bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021‒09‒12
74 papers selected by
Farah Jaber-Hijazi
University of the West of Scotland
  1. Protective Effect of Genistein on Cyclin D1 Expression in Malignant Ocular Melanoma Cells.
  2. Reflex Molecular Testing in Melanoma Diagnosis: When Should BRAF Mutation Testing Be Ordered and Who Should Order It?
  3. Melanoma in Pregnancy and Pediatrics.
  4. Melanoma Risk Factors and Prevention.
  5. Quantitative proteomic analysis uncovers inhibition of melanin synthesis by silk fibroin via MITF/tyrosinase axis in B16 melanoma cells.
  6. Activin A sustains the metastatic phenotype of tumor associated macrophages and is a prognostic marker in human cutaneous melanoma.
  7. Histopathologic and Molecular Diagnosis of Melanoma.
  8. Adjuvant immunotherapy recommendations for stage III melanoma: physician and nurse interviews.
  9. Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry.
  10. Diagnostic and prognostic value of Beclin 1 expression in melanoma: a meta-analysis.
  11. Non-Operative Options for Loco-regional Melanoma.
  12. Lentigo Maligna.
  13. Radiation Therapy for Local Cutaneous Melanoma.
  14. Acetate decreases PVR/CD155 expression via PI3K/AKT pathway in cancer cells.
  15. Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways.
  16. Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.
  17. Melanoma cells adopt features of both mesenchymal and amoeboid migration within confining channels.
  18. Intracranial Treatment in Melanoma Patients with Brain Metastasis Is Associated with Improved Survival in the Era of Immunotherapy and Anti-BRAF Therapy.
  19. Canonical Signaling Pathways in Melanoma.
  20. Integrative Analysis of Minichromosome Maintenance Proteins and Their Prognostic Significance in Melanoma.
  21. Podoplanin drives dedifferentiation and amoeboid invasion of melanoma.
  22. An Oncolytic Coxsackievirus Causes Melanoma Regression with Few Adverse Events.
  23. The long non-coding RNA SAMMSON is essential for uveal melanoma cell survival.
  24. Case report of a primary subcutaneous melanoma; a surprising entity for a subcutaneous nodule.
  25. H2AFZ: A Novel Prognostic Marker in Canine Melanoma and a Predictive Marker for Resistance to CDK4/6 Inhibitor Treatment.
  26. Malignant melanoma of the prostate gland: A systematic review.
  27. Salicylic acid in ginseng root alleviates skin hyperpigmentation disorders by inhibiting melanogenesis and melanosome transport.
  28. Emerging Therapies in the Treatment of Advanced Melanoma.
  29. Adjuvant and Neoadjuvant Therapeutics for the Treatment of Cutaneous Melanoma.
  30. Spitz Nevus: Review and Update.
  31. LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma.
  32. 18F-BMS986192 PET imaging of PD-L1 in metastatic melanoma patients with brain metastases treated with immune checkpoint inhibitors. A pilot study.
  33. Extirpative Considerations of Melanoma of the Head and Neck.
  34. Proposed Quality Performance Indicators (QPI's) for axillary lymphadenectomy in metastatic cutaneous melanoma.
  35. Incorporating clinical knowledge with constrained classifier chain into a multimodal deep network for melanoma detection.
  36. Immunobiology of Melanoma.
  37. Neratinib kills B-RAF V600E melanoma via ROS-dependent autophagosome formation and death receptor signaling.
  38. ZnO nanoparticles stimulate oxidative stress to induce apoptosis of B16F10 melanoma cells：In vitro and in vivo studies.
  39. Metformin pretreatment reduces effect to dacarbazine and suppresses melanoma cell resistance.
  40. Targeting cyclin-dependent kinase 4/6 as a therapeutic approach for mucosal melanoma.
  41. Melanoma of the Hands and Feet (With Reconstruction).
  42. Assessment of early metabolic progression in melanoma patients under immunotherapy: an 18F-FDG PET/CT study.
  43. A Comprehensive Evaluation and Benchmarking of Convolutional Neural Networks for Melanoma Diagnosis.
  44. Cationic Liposome Decorated with Cyclic RGD Peptide for Targeted Delivery of anti-STAT3 siRNA to Melanoma Cancer Cells.
  45. A Melanoma Update.
  46. Primary Melanoma Characteristics of Metastatic Disease: A Nationwide Cancer Registry Study.
  47. Evaluation of eye melanoma treatments in rabbits: A systematic review.
  48. Validation of the Relationship Between Iris Color and Uveal Melanoma Using Artificial Intelligence With Multiple Paths in a Large Chinese Population.
  49. Unraveling the Relevance of ARL GTPases in Cutaneous Melanoma Prognosis through Integrated Bioinformatics Analysis.
  50. Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1/5 signaling pathway.
  51. [Updated Molecular Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells].
  52. Broad-Spectrum Antibiotic Use and Disease Progression in Early-Stage Melanoma Patients: A Retrospective Cohort Study.
  53. Quality of life and treatment-related burden during ocular proton therapy: a prospective trial of 131 patients with uveal melanoma.
  54. Dermoscopy revealing an amelanotic subungual melanoma masked as contact dermatitis.
  55. Trigeminal Metastasis of Malignant Melanoma: Clinical, Neuroradiological, and Pathological Features. A Case Report.
  56. Toxicity of carbon ion radiotherapy and immune checkpoint inhibitors in advanced melanoma.
  57. Blockade of TGF-βR improves the efficacy of doxorubicin by modulating the tumor cell motility and affecting the immune cells in a melanoma model.
  58. Anti-Cancer Effects of Cyclic Peptide ALOS4 in a Human Melanoma Mouse Model.
  59. Autoimmunity in vitiligo: Therapeutic implications and opportunities.
  60. HMB45/PRAME, a Novel Double Staining for the Diagnosis of Melanocytic Neoplasms: Technical Aspects, Results, and Comparison With Other Commercially Available Staining (PRAME and Melan A/PRAME).
  61. Upregulation of miR-29c-3p Hinders Melanoma Progression by Inhibiting CDCA4 Expression.
  62. Human amniotic stem cells-derived exosmal miR-181a-5p and miR-199a inhibit melanogenesis and promote melanosome degradation in skin hyperpigmentation, respectively.
  63. Novel strategy for applying hierarchical density-based spatial clustering of applications with noise towards spectroscopic analysis and detection of melanocytic lesions.
  64. Circadian disruption induced by tumor development in a murine model of melanoma.
  65. Clotrimazole presents anticancer properties against a mouse melanoma model acting as a PI3K inhibitor and inducing repolarization of tumor-associated macrophages.
  66. CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma.
  67. Pro-pigmentary action of 5-fluorouracil through the stimulated secretion of CXCL12 by dermal fibroblasts.
  68. [Update of the diagnosis and treatment of anti-melanoma differentiation associated gene-5 related rapid progressive interstitial lung disease].
  69. Vitiligo, alkaptonuria, and nitisinone-A report of three families and review of the literature.
  70. Identification of HIF-1α/VEGFA signaling pathway and transcription factors in Kashin-Beck disease by integrated bioinformatics analysis.
  71. Skin Cancers and the Contribution of Rho GTPase Signaling Networks to Their Progression.
  72. Characterization of Multiple Diagnostic Terms in Melanocytic Skin Lesion Pathology Reports.
  73. Developmental genetics of color pattern establishment in cats.
  74. Rolled Hairs in Two Cases of Naevus Comedonicus of the Scalp.
  1. Med Arch. 2021 Jun;75(3): 180-183
    Protective Effect of Genistein on Cyclin D1 Expression in Malignant Ocular Melanoma Cells.
    Yasmin Sani Aprilliantina, Hera Dwi Novita, Elfina G Sadono, Rosy Aldina.
      Background: Ocular melanoma is a disorder that is rarely found but is deadly. Four tissues in the eye that can be attacked by melanoma include the uveal tract, conjunctiva, eyelids, and orbit. Uveal melanoma is the most common case, while melanoma conjunctiva is very rare.Objective: This study aimed to investigate the effect of giving genistein on cyclin D1 expression in malignant melanoma.
    Methods: When confluent, CRL1872 malignant melanoma cells will be divided into treatment groups, the group giving genistein dose 25 μM, the group giving genistein a dose of 50 μM, and the group giving genistein a dose of 100 μM. Cyclin D1 analysis was measured by immunofluorescence using confocal laser scan microscopy.
    Results: There was a significant increase in the expression of cyclin D1, in the group given genistein 25 μM and 50 μM (p < 0.05). For the administration of the genistein dose of 100 μM, cyclin D1 expression decreased significantly compared to the control group (p < 0.05).
    Conclusion: It was concluded that genistein had a biphasic effect on cyclin D1 expression in malignant melanoma cells. Thus, genistein at the right dose can be a treatment of malignant melanoma.
    Keywords:  biphasic effect; chemotherapy; ocular melanoma; soybeans
    DOI:  https://doi.org/10.5455/medarh.2021.75.180-183
  2. J Cutan Med Surg. 2021 Sep 08. 12034754211045380
    Reflex Molecular Testing in Melanoma Diagnosis: When Should BRAF Mutation Testing Be Ordered and Who Should Order It?
    Sarah Zhou, Sriraam Sivachandran, Daniel Sikorski, Hong Hao Xu, François Lagacé, Joël Claveau, Thomas G Salopek, Robert Gniadecki, Ivan V Litvinov.
      
    Keywords:  BRAF inhibitor; BRAF mutation; MAPK pathway; advanced melanoma; metastatic melanoma; reflex testing; stage II; targeted therapy
    DOI:  https://doi.org/10.1177/12034754211045380
  3. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00063-8. [Epub ahead of print]48(4): 699-705
    Melanoma in Pregnancy and Pediatrics.
    Michael R Romanelli, Alaa Mansour, Allyne Topaz, Danielle Olla, Michael W Neumeister.
      Rare variants of melanoma include melanoma in pregnancy and pediatric melanoma. Because of their low incidence, treatment recommendations are based on standards of treatment for cutaneous melanoma; however, each of these forms requires specific considerations during diagnosis, staging, and treatment.
    Keywords:  Melanoma; Pediatric melanoma; Pediatrics; Pregnancy; Pregnancy-associated melanoma
    DOI:  https://doi.org/10.1016/j.cps.2021.06.004
  4. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00048-1. [Epub ahead of print]48(4): 543-550
    Melanoma Risk Factors and Prevention.
    William W Dzwierzynski.
      In the Western population, 1 out of every 50 individuals will develop melanoma. The incidence of melanoma is increasing faster than any other malignancy. The development of melanoma is multifactorial arising from an interaction between genetic susceptibility and environmental exposures. Sixty to seventy percent of melanomas are thought to be caused by ultraviolet radiation. Most cutaneous melanomas are of increased risk. Prevention strategies involve mitigating the environmental risk factors and identifying individuals with phenotypic risk factors for increased surveillance.
    Keywords:  Melanoma; Prevention; Risk factors; UV radiation
    DOI:  https://doi.org/10.1016/j.cps.2021.05.001
  5. Life Sci. 2021 Sep 01. pii: S0024-3205(21)00917-6. [Epub ahead of print] 119930
    Quantitative proteomic analysis uncovers inhibition of melanin synthesis by silk fibroin via MITF/tyrosinase axis in B16 melanoma cells.
    Yuqiu Wang, Tianbi Duan, Minhua Hong, Yanting Zhou, Hui Huang, Xiao Xiao, Jing Zheng, Hu Zhou, Zhi Lu.
      AIMS: Silk fibroin (SF), a natural product from silkworms, has been used to promote anti-inflammation, induce wound healing, and reduce melanin production. However, the underlying regulatory mechanism of SF on melanin production remains unknown. The aim of this study was to investigate the distinct regulatory mechanism of SF in B16 melanoma cells by applying quantitative proteomic approach.MATERIALS AND METHODS: B16 melanoma cells were treated with PBS, KA or SF for 48 h, respectively. Cell viability, melanin content, and tyrosinase activity were examined. A label-free quantitative proteomic approach was utilized to investigate the regulatory mechanism of SF. The differentially expressed proteins and their related biological processes were subsequently identified by bioinformatics methods. Furthermore, the identified differentially expressed proteins were validated by western blot.
    KEY FINDINGS: Both SF and KA were able to suppress the melanin synthesis of B16 melanoma cells without appreciable toxicity; yet, SF had a distinct effect on mushroom tyrosinase activity in vitro. Moreover, quantitative proteomic approach identified 141 proteins differentially expressed only in SF/Con group. Bioinformatic analysis of these proteins revealed that oxidation-reduction process, RNA processing, fatty acid degradation, as well as melanin biosynthetic process were enriched with SF treatment. The proteins associated with melanin biosynthetic process, including microphthalmia-associated transcription factor (MITF) and tyrosinase, were down-regulated in SF group, which was confirmed by western blot.
    SIGNIFICANCE: SF inhibited melanin synthesis in B16 melanoma cells via down-regulation of MITF and tyrosinase expression, which provides a rationale for future utilization of SF.
    Keywords:  Melanin; Microphthalmia-associated transcription factor; Quantitative proteomics; Silk fibroin; Tyrosinase
    DOI:  https://doi.org/10.1016/j.lfs.2021.119930
  6. J Invest Dermatol. 2021 Sep 06. pii: S0022-202X(21)02171-0. [Epub ahead of print]
    Activin A sustains the metastatic phenotype of tumor associated macrophages and is a prognostic marker in human cutaneous melanoma.
    Alba Gutiérrez-Seijo, Elena García-Martínez, Celia Barrio-Alonso, Verónica Parra-Blanco, José Antonio Avilés-Izquierdo, Paloma Sánchez-Mateos, Rafael Samaniego.
      Tumor cells attract and dynamically interact with monocytes/macrophages to subvert their differentiation into tumor associated macrophages (TAMs), which mainly promote immune suppression and neoplastic progression, but the pathways and microenvironmental cues governing their protumoral deviation are not completely understood. To identify molecular pathways responsible for TAM differentiation we screened biomarkers secreted during melanoma-macrophage interactions using Quantibody® microarrays and RNAseq of macrophages. We found that Activin A, a member of the transforming growth factor family, plays an instrumental role in the crosstalk between melanoma cells and monocytes/macrophages, which results in the upregulation of distinct tumor-sustaining genes and the achievement of pro-invasive and immunosuppressive functions of TAMs. Blockade of Activin declines the upregulation of part of these genes and prevents the acquisition of protumoral functions, facilitating human melanoma rejection by transferred human lymphocytes in a xenograft mouse model. Remarkably, screening of two independent cutaneous primary melanoma collections showed that Activin A is enriched in TAMs and melanoma cells from patients with worse outcome and constitutes a new and independent prognostic marker. Thus, we identify Activin A as a key intermediary in the protumoral and immunosuppressive functions of TAMs, with significant potential as a disease biomarker as well as an immunotherapeutic target.
    Keywords:  Activin; macrophage; melanoma; prognostic-marker; tumor-microenvironment
    DOI:  https://doi.org/10.1016/j.jid.2021.07.179
  7. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00050-X. [Epub ahead of print]48(4): 587-598
    Histopathologic and Molecular Diagnosis of Melanoma.
    Morgan L Wilson.
      Conventional histopathology is the primary means of melanoma diagnosis. Both architectural and cytologic features aid in discrimination of melanocytic nevi from melanoma. Communication between the clinician and pathologist regarding the history, examination, differential diagnosis, prior biopsy findings, method of sampling, and specimen orientation is critical to an accurate diagnosis. A melanoma pathology report includes multiple prognostic indicators to guide surgical and medical management. In challenging cases, immunohistochemistry and molecular diagnostics may be of benefit.
    Keywords:  Diagnosis; Histopathology; Melanoma; Pathology; Plastic surgery; Report
    DOI:  https://doi.org/10.1016/j.cps.2021.05.003
  8. BMC Cancer. 2021 Sep 10. 21(1): 1014
    Adjuvant immunotherapy recommendations for stage III melanoma: physician and nurse interviews.
    Ann Livingstone, Kathy Dempsey, Martin R Stockler, Kirsten Howard, Georgina V Long, Matteo S Carlino, Alexander M Menzies, Rachael L Morton.
      BACKGROUND: Adjuvant immunotherapy is revolutionising care for patients with resected stage III and IV melanoma. However, immunotherapy may be associated with toxicity, making treatment decisions complicated. This study aimed to identify factors physicians and nurses considered regarding adjuvant immunotherapy for melanoma.METHODS: In-depth interviews were conducted with physicians (medical oncologists, surgeons and dermatologists) and nurses managing patients with resected stage III melanoma at three Australian tertiary melanoma centres between July 2019 and March 2020. Factors considered regarding adjuvant immunotherapy were explored. Recruitment continued until data saturation and thematic analysis was undertaken.
    RESULTS: Twenty-five physicians and nurses, aged 28-68 years, 60% females, including eleven (44%) medical oncologists, eight (32%) surgeons, five (20%) nurses, and one (4%) dermatologist were interviewed. Over half the sample managed five or more new resected stage III patients per month who could be eligible for adjuvant immunotherapy. Three themes about adjuvant immunotherapy recommendations emerged: [1] clinical and patient factors, [2] treatment information provision, and [3] individual physician/nurse factors. Melanoma sub-stage and an individual patient's therapy risk/benefit profile were primary considerations. Secondary factors included uncertainty about adjuvant immunotherapy's effectiveness and their views about treatment burden patients might consider acceptable.
    CONCLUSIONS: Patients' disease sub-stage and their treatment risk versus benefit drove the melanoma health care professionals' adjuvant immunotherapy endorsement. Findings clarify clinician preferences and values, aiding clinical communication with patients and facilitating clinical decision-making about management options for resected stage III melanoma.
    Keywords:  Decision making; Immunotherapy; Interviews; Melanoma; Nurse clinicians; Physicians; Professional role; Surgeons
    DOI:  https://doi.org/10.1186/s12885-021-08752-1
  9. Int J Mol Sci. 2021 Sep 03. pii: 9556. [Epub ahead of print]22(17):
    Metastatic Melanoma Progression Is Associated with Endothelial Nitric Oxide Synthase Uncoupling Induced by Loss of eNOS:BH4 Stoichiometry.
    Fabiana Henriques Machado de Melo, Diego Assis Gonçalves, Ricardo Xisto de Sousa, Marcelo Yudi Icimoto, Denise de Castro Fernandes, Francisco R M Laurindo, Miriam Galvonas Jasiulionis.
      Melanoma is the most aggressive type of skin cancer due to its high capability of developing metastasis and acquiring chemoresistance. Altered redox homeostasis induced by increased reactive oxygen species is associated with melanomagenesis through modulation of redox signaling pathways. Dysfunctional endothelial nitric oxide synthase (eNOS) produces superoxide anion (O2-•) and contributes to the establishment of a pro-oxidant environment in melanoma. Although decreased tetrahydrobiopterin (BH4) bioavailability is associated with eNOS uncoupling in endothelial and human melanoma cells, in the present work we show that eNOS uncoupling in metastatic melanoma cells expressing the genes from de novo biopterin synthesis pathway Gch1, Pts, and Spr, and high BH4 concentration and BH4:BH2 ratio. Western blot analysis showed increased expression of Nos3, altering the stoichiometry balance between eNOS and BH4, contributing to NOS uncoupling. Both treatment with L-sepiapterin and eNOS downregulation induced increased nitric oxide (NO) and decreased O2• levels, triggering NOS coupling and reducing cell growth and resistance to anoikis and dacarbazine chemotherapy. Moreover, restoration of eNOS activity impaired tumor growth in vivo. Finally, NOS3 expression was found to be increased in human metastatic melanoma samples compared with the primary site. eNOS dysfunction may be an important mechanism supporting metastatic melanoma growth and hence a potential target for therapy.
    Keywords:  L-sepiapterin; eNOS uncoupling; eNOS:BH4 stoichiometry; metastatic melanoma; tetrahydrobiopterin
    DOI:  https://doi.org/10.3390/ijms22179556
  10. Melanoma Res. 2021 Sep 07.
    Diagnostic and prognostic value of Beclin 1 expression in melanoma: a meta-analysis.
    Meiling Chen, Qian Li, Weimin Chen, Jiarui Bi, Ping Huang.
      Autophagy plays a complicated role in the occurrence and development of cancer. Beclin 1 is a significant autophagy-related protein that plays an essential role in tumorigenesis, but its expression is controversial in melanoma. In this meta-analysis, we searched seven studies involving 638 melanoma patients. PubMed, Web of Science, Google Scholar, Elsevier, and Chinese National Knowledge Infrastructure were used for literature retrieval. The I2 index was used to assess heterogeneity. The expression of Beclin 1 in the primary melanoma group was significantly lower than the non-tumor group tissues (P < 0.01), while higher than the metastatic melanoma group (P < 0.01). Beclin 1 expression status could not distinguish between patients with melanoma by sex (male vs. female), lymph node metastasis (metastasis vs. non-metastasis), melanin deposition (present vs. absent), ulcer formation (present vs. absent), tumor necrosis status (present vs. absent), and Breslow thickness (<1.5 mm vs. ≥1.5 mm) for the subgroups (all P values > 0.05). Different expression intensities of Beclin 1 did not affect the overall survival and disease-free survival of melanoma patients. This study showed a trend of low expression of Beclin 1 in melanoma; patients with low expression of Beclin 1 were prone to the possibility of distant metastasis. The inconsistent profile of Beclin 1 expression in the prognosis of melanoma patients warrants further clinical investigation.
    DOI:  https://doi.org/10.1097/CMR.0000000000000780
  11. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00054-7. [Epub ahead of print]48(4): 631-642
    Non-Operative Options for Loco-regional Melanoma.
    Rebecca Knackstedt, Timothy Smile, Jennifer Yu, Brian R Gastman.
      Malignant melanoma is the 5th most common cancer and stage IV melanoma accounts for approximately 4% of new melanoma diagnoses in the United States. The prognosis for regionally advanced disease is poor, but there have been numerous recent advances in the medical management of melanoma in-transit metastases. The goal of this paper is to review currently accepted treatment options for in-transit metastases and introduce emerging therapies. Therapies to be discussed include limb perfusion and infusion, immunotherapy, checkpoint inhibitors, and radiation therapy.
    Keywords:  Checkpoint inhibitors; Immunotherapy; Injectable therapy; Melanoma; Radiation therapy
    DOI:  https://doi.org/10.1016/j.cps.2021.05.007
  12. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00066-3. [Epub ahead of print]48(4): 669-675
    Lentigo Maligna.
    Jacob D Franke, Katlyn M Woolford, Michael W Neumeister.
      Lentigo maligna (LM) is a melanocytic neoplasm found on chronically sun-exposed areas of the body, particularly the head and neck. It commonly occurs in the elderly and has been referred to as a "senile freckle." It has also been termed "Hutchinson melanotic freckle," as it was first described by John Hutchinson in 1892. LM is defined as melanoma in situ and thus confined to the epidermis. LM lesions that invade the dermis are termed lentigo maligna melanoma, 1 of the 4 subtypes of malignant melanoma.
    Keywords:  Lentigo Maligna; Lentigo Maligna Melanoma; Melanoma in situ
    DOI:  https://doi.org/10.1016/j.cps.2021.06.007
  13. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00055-9. [Epub ahead of print]48(4): 643-649
    Radiation Therapy for Local Cutaneous Melanoma.
    Parinaz J Dabestani, Amanda J Dawson, Michael W Neumeister, C Matthew Bradbury.
      While primary treatment for melanoma consists of surgical resection and chemotherapeutics, radiation can be used as either definitive or adjuvant therapy in certain clinical scenarios. This chapter aims to explore the indications for primary definitive radiotherapy as well as adjuvant treatment following resection. Delivery, dose, fractionation, and toxicity of radiation treatment will be discussed. As our understanding of melanoma tumor biology increases, the role of radiotherapy may expand for more effective treatment of oligometastatic disease.
    Keywords:  Adjuvant radiotherapy; Cutaneous melanoma; Definitive radiotherapy; Lentigo maligna; Radiation
    DOI:  https://doi.org/10.1016/j.cps.2021.05.008
  14. BMB Rep. 2021 Sep 07. pii: 5319. [Epub ahead of print]
    Acetate decreases PVR/CD155 expression via PI3K/AKT pathway in cancer cells.
    Bok-Soon Lee, Sung Un Kang, Mei Huang, Yeon Soo Kim, Young-Sun Lee, Jae-Yong Park, Chul-Ho Kim.
      Melanoma, the most serious type of skin cancer, exhibits a high risk of metastasis. Although chemotherapeutic treatment for metastatic melanoma improves disease outcome and patient survival, some patients exhibit resistance or toxicity to the drug treatment regime. OTUB1 is a deubiquitinating enzyme overexpressed in several cancers. In this study, we investigated the effects of inhibiting OTUB1 expression on melanoma-cell proliferation and viability and identified the underlying molecular mechanism of action of OTUB1. We did endogenous OTUB1 knockdown in melanoma cells using short interfering RNA, and assessed the resulting phenotypes via MTT assays, Western blotting, and cell-cycle analysis. We identified differentially expressed genes between OTUB1-knockdown cells and control cells using RNA sequencing and confirmed them via Western blotting and reverse transcription polymerase chain reaction. Furthermore, we investigated the involvement of apoptotic and cell survival signaling pathways upon OTUB1 depletion. OTUB1 depletion in melanoma cells decreased cell viability and caused simultaneous accumulation of cells in the sub-G1 phase, indicating an increase in the apoptotic-cell population. RNA sequencing of OTUB1-knockdown cells revealed an increase in the levels of the apoptosis-inducing protein TRAIL. Additionally, OTUB1-knockdown cells exhibited increased sensitivity to PLX4032, a BRAF inhibitor, implying that OTUB1 and BRAF act collectively in regulating apoptosis. Taken together, our findings show that OTUB1 induces apoptosis of melanoma cells in vitro, likely by upregulating TRAIL, and suggest that approaches targeting OTUB1 can be developed to provide novel therapeutic strategies for treating melanoma.
  15. Cancers (Basel). 2021 Aug 24. pii: 4250. [Epub ahead of print]13(17):
    Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways.
    Antonio Ahn, Euan J Rodger, Jyoti Motwani, Gregory Gimenez, Peter A Stockwell, Matthew Parry, Peter Hersey, Aniruddha Chatterjee, Michael R Eccles.
      Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated transcriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumour necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression.
    Keywords:  LncRNA; PD-L1; RNA-Seq; dedifferentiation; drug resistance; gene expression; immunotherapy resistance; melanoma; transcriptome
    DOI:  https://doi.org/10.3390/cancers13174250
  16. Expert Rev Precis Med Drug Dev. 2021 ;6(4): 281-294
    Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.
    Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B Johnson, Jeffrey A Sosman.
      Introduction: NRAS was the first mutated oncogene identified in melanoma and is currently the second most common driver mutation in this malignancy. For patients with NRASmutant advanced stage melanoma refractory to immunotherapy or with contraindications to immune-based regimens, there are few therapeutic options including low-efficacy chemotherapy regimens and binimetinib monotherapy. Here, we review recent advances in preclinical studies of molecular targets for NRAS mutant melanoma as well as the failures and successes of early-phase clinical trials. While there are no targeted therapies for NRAS-driven melanoma, there is great promise in approaches combining MEK inhibition with inhibitors of the focal adhesion kinase (FAK), inhibitors of autophagy pathways, and pan-RAF inhibitors.Areas Covered: This review surveys new developments in all aspects of disease pathogenesis and potential treatment - including those that have failed, stalled, or progressed through various phases of preclinical and clinical development.
    Expert Opinion: There are no currently approved targeted therapies for BRAF wild-type melanoma patients harboring NRAS driver mutations though an array of agents are in early phase clinical trials. The diverse strategies taken exploit combined MAP kinase signaling blockade with inhibition of cell cycle mediators, inhibition of the autophagy pathway, and alteration of kinases involved in actin cytoskeleton signaling. Future advances of developmental therapeutics into late stage trials may yield new options beyond immunotherapy for patients with advanced stage disease and NRAS mutation status.
    Keywords:  NRAS; clinical trials; drug development; genomics; melanocyte; melanoma; molecular genetics; oncology; pharmacology; precision medicine; targeted therapies; tumor biology
    DOI:  https://doi.org/10.1080/23808993.2021.1938545
  17. Sci Rep. 2021 Sep 07. 11(1): 17804
    Melanoma cells adopt features of both mesenchymal and amoeboid migration within confining channels.
    Sairisheel R Gabbireddy, Karl W Vosatka, Aram J Chung, Jeremy S Logue.
      For metastasis to occur, cancer cells must traverse a range of tissue environments. In part, this is accomplished by cells adjusting their migration mode to one that is best suited to the environment. Melanoma cells have been shown to be particularly plastic, frequently using both mesenchymal and amoeboid (bleb-based) modes of migration. It has been demonstrated that 2D confinement will promote the transition from mesenchymal to bleb-based migration. However, if melanoma cells similarly transition to bleb-based migration in response to 3D confinement, such as within narrow channels, is unknown. Here, using micro-fabricated channels, we demonstrate that metastatic, A375-M2, melanoma cells adopt features of both mesenchymal and bleb-based migration. In narrow (8 µm; height and width) channels coated with fibronectin, ~ 50% of melanoma cells were found to use either mesenchymal or bleb-based migration modes. In contrast, the inhibition of Src family kinases or coating channels with BSA, completely eliminated any features of mesenchymal migration. Detailed comparisons of migration parameters revealed that blebbing cells, particularly in the absence of adhesions, were faster than mesenchymal cells. In contrast to what has been previously shown under conditions of 2D confinement, pharmacologically inhibiting Arp2/3 promoted a fast filopodial-based mode of migration. Accordingly, we report that melanoma cells adopt a unique range of phenotypes under conditions of 3D confinement.
    DOI:  https://doi.org/10.1038/s41598-021-97348-7
  18. Cancers (Basel). 2021 Sep 06. pii: 4493. [Epub ahead of print]13(17):
    Intracranial Treatment in Melanoma Patients with Brain Metastasis Is Associated with Improved Survival in the Era of Immunotherapy and Anti-BRAF Therapy.
    Céline Dalmasso, Cécile Pagès, Léonor Chaltiel, Vincent Sibaud, Elisabeth Moyal, Ciprian Chira, Jean Christophe Sol, Igor Latorzeff, Nicolas Meyer, Anouchka Modesto.
      Metastatic melanoma patients are at high risk of brain metastases (BM). Although intracranial control is a prognostic factor for survival, impact of local (intracranial) treatment (LT), surgery and/or radiotherapy (stereotactic or whole brain) in the era of novel therapies remains unknown. We evaluated BM incidence in melanoma patients receiving immune checkpoint inhibitors (ICI) or anti-BRAF therapy and identified prognostic factors for overall survival (OS). Clinical data and treatment patterns were retrospectively collected from all patients treated for newly diagnosed locally advanced or metastatic melanoma between May 2014 and December 2017 with available BRAF mutation status and receiving systemic therapy. Prognostic factors for OS were analyzed with univariable and multivariable survival analyses. BMs occurred in 106 of 250 eligible patients (42.4%), 64 of whom received LT. Median OS in patients with BM was 7.8 months (95% CI [5.4-10.4]). In multivariable analyses, LT was significantly correlated with improved OS (HR 0.21, p < 0.01). Median OS was 17.3 months (95% CI [8.3-22.3]) versus 3.6 months (95% CI [1.4-4.8]) in patients with or without LT. LT correlates with improved OS in melanoma patients with BM in the era of ICI and anti-BRAF therapy. The use of LT should be addressed at diagnosis of BM while introducing systemic treatment.
    Keywords:  anti-BRAF therapy; anti-PD-1; brain metastases; immunotherapy; intracranial treatment; melanoma; stereotactic radiation therapy
    DOI:  https://doi.org/10.3390/cancers13174493
  19. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00049-3. [Epub ahead of print]48(4): 551-560
    Canonical Signaling Pathways in Melanoma.
    Lillian Sun, Joshua Arbesman.
      Melanoma is the most lethal type of skin cancer, originating from the uncontrolled proliferation of melanocytes. The transformation of normal melanocytes into malignant tumor cells has been a focus of research seeking to better understand melanoma's pathogenesis and develop new therapeutic targets. Over the past few decades, a conglomeration of studies has pinpointed several driver mutations and their associated signaling pathways. In this review, we summarize the key signaling pathways and the driver mutations involved in melanoma tumorigenesis and also discuss the potential underlying mechanisms.
    Keywords:  Drug targets; Melanoma; Mutations; Signaling pathways; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.cps.2021.05.002
  20. Front Oncol. 2021 ;11 715173
    Integrative Analysis of Minichromosome Maintenance Proteins and Their Prognostic Significance in Melanoma.
    Wei Han, Yi-Zhu Wu, Xiao-Yu Zhao, Zhen-Hua Gong, Guo-Liang Shen.
      Background: Minichromosome maintenance (MCM) is known for participating in cell cycle progression, as well as DNA replication. While the diverse expression patterns and prognostic values of MCMs in melanoma still remained unclear.Methods: In the present study, the transcriptional and clinical profiles of MCMs were explored in patients with melanoma from multiple databases, including GEO, TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, and TIMER databases.
    Results: We found that the elevated expressions of MCM2-6 and MCM10 were significantly expressed in melanoma compared to normal skin. High mRNA levels of MCM4, MCM5, and MCM10 were closely related to worse prognosis in patients with melanoma. GSEA showed hallmark pathways were most involved in mTORC1 signaling, G2M checkpoint, E2F targets, and mitotic spindle. Furthermore, we found potential correlations between the MCM expression and the immune cell infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells.
    Conclusion: Upregulated MCM gene expression in melanoma probably played a crucial part in the development and progression of melanoma. The upregulated MCM4/5/10 expressions could be used as potential prognostic markers to improve the poor outcome and prognostic accuracy in patients with melanoma. Our study might shed light on the selection of prognostic biomarkers as well as the underlying molecular pathogenesis of melanoma.
    Keywords:  TCGA; bioinformatics; melanoma; minichromosome maintenance; prognosis
    DOI:  https://doi.org/10.3389/fonc.2021.715173
  21. iScience. 2021 Sep 24. 24(9): 102976
    Podoplanin drives dedifferentiation and amoeboid invasion of melanoma.
    Charlotte M de Winde, Samantha L George, Eva Crosas-Molist, Yukti Hari-Gupta, Abbey B Arp, Agnesska C Benjamin, Lindsey J Millward, Spyridon Makris, Alexander Carver, Valerio Imperatore, Víctor G Martínez, Victoria Sanz-Moreno, Sophie E Acton.
      Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. Melanoma cells utilize amoeboid migration as mode of local invasion. Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by Rho GTPase signalling. Migrastatic drugs targeting actin polymerization and contractility are therefore a promising treatment option for metastatic melanoma. To predict amoeboid invasion and metastatic potential, biomarkers functionally linked to contractility pathways are needed. The glycoprotein podoplanin drives actomyosin contractility in lymphoid fibroblasts and is overexpressed in many cancers. We show that podoplanin enhances amoeboid invasion in melanoma. Podoplanin expression in murine melanoma drives rounded cell morphology, increasing motility, and invasion in vivo. Podoplanin expression is increased in a subset of dedifferentiated human melanoma, and in vitro is sufficient to upregulate melanoma-associated marker Pou3f2/Brn2. Together, our data define podoplanin as a functional biomarker for dedifferentiated invasive melanoma and a promising migrastatic therapeutic target.
    Keywords:  Cell biology; Molecular biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2021.102976
  22. Cancer Discov. 2021 Sep 10.
    An Oncolytic Coxsackievirus Causes Melanoma Regression with Few Adverse Events.
      Median overall survival was 26.7 months in patients who received 80% or more of scheduled injections.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-129
  23. Oncogene. 2021 Sep 10.
    The long non-coding RNA SAMMSON is essential for uveal melanoma cell survival.
    Shanna Dewaele, Louis Delhaye, Boel De Paepe, Eric James de Bony, Jilke De Wilde, Katrien Vanderheyden, Jasper Anckaert, Nurten Yigit, Justine Nuytens, Eveline Vanden Eynde, Joél Smet, Maxime Verschoore, Fariba Nemati, Didier Decaudin, Manuel Rodrigues, Peihua Zhao, Aart Jochemsen, Eleonora Leucci, Jo Vandesompele, Jo Van Dorpe, Jean-Christophe Marine, Rudy Van Coster, Sven Eyckerman, Pieter Mestdagh.
      Long non-coding RNAs (lncRNAs) can exhibit cell-type and cancer-type specific expression profiles, making them highly attractive as therapeutic targets. Pan-cancer RNA sequencing data revealed broad expression of the SAMMSON lncRNA in uveal melanoma (UM), the most common primary intraocular malignancy in adults. Currently, there are no effective treatments for UM patients with metastatic disease, resulting in a median survival time of 6-12 months. We aimed to investigate the therapeutic potential of SAMMSON inhibition in UM. Antisense oligonucleotide (ASO)-mediated SAMMSON inhibition impaired the growth and viability of a genetically diverse panel of uveal melanoma cell lines. These effects were accompanied by an induction of apoptosis and were recapitulated in two uveal melanoma patient derived xenograft (PDX) models through subcutaneous ASO delivery. SAMMSON pulldown revealed several candidate interaction partners, including various proteins involved in mitochondrial translation. Consequently, inhibition of SAMMSON impaired global, mitochondrial and cytosolic protein translation levels and mitochondrial function in uveal melanoma cells. The present study demonstrates that SAMMSON expression is essential for uveal melanoma cell survival. ASO-mediated silencing of SAMMSON may provide an effective treatment strategy to treat primary and metastatic uveal melanoma patients.
    DOI:  https://doi.org/10.1038/s41388-021-02006-x
  24. Int J Surg Case Rep. 2021 Aug 31. pii: S2210-2612(21)00861-0. [Epub ahead of print]86 106359
    Case report of a primary subcutaneous melanoma; a surprising entity for a subcutaneous nodule.
    E Jutten, M F Lutke Holzik, A Baidoshvili, R R Dulfer.
      INTRODUCTION: A melanoma can originate at the subcutis without any visible skin lesion.CASE PRESENTATION: A 73-year old patient came to the outpatient clinic with a subcutaneous nodule on the right thigh without any visible lesion of the skin. It turned out to be a primary subcutaneous melanoma that could be classified as a primary dermal melanoma (PDM).
    DISCUSSION: A PDM is a very rare subtype of melanoma that stands out for its excellent prognosis in comparison to cutaneous melanomas. No valid reliable staging system or treatment guideline exists for this entity, Breslow depth might overestimate the clinical aggressiveness possibly leading to overtreatment.
    CONCLUSION: It is of great importance for the clinician to be familiar with a primary dermal melanoma. It deserves an appropriate place in the current AJCC system and a treatment guideline for this unique melanoma subtype with relativity excellent prognosis would be beneficial.
    Keywords:  Case report; PDM; Primary dermal melanoma; Subcutaneous melanoma
    DOI:  https://doi.org/10.1016/j.ijscr.2021.106359
  25. Front Vet Sci. 2021 ;8 705359
    H2AFZ: A Novel Prognostic Marker in Canine Melanoma and a Predictive Marker for Resistance to CDK4/6 Inhibitor Treatment.
    Laura Bongiovanni, Anneloes Andriessen, Serenella Silvestri, Ilaria Porcellato, Chiara Brachelente, Alain de Bruin.
      Uncontrolled proliferation is a key feature of tumor progression and malignancy. This suggests that cell-cycle related factors could be exploited as cancer biomarkers and that pathways specifically involved in the cell cycle, such as the Rb-E2F pathway, could be targeted as an effective anti-tumor therapy. We investigated 34 formalin-fixed paraffin-embedded (FFPE) tissue samples of canine cutaneous melanocytoma, cutaneous melanoma, and oral melanoma. Corresponding clinical follow-up data were used to determine the prognostic value of the mRNA expression levels of several cell cycle regulated E2F target genes (E2F1, DHFR, CDC6, ATAD2, MCM2, H2AFZ, GINS2, and survivin/BIRC5). Moreover, using four canine melanoma cell lines, we explored the possibility of blocking the Rb-E2F pathway by using a CDK4/6 inhibitor (Palbociclib) as a potential anti-cancer therapy. We investigated the expression levels of the same E2F target gene transcripts before and after treatment to determine the potential utility of these molecules as predictive markers. The E2F target gene H2AFZ was expressed in 91.43% of the primary tumors and H2AFZ expression was significantly higher in cases with unfavorable clinical outcome. Among the other tested genes, survivin/BIRC5 showed as well-promising results as a prognostic marker in canine melanoma. Three of the four tested melanoma cell lines were sensitive to the CDK4/6 inhibitor. The resistant cell line displayed higher expression levels of H2AFZ before treatment compared to the CDK4/6 inhibitor-sensitive cell lines. The present results suggest that CDK4/6 inhibitors could potentially be used as a new anti-cancer treatment for canine melanoma and that H2AFZ could serve as a prognostic and predictive marker for patient selection.
    Keywords:  CDK4/6 inhibitor; E2F target genes; cancer biomarker; dog; melanoma
    DOI:  https://doi.org/10.3389/fvets.2021.705359
  26. Pathol Res Pract. 2021 Aug 24. pii: S0344-0338(21)00255-7. [Epub ahead of print]226 153594
    Malignant melanoma of the prostate gland: A systematic review.
    Alessandro Caputo, Maria Addesso, Pio Zeppa, Antonio D'Antonio.
      AIMS: Prostatic melanoma is a rare malignancy about which only scattered case reports and no systematic reviews have been published to date. We sought to better inform clinicians and pathologists caring for these patients by gathering all available evidence on the topic.METHODS: We performed a systematic review of English and non-English articles indexed in PubMed, EMBASE, Scopus and Google Scholar about primary and metastatic prostatic melanoma.
    RESULTS: In total, 25 studies describing 45 cases were identified. Most cases were metastases to the prostate, with only 10 primary prostatic cases. The median age of patients was 61 years with a wide range, and 89% were symptomatic at presentation, most commonly with obstructive symptoms (83%). Diagnosis requires histopathological analysis and often immunohistochemistry. Metastatic melanoma in the prostate carries a dismal prognosis with median overall survival of 3 months; on the other hand, among primary prostatic melanomas reported in the literature, 29% survived longer than 5 years. The most reasonable therapeutic approach consists in radical surgery possibly followed by adjuvant therapy.
    Keywords:  Diagnosis; Melanin; Melanoma; Pigment; Prostate; Review
    DOI:  https://doi.org/10.1016/j.prp.2021.153594
  27. Eur J Pharmacol. 2021 Sep 01. pii: S0014-2999(21)00612-9. [Epub ahead of print] 174458
    Salicylic acid in ginseng root alleviates skin hyperpigmentation disorders by inhibiting melanogenesis and melanosome transport.
    Jianzeng Liu, Rui Jiang, Jingyuan Zhou, Xiaohao Xu, Zhuo Sun, Jing Li, Xuenan Chen, Zhenzhuo Li, Xiuci Yan, Daqing Zhao, Zemiao Zheng, Liwei Sun.
      Abnormal melanogenesis and melanosome transport can cause skin pigmentation disorders that are often treated using ginseng-based formulation. We previously found that phenolic acid compounds in ginseng root could inhibit melanin production and as a skin-whitening agents. However, mechanisms of action underlying effects of ginseng phenolic acid monomers on melanogenesis remain unclear. This study was conducted to investigate effects of salicylic acid, a main ginseng root phenolic acid component, on melanogenesis and melanosome functions in melanocytes of zebrafish and other species. Salicylic acid exhibited no cytotoxicity and reduced melanin levels and tyrosinase activity in B16F10 murine melanoma cells and normal human epidermal melanocytes regardless of prior cell stimulation with α-melanocyte stimulating hormone. Additionally, salicylic acid treatment reduced expression of melanogenic enzymes tyrosinase, tyrosinase-related protein 1 and tyrosinase-related protein 2, while reducing expression of their master transcriptional regulator, microphthalmia-associated transcription factor. Moreover, reduced phosphorylation of cAMP response-element binding protein was observed due to reduced cAMP levels resulting from salicylic acid inhibition of upstream signal regulators (adenylyl cyclase and protein kinase A). Furthermore, salicylic acid treatment suppressed expression of transport complex-associated proteins melanophilin and myosin Va in two UVB-treated melanocytic cell lines, suppressed phagocytosis of fluorescent microspheres by UVB-stimulated human keratinocytes (HaCaT), inhibited protease-activated receptor 2 activation by reducing both Ca2+ release and activation of phosphoinositide 3 kinase/AKT and mitogen-activated protein kinases and induced anti-melanogenic effects in zebrafish. Collectively, these results indicate that salicylic acid within ginseng root can inhibit melanocyte melanogenesis and melanin transport, while also suppressing keratinocyte phagocytic function.
    Keywords:  Ginseng roots; Melanogenesis; Melanosome transport; Pigmentation; Salicylic acid
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174458
  28. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00067-5. [Epub ahead of print]48(4): 713-733
    Emerging Therapies in the Treatment of Advanced Melanoma.
    Sameer Massand, Rogerio I Neves.
      Great strides in immunotherapy and targeted therapy have revolutionized the management of previously devastating, advanced melanomas. Although these subfields continue to progress, novel approaches in intratumoral oncolytic therapy, adoptive cell therapy, and vaccine therapies are being developed as adjuncts or alternatives. Cytokines, meanwhile, are seeing a resurgence as a viable option as well. The array of effective agents will, in the next few years, provide options for therapy not only in the adjuvant or unresectable settings but also in the neoadjuvant settings. Perhaps, too, in earlier stage melanomas.
    Keywords:  Clinical trials; Emerging therapies; Oncolytic therapy; Vaccine therapy
    DOI:  https://doi.org/10.1016/j.cps.2021.06.008
  29. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00060-2. [Epub ahead of print]48(4): 651-658
    Adjuvant and Neoadjuvant Therapeutics for the Treatment of Cutaneous Melanoma.
    William J Bruce, Jessie L Koljonen, Michael R Romanelli, Aziz U Khan, Michael W Neumeister.
      Adjuvant therapy plays an integral role in the treatment algorithm for stage III and stage IV cutaneous melanoma. Current ongoing clinical trials are exploring the effects of neoadjuvant therapeutics, specifically for the presurgical treatment of high-risk, borderline resectable disease. In both the adjuvant and neoadjuvant settings, the early chemotherapeutic and biochemical antitumor agents are making way to newer immune therapies, mutation-specific targeted therapies, and oncolytic vaccines that are transforming the treatment of malignant melanoma. The use of these systemic therapies in addition to surgical resection has been shown to increase both overall and progression-free survival.
    Keywords:  Adjuvant; Cancer vaccines; Chemotherapy; Immunotherapy; Melanoma; Neoadjuvant; Targeted therapy
    DOI:  https://doi.org/10.1016/j.cps.2021.06.001
  30. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00061-4. [Epub ahead of print]48(4): 677-686
    Spitz Nevus: Review and Update.
    Amanda Brown, Justin D Sawyer, Michael W Neumeister.
      The Spitz nevus is an uncommon melanocytic nevus. These lesions classically appear in childhood as a red, dome-shaped papule. They appear rarely in adults and may be pigmented. The Spitz nevus can develop suddenly and grow rapidly, reaching a 1-cm diameter in 6 months or less. There are 3 classes of spitzoid neoplasms: typical Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. The diagnosis should be cautiously differentiated, especially in children. Immunohistochemistry and molecular studies have been helpful in differentiating difficult cases; however, no set of criteria has been accepted to predict biological behavior of atypical Spitz nevi.
    Keywords:  Atypical Spitz nevus; Juvenile melanoma; Skin neoplasm; Spindle and epithelioid cell nevus; Spitz nevus; Spitz tumor; Spitzoid lesion; Spitzoid melanoma
    DOI:  https://doi.org/10.1016/j.cps.2021.06.002
  31. Cancers (Basel). 2021 Sep 03. pii: 4445. [Epub ahead of print]13(17):
    LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma.
    Zahra Souri, Annemijn P A Wierenga, Wilma G M Kroes, Pieter A van der Velden, Robert M Verdijk, Michael Eikmans, Gregorius P M Luyten, Martine J Jager.
      Uveal melanoma (UM) is a rare ocular malignancy which originates in the uveal tract, and often gives rise to metastases. Potential targets for immune checkpoint inhibition are lymphocyte-activation gene 3 (LAG3) and its ligands. We set out to analyse the distribution of these molecules in UM. The expression of mRNA was determined using an Illumina array in 64 primary UM from Leiden. The T lymphocyte fraction was determined by digital droplet PCR. In a second cohort of 15 cases from Leiden, mRNA expression was studied by Fluidigm qPCR, while a third cohort consisted of 80 UM from TCGA. In the first Leiden cohort, LAG3 expression was associated with the presence of epithelioid cells (p = 0.002), monosomy of chromosome 3 (p = 0.004), and loss of BAP1 staining (p = 0.001). In this Leiden cohort as well as in the TCGA cohort, LAG3 expression correlated positively with the expression of its ligands: LSECtin, Galectin-3, and the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP (all p < 0.001). Furthermore, ligands Galectin-3 and HLA class II were increased in monosomy 3 tumours and the expression of LAG3 correlated with the presence of an inflammatory phenotype (T cell fraction, macrophages, HLA-A and HLA-B expression: all p < 0.001). High expression levels of LAG3 (p = 0.01), Galectin-3 (p = 0.001), HLA-DRA1 (p = 0.002), HLA-DQA1 (p = 0.04), HLA-DQB2 (p = 0.03), and HLA-DPA1 (p = 0.007) were associated with bad survival. We conclude that expression of the LAG ligands Galectin-3 and HLA class II strongly correlates with LAG3 expression and all are increased in UM with Monosomy 3/BAP1 loss. The distribution suggests a potential benefit of monoclonal antibodies against LAG3 or Galectin-3 as adjuvant treatment in patients with high-risk UM.
    Keywords:  Galectin-3; LAG3; immunotherapy; inflammation; metastasis; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13174445
  32. J Nucl Med. 2021 Sep 09. pii: jnumed.121.262368. [Epub ahead of print]
    18F-BMS986192 PET imaging of PD-L1 in metastatic melanoma patients with brain metastases treated with immune checkpoint inhibitors. A pilot study.
    Pieter H Nienhuis, Ines F Antunes, Andor W J M Glaudemans, Mathilde Jalving, David Leung, Walter Noordzij, Riemer H J A Slart, Erik F de Vries, Geke A P Hospers.
      Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 frequently induces tumor response in metastatic melanoma patients. However, tumor response often takes months and may be heterogeneous. Consequently, additional local treatment for non-responsive metastases may be needed, especially in the case of brain metastases. Non-invasive imaging may allow the characterization of (brain) metastases to predict response. This pilot study uses 18F-BMS986192 PET for PD-L1 expression to explore the variability in metastatic tracer uptake and its relation to tumor response, with a special focus on brain metastases. Methods: Metastatic melanoma patients underwent whole-body 18F-BMS986192 PET/CT scanning before and 6 weeks after starting ICI therapy. 18F-BMS986192 uptake was measured in healthy tissues, organs, and tumor lesions. Tumor response was evaluated at 12 weeks using CT thorax/abdomen and MRI brain. RECIST v 1.1 was used to define therapy response per patient. Response per lesion was measured by the percentage change in lesion diameter. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Results: Baseline 18F-BMS986192 PET/CT was performed in 8 patients, with follow-up scans in 4 patients. The highest tracer uptake was observed in the spleen, bone marrow, kidneys, and liver. Tracer uptake in tumor lesions was heterogeneous. In total, 42 tumor lesions were identified at baseline with most lesions in the lungs (n = 21) and brain (n = 14). Tracer uptake was similar between tumor locations. 18F-BMS986192 uptake in lesions at baseline, corrected for blood pool activity, was negatively correlated with the change lesion diameter at response evaluation (r=-0.49, P = 0.005), both in intra- and extracerebral lesions. Receiver operating characteristic (ROC) analysis demonstrated that 18F-BMS986192 uptake can discriminate between responding and nonresponding lesions with an area under the curve of 0.82. At the follow-up scan an increased 18F-BMS986192 uptake compared to baseline scan was correlated with an increased lesion diameter at response evaluation. In the follow-up 18F-BMS986192-PET scan of two patients, ICI-related toxicity (thyroiditis and colitis) was detected. Conclusion: In this pilot study, 18F-BMS986192 PET showed heterogeneous uptake in intra and extracerebral metastatic lesions in melanoma patients. Baseline 18F-BMS986192 uptake was able to predict an ICI treatment-induced reduction in lesion volume, whereas the follow-up PET scan allowed the detection of treatment-induced toxicity.
    Keywords:  Brain Metastasis; Immune Checkpoint Inhibition; Metastatic Melanoma; Molecular Imaging; Oncology: Melanoma; PD-L1 Expression; PET/CT; Positron Emission Tomography
    DOI:  https://doi.org/10.2967/jnumed.121.262368
  33. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00062-6. [Epub ahead of print]48(4): 659-668
    Extirpative Considerations of Melanoma of the Head and Neck.
    Danielle Olla, Anthony P Tufaro, Michael W Neumeister.
      The incidence of melanoma is continuing to rise in the United States, and head and neck melanomas account for 25% of all cutaneous melanomas. The National Comprehensive Cancer Network guideline recommendations for surgical margins and sentinel lymph node biopsy in head and neck melanomas are the same as cutaneous melanoma located in other regions, but require special considerations when performing wide local excision, sentinel lymph node biopsy, and completion lymph node dissection and reconstruction taking into account the location of the melanoma and structures involved in and around the suggested margins.
    Keywords:  Head and neck; Head and neck melanoma; Melanoma; Sentinel lymph node biopsy; Surgical considerations; Surgical management
    DOI:  https://doi.org/10.1016/j.cps.2021.06.003
  34. Eur J Surg Oncol. 2021 Aug 03. pii: S0748-7983(21)00652-1. [Epub ahead of print]
    Proposed Quality Performance Indicators (QPI's) for axillary lymphadenectomy in metastatic cutaneous melanoma.
    Sita Ollek, Daniel Wen, Ian Ong, William Anderson, Richard Harman, Richard Martin.
      INTRODUCTION: Axillary lymph node clearance (ALNC) continues to play a central role in the management of melanoma. However, what defines an adequate lymphadenectomy remains unclear. We aimed to propose Quality Performance Indicators (QPIs) for ALNC and to determine if the number of lymph nodes (LNs) removed impacts survival.METHODS: We reviewed patients who underwent ALNC for melanoma at the Waitemata District Health Board and Melanoma Unit between February 2005 and October 2019, performed by two surgeons with standardized technique and surveillance.
    RESULTS: 105 patients with stage III melanoma were included, of which 73 had clinically evident disease and 32 had clinically occult disease. The mean total number of LNs excised was 29 (SD 10.90, range 10-76). On multivariate analysis, lymph node ratio (HR 4.48, 95% CI 1.55-12.93, p = 0.006), extracapsular spread (HR 2.53, 95% CI 1.06-6.05, p = 0.036) and distant recurrence (HR 11.24, 95% CI 3.79-33.31, p < 0.001) were significant predictors of mortality. The number of LNs removed did not predict survival outcomes, while the lymph node ratio did significantly predict survival outcomes. The regional recurrence rate was 3.8%.
    DISCUSSION: We propose that QPIs for ALNC in melanoma include a 90th percentile LN yield of greater than 15, a mean LN yield of 20, a regional recurrence rate of less than 10%, and an overall complication rate of less than 50%.
    CONCLUSION: The establishment of QPIs can help ensure that surgical oncology patients receive the highest quality of care.
    Keywords:  Axillary lymph node clearance; Lymph nodes; Melanoma; Quality performance
    DOI:  https://doi.org/10.1016/j.ejso.2021.07.030
  35. Comput Biol Med. 2021 Aug 28. pii: S0010-4825(21)00606-5. [Epub ahead of print]137 104812
    Incorporating clinical knowledge with constrained classifier chain into a multimodal deep network for melanoma detection.
    Yuheng Wang, Jiayue Cai, Daniel C Louie, Z Jane Wang, Tim K Lee.
      In recent years, vast developments in Computer-Aided Diagnosis (CAD) for skin diseases have generated much interest from clinicians and other eventual end-users of this technology. Introducing clinical domain knowledge to these machine learning strategies can help dispel the black box nature of these tools, strengthening clinician trust. Clinical domain knowledge also provides new information channels which can improve CAD diagnostic performance. In this paper, we propose a novel framework for malignant melanoma (MM) detection by fusing clinical images and dermoscopic images. The proposed method combines a multi-labeled deep feature extractor and clinically constrained classifier chain (CC). This allows the 7-point checklist, a clinician diagnostic algorithm, to be included in the decision level while maintaining the clinical importance of the major and minor criteria in the checklist. Our proposed framework achieved an average accuracy of 81.3% for detecting all criteria and melanoma when testing on a publicly available 7-point checklist dataset. This is the highest reported results, outperforming state-of-the-art methods in the literature by 6.4% or more. Analyses also show that the proposed system surpasses the single modality system of using either clinical images or dermoscopic images alone and the systems without adopting the approach of multi-label and clinically constrained classifier chain. Our carefully designed system demonstrates a substantial improvement over melanoma detection. By keeping the familiar major and minor criteria of the 7-point checklist and their corresponding weights, the proposed system may be more accepted by physicians as a human-interpretable CAD tool for automated melanoma detection.
    Keywords:  7-Point checklist; Constrained classifier chain; Melanoma detection; Multi-modality
    DOI:  https://doi.org/10.1016/j.compbiomed.2021.104812
  36. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00064-X. [Epub ahead of print]48(4): 561-576
    Immunobiology of Melanoma.
    Yee Peng Phoon, Charles Tannenbaum, C Marcela Diaz-Montero.
      Despite the ability of immune-based interventions to dramatically increase the survival of patients with melanoma, a significant subset fail to benefit from this treatment, underscoring the need for accurate means to identify the patient population likely to respond to immunotherapy. Understanding how melanoma evades natural or manipulated immune responses could provide the information needed to identify such resistant individuals. Efforts to address this challenge are hampered by the vast immune diversity characterizing tumor microenvironments that remain largely understudied. It is thus important to more clearly elucidate the complex interactions that take place between the tumor microenvironment and host immune system.
    Keywords:  Immunoediting; Immunosuppression; Immunosurveillance; Melanoma
    DOI:  https://doi.org/10.1016/j.cps.2021.06.005
  37. Pigment Cell Melanoma Res. 2021 Sep 04.
    Neratinib kills B-RAF V600E melanoma via ROS-dependent autophagosome formation and death receptor signaling.
    Paul Dent, Laurence Booth, Andrew Poklepovic, John M Kirkwood.
      Melanoma cells expressing mutant B-RAF V600E are susceptible to treatment with the combination of a B-RAF inhibitor and a MEK1/2 inhibitor. We investigated the impact of the ERBB family and MAP4K inhibitor neratinib on the biology of PDX isolates of cutaneous melanoma expressing B-RAF V600E. Neratinib synergized with HDAC inhibitors to kill melanoma cells at their physiologic concentrations. Neratinib activated ATM, AMPK, ULK1, and PERK and inactivated mTORC1/2, ERK1/2, eIF2 alpha, and STAT3. Neratinib increased expression of Beclin1, ATG5, CD95, and FAS-L and decreased levels of multiple toxic BH3 domain proteins, MCL1, BCL-XL, FLIP-s, and ERBB1/2/4. ATG13 S318 phosphorylation and autophagosome formation was dependent upon ATM, and activation of ATM was dependent on reactive oxygen species. Reduced expression of ERBB1/2/4 required autophagosome formation and reduced MCL1/BCL-XL levels required eIF2 alpha phosphorylation. Maximal levels of eIF2 alpha phosphorylation required signaling by ATM-AMPK and autophagosome formation. Knock down of eIF2 alpha, CD95, FAS-L, Beclin1, and ATG5 or over-expression of FLIP-s significantly reduced killing. Combined knock down of Beclin1 and CD95 abolished cell death. Our data demonstrate that PDX melanoma cells expressing B-RAF V600E are susceptible to being killed by neratinib and more so when combined with HDACi.
    Keywords:  B-RAF; CD95; HDAC inhibitor; autophagy; endoplasmic reticulum (ER) stress; neratinib
    DOI:  https://doi.org/10.1111/pcmr.13014
  38. Biomed Phys Eng Express. 2021 Sep 09.
    ZnO nanoparticles stimulate oxidative stress to induce apoptosis of B16F10 melanoma cells：In vitro and in vivo studies.
    Ping Fan, Congling Yang, Li Wang, Qiling Wang, Yan Zhang, Jie Zhou, Jie Weng, Bo Feng.
      Melanoma is one of the most aggressive skin cancers. However, there remain many limitations in the current clinical treatments of it. Zinc oxide nanoparticles (ZnO NPs) have been considered to be a promising antitumor drug due to their excellent biocompatibility, biodegradability and biofunctionality. In this study, we prepared spherical ZnO NPs with an average diameter of less than 10 nm by a simple chemical method. According to thein vitrocytotoxicity assay, ZnO NPs in a certain concentration range (20-35 μg/mL) showed significant cytotoxicity to B16F10 melanoma cells, while having little effect on the viability of 3T3L1 fibroblasts. When cultured with B16F10 melanoma cells, ZnO NPs induced the generation of reactive oxygen and mitochondrial superoxide through the release of Zn2+, leading to oxidative stress in the cells, further reducing the mitochondrial membrane potential and decreasing the number of mitochondrial cristae. Furthermore, damaged mitochondria induced the release of apoptosis factors to promote cell apoptosis. FITC-Annexin V/propidium iodide double staining assay was used to analyze different apoptosis stages of B16F10 cells induced by ZnO NPs. A polymer hydrogel (Gel-F127-ZnO NPs) with Pluronic F127 as the carrier of ZnO NPs was fabricated for evaluating the antitumor effect of ZnO NPsin vivo. Thein vivoexperiment indicated that the tumor recurrence was significantly inhibited in tumor-bearing mice after treated with Gel-F127-ZnO NPs. Conclusively, ZnO NPs showed a strong antitumor effect bothin vitroandin vivo.
    Keywords:  Antitumor; Apoptosis; Melanoma; Mitochondrial; ZnO nanoparticles
    DOI:  https://doi.org/10.1088/2057-1976/ac251f
  39. Cell Biol Int. 2021 Sep 10.
    Metformin pretreatment reduces effect to dacarbazine and suppresses melanoma cell resistance.
    Larissa Juliani Sanches, Poliana Camila Marinello, Walison Augusto da Silva Brito, Natália Medeiros Dias Lopes, Rodrigo Cabral Luiz, Rubens Cecchini, Alessandra Lourenço Cecchini.
      Oxidative stress role on Metformin process of dacarbazine (DTIC) inducing resistance of B16F10 melanoma murine cells are investigated. To induce resistance to DTIC, murine melanoma cells were exposed to increasing concentrations of dacarabazine (DTIC-res group). Metformin was administered before and during the induction of resistance to DTIC (MET-DTIC). The oxidative stress parameters of DTIC-res group showed increased levels of malondialdehyde (MDA), thiol and reduced nuclear p53, 8-hydroxy-2'-deoxyguanosine (8-OH-DG), NF-ĸB and Nrf2. In presence of metformin in the resistant induction process to DTIC, (MET-DTIC) cells had increased antioxidant thiols, MDA, nuclear p53, 8-OH-DG, Nrf2 and reducing NF-ĸB, weakening the DTIC-resistant phenotype. The exclusive administration of metformin (MET group) also induced the cellular resistance to DTIC. The MET group presented high levels of total thiols, MDA, and reduced percentage of nuclear p53. It also presented reduced nuclear 8-OH-DG, NF-ĸB and Nrf2 when compared to the control. Oxidative stress and the studied biomarkers seem to be part of the alterations evidenced in DTIC-resistant B16F10 cells In addition, metformin administration is able to play a dual role according to the experimental protocol, preventing or inducing a DTIC-resistant phenotype. These findings should help future research with the aim of investigating DTIC resistance in melanoma. This article is protected by copyright. All rights reserved.
    Keywords:  B16F10; Nrf2; adjuvant therapy.; chemoresistance; p53
    DOI:  https://doi.org/10.1002/cbin.11700
  40. Melanoma Res. 2021 Sep 03.
    Targeting cyclin-dependent kinase 4/6 as a therapeutic approach for mucosal melanoma.
    Chao-Ji Shi, Sheng-Ming Xu, Yong Han, Rong Zhou, Zhi-Yuan Zhang.
      Mucosal melanoma is a rare but devastating subtype of melanoma which typically has a worse prognosis than other melanoma subtypes. Large-scale next-generation sequencing studies, including our recent research, have also proved that the molecular landscape and potential oncogenic drivers of mucosal melanoma remain distinct from that of cutaneous melanoma. Recently, a number of selective cyclin-dependent kinase 4 (CDK4)/6 inhibitors have been approved for clinical application in breast cancer or entered phase III clinical trial in other solid tumors. Additionally, we have revealed that the dysregulation of cell cycle progression, caused by CDK4 amplification, is a key genetic feature in half of mucosal melanoma and targeting of CDK4 in selected mucosal melanoma patients is a potentially promising direction for precision cancer treatment by using molecular-characterized mucosal melanoma patient-derived-xenograft models. This review summarizes the current literature regarding CDK4/6 dysregulation in mucosal melanoma, preclinical and clinical studies of CDK4/6 inhibitors and potential combinational strategies in treating mucosal melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000777
  41. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00056-0. [Epub ahead of print]48(4): 687-698
    Melanoma of the Hands and Feet (With Reconstruction).
    Alexis M Ruffolo, Ashwath J Sampath, Jeffrey H Kozlow, Michael W Neumeister.
      Melanomas only account for 4% of all dermatologic cancers yet are responsible for 80% of deaths. Notably, melanomas of the hand and foot have a worse prognosis when compared with melanomas of other anatomic regions. Likely this is due to intrinsic biologic characteristics, delayed diagnosis, difficult surgical excision due to delicate anatomy, and lack of definitive diagnostic and therapeutic guidelines. The most common locations of melanoma of the hand, in order of decreasing frequency, are subungual area, dorsal surface, and palmar surface. The most common locations of melanoma of the foot are the plantar surface, dorsal surface, and subungual area, in decreasing frequency. Diagnosis of melanoma of the hand and foot can be difficult because the traditional "ABCDE" (asymmetric shape, border, color, diameter, evolution) rules do not apply. Newer acronyms have been proposed in literature including "CUBED" (colored, uncertain, bleeding, enlarged, delayed) and "ABC rule for Subungual Melanoma." Once diagnosed, treatment is primarily surgical excision and reconstruction. The goal for the surgeon is to maintain the function and anatomy of the hand or foot.
    Keywords:  Melanoma; Reconstruction; Subungual melanoma
    DOI:  https://doi.org/10.1016/j.cps.2021.05.009
  42. EJNMMI Res. 2021 Sep 08. 11(1): 89
    Assessment of early metabolic progression in melanoma patients under immunotherapy: an 18F-FDG PET/CT study.
    Christos Sachpekidis, Annette Kopp-Schneider, Jessica C Hassel, Antonia Dimitrakopoulou-Strauss.
      BACKGROUND: The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs.METHODS: Thirty-one patients under ICIs serially monitored with 18F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs' cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLRmean, SLRmax) of 18F-FDG uptake were measured.
    RESULTS: Median follow up was 69.7 months [64.6-NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD (n = 26) had a median OS of 10.9 months [8.5-NA], while those with pseudoprogression (n = 5) did not reach a median OS [40.9-NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLRmean than those showing pseudoprogression after two ICIs' cycles (p = 0.038).
    CONCLUSION: PET/CT, performed already after administration of two ICIs' cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs.
    Keywords:  18F-FDG PET/CT; Confirmed progressive disease; Immunotherapy; Metastatic melanoma; Pseudoprogression; Spleen glucose metabolism; Unconfirmed progressive disease
    DOI:  https://doi.org/10.1186/s13550-021-00832-4
  43. Cancers (Basel). 2021 Sep 06. pii: 4494. [Epub ahead of print]13(17):
    A Comprehensive Evaluation and Benchmarking of Convolutional Neural Networks for Melanoma Diagnosis.
    Saeed Alzahrani, Baidaa Al-Bander, Waleed Al-Nuaimy.
      Melanoma is the most invasive skin cancer with the highest risk of death. While it is a serious skin cancer, it is highly curable if detected early. Melanoma diagnosis is difficult, even for experienced dermatologists, due to the wide range of morphologies in skin lesions. Given the rapid development of deep learning algorithms for melanoma diagnosis, it is crucial to validate and benchmark these models, which is the main challenge of this work. This research presents a new benchmarking and selection approach based on the multi-criteria analysis method (MCDM), which integrates entropy and the preference ranking organization method for enrichment of evaluations (PROMETHEE) methods. The experimental study is carried out in four phases. Firstly, 19 convolution neural networks (CNNs) are trained and evaluated on a public dataset of 991 dermoscopic images. Secondly, to obtain the decision matrix, 10 criteria, including accuracy, classification error, precision, sensitivity, specificity, F1-score, false-positive rate, false-negative rate, Matthews correlation coefficient (MCC), and the number of parameters are established. Third, entropy and PROMETHEE methods are integrated to determine the weights of criteria and rank the models. Fourth, the proposed benchmarking framework is validated using the VIKOR method. The obtained results reveal that the ResNet101 model is selected as the optimal diagnosis model for melanoma in our case study data. Thus, the presented benchmarking framework is proven to be useful at exposing the optimal melanoma diagnosis model targeting to ease the selection process of the proper convolutional neural network architecture.
    Keywords:  benchmarking; convolution neural networks; melanoma
    DOI:  https://doi.org/10.3390/cancers13174494
  44. J Drug Target. 2021 Sep 06. 1-34
    Cationic Liposome Decorated with Cyclic RGD Peptide for Targeted Delivery of anti-STAT3 siRNA to Melanoma Cancer Cells.
    Ehsan Khabazian, Faezeh Vakhshiteh, Parisa Norouzi, Yousef Fatahi, Rassoul Dinarvand, Fatemeh Atyabi.
      Gene therapy is regarded as a valuable strategy for efficient cancer treatment. However, the design of effective delivery systems that can deliver gene materials such as siRNA specifically to the tumour tissues plays a pivotal role in cancer therapy. For this reason, a targeted cationic liposome for melanoma treatment was developed. This system consists of cyclic RGD peptide conjugated to DSPE-PEG2000, cholesterol, DOTAP, and DSPC as cationic and neutral lipids, respectively. Cyclic RGD was selected based on speculation that cyclic RGD would effectively transport anti-signal transducer and activator of transcription 3 (STAT3) siRNA into melanoma cell via integrin receptors. The prepared liposomes provided excellent stability against electrolyte and serum nucleases. Targeted liposomes remarkably exhibited higher cellular internalisation in comparison with the non-targeted system in flow cytometry and confocal microscopy. Furthermore, incorporating peptide on the surface of liposomes resulted in considerably high cytotoxicity, a 2.1-times raise in apoptosis induction, and a significantly enhanced STAT3 gene suppression as compared with the corresponding non-targeted formulation on B16F10 murine melanoma cells. Whole-body imaging confirmed the more significant tumour accumulation of targeted liposomes in B16F10 melanoma xenograft tumour-bearing mice. Consequently, c-RGD peptide modified liposome suggests a promising option for specific siRNA delivery into melanoma cells.
    Keywords:  Gene delivery carrier; Melanoma; STAT3 Transcription Factor; c-RGD peptide; cationic liposome; siRNA
    DOI:  https://doi.org/10.1080/1061186X.2021.1973481
  45. Clin Plast Surg. 2021 Oct;pii: S0094-1298(21)00068-7. [Epub ahead of print]48(4): xiii-xiv
    A Melanoma Update.
    Brian R Gastman, Michael W Neumeister.
      
    DOI:  https://doi.org/10.1016/j.cps.2021.07.001
  46. Cancers (Basel). 2021 Sep 02. pii: 4431. [Epub ahead of print]13(17):
    Primary Melanoma Characteristics of Metastatic Disease: A Nationwide Cancer Registry Study.
    Catherine Zhou, Marieke Louwman, Marlies Wakkee, Astrid van der Veldt, Dirk Grünhagen, Cornelis Verhoef, Antien Mooyaart, Tamar Nijsten, Loes Hollestein.
      The characteristics and disease patterns of primary stage I and II cutaneous melanomas that progress to stage III or IV disease were investigated based on data from the Netherlands Cancer Registry (NCR). Data on stage III or IV melanomas at first diagnosis or during follow-up between 2017 and 2019 were retrieved. Patient and primary tumour characteristics were investigated in relation to time to disease progression and the number of organ sites with metastatic disease using regression models. In total, 2763 patients were included, of whom 1613 were diagnosed with stage IV disease. Among the patients with stage IV disease, 60% (n = 963) were initially diagnosed with stage I or II disease. The proportion of patients who received a sentinel lymph node biopsy increased after the introduction of adjuvant therapy in 2019 from 61% to 87%. Among all patients with stage III disease who were eligible for adjuvant systemic therapy (n = 453) after 2019, 37% were not treated with this therapy. Among patients with stage IV disease, lung metastases were most often detected as the first metastatic site and females presented with more metastatic sites than males. Most patient and primary tumour characteristics were not associated with the distant metastatic organ site, except melanoma localisation in the lower extremities and the head or neck. Our observation that most stage IV patients were initially diagnosed with early-stage disease highlights the need for more accurate risk prediction models.
    Keywords:  disease progression; melanoma; metastasis
    DOI:  https://doi.org/10.3390/cancers13174431
  47. Lab Anim. 2021 Sep 09. 236772211039333
    Evaluation of eye melanoma treatments in rabbits: A systematic review.
    Tarcísio Guerra Guimarães, Carlos Miguel Marto, Karla Menezes Cardoso, Nuno Alexandre, Maria Filomena Botelho, Mafalda Laranjo.
      Melanomas are the most common cancer of the eye in canines, felines and humans. The treatment approaches vary, since no gold standard exists. Therefore, this systematic review aimed to compare the treatment modalities in ocular melanoma in rabbits. Medline/PubMed, Cochrane Library, Web of Science and Embase were searched for articles published until 21 April 2021 in English, Portuguese or Spanish, reporting animal studies evaluating photodynamic therapy (PDT), laser, radiotherapy or surgical excision. Twenty-seven articles were included for the qualitative synthesis, with publication dates from 1970 to 2018. Of the selected studies, 19 used PDT, six used radiotherapy and two used laser as treatment. No studies regarding surgical therapy that met the inclusion criteria were obtained. The tumour therapy results were evaluated in a heterogeneous manner for different periods and various methods, including microscopy, angiographic, histological examination, fundoscopy, ultrasound exam and electroretinogram. The treatment modalities analysed successfully treated the ocular melanoma, with tumour necrosis being commonly observed. Despite the therapeutic efficacy shown, side effects have been reported for all the therapies. The studies showed high heterogeneity, and therefore, in the future, new studies should be carried out to increase knowledge about ocular melanoma treatment. The analysed therapies can be used successfully in the treatment of ocular melanoma, with more conservative options such as PDT presenting great potential.
    Keywords:  Eye; lasers; melanoma; microsurgery; photochemotherapy; radiotherapy
    DOI:  https://doi.org/10.1177/00236772211039333
  48. Front Cell Dev Biol. 2021 ;9 713209
    Validation of the Relationship Between Iris Color and Uveal Melanoma Using Artificial Intelligence With Multiple Paths in a Large Chinese Population.
    Haihan Zhang, Yueming Liu, Kai Zhang, Shiqi Hui, Yu Feng, Jingting Luo, Yang Li, Wenbin Wei.
      Previous studies have shown that light iris color is a predisposing factor for the development of uveal melanoma (UM) in a population of Caucasian ancestry. However, in all these studies, a remarkably low percentage of patients have brown eyes, so we applied deep learning methods to investigate the correlation between iris color and the prevalence of UM in the Chinese population. All anterior segment photos were automatically segmented with U-NET, and only the iris regions were retained. Then the iris was analyzed with machine learning methods (random forests and convolutional neural networks) to obtain the corresponding iris color spectra (classification probability). We obtained satisfactory segmentation results with high consistency with those from experts. The iris color spectrum is consistent with the raters' view, but there is no significant correlation with UM incidence.
    Keywords:  Chinese population; artificial intelligence; iris color; machine learning; uveal melanoma
    DOI:  https://doi.org/10.3389/fcell.2021.713209
  49. Int J Mol Sci. 2021 Aug 26. pii: 9260. [Epub ahead of print]22(17):
    Unraveling the Relevance of ARL GTPases in Cutaneous Melanoma Prognosis through Integrated Bioinformatics Analysis.
    Cheila Brito, Bruno Costa-Silva, Duarte C Barral, Marta Pojo.
      Cutaneous melanoma (CM) is the deadliest skin cancer, whose molecular pathways underlying its malignancy remain unclear. Therefore, new information to guide evidence-based clinical decisions is required. Adenosine diphosphate (ADP)-ribosylation factor-like (ARL) proteins are membrane trafficking regulators whose biological relevance in CM is undetermined. Here, we investigated ARL expression and its impact on CM prognosis and immune microenvironment through integrated bioinformatics analysis. Our study found that all 22 ARLs are differentially expressed in CM. Specifically, ARL1 and ARL11 are upregulated and ARL15 is downregulated regardless of mutational frequency or copy number variations. According to TCGA data, ARL1 and ARL15 represent independent prognostic factors in CM as well as ARL11 based on GEPIA and OncoLnc. To investigate the mechanisms by which ARL1 and ARL11 increase patient survival while ARL15 reduces it, we evaluated their correlation with the immune microenvironment. CD4+ T cells and neutrophil infiltrates are significantly increased by ARL1 expression. Furthermore, ARL11 expression was correlated with 17 out of 21 immune infiltrates, including CD8+ T cells and M2 macrophages, described as having anti-tumoral activity. Likewise, ARL11 is interconnected with ZAP70, ADAM17, and P2RX7, which are implicated in immune cell activation. Collectively, this study provides the first evidence that ARL1, ARL11, and ARL15 may influence CM progression, prognosis, and immune microenvironment remodeling.
    Keywords:  ADP-ribosylation factor-like (ARL); biomarkers; cutaneous melanoma; immune microenvironment; in silico study; metastasis; prognosis; small GTPases
    DOI:  https://doi.org/10.3390/ijms22179260
  50. Lab Invest. 2021 Sep 09.
    Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1/5 signaling pathway.
    Jing Gao, Ryusuke Muroya, Fei Huang, Kengo Nagata, Masashi Shin, Ryoko Nagano, Yudai Tajiri, Shinsuke Fujii, Takayoshi Yamaza, Kazuhiro Aoki, Yukihiko Tamura, Mayuko Inoue, Sakura Chishaki, Toshio Kukita, Koji Okabe, Miho Matsuda, Yoshihide Mori, Tamotsu Kiyoshima, Eijiro Jimi.
      Oral malignant melanoma, which frequently invades the hard palate or maxillary bone, is extremely rare and has a poor prognosis. Bone morphogenetic protein (BMP) is abundantly expressed in bone matrix and is highly expressed in malignant melanoma, inducing an aggressive phenotype. We examined the role of BMP signaling in the acquisition of an aggressive phenotype in melanoma cells in vitro and in vivo. In five cases, immunohistochemistry indicated the phosphorylation of Smad1/5 (p-Smad1/5) in the nuclei of melanoma cells. In the B16 mouse and A2058 human melanoma cell lines, BMP2, BMP4, or BMP7 induces morphological changes accompanied by the downregulation of E-cadherin, and the upregulation of N-cadherin and Snail, markers of epithelial-mesenchymal transition (EMT). BMP2 also stimulates cell invasion by increasing matrix metalloproteinase activity in B16 cells. These effects were canceled by the addition of LDN193189, a specific inhibitor of Smad1/5 signaling. In vivo, the injection of B16 cells expressing constitutively activated ALK3 enhanced zygoma destruction in comparison to empty B16 cells by increasing osteoclast numbers. These results suggest that the activation of BMP signaling induces EMT, thus driving the acquisition of an aggressive phenotype in malignant melanoma.
    DOI:  https://doi.org/10.1038/s41374-021-00661-y
  51. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2021 Aug;43(4): 607-611
    [Updated Molecular Regulation of Hair Growth and Pigmentation by Dermal Papilla Cells].
    Chao Sun, Tie-Chi Lei.
      There is growing evidence that dermal papilla cells(DPCs)act as the organizing center to induce the cyclic hair regeneration.On one hand,DPCs secrete cytokines or growth factors to regulate the differentiation,proliferation,and migration of epithelial stem cells(EpSCs)and melanocyte stem cells(MeSCs)residing in the bulge region.On the other hand,DPCs manipulate the microenvironment(also termed as niche)for both EpSCs and MeSCs,such as the size of dermal papilla,the distance between dermal papilla and the bulge region,and the lymphatic drainage and sympathetic nerve innervation surrounding the bulge region,thereby orchestrating the cycling hair growth.Recent studies have demonstrated at least four subpopulations existing in dermal papillae,which induce the unilineage transit-amplifying epithelial cells to form the concentric multilayers of hair shafts and sheaths.In addition,emerging study has indicated that sustained psychological stress potentially leads to hyperactivation of the sympathetic nerves that innervate the bulge region.The large amount of norepinephrine released by the nerve endings forces MeSCs to rapidly and abnormally proliferate,resultantly causing the depletion of MeSC pool and the loss of hair pigment.Understanding the molecular regulation of hair growth and pigmentation by DPCs holds substantial promise for the future use of cultured DPCs in vitro to treat hair loss.
    Keywords:  dermal papilla cell; epithelial stem cell; hair growth; melanocyte stem cell; pigmentation
    DOI:  https://doi.org/10.3881/j.issn.1000-503X.12594
  52. Cancers (Basel). 2021 Aug 29. pii: 4367. [Epub ahead of print]13(17):
    Broad-Spectrum Antibiotic Use and Disease Progression in Early-Stage Melanoma Patients: A Retrospective Cohort Study.
    Mahip Acharya, Thomas Kim, Chenghui Li.
      Animal studies and a few clinical studies have reported mixed findings on the association between antibiotics and cancer incidence. Antibiotics may inhibit tumor cell growth, but could also alter the gut-microbiome-modulated immune system and increase the risk of cancer. Studies that assess how antibiotics affect the progression of cancer are limited. We evaluated the association between broad-spectrum antibiotic use and melanoma progression. We conducted a retrospective cohort study using IQVIA PharMetrics® Plus data (2008-2018). We identified patients with malignant melanoma who underwent wide local excision or Mohs micrographic surgery within 90 days of first diagnosis. Surgery date was the index date. Patients were excluded if they had any other cancer diagnosis or autoimmune disorders in 1 year before the index date ("baseline"). Exposure to broad-spectrum antibiotics was identified in three time windows using three cohorts: 3 months prior to the index date, 1 month after the index date, and 3 months after the index date. The covariates were patients' demographic and clinical characteristics identified in the 1-year baseline period. The patients were followed from the index date until cancer progression, loss of enrollment, or the end of 2 years after the index date. Progression was defined as: (i) any hospice care after surgery, (ii) a new round of treatment for melanoma (surgery, chemotherapy, immunotherapy, targeted therapy, or radiotherapy) 180 days after prior treatment, or (iii) a metastasis diagnosis or a diagnosis of a new nonmelanoma primary cancer at least 180 days after first melanoma diagnosis or prior treatment. A high-dimensional propensity score approach with inverse weighting was used to adjust for the patients' baseline differences. Cox proportional hazard regression was used for estimating the association. The final samples included 3930, 3831, and 3587 patients (mean age: 56 years). Exposure to antibiotics was 16% in the prior-3-months, 22% in the post-1-month, and 22% in the post-3-months. In the pre-3-months analysis, 9% of the exposed group and 9% of the unexposed group had progressed. Antibiotic use was not associated with melanoma progression (HR: 0.81; 95% CI: 0.57-1.14). However, antibiotic use in subsequent 1 month and subsequent 3 months was associated with 31% reduction (HR: 0.69; 95% CI: 0.51-0.92) and 32% reduction (HR: 0.68; 95% CI: 0.51-0.91) in progression, respectively. In this cohort of patients with likely early-stage melanoma cancer, antibiotic use in 1 month and 3 months after melanoma surgery was associated with a lower risk of melanoma progression. Future studies are warranted to validate the findings.
    Keywords:  broad-spectrum antibiotics; claims data; melanoma; progression
    DOI:  https://doi.org/10.3390/cancers13174367
  53. Radiat Oncol. 2021 Sep 08. 16(1): 174
    Quality of life and treatment-related burden during ocular proton therapy: a prospective trial of 131 patients with uveal melanoma.
    Johannes Gollrad, Christopher Rabsahl, Aline-Isabel Riechardt, Jens Heufelder, Andrea Stroux, Ute Goerling, Antonia Joussen, Volker Budach, Dirk Boehmer.
      BACKGROUND: Proton beam therapy is a well-established treatment option for patients with uveal melanoma (UM). The treatment procedure, in general, includes placing radiopaque clips to ensure exact eye-positioning during radiotherapy, followed by the delivery of proton irradiation. The short-term burden associated with proton therapy in patients with UM has rarely been addressed. In this prospective study, we investigated the physiological and psychological aspects of proton therapy that might affect the well-being of patients during the different stages of treatment.METHODS: During the treatment procedure, we conducted longitudinal assessments of the Quality of life (QOL), organ-specific symptoms, and psychological aspects in patients with UM with three questionnaires (EORTC QLQ-C30, EORTC QLQ-OPT30, and GAD-7). Patients completed questionnaires before clip surgery (T0), before proton therapy (T1), after completing treatment (T2), and three months after treatment completion (T3). We also collected data on tumor characteristics and socio-demographics to identify potential risk factors associated with high treatment burdens.
    RESULTS: We prospectively included 131 consecutive patients. Questionnaire data showed a significant, temporary decline in global QOL and an increase in eye-related symptoms, as a result of the clip surgery (T0-T1). After treatment completion (T2), global QOL improved gradually, and none of the eye-related symptoms significantly deteriorated over the course of proton therapy. The global QOL returned to baseline levels three months after treatment (T3). We identified baseline anxiety as an independent risk factor for experiencing an acute treatment-related burden. Furthermore, we found interactions between GAD7 and patient sex showing that anxiety had a more pronounced effect on QOL outcome in female patients.
    CONCLUSION: The short-term treatment-related burden of ocular proton therapy appeared to be largely associated with the preceding clip surgery, rather than the irradiation procedure. We found that anxiety was strongly associated with experiencing QOL issues during the treatment procedure. Our findings could contribute to the development of future strategies for improving the treatment process and psycho-oncologic patient care.
    Keywords:  Proton therapy; Quality of life; Uveal melanoma
    DOI:  https://doi.org/10.1186/s13014-021-01902-6
  54. Indian J Dermatol Venereol Leprol. 2021 Aug 24. pii: 10.25259/IJDVL_1292_20. [Epub ahead of print] 1-3
    Dermoscopy revealing an amelanotic subungual melanoma masked as contact dermatitis.
    Ignasi Marti-Marti, Ramon Pigem, Maria Margarita Narvaez, Llúcia Alós, Susana Puig.
      
    DOI:  https://doi.org/10.25259/IJDVL_1292_20
  55. Neurologist. 2021 Sep 07. 26(5): 170-171
    Trigeminal Metastasis of Malignant Melanoma: Clinical, Neuroradiological, and Pathological Features. A Case Report.
    Sara Pompanin, Costanza De Rossi, Francesco La Marra.
      INTRODUCTION: Perineural spread of malignant melanoma (MM) along cranial nerves is a rare complication of MM of the head and neck.CASE REPORT: A 78-year-old man presented with untreatable facial pain and cutaneous hypoesthesia in V2/V3 branches of right trigeminal nerve. Six months earlier patient removed a lentigo maligna melanoma in his right upper lip and a MM in his right gingiva. Brain magnetic resonance imaging showed pathologic thickening of the right maxillary and mandibular nerves and of the intracranial trigeminal nerve. Infraorbital nerve biopsy confirms MM neural metastasis. BRAFV600E mutation was identified only in the lentigo maligna melanoma. Patient was treated with brain proton therapy but 5 months later developed sensorimotor deficit of his right arm because of a cervical metastasis.
    CONCLUSIONS: In patients presenting with atypical facial pain and history of head and neck melanoma a trigeminal spreading should be considered. Magnetic resonance imaging can detect early perineural spread and target biopsy.
    DOI:  https://doi.org/10.1097/NRL.0000000000000336
  56. Radiother Oncol. 2021 Sep 07. pii: S0167-8140(21)06715-3. [Epub ahead of print]
    Toxicity of carbon ion radiotherapy and immune checkpoint inhibitors in advanced melanoma.
    Stefano Cavalieri, Sara Ronchi, Amelia Barcellini, Maria Bonora, Barbara Vischioni, Viviana Vitolo, Riccardo Villa, Michele Del Vecchio, Lisa Licitra, Ester Orlandi.
      We analyzed CTCAE adverse events of sequential Carbon Ion radiotherapy (CIRT) and immune checkpoint inhibitors (ICIs) in advanced melanoma patients. The frequencies of early and late adverse events (AEs) were 100% and 82% of patients, respectively. The frequency of G3+ AEs was in line with the literature.
    DOI:  https://doi.org/10.1016/j.radonc.2021.08.021
  57. Naunyn Schmiedebergs Arch Pharmacol. 2021 Sep 09.
    Blockade of TGF-βR improves the efficacy of doxorubicin by modulating the tumor cell motility and affecting the immune cells in a melanoma model.
    Alireza Mardomi, Marzieh Ghollasi, Mohsen Korani, Mahsa Panahi, Mohammad Parsa-Kondelaji, Mehdi Sabzichi, Ali Salimi.
      TGF-β contributes to drug resistance and the invasiveness of tumor cells and weakens the anti-tumor immune responses. The present study aimed at examining the efficacy of the combination of SB431542, as a specific inhibitor of TGF-βR, and doxorubicin in controlling the melanoma tumor in mice. The impact of the combination of the doxorubicin and SB431542 on the cell growth, apoptosis, migration, and invasiveness of B16-F10 cells was examined. Besides, the B16-F10 tumor was induced in C57BL/6 mice, and the effects of the mentioned treatment on the tumor volume, survival, and the exhaustion state of T cells were evaluated. Although the combination of doxorubicin and SB431542 did not exhibit synergism in the inhibition of cell growth and apoptosis induction, it efficiently prohibited the migration and the epithelial to mesenchymal transition of B16-F10 cells, and the combination of doxorubicin and SB431542 caused an increase in mRNA levels of E-cadherin and, on the other hand, led to a decline in the expression of Vimentin. Tumor volume and the survival of tumor-bearing mice were efficiently controlled by the combination therapy. This treatment also eventuated in a decrease in the percentage of PD-L1+, TCD4+, and TCD8+ cells as indicators of exhausted T cells within the spleens of tumor-bearing mice. Blockade of TGF-βR also propelled the RAW 264.7 cells towards an anti-tumor M1 macrophage phenotype. The inhibition of TGF-βR demonstrated a potential to increase the efficacy of doxorubicin chemotherapy by the means of affecting cellular motility and restoring the anti-tumor immune responses.
    Keywords:  Doxorubicin; EMT; Macrophage polarization; SB431542; TGF-β
    DOI:  https://doi.org/10.1007/s00210-021-02134-x
  58. Int J Mol Sci. 2021 Sep 03. pii: 9579. [Epub ahead of print]22(17):
    Anti-Cancer Effects of Cyclic Peptide ALOS4 in a Human Melanoma Mouse Model.
    Bar Levi, Shiri Yacobovich, Michael Kirby, Maria Becker, Oryan Agranyoni, Boris Redko, Gary Gellerman, Albert Pinhasov, Igor Koman, Elimelech Nesher.
      We examined the effects of ALOS4, a cyclic peptide discovered previously by phage library selection against integrin αvβ3, on a human melanoma (A375) xenograft model to determine its abilities as a potential anti-cancer agent. We found that ALOS4 promoted healthy weight gain in A375-engrafted nude mice and reduced melanoma tumor mass and volume. Despite these positive changes, examination of the tumor tissue did not indicate any significant effects on proliferation, mitotic index, tissue vascularization, or reduction of αSMA or Ki-67 tumor markers. Modulation in overall expression of critical downstream αvβ3 integrin factors, such as FAK and Src, as well as reductions in gene expression of c-Fos and c-Jun transcription factors, indirectly confirmed our suspicions that ALOS4 is likely acting through an integrin-mediated pathway. Further, we found no overt formulation issues with ALOS4 regarding interaction with standard inert laboratory materials (polypropylene, borosilicate glass) or with pH and temperature stability under prolonged storage. Collectively, ALOS4 appears to be safe, chemically stable, and produces anti-cancer effects in a human xenograft model of melanoma. We believe these results suggest a role for ALOS4 in an integrin-mediated pathway in exerting its anti-cancer effects possibly through immune response modulation.
    Keywords:  ALOS4; cancer; cyclic peptide; integrin; melanoma; αvβ3
    DOI:  https://doi.org/10.3390/ijms22179579
  59. Autoimmun Rev. 2021 Sep 07. pii: S1568-9972(21)00207-X. [Epub ahead of print] 102932
    Autoimmunity in vitiligo: Therapeutic implications and opportunities.
    Binod K Khaitan, Tekumalla Sindhuja.
      Vitiligo is an acquired chronic pigmentary disorder affecting the melanocytes, mainly in the skin and mucosae. It occurs due to the dynamic interaction between genetic and environmental factors leading to autoimmune destruction of melanocytes. Defects in melanocyte adhesion and increased oxidative stress further augment the immune response in vitiligo. It is a cosmetically disfiguring condition with a substantial psychological burden. Its autoimmune nature with resultant chronicity, variable responses to therapeutic modalities, and frequent recurrences have further diminished the quality of life. Hence, treatment should aim to provide more extended remission periods, prevent recurrences, provide good cosmetic outcomes and ensure patient satisfaction. These treatment goals seem plausible with the recent progress in our understanding of the complex pathogenic mechanisms underlying vitiligo at a molecular and genetic level. We provide a literature review of the pathogenic mechanisms and the therapies targeting these mechanisms.
    Keywords:  Autoimmunity; Corticosteroids; Immunosuppressants; Pathogenesis; Therapeutics; Vitiligo
    DOI:  https://doi.org/10.1016/j.autrev.2021.102932
  60. Appl Immunohistochem Mol Morphol. 2021 Sep 10.
    HMB45/PRAME, a Novel Double Staining for the Diagnosis of Melanocytic Neoplasms: Technical Aspects, Results, and Comparison With Other Commercially Available Staining (PRAME and Melan A/PRAME).
    Marco Grillini, Costantino Ricci, Vincenzo Pino, Silvia Pedrini, Michelangelo Fiorentino, Barbara Corti.
      PRAME (PReferentially expressed Antigen in MElanoma) is a tumor-associated antigen that was recently found to be expressed by malignant melanocytic lesions but not by benign ones, thus resulting useful in this diagnostic field. PRAME could also be expressed by some normal tissues and nonmelanocytic tumors, suggesting as caution should be adopted to use PRAME as a "pan-melanoma" marker for the differential diagnosis with other malignant tumors. Until now, PRAME expression was exclusively investigated through single staining with a monoclonal antibody targeting PRAME and with double staining for Melan A/PRAME found to be useful in specific diagnostic sets. Herein, we studied the expression of PRAME in 40 melanocytic lesions and 23 nonmelanocytic ones using PRAME, Melan A/PRAME, and novel double staining for HMB45/PRAME. Although our results need to be validated, they support the adoption of HMB45/PRAME, alone or in combination with PRAME and Melan A/PRAME, as a helpful marker in the diagnosis of melanocytic neoplasms with a high concordance rate between primary melanoma and corresponding metastases.
    DOI:  https://doi.org/10.1097/PAI.0000000000000972
  61. Biomed Res Int. 2021 ;2021 7065963
    Upregulation of miR-29c-3p Hinders Melanoma Progression by Inhibiting CDCA4 Expression.
    Jiazheng Liu, Guilu Tao, Cundi Zhong, Xiao Liu.
      Objective: To investigate the expression and regulation mechanism of miR-29c-3p and cell division cycle associated 4 (CDCA4) in melanoma (MM). Data and Methods. Fifty-nine patients with MM admitted to our hospital were enrolled as the MM group. They were followed up for 3 years to analyze the prognostic factors; meanwhile, 51 healthy subjects were allocated into a normal group. MM cell lines (M21 and C8161) were transfected with miR-29c-3p-mimics, miR-29c-3p-inhibitor, miR-NC, si-CDCA4, and sh-CDCA4. The expression of miR-29c-3p, CDCA4, Bax, Caspase3, Bcl-2, N-cadherin, vimentin, and E-cadherin was quantified, and cell proliferation, migration, invasion, and apoptosis, as well as epithelial-mesenchymal transition (EMT), were determined.Results: Serum miR-29c-3p was lowly expressed and CDCA4 was highly expressed in the MM group. The area under the curve (AUC) of both for diagnosing MM was greater than 0.9. miR-29c-3p and CDCA4 were related to regional lymph node staging (N staging), distant metastasis (M staging), tumor diameter, and pathological differentiation. Low miR-29c-3p and high CDCA4 were associated with poor prognosis of MM. Overexpression of miR-29c-3p and suppression of CDCA4 hindered cell proliferation, migration, invasion, and expression of Bax, Caspase3, N-cadherin, and vimentin, but cell apoptosis and expression of Bcl-2 and E-cadherin were enhanced. Dual-luciferase reporter (DLR) assay confirmed the targeted relationship between miR-29c-3p and CDCA4. After miR-29c-3p-mimics+sh-CDCA4 was transfected into M21 and C8161 cells, the proliferation, invasion, and apoptosis were not different from those in the miR-NC group transfected with unrelated sequences.
    Conclusion: Overexpression of miR-29c-3p suppresses CDCA4 expression and decreases proliferation, migration, invasion, apoptosis, and EMT of MM cells, thus hindering MM progression.
    DOI:  https://doi.org/10.1155/2021/7065963
  62. Stem Cell Res Ther. 2021 Sep 10. 12(1): 501
    Human amniotic stem cells-derived exosmal miR-181a-5p and miR-199a inhibit melanogenesis and promote melanosome degradation in skin hyperpigmentation, respectively.
    Xiao-Yu Wang, Xiao-Hui Guan, Zhen-Ping Yu, Jie Wu, Qi-Ming Huang, Ke-Yu Deng, Hong-Bo Xin.
      BACKGROUND: Hyperpigmentation of skin is caused by an imbalance between the melanosome/melanin synthesis in melanocytes and the melanosome/melanin degradation in keratinocytes. Although studies showed that stem cells play a role in hypopigmentation, the underlying mechanisms are far not elucidated. Human amniotic stem cells (hASCs) including human amniotic mesenchymal stem cells (hAMSCs) and human amniotic epithelial stem cells (hAESCs) were considered to be a promising cell source for stem cells-based therapy of many diseases clinically due to their pluripotent potential, no tumorigenesis and immunogenicity, no ethical issues, and potent paracrine effects. Here, we reported that both hASCs and their conditional medium (CM) had a potent anti-hyperpigmentation in skin in vivo and in vitro.METHODS: hAESCs and hAMSCs were identified by RT-PCR, flow cytometric analysis and immunofluorescence. Effects of hASCs and hASC-CM on pigmentation were evaluated in B16F10 cells stimulated with α-melanocyte-stimulating hormone (α-MSH), and mouse ears or human skin substitutes treated with ultraviolet radiation B (UVB). Expressions of the key proteins related with melanogenesis and autophagic flux were detected by western blot in B16F10 cells for further exploring the effects and the underlying mechanisms of hAESC-CM and hAMSC-CM on melanogenesis and melanosome degradation. The hAMSCs exosomes-derived miRNAs were determined by sequencing. RT-PCR, western blot, melanin content analysis and luciferase activity assay were used to determine the hypopigmentation of miR-181a-5p and miR-199a.
    RESULTS: In our study, we observed that both hASCs and their CM significantly alleviated the α-MSH in B16F10 cells or UVB-induced hyperpigmentation in mouse ears or human skin substitutes by suppressing melanin synthesis and promoting melanosome degradation in vivo and in vitro. Furthermore, we demonstrated that miR-181a-5p and miR-199a derived from hASCs exosomes remarkably inhibited melanogenesis by suppressing MITF (microphthalmia-associated transcription factor) which is a master regulator for governing melanogenesis and promoting melanosome degradation through activating autophagy, respectively.
    CONCLUSIONS: Our studies provided strong evidence that the conditional medium and exosomes derived from hAMSCs inhibit skin hyperpigmentation by suppressing melanogenesis and promoting melanosome degradation, indicating that the hASCs exosomes or their released microRNAs might be as reagents for cell-free therapy in hyperpigmented disorders clinically.
    Keywords:  Autophagy; Exosomes; Human amniotic stem cells; Hyperpigmentation; miRNA
    DOI:  https://doi.org/10.1186/s13287-021-02570-9
  63. Melanoma Res. 2021 Sep 07.
    Novel strategy for applying hierarchical density-based spatial clustering of applications with noise towards spectroscopic analysis and detection of melanocytic lesions.
    Jason Yuan Ye, Christopher Yu, Tiffany Husman, Bryan Chen, Aryaman Trikala.
      Advancements in dermoscopy techniques have elucidated identifiable characteristics of melanoma which revolve around the asymmetrical constitution of melanocytic lesions consequent of unfettered proliferative growth as a malignant lesion. This study explores the applications of hierarchical density-based spatial clustering of applications with noise (HDBSCAN) in terms of the direct diagnostic implications of applying agglomerative clustering in the spectroscopic analysis of malignant melanocytic lesions and benign dermatologic spots. 100 images of benign (n = 50) and malignant moles (n = 50) were sampled from the International Skin Imaging Collaboration Archive and processed through two separate Python algorithms. The first of which deconvolutes the three-digit tupled integer identifiers of pixel color in image composition into three separate matrices corresponding to the red, green and blue color channel. Statistical characterization of integer variance was utilized to determine the optimal channel for comparative analysis between malignant and benign image groups. The second applies HDBSCAN to the matrices, identifying agglomerative clustering in the dataset. The results indicate the potential diagnostic applications of HDBSCAN analysis in fast-processing dermoscopy, as optimization of clustering parameters according to a binary search strategy produced an accuracy of 85% in the classification of malignant and benign melanocytic lesions.
    DOI:  https://doi.org/10.1097/CMR.0000000000000771
  64. Chronobiol Int. 2021 Sep 06. 1-14
    Circadian disruption induced by tumor development in a murine model of melanoma.
    Ignacio Aiello, Malena Lis Mul Fedele, Fernanda Ruth Román, Diego Andrés Golombek, Natalia Paladino.
      The circadian system induces oscillations in most physiological variables, with periods close to 24 hours. Dysfunctions in clock-controlled body functions, such as sleep disorders, as well as deregulation of clock gene expression or glucocorticoid levels have been observed in cancer patients. Moreover, these disorders have been associated with a poor prognosis or worse response to treatment. This work explored the circadian rhythms at behavioral and molecular levels in a murine melanoma model induced by subcutaneous inoculation of B16 tumoral cells. We observed that the presence of the tumors induced a decrease in the robustness of the locomotor activity rhythms and in the amount of nighttime activity, together with a delay in the acrophase and in the activity onset. Moreover, these differences were more marked when the tumor size was larger than in the initial stages of the tumorigenesis protocol. In addition, serum glucocorticoids, which exhibit strong clock-controlled rhythms, lost their circadian patterns. Similarly, the rhythmic expression of the clock genes Bmal1 and Cry1 in the hypothalamic Suprachiasmatic Nuclei (SCN) were also deregulated in mice carrying tumors. Altogether, these results suggest that tumor-secreted molecules could modulate the function of the central circadian pacemaker (SCN). This could account for the worsening of the peripheral biological rhythms such as locomotor activity or serum glucocorticoids. Since disruption of the circadian rhythms might accelerate tumorigenesis, monitoring circadian patterns in cancer patients could offer a new tool to get a better prognosis for this disease.
    Keywords:  Circadian rhythms; SCN; Suprachiasmatic Nuclei; clock genes; glucocorticoids; tumor growth
    DOI:  https://doi.org/10.1080/07420528.2021.1964519
  65. Biochim Biophys Acta Mol Basis Dis. 2021 Sep 02. pii: S0925-4439(21)00196-4. [Epub ahead of print]1867(12): 166263
    Clotrimazole presents anticancer properties against a mouse melanoma model acting as a PI3K inhibitor and inducing repolarization of tumor-associated macrophages.
    Alan C Ochioni, Ricardo Imbroisi Filho, Amanda M Esteves, João G B Leandro, Thainá M Demaria, José Xavier do Nascimento Júnior, Filipe S Pereira-Dutra, Patricia T Bozza, Mauro Sola-Penna, Patricia Zancan.
      The immune system is a key component of tumorigenesis, with the latter promoting the development of cancer, its progression and metastasis. In fact, abundant infiltration of tumor-associated macrophages (TAM), which are M2-like macrophages, has been associated with a poor outcome in most types of cancers. Here, we show that lactate produced by murine melanoma B16F10 cells induces an M2-like profile in cultured macrophages. Further, we demonstrate that clotrimazole (CTZ), an off-target anti-tumor drug, abolishes lactate effects on the activation of macrophages and induces the expression of M1-like markers. We show that clotrimazole has cytotoxic effects on tumor cells by negatively modulating PI3K, which inhibits glycolytic metabolism and leads to a diminishing lactate production by these cells. These effects are more pronounced in cancer cells exposed to conditioned media of M2-polarized macrophages. Moreover, clotrimazole inhibits tumor growth in a murine model of implanted melanoma, reduces lactate content in a tumor microenvironment and decreases vascular endothelial growth factor expression. Finally, clotrimazole drastically diminishes TAM infiltration in the tumors, thereby inducing M1 polarization. Collectively, these findings identify a new antitumor mechanism of clotrimazole by modulating the tumor microenvironment (TME), particularly the activation and viability of TAM.
    Keywords:  Cancer; Cytotoxicity; Inflammation; Lactate; PI3K pathway; TAMs
    DOI:  https://doi.org/10.1016/j.bbadis.2021.166263
  66. EMBO J. 2021 Sep 06. e107795
    CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma.
    Smitha Sivapragasam, Bastian Stark, Amanda V Albrecht, Kaitlynne A Bohm, Peng Mao, Raymond G Emehiser, Steven A Roberts, Patrick J Hrdlicka, Gregory M K Poon, John J Wyrick.
      Somatic mutations in DNA-binding sites for CCCTC-binding factor (CTCF) are significantly elevated in many cancers. Prior analysis has suggested that elevated mutation rates at CTCF-binding sites in skin cancers are a consequence of the CTCF-cohesin complex inhibiting repair of UV damage. Here, we show that CTCF binding modulates the formation of UV damage to induce mutation hot spots. Analysis of genome-wide CPD-seq data in UV-irradiated human cells indicates that formation of UV-induced cyclobutane pyrimidine dimers (CPDs) is primarily suppressed by CTCF binding but elevated at specific locations within the CTCF motif. Locations of CPD hot spots in the CTCF-binding motif coincide with mutation hot spots in melanoma. A similar pattern of damage formation is observed at CTCF-binding sites in vitro, indicating that UV damage modulation is a direct consequence of CTCF binding. We show that CTCF interacts with binding sites containing UV damage and inhibits repair by a model repair enzyme in vitro. Structural analysis and molecular dynamic simulations reveal the molecular mechanism for how CTCF binding modulates CPD formation.
    Keywords:  CCCTC-binding factor; DNA damage; DNA repair; skin cancer; ultraviolet light
    DOI:  https://doi.org/10.15252/embj.2021107795
  67. Chin Med J (Engl). 2021 Sep 09.
    Pro-pigmentary action of 5-fluorouracil through the stimulated secretion of CXCL12 by dermal fibroblasts.
    Zhi-Kai Liao, Shuang-Hai Hu, Bin-Yu Han, Xie Qiu, Shan Jiang, Tie-Chi Lei.
      BACKGROUND: There is growing evidence that 5-fluorouracil (5-FU) combined with therapeutic trauma can effectively induce skin repigmentation in vitiligo patients who are unresponsive to conventional treatments. Previous studies have mainly focused on identifying the antimitotic activity of 5-FU for the treatment of skin cancer, but few studies have investigated its extra-genotoxic actions favoring melanocyte recruitment.METHODS: We utilized the full thickness excisional skin wound model in Dct-LacZ transgenic mice to dynamically assess the migration of melanocytes in the margins of wounds treated with or without 5-FU. The in-situ expression of CXCL12 was examined in the wound beds using immunofluorescence staining. Quantitative real-time polymerase chain reaction and Western blotting analyses were performed to detect the expression levels of CXCL12 mRNA and protein in primary mouse dermal fibroblasts treated with or without 5-FU. Transwell assays and fluorescein isothiocyanate (FITC)-phalloidin staining were used to observe cell migration and filamentous actin (F-actin) changes of melan-a murine melanocytes.
    RESULTS: Whole mount and cryosection X-gal staining showed that the cell numbers of LacZ-positive melanocytes were much higher in the margins of dorsal and tail skin wounds treated with 5-FU compared with the controls. Meanwhile, CXCL12 immunostaining was significantly increased in the dermal compartment of wounds treated with 5-FU (control vs. 5-FU, 22.47 ± 8.85 vs. 44.69 ± 5.97, P < 0.05). Moreover, 5-FU significantly upregulated the expression levels of CXCL12 mRNA (control vs. 5-FU, 1.00 ± 0.08 vs. 1.54 ± 0.06, P < 0.05) and protein (control vs. 5-FU, 1.00 ± 0.06 vs. 2.93 ± 0.10, P < 0.05) in cultured fibroblasts. Inhibition of the CXCL12/CXCR4 axis suppressed melanocyte migration in vitro using a CXCL12 small interfering RNA (siRNA) or a CXCR4 antagonist (AMD3100).
    CONCLUSION: 5-FU possesses a pro-pigmentary activity through activation of the CXCL12/CXCR4 axis to drive the chemotactic migration of melanocytes.
    DOI:  https://doi.org/10.1097/CM9.0000000000001689
  68. Zhonghua Jie He He Hu Xi Za Zhi. 2021 Sep 12. 44(9): 837-839
    [Update of the diagnosis and treatment of anti-melanoma differentiation associated gene-5 related rapid progressive interstitial lung disease].
    Y X Sun, Z Y Zhang, C Shao, H Huang, Z J Xu.
      
    DOI:  https://doi.org/10.3760/cma.j.cn112147-20201105-01083
  69. JIMD Rep. 2021 Sep;61(1): 25-33
    Vitiligo, alkaptonuria, and nitisinone-A report of three families and review of the literature.
    Lakshminarayan Ranganath, Milad Khedr, Leanne A Evans, Helen Bygott, Emily Luangrath, Elizabeth West.
      Four patients, from three families, with alkaptonuria receiving 4-hydroxyphenylpyruvate dioxygenase-inhibiting nitisinone therapy, which lowers homogentisic acid and increases tyrosine, developed vitiligo. Three of the four patients were receiving nitisinone 2 mg daily, while the fourth was on 10 mg daily. All four patients were either receiving or had received transiently proton-pump inhibitors as therapy for dyspepsia. The ages of the patients were 35, 42, 40, and 67 years, respectively. Three patients were men and one was a woman. All four patients were either taking a proton-pump inhibitor or had been taking one at some point. Three of the four were of South Asian and one of Caucasian background. The three patients with South Asian background also had either a personal or family history of autoimmune disease. Distressing vitiligo, initially in an acrofacial distribution, developed unexpectedly in these four patients, before then progressing to involve other parts of the body. Potential factors in the appearance of vitiligo in this setting, including nitisinone and other drug therapy, are explored and responses to the appearance of vitiligo are discussed.
    Keywords:  alkaptonuria; homogentisic acid; nitisinone; proton‐pump inhibitors; tyrosine; vitiligo
    DOI:  https://doi.org/10.1002/jmd2.12225
  70. Exp Ther Med. 2021 Oct;22(4): 1115
    Identification of HIF-1α/VEGFA signaling pathway and transcription factors in Kashin-Beck disease by integrated bioinformatics analysis.
    Bin Xiao, Guozhu Wang, Hongliang Huo, Weiwei Li.
      Kashin-Beck disease (KBD) is a chronic and endemic osteoarthropathy. The pathogenesis of KBD has yet to be fully elucidated, although previous studies have shown that its etiology may be associated with low selenium abundance and high exposure to mycotoxins, such as T-2 toxin. In the present study, the Comparative Toxicogenomics Database was used to identify key genes associated with KBD, T-2 toxin and selenium. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to identify the biological processes and pathways that key genes may be associated with. By searching the Search Tool for the Retrieval of Interacting Genes database and the Molecular Complex Detection plug-in with Cytoscape, it was possible to construct a KBD-associated protein-protein interaction (PPI) network, and screen the core modules and genes. Western blot analysis was subsequently used to verify the expression levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA), two components that are associated with the HIF-1 signaling pathway in KBD disease. Via this approach, a total of 301 key genes were identified that were associated with KBD, T-2 toxin and selenium. The results of the GO and KEGG enrichment analyses demonstrated that these key genes were mainly involved in the process of apoptosis. Previous studies have demonstrated that excessive apoptosis of chondrocytes plays a crucial role in the pathophysiology of KBD, and that HIF-1α has an important role in chondrocyte apoptosis; therefore, the present study was focused on the expression level of HIF-1α in KBD. By analyzing the PPI network constructed from the key genes, a total of 10 core genes were obtained that may be associated with KBD. The results of western blotting experiments revealed that, after treating chondrocytes with different concentrations of T-2 toxin, the expression levels of HIF-1α and VEGFA were markedly downregulated. The iRegulon plug-in for Cytoscape was used to predict the transcription factors that may regulate HIF-1α and VEGFA in the HIF-1 signaling pathway. Using this approach, 10 core genes and 15 transcription factors were obtained. These results may help to clarify the pathogenesis of KBD, thereby providing further avenues for the therapeutic treatment of KBD.
    Keywords:  Kashin-Beck disease; T-2 toxin; chondrocyte; hypoxia-inducible factor/1α; vascular endothelial growth factor A
    DOI:  https://doi.org/10.3892/etm.2021.10549
  71. Cancers (Basel). 2021 Aug 28. pii: 4362. [Epub ahead of print]13(17):
    Skin Cancers and the Contribution of Rho GTPase Signaling Networks to Their Progression.
    Alessandra Pecora, Justine Laprise, Manel Dahmene, Mélanie Laurin.
      Skin cancers are the most common cancers worldwide. Among them, melanoma, basal cell carcinoma of the skin and cutaneous squamous cell carcinoma are the three major subtypes. These cancers are characterized by different genetic perturbations even though they are similarly caused by a lifelong exposure to the sun. The main oncogenic drivers of skin cancer initiation have been known for a while, yet it remains unclear what are the molecular events that mediate their oncogenic functions and that contribute to their progression. Moreover, patients with aggressive skin cancers have been known to develop resistance to currently available treatment, which is urging us to identify new therapeutic opportunities based on a better understanding of skin cancer biology. More recently, the contribution of cytoskeletal dynamics and Rho GTPase signaling networks to the progression of skin cancers has been highlighted by several studies. In this review, we underline the various perturbations in the activity and regulation of Rho GTPase network components that contribute to skin cancer development, and we explore the emerging therapeutic opportunities that are surfacing from these studies.
    Keywords:  Rho GTPase; RhoGAP; RhoGEF; basal cell carcinoma; cancer; melanoma; skin; squamous cell carcinoma
    DOI:  https://doi.org/10.3390/cancers13174362
  72. J Cutan Pathol. 2021 Sep 06.
    Characterization of Multiple Diagnostic Terms in Melanocytic Skin Lesion Pathology Reports.
    Oliver H Chang, David E Elder, Raymond L Barnhill, Michael W Piepkorn, Megan M Eguchi, Stevan R Knezevich, Annie C Lee, Raul J Moreno, Kathleen F Kerr, Joann G Elmore.
      BACKGROUND: Histopathologically ambiguous melanocytic lesions lead some pathologists to list multiple diagnostic considerations in the pathology report. The frequency and circumstance of multiple diagnostic considerations remain poorly characterized.METHODS: 240 skin biopsy samples were interpreted by 187 pathologists (8976 independent diagnoses) and classified according to a diagnostic/treatment stratification (MPATH-Dx).
    RESULTS: Multiple diagnoses in different MPATH-Dx classes were used in N = 1320 (14.7%) interpretations, with 97% of pathologists and 91% of cases having at least one such interpretation. Multiple diagnoses were more common for intermediate risk lesions and are associated with greater subjective difficulty and lower confidence. We estimate that 6% of pathology reports for melanocytic lesions in the U.S. contain two diagnoses of different MPATH-Dx prognostic classes, and 2% of cases are given two diagnoses with significant treatment implications.
    CONCLUSIONS: Difficult melanocytic diagnoses in skin may necessitate multiple diagnostic considerations; however, as patients increasingly access their health records and retrieve pathology reports (as mandated by US law), uncertainty should be expressed unambiguously. This article is protected by copyright. All rights reserved.
    Keywords:  MELTUMP; borderline diagnosis; dermatopathologists; dermatopathology; diagnostic dilemma; melanoma
    DOI:  https://doi.org/10.1111/cup.14126
  73. Nat Commun. 2021 09 07. 12(1): 5127
    Developmental genetics of color pattern establishment in cats.
    Christopher B Kaelin, Kelly A McGowan, Gregory S Barsh.
      Intricate color patterns are a defining aspect of morphological diversity in the Felidae. We applied morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established. Early in development, we identify stripe-like alterations in epidermal thickness preceded by a gene expression pre-pattern. The secreted Wnt inhibitor encoded by Dickkopf 4 plays a central role in this process, and is mutated in cats with the Ticked pattern type. Our results bring molecular understanding to how the leopard got its spots, suggest that similar mechanisms underlie periodic color pattern and periodic hair follicle spacing, and identify targets for diverse pattern variation in other mammals.
    DOI:  https://doi.org/10.1038/s41467-021-25348-2
  74. Acta Derm Venereol. 2021 Sep 07.
    Rolled Hairs in Two Cases of Naevus Comedonicus of the Scalp.
    Umi Tahara, Sachiko Ishihara, Satomi Aoki, Manabu Ohyama, Akiharu Kubo.
      
    Keywords:   NEK9 protein; Nevus; Hair Diseases
    DOI:  https://doi.org/10.2340/00015555-3920
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