MC1R is a potent regulator of PTEN after UV exposure in melanocytes.

The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.

Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group.

BACKGROUND: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. OBJECTIVE: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions. METHODS: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. RESULTS: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91. LIMITATIONS: This was a small sample size of experienced pathologists in a testing situation. CONCLUSION: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.

Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology.

Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.

Development of a geometry-based respiratory motion-simulating patient model for radiation treatment dosimetry.

Temporal and spatial anatomical changes caused by respiration during radiation treatment delivery can lead to discrepancies between the prescribed and actually received radiation doses. This paper presents a study to construct a respiratory-motion-simulating, four-dimensional (4D) patient anatomical and dosimetry model for the study of dosimetric effects of organ motion on various radiation treatment plans and delivery strategies. A 3D VIP-Man (VIsible Photographic Man) model has been reconstructed using the Non-Uniform Rational B-Splines (NURBS) method to reflect the deformation of organs during respiration by manipulating surface control points as time-dependent equations. The 4D model is applied to dose simulation using the Monte Carlo code EGS4 (Electron Gamma Shower, version 4). Two delivery scenarios in radiation therapy were simulated: "gating" treatment and 4D "image-guided" treatment. For each delivery scenario, one conformal plan and one Intensity Modulated Radiation Therapy (IMRT) plan were developed. A lesion in the left lung was modeled to investigate the impact of respiratory motion on radiation dose distributions. Based on target dose volume histograms (DVHs), it is demonstrated that it is important to use accurate "gating" to improve the dose distribution. The results also suggest that, during a 4D "image-guided" treatment delivery, monitoring of patient breathing pattern is critical. This study demonstrates the potential of using "standard" motion-simulating patient model for 4D treatment planning and motion management.

Uveal melanocytomas: genetic comparison with uveal and dermal melanomas.

OBJECTIVE: Melanocytomas of the eye are typically benign tumors that may be associated with nevi and melanomas. In this study, we assessed the genetic data of melanocytomas and compared them with nevi and melanomas of both the eyes and the skin. DESIGN: We microdissected 8 melanocytomas, 13 uveal melanomas, and 10 cutaneous melanomas and analyzed loss of heterozygosity markers on chromosome bands 1p36, 6q22-23.3, 9p21, and 10q23, which represent genetic loci associated with advanced dermal melanocytic lesions. RESULTS: There was no loss of heterozygosity in any of the melanocytomas. However, many loss of heterozygosity events were found in uveal and cutaneous melanomas, most frequently involving chromosome 1 damage followed by chromosome 9 and 10 alterations. CONCLUSION: Based on the absence of loss of heterozygosity in melanocytomas, specifically the locus that is lost most often in dysplastic nevi of the skin, we conclude that melanocytomas represent an entity that is different from melanomas or may be similar to that of dermal benign nevi. CLINICAL RELEVANCE: Our results confirm that melanocytomas represent nonagressive lesions that do not demand radical surgery.

TBX2 expression is regulated by PAX3 in the melanocyte lineage.

The paired box homeotic gene 3 (PAX3) is a crucial regulator for the maintenance of melanocytic progenitor cells and has a poorly defined role in melanoma. To understand how PAX3 affects melanocyte and melanoma proliferation, we identified potential PAX3 downstream targets through gene expression profiling. Here, we identify T-box 2 (TBX2), a key developmental regulator of cell identity and an antisenescence factor in melanoma, as a directly regulated PAX3 target. We also found that TBX2 is involved in the survival of melanoma cells and is overexpressed in some melanoma specimens. The identification of TBX2 as a target for PAX3 provides a key insight into how PAX3 may contribute to melanoma evolution and may provide opportunities for prosenescence therapeutic intervention aimed at disrupting the ability of PAX3 to regulate TBX2.