Journal of dermatological science最新文献

英文中文

Difamilast induces human beta defensin 3 production via CREB and NRF2 in human keratinocytes Difamilast通过人角质形成细胞的CREB和NRF2诱导人β -防御蛋白3的产生。

IF 4.6

Journal of dermatological science

Pub Date : 2025-09-01 DOI: 10.1016/j.jdermsci.2025.07.003

Gaku Tsuji , Ayako Yumine , Masaki Takemura , Takeshi Nakahara

引用次数: 0

Integrative genomic and transcriptomic profiling reveals dysregulation of FOXA1-AGR2 axis in penoscrotal extramammary Paget's disease 综合基因组学和转录组学分析揭示了在阴囊乳腺外佩吉特病中FOXA1-AGR2轴的失调。

IF 4.6

Journal of dermatological science

Pub Date : 2025-09-01 DOI: 10.1016/j.jdermsci.2025.06.002

Daoning Zhang , Sini Gao , Chunxia Zhao , Xiaomin Cai , Ruiqin Mai , Guohong Zhang , Hang Li

Background

Extramammary Paget's disease (EMPD) is a rare cutaneous mucinous adenocarcinoma primarily affect the penoscrotal skin, characterized by the presence of Paget cells scattered within the epidermis. The molecular features of Paget cells remain poorly understood.

Objectives

To describe the genomic and transcriptomic landscape of penoscrotal EMPD, identify the driver mutation or core transcription factor through integrative analysis, identify biological markers and provide new insights for the pathogenesis of penoscrotal EMPD.

Methods

Whole exome sequencing was performed on penoscrotal EMPD tissues from 37 patients, of whom 28 patients also underwent RNA sequencing, and the findings was validated in an additional 72 patients, encompassing 120 multi-region tumor tissues to identify core transcription factors. The dysregulation was further confirmed by immunohistochemistry.

Results

Genomic landscape did not reveal FOXA1 or SPDEF mutations penoscrotal EMPD. Transcriptomic profiling identified the upregulation of lineage-specific transcription factors FOXA1 and SPDEF, along with their targeted genes AGR2 and MUC5AC. Upregulation of FOXA1, SPDEF and AGR2 without gene fusion were consistently replicated in the validation cohort. Further analysis of multiple tissue regions confirmed FOXA1 and SPDEF as driver transcription factors in penoscrotal EMPD. We identify key transcription factors regulating co-expressed modules FOXA1-SPDEF-AGR2, suggesting goblet cells features of penoscrotal EMPD. The immunohistochemistry confirmed the co-expression of FOXA1-AGR2 pattern in Paget cells.

Conclusions

Our study provides novel insights into the molecular characteristics of Paget cells, and also highlights the critical role of FOXA1 in Paget cell development in EMPD.

背景：乳腺外佩吉特病（EMPD）是一种罕见的皮肤粘液腺癌，主要影响阴囊皮肤，其特征是表皮内分散存在佩吉特细胞。Paget细胞的分子特征仍然知之甚少。目的：描述阴部EMPD的基因组和转录组学格局，通过综合分析确定驱动突变或核心转录因子，鉴定生物学标志物，为阴部EMPD的发病机制提供新的见解。方法：对37例患者的阴部EMPD组织进行全外显子组测序，其中28例患者也进行了RNA测序，并在另外72例患者的120个多区域肿瘤组织中验证了研究结果，以确定核心转录因子。免疫组织化学进一步证实了这种失调。结果：基因组图谱未显示FOXA1或SPDEF在阴囊EMPD中发生突变。转录组学分析鉴定了谱系特异性转录因子FOXA1和SPDEF及其靶基因AGR2和MUC5AC的上调。在验证队列中，FOXA1、SPDEF和AGR2的上调没有基因融合，结果一致。多个组织区域的进一步分析证实FOXA1和SPDEF是阴茎EMPD的驱动转录因子。我们确定了调节共表达模块FOXA1-SPDEF-AGR2的关键转录因子，提示了阴茎EMPD的杯状细胞特征。免疫组化证实FOXA1-AGR2基因在Paget细胞中共表达。结论：我们的研究为Paget细胞的分子特征提供了新的见解，并强调了FOXA1在EMPD Paget细胞发育中的关键作用。

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引用次数: 0

Preferential CD101 expression on resident memory regulatory T cells and IFN-γ-producing CD8+ resident memory T cells in human epidermis CD101在人表皮常驻记忆调节性T细胞和产生IFN-γ的CD8+常驻记忆T细胞中的优先表达。

IF 4.6

Journal of dermatological science

Pub Date : 2025-09-01 DOI: 10.1016/j.jdermsci.2025.07.002

Takuya Sato , Youichi Ogawa , Manao Kinoshita , Yuka Nagasaka , Shinji Shimada , Akira Momosawa , Tatsuyoshi Kawamura

引用次数: 0

17β-Estradiol promotes LL37-induced rosacea-like skin inflammation via G protein-coupled estrogen receptor 30 17β-雌二醇通过G蛋白偶联雌激素受体30促进ll37诱导的酒渣鼻样皮肤炎症。

IF 4.6

Journal of dermatological science

Pub Date : 2025-09-01 DOI: 10.1016/j.jdermsci.2025.05.005

Jin Tang , Peng Chen , Chuchu Huang , Wanjing Wang , Ben Wang , Wei Shi , Yan Tang , Zhili Deng , Yiya Zhang , Ji Li , Dan Jian

Background

Rosacea is a common chronic inflammatory skin condition that predominantly affects females, though its underlying mechanisms remain unclear.

Objective

To explore the role of 17β-estradiol (E2) and the G-coupled estrogen receptor 30 (GPR30) in the pathogenesis of rosacea.

Methods

We conducted a cross-sectional analysis of UK Biobank data to investigate the association between exogenous hormone use and rosacea risk in females. Additionally, ovariectomized (OVX) LL37-induced rosacea mouse models were utilized to evaluate the effects of ovarian E2 loss and exogenous E2 supplementation. GPR30 expression was measured in rosacea skin lesions, LL37-treated mice, and HaCaT keratinocytes. The impact of GPR30 deletion on rosacea inflammation was assessed using GPR30 knockout mice. Finally, the efficacy of GPR30 inhibition or silencing in reducing inflammation was examined in LL37 or LL37 plus E2 treated mice and HaCaT cells.

Results

UK Biobank data revealed significant associations between oral contraceptive use (OR: 1.20; 95 % CI: 1.06, 1.37) and hormone-replacement therapy (OR: 1.31; 95 % CI: 1.18, 1.46) with increased rosacea risk. OVX mice exhibited reduced skin erythema and dermal infiltration, effects reversed by E2 supplementation, which exacerbated rosacea inflammation. GPR30 was overexpressed in rosacea lesions, LL37-treated mice, and HaCaT cells, with TFAP2C potentially mediating this effect. GPR30-deficient mice showed reduced inflammation, while GPR30 inhibition or knockdown significantly improved rosacea-like inflammation in LL37 or LL37 plus E2 treated models.

Conclusion

Activation of the E2/GPR30 pathway plays a significant role in rosacea inflammation, and GPR30 inhibition may represent a novel therapeutic strategy for rosacea.

背景：酒渣鼻是一种常见的慢性炎症性皮肤病，主要影响女性，但其潜在机制尚不清楚。目的：探讨17β-雌二醇（E2）和g偶联雌激素受体30 （GPR30）在酒渣鼻发病中的作用。方法：我们对UK Biobank数据进行了横断面分析，以调查外源性激素使用与女性酒渣鼻风险之间的关系。此外，利用卵巢切除（OVX） ll37诱导的酒渣鼻小鼠模型来评估卵巢E2丢失和外源性E2补充的影响。测量GPR30在酒渣鼻皮损、ll37处理小鼠和HaCaT角质形成细胞中的表达。使用GPR30敲除小鼠评估GPR30缺失对酒渣鼻炎症的影响。最后，在LL37或LL37 + E2处理的小鼠和HaCaT细胞中检测GPR30抑制或沉默减轻炎症的效果。结果：UK Biobank数据显示口服避孕药的使用之间存在显著关联(OR: 1.20；95 % CI: 1.06, 1.37)和激素替代疗法(OR: 1.31；95 % CI: 1.18, 1.46)，酒渣鼻风险增加。OVX小鼠表现出皮肤红斑和真皮浸润减少，E2补充逆转了这一作用，但加重了酒渣鼻炎症。GPR30在酒渣鼻病变、ll37处理小鼠和HaCaT细胞中过表达，TFAP2C可能介导了这种作用。GPR30缺失小鼠显示炎症减轻，而抑制或敲低GPR30可显著改善LL37或LL37加E2处理模型的酒渣鼻样炎症。结论：E2/GPR30通路的激活在酒渣鼻炎症中起重要作用，抑制GPR30可能是一种新的治疗酒渣鼻的策略。

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引用次数: 0

Mast cells express IL17A, IL17F and RORC in lesional psoriatic skin, are activated before therapy and persist in high numbers in a resting state with IL-17A positivity after treatment 病变银屑病皮肤肥大细胞表达IL17A、IL17F和RORC，在治疗前被激活，在治疗后IL-17A呈阳性的静息状态下仍大量存在。

IF 4.6

Journal of dermatological science

Pub Date : 2025-08-01 DOI: 10.1016/j.jdermsci.2025.05.006

Theresa Benezeder , Natalie Bordag , Johannes Woltsche , Andrea Teufelberger , Isabella Perchthaler , Wolfgang Weger , Wolfgang Salmhofer , Alexandra Gruber-Wackernagel , Clemens Painsi , Qian Zhan , Amin El-Heliebi , Magda Babina , Rachael Clark , Peter Wolf

Background

The proinflammatory cytokine IL-17 is known to play an important role in psoriasis pathogenesis, but little is known about its regulation in psoriasis or after treatment.

Objective

Aiming to investigate the role of IL-17 regulation in the resolution of psoriasis, we analyzed biopsy samples from patients with plaque psoriasis, including non-lesional and lesional skin at baseline and after anti-IL-17 and -IL-23 antibody, topical dithranol or UVB treatment as well as skin from healthy donors.

Methods

Skin biopsy samples were analyzed using immunostaining, RNA sequencing and in situ mRNA detection. In addition, we investigated IL-17 concentration of primary human skin mast cell supernatants after stimulation with the pro-inflammatory cytokines TNFα, IL-22, IL-23 and IFNγ.

Results

A high number of IL-17A+ mast cells persisted in resolved lesions after treatment and correlated inversely with the time span in remission. IL-17A+ mast cells were found in T cell-rich areas and near resident memory T cells in active and resolved lesions. CIBERSORTx deconvolution of RNA-seq data of active and dithranol-treated psoriasis lesions showed that activated mast cells were increased in psoriatic skin but returned to normal levels after treatment. Primary skin mast cells responded with an increased release of IL-17A after stimulation with the pro-inflammatory cytokines and in situ mRNA detection revealed positive signals for IL17A, IL17F and RORC in mast cells.

Conclusion

Thus, together with T cells, mast cells seem to be important players of the IL-23/IL17 axis underlying psoriasis pathogenesis and relevant for early disease recurrence.

背景：促炎细胞因子IL-17在银屑病发病过程中发挥重要作用，但其在银屑病发病及治疗后的调节作用尚不清楚。目的：为了研究IL-17调节在银屑病治疗中的作用，我们分析了斑块型银屑病患者的活检样本，包括基线和抗IL-17和-IL-23抗体、局部双糖醇或UVB治疗后的非病变和病变皮肤，以及健康供者的皮肤。方法：采用免疫染色、RNA测序和原位mRNA检测对皮肤活检标本进行分析。此外，我们研究了促炎细胞因子TNFα、IL-22、IL-23和IFNγ刺激后人皮肤肥大细胞上清的IL-17浓度。结果：IL-17A+ 肥大细胞在治疗后持续存在于消退病变中，且与缓解时间呈负相关。IL-17A+ 肥大细胞存在于T细胞富集区和活性和消退病变的常驻记忆T细胞附近。CIBERSORTx对活性和二醇治疗的银屑病病变的RNA-seq数据进行反卷积显示，银屑病皮肤中活化的肥大细胞增加，但治疗后恢复到正常水平。原代皮肤肥大细胞受到促炎细胞因子刺激后，IL-17A释放增加，原位mRNA检测显示肥大细胞中IL-17A、IL17F和RORC表达阳性。结论：肥大细胞与T细胞一起是银屑病发病机制中IL-23/ il - 17轴的重要参与者，与银屑病早期复发有关。

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引用次数: 0

Salivary metabolomics for skin cancer screening 唾液代谢组学用于皮肤癌筛查。

IF 4.6

Journal of dermatological science

Pub Date : 2025-08-01 DOI: 10.1016/j.jdermsci.2025.05.003

Masahiro Hayashi , Shigeo Ishikawa , Masahiro Sugimoto , Naoki Okuyama , Kaoru Edamatsu , Kazuyuki Yusa , Tomoharu Hemmi , Takayuki Konno , Ken Okamura , Yuta Araki , Mariko Nikaido , Yoriko Yaguchi , Toru Saito , Shoko Nakano , Ami Hemmi , Yutaka Hozumi , Tamio Suzuki

Background

If skin cancer (SC) can be screened using saliva, it would be extremely important for improving the prognosis of skin cancer. However, there is currently no available data on salivary screening for SC.

Objective

This study aimed to identify salivary metabolomic biomarkers for SC screening by comparing tissue and saliva samples.

Methods

This single-center study involved SC patients from Yamagata University Hospital, enrolled between May 2017 and April 2020. For the healthy controls (HCs), our database comprising salivary metabolomics data of HCs was used. Whole unstimulated saliva samples were collected from patients with SC (n = 75) and HCs (n = 77). Paired tumor and control tissues after SC resection were obtained from the same patients who donated saliva. Hydrophilic metabolites in the tissue and saliva samples were comprehensively analyzed using capillary electrophoresis–mass spectrometry. Using these candidate metabolites, a multiple logistic regression (MLR) model was developed to differentiate SC from HCs

Results

Sixty-six and 12 metabolites showed significant differences in tissues and saliva, respectively. Of these, six metabolites were commonly different between SC and HCs. Spermidine, 2-aminobutyric acid, and isoleucine were selected to develop the MLR model. The model exhibited a large area under the receiver operating characteristic curve (0.802, 95 % confidence interval: 0.731–0.874, P < 0.0001). Additionally, no significant differences were shown in candidate salivary metabolites between stages in both malignant melanoma and squamous cell carcinoma.

Conclusions

The salivary metabolomic profiles between SC and HCs differed clearly. This combination of salivary metabolites could serve as non-invasive biomarkers for screening SC.

背景：如果能够利用唾液筛查皮肤癌，对于改善皮肤癌的预后具有极其重要的意义。目的：本研究旨在通过比较组织和唾液样本，确定用于SC筛查的唾液代谢组学生物标志物。方法：这项单中心研究纳入了2017年5月至2020年4月期间来自山形大学医院的SC患者。对于健康对照（hc），我们使用了包含hc唾液代谢组学数据的数据库。采集SC （n = 75）和hc （n = 77）患者未受刺激的完整唾液样本。SC切除后的配对肿瘤组织和对照组织来自捐献唾液的同一患者。采用毛细管电泳-质谱联用技术对组织和唾液样品中的亲水代谢物进行综合分析。利用这些候选代谢物，建立了多元逻辑回归（MLR）模型来区分SC和hc。结果：66种代谢物和12种代谢物分别在组织和唾液中显示显著差异。其中，6种代谢物在SC和hc之间普遍不同。选取亚精胺、2-氨基丁酸和异亮氨酸建立MLR模型。该模型在受试者工作特征曲线下显示出较大的面积（0.802,95 %置信区间：0.731-0.874,P ）结论：SC和hc之间的唾液代谢组学特征存在明显差异。这种唾液代谢物的组合可以作为筛选SC的非侵入性生物标志物。

{"title":"Salivary metabolomics for skin cancer screening","authors":"Masahiro Hayashi , Shigeo Ishikawa , Masahiro Sugimoto , Naoki Okuyama , Kaoru Edamatsu , Kazuyuki Yusa , Tomoharu Hemmi , Takayuki Konno , Ken Okamura , Yuta Araki , Mariko Nikaido , Yoriko Yaguchi , Toru Saito , Shoko Nakano , Ami Hemmi , Yutaka Hozumi , Tamio Suzuki","doi":"10.1016/j.jdermsci.2025.05.003","DOIUrl":"10.1016/j.jdermsci.2025.05.003","url":null,"abstract":"<div><h3>Background</h3><div>If skin cancer (SC) can be screened using saliva, it would be extremely important for improving the prognosis of skin cancer. However, there is currently no available data on salivary screening for SC.</div></div><div><h3>Objective</h3><div>This study aimed to identify salivary metabolomic<span> biomarkers for SC screening by comparing tissue and saliva samples.</span></div></div><div><h3>Methods</h3><div>This single-center study involved SC patients from Yamagata University Hospital, enrolled between May 2017 and April 2020. For the healthy controls (HCs), our database comprising salivary metabolomics data of HCs was used. Whole unstimulated saliva samples were collected from patients with SC (n = 75) and HCs (n = 77). Paired tumor and control tissues after SC resection were obtained from the same patients who donated saliva. Hydrophilic metabolites in the tissue and saliva samples were comprehensively analyzed using capillary electrophoresis–mass spectrometry. Using these candidate metabolites, a multiple logistic regression (MLR) model was developed to differentiate SC from HCs</div></div><div><h3>Results</h3><div>Sixty-six and 12 metabolites showed significant differences in tissues and saliva, respectively. Of these, six metabolites were commonly different between SC and HCs. Spermidine<span><span><span>, 2-aminobutyric acid, and isoleucine were selected to develop the MLR model. The model exhibited a large area under the receiver operating characteristic curve (0.802, 95 % confidence interval: 0.731–0.874, P < 0.0001). Additionally, no significant differences were shown in candidate salivary metabolites between stages in both </span>malignant melanoma and </span>squamous cell carcinoma.</span></div></div><div><h3>Conclusions</h3><div>The salivary metabolomic profiles between SC and HCs differed clearly. This combination of salivary metabolites could serve as non-invasive biomarkers for screening SC.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 2","pages":"Pages 90-96"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251610","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

Long-read sequencing cracks unsolved cases and further improves genome diagnostics in epidermolysis bullosa 长读测序解决了未解决的病例，并进一步提高了大疱性表皮松解症的基因组诊断。

IF 4.6

Journal of dermatological science

Pub Date : 2025-08-01 DOI: 10.1016/j.jdermsci.2025.04.014

Eddy N. de Boer , L. Agnes Grutters , Rosalie Baardman , Daniëlle Schoonhoven , Jeroen Bremer , Rindert R. Venema , Femke Boorsma , Jelkje J. de Boer-Bergsma , Gilles F.H. Diercks , Henny H. Lemmink , Sabrina Z. Commandeur-Jan , Dorieke. J. Dijkstra , Lennart F. Johansson , Marieke C. Bolling , Cleo C. van Diemen , Peter C. van den Akker

引用次数: 0

Eribulin inhibits tumor growth of two novel patient-derived xenograft models of Merkel cell carcinoma 艾里布林抑制两种新型患者来源的梅克尔细胞癌异种移植模型的肿瘤生长。

IF 4.6

Journal of dermatological science

Pub Date : 2025-08-01 DOI: 10.1016/j.jdermsci.2025.05.007

Kodai Miyamoto , Teruki Yanagi , Takuya Maeda , Shinya Kitamura , Hiroshi Nishihara , Ririko Iwamoto , Kenzo Takahashi , Hideyuki Ujiie

Background

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with a poor prognosis in advanced cases. Despite reported sensitivities to chemotherapy and immunotherapy, response rates remain limited to approximately 50 % of cases. Although developing novel therapeutic strategies against MCC has been desired, few preclinical models, including cell lines and patient-derived xenografts (PDXs), are available.

Objectives

This study aimed to establish novel preclinical research models and develop novel therapeutic strategies for MCC.

Methods

We analyzed 19 clinical MCC samples in our department. Moreover, to establish novel PDX tumors, we transplanted MCC tissues from Japanese patients into immunodeficient NOD/SCID mice.

Results

Histopathological analyses of 19 clinical MCC samples in our department revealed the tumors to either be infected with the Merkel cell polyomavirus or have lost the expression of tumor suppressors (tumor protein p53 [p53] or RB transcriptional corepressor 1 [Rb1]). To establish novel PDX tumors, we transplanted MCC tissues from Japanese patients into immunodeficient NOD/SCID mice. Two MCC-PDX tumors were successfully implanted (MCC-PDX-MK1 and -MK2), and their histopathological and genetic characteristics were consistent with those of the original tumor. As in vivo preclinical treatments, we administered cisplatin, etoposide, docetaxel, or eribulin to the NOD/SCID mice. Eribulin showed antitumor activity in both MCC-PDX models.

Conclusion

Two MCC-PDX models were established successfully, and therapeutic experiments suggest that eribulin could inhibit MCC tumor growth.

背景：默克尔细胞癌（MCC）是一种罕见的侵袭性神经内分泌皮肤癌，晚期预后较差。尽管有报道对化疗和免疫治疗敏感，但反应率仍然限制在约50% %的病例。尽管开发针对MCC的新治疗策略是必要的，但很少有临床前模型，包括细胞系和患者来源的异种移植物（PDXs）。目的：本研究旨在建立新的临床前研究模型和开发新的MCC治疗策略。方法：对我科19例临床MCC标本进行分析。此外，为了建立新的PDX肿瘤，我们将日本患者的MCC组织移植到免疫缺陷的NOD/SCID小鼠中。结果：对我科19例临床MCC标本进行组织病理学分析，发现肿瘤感染了默克尔细胞多瘤病毒或肿瘤抑制因子（肿瘤蛋白p53 [p53]或RB转录辅助抑制因子1 [Rb1]）表达缺失。为了建立新的PDX肿瘤，我们将日本患者的MCC组织移植到免疫缺陷的NOD/SCID小鼠体内。成功植入2个MCC-PDX肿瘤（MCC-PDX- mk1和-MK2），其组织病理学和遗传学特征与原肿瘤一致。作为体内临床前治疗，我们给NOD/SCID小鼠施用顺铂、依托泊苷、多西他赛或伊瑞布林。艾力布林在两种MCC-PDX模型中均表现出抗肿瘤活性。结论：成功建立了2个MCC- pdx模型，治疗实验表明伊瑞布林能抑制MCC肿瘤的生长。

{"title":"Eribulin inhibits tumor growth of two novel patient-derived xenograft models of Merkel cell carcinoma","authors":"Kodai Miyamoto , Teruki Yanagi , Takuya Maeda , Shinya Kitamura , Hiroshi Nishihara , Ririko Iwamoto , Kenzo Takahashi , Hideyuki Ujiie","doi":"10.1016/j.jdermsci.2025.05.007","DOIUrl":"10.1016/j.jdermsci.2025.05.007","url":null,"abstract":"<div><h3>Background</h3><div><span><span>Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with a poor prognosis in advanced cases. Despite reported sensitivities to chemotherapy and </span>immunotherapy, response rates remain limited to approximately 50 % of cases. Although developing novel therapeutic strategies against MCC has been desired, few preclinical models, including cell lines and patient-derived </span>xenografts (PDXs), are available.</div></div><div><h3>Objectives</h3><div>This study aimed to establish novel preclinical research models and develop novel therapeutic strategies for MCC.</div></div><div><h3>Methods</h3><div>We analyzed 19 clinical MCC samples in our department. Moreover, to establish novel PDX tumors, we transplanted MCC tissues from Japanese patients into immunodeficient NOD/SCID mice.</div></div><div><h3>Results</h3><div><span>Histopathological analyses of 19 clinical MCC samples in our department revealed the tumors to either be infected with the Merkel cell polyomavirus<span> or have lost the expression of tumor suppressors (tumor protein p53 [p53] or RB transcriptional corepressor 1 [Rb1]). To establish novel PDX tumors, we transplanted MCC tissues from Japanese patients into immunodeficient NOD/SCID mice. Two MCC-PDX tumors were successfully implanted (MCC-PDX-MK1 and -MK2), and their histopathological and genetic characteristics were consistent with those of the original tumor. As in vivo preclinical treatments, we administered cisplatin<span>, etoposide<span>, docetaxel, or </span></span></span></span>eribulin<span> to the NOD/SCID mice. Eribulin showed antitumor activity in both MCC-PDX models.</span></div></div><div><h3>Conclusion</h3><div>Two MCC-PDX models were established successfully, and therapeutic experiments suggest that eribulin could inhibit MCC tumor growth.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 2","pages":"Pages 82-89"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268247","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

A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma SERPINB7基因中引起异常剪接的深内含子奠基者变异是nagashima型掌跖角化病的潜在治疗靶点。

IF 4.6

Journal of dermatological science

Pub Date : 2025-08-01 DOI: 10.1016/j.jdermsci.2025.05.004

Yuqi Chen , Zhiming Chen , Siyuan Li , Juan Liu , Yihe Liu , Qingyue Fu , Wenbo Bu , Shuya Sun , Tianxiao Li , Ruiyu Xiang , Zhongya Song , Ran Mo , Yong Yang

Background

Nagashima-type palmoplantar keratoderma (NPPK), caused by biallelic SERPINB7 loss-of-function variants, lacks effective treatments. Intriguingly, monoallelic exonic variants are observed in some patients with NPPK, suggesting additional genetic variants.

Objective

To characterize a deep intronic SERPINB7 variant’s pathogenicity, elucidate its splicing dysregulation, and evaluate antisense oligonucleotide (ASO) therapy.

Methods

A customized next-generation sequencing panel was applied to six Chinese NPPK patients. Pathological changes were analyzed by H&E staining and immunofluorescence. RNA extracted from palmar skin was assessed for splicing alterations. Plasmids were generated to evaluate the expression and function of mutant SERPINB7 protein. Haplotype analysis was conducted to confirm the founder effect. RNA pull-down assays and mass spectrometry were used to identify the key splicing factor. Minigene constructs were developed to characterize the splicing process in vitro. Finally, an ASO was designed to target this variant.

Results

A deep intronic SERPINB7 variant was identified in six NPPK patients, leading to pseudo-exon inclusion and the production of a truncated, dysfunctional SERPINB7 protein. Haplotype analysis confirmed it as a Chinese founder variant. RNA pull-down assays revealed excessive SRSF9 binding to the abnormal transcript. In vitro, the ASO successfully corrected the aberrant splicing.

Conclusion

This study established the pathogenicity of a deep intronic founder variant in SERPINB7 driving NPPK via SRSF9-mediated splicing dysregulation, demonstrating ASO therapeutic potential. Findings provide mechanistic insights and a targeted approach for precision therapy development for NPPK.

背景：由双等位基因SERPINB7功能丧失变异引起的nagashima型掌跖角化病（NPPK）缺乏有效的治疗方法。有趣的是，在一些NPPK患者中观察到单等位外显子变异，这表明存在其他遗传变异。目的：研究深内含子SERPINB7变异的致病性，阐明其剪接失调，并评价反义寡核苷酸（ASO）的治疗效果。方法：对6例中国NPPK患者应用定制的下一代测序面板。H&E染色及免疫荧光分析病理变化。从手掌皮肤中提取的RNA被评估剪接改变。制备质粒以评价突变体SERPINB7蛋白的表达和功能。单倍型分析证实了始祖效应。采用RNA拉下法和质谱法鉴定关键剪接因子。构建了Minigene结构来表征体外剪接过程。最后，针对这种变异设计了ASO。结果：在6例NPPK患者中鉴定出深内含子SERPINB7变异，导致假外显子包绕和产生截断的功能失调的SERPINB7蛋白。单倍型分析证实其为中国始祖变异。RNA下拉实验显示过量的SRSF9与异常转录物结合。在体外，ASO成功地纠正了异常剪接。结论：本研究证实了SERPINB7深层内含子奠基者变异通过srsf9介导的剪接失调驱动NPPK的致病性，显示了ASO的治疗潜力。研究结果为NPPK的精确治疗发展提供了机制见解和有针对性的方法。

{"title":"A deep intronic founder variant in the SERPINB7 gene causing aberrant splicing is a potential therapeutic target for Nagashima-type palmoplantar keratoderma","authors":"Yuqi Chen , Zhiming Chen , Siyuan Li , Juan Liu , Yihe Liu , Qingyue Fu , Wenbo Bu , Shuya Sun , Tianxiao Li , Ruiyu Xiang , Zhongya Song , Ran Mo , Yong Yang","doi":"10.1016/j.jdermsci.2025.05.004","DOIUrl":"10.1016/j.jdermsci.2025.05.004","url":null,"abstract":"<div><h3>Background</h3><div><span>Nagashima-type palmoplantar keratoderma (NPPK), caused by biallelic </span><em>SERPINB7</em><span> loss-of-function variants, lacks effective treatments. Intriguingly, monoallelic exonic variants are observed in some patients with NPPK, suggesting additional genetic variants.</span></div></div><div><h3>Objective</h3><div>To characterize a deep intronic <em>SERPINB7</em><span><span> variant’s pathogenicity, elucidate its splicing dysregulation, and evaluate antisense </span>oligonucleotide (ASO) therapy.</span></div></div><div><h3>Methods</h3><div><span><span>A customized next-generation sequencing panel was applied to six Chinese NPPK patients. Pathological changes were analyzed by H&E staining and immunofluorescence. </span>RNA<span> extracted from palmar skin was assessed for splicing alterations. Plasmids were generated to evaluate the expression and function of mutant SERPINB7 protein. Haplotype analysis was conducted to confirm the founder effect. RNA pull-down assays and mass spectrometry<span> were used to identify the key splicing factor. Minigene constructs were developed to characterize the splicing process </span></span></span><em>in vitro</em><span>. Finally, an ASO was designed to target this variant.</span></div></div><div><h3>Results</h3><div>A deep intronic <em>SERPINB7</em> variant was identified in six NPPK patients, leading to pseudo-exon inclusion and the production of a truncated, dysfunctional SERPINB7 protein. Haplotype analysis confirmed it as a Chinese founder variant. RNA pull-down assays revealed excessive SRSF9 binding to the abnormal transcript. <em>In vitro</em>, the ASO successfully corrected the aberrant splicing.</div></div><div><h3>Conclusion</h3><div>This study established the pathogenicity of a deep intronic founder variant in <em>SERPINB7</em> driving NPPK via SRSF9-mediated splicing dysregulation, demonstrating ASO therapeutic potential. Findings provide mechanistic insights and a targeted approach for precision therapy development for NPPK.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 2","pages":"Pages 73-81"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512866","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

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IF 4.6

Journal of dermatological science

Pub Date : 2025-08-01 DOI: 10.1016/S0923-1811(25)00135-5

引用次数: 0

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