Pub Date : 2026-01-13DOI: 10.1016/j.xjidi.2026.100450
Rachel C. Chang , Henning Olbrich , Yulu F. Wang , Haley Gainer , Nina Curkovic , Theresa L. Walunas , Jessica Shiu , Parul Goyal , Adrian P. Mansini , Ralf J. Ludwig , Kyle T. Amber
Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies to collagen type 17 (COL17A1) and is a recognized immune-related adverse event in patients receiving immune checkpoint inhibitors (ICIs). We investigated whether cancer type influences the risk of developing ICI-induced BP and whether COL17A1 mutations or dysregulation in tumor tissue contributes to disease-specific variation. Using TriNetX, systematic review, and bioinformatics datasets, we comprehensively assessed the associations of ICI-induced BP with different malignancy types as well as COL17A1 gene expression, mutation frequency, and immune correlations across cancers. Lung cancer was the most common underlying malignancy in ICI-induced BP, but nonmelanoma skin cancer and renal cell carcinoma had the highest relative risk, whereas lung cancer had the lowest. ICI-induced BP was associated with improved survival across several cancers. Urothelial cancer showed the shortest time to onset, whereas renal cell carcinoma showed the longest. Cutaneous squamous cell carcinoma and melanoma exhibited the highest COL17A1 mutation burden, whereas renal cell carcinoma had a low burden. COL17A1 was overexpressed in several cancers but underexpressed in melanoma, without strong correlation to tumor-infiltrating immune cells. Although the incidence of ICI-induced BP significantly differed on the basis of cancer type, COL17A1 mutations or dysregulation do not appear to drive this phenomenon, suggesting alternative immune mechanisms.
{"title":"Association of immune checkpoint inhibitor-induced bullous pemphigoid with underlying cancer type: A lack of association with cancer tissue COL17A1 mutations and dysregulation","authors":"Rachel C. Chang , Henning Olbrich , Yulu F. Wang , Haley Gainer , Nina Curkovic , Theresa L. Walunas , Jessica Shiu , Parul Goyal , Adrian P. Mansini , Ralf J. Ludwig , Kyle T. Amber","doi":"10.1016/j.xjidi.2026.100450","DOIUrl":"10.1016/j.xjidi.2026.100450","url":null,"abstract":"<div><div>Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies to collagen type 17 (<em>COL17A1</em>) and is a recognized immune-related adverse event in patients receiving immune checkpoint inhibitors (ICIs). We investigated whether cancer type influences the risk of developing ICI-induced BP and whether <em>COL17A1</em> mutations or dysregulation in tumor tissue contributes to disease-specific variation. Using TriNetX, systematic review, and bioinformatics datasets, we comprehensively assessed the associations of ICI-induced BP with different malignancy types as well as <em>COL17A1</em> gene expression, mutation frequency, and immune correlations across cancers. Lung cancer was the most common underlying malignancy in ICI-induced BP, but nonmelanoma skin cancer and renal cell carcinoma had the highest relative risk, whereas lung cancer had the lowest. ICI-induced BP was associated with improved survival across several cancers. Urothelial cancer showed the shortest time to onset, whereas renal cell carcinoma showed the longest. Cutaneous squamous cell carcinoma and melanoma exhibited the highest <em>COL17A1</em> mutation burden, whereas renal cell carcinoma had a low burden. <em>COL17A1</em> was overexpressed in several cancers but underexpressed in melanoma, without strong correlation to tumor-infiltrating immune cells. Although the incidence of ICI-induced BP significantly differed on the basis of cancer type, <em>COL17A1</em> mutations or dysregulation do not appear to drive this phenomenon, suggesting alternative immune mechanisms.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100450"},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/S2667-0267(25)00104-3
{"title":"Cover","authors":"","doi":"10.1016/S2667-0267(25)00104-3","DOIUrl":"10.1016/S2667-0267(25)00104-3","url":null,"abstract":"","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100448"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.xjidi.2025.100446
Mehdi Boostani , Ximena Wortsman , Giovanni Pellacani , Krisztián Füzesi , Mariano Suppa , Veronique Del Marmol , Florencia Vera Morandini , Javiera Perez-Anker , Priscila Giavedoni , Carmen Cantisani , Lucas Boussingault , Miklós Gyöngy , Gyorgy Paragh , Kamran Avanaki , Norbert Kiss
Conventional skin imaging modalities are often bulky, expensive, and impractical for routine dermatology practice. There is a need for a portable, multimodal imaging tool that integrates high-resolution surface and subsurface visualization at the point of care. The aim of this study was to describe the design, technical capabilities, and clinical application of dermoscopy-guided high-frequency ultrasound and to evaluate its performance across a range of dermatologic conditions. Dermoscopy-guided high-frequency ultrasound was applied to a total of 130 lesions from 122 patients at the Department of Dermatology, Semmelweis University (Budapest, Hungary); Université Libre de Bruxelles (Brussels, Belgium); and Hospital Clínic, Universidad de Barcelona (Barcelona, Spain). The examined cases included malignant skin cancers and inflammatory disorders. Dermoscopy-guided high-frequency ultrasound enabled simultaneous visualization and correlation of surface dermoscopic patterns with underlying structural alterations in real time. The device identified disease-specific imaging features for both malignant and inflammatory lesions. Artificial intelligence-based segmentation improved image interpretability. Dermoscopy-guided high-frequency ultrasound bridges a critical gap between surface and subsurface dermatologic imaging, offering a practical, portable, and cost-effective solution that could enhance noninvasive diagnosis and management in dermatologic care.
{"title":"Dermoscopy-guided high-frequency ultrasound: Principles and applications in dermatology","authors":"Mehdi Boostani , Ximena Wortsman , Giovanni Pellacani , Krisztián Füzesi , Mariano Suppa , Veronique Del Marmol , Florencia Vera Morandini , Javiera Perez-Anker , Priscila Giavedoni , Carmen Cantisani , Lucas Boussingault , Miklós Gyöngy , Gyorgy Paragh , Kamran Avanaki , Norbert Kiss","doi":"10.1016/j.xjidi.2025.100446","DOIUrl":"10.1016/j.xjidi.2025.100446","url":null,"abstract":"<div><div>Conventional skin imaging modalities are often bulky, expensive, and impractical for routine dermatology practice. There is a need for a portable, multimodal imaging tool that integrates high-resolution surface and subsurface visualization at the point of care. The aim of this study was to describe the design, technical capabilities, and clinical application of dermoscopy-guided high-frequency ultrasound and to evaluate its performance across a range of dermatologic conditions. Dermoscopy-guided high-frequency ultrasound was applied to a total of 130 lesions from 122 patients at the Department of Dermatology, Semmelweis University (Budapest, Hungary); Université Libre de Bruxelles (Brussels, Belgium); and Hospital Clínic, Universidad de Barcelona (Barcelona, Spain). The examined cases included malignant skin cancers and inflammatory disorders. Dermoscopy-guided high-frequency ultrasound enabled simultaneous visualization and correlation of surface dermoscopic patterns with underlying structural alterations in real time. The device identified disease-specific imaging features for both malignant and inflammatory lesions. Artificial intelligence-based segmentation improved image interpretability. Dermoscopy-guided high-frequency ultrasound bridges a critical gap between surface and subsurface dermatologic imaging, offering a practical, portable, and cost-effective solution that could enhance noninvasive diagnosis and management in dermatologic care.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100446"},"PeriodicalIF":0.0,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The distribution of receptors and cellular factors across tissues determines differential susceptibility of cells to viral infection. For severe acute respiratory syndrome coronavirus 2, viral spike and nucleocapsid proteins have been detected in the skin of infected patients. Whether the virus can directly infect skin cells has yet to be fully evaluated. Severe acute respiratory syndrome coronavirus 2 enters cells through 2 routes: ACE2-driven endocytosis and TMPRSS2-mediated plasma membrane fusion or ACE2/alternative receptors-driven endocytosis and cathepsin L–dependent fusion. This study assessed the gene and protein expression of these entry receptors and coreceptors in primary keratinocytes and fibroblasts. We found that the main severe acute respiratory syndrome coronavirus 2 receptor ACE2 is present in human keratinocytes and is upregulated during their differentiation and toll-like receptor 3–mediated activation, whereas the coreceptor TMPRSS2 for fusion is absent, but mature cathepsin L is expressed. In vitro infection assays using the severe acute respiratory syndrome coronavirus 2 Delta variant showed that the virus can bind to the cell surface but cannot replicate within the cells. These findings suggest that although active viral replication in keratinocytes is unlikely, the presence and inducible upregulation of ACE2 in response to inflammatory stimuli may confer a limited potential for cutaneous viral entry, warranting further investigation into the consequences in terms of local inflammation and viral transmission.
{"title":"Human keratinocytes exhibit limited potential for SARS-CoV-2 infection despite ACE2 and mature cathepsin L expression","authors":"Leslie Hertereau , Manon Barthe , Noura Lamghari , Peggy Merida , Gaelle Pommier , Elisabeth Pinel , Jitendriya Swain , Delphine Muriaux , Hanan Osman-Ponchet , Véronique M. Braud","doi":"10.1016/j.xjidi.2025.100447","DOIUrl":"10.1016/j.xjidi.2025.100447","url":null,"abstract":"<div><div>The distribution of receptors and cellular factors across tissues determines differential susceptibility of cells to viral infection. For severe acute respiratory syndrome coronavirus 2, viral spike and nucleocapsid proteins have been detected in the skin of infected patients. Whether the virus can directly infect skin cells has yet to be fully evaluated. Severe acute respiratory syndrome coronavirus 2 enters cells through 2 routes: ACE2-driven endocytosis and TMPRSS2-mediated plasma membrane fusion or ACE2/alternative receptors-driven endocytosis and cathepsin L–dependent fusion. This study assessed the gene and protein expression of these entry receptors and coreceptors in primary keratinocytes and fibroblasts. We found that the main severe acute respiratory syndrome coronavirus 2 receptor ACE2 is present in human keratinocytes and is upregulated during their differentiation and toll-like receptor 3–mediated activation, whereas the coreceptor TMPRSS2 for fusion is absent, but mature cathepsin L is expressed. In vitro infection assays using the severe acute respiratory syndrome coronavirus 2 Delta variant showed that the virus can bind to the cell surface but cannot replicate within the cells. These findings suggest that although active viral replication in keratinocytes is unlikely, the presence and inducible upregulation of ACE2 in response to inflammatory stimuli may confer a limited potential for cutaneous viral entry, warranting further investigation into the consequences in terms of local inflammation and viral transmission.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100447"},"PeriodicalIF":0.0,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.xjidi.2025.100440
Russell P. Hall III MD (Editor, JID Innovations), J. Lamar Callaway Professor
{"title":"JID Innovations: 5-Years old: Origins and opportunities","authors":"Russell P. Hall III MD (Editor, JID Innovations), J. Lamar Callaway Professor","doi":"10.1016/j.xjidi.2025.100440","DOIUrl":"10.1016/j.xjidi.2025.100440","url":null,"abstract":"","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100440"},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.xjidi.2025.100445
Árpád Ármin Balogh , Márta Széll , Nikoletta Nagy
The common missense variant rs1126809 in the TYR gene, encoding a key enzyme in melanin synthesis, is linked to both albinism and melanoma susceptibility. Although its role in hypopigmentation as part of a risk haplotype is established, its function in melanoma is less understood. To investigate population- and haplotype-dependent associations surrounding TYR rs1126809 that may suggest directions for future studies on melanoma risk and melanocyte biology, we analyzed melanoma GWAS summary statistics using FUMA to identify lead SNPs in linkage disequilibrium with rs1126809 and assessed their regulatory potential using chromatin state data from melanocytes, keratinocytes, and fibroblasts. Haplotype structures were examined in European, American, and South Asian populations using LDlink. rs1126809 emerged as lead SNP in the TYR locus. Thirty SNPs were in high linkage disequilibrium, 6 of which reside in melanocyte-specific regulatory regions. These variants form population-specific haplotypes that may modulate TYR expression. In Europeans and Americans, 2 distinct haplotypes carrying the risk allele showed different linked SNP profiles, suggesting haplotype-dependent effects. The findings suggest that variations surrounding TYR rs1126809 may exhibit population- and haplotype-dependent patterns relevant to melanoma risk, pointing to previously unreported directions for future research and refinement of polygenic risk modeling.
{"title":"Population- and haplotype-dependent variation around TYR rs1126809: An in silico study for melanoma risk research","authors":"Árpád Ármin Balogh , Márta Széll , Nikoletta Nagy","doi":"10.1016/j.xjidi.2025.100445","DOIUrl":"10.1016/j.xjidi.2025.100445","url":null,"abstract":"<div><div>The common missense variant rs1126809 in the <em>TYR</em> gene, encoding a key enzyme in melanin synthesis, is linked to both albinism and melanoma susceptibility. Although its role in hypopigmentation as part of a risk haplotype is established, its function in melanoma is less understood. To investigate population- and haplotype-dependent associations surrounding <em>TYR</em> rs1126809 that may suggest directions for future studies on melanoma risk and melanocyte biology, we analyzed melanoma GWAS summary statistics using FUMA to identify lead SNPs in linkage disequilibrium with rs1126809 and assessed their regulatory potential using chromatin state data from melanocytes, keratinocytes, and fibroblasts. Haplotype structures were examined in European, American, and South Asian populations using LDlink. rs1126809 emerged as lead SNP in the <em>TYR</em> locus. Thirty SNPs were in high linkage disequilibrium, 6 of which reside in melanocyte-specific regulatory regions. These variants form population-specific haplotypes that may modulate TYR expression. In Europeans and Americans, 2 distinct haplotypes carrying the risk allele showed different linked SNP profiles, suggesting haplotype-dependent effects. The findings suggest that variations surrounding <em>TYR</em> rs1126809 may exhibit population- and haplotype-dependent patterns relevant to melanoma risk, pointing to previously unreported directions for future research and refinement of polygenic risk modeling.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100445"},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.xjidi.2025.100443
Cristina de Guzman Strong
{"title":"JID Innovations: Supporting innovative skin science in 2025 and beyond with new perspectives","authors":"Cristina de Guzman Strong","doi":"10.1016/j.xjidi.2025.100443","DOIUrl":"10.1016/j.xjidi.2025.100443","url":null,"abstract":"","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100443"},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.xjidi.2025.100444
Alejandro Gonzalez Torres , Fabien P. Chevalier , Ruth Aquino , Mélanie Aimard , Patrick Baril , Jérôme Lamartine
MicroRNAs are short noncoding RNAs that play important roles in fine tuning genetic networks as genes post-transcriptional regulators. Monitoring the regulatory activity of microRNAs is technically challenging, especially in primary cells and 3-dimensional (3D) organotypic cultures. We optimized the previously reported RILES miRNA-ON sensor system to visualize the spatial expression of miR-203 and miR-30a by fluorescence imaging in 2-dimensional and 3D cultures of human primary keratinocytes. The generated system, called RIFES (RNAi-inducible fluorescence expression system), successfully imaged the expression of miR-30a-5p and miR-30a-3p in the suprabasal layers of the epidermis. This information was exploited to uncover the molecular mechanisms regulating the expression of miR-30a in human keratinocytes. We demonstrate that chemical inhibition of the Notch1 pathway induced GFP expression in undifferentiated RIFES/miR-30a keratinocyte cells, with fluorescence redistribution in the basal layers of 3D RIFES/miR-30a epidermis. Moreover, overexpressing miR-30a in 3D epidermal models resulted in NOTCH1 downregulation, suggesting a negative feedback loop between miR-30a and Notch. Because the Notch pathway was found downregulated in aged epidermis biopsies, we propose that Notch downregulation contributes to miR-30a induction during aging. Therefore, the RIFES system appears as a powerful tool to visualize the expression of microRNAs in 3D epidermis and to identify their potential upstream regulators.
{"title":"Spatiotemporal fluorescence imaging of microRNA activity in 3-D models of human epidermis reveals contribution of the Notch pathway in the regulation of miR-30a in aging skin","authors":"Alejandro Gonzalez Torres , Fabien P. Chevalier , Ruth Aquino , Mélanie Aimard , Patrick Baril , Jérôme Lamartine","doi":"10.1016/j.xjidi.2025.100444","DOIUrl":"10.1016/j.xjidi.2025.100444","url":null,"abstract":"<div><div>MicroRNAs are short noncoding RNAs that play important roles in fine tuning genetic networks as genes post-transcriptional regulators. Monitoring the regulatory activity of microRNAs is technically challenging, especially in primary cells and 3-dimensional (3D) organotypic cultures. We optimized the previously reported RILES miRNA-ON sensor system to visualize the spatial expression of miR-203 and miR-30a by fluorescence imaging in 2-dimensional and 3D cultures of human primary keratinocytes. The generated system, called RIFES (RNAi-inducible fluorescence expression system), successfully imaged the expression of miR-30a-5p and miR-30a-3p in the suprabasal layers of the epidermis. This information was exploited to uncover the molecular mechanisms regulating the expression of miR-30a in human keratinocytes. We demonstrate that chemical inhibition of the Notch1 pathway induced GFP expression in undifferentiated RIFES/miR-30a keratinocyte cells, with fluorescence redistribution in the basal layers of 3D RIFES/miR-30a epidermis. Moreover, overexpressing miR-30a in 3D epidermal models resulted in NOTCH1 downregulation, suggesting a negative feedback loop between miR-30a and Notch. Because the Notch pathway was found downregulated in aged epidermis biopsies, we propose that Notch downregulation contributes to miR-30a induction during aging. Therefore, the RIFES system appears as a powerful tool to visualize the expression of microRNAs in 3D epidermis and to identify their potential upstream regulators.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100444"},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.xjidi.2025.100441
Elisabeth A. Pedersen , Marina Grachtchouk , Paul W. Harms , Allison K.C. Furgal , Dawn Wilbert , Allesandra Hoover , Daryna V. Hodgson , Katelyn Fiehler , Anissa Alam , Nihal Lingam , Sunny Y. Wong , Monique E. Verhaegen , Andrzej A. Dlugosz
Basal cell carcinoma (BCC) is the most common skin malignancy, and the risk of developing BCC increases with age. BCC results from dysregulated Hedgehog signaling leading to activation of GLI transcription factors. In this study, we examined the impact of aging on BCC in cohorts of young (n = 37) versus aged (n = 97) mice using a transgenic mouse model in which GLI2A (GLI2 activator) was induced in mice at either the age of 7 weeks or 22–24 months, and BCC tumor development was monitored by weekly imaging. Young mice developed tumors slightly sooner and in greater numbers than aged mice but demonstrated similar growth rates once tumors appeared. However, BCC-associated increases in blood vessel diameter, tortuosity, and ulceration were impacted by age. BCCs in both young and aged mice underwent similarly rapid regression after GLI2A transgene inactivation. Taken together, our findings reveal that aging affects tumor-associated vasculature but not BCC formation or regression in our model. These results are in keeping with the notion that a major contributor to the increased incidence of BCCs in elderly patients is the accumulation of oncogenic driver mutations over time rather than intrinsic changes in aged skin that promote BCC tumorigenesis.
{"title":"Spatially controlled induction and regression of basal cell carcinoma, visualized by serial imaging in young and old mice","authors":"Elisabeth A. Pedersen , Marina Grachtchouk , Paul W. Harms , Allison K.C. Furgal , Dawn Wilbert , Allesandra Hoover , Daryna V. Hodgson , Katelyn Fiehler , Anissa Alam , Nihal Lingam , Sunny Y. Wong , Monique E. Verhaegen , Andrzej A. Dlugosz","doi":"10.1016/j.xjidi.2025.100441","DOIUrl":"10.1016/j.xjidi.2025.100441","url":null,"abstract":"<div><div>Basal cell carcinoma (BCC) is the most common skin malignancy, and the risk of developing BCC increases with age. BCC results from dysregulated Hedgehog signaling leading to activation of GLI transcription factors. In this study, we examined the impact of aging on BCC in cohorts of young (n = 37) versus aged (n = 97) mice using a transgenic mouse model in which GLI2A (GLI2 activator) was induced in mice at either the age of 7 weeks or 22–24 months, and BCC tumor development was monitored by weekly imaging. Young mice developed tumors slightly sooner and in greater numbers than aged mice but demonstrated similar growth rates once tumors appeared. However, BCC-associated increases in blood vessel diameter, tortuosity, and ulceration were impacted by age. BCCs in both young and aged mice underwent similarly rapid regression after GLI2A transgene inactivation. Taken together, our findings reveal that aging affects tumor-associated vasculature but not BCC formation or regression in our model. These results are in keeping with the notion that a major contributor to the increased incidence of BCCs in elderly patients is the accumulation of oncogenic driver mutations over time rather than intrinsic changes in aged skin that promote BCC tumorigenesis.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100441"},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Congenital ichthyoses, now renamed epidermal differentiation disorders (EDDs) (syndromic EDD or nonsyndromic EDD), are rare, disabling conditions caused by sequence variations in epidermal barrier genes. However, 5–10% of variants, called “variants of uncertain significance” (VUS), remain uncharacterized, and their pathogenicity is not demonstrated. We developed an approach for classifying VUS in nonsyndromic EDD associated with variant in PNPLA1. We generated PNPLA1-knockout human keratinocytes. PNPLA1, encoded by a missense VUS or by the reference coding sequence, was expressed after lentiviral transduction in the PNPLA1-knockout cells. Transduced cells were used to produce human epidermal equivalents, and the functionality of the normal or VUS-encoded proteins was evaluated. Compared with PNPLA1-knockout human epidermal equivalents re-expressing normal PNPLA1, PNPLA1-knockout human epidermal equivalents showed disrupted synthesis of ω-O-acylceramide, the normal product of PNPLA1, as well as abnormal vesicle-like structures and immature cornified envelopes, characteristic of the epidermis of patients with PNPLA1 variants. Human epidermal equivalents expressing the PNPLA1 VUS showed similar abnormalities, consistent with an impaired PNPLA1 function. This work demonstrated a feasible strategy to help reclassifying missense VUS, which can be extended to other EDD-related genes. Although further efforts are needed to translate this approach into clinical practice and help overcome current diagnostic limitations, such models are valuable tools for pathophysiological and preclinical research on EDDs.
先天性鱼鳞病，现在更名为表皮分化障碍（EDDs）（综合征型EDD或非综合征型EDD），是由表皮屏障基因序列变异引起的罕见致残性疾病。然而，5-10%的变异，称为“不确定意义的变异”（VUS），仍然没有特征，它们的致病性也没有得到证实。我们开发了一种方法对与PNPLA1变异相关的非综合征性EDD的VUS进行分类。我们产生了pnpla1敲除的人角质形成细胞。PNPLA1由错义VUS或参考编码序列编码，在PNPLA1敲除细胞中经过慢病毒转导后表达。转导的细胞用于产生人表皮等价物，并评估正常或vus编码蛋白的功能。与敲除PNPLA1后重新表达正常PNPLA1的人表皮等效物相比，敲除PNPLA1后的人表皮等效物显示出PNPLA1正常产物ω- o -酰基神经酰胺的合成中断，以及PNPLA1变异患者表皮特征的异常囊泡样结构和未成熟的角质包膜。表达PNPLA1 VUS的人表皮等同物也表现出类似的异常，与PNPLA1功能受损一致。这项工作证明了一种可行的策略来帮助重新分类错义VUS，这可以扩展到其他edd相关基因。尽管将这种方法转化为临床实践并帮助克服当前的诊断局限性还需要进一步的努力，但这些模型对于EDDs的病理生理和临床前研究是有价值的工具。
{"title":"A standardized approach to test missense PNPLA1 rare genetic variants of uncertain significance in epidermal differentiation disorders","authors":"Nuria Pell , Pauline Bernard , Séverine Courrech , Lukas Opalka , Aina Millán-Sánchez , Elise Levy , Séverine Garnier , Cyrielle Clément , Pauline Le Faouder , Katerina Vávrová , Olga López , Justine Bertrand-Michel , Corinne Leprince , Isabelle Fourquaux , José-Enrique Mejia , Jean-Christophe Pagès , Juliette Mazereeuw-Hautier , Nathalie Jonca","doi":"10.1016/j.xjidi.2025.100442","DOIUrl":"10.1016/j.xjidi.2025.100442","url":null,"abstract":"<div><div>Congenital ichthyoses, now renamed epidermal differentiation disorders (EDDs) (syndromic EDD or nonsyndromic EDD), are rare, disabling conditions caused by sequence variations in epidermal barrier genes. However, 5–10% of variants, called “variants of uncertain significance” (VUS), remain uncharacterized, and their pathogenicity is not demonstrated. We developed an approach for classifying VUS in nonsyndromic EDD associated with variant in <em>PNPLA1</em>. We generated <em>PNPLA1</em>-knockout human keratinocytes. PNPLA1, encoded by a missense VUS or by the reference coding sequence, was expressed after lentiviral transduction in the <em>PNPLA1</em>-knockout cells. Transduced cells were used to produce human epidermal equivalents, and the functionality of the normal or VUS-encoded proteins was evaluated. Compared with <em>PNPLA1</em>-knockout human epidermal equivalents re-expressing normal PNPLA1, <em>PNPLA1</em>-knockout human epidermal equivalents showed disrupted synthesis of ω-O-acylceramide, the normal product of PNPLA1, as well as abnormal vesicle-like structures and immature cornified envelopes, characteristic of the epidermis of patients with <em>PNPLA1</em> variants. Human epidermal equivalents expressing the <em>PNPLA1</em> VUS showed similar abnormalities, consistent with an impaired PNPLA1 function. This work demonstrated a feasible strategy to help reclassifying missense VUS, which can be extended to other EDD-related genes. Although further efforts are needed to translate this approach into clinical practice and help overcome current diagnostic limitations, such models are valuable tools for pathophysiological and preclinical research on EDDs.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100442"},"PeriodicalIF":0.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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