bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–08–15
sixty-two papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Ferroptosis Is Inhibited in Lymph, Promoting Metastasis of Melanoma.
  2. Antitumor Effect of Metformin in Combination with Binimetinib on Melanoma Cells.
  3. Circular RNA ZNF609 drives tumor progression by regulating the miR-138-5p/SIRT7 axis in melanoma.
  4. Intermittent Inhibition of BRAF plus MEK Is Not Beneficial in Melanoma.
  5. Pseudopodium enriched atypical kinase 1(PEAK1) promotes invasion and of melanoma cells by activating JAK/STAT3 signals.
  6. Synergistic inhibitory effects of the oxyresveratrol and dacarbazine combination against melanoma cells.
  7. An RNA Vaccine Promotes Response with or without Anti-PD-1 in Melanoma.
  8. Midkine Promotes Immunosuppression and Reduces Immunotherapy Efficacy.
  9. Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor resistant melanoma.
  10. The Genetics of Uveal Melanoma: Overview and Clinical Relevance.
  11. RNA editing signatures identify melanoma patients who respond to Pembrolizumab or Nivolumab treatment.
  12. Hemorrhagic choroidal detachment as the presenting sign of uveal melanoma.
  13. Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression.
  14. In Sentinel Node-Positive Melanoma Patients, Does Omission of Completion Lymph Node Dissection Make More Intensive Follow-Up Necessary, and Does Adjuvant Systemic Therapy Permit Less Intensive Follow-Up?
  15. Fine-needle aspiration of metastatic melanoma with signet-ring cell features.
  16. Uveal Melanoma - Standardised Procedure in Diagnosis, Therapy and Surveillance.
  17. Inhibitory effect of kaempferol on mouse melanoma cell line B16 in vivo and in vitro.
  18. Identification of Potential Prognostic Biomarkers Associated With Cancerometastasis in Skin Cutaneous Melanoma.
  19. Characteristics of CircRNA and its approach as diagnostic tool in melanoma.
  20. Adenoviral CD40 Ligand Immunotherapy in 32 Canine Malignant Melanomas-Long-Term Follow Up.
  21. Efficient killing of tumor cells by CAR-T cells demands engagement of a larger number of CARs as opposed to TCRs.
  22. Convolutional neural networks for the detection of malignant melanoma in dermoscopy images.
  23. Immune implication of an autophagy-related prognostic signature in uveal melanoma.
  24. The Tumorigenic Properties of EZH2 are Mediated by MiR-26a in Uveal Melanoma.
  25. Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.
  26. TMB and Inflammatory Gene Expression Associated With Clinical Outcomes Following Immunotherapy in Advanced Melanoma.
  27. Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.
  28. Glycyrrhizin ameliorates melanoma cell extravasation into mouse lungs by regulating signal transduction through HMGB1 and its receptors.
  29. Anticancer effects of oleanolic acid on human melanoma cells.
  30. Current concepts of ectopic nodal inclusions with special emphasis on nodal nevi.
  31. Recent Advances in Lipid-Based Nanovesicular Delivery Systems for Melanoma Therapy.
  32. Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma.
  33. Inflammatory Myositis in a Patient With Melanoma.
  34. Evaluation of TTV replication as a biomarker of immune checkpoint inhibitors efficacy in melanoma patients.
  35. Iron regulatory protein 1 promotes ferroptosis by sustaining cellular iron homeostasis in melanoma.
  36. Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma.
  37. Tumor Microenvironment-Activated Nanoparticles Loaded with an Iron-Carbonyl Complex for Chemodynamic Immunotherapy of Lung Metastasis of Melanoma In Vivo.
  38. Investigation of skin self-examination and sunscreen use in adolescents in northern Cyprus.
  39. Codonopsis pilosula polysaccharide in synergy with dacarbazine inhibits mouse melanoma by repolarizing M2-like tumor-associated macrophages into M1-like tumor-associated macrophages.
  40. Corrigendum: Proteome Analysis of USP7 Substrates Revealed Its Role in Melanoma Through PI3K/Akt/FOXO and AMPK Pathways.
  41. Author Correction: PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.
  42. [Retracted] MicroRNA‑18b inhibits the growth of malignant melanoma via inhibition of HIF‑1α‑mediated glycolysis.
  43. Early use of high-dose-glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy.
  44. Hypoxia increases melanoma-associated fibroblasts immunosuppressive potential and inhibitory effect on T cell-mediated cytotoxicity.
  45. Comparison of tyrosinase antibody, tyrosinase-related protein-1 and -2 antibodies, melanin-concentrating hormone receptor antibody levels with autologous serum skin test and autologous plasma skin test results in patients with vitiligo.
  46. CARD11 is a prognostic biomarker and correlated with immune infiltrates in uveal melanoma.
  47. A benchmark for neural network robustness in skin cancer classification.
  48. Treatment of Melanoma by Nano-conjugate-Delivered Wee1 siRNA.
  49. An anti-cancer effect of Sambou bamboo saltTM in melanoma skin cancer both in vivo and in vitro models.
  50. Non-thermal atmospheric pressure plasma activates Wnt/β-catenin signaling in dermal papilla cells.
  51. A systematic summary of survival and death signalling during the life of hair follicle stem cells.
  52. Antibacterial, Antioxidant and Melanogenesis Inhibitory Activity of Auraptene, a Coumarin from Ferula szowitsiana Root.
  53. The Additive Value of 3D Total Body Imaging for Sequential Monitoring of Skin Lesions: A Case Series.
  54. Cultured epithelial autografts for the treatment of large-to-giant congenital melanocytic nevus in 31 patients.
  55. Cyclophosphamide abrogates the expansion of CD4+Foxp3+ regulatory T cells and enhances the efficacy of bleomycin in the treatment of mouse B16-F10 melanomas.
  56. Acquired unilateral facial melanocytosis: nevus of Sun.
  57. Author Correction: Long-term voluntary running prevents the onset of symptomatic Friedreich's ataxia in mice.
  58. Antimelanogenesis Effects of Leaf Extract and Phytochemicals from Ceylon Olive (Elaeocarpus serratus) in Zebrafish Model.
  59. Amphiregulin promotes hair regeneration of skin-derived precursors via the PI3K and MAPK pathways.
  60. Fractional Erbium:YAG Laser (2940 nm) plus Topical Hydroquinone Compared to Intradermal Tranexamic Acid plus Topical Hydroquinone for the Treatment of Refractory Melasma: A Randomized Controlled Trial.
  61. Environmental impacts of COVID-19 treatment: Toxicological evaluation of azithromycin and hydroxychloroquine in adult zebrafish.
  62. Black is beautiful (and protective): melanin synthesis in animals and plants.
  1. Cancer Discov. 2020 Nov;10(11): 1621
    Ferroptosis Is Inhibited in Lymph, Promoting Metastasis of Melanoma.
      Lymphatic melanoma cells had less ferroptosis than cells injected intravenously or subcutaneously.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-128
  2. Dev Reprod. 2021 Jun;25(2): 93-104
    Antitumor Effect of Metformin in Combination with Binimetinib on Melanoma Cells.
    Eunsung Lee, Yongjae Kwon, Jiwon Kim, Deokbae Park, Youngki Lee.
      Cutaneous melanoma is a fatal disease for patients with distant metastasis. Metformin is the most widely used anti-diabetic drug, and proved to suppress cell proliferation and metastasis in diverse cancers including melanoma. We previously reported that MEK inhibitor trametinib increases the expression of epithelial-mesenchymal transition (EMT) regulators and melanoma cell motility, which are suppressed by addition of metformin in A375 melanoma cells. To confirm our findings further, we first evaluated the effect of metformin in combination with another MEK inhibitor binimetinib on cell viability in G361 melanoma cells. We then investigated whether binimetinib affects the expression of EMT regulators and cell motility. We finally monitored the effect of metformin on binimetinib-induced cell migration. Cell viability assay showed that combination index (CI) value at ED50 is 0.80, suggesting synergy for the combination of metformin with binimetinib. Our results also revealed that binimetinib increased the expression of EMT regulators such as integrin αV, fibronectin and slug, which correlate well with the enhanced cell migration in wound healing assay. Metformin, on the contrary, suppressed the expression of sparc, integrin αV, fibronectin and N-cadherin with the reduced cell motility. The combination treatment showed that metformin counteracts the binimetinib-induced increase of cell motility. Overall, these results suggest that metformin with binimetinib might be useful as a potential therapeutic adjuvant against cell survival and metastatic activity in melanoma patients.
    Keywords:  Binimetinib; Cell viability; Melanoma cell; Metastasis; Metformin
    DOI:  https://doi.org/10.12717/DR.2021.25.2.93
  3. Aging (Albany NY). 2021 Aug 09. 13(undefined):
    Circular RNA ZNF609 drives tumor progression by regulating the miR-138-5p/SIRT7 axis in melanoma.
    Quan Liu, Wei Cui, Chao Yang, Li-Ping Du.
      Melanoma serves as a prevailing and lethal skin malignancy with high mortality and a growing number of patients globally. Circular RNAs (circRNAs), as a type of emerging cellular regulator, are involved in the modulation of melanoma. Nevertheless, the function of circZNF609 in melanoma development remains obscure. In this study, we were interested in the effect and the underlying mechanism of circZNF609 on DNA damage during melanoma progression. The circZNF609 depletion significantly suppressed melanoma cell invasion, migration, and proliferation, and stimulated apoptosis. Meanwhile, comet assays showed that the tail length and γH2AX levels were elevated by circZNF609 depletion. Mechanically, circZNF609 sponged miR-138-5p and miR-138-5p targeted SIRT7 in the melanoma cells. The SIRT7 overexpression and miR-138-5p inhibitor could reverse circZNF609 depletion-mediated DNA damage and malignant progression in melanoma cells. Functionally, CircZNF609 promoted cell growth of melanoma in the nude mice. Consequently, we conclude that circZNF609 suppresses DNA damage and potentially enhances melanoma progression at the experimental condition by modulating the miR-138-5p/SIRT7 axis. Our finding provides new insights into the mechanism by which circZNF609 modulates the development of melanoma. CircZNF609 and miR-138-5p may be utilized as therapeutic targets for melanoma.
    Keywords:  DNA damage; SIRT7; circZNF609; melanoma; miR-138-5p; progression
    DOI:  https://doi.org/10.18632/aging.203394
  4. Cancer Discov. 2020 Dec;10(12): OF7
    Intermittent Inhibition of BRAF plus MEK Is Not Beneficial in Melanoma.
      Compared with standard continuous dosing, intermittent dosing did not improve patient outcomes.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-152
  5. Bioengineered. 2021 Dec;12(1): 5045-5055
    Pseudopodium enriched atypical kinase 1(PEAK1) promotes invasion and of melanoma cells by activating JAK/STAT3 signals.
    Min Pan, Xiaohui Yin, Yi-Chuan Huang.
      Pseudopodium enriched atypical kinase 1(PEAK1) is a non-receptor tyrosine kinase, which is enriched in the pseudopodia of migrating cells and plays an important role in regulating cell migration and proliferation. In the study, we investigate the therapeutic effect of PEAK1 on melanoma cells in vitro and in vivo. We used a lentiviral vector to express short hairpin RNAs (Lv-PEAK1 shRNA) for inhibiting PEAK1 expression in the melanoma SKMEL28 cells. A full-length PEAK1 gene was cloned into the pcDNA 3.1 (+) plasmid and used to infect the melanoma SKMEL19 cells. P6 (also known as Pyridines 6, EMD Chemicals), the Pan-JAK inhibitor, was used to inhibit the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. The cell counting kit-8 (CCK-8), colony formation assay and transwell assay were used to detect cell proliferation, growth and invasion in vitro. The effect of PEAK1 on melanoma progression in vivo was also evaluated. Protein expression of PEAK1, E-cadherin, vimentin and JAK/STAT3 was measured using western blot assay or immunohistochemistry. The results showed that enforced PEAK1 expression facilitated melanoma cell growth, invasion and metastasis via activating JAK/STAT3 signals, and PEAK1 knockdown inhibited melanoma cell growth, invasion and metastasis via inactivating JAK/STAT3 signals. Further work demonstrated that P6 (500 nM) treatment reversed PEAK1-induced effect in melanoma cells. PEAK1 promotes tumorigenesis and metastasis via activating JAK/STAT3 signals, and PEAK1 knockdown reduced tumorigenesis and metastasis in melanoma via inactivating JAK/STAT3 signals, providing a novel therapeutic strategy for melanoma treatment.
    Keywords:  JAK/STAT3 signals; Melanoma; metastasis; pseudopodium enriched atypical kinase
    DOI:  https://doi.org/10.1080/21655979.2021.1961661
  6. Oncol Lett. 2021 Sep;22(3): 667
    Synergistic inhibitory effects of the oxyresveratrol and dacarbazine combination against melanoma cells.
    Sang Gyu Lee, Dong Gun Lee, Yong Hoon Joo, Namhyun Chung.
      Various therapies have been developed to target malignant melanoma, which is associated with a high mortality rate worldwide. Although dacarbazine (DTIC) is employed for treating melanoma, it is associated with several side effects. Hence, patients with melanoma are co-treated with additional drugs to mitigate the side effects of DTIC. In the present study, synergistic therapeutic effects of the DTIC/oxyresveratrol (ORT) combination were examined using the human malignant melanoma WM-266-4 cell line. Treatment with ORT and DTIC inhibited the proliferation of WM-266-4 cells. Compared with those in the ORT- and DTIC-treated groups, the proportion of cells arrested at the S phase, as well as apoptotic rates, were increased in the ORT and DTIC co-treatment group. In WM-266-4 cells, synergistic proliferation-inhibitory activities of the ORT/DTIC combination were assessed based on cell viability and migration, antioxidant capacity, cytokine production, cell cycle arrest, apoptotic rate and protein expression through WST-1 assay, wound healing assay, flow cytometry and western blotting. Furthermore, the expression levels of proteins, including NOTCH, involved in the pathogenesis of solid cancers, such as melanoma, were examined. Overall, the ORT/DTIC combination synergistically promoted cell cycle arrest at the S phase and the apoptosis of WM-266-4 cells. Thus, this combination treatment may serve as a novel therapeutic strategy for treating malignant melanoma.
    Keywords:  Notch signaling; S phase arrest; chemical drug; stilbenoid; synergistic effect
    DOI:  https://doi.org/10.3892/ol.2021.12928
  7. Cancer Discov. 2020 Oct;10(10): OF7
    An RNA Vaccine Promotes Response with or without Anti-PD-1 in Melanoma.
      An RNA vaccine against nonmutated, shared tumor antigens promoted T-cell responses in melanoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-115
  8. Cancer Discov. 2020 Dec;10(12): OF5
    Midkine Promotes Immunosuppression and Reduces Immunotherapy Efficacy.
      Expression of MDK, encoding the growth factor midkine, led to immunotherapy resistance in melanoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-157
  9. Mol Cancer Ther. 2021 Aug 10. pii: molcanther.1126.2021. [Epub ahead of print]
    Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor resistant melanoma.
    Kelsey W Nassar, Jennifer D Hintzsche, Stacey M Bagby, Veronica Espinoza, Christophe Langouët-Astrié, Carol M Amato, Tugs-Saikhan Chimed, Mayumi Fujita, William Robinson, Aik Choon Tan, Rebecca E Schweppe.
      There is a clear need to identify targetable drivers of resistance and potential biomarkers for salvage therapy for melanoma patients refractory to the combination of BRAF and MEK inhibition. In the present study, we performed whole exome sequencing on BRAF-V600E mutant melanoma patient tumors refractory to the combination of BRAF/MEK inhibition and identified acquired oncogenic mutations in NRAS and loss of the tumor suppressor gene CDKN2A. We hypothesized the acquired resistance mechanisms to BRAF/MEK inhibition were reactivation of the MAPK pathway and activation of the cell cycle pathway, which can both be targeted pharmacologically with the combination of a MEK inhibitor (trametinib) and a CDK4/6 inhibitor (palbociclib). In vivo, we found that combination of CDK4/6 and MEK inhibition significantly decreased tumor growth in two BRAF/MEK inhibitor resistant patient derived xenograft models. In vitro, we observed that the combination of CDK4/6 and MEK inhibition resulted in synergy and significantly reduced cellular growth, promoted cell cycle arrest and effectively inhibited downstream signaling of MAPK and cell cycle pathways in BRAF inhibitor resistant cell lines. Knockdown of CDKN2A in BRAF inhibitor resistant cells increased sensitivity to CDK4/6 inhibition alone and in combination with MEK inhibition. A key implication of our study is that the combination of CDK4/6 and MEK inhibitors overcomes acquired resistance to BRAF/MEK inhibitors, and loss of CDKN2A may represent a biomarker of response to the combination. Inhibition of the cell cycle and MAPK pathway represents a promising strategy for patients with metastatic melanoma who are refractory to BRAF/MEK inhibitor therapy.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-1126
  10. Klin Monbl Augenheilkd. 2021 Jul;238(7): 773-780
    The Genetics of Uveal Melanoma: Overview and Clinical Relevance.
    Aline Isabel Riechardt, Emine Kilic, Antonia M Joussen.
      Over the last ten years, much has been learnt about the genetic characteristics and genetic evolution of uveal melanoma. It has been shown that uveal melanoma differs fundamentally from non-uveal melanoma and is an independent genetic subtype. Compared to other tumours, uveal melanoma has a low mutational burden. There are recurring chromosomal aberrations with losses of 1p, 6q, 8p and 16q, gains of 6p and 8q, and the presence of monosomy 3. GNAQ, GNA11, PLCB4, CYSLTR2, MAPKAPK5, as well as mutations in BAP1, SF3B1, SRSF2 and EIF1AX, the latter being linked to a higher risk of metastasis, have been identified as significantly mutated genes. In rare cases, a BAP1 germline mutation may also be present. In addition to higher risk of uveal melanoma, this variant is also linked with other tumours. In this case, additional work-up, genetic counselling and screening of family members should be offered. While the knowledge about the genetic characteristics of uveal melanoma is already routinely used for diagnostic and prognostic purposes, targeted genotype-dependent therapy of uveal melanoma is currently still missing.
    DOI:  https://doi.org/10.1055/a-1513-0789
  11. Transl Oncol. 2021 Aug 10. pii: S1936-5233(21)00189-3. [Epub ahead of print]14(11): 101197
    RNA editing signatures identify melanoma patients who respond to Pembrolizumab or Nivolumab treatment.
    Jalal Siddiqui, Wayne O Miles.
      Immunotherapy has improved the prognosis for many melanoma patients; however, our capacity to predict patient responses and to understand the biological differences between patients who will or will not respond is limited. Gene expression profiling of tumors from patients who respond to immunotherapy has focused on deriving primarily immune-related signatures; however, these have shown limited predictive power. Recent studies have highlighted the role of RNA editing in modulating resistance to immunotherapy. To evaluate the utility of RNA editing activity as a discriminative tool in predicting immunotherapy response, we conducted a retrospective analysis of RNA-sequencing data from melanoma patients treated with Pembrolizumab or Nivolumab. Here, we developed RNA editing signatures that can identify patients who will respond to immunotherapy with very high accuracy and confidence. Our analysis demonstrates that RNA editing is a strong discriminative tool for examining sensitivity of melanoma patients to immunotherapy.
    DOI:  https://doi.org/10.1016/j.tranon.2021.101197
  12. Am J Ophthalmol Case Rep. 2021 Sep;23 101173
    Hemorrhagic choroidal detachment as the presenting sign of uveal melanoma.
    Yewlin E Chee, Raghu Mudumbai, Steven S Saraf, Thellea Leveque, Verena S Grieco, Monique A Mogensen, Rebecca A Yoda, Luis F Gonzalez-Cuyar, Andrew W Stacey.
       Purpose: To describe two cases of medium-sized uveal melanoma presenting with hemorrhagic choroidal detachments.
    Observations: The first case is a 39-year-old man who presented with choroidal hemorrhage and angle closure glaucoma. The second case is a 42-year-old man who presented with choroidal hemorrhage and posterior scleritis. Vitrectomy with transvitreous fine needle aspiration biopsy was ultimately required to diagnose malignant uveal melanoma in each case.
    Conclusions and importance: Intraocular hemorrhage is a rare presenting sign of uveal melanoma. When it does occur, it is typically associated with large tumors. Hemorrhagic choroidal detachments are particularly rare in uveal melanoma, and can limit the diagnostic utility of clinical exam, B-scan ultrasonography, and magnetic resonance imaging. Although it is uncommon, it is important to maintain a high index of suspicion for choroidal melanoma in any patient with unexplained choroidal hemorrhage.
    Keywords:  Adult ocular oncology; Choroidal hemorrhage; Choroidal melanoma; Retinal and vitreous surgery
    DOI:  https://doi.org/10.1016/j.ajoc.2021.101173
  13. Br J Cancer. 2021 Aug 09.
    Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression.
    Gabriela Marsavela, Ashleigh C McEvoy, Michelle R Pereira, Anna L Reid, Zeyad Al-Ogaili, Lydia Warburton, Muhammad A Khattak, Afaf Abed, Tarek M Meniawy, Michael Millward, Melanie R Ziman, Leslie Calapre, Elin S Gray.
       BACKGROUND: The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation.
    METHODS: Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy.
    RESULTS: ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P < 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15).
    CONCLUSIONS: These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.
    DOI:  https://doi.org/10.1038/s41416-021-01507-6
  14. Ann Surg Oncol. 2021 Aug 07.
    In Sentinel Node-Positive Melanoma Patients, Does Omission of Completion Lymph Node Dissection Make More Intensive Follow-Up Necessary, and Does Adjuvant Systemic Therapy Permit Less Intensive Follow-Up?
    John F Thompson.
      
    DOI:  https://doi.org/10.1245/s10434-021-10572-3
  15. Diagn Cytopathol. 2021 Aug 13.
    Fine-needle aspiration of metastatic melanoma with signet-ring cell features.
    Stephanie L Holdener, Yun Gong.
      
    DOI:  https://doi.org/10.1002/dc.24850
  16. Klin Monbl Augenheilkd. 2021 Jul;238(7): 761-772
    Uveal Melanoma - Standardised Procedure in Diagnosis, Therapy and Surveillance.
    Nikolaos E Bechrakis, Norbert Bornfeld, Ludwig M Heindl, Nicole Skoetz, Serge Leyvraz, Antonia M Joussen.
       BACKGROUND: Uveal melanoma is a rare intraocular tumour, for which there is currently no national evidence-based guideline in Germany. The aim of this project was to provide a common standard operating procedure (SOP) for the diagnosis, treatment and follow-up care of uveal melanoma, within the network of German leading oncology centres funded by German Cancer Aid. The SOP was created as part of a moderated consensus process.
    RESULTS AND CONCLUSION: In a multistage process, a common SOP was developed for the diagnosis, therapy and follow-up of uveal melanoma, as based on current knowledge of the subject.
    DOI:  https://doi.org/10.1055/a-1534-0198
  17. Postepy Dermatol Alergol. 2021 Jun;38(3): 498-504
    Inhibitory effect of kaempferol on mouse melanoma cell line B16 in vivo and in vitro.
    Di Qiang, Cao Ci, Wenbei Liu, Jun Wang, Caifeng He, Bihua Ji, Xuefei Shao.
       Introduction: Melanoma is a malignant tumour and is the leading cause of death in patients with skin tumours.
    Aim: Kaempferol belongs to a class of flavonoids, and is associated with many biological functions such as anti-inflammatory, anti-oxidation and anti-cancer. However, the inhibitory effect of kaempferol on melanoma still remains unclear.
    Material and methods: The effect of kaempferol on melanoma was determined by conducting both in vitro and in vivo experiments using MTT assay and flow cytometry.
    Results: The in vitro results revealed that kaempferol obviously inhibited cell viability of melanoma B16 cells, induced cell cycle arrest and cell apoptosis. The in vivo results showed that kaempferol effectively inhibited the growth of mice xenografts. More importantly, kaempferol down-regulated the number of MDSC cells and up-regulated the number of NKT cells and CD8 T cells in the spleen.
    Conclusions: Taken together, these findings indicate that kaempferol might play an inhibitory role in the growth of melanoma by enhancing anti-tumour immunity of organisms.
    Keywords:  apoptosis; inhibitory effect; kaempferol; melanoma; proliferation; tumour immunity
    DOI:  https://doi.org/10.5114/ada.2020.94257
  18. Front Genet. 2021 ;12 687979
    Identification of Potential Prognostic Biomarkers Associated With Cancerometastasis in Skin Cutaneous Melanoma.
    Yang Li, Shanshan Lyu, Zhe Gao, Weifeng Zha, Ping Wang, Yunyun Shan, Jianzhong He, Suyang Huang.
      Skin cutaneous melanoma (SKCM) is a highly aggressive tumor. The mortality and drug resistance among it are high. Thus, exploring predictive biomarkers for prognosis has become a priority. We aimed to find immune cell-based biomarkers for survival prediction. Here 321 genes were differentially expressed in immune-related groups after ESTIMATE analysis and differential analysis. Two hundred nineteen of them were associated with the metastasis of SKCM via weighted gene co-expression network analysis. Twenty-six genes in this module were hub genes. Twelve of the 26 genes were related to overall survival in SKCM patients. After a multivariable Cox regression analysis, we obtained six of these genes (PLA2G2D, IKZF3, MS4A1, ZC3H12D, FCRL3, and P2RY10) that were independent prognostic signatures, and a survival model of them performed excellent predictive efficacy. The results revealed several essential genes that may act as significant prognostic factors of SKCM, which could deepen our understanding of the metastatic mechanisms and improve cancer treatment.
    Keywords:  WGCNA; immune microenvironment; metastasis; prognostic biomarkers; skin cutaneous melanoma
    DOI:  https://doi.org/10.3389/fgene.2021.687979
  19. Expert Rev Mol Diagn. 2021 Aug 11.
    Characteristics of CircRNA and its approach as diagnostic tool in melanoma.
    Khatereh Khorsandi, Homa Sadat Esfahani, Heidi Abrahamse.
       INTRODUCTION: One of the most common types of cancer in the world is skin cancer, which has been divided into two groups: non-melanoma and melanoma skin cancer. Different external and internal agents are considered as risk factors for melanoma skin cancer pathogenesis but the exact mechanisms are not yet confirmed. Genetic and epigenetic changes, UV exposure, arsenic compounds, and chemical substances are contributory factors to the development of melanoma.
    AREAS COVERED: A correlation has emerged between new therapies and the discovery of a basic molecular pattern for skin cancer patients. Circular RNAs (circRNAs) are described as a unique group of extensively expressed endogenous regulatory RNAs with closed-loop structure bonds connecting the 5' and 3' ends, which are commonly expressed in mammalian cells. In this review, we describe the biogenesis of circular RNAs and its function in cancerous conditions focusing on the crosstalk between different circRNAs and melanoma.
    EXPERT OPINION: Increasing evidence suggests that circRNAs appears to be relative to the origin and development of skin-related diseases like malignant melanoma. Different circular RNAs like hsa_circ_0025039, hsa_circRNA006612, circRNA005537, and circANRIL, by targeting different cellular and molecular targets (e.g., CDK4, DAB2IP, ZEB1, miR-889, and let-7c-3p), can participate in melanoma cancer progression.
    Keywords:  Biomarkers; CeRNAs; Circular RNAs; Melanoma; MicroRNA sponge
    DOI:  https://doi.org/10.1080/14737159.2021.1967749
  20. Front Vet Sci. 2021 ;8 695222
    Adenoviral CD40 Ligand Immunotherapy in 32 Canine Malignant Melanomas-Long-Term Follow Up.
    Sara Saellstrom, Arian Sadeghi, Emma Eriksson, Thomas Segall, Maria Dimopoulou, Olle Korsgren, Angelica Si Loskog, Thomas H Tötterman, Akseli Hemminki, Henrik Ronnberg.
      Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. Gene therapy using adenoviruses encoding the immunostimulatory gene CD40L (AdCD40L) has shown promise in initial clinical trials enrolling human patients with various malignancies including melanoma. We report a study of local AdCD40L treatment in 32 cases of canine melanoma (23 oral, 5 cutaneous, 3 ungual and 1 conjunctival). Eight patients were World Health Organization (WHO) stage I, 9 were stage II, 12 stage III, and 3 stage IV. One to six intratumoral injections of AdCD40L were given every seven days, combined with cytoreductive surgery in 20 cases and only immunotherapy in 12 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response based on result of immunotherapy included 7 complete responses, 5 partial responses, 5 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 285 days (range 20-3435 d). Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is ongoing.
    Keywords:  AdCD40L; adenoviral vectors; canine malignant melanoma; clinical trials; immuno oncology; translational medicine
    DOI:  https://doi.org/10.3389/fvets.2021.695222
  21. J Biol Chem. 2021 Aug 06. pii: S0021-9258(21)00835-8. [Epub ahead of print] 101033
    Efficient killing of tumor cells by CAR-T cells demands engagement of a larger number of CARs as opposed to TCRs.
    Nadia Anikeeva, Sergey Panteleev, Nicholas W Mazzanti, Mizue Terai, Takami Sato, Yuri Sykulev.
      Although CAR T cells are widely used to treat cancer, efficiency of CAR-T cell cytolytic responses has not been carefully examined. We engineered CAR specific for HMW-MAA (high molecular weight melanoma-associated antigen) and evaluated potency of CD8+ CAR-T cells to release cytolytic granules and to kill tissue-derived melanoma cells, which express different levels of HMW-MAA. CAR T cells efficiently killed melanoma cells expressing high level of HMW-MAA, but not melanoma cells with lower levels of HMW-MAA. The same melanoma cells presenting significantly lower level of stimulatory peptide-MHC ligand were readily lysed by T cells transduced with genes encoding α,β-TCR specific for the peptide-MHC ligand. The data suggest that higher level of targeted molecules is required to engage a larger number of CARs than TCRs to induce efficient cytolytic granule release and destruction of melanoma cells. Understanding the difference in molecular mechanisms controlling activation thresholds of CAR- versus TCR-mediated responses will contribute to improving efficiency of CAR T cells required to eliminate solid tumors presenting low levels of targeted molecules.
    Keywords:  T‐cell bioengineering; T‐cell receptor (TCR); chimeric antigen receptor (CAR); immunotherapy; killing efficiency of various melanoma cells by CAR- or TCR-triggered T-cells; receptor regulation; tumor immunology
    DOI:  https://doi.org/10.1016/j.jbc.2021.101033
  22. Postepy Dermatol Alergol. 2021 Jun;38(3): 412-420
    Convolutional neural networks for the detection of malignant melanoma in dermoscopy images.
    Dominika Kwiatkowska, Piotr Kluska, Adam Reich.
       Introduction: Convolutional neural networks gained popularity due to their ability to detect and classify objects in images and videos. It gives also an opportunity to use them for medical tasks in such specialties like dermatology, radiology or ophthalmology. The aim of this study was to investigate the ability of convolutional neural networks to classify malignant melanoma in dermoscopy images.
    Aim: To examine the usefulness of deep learning models in malignant melanoma detection based on dermoscopy images.
    Material and methods: Four convolutional neural networks were trained on open source dataset containing dermoscopy images of seven types of skin lesions. To evaluate the performance of artificial neural networks, the precision, sensitivity, F1 score, specificity and area under the receiver operating curve were calculated. In addition, an ensemble of all neural networks' ability of proper malignant melanoma classification was compared with the results achieved by every single network.
    Results: The best convolutional neural network achieved on average 0.88 precision, 0.83 sensitivity, 0.85 F1 score and 0.99 specificity in the classification of all skin lesion types.
    Conclusions: Artificial neural networks might be helpful in malignant melanoma detection in dermoscopy images.
    Keywords:  deep learning; dermoscopy; melanoma; neural networks
    DOI:  https://doi.org/10.5114/ada.2021.107927
  23. Biosci Rep. 2021 Aug 10. pii: BSR20211098. [Epub ahead of print]
    Immune implication of an autophagy-related prognostic signature in uveal melanoma.
    Samuel Chuah, Valerie Chew.
      Uveal Melanoma (UM) is a rare cancer deriving from melanocytes within the uvea. It has a high rate of metastasis, especially to the liver, and a poor prognosis thereafter. Autophagy, an intracellular programmed digestive process, has been associated with the development and progression of cancers, with controversial pro- and anti-tumour roles. Although previous studies have been conducted on autophagy-related genes (ARGs) in various cancer types, its role in UM requires a deeper understanding for improved diagnosis and development of novel therapeutics. In the current study, Zheng et al. used univariate Cox regression followed by least absolute shrinkage and selection operator (Lasso) regression to identify a robust 9-ARG signature prognostic of survival in a total of 230 patients with UM. The authors used the Cancer Genome Atlas (TCGA) UM cohort as a training cohort (n=80) to identify the signature and validated it in another four independent cohorts of 150 UM patients from the Gene Expression Omnibus (GEO) repository (GSE22138, GSE27831, GSE44295 and GSE84976). This 9-ARG signature was also significantly associated with the enrichment of cancer hallmarks, including angiogenesis, IL6-KJAK-STAT3 signalling, reactive oxygen species pathway and oxidative phosphorylation. More importantly, this signature is associated with immune-related functional pathways and immune cell infiltration. Thus, this 9-ARG signature predicts prognosis and provides deeper insights into the immune mechanisms in UM, with potential implications for future immunotherapy.
    Keywords:  Prognostic signature; autophagy; immune microenvironment; uveal melanoma
    DOI:  https://doi.org/10.1042/BSR20211098
  24. Front Mol Biosci. 2021 ;8 713542
    The Tumorigenic Properties of EZH2 are Mediated by MiR-26a in Uveal Melanoma.
    Yao Li, Mingmei Zhang, Huayin Feng, Shaya Mahati.
      Background: The polycomb group protein enhancer of zeste homolog 2 (EZH2) has been found to be highly expressed in various tumors, and microRNA-26a (miR-26a) is often unmodulated in cancers. However, the functions of these two molecules in uveal melanoma (UM) and their relationships have not been reported. Methods: We explored the effects of the miR-26a-EZH2 axis in UM by examining the levels of miR-26a and EZH2. The EZH2 levels in various tumor types and the correlations between EZH2 levels and overall survival and disease-free survival were reanalyzed. The binding of miR-26a to the 3'-untranslated region of EZH2 mRNA was measured using the luciferase reporter assay. The regulation of EZH2 gene expression by miR-26a was also identified, and the effect of elevated EZH2 expression on UM cell function was further examined. Results: miR-26a was downregulated and EZH2 was upregulated in UM cells. Overexpression of miR-26a inhibited cell proliferation, and knockdown of EZH2 suppressed cell growth. EZH2 was a direct target of miR-26a in UM cells. The knockout of EZH2 mimicked the tumor inhibition of miR-26a in UM cells, whereas the reintroduction of EZH2 abolished this effect. In addition, a network of EZH2 and its interacting proteins (UBC, CDK1, HDAC1, SUZ12, EED) was found to participate in miR-26a-mediated tumor progression. Conclusion: The newly identified miR-26a-EZH2 axis may be a potential target for the development of treatment strategies for UM.
    Keywords:  EZH2; cell proliferation; microRNA-26a; tumor progression; uveal melanoma
    DOI:  https://doi.org/10.3389/fmolb.2021.713542
  25. Cancer Sci. 2021 Aug 10.
    Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.
    Yuanmin He, Hongliang Liu, Sheng Luo, Christopher I Amos, Jeffrey E Lee, Xin Li, Hongmei Nan, Qingyi Wei.
      Mitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed mitotic rate as a category criterion of the tumor T-category, based on the evidence that mitotic rate was not an independent prognostic factor for melanoma survival. Since single-nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma-specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis-related pathway genes in CMSS by analyzing their associations with outcomes of 850 CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of 409 CM patients from the Harvard University Nurses' Health Study and Health Professionals Follow-up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.49 (95% confidence interval=1.17-1.90, P=0.001) and 1.45 (1.13-1.86, P=0.003), respectively. Furthermore, their combined unfavorable alleles also predicted poor survival in both discovery and validation datasets in a dose-response manner (Ptrend =0.0006 and 0.0001, respectively). Additional functional analysis revealed that both SDCCAG8 rs10803138 A and MAGI2 rs3807694 T alleles were associated with elevated mRNA expression levels in normal tissues. Therefore, these findings suggest that SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T are independent prognostic biomarkers for CMSS, possibly by regulating the mRNA expression of the corresponding genes involved in mitosis.
    Keywords:  Cutaneous melanoma; mitosis; single-nucleotide polymorphism; survival
    DOI:  https://doi.org/10.1111/cas.15102
  26. Cancer Immunol Res. 2021 Aug 13. pii: canimm.0983.2020. [Epub ahead of print]
    TMB and Inflammatory Gene Expression Associated With Clinical Outcomes Following Immunotherapy in Advanced Melanoma.
    F Stephen Hodi, Jedd D Wolchok, Dirk Schadendorf, James Larkin, Georgina V Long, Xiaozhong Qian, Abdel Saci, Tina C Young, Sujaya Srinivasan, Han Chang, Hao Tang, Megan Wind-Rotolo, Jasmine I Rizzo, Donald G Jackson, Paolo A Ascierto.
      Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4 gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti-PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti-CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (>median) versus low ({less than or equal to}median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of BRAF mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-20-0983
  27. Genet Med. 2021 Aug 12.
    Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.
    Amelia K Smit, Martin Allen, Brooke Beswick, Phyllis Butow, Hugh Dawkins, Suzanne J Dobbinson, Kate L Dunlop, David Espinoza, Georgina Fenton, Peter A Kanetsky, Louise Keogh, Michael G Kimlin, Judy Kirk, Matthew H Law, Serigne Lo, Cynthia Low, Graham J Mann, Gillian Reyes-Marcelino, Rachael L Morton, Ainsley J Newson, Jacqueline Savard, Lyndal Trevena, Sarah Wordsworth, Anne E Cust.
       PURPOSE: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes.
    METHODS: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline.
    RESULTS: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54-0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress.
    CONCLUSION: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.
    DOI:  https://doi.org/10.1038/s41436-021-01292-w
  28. J Clin Biochem Nutr. 2021 Jul;69(1): 52-60
    Glycyrrhizin ameliorates melanoma cell extravasation into mouse lungs by regulating signal transduction through HMGB1 and its receptors.
    Keiichi Hiramoto, Yurika Yamate, Kenji Goto, Shiho Ohnishi, Akihiro Morita, Nobuji Yoshikawa, Shosuke Kawanishi.
      Metastasis, which accounts for the majority of all cancer-related deaths, occurs through several steps, namely, local invasion, intravasation, transport, extravasation, and colonization. Glycyrrhizin has been reported to inhibit pulmonary metastasis in mice inoculated with B16 melanoma. This study aimed to identify the mechanism through which glycyrrhizin ameliorates the extravasation of melanoma cells into mouse lungs. Following B16 melanoma cell injection, mice were orally administered glycyrrhizin once every two days over 2 weeks; lung samples were then obtained and analyzed. Blood samples were collected on the final day, and cytokine plasma levels were determined. We found that glycyrrhizin ameliorated the extravasation of melanoma cells into the lungs and suppressed the plasma levels of interleukin-6, tumor necrosis factor-α, and transforming growth factor-β. Furthermore, glycyrrhizin ameliorated the lung tissue expression of high mobility group box-1 protein (HMGB1), receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)-4, RAS, extracellular signal-related kinase, NF-κB, myeloid differentiation primary response 88, IκB kinase complex, epithelial-mesenchymal transition markers, and vascular endothelial growth factor-A. Our study demonstrates that glycyrrhizin ameliorates melanoma metastasis by regulating the HMGB1/RAGE and HMGB1/TLR-4 signal transduction pathways.
    Keywords:  epithelial-mesenchymal transition; glycyrrhizin; high mobility group box-1 protein; melanoma; receptor for advanced glycation end product
    DOI:  https://doi.org/10.3164/jcbn.20-125
  29. Chem Biol Interact. 2021 Aug 05. pii: S0009-2797(21)00257-X. [Epub ahead of print]347 109619
    Anticancer effects of oleanolic acid on human melanoma cells.
    Joong-Seok Woo, Eun-Seon Yoo, Sung-Hyun Kim, Jae-Han Lee, So-Hee Han, Soo-Hyun Jung, Gi-Hwan Jung, Ji-Youn Jung.
      Owing to the ineffectiveness of the currently used therapies against melanoma, there has been a shift in focus toward alternative therapies involving the use of natural compounds. This study assessed the anticancer effects of oleanolic acid (OA) and its ability to induce apoptosis in A375SM and A375P melanoma cells in vivo. Compared to the control group, viability of A375P and A375SM cells decreased following OA treatment. In OA-treated A375SM and A375P cells, 4',6-diamidino-2-phenylindole staining showed an increase in the apoptotic body, and flow cytometry revealed increased number of apoptotic cells compared to that in the control group. OA-treated A375SM cells exhibited an increased expression of the apoptotic proteins, cleaved poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma (Bcl)-2-associated X protein (Bax) as well as decreased expression of the antiapoptotic protein Bcl-2 compared to that in the control group. In OA-treated A375P cells, expression patterns of cleaved PARP and Bcl-2 were similar to those in OA-treated A375SM cells; however, no difference was reported in the expression of Bax compared to that in the control group. Additionally, OA-treated melanoma cells showed decreased expression of phospho-nuclear factor-κB (p-NF-κB), phospho-inhibitor of nuclear factor-κBα (p-IκBα), and phospho-IκB kinase αβ than that in the control group. Moreover, immunohistochemistry showed a comparatively decreased level of p-NF-κB in the OA-treated group than that in the control group. Xenograft analysis confirmed the in vivo anticancer effects of OA against A375SM cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed an increased number of TUNEL-positive cells in the OA-treated group compared to that in the control group. In conclusion, the study results suggest that OA induces apoptosis of A375SM and A375P cells in vitro and apoptosis of A375SM cells in vivo. Furthermore, the in vitro and in vivo anticancer effects were mediated by the NF-κB pathway.
    Keywords:  A375P; A375SM; Anticancer effects; Apoptosis; Melanoma; Nuclear factor-κB (NF-κB)
    DOI:  https://doi.org/10.1016/j.cbi.2021.109619
  30. J Dtsch Dermatol Ges. 2021 Aug;19(8): 1145-1157
    Current concepts of ectopic nodal inclusions with special emphasis on nodal nevi.
    Cornelia Sigrid Lissi Müller, Stephan G Müller, Thomas Vogt, Claudia Pföhler.
      Nodal inclusions of ectopic tissue within lymph nodes are seen comparatively often in dermatopathology and general pathology. Glandular and nonglandular epithelium, as well as melanocytic nevi can be observed within lymph nodes and represent mostly incidental findings without any relevance. The main challenge in reporting these morphologic features is to differentiate such benign inclusions from metastatic settlements of distinct organ tumors. As sentinel node biopsy and lymph node dissection have become standard procedure in clinical oncology and have an immense clinical impact, the correct evaluation of these nodal inclusions is indispensable to avoid undertreatment or overtreatment of patients. In addition, the genesis of these inclusions has not yet been satisfactorily clarified. Two concepts have been laid out: the theory of benign metastases and the migration arrest theory. However, neither theory has so far been able to answer the following questions: Why do we find more nodal nevi in patients with melanoma who had a sentinel node biopsy than in patients without melanoma, and why do we not find nodal nevi in deep visceral lymph nodes? We present a comprehensive review of the current knowledge on nodal inclusions, proposing a concept for the pathogenesis of nodal nevi, to answer these questions.
    DOI:  https://doi.org/10.1111/ddg.14521
  31. Crit Rev Ther Drug Carrier Syst. 2021 ;38(4): 1-38
    Recent Advances in Lipid-Based Nanovesicular Delivery Systems for Melanoma Therapy.
    Mallesh Kurakula, Li Chen, Amit K Tiwari, Nuggehally R Srinivas, Ranjeet Prasad Dash, Peter R Panizzi, Robert D Arnold, R Jayachandra Babu.
      Melanoma is one of the most aggressive forms of cancer with limited treatment options available. Successful treatment involves a combination of surgical resection of the tumor; chemotherapy and immunotherapy. Given their complex nature, the rapid development of drug resistance and metastatic spread, nanotechnology-based therapeutics are an attractive option for effective melanoma treatment. Nano-vesicular-based delivery systems hold the promise of aiding in the diagnosis and treatment of melanoma. These formulations can improve targeted delivery, deliver insoluble drugs belonging to class II, biopharmaceutical classification system, and alter drug pharmacokinetics and exposure profiles. These nanometer-sized carriers predominantly bypass the reticuloendothelial system and, thereby, improve blood circulation time and enhance tumor cell uptake with reduced toxicity. In this review, various lipid-based nano-formulations used in the diagnosis, treatment, or both for melanoma are discussed. Utilization of these na-no-formulations with a single drug or a combination of drugs, nucleic acid-based compounds (small interfering RNA, DNA) and targeting antibodies as other possibilities for melanoma are reviewed. We also present a state-of-the-art overview of alternative therapeutic approaches for the treatment of melanoma, such as photodynamic, immune, and gene therapies.
    DOI:  https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2021034903
  32. Pharmaceutics. 2021 Jul 01. pii: 1005. [Epub ahead of print]13(7):
    Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma.
    Yige Fu, Aishwarya Saraswat, Zenghui Wei, Manas Yogendra Agrawal, Vikas V Dukhande, Sandra E Reznik, Ketan Patel.
      A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A modified hydration method with citric acid was used to improve the loading of both the molecules in liposomes. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency for both the drugs and was found to be physically stable for a month at 4 °C. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and down-regulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroids with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma.
    Keywords:  ARV-825; PEGylated nanoliposomes; combination therapy; nintedanib; proteolysis targeting chimera; synergistic interaction; vemurafenib-resistant melanoma
    DOI:  https://doi.org/10.3390/pharmaceutics13071005
  33. JAMA. 2021 Aug 09.
    Inflammatory Myositis in a Patient With Melanoma.
    Mithu Maheswaranathan, Michel G Khouri, Sophia C Weinmann.
      
    DOI:  https://doi.org/10.1001/jama.2021.9025
  34. PLoS One. 2021 ;16(8): e0255972
    Evaluation of TTV replication as a biomarker of immune checkpoint inhibitors efficacy in melanoma patients.
    Rémi Pescarmona, William Mouton, Thierry Walzer, Stéphane Dalle, Anaïs Eberhardt, Karen Brengel-Pesce, Marine Villard, Christine Lombard, Sophie Trouillet-Assant, Sébastien Viel.
      Torque Teno Virus (TTV) is a small, non-enveloped, single-stranded and circular DNA virus that infects the majority of the population worldwide. Increased levels of plasma TTV viral load have been observed in various situations of immune deficiency or dysregulation, and several studies have suggested that TTV levels may be inversely correlated with immune competence. The measurement of TTV viremia by qPCR has been proposed as a potential biomarker for the follow-up of functional immune competence in immunosuppressed individuals, particularly hematopoietic stem cell transplant recipients. We hypothesized that TTV viral load could be used as a prognostic marker of immune checkpoint inhibitor (ICI) efficacy, and therefore investigated the TTV viral load in melanoma patients treated with nivolumab or pembrolizumab before and after 6 months of treatment. In the present study, TTV viral load was not different in melanoma patients before anti-PD-1 introduction compared to healthy volunteers, was not modified by ICI treatment and did not allowed to distinguish patients with treatment-sensitive tumor from patients with treatment-resistant tumor.
    DOI:  https://doi.org/10.1371/journal.pone.0255972
  35. Oncol Lett. 2021 Sep;22(3): 657
    Iron regulatory protein 1 promotes ferroptosis by sustaining cellular iron homeostasis in melanoma.
    Fengping Yao, Xiaohong Cui, Ying Zhang, Zhuchun Bei, Hongquan Wang, Dongxu Zhao, Hong Wang, Yongfei Yang.
      Melanoma, the most aggressive skin cancer, is mainly treated with BRAF inhibitors or immunotheareapy. However, most patients who initially responded to BRAF inhibitors or immunotheareapy become resistant following relapse. Ferroptosis is a form of regulated cell death characterized by its dependence on iron ions and the accumulation of lipid reactive oxygen species (ROS). Recent studies have demonstrated that ferroptosis is a good method for tumor treatment, and iron homeostasis is closely associated with ferroptosis. Iron regulatory protein (IRP)1 and 2 play important roles in maintaining iron homeostasis, but their functions in ferroptosis have not been investigated. The present study reported that the expression of IRP1 and IRP2 was increased by the ferroptosis inducers erastin and RSL3 in melanoma cells. Depletion of IRP1 significantly suppressed erastin- and RSL3-induced ferroptosis. IRP2 had a weak effect but could enhance the promoting function of IRP1 on ferroptosis. Further, erastin and RSL3 promoted the transition of aconitase 1 to IRP1, which regulated downstream iron metabolism proteins, including transferrin receptor (TFRC), ferroportin (FPN) and ferritin heavy chain 1 (FTH1). Moreover, overexpression of TFRC and knockdown of FPN and FTH1 significantly promoted erastin- and RSL3-induced ferroptosis in IRP1 knockdown melanoma cells. Collectively, the present findings indicate that IRP1 plays an essential role in erastin- and RSL3-induced ferroptosis by regulating iron homeostasis.
    Keywords:  ferritin; ferroportin; ferroptosis; iron regulatory protein 1; melanoma; transferrin receptor
    DOI:  https://doi.org/10.3892/ol.2021.12918
  36. Front Cell Dev Biol. 2021 ;9 685120
    Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma.
    Yi Jin, Zhanwang Wang, Dong He, Yuxing Zhu, Lian Gong, Mengqing Xiao, Xingyu Chen, Ke Cao.
      Uveal melanoma (UVM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic disease and have a poor prognosis. The need for immunotherapies has rapidly emerged, and recent research has yielded impressive results. Emerging evidence has implicated ferroptosis as a novel type of cell death that may mediate tumor-infiltrating immune cells to influence anticancer immunity. In this study, we first selected 11 ferroptosis regulators in UVM samples from the training set (TCGA and GSE84976 databases) by Cox analysis. We then divided these molecules into modules A and B based on the STRING database and used consensus clustering analysis to classify genes in both modules. According to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the results revealed that the clusters in module A were remarkably related to immune-related pathways. Next, we applied the ESTIMATE and CIBERSORT algorithms and found that these ferroptosis-related patterns may affect a proportion of TME infiltrating cells, thereby mediating the tumor immune environment. Additionally, to further develop the prognostic signatures based on the immune landscape, we established a six-gene-regulator prognostic model in the training set and successfully verified it in the validation set (GSE44295 and GSE27831). Subsequently, we identified the key molecules, including ABCC1, CHAC1, and GSS, which were associated with poor overall survival, progression-free survival, disease-specific survival, and progression-free interval. We constructed a competing endogenous RNA network to further elucidate the mechanisms, which consisted of 29 lncRNAs, 12 miRNAs, and 25 ferroptosis-related mRNAs. Our findings indicate that the ferroptosis-related genes may be suitable potential biomarkers to provide novel insights into UVM prognosis and decipher the underlying mechanisms in tumor microenvironment characterization.
    Keywords:  Uveal melanoma; ferroptosis; prognostic model; tumor immune environment; tumor-infiltrating immune cells
    DOI:  https://doi.org/10.3389/fcell.2021.685120
  37. ACS Appl Mater Interfaces. 2021 Aug 12.
    Tumor Microenvironment-Activated Nanoparticles Loaded with an Iron-Carbonyl Complex for Chemodynamic Immunotherapy of Lung Metastasis of Melanoma In Vivo.
    Tianli Zhai, Wei Zhong, Yucong Gao, Han Zhou, Zhiguo Zhou, Xiaoming Liu, Shiping Yang, Hong Yang.
      In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.
    Keywords:  Iron-carbonyl complex; chemodynamic therapy; immunogenic cell death; lung metastasis of melanoma; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsami.1c11485
  38. Postepy Dermatol Alergol. 2021 Jun;38(3): 505-509
    Investigation of skin self-examination and sunscreen use in adolescents in northern Cyprus.
    Didem Mullaaziz, Aslı Kaptanoğlu, Evren Hınçal, Emel Erdal Çalıkoğlu.
       Introduction: Regular skin self-examination (SSE) is very important for the early diagnosis of malignant melanoma (MM). Since sun exposure is the most important trigger factor for the development of skin cancers, effective and regular sun protection is the main preventive method.
    Aim: To investigate the awareness of SSE, risky nevus and sun protection of the adolescents in the Turkish Republic of Northern Cyprus (TRNC).
    Material and methods: The data used within this research were obtained from questionnaires administered to volunteer high school students in the TRNC.
    Results: 39.8% of the participants included in the study stated that they conducted SSE. All the participants who said they conducted SSE reported that they performed a face exam. The body regions that the participants did not examine were the scalp (47.7%), foot (36.9%), back (35.4%) and genital area (35.4%). The features of the nevus perceived by the participants as risk factors included rapid growth, bleeding and itching. While 74% of respondents said they used sunscreen products, only 9% of users reported using them every day.
    Conclusions: In the TRNC where the exposure to the sun is high, young people perform skin examinations at high rates in order to monitor their nevi. Nevertheless, the results of this research show that hard-to-reach areas are neglected.
    Keywords:  melanoma; nevus; skin self-examination
    DOI:  https://doi.org/10.5114/ada.2021.107937
  39. Biomed Pharmacother. 2021 Aug 09. pii: S0753-3322(21)00799-X. [Epub ahead of print]142 112016
    Codonopsis pilosula polysaccharide in synergy with dacarbazine inhibits mouse melanoma by repolarizing M2-like tumor-associated macrophages into M1-like tumor-associated macrophages.
    Hongxu Liu, William Kwame Amakye, Jiaoyan Ren.
       BACKGROUND: The incidence and associated mortality of melanoma have increased significantly in recent years but treatment options are plagued with many undesirable side effects. Traditional Chinese herbal medicine polysaccharides are gaining increasing attention due to their potential role in the treatment of chronic diseases including tumors and the regulation of the immune system.
    METHODS: In this study, the potential effects of Ganoderma lucidum crude polysaccharides (GLCP) and Codonopsis pilosula crude polysaccharides (CPCP) on melanoma in C57 mice were explored. In addition, the inhibition and repolarization effect of digested Codonopsis pilosula polysaccharide (dCPP) on the proliferation of tumor-associated macrophages (TAMs) with M2-like phenotype induced by IL-4 were investigated.
    RESULTS: The results showed that the various polysaccharides could significantly reduce tumor volume in melanoma mice. GLCP and GLCP + CPCP could further significantly reduce the number of CD68+ macrophages in tumors and also prolong survival in melanoma mice to a certain extent. Significantly, dCPP could inhibit the proliferation of IL-4-induced M2-like TAMs, and significantly increase the mRNA expression levels of IL-1, IL-6, iNOS and TNF-a, thereby promoting the repolarization of M2-like TAMs to M1-like TAMs.
    CONCLUSION: Overall, it could be deduced that GLCP, CPCP and dCPP hold great potential as safe therapeutic options for melanoma and an immune-modulator which may require further exploration.
    Keywords:  Antitumor; Chinese herbal medicine polysaccharides; In vitro simulated digestion; M2 tumor-associated macrophages (TAMs) repolarization
    DOI:  https://doi.org/10.1016/j.biopha.2021.112016
  40. Front Oncol. 2021 ;11 736438
    Corrigendum: Proteome Analysis of USP7 Substrates Revealed Its Role in Melanoma Through PI3K/Akt/FOXO and AMPK Pathways.
    Lanyang Gao, Danli Zhu, Qin Wang, Zheng Bao, Shigang Yin, Huiyan Qiang, Heinrich Wieland, Jinyue Zhang, Alexander Teichmann, Jing Jia.
      [This corrects the article DOI: 10.3389/fonc.2021.650165.].
    Keywords:  PI3K/Akt/FOXO pathways; USP7; deubiquitinating enzyme; melanoma; quantitative proteomics
    DOI:  https://doi.org/10.3389/fonc.2021.736438
  41. Nat Commun. 2021 Aug 12. 12(1): 5022
    Author Correction: PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.
    Antoni Ribas, Alain Algazi, Paolo A Ascierto, Marcus O Butler, Sunandana Chandra, Michael Gordon, Leonel Hernandez-Aya, Donald Lawrence, Jose Lutzky, Wilson H Miller, Katie M Campbell, Bruno Delafont, Shannon Marshall, Nancy Mueller, Caroline Robert.
      
    DOI:  https://doi.org/10.1038/s41467-021-25285-0
  42. Oncol Rep. 2021 Oct;pii: 210. [Epub ahead of print]46(4):
    [Retracted] MicroRNA‑18b inhibits the growth of malignant melanoma via inhibition of HIF‑1α‑mediated glycolysis.
    Yao Chen, Ziqing Zhang, Chengqun Luo, Zizi Chen, Jianda Zhou.
      Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the flow cytometric data shown in Fig. 3, and western blotting assay data shown in Fig. 6F, were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 36: 471‑479, 2016; DOI: 10.3892/or.2016.4824].
    Keywords:  HIF-1α; glycolysis; malignant melanoma; microRNA-18b; proliferation
    DOI:  https://doi.org/10.3892/or.2021.8161
  43. Clin Cancer Res. 2021 Aug 10. pii: clincanres.1283.2021. [Epub ahead of print]
    Early use of high-dose-glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy.
    Xue Bai, Jiani Hu, Allison Betof Warner, Henry T Quach, Christopher G Cann, Michael Z Zhang, Lu Si, Bixia Tang, Chuanliang Cui, Xiaoling Yang, Xiaoting Wei, Lalit Pallan, Catriona Harvey, Michael P Manos, Olivia Ouyang, Michelle S Kim, Gyulnara Kasumova, Justine V Cohen, Donald P Lawrence, Christine Freedman, Riley M Fadden, Krista M Rubin, Tatyana Sharova, Dennie T Frederick, Keith T Flaherty, Osama E Rahma, Georgina V Long, Alexander M Menzies, Jun Guo, Alexander N Shoushtari, Douglas B Johnson, Ryan J Sullivan, Genevieve M Boland.
       BACKGROUND: Programmed cell death receptor-1 (PD-1) inhibitors are front-line therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear.
    METHODS: In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed.
    RESULTS: Of the entire cohort of 947 patients, 509(54%) developed irAEs. In the MGH cohort (irAE(+)n=90), early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose-GCC use ({greater than or equal to}60mg prednisone equivalent qd) was independently associated with poorer post-irAE PFS/OS (post-irAE PFS: HR5.37, 95%CI 2.10-13.70, P<.001; post-irAE OS: HR5.95, 95%CI 2.20-16.09, P<.001) compared to irAE without early-high-dose-GCC use. These findings were validated in the combined validation cohort (irAE(+)n=419, post-irAE PFS: HR1.69, 95%CI 1.04-2.76, P=.04; post-irAE OS: HR1.97, 95%CI 1.15-3.39, P=.01). Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results.
    CONCLUSIONS: Early high-dose-GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1283
  44. Oncoimmunology. 2021 ;10(1): 1950953
    Hypoxia increases melanoma-associated fibroblasts immunosuppressive potential and inhibitory effect on T cell-mediated cytotoxicity.
    Linda Ziani, Stéphanie Buart, Salem Chouaib, Jerome Thiery.
      Cancer-associated fibroblasts (CAFs) and hypoxia are central players in the complex process of tumor cell-stroma interaction and are involved in the alteration of the anti-tumor immune response by impacting both cancer and immune cell populations. However, even if their independent immunomodulatory properties are now well documented, whether the interaction between these two components of the tumor microenvironment can affect CAFs ability to alter the anti-tumor immune response is still poorly defined. In this study, we provide evidence that hypoxia increases melanoma-associated fibroblasts expression and/or secretion of several immunosuppressive factors (including TGF-β, IL6, IL10, VEGF and PD-L1). Moreover, we demonstrate that hypoxic CAF secretome exerts a more profound effect on T cell-mediated cytotoxicity than its normoxic counterpart. Together, our data suggest that the crosstalk between hypoxia and CAFs is probably an important determinant in the complex immunosuppressive tumor microenvironment.
    Keywords:  CTL; Cancer-associated fibroblasts; hypoxia; immunosuppression
    DOI:  https://doi.org/10.1080/2162402X.2021.1950953
  45. Postepy Dermatol Alergol. 2021 Jun;38(3): 473-479
    Comparison of tyrosinase antibody, tyrosinase-related protein-1 and -2 antibodies, melanin-concentrating hormone receptor antibody levels with autologous serum skin test and autologous plasma skin test results in patients with vitiligo.
    Abdullah Unal, Hatice Uce Ozkol, Yasemin Bayram, Necmettin Akdeniz.
       Introduction: Although the exact etiopathogenesis of vitiligo is unknown, the autoimmunity hypothesis is much in evidence. The autologous serum skin test (ASST) and autologous plasma skin test (APST) are in vivo methods used in the diagnosis of some autoimmune diseases, which are easy and inexpensive to perform.
    Aim: In this study, we investigated whether or not ASST and APST could determine autoimmunity in patients with vitiligo.
    Material and methods: In this study, 30 vitiligo patients presenting to the dermatology outpatient clinic and 30 healthy volunteers without any known autoimmune diseases were included. Antibodies such as tyrosinase, tyrosinase-related protein-1 (TYRP1), tyrosinase-related protein-2 (TYRP2) and melanin-concentrating hormone receptor 1 (MCHR1) antibodies determined to be associated with vitiligo were examined. In addition, the association of these antibodies with the positivity of ASST and APST, which were suggested to be associated with autoimmunity, were examined.
    Results: In our study, tyrosinase antibody was found to be significantly higher in vitiligo patients. ASST was positive in 12 (40%) patients with vitiligo and 8 (26.6%) control subjects. APST was positive in 8 (26.6%) of the patients with vitiligo and in 2 (6.6%) of the controls, and there was a significant difference between the groups in terms of APST positivity (p = 0.032). In addition, in our study, a significant correlation was found between TYRP1 antibody positivity and APST positivity in the patient group (p = 0.005).
    Conclusions: These findings suggest that we may use APST to investigate the autoimmune etiopathogenesis of vitiligo.
    Keywords:  antibodies; autoimmunity; autologous serum skin test; vitiligo
    DOI:  https://doi.org/10.5114/ada.2020.93272
  46. PLoS One. 2021 ;16(8): e0255293
    CARD11 is a prognostic biomarker and correlated with immune infiltrates in uveal melanoma.
    Xueying Shi, Shilin Xia, Yingming Chu, Nan Yang, Jingyuan Zheng, Qianyi Chen, Zeng Fen, Yuankuan Jiang, Shifeng Fang, Jingrong Lin.
      Uveal melanoma (UVM), the most common primary intraocular malignancy, has a high mortality because of a high propensity to metastasize. Our study analyzed prognostic value and immune-related characteristics of CARD11 in UVM, hoping to provide a potential management and research direction. The RNA-sequence data of 80 UVM patients were downloaded from The Cancer Genome Atlas database and divided them into high- and low-expression groups. We analyzed the differentially expressed genes, enrichment analyses and the infiltration of immune cells using the R package and Gene-Set Enrichment Analysis. A clinical prediction nomogram and protein-protein interaction network were constructed and the first 8 genes were considered as the hub-genes. Finally, we constructed a competing endogenous RNA (ceRNA) network by Cytoscape and analyzed the statistical data via the R software. Here we found that CARD11 expression had notable correlation with UVM clinicopathological features, which was also an independent predictor for overall survival (OS). Intriguingly, CARD11 had a positively correlation to autophagy, cellular senescence and apoptosis. Infiltration of monocytes was significantly higher in low CARD11 expression group, and infiltration of T cells regulatory was lower in the same group. Functional enrichment analyses revealed that CARD11 was positively related to T cell activation pathways and cell adhesion molecules. The expressions of hub-genes were all increased in the high CARD11 expression group and the ceRNA network showed the interaction among mRNA, miRNA and lncRNA. These findings show that high CARD11 expression in UVM is associated with poor OS, indicating that CARD11 may serve as a potential biomarker for the diagnosis and prognosis of the UVM.
    DOI:  https://doi.org/10.1371/journal.pone.0255293
  47. Eur J Cancer. 2021 Aug 10. pii: S0959-8049(21)00442-1. [Epub ahead of print]155 191-199
    A benchmark for neural network robustness in skin cancer classification.
    Roman C Maron, Justin G Schlager, Sarah Haggenmüller, Christof von Kalle, Jochen S Utikal, Friedegund Meier, Frank F Gellrich, Sarah Hobelsberger, Axel Hauschild, Lars French, Lucie Heinzerling, Max Schlaak, Kamran Ghoreschi, Franz J Hilke, Gabriela Poch, Markus V Heppt, Carola Berking, Sebastian Haferkamp, Wiebke Sondermann, Dirk Schadendorf, Bastian Schilling, Matthias Goebeler, Eva Krieghoff-Henning, Achim Hekler, Stefan Fröhling, Daniel B Lipka, Jakob N Kather, Titus J Brinker.
       BACKGROUND: One prominent application for deep learning-based classifiers is skin cancer classification on dermoscopic images. However, classifier evaluation is often limited to holdout data which can mask common shortcomings such as susceptibility to confounding factors. To increase clinical applicability, it is necessary to thoroughly evaluate such classifiers on out-of-distribution (OOD) data.
    OBJECTIVE: The objective of the study was to establish a dermoscopic skin cancer benchmark in which classifier robustness to OOD data can be measured.
    METHODS: Using a proprietary dermoscopic image database and a set of image transformations, we create an OOD robustness benchmark and evaluate the robustness of four different convolutional neural network (CNN) architectures on it.
    RESULTS: The benchmark contains three data sets-Skin Archive Munich (SAM), SAM-corrupted (SAM-C) and SAM-perturbed (SAM-P)-and is publicly available for download. To maintain the benchmark's OOD status, ground truth labels are not provided and test results should be sent to us for assessment. The SAM data set contains 319 unmodified and biopsy-verified dermoscopic melanoma (n = 194) and nevus (n = 125) images. SAM-C and SAM-P contain images from SAM which were artificially modified to test a classifier against low-quality inputs and to measure its prediction stability over small image changes, respectively. All four CNNs showed susceptibility to corruptions and perturbations.
    CONCLUSIONS: This benchmark provides three data sets which allow for OOD testing of binary skin cancer classifiers. Our classifier performance confirms the shortcomings of CNNs and provides a frame of reference. Altogether, this benchmark should facilitate a more thorough evaluation process and thereby enable the development of more robust skin cancer classifiers.
    Keywords:  Artificial intelligence; Benchmarking; Deep learning; Dermatology; Melanoma; Nevus; Skin neoplasms
    DOI:  https://doi.org/10.1016/j.ejca.2021.06.047
  48. Mol Pharm. 2021 Aug 10.
    Treatment of Melanoma by Nano-conjugate-Delivered Wee1 siRNA.
    Xueyan Zhang, Anqi Cai, Yan Gao, Yuanfa Zhang, Xingmei Duan, Ke Men.
      Small interfering RNA (siRNA)-based drugs have shown tremendous potential to date in cancer gene therapy. Despite the considerable efforts in siRNA design and manufacturing, unsatisfactory delivery systems persist as a limitation for the application of siRNA-based drugs. In this work, the cholesterol, cell-penetrating peptide conjugate cRGD (R8-cRGD), and polyethylene glycol (PEG) were introduced into low-molecular-weight polyethyleneimine (LMW PEI) to form cRGD-R9-cholesterol-PEI-PEG (RRCPP) nanoparticles with specific targeting and highly penetrating abilities. The enhanced siRNA uptake efficiency of the RRCPP delivery system benefited from R8-cRGD modification. Wee1 is an oncogenic nuclear kinase that can regulate the cell cycle as a crucial G2/M checkpoint. Overexpression of Wee1 in melanoma may lead to a poor prognosis. In the present study, RRCPP nanoparticles were designed for Wee1 siRNA delivery to form an RRCPP/siWee1 complex, which significantly silenced the expression of the WEE1 gene (>60% inhibition) and induced B16 tumor cell apoptosis by abrogating the G2M checkpoint and DNA damage in vitro. Furthermore, the RRCPP/siWee1 complex suppressed B16 tumor growth in a subcutaneous xenograft model (nearly 85% inhibition rate) and lung metastasis (nearly 66% inhibition rate) with ideal in vivo safety. Briefly, our results support the validity of RRCPP as a potential Wee1 siRNA carrier for melanoma gene therapy.
    Keywords:  RNA interference; WEE1 gene; low-molecular weight polyethyleneimine; melanoma gene therapy
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00316
  49. J Food Biochem. 2021 Aug 13. e13903
    An anti-cancer effect of Sambou bamboo saltTM in melanoma skin cancer both in vivo and in vitro models.
    Hee-Yun Kim, Dongkyun Han, Jungeun Kim, Min-Sun Yoo, Jin-Soo Lee, Hyunyong Kim, Hyung-Min Kim, Hyun-Ja Jeong.
      Bamboo salt has anti-allergic, anti-inflammatory, anti-oxidant, diabetics, anti-aging, and immune-enhancing effects, which are closely related to anti-cancer effect. The aim of this study was to investigate the anti-cancer effects of Sambou bamboo saltTM (SBS) in melanoma skin cancer in vivo and in vitro models. SBS-administered mice effectively reduced tumor growth and increased survival rate compared with B16F10 cell-inoculated mice without tissue damage, hepatotoxicity, and nephrotoxicity. SBS enhanced levels of immune-enhancing mediators, such as interferon-γ, interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor-α, and IgE in serum and melanoma tissues. Furthermore, SBS enhanced activities of caspases and levels of Bax and p53, whereas decreased levels of Bcl-2. This reduction was a consequence of apoptosis signaling pathway. In conclusion, these results suggest that SBS is a potential substance for cancer therapy. SBS has the potential to be developed either as Korean traditional medicine or as a health functional food for cancer therapy. PRACTICAL APPLICATIONS: In these days cancer is one of the world's largest health problems. Bamboo salt is used as a Korean traditional food or medicine and has beneficial effect on inflammation. We have identified Sambou bamboo saltTM (SBS) is a potential substance for cancer therapy. These insights suggest that SBS can potentially be utilized for health functional foods for cancer treatment as well as improve various cancer diseases such as melanoma skin cancer.
    Keywords:  apoptosis; bamboo salt; caspase; cytokine; melanoma
    DOI:  https://doi.org/10.1111/jfbc.13903
  50. Sci Rep. 2021 Aug 09. 11(1): 16125
    Non-thermal atmospheric pressure plasma activates Wnt/β-catenin signaling in dermal papilla cells.
    Ji-Hye Hwang, Hyun-Young Lee, Kyung Bae Chung, Hae June Lee, Jino Kim, Kiwon Song, Do-Young Kim.
      There is an unmet need for novel, non-pharmacological therapeutics to treat alopecia. Recent studies have shown the potential biological benefits of non-thermal atmospheric pressure plasma (NTAPP), including wound healing, angiogenesis, and the proliferation of stem cells. We hypothesized that NTAPP might have a stimulatory effect on hair growth or regeneration. We designed an NTAPP-generating apparatus which is applicable to in vitro and in vivo experiments. The human dermal papilla (DP) cells, isolated fresh hair follicles, and mouse back skin were exposed with the NTAPP. Biological outcomes were measured using RNA-sequencing, RT-PCR, Western blots, and immunostaining. The NTAPP treatment increased the expression levels of Wnt/β-catenin pathway-related genes (AMER3, CCND1, LEF1, and LRG1) and proteins (β-catenin, p-GSK3β, and cyclin D1) in human DP cells. In contrast, inhibitors of Wnt/β-catenin signaling, endo-IWR1 and IWP2, attenuated the levels of cyclin D1, p-GSK3β, and β-catenin proteins induced by NTAPP. Furthermore, we observed that NTAPP induced the activation of β-catenin in DP cells of hair follicles and the mRNA levels of target genes of the β-catenin signaling pathway (CCND1, LEF1, and TCF4). NTAPP-treated mice exhibited markedly increased anagen induction, hair growth, and the protein levels of β-catenin, p-GSK3β, p-AKT, and cyclin D1. NTAPP stimulates hair growth via activation of the Wnt/β-catenin signaling pathway in DP cells. These findings collectively suggest that NTAPP may be a potentially safe and non-pharmacological therapeutic intervention for alopecia.
    DOI:  https://doi.org/10.1038/s41598-021-95650-y
  51. Stem Cell Res Ther. 2021 Aug 11. 12(1): 453
    A systematic summary of survival and death signalling during the life of hair follicle stem cells.
    Xi-Min Hu, Zhi-Xin Li, Dan-Yi Zhang, Yi-Chao Yang, Shen-Ao Fu, Zai-Qiu Zhang, Rong-Hua Yang, Kun Xiong.
      Hair follicle stem cells (HFSCs) are among the most widely available resources and most frequently approved model systems used for studying adult stem cells. HFSCs are particularly useful because of their self-renewal and differentiation properties. Additionally, the cyclic growth of hair follicles is driven by HFSCs. There are high expectations for the use of HFSCs as favourable systems for studying the molecular mechanisms that contribute to HFSC identification and can be applied to hair loss therapy, such as the activation or regeneration of hair follicles, and to the generation of hair using a tissue-engineering strategy. A variety of molecules are involved in the networks that critically regulate the fate of HFSCs, such as factors in hair follicle growth and development (in the Wnt pathway, Sonic hedgehog pathway, Notch pathway, and BMP pathway), and that suppress apoptotic cues (the apoptosis pathway). Here, we review the life cycle, biomarkers and functions of HFSCs, concluding with a summary of the signalling pathways involved in HFSC fate for promoting better understanding of the pathophysiological changes in the HFSC niche. Importantly, we highlight the potential mechanisms underlying the therapeutic targets involved in pathways associated with the treatment of hair loss and other disorders of skin and hair, including alopecia, skin cancer, skin inflammation, and skin wound healing.
    Keywords:  Apoptosis; BMP; Hair follicle stem cells (HFSCs); Notch; Shh; Signalling; Wnt
    DOI:  https://doi.org/10.1186/s13287-021-02527-y
  52. Nutr Cancer. 2021 Aug 11. 1-8
    Antibacterial, Antioxidant and Melanogenesis Inhibitory Activity of Auraptene, a Coumarin from Ferula szowitsiana Root.
    Ensiyeh Charmforoshan, Ehsan Karimi, Ehsan Oskoueian, Mehrdad Iranshahi.
      The auraptene is a geranyloxyn coumarin found in the Ferula species. The plant is endemic in Central Asia and it is used as a medicinal food in Iran. This research aimed to evaluate the antibacterial, antioxidant, and anti-melanogenic properties of auraptene, a coumarin from Ferula szowitsiana root. The results revealed that auraptene possessed antibacterial activity with minimum inhibitory and minimum bactericidal concentrations ranged from 2.5 up to 10 mg/ml against human pathogenic bacteria (Escherichia coli, Salmonella typhimurium, Salmonella paratyphi, Clostridium perfringens, Staphylococcus aureus). The nitric oxide scavenging activity (IC50: 670.9 µg/ml) showed its moderate antioxidant potential. Similarly, the results of ferric thiocyanate and thiobarbituric acid assays reconfirmed the moderate antioxidant activity of auraptene and indicated the percentage inhibitions of hydroxyl radicals to be 31.87 and 14%, respectively. The cell-based antioxidant evaluation confirmed the antioxidant activity of auraptene through up-regulation of the antioxidant-related genes including superoxide dismutase, catalase, and glutathione peroxidase in the human foreskin fibroblast (HFF). The auraptene has also displayed the anti-melanogenic activity through direct tyrosinase enzyme inhibition (IC50 of 29.7 µg/ml) and could modulate the expression of major melanogenesis-related genes including tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase in the murine melanoma cell line. The auraptene from Ferula szowitsiana root exhibited antibacterial, antioxidant, and melanogenesis inhibitory activities.
    DOI:  https://doi.org/10.1080/01635581.2021.1962922
  53. Dermatology. 2021 Aug 11. 1-6
    The Additive Value of 3D Total Body Imaging for Sequential Monitoring of Skin Lesions: A Case Series.
    Katarzyna Grochulska, Brigid Betz-Stablein, Chantal Rutjes, Frank Po-Chao Chiu, Scott W Menzies, H Peter Soyer, Monika Janda.
       BACKGROUND: Timely diagnosis is the cornerstone of melanoma morbidity and mortality reduction. 2D total body photography and dermoscopy are routinely used to assist with early detection of skin malignancies. Polarized 3D total body photography is a novel technique that enables fast image acquisition of almost the entire skin surface. We aimed to determine the added value of 3D total body photography alongside dermoscopy for monitoring cutaneous lesions.
    METHODS: Lesion images from high-risk individuals were assessed for long-term substantial changes via dermoscopy and 3D total body photography. Three case studies are presented demonstrating how 3D total body photography may enhance lesion analysis alongside traditional dermoscopy.
    RESULTS: 3D total body photography can assist clinicians by presenting cutaneous lesions in their skin ecosystem, thereby providing additional clinical context and enabling a more holistic assessment to aid dermoscopy interpretation. For lesion cases where previous dermoscopy is unavailable, corresponding 3D images can substitute for baseline dermoscopy. Additionally, 3D total body photography is not susceptible to artificial stretch artefacts.
    CONCLUSION: 3D total body photography is valuable alongside dermoscopy for monitoring cutaneous lesions. Furthermore, it is capable of surveilling almost the entire skin surface, including areas not traditionally monitored by sequential imaging.
    Keywords:  3D total body imaging; Digital dermoscopy; Early detection; Long-term monitoring; Melanoma
    DOI:  https://doi.org/10.1159/000517900
  54. Regen Ther. 2021 Dec;18 217-222
    Cultured epithelial autografts for the treatment of large-to-giant congenital melanocytic nevus in 31 patients.
    Naoki Morimoto, Toshihito Mitsui, Yasuhiro Katayama, Natsuko Kakudo, Shuichi Ogino, Itaru Tsuge, Michiharu Sakamoto, Masakatsu Hihara, Kenji Kusumoto.
       Introduction: Giant congenital melanocytic nevus (GCMN) is a large melanocytic nevus, and its full-thickness removal is usually difficult due to the lack of skin available for reconstruction. Curettage is an alternative approach in cases of GCMN to remove the superficial dermis above the cleavage plane with a curette in the neonatal period, and its major complications include repigmentation, retarded epithelization, and hypertrophic scar formation. In Japan, the JACE® cultured epidermal autograft (CEA) was approved and covered by public healthcare insurance for the treatment of congenital melanocytic nevus (CMN) that is difficult to treat with conventional methods in 2016. We have used CEA for wounds after curettage in the neonatal period or following ablation after the neonatal period in combination with laser therapies to reduce the above-mentioned complications.
    Methods: In this study, we summarized all consecutive CMN patients treated using CEA from December 2016 to April 2019 and evaluated the duration required for epithelialization, incidence of hypertrophic scar, and color change in the target nevus by comparing the L∗ values one year later between the Curettage group, the non-Curettage group with initial treatment or the subsequent group.
    Results: No significant differences were seen in the epithelization period or incidence of hypertrophic scars among the groups, but the color of the target nevus was improved significantly in the Curettage group (p < 0.01) and non-Curettage group with initial treatment (p < 0.01).
    Conclusions: In conclusion, CEA seems to accelerate epithelization after curettage or ablation of CMN, and this treatment could improve the color of CMN when applied initially.
    Keywords:  Cultured epithelial autograft; Curettage; Giant congenital melanocytic nevus; L∗a∗b∗ color space
    DOI:  https://doi.org/10.1016/j.reth.2021.07.001
  55. Cancer Biol Med. 2021 Aug 11. pii: j.issn.2095-3941.2021.0027. [Epub ahead of print]
    Cyclophosphamide abrogates the expansion of CD4+Foxp3+ regulatory T cells and enhances the efficacy of bleomycin in the treatment of mouse B16-F10 melanomas.
    Ping Li, Fengyang Chen, Jingbin Zheng, Yang Yang, Yuan Li, Yifei Wang, Xin Chen.
       OBJECTIVE: Promotion of the proliferative expansion of CD4+Foxp3+ regulatory T cells (Tregs) is one of the side effects that limits the use of bleomycin (BLM) in the treatment of tumors. In this study, we examined the hypothesis that cyclophosphamide (CY), a chemotherapeutic agent with the capacity to eliminate tumor infiltrating Tregs, abrogated BLM-induced expansion of Tregs and consequently resulted in a better anti-tumor effect.
    METHODS: The in vitro effects of BLM, with or without mafosfamide (MAF, the active metabolite of CY), on both TGF-β-induced differentiation of Tregs (iTregs), and TNF-induced expansion of naturally occurring Tregs (nTregs) were assessed. The in vivo effect of low doses of BLM and CY on tumor-infiltrating Tregs, as well as on the growth of mouse B16-F10 melanomas, was also studied.
    RESULTS: In vitro treatment with BLM promoted the differentiation of iTregs, as well as TNF-induced expansion of nTregs. These effects of BLM were completely abrogated by MAF. Furthermore, in the mouse B16-F10 melanoma model, treatment with low doses of BLM increased the number of tumor-infiltrating Tregs, and this effect of BLM was also abrogated by CY. Importantly, combination therapy with low doses of BLM and CY showed synergistic anti-tumor effects.
    CONCLUSIONS: CY abrogated the effect of BLM on the expansion of Tregs. The combination of these 2 chemotherapeutic agents may represent a safer and more effective therapy in the treatment of cancer patients, and thus merits future clinical evaluation.
    Keywords:  Bleomycin; TNFR2; Tregs; cyclophosphamide; tumor necrosis factor
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0027
  56. Dermatol Online J. 2021 Jun 15. 27(6):
    Acquired unilateral facial melanocytosis: nevus of Sun.
    Gianluca Nazzaro, Paolo Bortoluzzi, Serena Giacalone, Stefano Veraldi.
      Acquired dermal melanocytoses include pigmented lesions with a clear late onset, histologically characterized by the presence of melanocytes in the dermis. In this report, we describe a rare case of acquired unilateral facial melanocytosis, also called nevus of Sun, in a Caucasian woman.
    DOI:  https://doi.org/10.5070/D327654061
  57. Sci Rep. 2021 Aug 09. 11(1): 16488
    Author Correction: Long-term voluntary running prevents the onset of symptomatic Friedreich's ataxia in mice.
    Henan Zhao, Bevan M Lewellen, Rebecca J Wilson, Di Cui, Joshua C Drake, Mei Zhang, Zhen Yan.
      
    DOI:  https://doi.org/10.1038/s41598-021-96112-1
  58. Pharmaceutics. 2021 Jul 10. pii: 1059. [Epub ahead of print]13(7):
    Antimelanogenesis Effects of Leaf Extract and Phytochemicals from Ceylon Olive (Elaeocarpus serratus) in Zebrafish Model.
    Chi-Ya Huang, I-Hsuan Liu, Xiang-Zhe Huang, Hui-Jen Chen, Shang-Tzen Chang, Mei-Ling Chang, Yu-Tung Ho, Hui-Ting Chang.
      The melanogenesis inhibition effect in zebrafish (Danio rerio) and antityrosinase activity of the ethanolic extract and its phytochemicals from Ceylon olive (Elaeocarpus serratus Linn.) leaves were investigated in this study. Among the leaf extract and four soluble fractions, the ethyl acetate soluble fraction exhibits the best antityrosinase and antimelanogenesis activities. One phenolic acid, gallic acid, and two flavonoids, myricetin and mearnsetin, are isolated from the active subfractions through the bioassay-guided isolation; their structures are elucidated based on the 1D and 2D NMR, FTIR, UV, and MS spectroscopic analyses. These compounds have significant antityrosinase activity whether using l-tyrosine or l-DOPA as the substrate; mearnsetin shows the optimal activity. In the enzyme kinetic investigation, both gallic acid and mearnsetin are the competitive-type inhibitors against mushroom tyrosinase, and myricetin acts as a mixed-type tyrosinase inhibitor. Leaf extract and an ethyl acetate soluble fraction show effective performance in the inhibition of melanin formation in zebrafish embryos. Mearnsetin also possesses a promising antimelanogenesis effect, which is superior to the positive control, arbutin. Results reveal that the Ceylon olive leaf extract and its phytochemicals, especially mearnsetin, have the potential to be used as antimelanogenesis and skin-whitening ingredients.
    Keywords:  Elaeocarpus serratus; antimelanogenesis effect; melanin; tyrosinase inhibitor; zebrafish
    DOI:  https://doi.org/10.3390/pharmaceutics13071059
  59. Cell Prolif. 2021 Aug 12. e13106
    Amphiregulin promotes hair regeneration of skin-derived precursors via the PI3K and MAPK pathways.
    Qiumei Lu, Ying Gao, Zhimeng Fan, Xing Xiao, Yu Chen, Yuan Si, Deqiang Kong, Shuai Wang, Meijian Liao, Xiaodong Chen, Xusheng Wang, Weiwei Chu.
       OBJECTIVES: There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin-derived precursors (SKPs) exhibit great potential as stem cell-based therapies for hair regeneration; however, the proliferation and hair-inducing capacity of SKPs gradually decrease during culturing.
    MATERIALS AND METHODS: We describe a 3D co-culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki-67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small-interfering RNA silencing in vitro, as well as the evaluation of telogen-to-anagen transition and HF reconstitution in vivo.
    RESULTS: The 3D co-culture system revealed that epidermal stem cells and adipose-derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen-to-anagen transition and high-efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.
    CONCLUSIONS: By exploiting a 3D co-culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair-inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.
    Keywords:  3D co-culture system; MAPK; PI3K; amphiregulin; hair follicle; skin-derived precursors
    DOI:  https://doi.org/10.1111/cpr.13106
  60. J Dermatolog Treat. 2021 Aug 13. 1-21
    Fractional Erbium:YAG Laser (2940 nm) plus Topical Hydroquinone Compared to Intradermal Tranexamic Acid plus Topical Hydroquinone for the Treatment of Refractory Melasma: A Randomized Controlled Trial.
    Fatemeh Mokhtari, Bahareh Bahrami, Gita Faghihi, Ali Asilian, Fariba Iraji.
       OBJECTIVES: Melasma is a chronic acquired condition characterized by grayish-brown macules and patches with a distinct border on the face. Although various treatments methods have been suggested for treating melasma, none has been completely successful. The aim of the study was to compare the efficiency of erbium: yttrium-aluminum-garnet (Er:YAG) laser and 4% hydroquinone (HQ) with the effects of intradermal tranexamic acid (TA) and 4% HQ for the treatment of refractory melasma.
    METHODS: The study included 31 female patients with refractory melasma. The left or right side of the patient's face was chosen randomly to receive laser therapy with topical HQ on the one side (i.e., the laser side) and intradermal injection of TA plus topical HQ on the other side (i.e., the mesotherapy side). Digital photography was performed at baseline, at the end of the treatment, and three months after the treatment as follow-up. Two independent dermatologists evaluated the modified Melasma Area and Severity Index (mMASI) score according to the pictures. Overall, 27 patients completed the study and went through the clinical evaluation.
    RESULTS: Treatment using HQ in combination with either Er:YAG laser therapy or intradermal injection of TA significantly improved the hemi-mMASI and resulted in higher patient satisfaction. While the improvement was not significantly different between the two regiments after the treatment and upon follow up and both were equally efficient in the treatment of refractory melasma (p = 1.308), recurrence rate was higher after treatment with Er:YAG laser than TA (12% vs 34%).
    CONCLUSION: This study confirmed the comparable efficacy of TA plus topical HQ versus Er:YAG laser plus topical HQ for the treatment of refractory melasma. Both groups improved significantly and no subject left the treatment because of adverse effects.
    Keywords:  erbium YAG laser; melasma; tranexamic acid
    DOI:  https://doi.org/10.1080/09546634.2021.1968996
  61. Sci Total Environ. 2021 Oct 10. pii: S0048-9697(21)03200-9. [Epub ahead of print]790 148129
    Environmental impacts of COVID-19 treatment: Toxicological evaluation of azithromycin and hydroxychloroquine in adult zebrafish.
    Juliana Moreira Mendonça-Gomes, Amanda Pereira da Costa Araújo, Thiarlen Marinho da Luz, Ives Charlie-Silva, Helyson Lucas Bezerra Braz, Roberta Jeane Bezerra Jorge, Mohamed Ahmed Ibrahim Ahmed, Rafael Henrique Nóbrega, Christoph F A Vogel, Guilherme Malafaia.
      One of the most impact issues in recent years refers to the COVID-19 pandemic, the consequences of which thousands of deaths recorded worldwide, are still inferior understood. Its impacts on the environment and aquatic biota constitute a fertile field of investigation. Thus, to predict the impact of the indiscriminate use of azithromycin (AZT) and hydroxychloroquine (HCQ) in this pandemic context, we aim to assess their toxicological risks when isolated or in combination, using zebrafish (Danio rerio) as a model system. In summary, we observed that 72 h of exposure to AZT and HCQ (alone or in binary combination, both at 2.5 μg/L) induced the reduction of total protein levels, accompanied by increased levels of thiobarbituric acid reactive substances, hydrogen peroxide, reactive oxygen species and nitrite, suggesting a REDOX imbalance and possible oxidative stress. Molecular docking analysis further supported this data by demonstrating a strong affinity of AZT and HCQ with their potential antioxidant targets (catalase and superoxide dismutase). In the protein-protein interaction network analysis, AZT showed a putative interaction with different cytochrome P450 molecules, while HCQ demonstrated interaction with caspase-3. The functional enrichment analysis also demonstrated diverse biological processes and molecular mechanisms related to the maintenance of REDOX homeostasis. Moreover, we also demonstrated an increase in the AChE activity followed by a reduction in the neuromasts of the head when zebrafish were exposed to the mixture AZT + HCQ. These data suggest a neurotoxic effect of the drugs. Altogether, our study demonstrated that short exposure to AZT, HCQ or their mixture induced physiological alterations in adult zebrafish. These effects can compromise the health of these animals, suggesting that the increase of AZT and HCQ due to COVID-19 pandemic can negatively impact freshwater ecosystems.
    Keywords:  Antibiotic; Antimalarial; Danio rerio; Ecotoxicity; SARs-Cov-2; Water pollution
    DOI:  https://doi.org/10.1016/j.scitotenv.2021.148129
  62. Protoplasma. 2021 Aug 12.
    Black is beautiful (and protective): melanin synthesis in animals and plants.
    Peter Nick.
      
    DOI:  https://doi.org/10.1007/s00709-021-01693-3
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