Narayana RVL, Lanier AL, Wajapeyee N
… +1 more, Gupta R
J Invest Dermatol
· 2026 May · PMID 42216948
·
Full text
Uveal melanoma (UM) is the most common intraocular malignancy, contributing to ∼5% of all melanomas. It arises from melanocytes in the uveal tract (choroid, ciliary body, and iris) and has a specific genetic and clinical...Uveal melanoma (UM) is the most common intraocular malignancy, contributing to ∼5% of all melanomas. It arises from melanocytes in the uveal tract (choroid, ciliary body, and iris) and has a specific genetic and clinical profile. Important genetic alterations shown to drive UM pathogenesis and influence prognosis include GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. In addition, monosomy 3 and 8q gains are strongly linked to poor outcomes, whereas disomy 3 and 6p gains are associated with better prognosis. Approximately half of patients with UM develop metastases, most commonly to the liver, leading to high mortality. Conventional chemotherapy has shown poor efficacy, and immune checkpoint inhibitors have demonstrated only modest benefits. The immunosuppressive tumor microenvironment, particularly in the liver, further limits treatment efficacy. NK cells offer a promising avenue to treat patients owing to their ability to recognize tumor cells independent of major histocompatibility complex. However, UM employs multiple immune evasion strategies, including the upregulation of HLA-E and the secretion of immunosuppressive factors inhibiting NK cell function. Despite these barriers, preclinical studies demonstrate that activated NK cells can reduce hepatic metastases. Emerging NK cell-based therapies, such as chimeric antigen receptor-engineered NK cells and NK cell engagers, could provide an effective therapeutic strategy to treat metastatic UM, warranting further clinical investigation.
UVB induces an epidermal damage response, including keratinocyte hyperplasia, immune cell infiltration, and the recruitment of follicular melanocyte stem cells to the interfollicular epidermis. In this study, we establis...UVB induces an epidermal damage response, including keratinocyte hyperplasia, immune cell infiltration, and the recruitment of follicular melanocyte stem cells to the interfollicular epidermis. In this study, we establish the oncofetal chromatin remodeling factor Hmga2 (high mobility group AT-hook 2) as a regulator of these phenotypes through a cAMP-driven process. In this study, we identify somatic tissue expression of Hmga2 in the basal layer of hyperplastic UVB-exposed keratinocytes. Loss of Hmga2 results in the near absence of epidermal hyperplasia, cutaneous neutrophil infiltration, and melanocyte stem cell migration to the interfollicular epidermis. RNA sequencing of UVB-exposed keratinocytes from wild-type and Hmga2 loss-of-function models reveals increased expression of Adora1 (adenosine A1 receptor), a negative regulator of cAMP. Administration of the cAMP pathway activator forskolin to Hmga2 animals is sufficient to rescue melanocyte stem cell migration, thus highlighting the Hmga2-cAMP axis as a regulator in the cutaneous UVB response.
Hirsutism is a condition characterized by excessive hair growth in women, with a prevalence of 5-10 %. The diagnostic criteria usually include hair appearing in male-pattern areas, such as the face, abdomen, and chest. T...Hirsutism is a condition characterized by excessive hair growth in women, with a prevalence of 5-10 %. The diagnostic criteria usually include hair appearing in male-pattern areas, such as the face, abdomen, and chest. The contributing factors for hirsutism symptoms are heterogeneous and vary from genetic and ethnic background to diverse endocrinological causes, most commonly polycystic ovary syndrome (PCOS). In this cross-ancestry genome-wide association study (GWAS) including 4,834 cases and 352,966 controls, we explored the genetic background of hirsutism and identified seven loci associated with hirsutism, four of which have not been previously reported in GWAS. To capture low-frequency variants, we analyzed the Finnish FinnGen cohort separately, leveraging its bottleneck history that enriches for rare variants with larger effects. A missense variant rs199649605 (MAF = 0.005) enriched in the Finnish population near FGF5, a gene regulating the hair follicle cycle, showed a particularly strong effect (p = 1.39e-10, OR = 5.02, 95 % CI = 3.06-8.21). Genetic correlation analyses revealed shared genetic architecture between hirsutism, PCOS, and metabolic traits such as obesity and type 2 diabetes. These findings uncover genetic contributors to hirsutism beyond PCOS, suggesting that both androgen-dependent and independent mechanisms underlie excessive hair growth in women.
Acne vulgaris, a chronic inflammatory skin condition affecting up to 85% of adolescents, has been linked to cardiometabolic traits, though causality remains unclear. Using large-scale genome-wide association study (GWAS)...Acne vulgaris, a chronic inflammatory skin condition affecting up to 85% of adolescents, has been linked to cardiometabolic traits, though causality remains unclear. Using large-scale genome-wide association study (GWAS) summary statistics, we assessed genetic correlations and causal relationships between acne and cardiometabolic traits via linkage disequilibrium score regression (LDSC) and bidirectional Mendelian Randomization (MR). Significant inverse genetic correlations were observed between acne and body mass index (BMI; genetic correlation estimate [rG]= -0.117, P= 1.14×10), body fat percentage (BFP; rG= -0.156, P=4.84×10), metabolic syndrome (MetS; rG= -0.140, P= 5.48×10), type-2 diabetes (rG= -0.124, P=1.00×10) and triglycerides (rG= -0.137, P= 1.19×10), and a positive correlation with HDL cholesterol (rG= 0.069, P= 1.50×10). MR analyses supported causal effects of higher BMI (inverse-variance weighted estimate [IVW] β= -0.230, P= 9.41×10), BFP (IVW β = -0.052, P= 1.41×10), and MetS (IVW β= -0.214, P= 1.58×10) on lower acne risk. Multivariable MR demonstrated that MetS risk remained associated with reduced acne susceptibility after adjustment for either BMI (β= -0.31, P=5.4×10) or BFP (β= -0.25, P=9.02×10). No evidence supported acne causing any of the cardiometabolic traits. These findings suggest shared genetic architecture and support a causal role of lower BMI, BFP and MetS risk on acne development.
The cyclic remodeling of hair follicles in mice has long served as an informative model for studying coordinated tissue transformation in an epithelial-mesenchymal mini-organ. Yet, previous comprehensive studies of the m...The cyclic remodeling of hair follicles in mice has long served as an informative model for studying coordinated tissue transformation in an epithelial-mesenchymal mini-organ. Yet, previous comprehensive studies of the murine hair cycle have been limited in both the timescale and anatomical regions evaluated. We have developed a methodology to assess growth pattern dynamics of cycling hair follicle populations using a highly resolved, wholemount approach. This approach uncovered previously unrecognized yet biologically essential insights into the natural variability of hair cycle patterns between anatomical skin domains and individual animals, as well as across sex and age groups, informing future murine dermatological research. We revealed that hair cycle dynamics are more variable between individual mice than previously appreciated, becoming complexified in late hair cycles. Moreover, prominent spatiotemporal variability exists not only in telogen but also anagen duration, reflected in significant hair fiber length differences between anatomical body regions and timepoints. Our skin-wide hair cycle analysis offers a practical guide for future dermatological studies aimed at determining subtle yet significant hair growth phenotypes, evaluating skin regeneration mechanisms, and uncovering hair growth inducing or suppressing candidate drugs and genetic mutations in mouse models.
Velasco-Herrera MDC, Cheema S, Wong K
… +19 more, Billington J, Vermes I, Anderson E, Ferla E, Harms PW, de Saint Aubain N, Clarke EL, Merchant W, Alomari AK, Rajan N, Ferguson P, Weigelt MA, Monteagudo C, Billings SD, Arends MJ, Ferreira I, Brenn T, van der Weyden L, Adams DJ
Cutaneous T-cell lymphoma is a rare form of non-Hodgkin lymphoma, characterized by the clonal proliferation of neoplastic T cells in the skin. Its early diagnosis is often challenging owing to overlapping clinical featur...Cutaneous T-cell lymphoma is a rare form of non-Hodgkin lymphoma, characterized by the clonal proliferation of neoplastic T cells in the skin. Its early diagnosis is often challenging owing to overlapping clinical features with inflammatory dermatoses. This study investigates TRBC1 as a marker for T-cell clonality in formalin-fixed, paraffin-embedded skin biopsies. We analyzed single-cell RNA-sequencing data from cutaneous T-cell lymphoma skin lesions to examine the expression of TRBC1 in T helper cells. To quantify the extent of TRBC1 polarization, we developed the TRBC1 clonality score (TRBC1-CS). Using patient-specific TRBV mRNA probes and TRBC1 antibodies, we demonstrated polarized TRBC1 expression in TRBV-defined clonal T helper cells in formalin-fixed, paraffin-embedded skin samples. Next, we established a simplified immunofluorescence panel consisting of T-cell markers and TRBC1 to differentiate between cutaneous T-cell lymphoma and benign dermatoses. The findings were validated in an independent cohort by comparing the TRBC1-CS with PCR-based T-cell clonality assays. The TRBC1-CS demonstrated high specificity for cutaneous T-cell lymphoma, enabling delineation from benign dermatoses. Validated in an independent cohort, TRBC1-CS exhibited specificity and positive predictive value superior to those of smaller panels and PCR-based methods. In conclusion, TRBC1 staining and TRBC1-CS provide practical and highly specific tools for assessing T-cell clonality in skin biopsies.
Sahu A, Gill M, Hermawan A
… +16 more, Shinde A, Harris U, Dusza S, Cordova M, Alessi-Fox C, Gonzalez S, Roberts S, Reiner T, Marghoob A, Rossi A, Jason Chen CS, Halpern A, Busam KJ, Guitera P, Jain M, Rajadhyaksha M