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Chi3l1 Knockout Mitigates Chronic Itch and Cutaneous Inflammation in Mice. Chi3l1 基因敲除可减轻小鼠的慢性瘙痒和皮肤炎症。
Pub Date : 2024-10-03 DOI: 10.1016/j.jid.2024.09.013
Xingyun Zhu, Xiaolong Dai, Weiwei Chen, Yanqing Li, Yang Liu, Chunxu Shan, Jiafu Wang, Jianghui Meng
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引用次数: 0
A tissue-engineered model of T-cell mediated oral mucosal inflammatory disease. T细胞介导的口腔黏膜炎症的组织工程模型。
Pub Date : 2024-10-02 DOI: 10.1016/j.jid.2024.07.038
Asma El-Howati, Jake G Edmans, Martin E Santocildes-Romero, Lars Siim Madsen, Craig Murdoch, Helen E Colley

T-cell-mediated oral mucocutaneous inflammatory conditions including oral lichen planus (OLP) are common but development of new treatments aimed at relieving symptoms and controlling OLP progression are hampered by the lack of experimental models. Here, we developed a tissue-engineered oral mucosal equivalent (OME) containing polarised T-cells to replicate OLP pathogenesis. Peripheral blood CD4+ and CD8+ T-cells were isolated, activated and polarised into Th1 and cytotoxic T-cells (Tc). OME were constructed by culturing oral keratinocytes on an oral fibroblast-populated hydrogel to produce a stratified squamous epithelium. OME stimulated with IFN-γ and TNF-α or medium from Th1 cells caused increased secretion of inflammatory cytokines/chemokines. A model of T-cell-mediated inflammatory disease was developed by combining OME on top of a Th1/Tc-containing hydrogel, followed by epithelial stimulation with IFN-γ/TNF-α. T-cell recruitment towards the epithelium was associated with increased secretion of T-cell chemoattractants CCL5, CXCL9 and CXCL10. Histological assessment showed tissue damage associated with cleaved-caspase-3 and altered laminin-5 expression. Treatment with inhibitors directed against JAK, KCa3.1 channels or clobetasol in solution and/or via a mucoadhesive patch prevented cytokine/chemokine release and tissue damage. This disease model has potential to probe for mechanisms of pathogenesis or as a test platform for novel therapeutics or treatment modalities.

T细胞介导的口腔黏膜炎症(包括口腔扁平苔藓)很常见,但由于缺乏实验模型,旨在缓解症状和控制口腔扁平苔藓进展的新疗法的开发受到阻碍。在这里,我们开发了一种含有极化 T 细胞的组织工程口腔黏膜等效物(OME)来复制 OLP 的发病机制。我们分离、激活了外周血CD4+和CD8+T细胞,并将其极化为Th1和细胞毒性T细胞(Tc)。通过在口腔成纤维细胞填充的水凝胶上培养口腔角质细胞来构建 OME,以产生分层鳞状上皮。OME 在 IFN-γ 和 TNF-α 或 Th1 细胞培养基的刺激下会增加炎性细胞因子/趋化因子的分泌。通过在含 Th1/Tc 水凝胶上结合 OME,然后用 IFN-γ/TNF-α 刺激上皮,建立了 T 细胞介导的炎症模型。T细胞向上皮细胞招募与T细胞趋化吸引剂CCL5、CXCL9和CXCL10的分泌增加有关。组织学评估显示,组织损伤与裂解的天冬酶-3 和层粘连蛋白-5 表达的改变有关。用针对 JAK、KCa3.1 通道或溶液中的氯倍他索的抑制剂和/或通过粘液贴片进行治疗,可防止细胞因子/趋化因子的释放和组织损伤。这种疾病模型具有探究发病机制或作为新型疗法或治疗模式测试平台的潜力。
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引用次数: 0
Combined Inhibition of MNK Signaling and BET Proteins Reveals TGM2 as a Novel Vulnerability in Melanoma. 联合抑制 MNK 信号传导和 BET 蛋白揭示了 TGM2 在黑色素瘤中的新弱点。
Pub Date : 2024-10-01 DOI: 10.1016/j.jid.2024.07.037
Antoine Méant, Omar Moussa, Benjamin Lebeau, Christophe Gonçalves, Vincent R Richard, Feiyang Cai, Sathyen A Prabhu, Marios Langke, Elizabeth M Guettler, Jie Su, Natascha Gagnon, Rene P Zahedi, Christoph H Borchers, Wilson H Miller, Sonia V Del Rincón, Michael Witcher
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引用次数: 0
A scalable approach to assess the safety of recently marketed systemic treatments for atopic dermatitis in clinical practice. 在临床实践中采用一种可扩展的方法来评估最近上市的特应性皮炎系统治疗方法的安全性。
Pub Date : 2024-10-01 DOI: 10.1016/j.jid.2024.08.034
Maria C Schneeweiss, Robert J Glynn, Richard Wyss, Priyanka Anand, Yinzhu Jin, Joan Landon, Arash Mostaghimi, Joseph F Merola, Jonathan I Silverberg, David M Rosmarin, Robert Sidbury, Sebastian Schneeweiss

Targeted systemic immune-modulating drugs (IMDs) to treat atopic dermatitis (AD) were highly efficacious in randomized trials. Trials with limited number of subjects leave questions about their safety. We describe a data and analytics structure for the production of timely, high-quality evidence on the comparative safety of recently approved IMDs in patients with AD in clinical practice. We established a series of sequential propensity score (PS)-balanced cohorts that grow in size with each annual data refresh. Nine health outcomes of interest plus conjunctivitis as a positive tracer outcome were identified. The initial treatment comparison was dupilumab, an interleukin-4/13 inhibitor, or tralokinumab, an interleukin-13 inhibitor, versus abrocitinib/upadacitinib, both JAK inhibitors. The first analysis cycle (December 2021-February 2023) compared 269 patients initiating JAK inhibitors and 2,650 initiating IL-4/IL-13 inhibitors. Patient characteristics were well balanced after PS-matching. Outpatient infections within 180 days occurred in 18% of JAK-1 inhibitor initiators versus 12% of dupilumab/ tralokinumab initiators (RR=1.50; 0.96 to 2.33) whereas acne risks were 7% vs. 3%, respectively (RR=2.29, 0.96 to 5.46). This sequential monitoring system will produce essential knowledge on the safety of IMDs to treat AD based on its growing study size of patients observed in clinical practice.

治疗特应性皮炎(AD)的靶向性全身免疫调节药物(IMDs)在随机试验中疗效显著。但受试者人数有限的试验对其安全性提出了质疑。我们介绍了一种数据和分析结构,用于及时提供高质量的证据,说明最近批准的 IMDs 在临床实践中对 AD 患者的安全性比较。我们建立了一系列连续的倾向得分(PS)平衡队列,其规模随着每年数据的更新而扩大。我们确定了九种相关的健康结果以及作为阳性示踪结果的结膜炎。最初的治疗比较是白细胞介素-4/13抑制剂杜必鲁单抗或白细胞介素-13抑制剂曲妥珠单抗与阿罗西替尼/乌帕他替尼(均为JAK抑制剂)。第一个分析周期(2021年12月至2023年2月)比较了269名开始使用JAK抑制剂的患者和2650名开始使用IL-4/IL-13抑制剂的患者。经过 PS 匹配后,患者特征非常均衡。JAK-1抑制剂启动者在180天内发生门诊感染的比例为18%,而杜比鲁单抗/曲妥珠单抗启动者为12%(RR=1.50;0.96-2.33),而痤疮风险分别为7%和3%(RR=2.29,0.96-5.46)。基于对临床实践中观察到的患者进行的研究规模不断扩大,这一连续监测系统将为IMDs治疗AD的安全性提供重要知识。
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引用次数: 0
Correlating Topographic Imaging and Raman Microscopy to Investigate Wound Re-Epithelialization. 将地形图成像和雷曼显微镜相关联,以研究伤口的再上皮化。
Pub Date : 2024-09-27 DOI: 10.1016/j.jid.2024.08.031
Pia Katharina Vestweber, Ines Ana Ederer, Ulrich Michael Rieger, Ernst H K Stelzer, Viktoria Planz, Maike Windbergs
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引用次数: 0
Profiling Long Noncoding RNA in Psoriatic Skin Using Single-Cell RNA Sequencing. 利用 scRNA-seq 分析银屑病皮肤中的 lncRNA。
Pub Date : 2024-09-27 DOI: 10.1016/j.jid.2024.09.010
Rachael Bogle, Matthew T Patrick, Sutharzan Sreeskandarajan, Mehrnaz Gharaee-Kermani, Haihan Zhang, Qinmengge Li, Ruiwen Zhou, Feiyang Ma, J Michelle Kahlenberg, Olesya Plazyo, James T Elder, Allison C Billi, Johann E Gudjonsson, Lam C Tsoi

The expressions of long noncoding RNAs (lncRNAs) and their roles in epidermal differentiation have been previously defined using bulk RNA sequencing. Despite their tissue-specific expression profiles, most lncRNAs are not well-annotated at the single-cell level. In this study, we evaluated the use of single-cell RNA sequencing to profile and characterize lncRNAs using data from 6 patients with psoriasis with paired uninvolved and lesional psoriatic skin. Despite their overall lower expression, we were able to detect >7000 skin-expressing lncRNAs and their cellular sources. Differential gene expression analysis revealed 137 differentially expressed lncRNAs in lesional psoriasis skin and identified 169 cell-type-specific lncRNAs. Keratinocytes had the highest number of differentially expressed lncRNA in psoriatic skin, which we validated using spatial transcriptomic data. We further showed that expression of the keratinocyte-specific lncRNA, AC020916.1, upregulated in lesional skin, is significantly correlated with expressions of genes participating in cell proliferation/epidermal differentiation, including SPRR2E and transcription factor ZFP36, particularly in the psoriatic skin. Our study highlights the potential for using single-cell RNA sequencing to profile skin-expressing lncRNA transcripts and to infer their cellular origins, providing a crucial approach that can be applied to the study of other inflammatory skin conditions.

以前曾利用批量 RNA-seq 确定了长非编码 RNA(lncRNA)的表达及其在表皮分化中的作用。尽管lncRNA具有组织特异性表达谱,但大多数lncRNA并没有在单细胞水平上得到很好的标注。在这里,我们使用来自 6 名银屑病患者的数据,评估了使用 scRNA-seq 对 lncRNAs 进行剖析和定性的情况。尽管它们的整体表达量较低,但我们还是检测到了超过 7,000 个皮肤表达的 lncRNA 及其细胞来源。差异基因表达分析揭示了银屑病(PP)皮损皮肤中137个差异表达的lncRNA,并确定了169个细胞类型特异的lncRNA。角质形成细胞在银屑病皮肤中差异表达的 lncRNA 数量最多,我们利用空间转录组数据验证了这一点。我们进一步发现,角质形成细胞特异性 lncRNA AC020916.1 的表达在病变皮肤中上调,与参与细胞增殖/表皮分化的基因(包括 SPRR2E 和转录因子 ZFP36)的表达显著相关,尤其是在银屑病皮肤中。我们的研究强调了利用 scRNA-seq 分析皮肤表达的 lncRNA 转录本并推断其细胞来源的潜力,提供了一种可用于研究其他炎症性皮肤病的重要方法。
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引用次数: 0
Evaluation of Benzene Presence and Formation in Benzoyl Peroxide Drug Products. 评估过氧化苯甲酰药物产品中苯的存在和形成。
Pub Date : 2024-09-27 DOI: 10.1016/j.jid.2024.09.009
Kaury Kucera, Nicola Zenzola, Amber Hudspeth, Mara Dubnicka, Wolfgang Hinz, Christopher G Bunick, Michael Girardi, Arash Dabestani, David Y Light

The potent carcinogen, benzene, is a known degradation product of benzoyl peroxide (BPO) and was recently reported to form when BPO drug products, used for acne and rosacea treatment, are incubated at body temperature and elevated temperatures expected during storage and transportation. This study provides evidence for a wide range of benzene concentrations (0.16 ppm to 35.30 ppm) detected by GC-MS in 111 over-the-counter BPO drug products tested and maintained at room temperature. A prescription encapsulated BPO drug product was stability tested at cold (2°C) and elevated temperature (50°C), resulting in no apparent benzene formation at 2°C, and high levels of benzene formation at 50°C, suggesting that encapsulation technology may not stabilize BPO drug products but cold storage may greatly reduce benzene formation. Face model experiments where BPO drug product was applied to PolyMethyl MethAcrylate (PMMA) photoprotection test skin plates and benzene was detected in surrounding air by SIFT-MS, showed detectable benzene through evaporation and substantial benzene formation when exposed to UV light at levels below peak sunlight. Results suggest that potential benzene exposure from formation during BPO drug product use poses significant risks independent of the starting benzene concentration.

苯是一种已知的过氧化苯甲酰(BPO)降解产物,最近有报告称,当用于治疗痤疮和红斑痤疮的 BPO 药物产品在体温以及储存和运输过程中的预期高温下孵育时,会产生苯。本研究提供的证据表明,在室温下测试和保存的 111 种非处方药 BPO 产品中,通过气相色谱-质谱仪检测到的苯浓度范围很广(0.16 ppm 至 35.30 ppm)。在低温(2°C)和高温(50°C)条件下对处方封装的 BPO 药物产品进行了稳定性测试,结果表明在 2°C 条件下没有明显的苯形成,而在 50°C 条件下苯的形成水平较高,这表明封装技术可能无法稳定 BPO 药物产品,但低温储存可能会大大减少苯的形成。在脸部模型实验中,将 BPO 药物产品涂抹在聚甲基丙烯酸甲酯(PMMA)光保护测试皮肤板上,并通过 SIFT-MS 检测周围空气中的苯,结果表明通过蒸发可检测到苯,当暴露在低于日照峰值水平的紫外线下时,会有大量苯形成。结果表明,在使用 BPO 药物产品的过程中,潜在的苯暴露会造成重大风险,与起始苯浓度无关。
{"title":"Evaluation of Benzene Presence and Formation in Benzoyl Peroxide Drug Products.","authors":"Kaury Kucera, Nicola Zenzola, Amber Hudspeth, Mara Dubnicka, Wolfgang Hinz, Christopher G Bunick, Michael Girardi, Arash Dabestani, David Y Light","doi":"10.1016/j.jid.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.jid.2024.09.009","url":null,"abstract":"<p><p>The potent carcinogen, benzene, is a known degradation product of benzoyl peroxide (BPO) and was recently reported to form when BPO drug products, used for acne and rosacea treatment, are incubated at body temperature and elevated temperatures expected during storage and transportation. This study provides evidence for a wide range of benzene concentrations (0.16 ppm to 35.30 ppm) detected by GC-MS in 111 over-the-counter BPO drug products tested and maintained at room temperature. A prescription encapsulated BPO drug product was stability tested at cold (2°C) and elevated temperature (50°C), resulting in no apparent benzene formation at 2°C, and high levels of benzene formation at 50°C, suggesting that encapsulation technology may not stabilize BPO drug products but cold storage may greatly reduce benzene formation. Face model experiments where BPO drug product was applied to PolyMethyl MethAcrylate (PMMA) photoprotection test skin plates and benzene was detected in surrounding air by SIFT-MS, showed detectable benzene through evaporation and substantial benzene formation when exposed to UV light at levels below peak sunlight. Results suggest that potential benzene exposure from formation during BPO drug product use poses significant risks independent of the starting benzene concentration.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142396483","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}
引用次数: 0
Molecular and Cellular Function of p63 in Skin Development and Genetic Diseases. p63 在皮肤发育和遗传疾病中的分子和细胞功能。
Pub Date : 2024-09-26 DOI: 10.1016/j.jid.2024.08.011
Daniela Di Girolamo, Enzo Di Iorio, Caterina Missero

The transcription factor p63 is a master regulator of multiple ectodermal derivatives. During epidermal commitment, p63 interacts with several chromatin remodeling complexes to transactivate epidermal-specific genes and repress transcription of simple epithelial and nonepithelial genes. In the postnatal epidermis, p63 is required to control the proliferative potential of progenitor cells, maintain epidermal integrity, and contribute to epidermal differentiation. Autosomal dominant sequence variant in p63 cause a spectrum of syndromic disorders that affect several tissues, including or derived from stratified epithelia. In this review, we describe the recent studies that have provided novel insights into disease pathogenesis and potential therapeutic targets.

转录因子 p63 是多种表皮衍生物的主调节因子。在表皮形成过程中,p63 与几种染色质重塑复合物相互作用,转激活表皮特异性基因,抑制简单上皮和非上皮基因的转录。在出生后的表皮中,p63 需要控制祖细胞的增殖潜能、维持表皮的完整性并促进表皮分化。p63 的常染色体显性序列变异会导致一系列综合症,影响多种组织,包括分层上皮或由分层上皮衍生的组织。在这篇综述中,我们将介绍最近的研究,这些研究为疾病的发病机制和潜在的治疗靶点提供了新的见解。
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引用次数: 0
Estimation of Body Mass Index from 3-Dimensional Total Body Photography. 通过三维全身摄影估算体重指数(BMI)。
Pub Date : 2024-09-26 DOI: 10.1016/j.jid.2024.06.1294
Sam Kahler, Brigid Betz-Stablein, Fabian Lee, Joachim Torrano, Monika Janda, Clare Primiero, H Peter Soyer, Dilki Jayasinghe
{"title":"Estimation of Body Mass Index from 3-Dimensional Total Body Photography.","authors":"Sam Kahler, Brigid Betz-Stablein, Fabian Lee, Joachim Torrano, Monika Janda, Clare Primiero, H Peter Soyer, Dilki Jayasinghe","doi":"10.1016/j.jid.2024.06.1294","DOIUrl":"10.1016/j.jid.2024.06.1294","url":null,"abstract":"","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335598","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}
引用次数: 0
Single-Cell RNA Sequencing Reveals Molecular Signatures that Distinguish Allergic from Irritant Contact Dermatitis. 单细胞 RNA 序列分析揭示了区分过敏性接触性皮炎和刺激性接触性皮炎的分子特征。
Pub Date : 2024-09-26 DOI: 10.1016/j.jid.2024.09.008
Michael L Frisoli, Wei-Che C Ko, Nuria Martinez, Khashayar Afshari, Yuqing Wang, Manuel Garber, John E Harris

Allergic contact dermatitis (ACD) is a pruritic skin disease caused by environmental chemicals that induce cell-mediated skin inflammation within susceptible individuals. Irritant contact dermatitis (ICD) is caused by direct damage to the skin barrier by environmental insults. Diagnosis can be challenging because both types of contact dermatitis can appear similar by visual examination, and histopathological analysis does not reliably distinguish ACD from ICD. To discover specific biomarkers of ACD and ICD, we characterized the transcriptomic and proteomic changes that occur within the skin during each type of contact dermatitis. We induced ACD and ICD in healthy human volunteers and sampled skin using a nonscarring suction blister biopsy method that collects interstitial fluid and cellular infiltrate. Single-cell RNA sequencing analysis revealed that cell-specific transcriptome differences rather than cell-type proportions best distinguished ACD from ICD. Allergy-specific genes were associated with upregulation of IFNG, and cell signaling network analysis implicated several other genes such as IL4, despite their low expression levels. We validated transcriptomic differences with proteomic assays on blister fluid and trained a logistic regression model on skin interstitial fluid proteins that could distinguish ACD from ICD and healthy control skin with 93% sensitivity and 93% specificity.

过敏性接触性皮炎(ACD)是一种瘙痒性皮肤病,由环境中的化学物质引起,诱发易感人群的细胞介导的皮肤炎症。刺激性接触性皮炎(ICD)是由环境刺激直接损伤皮肤屏障引起的。这两种类型的接触性皮炎在肉眼观察下可能相似,而组织病理学分析并不能可靠地区分刺激性接触性皮炎和刺激性接触性皮炎,因此诊断具有挑战性。为了发现 ACD 和 ICD 的特异性生物标志物,我们对每种类型的接触性皮炎期间皮肤内发生的转录组和蛋白质组变化进行了表征。我们在健康的人类志愿者身上诱发了 ACD 和 ICD,并使用非瘢痕吸疱活检法采集了皮肤样本,该方法可收集间质和细胞浸润。单细胞 RNA 序列分析显示,细胞特异性转录组差异而非细胞类型比例最能区分 ACD 和 ICD。过敏特异性基因与 IFNG 的上调有关,而细胞信号网络分析则牵涉到其他几个基因,如 IL4,尽管它们的表达水平较低。我们通过对水疱液的蛋白质组检测验证了转录组的差异,并对皮肤间质液蛋白质训练了一个逻辑回归模型,该模型能以 93% 的灵敏度和 93% 的特异性将 ACD 与 ICD 和健康对照皮肤区分开来。
{"title":"Single-Cell RNA Sequencing Reveals Molecular Signatures that Distinguish Allergic from Irritant Contact Dermatitis.","authors":"Michael L Frisoli, Wei-Che C Ko, Nuria Martinez, Khashayar Afshari, Yuqing Wang, Manuel Garber, John E Harris","doi":"10.1016/j.jid.2024.09.008","DOIUrl":"10.1016/j.jid.2024.09.008","url":null,"abstract":"<p><p>Allergic contact dermatitis (ACD) is a pruritic skin disease caused by environmental chemicals that induce cell-mediated skin inflammation within susceptible individuals. Irritant contact dermatitis (ICD) is caused by direct damage to the skin barrier by environmental insults. Diagnosis can be challenging because both types of contact dermatitis can appear similar by visual examination, and histopathological analysis does not reliably distinguish ACD from ICD. To discover specific biomarkers of ACD and ICD, we characterized the transcriptomic and proteomic changes that occur within the skin during each type of contact dermatitis. We induced ACD and ICD in healthy human volunteers and sampled skin using a nonscarring suction blister biopsy method that collects interstitial fluid and cellular infiltrate. Single-cell RNA sequencing analysis revealed that cell-specific transcriptome differences rather than cell-type proportions best distinguished ACD from ICD. Allergy-specific genes were associated with upregulation of IFNG, and cell signaling network analysis implicated several other genes such as IL4, despite their low expression levels. We validated transcriptomic differences with proteomic assays on blister fluid and trained a logistic regression model on skin interstitial fluid proteins that could distinguish ACD from ICD and healthy control skin with 93% sensitivity and 93% specificity.</p>","PeriodicalId":94239,"journal":{"name":"The Journal of investigative dermatology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335604","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}
引用次数: 0
期刊
The Journal of investigative dermatology
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