bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021‒09‒05
fifty-seven papers selected by
Farah Jaber-Hijazi
University of the West of Scotland
  1. MicroRNA-9 inhibits the proliferation and migration of malignant melanoma cells via targeting sirituin 1.
  2. Melanoma Controls the Metastatic Process only in Terms of Metastatic Cell Dissemination - What Is Responsible for Metastatic Cell Proliferation?
  3. YAP facilitates melanoma migration through regulation of actin-related protein 2/3 complex subunit 5 (ARPC5).
  4. ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1.
  5. Circ_0062270 upregulates EPHA2 to facilitate melanoma progression via sponging miR-331-3p.
  6. Phenotypic plasticity of melanocytes derived from human adult skin.
  7. The relationship between melanin production and lipofuscin formation in Tyrosinase gene knockout melanocytes using CRISPR/Cas9 system.
  8. Pharmacological inhibition of USP7 suppresses growth and metastasis of melanoma cells in vitro and in vivo.
  9. Treatment beyond progression and locoregional approaches in selected patients with BRAF-mutated metastatic melanoma.
  10. Increased expression of secreted protein acidic and rich in cysteine and tissue inhibitor of metalloproteinase-3 in epidermotropic melanoma metastasis.
  11. Magnetic Resonance Imaging Diagnosis of Choroidal Melanoma.
  12. Neural crest-like stem cell transcriptome analysis identifies LPAR1 in melanoma progression and therapy resistance.
  13. Amelanotic metastatic gastric malignant melanoma: a case report.
  14. Ultrasound Assessment of Regional Lymph Nodes in Melanoma Staging.
  15. Metastatic Malignant Melanoma Causing Small Bowel Intussusception: A Case Report with 4-year Follow-up.
  16. Overexpression of chemokine receptor CXCR4 predicts lymph node metastatic risk in patients with melanoma: A systematic review and meta-analysis.
  17. Loss of miR-1469 expression mediates melanoma cell migration and invasion.
  18. Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma.
  19. Dissecting melanocytes to predict melanoma.
  20. Engineering Exosomes Endowed with Targeted Delivery of Triptolide for Malignant Melanoma Therapy.
  21. Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma.
  22. Metastatic melanoma to the bladder presenting as autonomic dysreflexia in a patient with paraplegia.
  23. Suppression effect of a dual cancer-specific oncolytic adenovirus on luciferase-labeled human melanoma cells in vitro and in vivo.
  24. Association between melanoma thickness and clinical and demographic characteristics.
  25. Sendeng-4 Suppressed Melanoma Growth by Induction of Autophagy and Apoptosis.
  26. Bucket of Deep Transfer Learning Features and Classification Models for Melanoma Detection.
  27. Imaging and Detection of Cell Apoptosis byIn vitroPhotodynamic Therapy Applications of Zinc (II) Phthalocyanine on Human Melanoma Cancer.
  28. Green Synthesized Honokiol Transfersomes Relieve the Immunosuppressive and Stem-Like Cell Characteristics of the Aggressive B16F10 Melanoma.
  29. Transcriptome Analysis Reveals the Molecular Immunological Characteristics of Lesions in Patients with Halo Nevi When Compared to Stable Vitiligo, Normal Nevocytic Nevi and Cutaneous Melanoma.
  30. Real-life data for first-line combination immune-checkpoint inhibition and targeted therapy in patients with melanoma brain metastases.
  31. Transplantation of non-cultured epidermal cell suspension in a case of segmental vitiligo with post-treatment scarring.
  32. Neurocutaneous melanocytosis-associated malignant melanoma presenting with peritoneal seeding.
  33. Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis.
  34. Contrast-enhanced ultrasound for evaluation of tumor perfusion and outcome following treatment in a murine melanoma model.
  35. A biobanking turning-point in the use of formalin-fixed, paraffin tumor blocks to unveil kinase signaling in melanoma.
  36. Intra- and inter-tumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing.
  37. Human melanocyte development and melanoma dedifferentiation at single-cell resolution.
  38. Malignant melanoma with in-transit metastases refractory to programmed cell death-1 inhibitor successfully treated with local interferon-β injections: A case report.
  39. Visualizing murine breast and melanoma tumor microenvironment using intravital multiphoton microscopy.
  40. Novel Allosteric Inhibitors of Deoxyhypusine Synthase against Malignant Melanoma: Design, Synthesis, and Biological Evaluation.
  41. Transdermal delivery of multifunctional CaO2@Mn-PDA nanoformulations by microneedles for NIR-induced synergistic therapy against skin melanoma.
  42. Development and Validation of a Modified Pathologic Nodal Classification System for Cutaneous Melanoma.
  43. Semi-Automatic Tool for Vitiligo Detection and Analysis.
  44. Associations of immune cell homing gene signatures and infiltrates of lymphocyte subsets in human melanomas: discordance with CD163+ myeloid cell infiltrates.
  45. Core gene signatures of atopic dermatitis using public RNA-sequencing resources: Comparison of bulk vs. single-cell approach.
  46. TLR4 gene polymorphisms in Egyptian vitiligo patients: insights into emerging association with clinical activity, family history, and response to therapy.
  47. "Repeatability of Repeatability": the stability of self-reported melanoma risk factors in two independent samples.
  48. Prognostic significance of the aberrant expression of neuroendocrine markers in melanomas.
  49. Comparison of photoacoustic imaging and histopathological examination in determining the dimensions of 52 human melanomas and nevi ex vivo.
  50. Temporal Trends in the Incidence and Mortality of Skin Malignant Melanoma in China from 1990 to 2019.
  51. Suggested methodology for longitudinal evaluation of nevi based on clinical images.
  52. Skin pigmentation and vitamin D-folate interactions in vascular function: an update.
  53. Resident human dermal γδT-cells operate as stress-sentinels: Lessons from the hair follicle.
  54. UV-induced reduction in Polycomb repression promotes epidermal pigmentation.
  55. Treatment of melasma with a low-fluence 1064 nm Q-switched Nd:YAG laser: Laser toning in Caucasian women.
  56. Transfersomes improved delivery of ascorbic palmitate into the viable epidermis for enhanced treatment of melasma.
  57. Another step on the road towards standardized outcome reporting for congenital melanocytic naevi: one more to go!
  1. Exp Ther Med. 2021 Oct;22(4): 1135
    MicroRNA-9 inhibits the proliferation and migration of malignant melanoma cells via targeting sirituin 1.
    Pingyuan Bu, Chengqun Luo, Quanyong He, Ping Yang, Xi Li, Dan Xu.
      [This retracts the article DOI: 10.3892/etm.2017.4595.].
    DOI:  https://doi.org/10.3892/etm.2021.10569
  2. Acta Dermatovenerol Croat. 2021 Apr;291(1): 30-34
    Melanoma Controls the Metastatic Process only in Terms of Metastatic Cell Dissemination - What Is Responsible for Metastatic Cell Proliferation?
    Leo Čabrijan, Jasna Lipozenčić.
      The process of melanoma metastasis can be divided into two stages of metastatic cell dissemination and proliferation. The whole process should be observed and distinguished through the variable or prism of time. The fact that melanoma metastases are detected in visceral organs at the stage when they are macroscopically visible does not imply that their onset has occurred much earlier. Additionally, it is quite obvious that the entire process is not driven by melanoma but rather only the initial stage of metastatic cell dissemination, whereas the later stage of metastatic cell proliferation is driven by other factors, firstly by mutated genes in the presence of melanoma or without it. Dissemination of metastatic cells occurs at approximately the same time in all melanomas, at MIS transition to MM, but is not immediately followed by metastatic cell proliferation; instead, some time has to elapse for a particular gene mutation to occur, and this timing varies among melanomas. Following dissemination of metastatic cells to visceral organs, they remain inactive, and in this period the presence of melanoma is not necessary anymore for metastatic cell proliferation, as they are waiting for a signal to start multiplying. This is clearly discernible from the fact that melanoma is today detected and removed frequently and early, but visible metastases then develop in the absence of melanoma, which may also regress spontaneously. Accordingly, MM is no longer necessary for metastasis later on. Finally, let me rephrase the title: melanoma is only responsible for initial dissemination of metastatic cells, whereas subsequent proliferation of metastatic cells is driven by other factors, most probably mutated genes.
  3. Pigment Cell Melanoma Res. 2021 Sep 01.
    YAP facilitates melanoma migration through regulation of actin-related protein 2/3 complex subunit 5 (ARPC5).
    Jason W Lui, Stephen P G Moore, Lee Huang, Kelsey Ogomori, Yan Li, Deborah Lang.
      Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators that have been implicated in driving metastasis and progression in many cancers, mainly through their transcriptional regulation of downstream targets. Although YAP and TAZ have shown redundancy in many contexts, it is still unknown whether or not this is true in melanoma. Here, we show that while both YAP and TAZ are expressed in a panel of melanoma cell lines, depletion of YAP results in decreased cell numbers, focal adhesions, and the ability to invade matrigel. Using non-biased RNA-sequencing analysis, we find that melanoma cells depleted of YAP, TAZ, or YAP/TAZ exhibit drastically different transcriptomes. We further uncover the ARP2/3 subunit ARPC5 as a specific target of YAP but not TAZ and that ARPC5 is essential for YAP-dependent maintenance of melanoma cell focal adhesion numbers. Our findings suggest that in melanoma, YAP drives melanoma progression, survival, and invasion.
    Keywords:  ARP2/3 complex; cancer; melanoma; transcriptional coactivator; yes-associated protein (YAP)
    DOI:  https://doi.org/10.1111/pcmr.13013
  4. Front Oncol. 2021 ;11 721624
    ATG5 and ATG7 Expression Levels Are Reduced in Cutaneous Melanoma and Regulated by NRF1.
    Živa Frangež, Deborah Gérard, Zhaoyue He, Marios Gavriil, Yuniel Fernández-Marrero, S Morteza Seyed Jafari, Robert E Hunger, Philippe Lucarelli, Shida Yousefi, Thomas Sauter, Lasse Sinkkonen, Hans-Uwe Simon.
      Autophagy is a highly conserved cellular process in which intracellular proteins and organelles are sequestered and degraded after the fusion of double-membrane vesicles known as autophagosomes with lysosomes. The process of autophagy is dependent on autophagy-related (ATG) proteins. The role of autophagy in cancer is very complex and still elusive. We investigated the expression of ATG proteins in benign nevi, primary and metastatic melanoma tissues using customized tissue microarrays (TMA). Results from immunohistochemistry show that the expression of ATG5 and ATG7 is significantly reduced in melanoma tissues compared to benign nevi. This reduction correlated with changes in the expression of autophagic activity markers, suggesting decreased basal levels of autophagy in primary and metastatic melanomas. Furthermore, the analysis of survival data of melanoma patients revealed an association between reduced ATG5 and ATG7 levels with an unfavourable clinical outcome. Currently, the mechanisms regulating ATG expression levels in human melanoma remains unknown. Using bioinformatic predictions of transcription factor (TF) binding motifs in accessible chromatin of primary melanocytes, we identified new TFs involved in the regulation of core ATGs. We then show that nuclear respiratory factor 1 (NRF1) stimulates the production of mRNA and protein as well as the promoter activity of ATG5 and ATG7. Moreover, NRF1 deficiency increased in vitro migration of melanoma cells. Our results support the concept that reduced autophagic activity contributes to melanoma development and progression, and identifies NRF1 as a novel TF involved in the regulation of both ATG5 and ATG7 genes.
    Keywords:  ATG5; ATG7; NRF1; autophagy; melanoma; transcription factor
    DOI:  https://doi.org/10.3389/fonc.2021.721624
  5. J Dermatol Sci. 2021 Aug 19. pii: S0923-1811(21)00196-1. [Epub ahead of print]
    Circ_0062270 upregulates EPHA2 to facilitate melanoma progression via sponging miR-331-3p.
    Xiaogang Chen, Yichen Tang, Jianna Yan, Liang Li, Long Jiang, Yuchong Chen.
      BACKGROUND: Circular RNA (circRNA) has been confirmed to play a vital role in melanoma progression.OBJECTIVE: The regulatory function of circ_0062270, a novel circRNA, in melanoma progression is unclear.
    METHODS: Relative expression levels of circ_0062270 and microRNA (miR)-331-3p were determined using qRT-PCR. Cell counting kit 8 assay, EdU staining and flow cytometry were used to measure cell proliferation, cell cycle distribution and apoptosis. The protein levels of proliferation, apoptosis and metastasis-related markers, as well as EPH receptor A2 (EPHA2), were tested using western blot analysis. Besides, cell migration and invasion were evaluated using transwell assay. Meanwhile, the interaction between miR-331-3p and circ_0062270 or EPHA2 was confirmed by dual-luciferase reporter assay or RIP assay. Additionally, tumor xenograft models were constructed to investigate the function of circ_0062270 on melanoma tumor growth in vivo.
    RESULTS: The expression of circ_0062270 was increased in melanoma tissues and cells. Knockdown of circ_0062270 inhibited proliferation, promoted apoptosis, and repressed metastasis in melanoma. Moreover, circ_0062270 could serve as miR-331-3p sponge, and miR-331-3p could target EPHA2. Furthermore, miR-331-3p inhibitor and EPHA2 overexpression reversed the inhibitory effect of circ_0062270 silencing on melanoma progression. In addition, silenced circ_0062270 also could inhibit melanoma tumor growth in vivo.
    CONCLUSION: Circ_0062270 accelerated the progression of melanoma through regulating the miR-331-3p/EPHA2 axis, suggesting that circ_0062270 might be a novel potential therapeutic target for melanoma.
    Keywords:  EPHA2; Melanoma; circ_0062270; miR-331-3p
    DOI:  https://doi.org/10.1016/j.jdermsci.2021.08.005
  6. Pigment Cell Melanoma Res. 2021 Aug 31.
    Phenotypic plasticity of melanocytes derived from human adult skin.
    Dániel László Vidács, Zoltán Veréb, Renáta Bozó, Lili Borbála Flink, Hilda Polyánka, István Balázs Németh, Szilárd Póliska, Benjamin Tamás Papp, Máté Manczinger, Róbert Gáspár, Seyedmohsen Mirdamadi, Lajos Kemény, Zsuzsanna Bata-Csörgő.
      We previously described a novel in vitro culture technique for dedifferentiated human adult skin melanocytes. Melanocytes cultured in a defined, cholera toxin and PMA free medium became bipolar, unpigmented, and highly proliferative. Furthermore, TRP-1 and c-Kit expression disappeared and EGFR receptor and nestin expression were induced in the cells. Here, we further characterized the phenotype of these dedifferentiated cells and by comparing them to mature pigmented melanocytes we detected crucial steps in their phenotype change. Our data suggest that normal adult melanocytes easily dedifferentiate into pluripotent stem cells given the right environment. This dedifferentiation process described here for normal melanocyte is very similar to what has been described for melanoma cells, indicating that phenotype switching driven by environmental factors is a general characteristic of melanocytes that can occur independent of malignant transformation.
    Keywords:  dedifferentiation; melanocyte stem cells; melanocytes; melanoma; melanoma stem cells
    DOI:  https://doi.org/10.1111/pcmr.13012
  7. Life Sci. 2021 Aug 25. pii: S0024-3205(21)00902-4. [Epub ahead of print]284 119915
    The relationship between melanin production and lipofuscin formation in Tyrosinase gene knockout melanocytes using CRISPR/Cas9 system.
    Jae Ho Kim, Moon-Moo Kim.
      Age spots are a significant phenotypic marker of aging formed by lipofuscin. Melanin is another skin pigment molecule responsible for skin aging. The present study aims to investigate the relationship between melanin production and lipofuscin synthesis in normal mouse melanoma cell line B16F1 cells and Tyrosinase (TYR) gene knockout cells. TYR gene KO cells were successfully developed using CRISPR/Cas9 system and confirmed by Sanger DNA sequencing analysis. Furthermore, the melanin production and lipofuscin formation were validated through RT-PCR and Western blot analysis. The expression levels of gene microphthalmia-associated transcription factor (MITF), Tyrosinase, tyrosine-related protein-1 (TRP-1), tyrosine-related protein-2 (TRP-2), and antioxidant proteins such as methionine sulfoxide reductase A (MSRA), Catalase and Glutathione reductase (GR) related to melanogenesis was found to be decreased in TYR gene KO cells compared with normal cells. Moreover, lipofuscin formation was increased in TYR gene KO cells compared to normal cells. Therefore, the above findings suggest that melanin production and lipofuscin formation could be linked by the TYR gene in melanocytes.
    Keywords:  CRISPR/Cas9; Lipofuscin; MITF; Melanin; Tyrosinase; α-MSH
    DOI:  https://doi.org/10.1016/j.lfs.2021.119915
  8. J Cell Mol Med. 2021 Sep 01.
    Pharmacological inhibition of USP7 suppresses growth and metastasis of melanoma cells in vitro and in vivo.
    Minmin Xiang, Long Liang, Xinwei Kuang, Zuozhong Xie, Jing Liu, Shuang Zhao, Juan Su, Xiang Chen, Hong Liu.
      Melanoma is a highly aggressive type of skin cancer. The development of diverse resistance mechanisms and severe adverse effects significantly limit the efficiency of current therapeutic approaches. Identification of the new therapeutic targets involved in the pathogenesis will benefit the development of novel therapeutic strategies. The deubiquitinase ubiquitin-specific protease-7, a potential target for cancer treatment, is deregulated in types of cancer, but its role in melanoma is still unclear. We investigated the role and the inhibitor P22077 of ubiquitin-specific protease-7 in melanoma treatment. We found that ubiquitin-specific protease-7 was overexpressed and correlated with poor prognosis in melanoma. Further, pharmacological inhibition of ubiquitin-specific protease-7 by P22077 can effectively inhibit proliferation, and induce cell cycle arrest and apoptosis via ROS accumulation-induced DNA damage in melanoma cells. Inhibition of ubiquitin-specific protease-7 by P22077 also inhibits melanoma tumour growth in vivo. Moreover, inhibition of ubiquitin-specific protease-7 prevented migration and invasion of melanoma cells in vitro and in vivo by decreasing the Wnt/β-catenin signalling pathway. Taken together, our study revealed that ubiquitin-specific protease-7 acted as an oncogene involved in melanoma cell proliferation and metastasis. Therefore, ubiquitin-specific protease-7 may serve as potential candidates for the treatment of melanoma.
    Keywords:  ROS; USP7; apoptosis; invasion; melanoma
    DOI:  https://doi.org/10.1111/jcmm.16834
  9. Drugs Context. 2021 ;pii: 2021-3-1. [Epub ahead of print]10
    Treatment beyond progression and locoregional approaches in selected patients with BRAF-mutated metastatic melanoma.
    Francesco Serra, Carlotta Faverio, Angioletta Lasagna, Stefania Barruscotti, Tommaso Dominioni, Marco Benazzo, Paolo Pedrazzoli, Silvia Chiellino.
      The clinical management of BRAF-mutated metastatic melanoma had an important turning point after the introduction of the targeted therapy. Despite the efficacy and good tolerability of this treatment, the development of resistance mechanisms causes disease progression. The aim of this review is to investigate the role of treatment beyond progression and locoregional approaches in BRAF-mutated metastatic melanoma and provide oncologists dealing with this malignancy a useful road map on when and why to choose this strategy. The article is structured in the form of a narrative review reporting the most significant studies on the subject. Most of the available articles are represented by retrospective studies and case reports, leading to limitations in the final interpretations. Nevertheless, a correct analysis of the selected studies allows the drawing of some conclusions. In well-selected cases, treatment beyond progression could play an important role in the treatment sequence of patients with BRAF-mutated advanced melanoma and would seem to produce good disease control rates and positive survival outcomes. A careful evaluation of the radiological examinations and laboratory tests, based on the clinical conditions, allows the identification of which patients can benefit from this strategy. Such patients are those who, at the time of progression, have favourable features such as a lower performance status according to Eastern Cooperative Oncology Group (ECOG-PS), normal lactate dehydrogenase levels and lower disease burden. The clinical benefit is also consolidated by the addition of locoregional approaches. Locoregional approaches can include electrochemotherapy, radiotherapy or surgery, and their use provides local disease control and a better quality of life for patients.
    Keywords:  BRAF-mutated metastatic melanoma; locoregional approaches; targeted therapy; treatment beyond progression
    DOI:  https://doi.org/10.7573/dic.2021-3-1
  10. J Dermatol. 2021 Aug 29.
    Increased expression of secreted protein acidic and rich in cysteine and tissue inhibitor of metalloproteinase-3 in epidermotropic melanoma metastasis.
    Maureen Tania Meling, Yukiko Kiniwa, Eisaku Ogawa, Yuki Sato, Ryuhei Okuyama.
      Primary cutaneous melanoma generally arises in the epidermis, followed by invasion into the dermis. Although infrequent, invasive melanoma cells can, alternatively, migrate to the intraepidermal area and form epidermotropic melanoma metastasis (EMM). In this study, we focused on this unique manner of metastasis. To identify the key molecules which affect EMM, gene expression in EMM was compared with that in common skin metastasis (CSM). Polymerase chain reaction (PCR) analysis was performed for genes affecting the extracellular matrix, cellular adhesion, and tumor metastasis on three EMM and three CSM samples as an initial screening. For molecules showing altered expression in the EMM, expression levels were further verified using real-time quantitative PCR (qPCR) and immunohistochemistry. Five molecules showed an expression difference in the initial screening. Among these, secreted protein acidic and rich in cysteine (SPARC) was preferentially expressed in EMM (p = 0.01) by real-time qPCR. Another candidate molecule, tissue inhibitor of metalloproteinase-3 (TIMP3), was not statistically significant (p = 0.07), but showed the tendency of higher expression. These results correlated negatively to expression of N-cadherin and β-catenin. The upregulation of SPARC and TIMP3 may disrupt the continuity of the canonical Wnt pathway. This pathway regulates adhesion activity of melanoma cells to localize within the dermis, which consequently promotes EMM. Our study highlights the potential role of SPARC and TIMP3 as key molecules in EMM, and analysis of EMM may contribute for understanding melanoma invasion between the epidermis and the dermis.
    Keywords:  epidermotropic melanoma metastasis; neural cadherin; secreted protein acidic and rich in cysteine; tissue inhibitor of metalloproteinase-3; β-catenin
    DOI:  https://doi.org/10.1111/1346-8138.16125
  11. Cureus. 2021 Jul;13(7): e16628
    Magnetic Resonance Imaging Diagnosis of Choroidal Melanoma.
    Ahmad Jiblawi, Hani Chanbour, Azzam Tayba, Haissam Khayat, Khaled Jiblawi.
      Choroidal melanoma has a very rare incidence in Africa and Asia, especially in the Middle East. We report the first case of choroidal melanoma in Lebanon in a 33-year-old man presenting with progressive loss of vision in his right eye. MRI showed retinal detachment with evidence of a nodular-like lesion most consistent with choroidal melanoma. The patient underwent enucleation of the right eye globe and the diagnosis was confirmed on pathology.
    Keywords:  choroidal; flair; fovea; melanoma; retinal detachment
    DOI:  https://doi.org/10.7759/cureus.16628
  12. Cancer Res. 2021 Aug 30. pii: canres.1496.2020. [Epub ahead of print]
    Neural crest-like stem cell transcriptome analysis identifies LPAR1 in melanoma progression and therapy resistance.
    Jianglan Liu, Vito W Rebecca, Andrew V Kossenkov, Thomas Connelly, Qin Liu, Alexis Gutierrez, Min Xiao, Ling Li, Gao Zhang, Anastasia Samarkina, Delaine Zayasbazan, Jie Zhang, Chaoran Cheng, Zhi Wei, Gretchen M Alicea, Mizuho Fukunaga-Kalabis, Clemens Krepler, Pedro Aza-Blanc, Chih-Cheng Yang, Bela Delvadia, Cynthia Tong, Ye Huang, Maya Delvadia, Alice Santana Morais, Katrin Sproesser, Patricia Brafford, Joshua X Wang, Marilda Beqiri, Rajasekharan Somasundaram, Adina Vultur, Denitsa M Hristova, Lawrence W Wu, Yiling Lu, Gordon B Mills, Wei Xu, Giorgos C Karakousis, Xiaowei Xu, Lynn M Schuchter, Tara C Mitchell, Ravi K Amaravadi, Lawrence N Kwong, Dennie T Frederick, Genevieve M Boland, Joseph M Salvino, David W Speicher, Keith T Flaherty, Ze'ev A Ronai, Meenhard Herlyn.
      Metastatic melanoma is challenging to clinically address. Although standard of care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSCs) including high invasiveness, plasticity and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi +/- MEKi efficacy and ablated melanoma migration and invasion. Our data defines LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1496
  13. Anticancer Drugs. 2021 Aug 27.
    Amelanotic metastatic gastric malignant melanoma: a case report.
    Min Zhu, Da-Ya Zhang, Guan-Jun Zhang, Zhan-Bo Wang, Ming-Yang Lid.
      Melanoma is a malignant form of cutaneous cancer with an increasing incidence since 1970s, accounting for nearly 75% of the death related to skin cancer especially in western countries. Highest recurrence and mortality were observed for the subtype with distal metastasis, demonstrating poor outcomes. However, high incidence of gastrointestinal metastasis of malignant melanoma is frequently misdiagnosed due to lack of specific clinical manifestations, especially for the rare observed cases presented amelanotic appearance, accounting for about 2% of all metastatic cases. In the present study, we reported a 36-year-old male patient, who was firstly diagnosed as gastric cancer, and then was confirmed as amelanotic melanoma metastasis by pathological examination, demonstrating positive for melanoma markers including Melan A, S-100, Hmb45 and CD79a. In conclusion, for the amelanotic neoplasm observed during gastroscopy in patients with melanoma history, pathological examination should be carried out to confirm the possibility of melanoma metastasis, providing evidences for the following treatment.
    DOI:  https://doi.org/10.1097/CAD.0000000000001227
  14. Acta Dermatovenerol Croat. 2021 Jul;29(2): 80-87
    Ultrasound Assessment of Regional Lymph Nodes in Melanoma Staging.
    Ivana Prkačin, Mirna Šitum, Marija Delaš Aždajić, Zvonimir Puljiz.
      BACKGROUND: Melanoma can early metastasize to regional lymph nodes. The sentinel lymph node (SLN) is the first lymph node draining directly from the site of primary melanoma, and the pathohistological status of the SLN is the most significant prognostic factor for overall survival prevalence and prognosis in patients with melanoma. Ultrasound is a very useful for the imaging of regional lymph node metastases, combined with Doppler and cytopuncture.OBJECTIVE: The aim of this study was to investigate the role of ultrasound assessment of regional lymph nodes in melanoma staging.
    PATIENTS AND METHODS: The study included all patients with primary melanoma detected in the period between 2003 and 2012, in whom diagnostic processing has not proven distant metastases or physical examination did not find enlarged lymph nodes. In total, 202 surgically treated patients were included in the study, of which 101 patients underwent ultrasound examination of regional lymph nodes using a linear probe of at least 12 MHz, while ultrasound of regional lymph nodes was not performed for 101 patients.
    RESULTS: The results of this study emphasize the importance of ultrasound in the diagnostics and treatment of patients with melanoma. Based on the observation of the occasional positive ultrasound and fine needle aspiration cytology (FNAC) in regional lymph nodes, our results indicate that a proportion of patients can avoid sentinel lymph node biopsy (SLNB). In case of a positive ultrasound findings (complemented with FNAC of suspicious nodes), direct dissection of regional lymph nodes is recommended. However, negative ultrasound findings do not exclude the presence of micrometastases due to poor sensitivity of this method and is not a contraindication for SLNB.
    CONCLUSION: Therefore, there is a need for further studies on metastatic melanoma, especially those in the sentinel lymph nodes and in its early stage.
  15. Acta Dermatovenerol Croat. 2021 Apr;291(1): 35-38
    Metastatic Malignant Melanoma Causing Small Bowel Intussusception: A Case Report with 4-year Follow-up.
    Davorin Kozomara, Inga Marijanović, Nikica Šutalo, Marija Kraljević, Teo Buhovac.
      Primary mucosal malignant melanoma of the small bowel is extremely rare. The small bowel is mostly affected by metastases of the primary malignant melanoma of the skin. Bowel obstruction is a rare complication of metastatic melanoma. We present a case of small bowel obstruction in a 49-year-old man with history of skin malignant melanoma. A segmental resection of the ileum with termino-terminal anastomosis was performed. Pathohistological examination showed metastatic melanoma. After 4 years of follow-up, the patient is still free of the disease.
  16. Cytokine. 2021 Aug 28. pii: S1043-4666(21)00280-5. [Epub ahead of print]148 155691
    Overexpression of chemokine receptor CXCR4 predicts lymph node metastatic risk in patients with melanoma: A systematic review and meta-analysis.
    Mina Alimohammadi, Ali Rahimi, Fatemeh Faramarzi, Reza Alizadeh-Navaei, Alireza Rafiei.
      CXCR4 is a member of CXC-type and G protein-coupled receptors that can conduce many biological processes, including hemostasis, migration, and adhesion of different types of immune cells. Also, the contribution of CXCR4 in metastasis cascade and development of various malignancies has been addressed in previous reports. This meta-analysis was performed to explore whether the CXCR4 expression affects prognosis and clinicopathologic features in melanoma cancer. Our study involved 656 melanoma patients from 13 reports by detailed literature search from PubMed, Embase, Web of Science, and Google Scholar up to April 2021. To evaluate the association between CXCR4 expression and clinicopathological features of melanoma, we calculated odds ratios (ORs) with its 95% confidence intervals (CIs). We indicated that the CXCR4 overexpression was obviously correlated with ulceration (OR = 0.56, 95% CI: 0.38 to 0.74; I2 = 0.0%, P = 0.999), tumor thickness (OR = 0.56, 95% CI: 0.38 to 0.74; I2 = 0.0%, P = 0.999) and lymph node metastasis (OR = 8.54, 95% CI: 1.04 to 16.04; I2 = 98.9, P < 0.0001). In conclusion, our results reveal that CXCR4 is involved in enhancing the progression and metastasis of melanoma, and further clinical studies are necessary to investigate the role of CXCR4 as a diagnostic and therapeutic biomarker through the progress of melanoma cancer.
    Keywords:  CXCR4; Melanoma; Meta-analysis; Metastasis; Prognosis
    DOI:  https://doi.org/10.1016/j.cyto.2021.155691
  17. PLoS One. 2021 ;16(9): e0256629
    Loss of miR-1469 expression mediates melanoma cell migration and invasion.
    Mallory J DiVincenzo, Zoe Barricklow, Emily Schwarz, Maribelle Moufawad, J Harrison Howard, Lianbo Yu, Catherine Chung, Alejandro A Gru, William E Carson.
      Tumor ulceration is considered one of the most prognostically significant findings in primary cutaneous melanoma, associated with decreased disease-free and overall survival. However, the unique features associated with ulcerated melanoma that contribute to a poor prognosis in affected patients remain poorly defined. microRNAs are small, non-coding RNAs that function to inhibit expression of specific gene targets, therefore altering the functions of cells in which they are expressed. miR-1469 is a novel miR with significantly decreased expression in ulcerated melanoma tissue relative to non-ulcerated tumors. We hypothesized that loss of miR-1469 expression in melanoma contributes to altered tumor cell functions mediating disease progression. Transfection of a miR-1469 mimic resulted in a significant reduction in the migratory and invasive capacity of the CHL1 and MEL39 melanoma cell lines (>58.1% reduction, p < 0.0332), as well as the invasive capacity of the A375 melanoma cell line (>50% reduction, p < 0.0021). Expression of myeloid cell leukemia-1 (MCL1), a miR-1469 target gene, was reduced in the A375 and MEL39 cell lines by immunoblot. No significant differences in viability, resistance to apoptotic stimuli, or proliferation were observed following transfection. These findings together demonstrate how migration and invasion are specific functions through which miR-1469 expression in melanoma cells can contribute to the differences in disease progression associated with tumor ulceration.
    DOI:  https://doi.org/10.1371/journal.pone.0256629
  18. Cancer Sci. 2021 Sep 03.
    Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma.
    Erina Takai, Wataru Omata, Yasushi Totoki, Hiromi Nakamura, Satoshi Shiba, Akira Takahashi, Kenjiro Namikawa, Taisuke Mori, Naoya Yamazaki, Tatsuhiro Shibata, Shinichi Yachida.
      Assessment of treatment efficacy of immune checkpoint inhibitors in melanoma patients is difficult since the response to these therapies varies among patients or lesions. The clonal evolution of cancer during immune checkpoint blockade therapy could cause treatment resistance. We investigated the potential of liquid biopsy in monitoring the mutational profiles of metastatic melanoma during immunotherapy. Plasma samples collected from 21 Japanese metastatic melanoma patients before immune checkpoint blockade therapy were subjected to whole-exome sequencing (WES). Furthermore, 14 Japanese patients with melanoma were enrolled for longitudinal analysis of circulating tumor DNA (ctDNA). Plasma samples were prospectively collected before and during therapy and sequenced. WES of the pre-treatment plasma from Japanese melanoma patients showed detectable ctDNA levels with wide ranges of variant allele frequencies within a sample, suggesting clonal and subclonal mutations in ctDNA. In targeted sequencing using longitudinal samples, ctDNA levels correlated with increased tumor size, while ctDNA content immediately decreased after a surge in a patient exhibiting pseudo-progression, suggesting the potential of ctDNA analysis in discriminating between pseudo- and true progression. Mutant ctDNA levels showed different patterns within the clinical course of specific patients, suggesting that these mutations were derived from different tumor clones with distinct therapeutic responses. During further investigation, WES of plasma samples from one patient showed marked differences in the mutational profiles of ctDNA, including expansive tumor evolution during an acute exacerbation. Immunotherapy may induce characteristic clonal evolutions of tumors; longitudinal analysis of ctDNA has the potential of determining these tumor evolution patterns and therapeutic responses.
    Keywords:  circulating tumor DNA; clonal evolution; immune checkpoint inhibitor; liquid biopsy; melanoma
    DOI:  https://doi.org/10.1111/cas.15088
  19. Nat Cell Biol. 2021 Sep 02.
    Dissecting melanocytes to predict melanoma.
    Alicia M McConnell, Leonard I Zon.
      
    DOI:  https://doi.org/10.1038/s41556-021-00748-0
  20. ACS Appl Mater Interfaces. 2021 Aug 31.
    Engineering Exosomes Endowed with Targeted Delivery of Triptolide for Malignant Melanoma Therapy.
    Liangdi Jiang, Yongwei Gu, Yue Du, Xiaomeng Tang, Xin Wu, Jiyong Liu.
      Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.
    Keywords:  TRAIL; exosomes; malignant melanoma; targeting drug delivery; triptolide
    DOI:  https://doi.org/10.1021/acsami.1c10325
  21. Comput Struct Biotechnol J. 2021 ;19 4472-4485
    Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma.
    Qian Liu, Rongfang Nie, Mengyuan Li, Lin Li, Haiying Zhou, Hui Lu, Xiaosheng Wang.
      Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma.
    Keywords:  Clustering analysis; DMFS, distant-metastasis free survival; DSS, disease-specific survival; EMT, epithelial-mesenchymal transition; FDR, false discovery rate; GO, gene ontology; GSEA, gene-set enrichment analysis; HLA, human leukocyte antigen; HRD, homologous recombination deficiency; ICIs, immune checkpoint inhibitors; Immune subtypes; Immunotherapy; MDSC, myeloid-derived suppressor cell; Melanoma; NK, natural killer; OS, overall survival; SCNAs, somatic copy number alterations; TCGA, The Cancer Genome Atlas; TIME, tumor immune microenvironment; TMB, tumor mutation burden; TME, tumor microenvironment; Tumor immune microenvironment; WGCNA, weighted gene co-expression network analysis; ssGSEA, single-sample gene-set enrichment analysis
    DOI:  https://doi.org/10.1016/j.csbj.2021.08.005
  22. Urol Case Rep. 2021 Nov;39 101820
    Metastatic melanoma to the bladder presenting as autonomic dysreflexia in a patient with paraplegia.
    Cherry A Abdou, Eric H Wolff, Andrew T Tracey, Adam P Klausner.
      We report a case of a 66-year-old male with T2 American Spinal Injury Association Impairment Scale (AIS) A paraplegia who presented to Urology with worsening autonomic dysreflexia. Work-up identified a bladder mass treated by transurethral resection and pathologically confirmed as melanoma. Additional work-up revealed metastatic melanoma to the back and brain. The patient completely recovered with no evidence of disease more than two years after completing therapy. In this report, we review the presentation of metastatic bladder melanoma presenting with autonomic dysreflexia, which has never been previously described, and discuss the prognosis of metastatic melanoma to the bladder.
    Keywords:  Autonomic dysreflexia; Bladder cancer; Melanoma; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.eucr.2021.101820
  23. Cancer Biomark. 2021 Aug 20.
    Suppression effect of a dual cancer-specific oncolytic adenovirus on luciferase-labeled human melanoma cells in vitro and in vivo.
    Min Li, Yilong Zhu, Bing Bai, Jinbo Fang, Wei Yao, Yiquan Li, Shanzhi Li, Xiao Li, Ningyi Jin, Rihua Jiang.
      BACKGROUND: To explore the suppressive effect of Apoptin-loaded oncolytic adenovirus (Ad-VT) on luciferase-labeled human melanoma cells in vitro and in vivo.METHODS: The stable luciferase-expressing human melanoma cells A375-luc or M14-luc were obtained by transfecting the plasmid pGL4.51 and selection with G418, followed by luciferase activity, genetic stability and bioluminescence intensity assays. In vitro, the inhibitory effects of Ad-VT on A375-luc or M14-luc were evaluated using the MTS cell proliferation, FITC-Annexin V apoptosis detection, transwell migration, Matrigel invasion and scratch assays. The inhibition pathway in Ad-VT-infected A375-luc and M14-luc cells were analyzed by JC-1 staining and Western-blot detection of mitochondrial apoptosis-related proteins. In vivo, the suppressive effects of Ad-VT on A375-luc or M14-luc were assessed by living imaging technology, tumor volume, bioluminescence intensity, survival curves and immunohistochemical analysis of the tumors from the xenograft tumor model BALB/c nude mice.
    RESULTS: The growth and migration of A375-luc and M14-luc were significantly inhibited by Ad-VT in vitro. The evaluations of A375-luc and M14-luc tumor models in BALB/c nude mice were successfully performed using living imaging technology. Ad-VT had an anti-tumor effect by reducing tumor growth and increasing survival in vivo. Ad-VT significantly changed the mitochondrial membrane potential by triggering the the mitochondrial release of apoptosis-related proteins, AIF (apoptosis inducing factor), ARTS (Apoptosis-Related Proteins), and Cyto-c (cytochrome c) from the mitochondria.
    CONCLUSION: Ad-VT reduced the mitochondrial membrane potential in A375-luc or M14-luc cells and induced the mitochondrial release of AIF, ARTS and Cyto-C. Ad-VT induced apoptosis in A375-luc or M14-luc cells via the mitochondrial apoptotic pathway.
    Keywords:  BALB/C nude mice model; Luciferase labeled A375 or M14; living imaging technology; oncolytic adenovirus; tumor suppression
    DOI:  https://doi.org/10.3233/CBM-203150
  24. Eur J Dermatol. 2021 Aug 26.
    Association between melanoma thickness and clinical and demographic characteristics.
    Aram Boada, Antonio Tejera-Vaquerizo, Celia Requena, Esperanza Manrique-Silva, Victor Traves, Eduardo Nagore.
      The large-scale implementation of primary and secondary skin cancer prevention strategies in recent decades has led to an increase in the diagnosis of thin melanomas and a decrease in the mean thickness of tumours diagnosed. The number of newly diagnosed thick melanomas, however, has remained stable. To investigate associations between melanoma thickness, clinical presentation and demographic and phenotypic characteristics. The study is based on a cross-sectional study of 1,459 patients with melanoma from a dermatology department at a tertiary hospital in Spain between 2000 and 2017. We analysed associations between median Breslow thickness and demographic, phenotypic, and clinical characteristics, including the method of melanoma detection. Age ≥ 70 years (regression coefficient [RC] =  1.2, 95% CI: 1.1-1.3; p  <  0.001), male sex (RC  =  0.9, 95% CI: 0.8-0.9; p  <  0.001), symptom-based detection (RC  =  1.3, 95% CI: 1.1-1.4; p  <  0.001), and a history of sunburn at the melanoma site (RC  =  0.9, 95% CI: 0.8-0.9; p  =  0.04) were all associated with thicker tumours. Melanomas on the lower extremities, by contrast, were significantly thinner (RC  =  0.9, 95% CI: 0.8-0.9; p = 0.04). Thick melanomas occur preferentially in older men and show changes such as bleeding or an increase in volume or colour. This information should be incorporated into health training and education programs to design better prevention strategies and minimize diagnostic delays.
    Keywords:  Breslow thickness; age; bleeding melanoma; gender; thick melanoma; thin melanoma
    DOI:  https://doi.org/10.1684/ejd.2021.4096
  25. Evid Based Complement Alternat Med. 2021 ;2021 5519973
    Sendeng-4 Suppressed Melanoma Growth by Induction of Autophagy and Apoptosis.
    Rina Du, Pengwei Zhao, Shikui Wu, Yaoxing Gao, Rina Wu, Minli Yang, Wanying Song, Haining Gao.
      Sendeng-4 is a traditional Chinese medicine that has been successfully applied to anti-inflammatory diseases in clinical practice. Monomers within Sendeng-4 showed promising antitumor activity against lung cancer, colon cancer, and cutaneous cancer. However, potency of Sendeng-4 in melanoma has not been explored. This study aims to explore the potential application of Sendeng-4 in melanoma treatment. In the present study, we systemically investigate the possibility of Sendeng-4 for treatment of melanoma cancer in vitro by proliferation assay, colony formation, flow cell cytometry, RNA-seq, western blot, and fluorescence-based assay. Our data demonstrated that Sendeng-4 suppresses the proliferation and colony formation capacity of melanoma cells and induces cell cycle block at G2/M phase and eventually cell death. Mechanistically, transcriptome sequencing demonstrates that the PI3K-AKT pathway was significantly inactivated upon Sendeng-4 exposure, which was confirmed by western blot showing decreased phosphorylation of AKT. In addition, decreased BCL-2 expression and increased BAX expression were observed, suggesting programmed cell death via apoptosis. Moreover, LC3-II production as well as autophagosomes formation was observed as demonstrated by western blot and immunofluorescence, indicating elevated autophagy network by Sendeng-4 stimulation. Collectively, we concluded that Sendeng-4 might be used as an anticancer drug for melanoma.
    DOI:  https://doi.org/10.1155/2021/5519973
  26. J Imaging. 2020 Nov 26. pii: 129. [Epub ahead of print]6(12):
    Bucket of Deep Transfer Learning Features and Classification Models for Melanoma Detection.
    Mario Manzo, Simone Pellino.
      Malignant melanoma is the deadliest form of skin cancer and, in recent years, is rapidly growing in terms of the incidence worldwide rate. The most effective approach to targeted treatment is early diagnosis. Deep learning algorithms, specifically convolutional neural networks, represent a methodology for the image analysis and representation. They optimize the features design task, essential for an automatic approach on different types of images, including medical. In this paper, we adopted pretrained deep convolutional neural networks architectures for the image representation with purpose to predict skin lesion melanoma. Firstly, we applied a transfer learning approach to extract image features. Secondly, we adopted the transferred learning features inside an ensemble classification context. Specifically, the framework trains individual classifiers on balanced subspaces and combines the provided predictions through statistical measures. Experimental phase on datasets of skin lesion images is performed and results obtained show the effectiveness of the proposed approach with respect to state-of-the-art competitors.
    Keywords:  deep learning; ensemble classification; melanoma detection; transfer learning
    DOI:  https://doi.org/10.3390/jimaging6120129
  27. Photodiagnosis Photodyn Ther. 2021 Aug 31. pii: S1572-1000(21)00342-2. [Epub ahead of print] 102518
    Imaging and Detection of Cell Apoptosis byIn vitroPhotodynamic Therapy Applications of Zinc (II) Phthalocyanine on Human Melanoma Cancer.
    Sevda Zeinali, Ayca Tuncel, Abdulcelil Yüzer, Fatma Yurt.
      This study aims to investigate the photodynamic therapy (PDT) effects on MeWo (human melanoma cells) and HaCaT (normal human keratinocyte cells) by light stimulation of different concentrations of Zinc (II)-tetra-tert-butyl-phthalocyaninato (ZnPc). MTT viability assay data indicated that a 25 μM concentration of ZnPc is cytotoxic to the melanoma cancer cells while this concentration of ZnPc is not cytotoxic for the HaCaT cell line. Moreover, the results showed that photoactivated ZnPc at 12.5 μM concentration reduced the cell viability of the MeWo cell line to about 50 %. At this photosensitizing concentration, the efficacy of light doses of 20, 30, 40, and 50 J/cm2 was evaluated against MeWo and HaCaT cells. ZnPc at a concentration of 12.5 μM activated with a light dose of 50 J/cm2 was the most efficient for the killing of MeWo cells. In conclusion, the 12.5 μM of ZnPc with the treatment light dose of 50 J/cm2 from a RED light source was adequate to destroy MeWo cells by the ROS-induced apoptosis mechanism. It also exhibited low killing effects on healthy HaCaT cells. These findings are supported by the results of apoptosis with the Annexin V & Dead Cell Kit and fluorescence imaging.
    Keywords:  Photodynamic Therapy; human melanoma cells; melanoma; normal human keratinocyte cells; zinc phthalocyanine
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102518
  28. Int J Nanomedicine. 2021 ;16 5693-5712
    Green Synthesized Honokiol Transfersomes Relieve the Immunosuppressive and Stem-Like Cell Characteristics of the Aggressive B16F10 Melanoma.
    Yasmeen Ezzeldeen, Shady Swidan, Aliaa ElMeshad, Aya Sebak.
      Background: Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study.Methods: TFs were prepared using the modified scalable heating method. A three-factor, three-level Box-Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell-activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively).
    Results: The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the "do not eat me" signal - CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix-depleting enzyme, produced detrimental effects.
    Conclusion: HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.
    Keywords:  heating method; honokiol; immunosuppressive; melanoma; stem-like cell; transfersomes; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S314472
  29. J Inflamm Res. 2021 ;14 4111-4124
    Transcriptome Analysis Reveals the Molecular Immunological Characteristics of Lesions in Patients with Halo Nevi When Compared to Stable Vitiligo, Normal Nevocytic Nevi and Cutaneous Melanoma.
    Chun Pan, Jingzhe Shang, Haiqin Jiang, Ying Shi, Wenyue Zhang, Jingshu Xiong, Youming Mei, Siyu Long, Gai Ge, Zhenzhen Wang, Ziwei Wu, Hongsheng Wang, Aiping Wu.
      Background: Given their similar appearance and histology, halo nevi (HN) were considered as a type of vitiligo. However, whether HN have stronger immune response than stable vitiligo (VL) remains unclear. In addition, the molecular alterations in HN compared with normal nevocytic nevi (NN) and primary cutaneous melanoma (MM) must be determined. This study aimed to systematically characterize the molecular immunological features of HN.Methods: Skin samples from patients with HN, VL, NN, and MM were obtained with informed consent. Each of the four groups underwent transcriptome sequencing and data analysis were for pairwise comparison. Quantitative real-time PCR (RT-qPCR) was conducted to confirm the transcriptional expression of some differentially expressed genes (DEGs) that were closely related to immunity.
    Results: A total of 441 and 1507 DEGs were found in the HN/NN and HN/MM groups, respectively. Compared with those of VL, HN lesions contained 162 up-regulated DEGs and 12 down-regulated DEGs. Bioinformatics analysis showed that the up-regulated genes in HN were substantially enriched in immune response, immune deficiency, and immune rejection; biological stimulation (virus, bacteria); and proliferation and activation of immune cells. Immune cell composition analysis also confirmed high expression levels of multiple immunocytes in HN.
    Conclusion: The molecular immune mechanisms of HN and VL were similar, but the immune activity of HN was stronger than that of VL. Innate and adaptive immunity were involved in the pathogenesis and progression of HN and VL.
    Keywords:  differentially expressed genes; halo nevi; transcriptome sequencing; vitiligo
    DOI:  https://doi.org/10.2147/JIR.S321672
  30. Eur J Cancer. 2021 Aug 25. pii: S0959-8049(21)00486-X. [Epub ahead of print]156 149-163
    Real-life data for first-line combination immune-checkpoint inhibition and targeted therapy in patients with melanoma brain metastases.
    Marie-Luise Hilbers, Florentia Dimitriou, Peter Lau, Prachi Bhave, Grant A McArthur, Lisa Zimmer, Ken Kudura, Camille L Gérard, Mitchell P Levesque, Olivier Michielin, Reinhard Dummer, Phil F Cheng, Joanna Mangana.
      BACKGROUND: Melanoma brain metastases (MBM) have a poor prognosis. Systemic treatments that have improved outcomes in advanced melanoma have been shown to have an intracranial (IC) effect. We studied the efficacy and outcomes of combined immune checkpoint inhibitor ipilimumab/nivolumab (Combi-ICI) or targeted therapy (Combi-TT) as first-line treatment in MBM.METHODS: MBM patients treated with Combi-ICI or Combi-TT within 3 months after MBM diagnosis. Endpoints were progression-free survival (PFS) and overall survival (OS).
    RESULTS: 53 patients received Combi-ICI, 32% had symptomatic MBM and 33.9% elevated LDH. 71.7% required local treatment. The disease control rate was 60.3%. IC response rate (RR) was 43.8% at 3-months with durable responses at 6- (46.5%) and 12-months (53.1%). Extracranial (EC) RR was 44.7% at 3-months and 50% at 12-months. Median PFS was 9.6 months (95% CI 3.6-NR) and median overall survival (mOS) 44.8 months (95% CI; 26.2-NR). 63 patients received Combi-TT, 55.6% of patients had symptomatic MBM, 57.2% of patients had elevated LDH and 68.3% of patients required local treatment. The disease control rate was 60.4%. ICRR was 50% at 3-months, but dropped at 6-months (20.9%). ECRR was 69.2% at 3-months and 17.6% at 12-months. Median PFS was 5.8 months (95% CI 4.2-7.6) and mOS 14.2 months (95% CI 8.99-26.8). In BRAFV600 patients, 26.7% of patients received Combi-ICI and 73.3% Combi-TT with OS (p = 0.0053) and mPFS (p = 0.03) in favour to Combi-ICI.
    CONCLUSION: Combi-ICI showed prolonged mOS with sustainable IC and EC responses. Despite the initially increased efficacy, Combi-TT responses at 12 months were low. Combi-ICI appeared superior to Combi-TT for OS and PFS in BRAFV600 patients. Other clinical factors are determinants for first-line treatment choice.
    Keywords:  Immunotherapy; Melanoma brain metastasis; Stereotactic radiosurgery; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejca.2021.07.028
  31. J Cosmet Dermatol. 2021 Sep 02.
    Transplantation of non-cultured epidermal cell suspension in a case of segmental vitiligo with post-treatment scarring.
    Anubha Dev, Vishal Thakur, Keshavamurthy Vinay.
      
    Keywords:  non-cultured epidermal cell suspension; post-treatment scarring; segmental vitiligo
    DOI:  https://doi.org/10.1111/jocd.14424
  32. Pediatr Dermatol. 2021 Aug 31.
    Neurocutaneous melanocytosis-associated malignant melanoma presenting with peritoneal seeding.
    Ugur Sener, Kevin Elmore, Keerthana Jayaseelan, Joanne Porter, Ashfaq Marghoob, Marc K Rosenblum, Sofia Haque, Yasmin Khakoo.
      Neurocutaneous melanocytosis (NCM) is characterized by melanocyte deposition in the leptomeninges and brain parenchyma, primarily occurring in children with large or giant congenital melanocytic nevi (LCMN) or multiple congenital melanocytic nevi. Patients with NCM may develop hydrocephalus and increased intracranial pressure, which can be managed with ventriculoperitoneal (VP) shunting. We present the case of a 16-month-old girl who developed peritoneal carcinomatosis and malignant ascites following VP shunting for hydrocephalus secondary to NCM to increase awareness of this rare, but serious, complication of cerebrospinal fluid diversion.
    Keywords:  meningeal carcinomatosis; neoplasms malignant; neurocutaneous disorders; nevi-melanocytic; peritoneal carcinomatosis
    DOI:  https://doi.org/10.1111/pde.14789
  33. Front Oncol. 2021 ;11 714646
    Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis.
    Bochao Geng, Yuanzhang Zhu, Yingying Yuan, Jingyi Bai, Zhizhi Dou, Aihua Sui, Wenjuan Luo.
      Angiogenesis and vasculogenic mimicry (VM) are considered to be the main processes to ensure tumor blood supply during the proliferation and metastasis of choroidal melanoma (CM). The traditional antimalarial drug artesunate (ART) has some potential anti-CM effects; however, the underlying mechanisms remain unclarified. Recent studies have shown that the Wnt5a/calmodulin-dependent kinase II (CaMKII) signaling pathway has a close correlation with angiogenesis and VM formation. This study demonstrated that ART eliminated VM formation by inhibiting the aforementioned signaling pathway in CM cells. The microvessel sprouting of the mouse aortic rings and the microvessel density of chicken chorioallantoic membrane (CAM) decreased significantly after ART treatment. VM formation assay and periodic acid schiff (PAS) staining revealed that ART inhibited VM formation in CM. Moreover, ART downregulated the expression levels of the angiogenesis-related proteins vascular endothelial growth factor receptor (VEGFR) 2, platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor (VEGF) A, and VM-related proteins ephrin type-A receptor (EphA) 2 and vascular endothelial (VE)-cadherin. The expression of hypoxia-inducible factor (HIF)-1α, Wnt5a, and phosphorylated CaMKII was also downregulated after ART treatment. In addition, we further demonstrated that ART inhibited the proliferation, migration, and invasion of OCM-1 and C918 cells. Collectively, our results suggested that ART inhibited angiogenesis and VM formation of choroidal melanoma likely by regulating the Wnt5a/CaMKII signaling pathway. These findings further supported the feasibility of ART for cancer therapy.
    Keywords:  VE-cadherin; angiogenesis; artesunate; choroidal melanoma; vasculogenesis mimicry
    DOI:  https://doi.org/10.3389/fonc.2021.714646
  34. Bioelectrochemistry. 2021 Aug 18. pii: S1567-5394(21)00195-X. [Epub ahead of print]142 107932
    Contrast-enhanced ultrasound for evaluation of tumor perfusion and outcome following treatment in a murine melanoma model.
    Maja Brloznik, Nina Boc, Maja Cemazar, Masa Bosnjak, Monika Savarin, Natasa Kejzar, Gregor Sersa, Darja Pavlin, Simona Kranjc Brezar.
      Due to a lack of data on predictors of electroporation-based treatment outcomes, we investigated the potential predictive role of contrast-enhanced harmonic ultrasound (CEUS) in mice B16F10 melanoma treated by gene electrotransfer (GET) to silence melanoma cell adhesion molecule (MCAM) and radiotherapy, which has not been evaluated yet. CEUS evaluation was verified by tumor histological analysis. Mice bearing subcutaneous tumors were treated with GET to silence MCAM, irradiation or the combination of GET to silence MCAM and irradiation (combined treatment). CEUS of the tumors used to evaluate tumor perfusion was performed before and up to 10 days after the beginning of the experiment, and the CEUS results were compared with tumor growth and the number of blood vessels analyzed in the histological tumor sections. CEUS revealed a decrease in tumor perfusion in the combined therapy groups compared with the control groups and correlated with tumor histological analyses, which showed a decreased vascular density. In this study a trend of inverse correlation was observed between tumor perfusion and treatment efficacy. The greater the perfusion of the tumor, the shorter the expected doubling time. Furthermore, decreased perfusion showed a trend to correlate with higher antitumor efficacy. Thus, CEUS could be used to predict tumoral vascular density and treatment effectiveness.
    Keywords:  Antivascular effects; Contrast-enhanced harmonic ultrasound; Gene electrotransfer; Irradiation; Melanoma cell adhesion molecule; Murine melanoma B16F10
    DOI:  https://doi.org/10.1016/j.bioelechem.2021.107932
  35. Clin Transl Med. 2021 Aug;11(8): e466
    A biobanking turning-point in the use of formalin-fixed, paraffin tumor blocks to unveil kinase signaling in melanoma.
    Erika Velasquez, Leticia Szadai, Qimin Zhou, Yonghyo Kim, Indira Pla, Aniel Sanchez, Roger Appelqvist, Henriett Oskolas, Matilda Marko-Varga, Boram Lee, Ho Jeong Kwon, Johan Malm, Attila Marcell Szász, Jeovanis Gil, Lazaro Hiram Betancourt, István Balázs Németh, György Marko-Varga.
      
    DOI:  https://doi.org/10.1002/ctm2.466
  36. Cold Spring Harb Mol Case Stud. 2021 Sep 01. pii: mcs.a006111. [Epub ahead of print]
    Intra- and inter-tumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing.
    Weitao Lin, Aaron B Beasley, Nima Mesbah Ardakani, Elena Denisenko, Leslie Calapre, Matthew Jones, Benjamin A Wood, Lydia Warburton, Alistair R R Forrest, Elin S Gray.
      Tumour heterogeneity is a major obstacle to the success of cancer treatment. An accurate understanding and recognition of tumour heterogeneity is critical in the clinical management of cancer patients. Here, we utilised single-cell RNA sequencing (scRNA-seq) to uncover the intra- and inter-tumoural heterogeneity of liver metastases from a patient with metastatic uveal melanoma. The two metastases analysed were largely infiltrated by non-cancerous cells with significant variability in the proportion of different cell types. Analysis of copy number variations (CNVs) showed gain of 8q and loss of 6q in both tumours, but loss of chromosome 3 was only detected in one of the tumours. SNP array revealed a uniparental isodisomy 3 in the tumour with two copies of chromosome 3, indicating a re-gain of chromosome 3 during the development of the metastatic disease. In addition, both tumours harboured subclones with additional CNVs. Pathway enrichment analysis of differentially expressed genes revealed that cancer cells in the metastasis with isodisomy 3 showed up-regulation in epithelial-mesenchymal transition and myogenesis related genes. In contrast, upregulation in interferon signalling was observed in the metastasis with monosomy 3 and increased T-cell infiltrate. This study highlights the complexity and heterogeneity of different metastases within an individual case of uveal melanoma.
    Keywords:  Choroidal melanoma
    DOI:  https://doi.org/10.1101/mcs.a006111
  37. Nat Cell Biol. 2021 Sep 02.
    Human melanocyte development and melanoma dedifferentiation at single-cell resolution.
    Rachel L Belote, Daniel Le, Ashley Maynard, Ursula E Lang, Adriane Sinclair, Brian K Lohman, Vicente Planells-Palop, Laurence Baskin, Aaron D Tward, Spyros Darmanis, Robert L Judson-Torres.
      In humans, epidermal melanocytes are responsible for skin pigmentation, defence against ultraviolet radiation and the deadliest common skin cancer, melanoma. Although there is substantial overlap in melanocyte development pathways between different model organisms, species-dependent differences are frequent and the conservation of these processes in human skin remains unresolved. Here, we used a single-cell enrichment and RNA-sequencing pipeline to study human epidermal melanocytes directly from the skin, capturing transcriptomes across different anatomical sites, developmental age, sexes and multiple skin tones. We uncovered subpopulations of melanocytes that exhibit anatomical site-specific enrichment that occurs during gestation and persists through adulthood. The transcriptional signature of the volar-enriched subpopulation is retained in acral melanomas. Furthermore, we identified human melanocyte differentiation transcriptional programs that are distinct from gene signatures generated from model systems. Finally, we used these programs to define patterns of dedifferentiation that are predictive of melanoma prognosis and response to immune checkpoint inhibitor therapy.
    DOI:  https://doi.org/10.1038/s41556-021-00740-8
  38. Mol Clin Oncol. 2021 Oct;15(4): 212
    Malignant melanoma with in-transit metastases refractory to programmed cell death-1 inhibitor successfully treated with local interferon-β injections: A case report.
    Yui Takahara, Takanobu Kan, Yoshie Teshima, Daiki Matsubara, Shunsuke Takahagi, Akio Tanaka, Michihiro Hide.
      In-transit metastases (ITMs) in patients with malignant melanoma (MM) are associated with poor prognosis and a worse disease burden compared with MM without ITMs. A substantial population of patients with ITMs show no or only poor responses to newly developed therapies, such as immune checkpoint inhibitors or molecular-targeted agents. It is difficult to control the exudate and bleeding from ITMs when these medications are ineffective. In Japan, local injection of interferon-β (IFN-β) has been licensed for years as adjuvant therapy for MM. However, the evidence for IFN-β effectiveness for ITMs remains low. The present report describes a case of MM with multiple ITMs that did not respond to a programmed cell death-1 inhibitor and local injections of IFN-β at 3 million IU/day for 5 days/4 weeks but remitted upon increasing the amount of IFN-β injections to 10 consecutive days/4 weeks. Local IFN-β therapy could be an option for improving the quality of life of patients.
    Keywords:  in-transit metastasis; interferon-β; local injection; malignant melanoma; quality of life
    DOI:  https://doi.org/10.3892/mco.2021.2374
  39. STAR Protoc. 2021 Sep 17. 2(3): 100722
    Visualizing murine breast and melanoma tumor microenvironment using intravital multiphoton microscopy.
    Rohit Jain, Shweta Tikoo, Kathy On, Brendon Martinez, Suat Dervish, Lois L Cavanagh, Wolfgang Weninger.
      Intravital multiphoton imaging of the tumor milieu allows for the dissection of intricate and dynamic biological processes in situ. Herein, we present a step-by-step protocol for setting up an experimental cancer imaging model that has been optimized for solid tumors such as breast cancer and melanoma implanted in the flanks of mice. This protocol can be utilized for dissecting tumor-immune cell dynamics in vivo or other tumor-specific biological questions. For complete details on the use of this protocol for intravital imaging of breast cancer, please refer to Tikoo et al. (2021a), and for intravital imaging of melanoma, please refer to Tikoo et al. (2021b).
    Keywords:  Cancer; Immunology; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2021.100722
  40. J Med Chem. 2021 Sep 02.
    Novel Allosteric Inhibitors of Deoxyhypusine Synthase against Malignant Melanoma: Design, Synthesis, and Biological Evaluation.
    Kai-Li Liu, Xin-Yang Li, De-Pu Wang, Wen-Han Xue, Xin-Hua Qian, Yu-Heng Li, Qi-Qi Lin, Shuai Li, Fan-Hao Meng.
      Based on the novel allosteric site of deoxyhypusine synthase (DHPS), two series of 30 novel 5-(2-methoxyphenoxy)-2-phenylpyrimidin-4-amine derivatives as DHPS inhibitors were designed and synthesized. Among them, compound 8m, with the best DHPS inhibitory potency (IC50 = 0.014 μM), exhibited excellent inhibition against melanoma cells, which was superior to that of GC7. Besides, molecular docking and molecular dynamics (MD) simulations further proved that compound 8m was tightly bound to the allosteric site of DHPS. Flow cytometric analysis and enzyme-linked immunosorbent assay (ELISA) showed that compound 8m could inhibit the intracellular reactive oxygen species (ROS) level. Furthermore, by western blot analysis, compound 8m effectively activated caspase 3 and decreased the expressions of GP-100, tyrosinase, eIF5A2, MMP2, and MMP9. Moreover, both Transwell analysis and wound healing analysis showed that compound 8m could inhibit the invasion and migration of melanoma cells. In the in vivo study, the tumor xenograft model showed that compound 8m effectively inhibited melanoma development with low toxicity.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c00582
  41. Biomater Sci. 2021 Sep 02.
    Transdermal delivery of multifunctional CaO2@Mn-PDA nanoformulations by microneedles for NIR-induced synergistic therapy against skin melanoma.
    Liming Ruan, Gao Song, Xueya Zhang, Tianqi Liu, Yanfang Sun, Junlan Zhu, Zhiyong Zeng, Guohua Jiang.
      The development of multifunctional nanoformulations (NFs) include several features in a single nanosystem for these devices to overcome the disadvantages of inefficiency and undesirable toxicity of traditional therapies and provide new opportunities in the management of tumors. Herein, multifunctional CaO2@Mn-PDA NFs with a core-shell structure, integrating the photothermal conversion properties of Mn-PDA, the chemodynamic properties of doped Mn ions, and relieving hypoxia in the tumor microenvironment (TME) were developed. The as-fabricated CaO2@Mn-PDA NFs were embedded in microneedles (MNs) for transdermal delivery into tumor sites, leading to the generation of a new minimally invasive and synergistic therapeutic strategy against skin melanoma. Under near-infrared (NIR) light irradiation, the CaO2@Mn-PDA NFs exhibited a synergistic therapeutic effect, including photothermal therapy (PTT), chemodynamic therapy (CDT), and modulating hypoxia due to their high photothermal conversion efficiency, boosted intracellular production of reactive oxygen species, excellent chemodynamic reactions, etc. Therefore, the developed MN platform, which can build implanted multifunctional characteristics for on-demand NIR-induced synergistic therapy, have a bright future in tumor suppression.
    DOI:  https://doi.org/10.1039/d1bm01117k
  42. JAMA Surg. 2021 Sep 01. e214298
    Development and Validation of a Modified Pathologic Nodal Classification System for Cutaneous Melanoma.
    Anthony T Nguyen, Michael Luu, Vina P Nguyen, Omid Hamid, Mark B Faries, Nima M Gharavi, Diana J Lu, Jon Mallen-St Clair, Allen S Ho, Zachary S Zumsteg.
      Importance: Given the evolving patterns of lymph node evaluation for cutaneous melanoma, it is unclear whether the current nodal classification system will continue to accurately reflect prognosis in the modern era. Existing nodal staging for cutaneous melanoma was developed primarily for patients undergoing completion lymph node dissection (CLND) for node-positive disease and does not produce groups with continuously increasing mortality.Objective: To develop and validate a modified nodal classification system for cutaneous melanoma.
    Design, Setting, and Participants: This retrospective cohort analysis included 105 785 patients with cutaneous melanoma undergoing surgery and nodal evaluation from January 1, 2004, to December 31, 2015, in the National Cancer Database. Extent of lymph node dissection was available for patients diagnosed in 2012 and onward. Multivariable models were generated with number of positive lymph nodes modeled using restricted cubic splines. A modified nodal classification system was derived using recursive partitioning analysis (RPA). The proposed lymph node classification system was validated in 85 499 patients from the Surveillance, Epidemiology, and End Results (SEER-18) database. Data were analyzed from April 9, 2020, to May 28, 2021.
    Main Outcomes and Measures: Overall survival.
    Results: Among the 105 785 patients included in the analysis (62 496 men [59.1%]; mean [SD] age, 59.9 [15.5] years), number of positive lymph nodes (hazard ratio [HR] per lymph node for 0 to 2 positive lymph nodes, 2.48 [95% CI, 2.37-2-61; P < .001]; HR per lymph node for ≥3 positive lymph nodes, 1.10 [95% CI 1.07-1.13; P < .001]), clinically detected metastases (HR, 1.35; 95% CI, 1.27-1.42; P < .001), and in-transit metastases (HR, 1.48; 95% CI, 1.34-1.65; P < .001) were independently associated with mortality. An RPA-derived system using these variables demonstrated continuously increasing mortality for each proposed lymph node classification group, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 2.72 (95% CI, 2.58-2.86) for N1b, 3.79 (95% CI, 3.51-4.08) for N2a, 4.56 (95% CI, 4.22-4.92) for N2b, 6.15 (95% CI, 5.59-6.76) for N3a, and 8.25 (95% CI, 7.64-8.91) for N3b in the proposed system (P < .001). By contrast, the current American Joint Committee on Cancer (AJCC) nodal classification system produced a more haphazard mortality profile, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 3.81 (95% CI, 3.53-4.12) for N1b, 2.59 (95% CI, 2.30-2.93) for N1c, 2.71 (95% CI, 2.56-2.87) for N2a, 4.51 (95% CI, 4.17-4.87) for N2b, 3.44 (95% CI, 2.60-4.55) for N2c, 6.06 (95% CI, 5.51-6.67) for N3a, 8.15 (95% CI, 7.54-8.81) for N3b, and 6.90 (95% CI, 5.60-8.49) for N3c. As a sensitivity analysis, the proposed system continued to accurately stratify patients when excluding those undergoing CLND for microscopic lymph node metastases. This system was validated for overall survival and cause-specific mortality in SEER-18. Last, a new overall staging system for node-positive patients was developed by RPA and demonstrated improved concordance vs the AJCC, 8th edition system (C statistic, 0.690 [95% CI, 0.689-0.691] vs 0.666 [95% CI, 0.666-0.668]).
    Conclusions and Relevance: The findings of this cohort study suggest that a modified nodal classification system can accurately stratify mortality risk in cutaneous melanoma in an era of increasing use of sentinel lymph node biopsy without CLND and should be considered for future staging systems.
    DOI:  https://doi.org/10.1001/jamasurg.2021.4298
  43. J Imaging. 2020 Mar 24. pii: 14. [Epub ahead of print]6(3):
    Semi-Automatic Tool for Vitiligo Detection and Analysis.
    Paolo Neri, Michela Fiaschi, Giovanni Menchini.
      Vitiligo vulgaris is an autoimmune disease which causes a strong reduction of the cells producing melanin, which is the main skin pigment. This results in the growth of white patches on patients' skin, which are more or less visible, depending on the skin phototype. Precise, objective and fast detection of vitiligo patches would be crucial to produce statistically relevant data on huge populations, thus giving an insight on the disease. However, few methods are available in literature. In the present paper, a semi-automatic tool based on image processing to detect facial vitiligo patches is described. The tool requires pictures to be captured under black light illumination, which enhances patches contrast with respect to healthy skin. The user is only required to roughly define the regions of interest and set a global threshold, thus, no specific image-processing skills are required. An adaptive algorithm then automatically discerns between vitiligo and healthy skin pixels. The tools also allow for a statistical data interpretation by overlapping the detected patches of all patients on a face template through an occurrence map. Preliminary results obtained on a small population of 15 patients allowed us to assess the tool's performance. Patch detection was checked by an experienced dermatologist, who confirmed the detection for all the studied patients, thus supporting the effectiveness of the proposed tool.
    Keywords:  black light; image processing; semi-automatic vitiligo detection; vitiligo
    DOI:  https://doi.org/10.3390/jimaging6030014
  44. J Transl Med. 2021 Aug 28. 19(1): 371
    Associations of immune cell homing gene signatures and infiltrates of lymphocyte subsets in human melanomas: discordance with CD163+ myeloid cell infiltrates.
    Minyoung Kwak, Gulsun Erdag, Katie M Leick, Stefan Bekiranov, Victor H Engelhard, Craig L Slingluff.
      BACKGROUND: Immune cells in the tumor microenvironment have prognostic value. In preclinical models, recruitment and infiltration of these cells depends on immune cell homing (ICH) genes such as chemokines, cell adhesion molecules, and integrins. We hypothesized ICH ligands CXCL9-11 and CCL2-5 would be associated with intratumoral T-cells, while CXCL13 would be more associated with B-cell infiltrates.METHODS: Samples of human melanoma were submitted for gene expression analysis and immune cells identified by immunohistochemistry. Associations between the two were evaluated with unsupervised hierarchical clustering using correlation matrices from Spearman rank tests. Univariate analysis performed Mann-Whitney tests.
    RESULTS: For 119 melanoma specimens, analysis of 78 ICH genes revealed association among genes with nonspecific increase of multiple immune cell subsets: CD45+, CD8+ and CD4+ T-cells, CD20+ B-cells, CD138+ plasma cells, and CD56+ NK-cells. ICH genes most associated with these infiltrates included ITGB2, ITGAL, CCL19, CXCL13, plus receptor/ligand pairs CXCL9 and CXCL10 with CXCR3; CCL4 and CCL5 with CCR5. This top ICH gene expression signature was also associated with genes representing immune-activation and effector function. In contrast, CD163+ M2-macrophages was weakly associated with a different ICH gene signature.
    CONCLUSION: These data do not support our hypothesis that each immune cell subset is uniquely associated with specific ICH genes. Instead, a larger set of ICH genes identifies melanomas with concordant infiltration of B-cell and T-cell lineages, while CD163+ M2-macrophage infiltration suggesting alternate mechanisms for their recruitment. Future studies should explore the extent ICH gene signature contributes to tertiary lymphoid structures or cross-talk between homing pathways.
    Keywords:  Chemokines; Gene expression; Homing; Immune cells; Integrins; Lymphocytes; Melanoma
    DOI:  https://doi.org/10.1186/s12967-021-03044-5
  45. J Invest Dermatol. 2021 Aug 26. pii: S0022-202X(21)02091-1. [Epub ahead of print]
    Core gene signatures of atopic dermatitis using public RNA-sequencing resources: Comparison of bulk vs. single-cell approach.
    Kyung Bae Chung, Jongwook Oh, Won Seok Roh, Tae-Gyun Kim, Do-Young Kim.
      
    DOI:  https://doi.org/10.1016/j.jid.2021.07.169
  46. J Genet Eng Biotechnol. 2021 Sep 01. 19(1): 132
    TLR4 gene polymorphisms in Egyptian vitiligo patients: insights into emerging association with clinical activity, family history, and response to therapy.
    Maha Abdelsalam, Sherihan H Allam, Marwa Zohdy, Hend Magdy, Maged Mostafa.
      BACKGROUND: Vitiligo is a common pigmentary disorder in which autoimmunity has been suggested to play an important role. Toll-like receptor (TLR) family are recognized different molecular structures expressed on immune cells and have been implicated in a number of autoimmune diseases (AIDs) such as vitiligo. The purpose of this study was to investigate the possible association between TLR4 gene polymorphisms: rs11536858, rs1927911, rs1927914 in Egyptian vitiligo patients and their clinical data, their response to therapy. Using PCR-RFLP for TLR4 gene polymorphisms (rs11536858, rs1927911, and rs1927914), both alleles and genotypes were determined after extraction of DNA in a case-control study of 100 vitiligo Egyptian patients and 100 matched age and sex controls.RESULTS: The distribution of the protective CT genotype of rs1927914 was higher in the control group. After dividing both patients and controls into 2 age groups (below 18 and above 18 years), no significant associations between the genotypes of the selected TLR4 SNPs and the demographic and clinical data of the vitiligo patients in group 1 (below 18 years) were observed. For group 2 (above 18 years), also no significant associations were found except for the association between the CC genotype of rs1927914 and psychiatric trauma, from one side, and between the CT genotype of rs1927911 and alopecia, from the other side. The association between combined genotypes and the risk of vitiligo showed either higher frequency in patients (risky), or controls (protective), and some equal frequencies (non-significant). The association between haplotypes and risk of vitiligo in patients' group revealed the highest frequency for the risky ATT and the least frequency for ATC haplotypes. In control group, the protective GCT haplotype showed the highest frequency while the GTC and GCC showed the least frequency. No significant correlations of haplotypes with clinical and demographic data of selected patients' group were observed apart from that between ACC haplotype and family history of AIDs and between ATT haplotype and remission after phototherapy.
    CONCLUSIONS: The significant relationship between TLR4 gene polymorphisms and vitiligo patients charcteristics clarify the role of innate immunity in pathogensis of vitiligo and its effect on the used therapies.
    Keywords:  Autoimmunity; Egyptian; Innate immunity; TLR4; Vitiligo
    DOI:  https://doi.org/10.1186/s43141-021-00218-y
  47. Aust N Z J Public Health. 2021 Sep 02.
    "Repeatability of Repeatability": the stability of self-reported melanoma risk factors in two independent samples.
    Alexandra Mortimore, Nirmala Pandeya, Catherine M Olsen, David C Whiteman.
      OBJECTIVE: To determine the test-retest repeatability of a self-completed survey with items capturing skin cancer risk factors.METHODS: We invited 238 randomly selected participants of the QSkin II cohort to complete the baseline survey a second time. Responses were compared using kappa statistics and intraclass correlation coefficients to quantify agreement for categorical and continuous variables, respectively. We compared the performance of key items with that observed in an earlier repeatability study using the same survey instrument in an independent cohort.
    RESULTS: Measures of phenotypic characteristics had moderate to almost-perfect test-retest repeatability (e.g. eye colour weighted kappa (κw ) = 0.87, 95% confidence interval [CI]: 0.81, 0.92). Items measuring sun exposure showed lower agreement (κw range 0.36-0.54) compared with phenotypic characteristics (κw range 0.59-0.87). Items relating to treatment of skin cancers demonstrated almost-perfect test-retest repeatability (e.g. excisions for skin cancers κw 0.85, 95%CI: 0.80, 0.89). In aggregate, the repeatability of key items was very similar across the two independent repeatability samples.
    CONCLUSION: Fair to almost-perfect repeatability for self-reported skin cancer risk factors was robust across independent and temporally distant cohorts. Implications for public health: These self-assessed risk factors for skin cancer are repeatable and suitable for use in clinical practice and research.
    Keywords:  melanoma; repeatability; skin cancer; survey; validity
    DOI:  https://doi.org/10.1111/1753-6405.13147
  48. Diagn Pathol. 2021 Aug 28. 16(1): 78
    Prognostic significance of the aberrant expression of neuroendocrine markers in melanomas.
    Yan Wu, Yumei Lai, Miao Zhang, Zhongwu Li.
      BACKGROUND: Melanoma is a highly malignant tumor with diverse histopathological morphology and frequent aberrant expression of immunohistochemical markers. An occasionally reported phenomenon is the abnormal expression of neuroendocrine markers. Awareness of this situation is essential because such tumors need to be differentiated from neuroendocrine tumors because of their significant therapeutic and prognostic implications.METHODS: We retrospectively analyzed the expression of chromogranin A (CgA), synaptophysin (Syn) and CD56 as neuroendocrine markers in 308 cases with melanomas. Kaplan-Meier curves and Cox regression analyses were used for overall survival (OS) and progression-free survival (PFS) evaluation and comparison between neuroendocrine markers expression status in all melanoma cases or stage I-II cases.
    RESULTS: The expression of neuroendocrine markers in melanomas is not uncommon. CgA was positive in 6/304 (2.0%) cases, Syn in 26/304 (8.6%), and CD56 in 56/189 (29.6%). None of the cases co-expressed all the three markers. Focal or weak expression of at least one neuroendocrine marker was identified in 70/188 (37.2%) cases. The expression of CgA was correlated with age (p = 0.019), while the positive expression of Syn and CD56 showed borderline significance (p = 0.078 and 0.083, respectively), but not for any neuroendocrine marker expression. The expression of any neuroendocrine marker showed borderline significance with staging (p = 0.066). The expression of CgA, Syn, CD56, or any neuroendocrine marker did not correlate with clinicopathological features including sex, specimen type, origin, location, and histology subtype. Survival analyses revealed that the expression of neuroendocrine markers was not associated with OS or PFS.
    CONCLUSIONS: Our study confirms that neuroendocrine marker expression is a common phenomenon in melanomas, but it has no prognostic significance. Nevertheless, awareness can avoid misdiagnosis in cases of melanomas with unusual morphology and immunophenotypes.
    Keywords:  Immunohistochemistry; Melanoma; Neuroendocrine marker; Prognosis
    DOI:  https://doi.org/10.1186/s13000-021-01135-x
  49. Biomed Opt Express. 2021 Jul 01. 12(7): 4097-4114
    Comparison of photoacoustic imaging and histopathological examination in determining the dimensions of 52 human melanomas and nevi ex vivo.
    Jenny Hult, Aboma Merdasa, Agnes Pekar-Lukacs, Magne Tordengren Stridh, Azin Khodaverdi, John Albinsson, Bodil Gesslein, Ulf Dahlstrand, Linn Engqvist, Yousef Hamid, Douglas Larsson Albèr, Bertil Persson, Tobias Erlöv, Rafi Sheikh, Magnus Cinthio, Malin Malmsjö.
      Surgical excision followed by histopathological examination is the gold standard for the diagnosis and staging of melanoma. Reoperations and unnecessary removal of healthy tissue could be reduced if non-invasive imaging techniques were available for presurgical tumor delineation. However, no technique has gained widespread clinical use to date due to shallow imaging depth or the absence of functional imaging capability. Photoacoustic (PA) imaging is a novel technology that combines the strengths of optical and ultrasound imaging to reveal the molecular composition of tissue at high resolution. Encouraging results have been obtained from previous animal and human studies on melanoma, but there is still a lack of clinical data. This is the largest study of its kind to date, including 52 melanomas and nevi. 3D multiwavelength PA scanning was performed ex vivo, using 59 excitation wavelengths from 680 nm to 970 nm. Spectral unmixing over this broad wavelength range, accounting for the absorption of several tissue chromophores, provided excellent contrast between healthy tissue and tumor. Combining the results of spectral analysis with spatially resolved information provided a map of the tumor borders in greater detail than previously reported. The tumor dimensions determined with PA imaging were strongly correlated with those determined by histopathological examination for both melanomas and nevi.
    DOI:  https://doi.org/10.1364/BOE.425524
  50. J Oncol. 2021 ;2021 9989824
    Temporal Trends in the Incidence and Mortality of Skin Malignant Melanoma in China from 1990 to 2019.
    Ruhai Bai, Hui Huang, Minmin Li, Meng Chu.
      Purpose: Skin malignant melanoma (SMM) is one of the fastest-growing cancers in China, with a poor prognosis, high invasiveness, and high mortality rate. The aim of this study was to determine the long-term trends in the incidence and mortality of SMM in China between 1990 and 2019. Patients and Methods. Incidence and mortality data were extracted from the Global Burden of Disease Study 2019 and were analyzed using an age-period-cohort framework.Results: The annual incidence net drifts were 3.523% (95% confidence interval (CI): 3.318% to 3.728%) and 3.779% (95% CI: 3.585% to 3.974%) for males and females, respectively, while the corresponding annual net drifts of mortality were -0.754% (95% CI: -1.073% to -0.435%) and -0.826% (95% CI: -1.164% to -0.487%). The local drift from 1990 to 2019 was highest in males aged from 25 to 29 years. After controlling for period deviations in a single birth cohort, the SMM incidence and mortality increased exponentially with age for both sexes. Similar increasing monotonic trends were found for period and cohort effects on the incidence, while a declining trend was found for mortality.
    Conclusion: While the age-standardized mortality rate of SMM in China has decreased in both sexes over the past 30 years, the crude incidence rate, age-standardized incidence rate, and crude mortality rate have all increased. SMM may greatly threaten the health of the elderly in China due to the aging population. Appropriate changes should be made to raise the awareness, reduce the exposure to risk factors, and promote the early detection of SMM.
    DOI:  https://doi.org/10.1155/2021/9989824
  51. Skin Res Technol. 2021 Aug 29.
    Suggested methodology for longitudinal evaluation of nevi based on clinical images.
    Ofer Reiter, Shenara Musthaq, Nicholas R Kurtansky, Dulce M Barrios, Allan C Halpern, Michael A Marchetti, Ashfaq A Marghoob, Japbani K Nanda, Joseph Stoll, Veronica Rotemberg.
      BACKGROUND: Melanoma screening includes the assessment of changes in melanocytic lesions using images. However, previous studies of normal nevus temporal changes showed variable results and the optimal method for evaluating these changes remains unclear. Our aim was to evaluate the reproducibility of (a) nevus count done at a single time point (method I) versus two time points (method II); and (b) manual and automated nevus diameter measurements.MATERIALS AND METHODS: In a first experiment, participants used either a single time point or a two time point annotation method to evaluate the total number and size of nevi on the back of an atypical mole syndrome patient. A Monte Carlo simulation was used to calculate the variance observed. In a second experiment, manual measurements of nevi on 2D images were compared to an automated measurement on 3D images. Percent difference in the paired manual and automated measurements was calculated.
    RESULTS: Mean nevus count was 137 in method I and 115.5 in method II. The standard deviation was greater in method I (38.80) than in method II (4.65) (p = 0.0025). Manual diameter measurements had intraclass correlation coefficient of 0.88. The observed mean percent difference between manual and automated diameter measurements was 1.5%. Lightly pigmented and laterally located nevi had a higher percent difference.
    CONCLUSIONS: Comparison of nevi from two different time points is more consistent than nevus count performed separately at each time point. In addition, except for selected cases, automated measurements of nevus diameter on 3D images can be used as a time-saving reproducible substitute for manual measurement on 2D images.
    Keywords:  3-dimensional images; count; mole; nevus; size; total body photography
    DOI:  https://doi.org/10.1111/srt.13092
  52. Curr Opin Clin Nutr Metab Care. 2021 Aug 27.
    Skin pigmentation and vitamin D-folate interactions in vascular function: an update.
    S Tony Wolf, W Larry Kenney.
      PURPOSE OF REVIEW: Vitamin D and folate promote vascular endothelial health and may therefore help mitigate the development of cardiovascular disease (CVD). Ultraviolet radiation (UVR) exposure stimulates cutaneous vitamin D synthesis but degrades the bioactive metabolite of folate, 5-methyltetrahydrofolate (5-MTHF). Skin melanin absorbs UVR, thereby modulating the impact of UVR exposure on vitamin D and 5-MTHF metabolism. This review presents recent findings regarding the inter-relations among UVR, skin pigmentation, folate and vitamin D, and endothelial function.RECENT FINDINGS: Evidence for roles of folic acid or vitamin D supplementation on CVD endpoints is inconsistent, although preclinical and clinical studies have demonstrated the efficacy of both micronutrients for improving endothelial function. Vitamin D deficiency is most prevalent in darkly pigmented individuals living in relatively low-UVR environments. Conversely, there is a negative relation between accumulated UVR exposure and serum folate concentration in lightly pigmented adults. The interactions among UVR and bioavailable folate and vitamin D differentially impact endothelial function in differently pigmented skin.
    SUMMARY: UVR exposure disparately impacts folate and vitamin D metabolism in differently pigmented skin depending upon regional UVR intensity and seasonality. These findings present new clinical research questions regarding the interactions among UVR, skin pigmentation, folate and vitamin D bioavailability, and endothelial health.
    DOI:  https://doi.org/10.1097/MCO.0000000000000788
  53. J Autoimmun. 2021 Aug 31. pii: S0896-8411(21)00119-0. [Epub ahead of print]124 102711
    Resident human dermal γδT-cells operate as stress-sentinels: Lessons from the hair follicle.
    Youhei Uchida, Jennifer Gherardini, Karin Pappelbaum, Jérémy Chéret, Andreas Schulte-Mecklenbeck, Catharina C Gross, Natasa Strbo, Amos Gilhar, Alfredo Rossi, Wolfgang Funk, Takuro Kanekura, Luís Almeida, Marta Bertolini, Ralf Paus.
      Murine γδT-cells have stress-surveillance functions and are implicated in autoimmunity. Yet, whether human γδT-cells are also stress sentinels and directly promote autoimmune responses in the skin is unknown. Using a novel (mini-)organ assay, we tested if human dermis resident γδT-cells can recognize stressed human scalp hair follicles (HFs) to promote an alopecia areata (AA)-like autoimmune response. Accordingly, we show that γδT-cells from healthy human scalp skin are activated (CD69+), up-regulate the expression of NKG2D and IFN-γ, and become cytotoxic when co-cultured with autologous stressed HFs ex vivo. These autologous γδT-cells induce HF immune privilege collapse, dystrophy, and premature catagen, i.e. three hallmarks of the human autoimmune HF disorder, AA. This is mediated by CXCL12, MICA, and in part by IFN-γ and CD1d. In conclusion, human dermal γδT-cells exert physiological stress-sentinel functions in human skin, where their excessive activity can promote autoimmunity towards stressed HFs that overexpress CD1d, CXCL12, and/or MICA.
    Keywords:  Alopecia areata; Autoimmunity; Gamma delta T-cells; Hair follicle; MICA; NKG2D; Stress; ex vivo model
    DOI:  https://doi.org/10.1016/j.jaut.2021.102711
  54. Dev Cell. 2021 Aug 30. pii: S1534-5807(21)00636-5. [Epub ahead of print]
    UV-induced reduction in Polycomb repression promotes epidermal pigmentation.
    Meng-Yen Li, Pooja Flora, Hong Pu, Carmit Bar, Jose Silva, Idan Cohen, Phillip M Galbo, Hequn Liu, Xufen Yu, Jian Jin, Haruhiko Koseki, John A D'Orazio, Deyou Zheng, Elena Ezhkova.
      Ultraviolet (UV) radiation is a prime environmental stressor that our epidermis is exposed to on a daily basis. To avert UV-induced damage, epidermal stem cells (EpSCs) become pigmented via a process of heterotypic interaction between melanocytes and EpSCs; however, the molecular mechanisms of this interaction are not well understood. In this study, we show that the function of a key chromatin regulator, the Polycomb complex, was reduced upon UV exposure in human and mouse epidermis. Genetic ablation of key Polycomb subunits in murine EpSCs, mimicking depletion upon UV exposure, results in an increased number of epidermal melanocytes and subsequent epidermal pigmentation. Genome-wide transcriptional and chromatin studies show that Polycomb regulates the expression of UV-responsive genes and identifies type II collagen (COL2A1) as a critical secreted regulator of melanogenesis and epidermal pigmentation. Together, our findings show how UV exposure induces Polycomb-mediated changes in EpSCs to affect melanocyte behavior and promote epidermal pigmentation.
    Keywords:  Polycomb; UV; epidermis; melanocyte; pigmentation; stem cell; type II collagen
    DOI:  https://doi.org/10.1016/j.devcel.2021.08.006
  55. Lasers Surg Med. 2021 Sep 02.
    Treatment of melasma with a low-fluence 1064 nm Q-switched Nd:YAG laser: Laser toning in Caucasian women.
    Iwona Micek, Mariola Pawlaczyk, Anna Kroma, Agnieszka Seraszek-Jaros, Maria Urbańska, Justyna Gornowicz-Porowska.
      BACKGROUND AND OBJECTIVES: Melasma is a common, therapeutically challenging, and very often relapsing disorder of hyperpigmentation most often observed in women. Low-fluence, multipass technique with Q-switched-mode laser-"laser toning" is broadly used to treat melasma, especially in Asia. The study aimed to evaluate the effects of a series of laser treatments with very short, nanosecond pulses in the treatment of melasma in Caucasian women.MATERIAL AND METHODS: Forty polish females with Fitzpatrick skin phototype II-III and melasma were treated with 1064 nm Q-switched neodymium:yttrium-aluminum-garnet (QSNY) laser (pulse with 5 ns; spot size, 6-8 mm; fluence, 1.7-3.2 J/cm2 ; 2-8 passes; nine treatments). Melanin index (MI), erythema index (EI) by Mexameter MX18®, the modified Melasma Area Severity Index (mMASI), and the participant's self-assessment were used to evaluate the treatment results. Twenty-one patients were subjected to a 1-year follow-up.
    RESULTS: Significant improvement in melasma pigmentation was observed in the mean MI and mMASI score; both were significantly reduced (p < 0.0001). Significant erythema reduction was achieved (p < 0.001). In total, 70% of participants rated the laser as a method that met their expectations for treating melasma. Clinical follow-up after one year showed that the reduced melasma effect was still maintained. Patients also noticed improved skin conditions (radiance, smoothness, brightness, hydration, regeneration). No serious adverse effects were observed.
    CONCLUSIONS: Low-fluence 1064 nm QSNY laser is an effective, safe, and noninvasive method with long-term results in melasma treatment. QSNY (1064 nm) improves the condition of melasma patients with erythema.
    Keywords:  Caucasian women; Q-switched Nd:YAG laser; laser toning; melasma
    DOI:  https://doi.org/10.1002/lsm.23474
  56. Int J Pharm. 2021 Aug 30. pii: S0378-5173(21)00865-6. [Epub ahead of print] 121059
    Transfersomes improved delivery of ascorbic palmitate into the viable epidermis for enhanced treatment of melasma.
    Junjun Li, Nianxiu Duan, Sha Song, Di Nie, Miaorong Yu, Jie Wang, Ziyue Xi, Jingyi Li, Yingjie Sheng, Can Xu, Yan Wei, Yong Gan.
      Ascorbic palmitate (AP) is widely used in the topical pharmaceutical or cosmetic formulations for melasma treatment. However, the presence of the skin barriers makes it difficult for the highly lipophilic drug molecules to traverse the stratum corneum (SC) and diffuse into the viable epidermis (EP) to reach the melanocytes, thereby exerting suboptimal antimelasma effects. Herein, AP was encapsulated into the transfersomes (TFs), yielding AP-TFs. AP-TFs utilized the deformability of TFs to squeeze through the skin pores in the SC under the transepidermal hydration gradient forces, leading to 14.1-fold increase in AP accumulation to the EP. AP-TFs could slowly release the encapsulated AP, while whether the released AP or transfersomal AP showed comparable uptake into the melanocytes, thereby exerting similar inhibitory effects on tyrosinase activity and melanogenesis. Ultimately, in the rat melasma model, AP-TFs showed superior antimelasma efficacy to free AP, with effective relief of oxidative stress and inflammation in the skin. Moreover, AP-TFs did not induce skin irritation. Therefore, the study provides a safe and effective approach to elevating the delivery of highly lipophilic drugs to the EP for enhanced treatment of melasma.
    Keywords:  ascorbic palmitate; drug delivery; melasma treatment; transfersome; viable epidermis
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.121059
  57. Br J Dermatol. 2021 Sep 01.
    Another step on the road towards standardized outcome reporting for congenital melanocytic naevi: one more to go!
    M V Heppt, T Steeb, C Berking.
      
    DOI:  https://doi.org/10.1111/bjd.20691
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