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Advancements in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Treatment: Utilizing Fas-FasL Inhibition to Target Cell Death Signaling Pathways for Practical Human Application. 史蒂文斯-约翰逊综合征/毒性表皮坏死症治疗的进展:利用 Fas-Fas 配体抑制靶向细胞死亡信号通路的实际人体应用。
Pub Date : 2024-09-19 DOI: 10.1016/j.jid.2024.08.028
Yuki Saito, Roberta Lotti, Haruna Kimura, Akito Hasegawa, Brydon Bennett, Antonino Amato, Carlo Pincelli, Riichiro Abe
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引用次数: 0
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. 基于深度学习的早期真菌病和良性炎症性皮肤病分类:一项回顾性概念验证研究。
Pub Date : 2024-09-19 DOI: 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.

由于与良性炎症性皮肤病(BID)具有共同的临床和组织病理学特征,早期真菌病(MF)的诊断具有挑战性。最近的证据表明,深度学习(DL)可以帮助病理学家进行癌症分类,但这一领域在皮肤淋巴瘤方面基本上还没有探索。本研究使用一个独特的数据集评估了深度学习在区分早期 MF 和 BID 方面的作用,该数据集包含来自皮肤活检的 924 张苏木精和伊红染色全切片图像,其中包括 233 名早期 MF 患者和 353 名 BID 患者。所有多发性骨髓瘤患者都是在临床病理相关性检查后确诊的。弱监督 DL 模型的分类准确性以三位病理专家为基准。在放大 200 倍(每像素分辨率为 0.25 μm)的时间测试集上,该模型的性能最高,平均曲线下面积为 0.827 ± 0.044,平均平衡准确率为 76.2 ± 3.9%。这几乎与三位病理专家 77.7% 的平均均衡准确率相吻合。大多数(63.5%)注意力热图与病理学家的兴趣区域非常吻合。考虑到 MF 与 BID 分类任务的难度,本研究的结果显示了弱监督 DL 在诊断早期 MF 中的未来应用前景。要达到临床级别的性能,需要更大的多机构数据集和改进的方法,如结合临床数据的多模态 DL。
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引用次数: 0
Photoprotective Melanin Is Maintained within Keratinocytes in Storage Lysosomes. 具有光保护作用的黑色素保存在角质形成细胞的贮存溶酶体中。
Pub Date : 2024-09-18 DOI: 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.

在皮肤中,黑色素由黑色素细胞在黑色素体中合成,然后转移到角质形成细胞。黑色素被角质形成细胞吞噬后,极化为核上盖,从而抵御紫外线辐射的基因毒性影响。我们提供的证据表明,含黑色素的吞噬体经历了一个典型的成熟过程,依次获得早期和晚期内体标记。随后,这些吞噬体与活性溶酶体融合,形成含黑色素的吞噬溶酶体,我们将其命名为黑色素小体(melanokerasome)。黑色角质体通过溶酶体转运调节因子Rab7和RILP实现并核定位。成熟的黑色角酶体具有溶酶体标记,不与内吞噬/吞噬途径连接,降解能力弱,保留未消化的货物,并很可能被拴在核膜上。我们认为,它们代表了一种已退出溶酶体循环的溶酶体储存区,类似于衰老细胞中脂褐素的形成以及溶酶体储存和老年相关疾病中功能失调的溶酶体。这种贮存溶酶体可使黑色素长期存在,从而有效地发挥光保护作用。
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引用次数: 0
Current Insights on Lipidomics in Dermatology: A Systematic Review. 关于皮肤病学中脂质组学的最新见解:系统回顾
Pub Date : 2024-09-18 DOI: 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.

炎症性皮肤病和脂质紊乱是相互关联的,尤其是慢性炎症性皮肤病。本研究旨在调查有关脂质组学和皮肤病的最新发现,以及为研究体内脂质组学而开发的取样技术和采用的分析与统计方法。根据 PRISMA 指南,采用"(脂质组学)和(皮肤或皮肤病学或角质层或皮脂或表皮)"的搜索算法设计了一篇系统综述。文献检索发现了 1013 篇参考文献,最后只选择了 48 篇,共包括 2651 名参与者,平均年龄为(34.13±16.28)岁。评估的皮肤病包括特应性皮炎(AD)、痤疮、银屑病、化脓性扁桃体炎(HS)和其他皮肤病。Sebutape®是脂质组学研究的主要取样技术。大多数研究通过液相色谱-串联质谱(LC-MS/MS)技术进行非靶向分析,并使用主成分分析(PCA)、正交部分最小二乘判别分析(OPLS-DA)、热图和火山图模型进行统计分析。查阅最多的数据库是 LIPIDMAPS® Structure Database (LMSD)、MetaboAnalyst 和 Human Metabolome Database (HMDB)。在皮肤病患者中观察到的脂质组学和脂质代谢谱具有很大的异质性。皮肤脂质体分析对探索皮肤疾病很有价值,并具有很大的转化潜力。
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引用次数: 0
Boosting Skin Wound Healing by Agrin-Mediated YAP/TAZ Activation. 通过 Agrin 介导的 YAP/TAZ 激活促进皮肤伤口愈合
Pub Date : 2024-09-14 DOI: 10.1016/j.jid.2024.06.1291
Ute Jungwirth, Gernot Walko
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引用次数: 0
Flipping the Script: Are Cellular Assays and Wound Fluids the Next Frontier in Personalized Wound Care? 翻转剧本:细胞检测和伤口输液是个性化伤口护理的下一个前沿领域吗?
Pub Date : 2024-09-14 DOI: 10.1016/j.jid.2024.08.007
Ivan Jozic, Marjana Tomic-Canic
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引用次数: 0
Classification of Cutaneous Melanoma and Melanocytic Nevi with MicroRNA Ratios Is Preserved in the Acral Melanoma Subtype. 用 microRNA 比率对皮肤黑色素瘤和黑色素细胞痣进行分类在口腔黑色素瘤亚型中得以保留。
Pub Date : 2024-09-07 DOI: 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
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引用次数: 0
FGF21 Ameliorates Fibroblasts Activation and Systemic Sclerosis by Inhibiting CK2α/GLI2 Signaling Axis. FGF21通过抑制CK2α/GLI2信号轴改善成纤维细胞活化和系统性硬化症
Pub Date : 2024-09-07 DOI: 10.1016/j.jid.2024.07.026
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

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.

系统性硬化症(SSc)是一种病因不明的典型纤维化疾病,其特点是成纤维细胞异常活化和细胞外基质过度沉积。遗憾的是,目前尚缺乏有效的治疗方法。成纤维细胞生长因子 21(FGF21)在介导多种生物活性方面发挥着关键作用。然而,它在 SSc 中的具体功能尚不清楚。在这项研究中,我们发现在纤维化皮肤组织和转化生长因子-β(TGF-β)刺激的成纤维细胞中,FGF21 的表达明显下调。此外,我们的研究表明,在皮肤中使用重组 FGF21 能明显缓解博莱霉素(BLM)诱导的和 TGF-β 受体 I(TBRI)激活的纤维化,并抑制成纤维细胞的活化,而 FGF21 的缺失会加剧皮肤纤维化。从机制上讲,FGF21 可抑制 CK2α 的活性并促进 GLI2 的降解。总之,这些结果表明,FGF21可通过CK2α/GLI2信号通路减轻皮肤纤维化,因此可能成为系统性硬化症的潜在治疗靶点。
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引用次数: 0
Combining Automated Lesion Risk and Change Assessment Improves Melanoma Detection: A Retrospective Accuracy Study. 结合自动病变风险和变化评估可提高黑色素瘤检测率:回顾性准确性研究
Pub Date : 2024-09-07 DOI: 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
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引用次数: 0
Resolving 3-Dimensional Genomic Landscape of CD4+ T Cells in the Peripheral Blood of Patients with Psoriasis. 解析银屑病患者外周血中 CD4+ T 细胞的三维基因组图谱。
Pub Date : 2024-09-07 DOI: 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.

基因表达的精确调控取决于染色质三维(3D)结构的准确性;然而,三维基因组对银屑病基因表达的影响仍然未知。在这项研究中,我们对采集自5名银屑病患者和3名健康对照者的CD4+T细胞进行了Hi-C和RNA-seq分析,并构建了全面的三维染色质相互作用图谱,以划分基因组层次,包括A/B区、拓扑相关域(TAD)和染色质环。然后,通过Hi-C和H3K27ac ChIP-seq数据确定了与银屑病相关的特异性超级增强子(SEs)。随后,我们对银屑病中与TADs、环路和SEs改变相关的差异表达基因进行了综合分析。最后,我们筛选了候选靶基因,并研究了受空间组织破坏影响的银屑病中潜在的功能性单核苷酸多态性。本文为研究银屑病的三维基因组相互作用以及阐明空间组织破坏与基因调控之间的相互作用提供了全面的参考。我们希望我们的发现有助于阐明银屑病的发病机制,揭示三维基因组结构的作用,从而为潜在的治疗方法提供参考。
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引用次数: 0
期刊
The Journal of investigative dermatology
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