Pub Date : 2025-09-01DOI: 10.1016/j.jdermsci.2025.06.003
Daishi Li , Sitao Liu , Yi Ge , Hui Li , Xinchen Ke , Dongsheng Cao , Guangtong Deng , Lixia Lu , Juan Su
Background
The clinical efficacy of vemurafenib in melanoma patients has been hindered by the development of acquired resistance.
Objectives
To comprehend the molecular signaling pathways underlying this resistance and identify potential strategies to overcome it.
Methods
We first constructed the vemurafenib-resistant melanoma cell lines A375R and identified ABCB1 as a potential driver through RNA sequence. ABCB1 knockdown on vemurafenib sensitivity was assessed by CCK-8 and colony formation. FDA-approved eupatilin was identified as a novel ABCB1 inhibitor by employing the quantitative structure-activity relationship model and ADMETlab 2.0. The combined effect of eupatilin and vemurafenib was detected in in vitro and in vivo.
Results
The expression of ABCB1 was upregulated in A375R. The genetic inhibition of ABCB1 could restore sensitivity to vemurafenib in resistant cells. Eupatilin was a previously unexplored compound that can selectively target ABCB1 and exhibit favorable safety profiles. Notably, we identified eupatilin as a therapeutic intervention to counteract acquired resistance to vemurafenib in cell and animal experiments, resulting in the inhibition of tumor growth. Furthermore, we found upregulation of ABCB1 in resistant cells due to the activation of the PI3K-AKT-mTOR pathway.
Conclusion
These findings provided valuable insights into a novel molecular mechanism underlying vemurafenib resistance and highlighted potential ABCB1 as a viable target, in conjunction with its novel inhibitor eupatilin, to enhance effectiveness of vemurafenib.
{"title":"Eupatilin attenuates vemurafenib resistance through inhibition of ABCB1 in melanoma","authors":"Daishi Li , Sitao Liu , Yi Ge , Hui Li , Xinchen Ke , Dongsheng Cao , Guangtong Deng , Lixia Lu , Juan Su","doi":"10.1016/j.jdermsci.2025.06.003","DOIUrl":"10.1016/j.jdermsci.2025.06.003","url":null,"abstract":"<div><h3>Background</h3><div>The clinical efficacy of vemurafenib<span> in melanoma patients has been hindered by the development of acquired resistance.</span></div></div><div><h3>Objectives</h3><div>To comprehend the molecular signaling pathways underlying this resistance and identify potential strategies to overcome it.</div></div><div><h3>Methods</h3><div><span>We first constructed the vemurafenib-resistant melanoma cell lines A375R and identified ABCB1 as a potential driver through </span>RNA sequence<span>. ABCB1 knockdown on vemurafenib<span> sensitivity was assessed by CCK-8 and colony formation. FDA-approved eupatilin was identified as a novel ABCB1 inhibitor by employing the quantitative structure-activity relationship model and ADMETlab 2.0. The combined effect of eupatilin and vemurafenib was detected in in vitro and in vivo.</span></span></div></div><div><h3>Results</h3><div>The expression of ABCB1 was upregulated in A375R. The genetic inhibition of ABCB1 could restore sensitivity to vemurafenib in resistant cells. Eupatilin was a previously unexplored compound that can selectively target ABCB1 and exhibit favorable safety profiles. Notably, we identified eupatilin as a therapeutic intervention to counteract acquired resistance to vemurafenib in cell and animal experiments, resulting in the inhibition of tumor growth. Furthermore, we found upregulation of ABCB1 in resistant cells due to the activation of the PI3K-AKT-mTOR pathway.</div></div><div><h3>Conclusion</h3><div>These findings provided valuable insights into a novel molecular mechanism underlying vemurafenib resistance and highlighted potential ABCB1 as a viable target, in conjunction with its novel inhibitor eupatilin, to enhance effectiveness of vemurafenib.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 3","pages":"Pages 112-121"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593248","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}
{"title":"Difamilast induces human beta defensin 3 production via CREB and NRF2 in human keratinocytes","authors":"Gaku Tsuji , Ayako Yumine , Masaki Takemura , Takeshi Nakahara","doi":"10.1016/j.jdermsci.2025.07.003","DOIUrl":"10.1016/j.jdermsci.2025.07.003","url":null,"abstract":"","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 3","pages":"Pages 135-138"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812757","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 : 2025-09-01DOI: 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.
{"title":"Integrative genomic and transcriptomic profiling reveals dysregulation of FOXA1-AGR2 axis in penoscrotal extramammary Paget's disease","authors":"Daoning Zhang , Sini Gao , Chunxia Zhao , Xiaomin Cai , Ruiqin Mai , Guohong Zhang , Hang Li","doi":"10.1016/j.jdermsci.2025.06.002","DOIUrl":"10.1016/j.jdermsci.2025.06.002","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objectives</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>Genomic landscape did not reveal <em>FOXA1</em> or <em>SPDEF</em> mutations penoscrotal EMPD. Transcriptomic profiling identified the upregulation of lineage-specific transcription factors <em>FOXA1</em> and <em>SPDEF,</em> along with their targeted genes <em>AGR2</em> and <em>MUC5AC</em>. Upregulation of <em>FOXA1</em>, <em>SPDEF</em> and <em>AGR2</em> without gene fusion were consistently replicated in the validation cohort. Further analysis of multiple tissue regions confirmed <em>FOXA1</em> and <em>SPDEF</em> as driver transcription factors in penoscrotal EMPD. We identify key transcription factors regulating co-expressed modules <em>FOXA1-SPDEF-AGR2</em>, suggesting goblet cells features of penoscrotal EMPD. The immunohistochemistry confirmed the co-expression of FOXA1-AGR2 pattern in Paget cells.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 3","pages":"Pages 122-131"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700776","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}
{"title":"Preferential CD101 expression on resident memory regulatory T cells and IFN-γ-producing CD8+ resident memory T cells in human epidermis","authors":"Takuya Sato , Youichi Ogawa , Manao Kinoshita , Yuka Nagasaka , Shinji Shimada , Akira Momosawa , Tatsuyoshi Kawamura","doi":"10.1016/j.jdermsci.2025.07.002","DOIUrl":"10.1016/j.jdermsci.2025.07.002","url":null,"abstract":"","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 3","pages":"Pages 132-134"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818867","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 : 2025-09-01DOI: 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.
{"title":"17β-Estradiol promotes LL37-induced rosacea-like skin inflammation via G protein-coupled estrogen receptor 30","authors":"Jin Tang , Peng Chen , Chuchu Huang , Wanjing Wang , Ben Wang , Wei Shi , Yan Tang , Zhili Deng , Yiya Zhang , Ji Li , Dan Jian","doi":"10.1016/j.jdermsci.2025.05.005","DOIUrl":"10.1016/j.jdermsci.2025.05.005","url":null,"abstract":"<div><h3>Background</h3><div>Rosacea is a common chronic inflammatory skin condition that predominantly affects females, though its underlying mechanisms remain unclear.</div></div><div><h3>Objective</h3><div>To explore the role of 17β-estradiol (E2) and the G-coupled estrogen receptor 30 (GPR30) in the pathogenesis of rosacea.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>Activation of the E2/GPR30 pathway plays a significant role in rosacea inflammation, and GPR30 inhibition may represent a novel therapeutic strategy for rosacea.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 3","pages":"Pages 101-111"},"PeriodicalIF":4.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651667","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 : 2025-08-01DOI: 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。
{"title":"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","authors":"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","doi":"10.1016/j.jdermsci.2025.05.006","DOIUrl":"10.1016/j.jdermsci.2025.05.006","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 <em>IL17A, IL17F</em> and <em>RORC</em> in mast cells.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 2","pages":"Pages 53-63"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340712","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}
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.
{"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}
Pub Date : 2025-08-01DOI: 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
{"title":"Long-read sequencing cracks unsolved cases and further improves genome diagnostics in epidermolysis bullosa","authors":"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","doi":"10.1016/j.jdermsci.2025.04.014","DOIUrl":"10.1016/j.jdermsci.2025.04.014","url":null,"abstract":"","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"119 2","pages":"Pages 97-100"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113152","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}
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.
{"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}
Pub Date : 2025-08-01DOI: 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.
{"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}
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