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Abstract Background Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Methods An independent analysis of published sequencing data was performed to evaluate the frequency of receptor tyrosine kinase (RTK) ligands and adapter protein gene variants and expression. To target these genetic variants, a zebrafish acral melanoma model and preclinical patient-derived xenograft (PDX) mouse models were treated with a panel of RTK inhibitors. Residual PDX tumors were evaluated for changes in proliferation, vasculature, necrosis, and ferroptosis by histology and immunohistochemistry. Results RTK ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. Dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration in zebrafish, and the potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM PDX tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Conclusion Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

Basal cell carcinoma (BCC) is classified histologically into subtypes that determine treatment decisions. MicroRNAs (miRs) are short noncoding RNAs that may serve as diagnostic biomarkers. We investigated if particular miRs could distinguish BCC subtypes. We sequenced miRs from 55 archival BCC and 9 control skin specimens and then validated these miRs by qRT-PCR assay on a second BCC cohort (18 superficial, 16 nodular, 15 infiltrative) and control skin (n = 12). Expression values for individual miRs were normalized to miR-16-5p, which was the least variant among the control skin and BCC samples. We found that (i) miR-383-5p and miR-145-5p are downregulated in all BCC subtypes compared with control skin, (ii) miR-181c-5p is downregulated in superficial compared with invasive (nodular/infiltrative) BCC, and (iii) miR-22-5p and miR-708-5p are upregulated in infiltrative compared with superficial/nodular BCC and miR-30c-5p is downregulated in infiltrative compared with nodular BCC. Receiver operating characteristic analysis demonstrated excellent capacity of these miRs to discriminate between BCC and control skin (area under the curve, 0.94–0.98), whereas the capacity to discriminate between superficial and invasive subtypes was less robust (area under the curve, 0.7–0.8). Future prospective studies may determine the utility of these miRs as diagnostic biomarkers to guide biopsy and treatment of BCC.

This study describes a case of amelanotic lentigo maligna melanoma in a 69-year-old female that had been growing for approximately 5 years. The asymptomatic lesion had been previously diagnosed and treated as a fungal skin infection, an inflammatory rash, and an actinic keratosis that did not respond to standard treatments. Biopsy revealed confluent and nested atypical melanocytes at the dermal-epidermal junction, consistent with melanoma in situ. Excisional biopsy revealed invasive lentigo maligna melanoma, Breslow depth 0.3 mm, with positive melanoma in situ at margins. She is now 3 years post-Mohs surgery without recurrence. When working up a patient with a hypopigmented or inflammatory lesion not responding to standard therapies, physicians should always consider biopsy to rule out unusual neoplastic etiologies, such as amelanotic melanomas.

Despite significant progress in the development of treatment options, melanoma remains a leading cause of death due to skin cancer. Advances in our understanding of the genetic, transcriptomic, and morphologic spectrum of benign and malignant melanocytic neoplasia have enabled the field to propose biomarkers with potential diagnostic, prognostic, and predictive value. While these proposed biomarkers have the potential to improve clinical decision making at multiple critical intervention points, most remain unvalidated. Clinical validation of even the most commonly assessed biomarkers will require substantial resources, including limited clinical specimens. It is therefore important to consider the properties that constitute a relevant and clinically-useful biomarker-based test prior to engaging in large validation studies. In this review article we adapt an established framework for determining minimally-useful biomarker test characteristics, and apply this framework to a discussion of currently used and proposed biomarkers designed to aid melanoma detection, staging, prognosis, and choice of treatment.

Summary: To facilitate understanding of human cardiomyocyte (CM) subtype specification, and the study of ventricular CM biology in particular, we developed a broadly applicable strategy for enrichment of ventricular cardiomyocytes (VCMs) derived from human embryonic stem cells (hESCs). A bacterial artificial chromosome transgenic H9 hESC line in which GFP expression was driven by the human ventricular-specific myosin light chain 2 (MYL2) promoter was generated, and screened to identify cell-surface markers specific for MYL2-GFP-expressing VCMs. A CD77+/CD200− cell-surface signature facilitated isolation of >97% cardiac troponin I-positive cells from H9 hESC differentiation cultures, with 65% expressing MYL2-GFP. This study provides a tool for VCM enrichment when using some, but not all, human pluripotent stem cell lines. Tools generated in this study can be utilized toward understanding CM subtype specification, and enriching for VCMs for therapeutic applications. : In this article, Evans and colleagues generated an H9 BAC transgenic reporter cell line and performed a flow cytometry screen to identify a cell-surface signature specific for MYL2-GFP-expressing VCMs. The cell-surface signature, CD77+/CD200−, facilitated isolation of a nearly pure hESC-derived CM population, enriched for VCMs. VCM enrichment was achieved when using some, but not all, human pluripotent stem cell lines. Tools generated in this study serve to advance our understanding of CM subtype specification, commitment, and maturation. Keywords: cardiac differentiation, human embryonic stem cells, ventricular cardiomyocytes, cell-surface marker signature

Crossing over during meiotic prophase I is required for sexual reproduction in mice and contributes to genome-wide genetic diversity. Here we report on the characterization of an N-ethyl-N-nitrosourea-induced, recessive allele called mei4, which causes sterility in both sexes owing to meiotic defects. In mutant spermatocytes, chromosomes fail to congress properly at the metaphase plate, leading to arrest and apoptosis before the first meiotic division. Mutant oocytes have a similar chromosomal phenotype but in vitro can undergo meiotic divisions and fertilization before arresting. During late meiotic prophase in mei4 mutant males, absence of cyclin dependent kinase 2 and mismatch repair protein association from chromosome cores is correlated with the premature separation of bivalents at diplonema owing to lack of chiasmata. We have identified the causative mutation, a transversion in the 5' splice donor site of exon 1 in the mouse ortholog of Human Enhancer of Invasion 10 (Hei10; also known as Gm288 in mouse and CCNB1IP1 in human), a putative B-type cyclin E3 ubiquitin ligase. Importantly, orthologs of Hei10 are found exclusively in deuterostomes and not in more ancestral protostomes such as yeast, worms, or flies. The cloning and characterization of the mei4 allele of Hei10 demonstrates a novel link between cell cycle regulation and mismatch repair during prophase I.