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Unveiling Common Transcriptomic Features between Melanoma Brain Metastases and Neurodegenerative Diseases. 揭示黑色素瘤脑转移瘤与神经退行性疾病的共同转录组特征
Pub Date : 2024-09-24 DOI: 10.1016/j.jid.2024.09.005
Irene Soler-Sáez, Alcida Karz, Marta R Hidalgo, Borja Gómez-Cabañes, Adolfo López-Cerdán, José F Català-Senent, Kylie Prutisto-Chang, Nicole M Eskow, Benjamin Izar, Torben Redmer, Swaminathan Kumar, Michael A Davies, María de la Iglesia-Vayá, Eva Hernando, Francisco García-García

Melanoma represents a critical clinical challenge owing to its unfavorable outcomes. This type of skin cancer exhibits unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. Recent findings have suggested that melanoma brain metastases may share biological processes similar to those found in various neurodegenerative diseases. To further characterize melanoma brain metastasis development, we explore the relationship between the transcriptional profiles of melanoma brain metastases and the neurodegenerative diseases Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We take an in silico approach to unveil a neurodegenerative signature of melanoma brain metastases compared with those of melanoma nonbrain metastasis (53 dysregulated genes were enriched in 11 functional terms, such as associated terms to the extracellular matrix and development) and with those of nontumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers being dysregulated in both scenarios. Finally, we developed an open-source, user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) that allows interactive exploration of the complete results.

黑色素瘤因其不良后果而成为临床上的一大难题。这种类型的皮肤癌表现出对脑部微环境的独特适应性,但对其潜在的分子机制却知之甚少。最近的研究结果表明,黑色素瘤脑转移瘤(MBM)可能与各种神经退行性疾病的生物过程相似。为了进一步描述黑素瘤脑转移瘤的发展特征,我们探讨了黑素瘤脑转移瘤的转录谱与神经退行性疾病阿尔茨海默病、帕金森病和多发性硬化之间的关系。我们采用硅学方法揭示了MBM的神经退行性特征,并将其与黑色素瘤非脑转移(53个失调基因富集在11个功能术语中,如与细胞外基质和发育相关的术语)和非肿瘤脑对照(195个失调基因,主要涉及发育和细胞分化、染色质重塑和核小体组织以及翻译)进行了比较。ITGA10和DNAJC6这两个基因成为两种情况下均出现失调的关键潜在标记。最后,我们开发了一个开源、用户友好的网络工具(https://bioinfo.cipf.es/metafun-mbm/),允许对完整结果进行交互式探索。
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引用次数: 0
Anti-Laminin β4 IgG Drives Tissue Damage in Anti-p200 Pemphigoid and Shows Interactions with Laminin α3 and γ1/2 Chains. 抗层粘蛋白 β4 IgG 驱动抗 p200 丘疹性荨麻疹的组织损伤,并与层粘蛋白 α3 和 γ1/2 链相互作用
Pub Date : 2024-09-23 DOI: 10.1016/j.jid.2024.08.004
Manuela Pigors, Stephanie Goletz, Yao Wang, Shirin Emtenani, Christoph M Hammers, Maike M Holtsche, Sabrina Patzelt, Bianca Opelka, Felix H Stang, Inke R König, Christiane Radzimski, Lars Komorowski, Monique Aumailley, Cristina Has, Enno Schmidt

Laminin β4 was recently identified as a structural component of the dermal-epidermal junction and autoantigen of anti-p200 pemphigoid. In this study, we provided further evidence of the pathogenic effect of anti-laminin β4 IgG and identified potential binding partners of laminin β4. We showed that laminin β4 immune complexes led to activation of normal leukocytes and dose-dependent ROS release. Using cryosections of normal skin, we demonstrated that anti-laminin β4 patient serum IgG but not anti-laminin γ1 IgG, which are also detectable in patients with anti-p200 pemphigoid, cause dermal-epidermal separation in the presence of leukocytes. Proximity ligation assay and indirect immunofluorescence staining suggested that laminin β4 localizes closely to laminin α3 and γ2 in primary keratinocytes. Subsequent coimmunoprecipitation experiments using epidermal extracts confirmed the interaction of laminin β4 with the α3 and γ2 chains and indicated additional affinity to laminin γ1. The laminin β4-α3/β4-γ1 protein complexes were also detected using mass spectrometry. In conclusion, this study showed that anti-laminin β4 IgG can exert tissue damage in the skin, supporting their pathogenic role in anti-p200 pemphigoid. Our data further provide strong evidence for an interaction of laminin β4 with laminin α3, whereas its association to the laminin γ1 and γ2 chains is ambiguous.

最近,层粘连蛋白β4被确定为真皮-表皮交界处的结构成分和抗p200丘疹性荨麻疹的自身抗原。在本研究中,我们提供了抗层粘蛋白β4 IgG致病作用的进一步证据,并确定了层粘蛋白β4的潜在结合伙伴。我们发现,层粘连蛋白 β4 免疫复合物可导致正常白细胞活化和剂量依赖性 ROS 释放。利用正常皮肤的冰冻切片,我们证明了抗层粘蛋白β4患者血清中的IgG,而不是抗层粘蛋白γ1患者血清中的IgG(在抗p200丘疹性荨麻疹患者中也能检测到),会在白细胞存在的情况下导致真皮-表皮分离。近接实验和间接免疫荧光染色表明,层粘连蛋白β4在原代角质形成细胞中与层粘连蛋白α3和γ2紧密定位。随后使用表皮提取物进行的共免疫沉淀实验证实了层粘连蛋白β4与α3和γ2链的相互作用,并表明其与层粘连蛋白γ1有额外的亲和力。质谱也检测到了层粘连蛋白β4-α3/β4-γ1蛋白复合物。总之,本研究表明,抗层粘蛋白β4 IgG 可对皮肤组织造成损伤,支持其在抗 p200 丘疹性荨麻疹中的致病作用。我们的数据进一步为层粘蛋白β4与层粘蛋白α3的相互作用提供了强有力的证据,而层粘蛋白β4与层粘蛋白γ1和γ2链的关联则不明确。
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引用次数: 0
Cutaneous T-Cell Lymphoma and Dupilumab Use: A Multifactorial and Complex Story. 皮肤 T 细胞淋巴瘤与使用杜匹单抗:一个多因素的复杂故事
Pub Date : 2024-09-23 DOI: 10.1016/j.jid.2024.08.015
Marie Beylot-Barry, Delphine Staumont-Salle
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引用次数: 0
The Skinny on Dermal Fat and Its Anti-Inflammatory Role in Psoriasis. 真皮脂肪及其在银屑病中的抗炎作用。
Pub Date : 2024-09-20 DOI: 10.1016/j.jid.2024.07.031
Yoshiaki Matsushima, Sam T Hwang, Scott I Simon
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引用次数: 0
Ancestral Diversity of Skin Reaches Single-Cell Resolution. 皮肤的祖先多样性达到单细胞分辨率
Pub Date : 2024-09-20 DOI: 10.1016/j.jid.2024.08.009
Yingzi Liu, Bogi Andersen, Johann E Gudjonsson, Maksim V Plikus
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引用次数: 0
Optimizing Skin Surface Metabolomics: A Comprehensive Evaluation of Sampling Methods, Extraction Solvents, and Analytical Techniques. 优化皮肤表面代谢组学:取样方法、萃取溶剂和分析技术的综合评估。
Pub Date : 2024-09-19 DOI: 10.1016/j.jid.2024.08.027
Huizhen Chen, Yu Chen, Yi Zhou, Shensong Cao, Jing Lu, Lianyi Han, Thomas Worzfeld, Jean Krutmann, Jiucun Wang, Jingjing Xia

Characterizing the metabolite fingerprint from the skin surface provides invaluable insights into skin biology and microbe-host interactions. To ensure data accuracy and reproducibility, it is essential to develop standard operating procedures for skin surface metabolomics. However, there is a notable lack of studies in this area. In this study, we thoroughly evaluated different sampling materials, extraction solvents, taping methods (frequency and number of tapes), and analytical techniques to optimize skin surface metabolomics. Our results showed that the combination of D-Squame D100 tape with a methyl tert-butyl ether/methanol extractant is optimal for skin surface lipidomics. Performing the skin-taping procedure 5 times with 1 tape yields sufficient biomass for lipid analysis, whereas the optimal taping procedure varies for water-soluble compounds. In addition, our study identified associations among the skin surface metabolites, some of which potentially underlie the formation of microbial cutotypes and offer insights into host-microbe interactions.

表征皮肤表面的代谢物指纹为了解皮肤生物学和微生物与宿主的相互作用提供了宝贵的信息。为确保数据的准确性和可重复性,制定皮肤表面代谢组学的标准操作程序(SOP)至关重要。然而,这方面的研究明显不足。在此,我们全面评估了不同的取样材料、提取溶剂、绑带方法(绑带频率和数量)和分析技术,以优化皮肤表面代谢组学。结果表明,D-Squame® D100 胶带与甲基叔丁基醚/甲醇萃取剂的组合是皮肤表面脂质组学的最佳选择。用一种胶带进行五次皮肤绑带程序可产生足够的生物量用于脂质分析,而对于水溶性化合物,最佳绑带程序则各不相同。此外,我们的研究还发现了皮肤表面代谢物之间的关联,其中一些代谢物可能是微生物切割型形成的基础,并有助于深入了解宿主与微生物之间的相互作用。
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引用次数: 0
Superficial Conjunctival Cells from Dupilumab-Treated Patients with Atopic Dermatitis with Ocular Adverse Events Display a Transcriptomic Psoriasis Signature. 经杜比鲁单抗治疗的特应性皮炎患者的浅层结膜细胞显示出牛皮癣转录组特征
Pub Date : 2024-09-19 DOI: 10.1016/j.jid.2024.08.024
Myriam Cassagne, Stéphane Galiacy, Anna Kychygina, Eric Chapotot, Martin Wallaert, Bertrand Vabres, Marie Tauber, Sébastien Barbarot, Carle Paul, Pierre Fournié, Michel Simon

Dupilumab has demonstrated efficacy in the treatment of atopic dermatitis. However, a subset of patients experiences ocular adverse events (OAEs), including conjunctivitis and dry eye syndrome, the pathological mechanisms of which are still unknown. In a bicentric study, we used DNA microarray analysis to compare the transcriptome of conjunctival cells of patients with atopic dermatitis collected by impression cytology before (M0) and 4 months after (M4) initiating dupilumab treatment. Thirty-six patients were included and divided in 2 groups according to their ophthalmological status at M4: 12 with OAEs (OAE+) and 24 without (OAE-). The analysis revealed 52 differentially expressed genes between OAE+ and OAE- patients at M0 and 113 at M4. Ingenuity Pathway Analysis enrichment revealed a psoriasis signature in OAE+ patients, both before and after OAE outcomes. In addition, we noticed the overexpression of several genes involved in keratinocyte differentiation, particularly encoding cornified envelope components. Among the 16 differentially expressed genes selected for real-time RT-PCR validation, 9 were confirmed as upregulated at M4 in OAE+ versus OAE- patients, validating the psoriasis signature, whereas MUC7 was downregulated. In conclusion, these results suggest that a conjunctival transcriptomic profile predisposes some patients with atopic dermatitis to developing OAEs upon dupilumab treatment.

杜匹单抗在治疗特应性皮炎(AD)方面疗效显著。然而,一部分患者会出现眼部不良反应(OAE),包括结膜炎和干眼症,其病理机制尚不清楚。在一项双中心研究中,我们使用 DNA 微阵列分析比较了 AD 患者在开始杜比单抗治疗前(M0)和治疗 4 个月后(M4)通过印模细胞学收集的结膜细胞转录组。研究共纳入了 36 名患者,并根据他们在 M4 时的眼科状况分为两组:12 名有 OAE(OAE+),24 名无 OAE(OAE-)。分析发现,OAE+ 和 OAE- 患者在 M0 时有 52 个差异表达基因 (DEG),而在 M4 时则有 113 个差异表达基因 (DEG)。Ingenuity Pathway Analysis富集分析显示,OAE+患者在OAE结果之前和之后都有牛皮癣特征。此外,我们还注意到一些参与角质形成细胞分化的基因过度表达,尤其是编码粟粒状包膜成分的基因。在选定进行实时 RT-PCR 验证的 16 个 DEG 中,有 9 个被证实在 OAE+ 与 OAE- 患者的 M4 处上调,验证了银屑病特征,而 MUC-7 则下调。总之,这些结果表明,结膜转录组学特征使一些AD患者在接受杜匹单抗治疗后易患OAE。
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引用次数: 0
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
期刊
The Journal of investigative dermatology
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