Pub Date : 2024-09-19DOI: 10.1016/j.jid.2024.07.036
Thom Doeleman, Siemen Brussee, Liesbeth M Hondelink, Daniëlle W F Westerbeek, Ana M Sequeira, Pieter A Valkema, Patty M Jansen, Junling He, Maarten H Vermeer, Koen D Quint, Marijke R van Dijk, Fons J Verbeek, Jesper Kers, Anne M R Schrader
The diagnosis of early-stage mycosis fungoides (MF) is challenging owing to shared clinical and histopathological features with benign inflammatory dermatoses. Recent evidence has shown that deep learning (DL) can assist pathologists in cancer classification, but this field is largely unexplored for cutaneous lymphomas. This study evaluates DL in distinguishing early-stage MF from benign inflammatory dermatoses using a unique dataset of 924 H&E-stained whole-slide images from skin biopsies, including 233 patients with early-stage MF and 353 patients with benign inflammatory dermatoses. All patients with MF were diagnosed after clinicopathological correlation. The classification accuracy of weakly supervised DL models was benchmarked against 3 expert pathologists. The highest performance on a temporal test set was at ×200 magnification (0.50 μm per pixel resolution), with a mean area under the curve of 0.827 ± 0.044 and a mean balanced accuracy of 76.2 ± 3.9%. This nearly matched the 77.7% mean balanced accuracy of the 3 expert pathologists. Most (63.5%) attention heatmaps corresponded well with the pathologists' region of interest. Considering the difficulty of the MF versus benign inflammatory dermatoses classification task, the results of this study show promise for future applications of weakly supervised DL in diagnosing early-stage MF. Achieving clinical-grade performance will require larger multi-institutional datasets and improved methodologies, such as multimodal DL with incorporation of clinical data.
{"title":"Deep Learning-Based Classification of Early-Stage Mycosis Fungoides and Benign Inflammatory Dermatoses on H&E-Stained Whole-Slide Images: A Retrospective, Proof-of-Concept Study.","authors":"Thom Doeleman, Siemen Brussee, Liesbeth M Hondelink, Daniëlle W F Westerbeek, Ana M Sequeira, Pieter A Valkema, Patty M Jansen, Junling He, Maarten H Vermeer, Koen D Quint, Marijke R van Dijk, Fons J Verbeek, Jesper Kers, Anne M R Schrader","doi":"10.1016/j.jid.2024.07.036","DOIUrl":"10.1016/j.jid.2024.07.036","url":null,"abstract":"<p><p>The diagnosis of early-stage mycosis fungoides (MF) is challenging owing to shared clinical and histopathological features with benign inflammatory dermatoses. Recent evidence has shown that deep learning (DL) can assist pathologists in cancer classification, but this field is largely unexplored for cutaneous lymphomas. This study evaluates DL in distinguishing early-stage MF from benign inflammatory dermatoses using a unique dataset of 924 H&E-stained whole-slide images from skin biopsies, including 233 patients with early-stage MF and 353 patients with benign inflammatory dermatoses. All patients with MF were diagnosed after clinicopathological correlation. The classification accuracy of weakly supervised DL models was benchmarked against 3 expert pathologists. The highest performance on a temporal test set was at ×200 magnification (0.50 μm per pixel resolution), with a mean area under the curve of 0.827 ± 0.044 and a mean balanced accuracy of 76.2 ± 3.9%. This nearly matched the 77.7% mean balanced accuracy of the 3 expert pathologists. Most (63.5%) attention heatmaps corresponded well with the pathologists' region of interest. Considering the difficulty of the MF versus benign inflammatory dermatoses classification task, the results of this study show promise for future applications of weakly supervised DL in diagnosing early-stage MF. Achieving clinical-grade performance will require larger multi-institutional datasets and improved methodologies, such as multimodal DL with incorporation of clinical data.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305320","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 : 2024-09-18DOI: 10.1016/j.jid.2024.08.023
Matilde V Neto, Michael J Hall, João Charneca, Cristina Escrevente, Miguel C Seabra, Duarte C Barral
In the skin, melanin is synthesized by melanocytes within melanosomes and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of UVR. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning through lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo, and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This storage lysosome allows melanin to persist for long periods, where it can exert its photoprotective effect efficiently.
{"title":"Photoprotective Melanin Is Maintained within Keratinocytes in Storage Lysosomes.","authors":"Matilde V Neto, Michael J Hall, João Charneca, Cristina Escrevente, Miguel C Seabra, Duarte C Barral","doi":"10.1016/j.jid.2024.08.023","DOIUrl":"10.1016/j.jid.2024.08.023","url":null,"abstract":"<p><p>In the skin, melanin is synthesized by melanocytes within melanosomes and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of UVR. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning through lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo, and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This storage lysosome allows melanin to persist for long periods, where it can exert its photoprotective effect efficiently.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305324","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 : 2024-09-18DOI: 10.1016/j.jid.2024.09.003
Raquel Sanabria-de la Torre, Trinidad Montero-Vílchez, Juan García-Gavín, Salvador Arias-Santiago
Inflammatory dermatoses and lipid disturbances are interrelated, especially owing to chronic inflammatory conditions. This study aimed to investigate recent findings about lipidomic and dermatologic diseases as well as on the sampling techniques developed to study lipidomics in vivo and analytical and statistical approaches employed. A systematic review was designed using the search algorithm (lipidomics) AND (skin OR dermatology OR stratum corneum OR sebum OR epidermis), following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search identified 1013 references, and finally, only 48 were selected, including a total of 2651 participants with a mean age of 34.13 ± 16.28 years. The dermatologic diseases evaluated were atopic dermatitis, acne, psoriasis, hidradenitis suppurativa, and other skin diseases. Sebutape was the primary sampling technique for lipidomics research. Most of the studies performed untargeted profiling through liquid chromatography with tandem mass spectrometry statistically analyzed with principal component analysis, orthogonal partial least-squares discriminate analysis, heatmap, and volcano plot models. The most consulted databases were LIPIDMAPS Structure Database, MetaboAnalyst, and Human Metabolome Database. A large heterogeneity of lipidomic and lipid metabolism profiles was observed in patients with skin diseases. Skin lipidomic analysis is valuable in exploring skin disease and has ample translational potential.
{"title":"Current Insights on Lipidomics in Dermatology: A Systematic Review.","authors":"Raquel Sanabria-de la Torre, Trinidad Montero-Vílchez, Juan García-Gavín, Salvador Arias-Santiago","doi":"10.1016/j.jid.2024.09.003","DOIUrl":"10.1016/j.jid.2024.09.003","url":null,"abstract":"<p><p>Inflammatory dermatoses and lipid disturbances are interrelated, especially owing to chronic inflammatory conditions. This study aimed to investigate recent findings about lipidomic and dermatologic diseases as well as on the sampling techniques developed to study lipidomics in vivo and analytical and statistical approaches employed. A systematic review was designed using the search algorithm (lipidomics) AND (skin OR dermatology OR stratum corneum OR sebum OR epidermis), following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search identified 1013 references, and finally, only 48 were selected, including a total of 2651 participants with a mean age of 34.13 ± 16.28 years. The dermatologic diseases evaluated were atopic dermatitis, acne, psoriasis, hidradenitis suppurativa, and other skin diseases. Sebutape was the primary sampling technique for lipidomics research. Most of the studies performed untargeted profiling through liquid chromatography with tandem mass spectrometry statistically analyzed with principal component analysis, orthogonal partial least-squares discriminate analysis, heatmap, and volcano plot models. The most consulted databases were LIPIDMAPS Structure Database, MetaboAnalyst, and Human Metabolome Database. A large heterogeneity of lipidomic and lipid metabolism profiles was observed in patients with skin diseases. Skin lipidomic analysis is valuable in exploring skin disease and has ample translational potential.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305319","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 : 2024-09-14DOI: 10.1016/j.jid.2024.08.007
Ivan Jozic, Marjana Tomic-Canic
{"title":"Flipping the Script: Are Cellular Assays and Wound Fluids the Next Frontier in Personalized Wound Care?","authors":"Ivan Jozic, Marjana Tomic-Canic","doi":"10.1016/j.jid.2024.08.007","DOIUrl":"10.1016/j.jid.2024.08.007","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305321","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 : 2024-09-07DOI: 10.1016/j.jid.2024.07.030
Dekker C Deacon, Chris Stubben, Eleonora Marcacci, Caroline J Stone, Michael Birdsall, Scott R Florell, Ken Boucher, Douglas Grossman, Robert L Judson-Torres
{"title":"Classification of Cutaneous Melanoma and Melanocytic Nevi with MicroRNA Ratios Is Preserved in the Acral Melanoma Subtype.","authors":"Dekker C Deacon, Chris Stubben, Eleonora Marcacci, Caroline J Stone, Michael Birdsall, Scott R Florell, Ken Boucher, Douglas Grossman, Robert L Judson-Torres","doi":"10.1016/j.jid.2024.07.030","DOIUrl":"10.1016/j.jid.2024.07.030","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057728","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}
Systemic sclerosis is a typical fibrotic disease of unknown etiology that is characterized by abnormal fibroblast activation and excessive deposition of extracellular matrix. Unfortunately, effective therapeutic approaches are lacking. FGF21 plays a key role in mediating a variety of biological activities. However, its specific function in systemic sclerosis is unclear. In this study, we found that the expression of FGF21 was significantly downregulated in fibrotic skin tissue and in TGF-β-stimulated fibroblasts. Furthermore, our studies demonstrated that treatment with recombinant FGF21 in the skin significantly alleviated bleomycin-induced and TBRI-activated fibrosis and inhibited the activation of fibroblasts, whereas skin fibrosis was exacerbated by deletion of FGF21. Mechanistically, FGF21 inhibits the activity of CK2α and promotes the degradation of GLI2. In conclusion, these results indicate that FGF21 attenuates skin fibrosis through the CK2α/GLI2 signaling pathway and therefore may be a potential therapeutic target for systemic sclerosis.
{"title":"FGF21 Ameliorates Fibroblasts Activation and Systemic Sclerosis by Inhibiting CK2α/GLI2 Signaling Axis.","authors":"Yeyi Zheng, Wenjie Gong, Zhaohang Wu, Siyi Zhang, Nan Wang, Zhenyu Hu, Yanni Shou, Tianpeng Xu, Yingjie Shen, Xiaokun Li, Litai Jin, Weitao Cong, Zhongxin Zhu","doi":"10.1016/j.jid.2024.07.026","DOIUrl":"10.1016/j.jid.2024.07.026","url":null,"abstract":"<p><p>Systemic sclerosis is a typical fibrotic disease of unknown etiology that is characterized by abnormal fibroblast activation and excessive deposition of extracellular matrix. Unfortunately, effective therapeutic approaches are lacking. FGF21 plays a key role in mediating a variety of biological activities. However, its specific function in systemic sclerosis is unclear. In this study, we found that the expression of FGF21 was significantly downregulated in fibrotic skin tissue and in TGF-β-stimulated fibroblasts. Furthermore, our studies demonstrated that treatment with recombinant FGF21 in the skin significantly alleviated bleomycin-induced and TBRI-activated fibrosis and inhibited the activation of fibroblasts, whereas skin fibrosis was exacerbated by deletion of FGF21. Mechanistically, FGF21 inhibits the activity of CK2α and promotes the degradation of GLI2. In conclusion, these results indicate that FGF21 attenuates skin fibrosis through the CK2α/GLI2 signaling pathway and therefore may be a potential therapeutic target for systemic sclerosis.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057730","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 : 2024-09-07DOI: 10.1016/j.jid.2024.07.027
Chantal Rutjes, Adam Mothershaw, Brian M D'Alessandro, Clare A Primiero, Aideen McInerney-Leo, H Peter Soyer, Monika Janda, Brigid Betz-Stablein
{"title":"Combining Automated Lesion Risk and Change Assessment Improves Melanoma Detection: A Retrospective Accuracy Study.","authors":"Chantal Rutjes, Adam Mothershaw, Brian M D'Alessandro, Clare A Primiero, Aideen McInerney-Leo, H Peter Soyer, Monika Janda, Brigid Betz-Stablein","doi":"10.1016/j.jid.2024.07.027","DOIUrl":"10.1016/j.jid.2024.07.027","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057729","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 : 2024-09-07DOI: 10.1016/j.jid.2024.08.006
Yueqi Qiu, Wenjuan Jiang, Delong Feng, Yaqin Yu, Huihui Hou, Min Deng, Xiaoyun Chen, Lin Liu, Ruifang Wu, Qianjin Lu, Ming Zhao
A precise regulation of gene expression depends on the accuracy of the 3-dimensional (3D) structure of chromatin; however, the effects of the 3D genome on gene expression in psoriasis remain unknown. In this study, we conducted Hi-C and RNA sequencing on CD4+ T cells collected from 5 patients with psoriasis and 3 healthy controls and constructed a comprehensive 3D chromatin interaction map to delineate the genomic hierarchies, including A/B compartments, topologically associated domains, and chromatin loops. Then, the specific superenhancers related to psoriasis were identified by Hi-C and H3K27ac chromatin immunoprecipitation sequencing data. Subsequently, comprehensive analyses were carried out on the differentially expressed genes that are associated with altered topologically associated domains, loops, and superenhancers in psoriasis. Finally, we screened the candidate target genes and examined the potential functional SNP in psoriasis affected by disruptions of the spatial organization. This study provides a comprehensive reference for examining the 3D genome interactions in psoriasis and elucidating the interplay between spatial organization disruption and gene regulation. We hope that our findings can help clarify the mechanisms underlying the pathogenesis of psoriasis and shed light on the role of 3D genomic structure, therefore informing potential therapeutic approaches.
{"title":"Resolving 3-Dimensional Genomic Landscape of CD4+ T Cells in the Peripheral Blood of Patients with Psoriasis.","authors":"Yueqi Qiu, Wenjuan Jiang, Delong Feng, Yaqin Yu, Huihui Hou, Min Deng, Xiaoyun Chen, Lin Liu, Ruifang Wu, Qianjin Lu, Ming Zhao","doi":"10.1016/j.jid.2024.08.006","DOIUrl":"10.1016/j.jid.2024.08.006","url":null,"abstract":"<p><p>A precise regulation of gene expression depends on the accuracy of the 3-dimensional (3D) structure of chromatin; however, the effects of the 3D genome on gene expression in psoriasis remain unknown. In this study, we conducted Hi-C and RNA sequencing on CD4+ T cells collected from 5 patients with psoriasis and 3 healthy controls and constructed a comprehensive 3D chromatin interaction map to delineate the genomic hierarchies, including A/B compartments, topologically associated domains, and chromatin loops. Then, the specific superenhancers related to psoriasis were identified by Hi-C and H3K27ac chromatin immunoprecipitation sequencing data. Subsequently, comprehensive analyses were carried out on the differentially expressed genes that are associated with altered topologically associated domains, loops, and superenhancers in psoriasis. Finally, we screened the candidate target genes and examined the potential functional SNP in psoriasis affected by disruptions of the spatial organization. This study provides a comprehensive reference for examining the 3D genome interactions in psoriasis and elucidating the interplay between spatial organization disruption and gene regulation. We hope that our findings can help clarify the mechanisms underlying the pathogenesis of psoriasis and shed light on the role of 3D genomic structure, therefore informing potential therapeutic approaches.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057750","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}