expression. Rapamycin-induced autophagy significantly increased the melanin index, tyrosinase activity and expression of several proteins linked to melanosome biogenesis, including microphthalmia transcription factor (MITF), pre-melanosome protein and tyrosinase, in Melan-a melanocytes. siRNA-mediated knockdown of LC3 , but not beclin-1 or ATG5 , decreased melanin content and tyrosinase activity. LC3 knockdown also markedly inhibited MITF expression and subsequent rapamycin-induced melanosome formation. More importantly, LC3 knockdown suppressed α-MSH-mediated melanogenesis by attenuating cAMP response element-binding protein (CREB) phosphorylation and MITF expression in Melan-a cells via decreased extracellular signal-regulated kinase (ERK) activity. Overexpression of constitutively active ERK reversed the effect of LC3 knockdown on CREB phosphorylation and MITF expression. These findings demonstrate that LC3 contributes to melanogenesis by increasing ERK-dependent MITF expression, thereby providing a mechanistic insight into the signaling network that links autophagy to melanogenesis.

More people die from melanoma after a stage I diagnosis than after a stage IV diagnosis, because the tools available to clinicians do not readily identify which early-stage cancers will be aggressive. Near-infrared pump-probe microscopy detects fundamental differences in melanin structure between benign human moles and melanoma and also correlates with metastatic potential. However, the biological mechanisms of these changes have been difficult to quantify, as many different mechanisms can contribute to the pump-probe signal. We use model systems (sepia, squid, and synthetic eumelanin), cellular uptake studies, and a range of pump and probe wavelengths to demonstrate that the clinically observed effects come from alterations of the aggregated mode from \"thick oligomer stacks\" to \"thin oligomer stacks\" (due to changes in monomer composition) and (predominantly) deaggregation of the assembled melanin structure. This provides the opportunity to use pump-probe microscopy for the detection and study of melanin-associated diseases.

Thomas Wiesner and colleagues report that germline mutations in BAP1 predispose to melanocytic tumors ranging histopathologically from epithelioid nevi to atypical melanocytic proliferations. Some BAP1 mutation carriers also developed uveal or cutaneous melanomas. Common acquired melanocytic nevi are benign neoplasms that are composed of small, uniform melanocytes and are typically present as flat or slightly elevated pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple, skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected individuals developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of BAP1 , which encodes a ubiquitin carboxy-terminal hydrolase. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histological similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.

Cellular senescence permanently restricts the replicative capacity of cells in response to various stress signals, including aberrant activation of oncogenes. The presence of predictive senescence markers in human premalignant lesions suggests that senescence may function as a genuine tumor suppressor. These markers are not exclusive to the senescence program, however, and it is possible that their expression in vivo does not discriminate irreversible from reversible forms of proliferative arrest. In this study, we aimed to clarify whether human nevus cells can be distinguished from primary and transformed melanocytes by examining the expression of eight senescence markers, including those previously purported to define nevi as senescent tumors. Specifically, we analyzed effectors of senescence, including p16INK4a, p53, and DNA damage (γ-H2AX), as well as predictive markers of senescence including Ki67, PML, senescence-associated β-galactosidase, heterochromatic foci (H3K9Me, 4′-6-diamidino-2-phenylindole), and nuclear size. We found that these commonly accepted senescence markers do not in fact distinguish nevi from precursor/normal and transformed/malignant melanocytes. We conclude that on the basis of current evidence it cannot be reasonably inferred that nevi are permanently growth arrested via senescence.

The importance of extracellular vesicles (EVs) as signaling mediators has been emphasized for several pathways with only limited data regarding their role as protective messages during oxidative stress (OS). The ocular drainage system is unique by being continuously exposed to OS and having a one-way flow of the aqueous humor carrying EVs taking role in glaucoma disease. Here, we aimed to examine the ability of EVs derived from the non-pigmented ciliary epithelium (NPCE)—the aqueous humor producing cells exposed to OS—to deliver protecting messages to the trabecular meshwork (TM)—the aqueous humor draining cells—a process with significance to the pathophysiology of glaucoma disease. EVs extracted from media of NPCE cells exposed to non-lethal OS and their unstressed control were incubated with TM cells. The effects of EVs derived from oxidative stressed cells on the activation of the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1), a major OS pathway, and of the Wnt pathway, known for its role in primary open-angle glaucoma, were evaluated. EVs derived from oxidized NPCE cells significantly protected TM cells from direct OS. The TM cells uptake of EVs from oxidized NPCE and their cytosolic Nrf2 levels were significantly higher at 8 h post-exposure. EVs derived from oxidized NPCE cells significantly attenuated Wnt protein expression in TM cells and activated major antioxidant genes as measured by qRT-PCR. TM cells exposed to EVs derived from oxidized NPCE cells exhibited significantly lower OS and higher super oxide dismutase and catalase activity. Finally, we were able to show that carbonylated proteins and products of oxidized protein are presented in significantly higher levels in EVs derived from oxidized NPCE cells, supporting their suggested role in the signaling process. We hypothesize that these findings may have implications beyond understanding the pathophysiology of glaucoma disease and that transmitting signals that activate the antioxidant system in target cells represent a broad response common to many tissues communication.

Background Filamentous fungi produce a broad spectrum of colored secondary metabolites that are largely used in various industries, including food, cosmetics, fabrics, and medications. This study explores, for the first time, the potential of Aspergillus frequens to produce pigmented secondary metabolites and their application in various biotechnological treatments. Results Aspergillus frequens (Asmaa 2024) produced the highest concentration of pigmented secondary metabolites among the 20 tested fungal rhizospheric fungi, reaching 21.36 ± 1.8 AU/mL in potato dextrose broth (PDB) medium. Scanning electron microscopy (SEM) revealed that the extracted pigment has an irregular shape and particle size, ranging from 40 to 184 nm. The elemental composition revealed the presence of high ratios of carbon and oxygen using energy-dispersive X-ray (EDX). Many functional groups and chromophore compounds have been detected in the extracted pigment using Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography–mass spectrometry (GC-MS). Thirteen pathogenic species of bacteria were significantly inhibited in their development by the colored metabolites, whose minimum bactericidal concentrations (MBCs) varied from 4.5 to 16.7 mg/mL. The most notable percentages in suppression biofilm development, suggesting a major influence, were 66.8% for Klebsiella pneumoniae and 64.8% for Bacillus subtilis using the microtiter plate technique. Following assessment of zeta potential, particle size, and polydispersity index (PDI) of the target bacteria, the effective antibacterial efficacy of the pigmented secondary metabolites was confirmed. The viability of the osteosarcoma (HOS) and lung cancer (A549) cell lines was significantly diminished by the A. frequens ’ secondary metabolites, with IC50 values of 43.3 and 77.1 µg/mL, respectively. In contrast, the skin cancer cell line (A431) showed no signs of impact, using the MTT assay. Conclusion Based on the obtained findings, A. frequens pigmented secondary metabolites have promising potential in the biological control of pathogenic and biofilm-forming bacteria, as well as in the treatment of bone and lung cancer. While numerous studies have investigated pigment production in Aspergillus species, this research represents the first investigation into pigment synthesis by A. frequens .

Breast cancer (BC) continues to be one of the major causes of cancer deaths in women. Progress has been made in targeting hormone and growth factor receptor-positive BCs with clinical efficacy and success. However, little progress has been made to develop a clinically viable treatment for the triple-negative BC cases (TNBCs). The current study aims to identify potent agents that can target TNBCs. Extracts from microbial sources have been reported to contain pharmacological agents that can selectively inhibit cancer cell growth. We have screened and identified pigmented microbial extracts (PMBs) that can inhibit BC cell proliferation by targeting legumain (LGMN). LGMN is an oncogenic protein expressed not only in malignant cells but also in tumor microenvironment cells, including tumor-associated macrophages. An LGMN inhibition assay was performed, and microbial extracts were evaluated for in vitro anticancer activity in BC cell lines, angiogenesis assay with chick chorioallantoic membrane (CAM), and tumor xenograft models in Swiss albino mice. We have identified that PMB from the Exiguobacterium (PMB1), inhibits BC growth more potently than PMB2, from the Bacillus subtilis strain. The analysis of PMB1 by GC-MS showed the presence of a variety of fatty acids and fatty-acid derivatives, small molecule phenolics, and aldehydes. PMB1 inhibited the activity of oncogenic legumain in BC cells and induced cell cycle arrest and apoptosis. PMB1 reduced the angiogenesis and inhibited BC cell migration. In mice, intraperitoneal administration of PMB1 retarded the growth of xenografted Ehrlich ascites mammary tumors and mitigated the proliferation of tumor cells in the peritoneal cavity in vivo. In summary, our findings demonstrate the high antitumor potential of PMB1.

To elucidate the possible biological roles of fatty acid-binding protein 5 (FABP5) in the intraocular environment, the cells from which FABP5 originates were determined by using four different intraocular tissue-derived cell types including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cell lines, and the effects of FABP ligand 6, a specific inhibitor for FABP5 and FABP7 were analyzed by RNA sequencing and seahorse cellular metabolic measurements. Among these four different cell types, qPCR analysis showed that FABP5 was most prominently expressed in HNPCE cells, in which no mRNA expression of FABP7 was detected. In RNA sequencing analysis, 166 markedly up-regulated and 198 markedly down-regulated differentially expressed genes (DEGs) were detected between non-treated cells and cells treated with FABP ligand 6. IPA analysis of these DEGs suggested that FABP5 may be involved in essential roles required for cell development, cell survival and cell homeostasis. In support of this possibility, both mitochondrial and glycolytic functions of HNPCE cells, in which mRNA expression of FABP5, but not that of FABP7, was detected, were shown by using a Seahorse XFe96 Bioanalyzer to be dramatically suppressed by FABP ligand 6-induced inhibition of the activity of FABP5. Furthermore, in IPA upstream analysis, various unfolded protein response (UPR)-related factors were identified as upstream and causal network master regulators. Analysis by qPCR analysis showed significant upregulation of the mRNA expression of most of UPR-related factors and aquaporin1 (AQP1). The findings in this study suggest that HNPCE is one of intraocular cells producing FABP5 and may be involved in the maintenance of UPR and AQP1-related functions of HNPCE.