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BACKGROUND: Previous studies reported the mutational landscape in extramammary Paget's disease (EMPD); however, the prognostic implications of genetic alterations remain unexplored. While CDKN2A loss is known to be associated with tumor progression or poor prognosis in some types of cancer, its significance in EMPD has not been investigated. OBJECTIVES: To examine the association between common genetic alterations and prognosis in EMPD. METHODS: This is a retrospective cohort study analyzing EMPD cases registered until January 2024 in the Center for Cancer Genomics and Advanced Therapeutics database, which is a nationwide database recording clinical data and comprehensive genomic profiling (CGP) test results in Japan. RESULTS: A total of 167 cases were recorded in the database, with CDKN2A loss being the most frequent genetic variant. Survival analysis was conducted on 127 cases. Survival from chemotherapy initiation was analyzed with adjusting for length bias inherent in the database using the Kaplan-Meier estimator, an established adjustment method. Cases with BRCA2-mutant tumors (n=18) had a worse prognosis than those with BRCA2-wild-type tumors (n=109; HR=2.97, 95% CI 1.46-6.01, p=0.003). Additionally, CDKN2A-mutant group (n=72) had a significantly worse prognosis than those with CDKN2A-wild-type group (n=55; HR=1.81, 95% CI 1.06-3.07, p=0.029). Most CDKN2A variants were pathogenic, primarily characterized by loss, while most BRCA2 variants were variants of uncertain significance. In the analysis of survival from CGP enrollment based on Eastern Cooperative Oncology Group performance status (ECOG-PS), cases with ECOG-PS 1 at the time of CGP enrollment had significantly poorer prognosis than those with ECOG-PS 0 (p=0.034; median survival time, 531 vs. 259 days). CONCLUSIONS: Somatic CDKN2A variant, mainly exhibiting loss, may be associated with poor prognosis in EMPD. Cases with BRCA2-mutant cancer might also have a worse prognosis in EMPD. In addition, CGP testing before PS deteriorates is preferable, considering the observed median survival of individuals undergoing CGP tests in an ECOG-PS-1 condition was less than 9 months.
Extramammary Paget's Disease (EMPD) is a relatively rare skin cancer that typically appears in genital area. As a result, little is known about the association between genetic changes and prognosis for people diagnosed with this condition. This study was conducted in Japan using a national database. This database included people who had undergone comprehensive genomic profiling tests to examine genetic changes in their cancer. We aimed to explore the relationship between specific genetic changes and the prognosis of EMPD cases. To do this, we analyzed 167 cases from the database, focusing on 127 people for whom survival data was available. Our main goal was to see how genetic alterations might impact patient survival. In our cohort, a gene called 'CDKN2A' was most frequently altered (56%), and we found that changes to CDKN2A (such as loss) was linked to poorer prognosis. Similarly, cases with changes to a gene called 'BRCA2' were also associated with a poorer prognosis. We further noted that earlier testing for genetic changes could lead to better treatment planning and outcomes. In conclusion, identifying CDKN2A genetic changes in EMPD may be related to poor prognosis. These novel findings may help doctors create more personalized treatment plans for people with EMPD. Understanding these genetic factors also opens new research opportunities in EMPD.
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The microtubule-associated protein MAP1B has been implicated in axonal growth and brain development. We found that MAP1B is highly expressed in the most aggressive and deadliest breast cancer subtype, triple-negative breast cancer (TNBC), but not in other subtypes. Expression of MAP1B was found to be highly correlated with poor prognosis. Depletion of MAP1B in TNBC cells impairs cell migration and invasion concomitant with a defect in tumorigenesis. We found that MAP1B interacts with key components for invadopodia formation, cortactin, and Tks5, the latter of which is a PtdIns(3,4)P2-binding and scaffold protein that localizes to invadopodia. We also found that Tks5 associates with microtubules and supports the association between MAP1B and α-tubulin. In accordance with their interaction, depletion of MAP1B leads to Tks5 destabilization, leading to its degradation via the autophagic pathway. Collectively, these findings suggest that MAP1B is a convergence point of the cytoskeleton to promote malignancy in TNBC and thereby a potential diagnostic and therapeutic target for TNBC.
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Proteínas Adaptadoras de Transporte Vesicular , Cortactina , Proteínas Associadas aos Microtúbulos , Neoplasias de Mama Triplo Negativas , Humanos , Carcinogênese/genética , Transformação Celular Neoplásica , Cortactina/genética , Proteínas Associadas aos Microtúbulos/genética , Neoplasias de Mama Triplo Negativas/genética , Células MDA-MB-231 , Proteínas Adaptadoras de Transporte Vesicular/genética , Microtúbulos/metabolismo , Citoesqueleto/metabolismo , Feminino , Animais , Camundongos , Camundongos Endogâmicos BALB C , Podossomos/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
Information about extramammary Paget's (EMPD) treatment is limited because of the rarity of the disease. The prognosis differs between in situ EMPD and invasive EMPD; therefore, therapy should be planned according to the disease stage. We collected data on 643 EMPD cases treated between 2015 and 2019 in Japan and assessed recent trends in EMPD treatment and prognosis based on the EMPD-oriented TNM staging. Among the 643 patients, 317 had stage 0 (49.3%), 185 had stage I (28.8%), 51 had stage II (7.9%), 18 had stage IIIA (2.8%), 48 had stage IIIB (7.5%) and 24 had stage IV (3.7%) disease. Each stage showed a distinct survival curve, with the exception of stages II and IIIA. Curative surgery was most common in patients with stage 0-III disease. Chemotherapy was the first-line therapy, mainly in patients with stage IIIB and IV disease, most commonly with docetaxel (DTX), followed by DTX + tegafur gimeracil oteracil potassium (TS-1) and TS-1. Patients with local disease exhibited a 4.4% recurrence rate. Univariate analysis revealed no prognostic differences according to age, sex or primary tumour site. SLNB was not related to disease-specific survival. In multivariate analysis, female sex significantly predicted local relapse in stage 0-I (HR 3.09; 95% CI, 1.13-8.43), and initial treatment with curative surgery was significantly protective in terms of disease-specific survival in stage II-IIIA (HR, 0.17; 95% CI, 0.04-0.71) and stage IIIB-IV (HR 0.16; 95% CI, 0.05-0.51). Further clinical studies are needed to improve the prognosis of patients with stage II-IV EMPD.
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Doença de Paget Extramamária , Silicatos , Titânio , Humanos , Feminino , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. METHODS: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. RESULTS: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. CONCLUSIONS: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.
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Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Antígeno CTLA-4 , Estudos Retrospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Receptor de Morte Celular Programada 1 , Japão , Melanoma/tratamento farmacológico , Melanoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
An 84-year-old woman who was admitted for protein-losing gastroenteropathy associated with radiation enteritis 10 years after pelvic radiotherapy developed pyelonephritis. She became anuric despite having an indwelling bladder catheter. Imaging studies revealed bladder wall thickening, bilateral hydroureter formation, and hydronephrosis. Autopsy findings led to a diagnosis of gangrenous cystitis (GC). Our case indicates that radiation-induced late effects may be an indirect cause of GC, not a direct cause as previously suggested, and that GC may induce bilateral vesicoureteral junction obstruction.
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Melanoma , Neoplasias Cutâneas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , População do Leste Asiático , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/etiologia , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologiaRESUMO
Ultrasound is a minimally invasive examination method. Previous examinations have shown that the most common standard methods used to reveal the distal aspect of the congenital labial sinus, fistula probe or methylene blue dye, are highly invasive and ultrasound is less invasive. Of course, there are cases where CT is necessary, but CT carries the risk of radiation exposure.
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Background: Squamous cell carcinoma antigen (SCCA) was originally isolated as tumour-specific antigens in uterine cervix carcinoma. These comprise two similar proteins, SCCA1 and SCCA2, and both are induced by type 2 cytokines such as interleukin (IL)-4 and IL-13. The involvement of these antigens in atopic dermatitis has been reported, however, the role in mycosis fungoides (MF) and Sézary syndrome (SS), which are also linked with type 2 cytokines, remains to be seen. Objectives: This study investigated a possible association between SCCA1/2 and MF/SS. Materials & Methods: We compared serum levels of SCCA1/2 between MF/SS patients and healthy controls. We also examined the correlation between serum SCCA1/2 levels in MF/SS patients and clinical disease markers. The expression of SCCA1/2 in skin samples was examined by immunohistochemistry. Results: The serum levels of SCCA1/2 in MF/SS patients were significantly higher than those in normal controls and correlated with clinical disease markers. Immunohistochemical staining showed upregulated expression of SCCA1/2 in MF/SS lesional skin. Conclusion: Enhanced SCCA1/2 expression may contribute to the progression of MF/SS. Measurement of serum SCCA1/2 levels may become a useful tool to evaluate the progression or therapeutic effects of MF/SS.
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Antígenos de Neoplasias , Micose Fungoide , Serpinas , Síndrome de Sézary , Humanos , Antígenos de Neoplasias/genética , Biomarcadores , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Serpinas/genéticaRESUMO
Autoantibodies are found in various pathological conditions such as autoimmune diseases, infectious diseases, and malignant tumors. However their clinical implications have not yet been fully elucidated. Herein, we conducted proteome-wide autoantibody screening and quantification with wet protein arrays consisting of proteins synthesized from proteome-wide human cDNA library (HuPEX) maintaining their three-dimensional structure. A total of 565 autoantibodies were identified from the sera of three representative inflammatory disorders (systemic sclerosis, psoriasis, and cutaneous arteritis). Each autoantibody level either positively or negatively correlated with serum levels of C-reactive protein, the best-recognized indicator of inflammation. In particular, we discovered total levels of a subset of autoantibodies correlates with the severity of clinical symptoms. From the sera of malignant melanoma, 488 autoantibodies were detected. Notably, patients with metastases had increased overall autoantibody production compared to those with tumors limiting to the primary site. Collectively, proteome-wide screening of autoantibodies using the in vitro proteome can reveal the "autoantibody landscape" of human subjects and may provide novel clinical biomarkers.
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Doenças Autoimunes , Análise Serial de Proteínas , Autoanticorpos , Biomarcadores , Humanos , Análise Serial de Proteínas/métodos , ProteomaRESUMO
Basal cell carcinoma is the most common type of skin cancer, and surgical excision with clear margins is the standard of care. Surgical margins are determined based on risk factors (high or low risk) for recurrence according to the National Comprehensive Cancer Network and Japanese basal cell carcinoma guidelines. The clarity of the clinical tumor border (well-defined or poorly defined) is considered a risk factor, and significant discrepancies in the judgment of clinical tumor borders among dermato-oncologists may occur. Therefore, we analyzed the dermato-oncologists' concordance in judging the clinical tumor border of basal cell carcinoma. Forty-seven dermato-oncologists (experts: 37; young trainees: 10) participated in this study. The datasets of clinical and dermoscopic photographs of 79 Japanese cases of head and neck basal cell carcinoma were used to determine the concordance in the judgment of clinical tumor border. The probability of the border that was selected more often was used to calculate the rater agreement rate for each dataset. Correct judgment was defined as a more frequently selected border, and the concordance rate of clarity of clinical tumor border for each dermato-oncologist was calculated based on the definition of the correct judgment. A median concordance rate of 85% or higher for all dermato-oncologists was predefined as an acceptable rate for clinical use. Of the 79 datasets, rater agreement rates were 80-100%, 60-79%, and 51-59% for 55, 19, and five datasets, respectively. The median concordance rate for all dermato-oncologists was 86% (interquartile range: 82-89%). There was no significant difference in the concordance rate between the experts and the trainees (median, 87% vs. 85.5%; p = 0.58). The concordance rates of dermato-oncologists for all datasets were relatively high and acceptable for clinical use.
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Carcinoma Basocelular , Neoplasias de Cabeça e Pescoço , Neoplasias Cutâneas , Carcinoma Basocelular/patologia , Carcinoma Basocelular/cirurgia , Humanos , Japão , Julgamento , Margens de Excisão , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgiaAssuntos
Melanoma , Humanos , Melanoma/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , SíndromeRESUMO
Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma with unfavourable prognosis once it becomes invasive. A tumour marker that reflects disease progression is required for adequate management of EMPD. Cytokeratin 18 is highly expressed in many types of cancer and its soluble forms are detected by M30 (for caspase-cleaved form) and M65 (for both caspase-cleaved and intact forms) assays. We report here that tumour cells of EMPD in both lesional skin and lymph node metastasis are immunohistochemically positive for CK18, and the baseline serum M30 and M65 levels in patients with metastatic EMPD are significantly higher than those in non-metastatic patients. In addition, serial serum M30 and M65 levels might reflect recurrence of EMPD and response to chemotherapy. These results suggest that serum CK18 levels may be a useful tumour marker for advanced EMPD.
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Doença de Paget Extramamária , Neoplasias Cutâneas , Biomarcadores Tumorais , Humanos , Queratina-18 , Metástase Linfática , Doença de Paget Extramamária/tratamento farmacológico , Prognóstico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and T helper (Th)2/Th17 cytokines serve as critical disease drivers. LIGHT is a proinflammatory cytokine promoting IL-6 production in lung fibroblasts and Th1 chemokine expression in dermal fibroblasts (DFs) stimulated with IFN-γ. In this study, we investigated the potential contribution of LIGHT to SSc development using clinical samples and animal models. In SSc-involved skin, LIGHT was upregulated in inflammatory cells, whereas herpesvirus entry mediator (HVEM), a receptor of LIGHT, was downregulated in DFs. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter, and FLI1 small interfering RNA suppressed HVEM expression in normal DFs. In SSc DFs, LIGHT significantly increased IL-6 production, whereas IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with that in normal DFs. Importantly, LIGHT small interfering RNA significantly attenuated bleomycin-induced skin fibrosis, and serum LIGHT levels were elevated in patients with diffuse cutaneous SSc and positively correlated with clinical parameters reflecting skin and pulmonary fibrosis. Taken together, these results suggest that altered response of DFs to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.
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Interleucina-6 , Escleroderma Sistêmico , Animais , Bleomicina/toxicidade , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Humanos , Interleucina-6/metabolismo , Camundongos , Proteína Proto-Oncogênica c-fli-1 , RNA Interferente Pequeno/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/patologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: We have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the development of SSc vasculopathy. Therefore, we explored this hypothesis using clinical samples, cultured cells, and murine SSc models. METHODS: The expression levels of CCL20 and CCR6 in the skin, mRNA levels of target genes, and the binding of transcription factor FLI1 to the target gene promoter were evaluated by immunostaining, quantitative reverse transcription PCR, and chromatin immunoprecipitation, respectively. Vascular permeability was evaluated by Evans blue dye injection in bleomycin-treated mice. Angiogenic activity of endothelial cells was assessed by in vitro angiogenesis assay. RESULTS: CCL20 expression was significantly elevated in dermal fibroblasts of patients with early diffuse cutaneous SSc, while CCR6 was significantly up-regulated in dermal small vessels of SSc patients irrespective of disease subtypes and disease duration. In human dermal microvascular endothelial cells, FLI1 siRNA induced the expression of CCR6, but not CCL20, and FLI1 bound to the CCR6 promoter. Importantly, vascular permeability, a representative SSc-like vascular feature of bleomycin-treated mice, was attenuated by Ccr6 siRNA treatment, and CCR6 siRNA suppressed the angiogenic activity of human dermal microvascular endothelial cells assayed by in vitro tube formation. CONCLUSIONS: The increased expression of endothelial CCR6 due to FLI1 deficiency may contribute to the development of SSc vasculopathy.
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Receptores CCR6/genética , Esclerodermia Difusa , Escleroderma Sistêmico , Doenças Vasculares , Animais , Células Endoteliais , Humanos , Camundongos , Proteína Proto-Oncogênica c-fli-1/deficiência , Proteína Proto-Oncogênica c-fli-1/genética , Escleroderma Sistêmico/genética , Pele , Doenças Vasculares/genéticaRESUMO
Systemic inflammatory response markers, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and monocyte-to-lymphocyte ratio, are useful prognostic factors for various malignant tumours. The aim of this study was to investigate the clinical relevance of these markers in primary cutaneous angiosarcoma. Twenty-six patients were retrospectively divided into 2 groups according to pretreatment peri-pheral blood cell counts or systemic inflammatory response marker levels; overall survival and progression-free survival were compared. Univariate analysis found that high neutrophil count (> 3.1×109/l), high neutrophil-to-lymphocyte ratio (> 2.4), high platelet-to-lymphocyte ratio (> 175) and low lymphocyte count (≤ 1.3×109/l) were related to shorter overall survival, while high neutrophil and low lymphocyte groups had shorter progression-free survival. In multivariate analysis, high neutrophil count and high neutrophil-to- lymphocyte ratio (hazard ratio 7.44 and 5.04, 95% confidence interval 1.48-37.2 and 1.26-20.1, respectiv-ely) were identified as independent prognostic factors for poor overall survival. These results indicate that systemic inflammatory response markers serve as prognostic predictors in primary cutaneous angiosarcoma, as well as in other types of soft-tissue sarcoma.
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Hemangiossarcoma , Neutrófilos , Humanos , Linfócitos , Prognóstico , Estudos RetrospectivosRESUMO
Immune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.
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Insuficiência Adrenal/diagnóstico , Inibidores de Checkpoint Imunológico/efeitos adversos , Ipilimumab/efeitos adversos , Neoplasias/tratamento farmacológico , Nivolumabe/efeitos adversos , Insuficiência Adrenal/sangue , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/prevenção & controle , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/deficiência , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores/sangue , Diagnóstico Tardio , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/deficiência , Inibidores de Checkpoint Imunológico/administração & dosagem , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/patologia , Nivolumabe/administração & dosagem , Estudos RetrospectivosRESUMO
BACKGROUND: Aldehyde dehydrogenase 1 family member A1 (RALDH1)-producing dermal dendritic cells (DCs), a conventional DC subset regulating skin fibrosis, are decreased in the involved skin of patients with systemic sclerosis (SSc). In this study, we investigated the contribution of Fli1 deficiency, a potential predisposing factor of SSc, to the phenotypical alteration of RALDH1-producing dermal DCs by using SSc model mice and SSc skin samples. METHODS: Bleomycin (BLM)-induced skin fibrosis was generated with Fli1+/- and wild-type mice. The proportions of DC and CD4+ T cell subsets were determined by flow cytometry in the dermis of BLM-treated mice. Fli1 expression in dermal DCs was evaluated by immunofluorescence with skin samples of SSc and healthy control subjects. RESULTS: RALDH activity of dermal DCs was significantly decreased in BLM-treated Fli1+/- mice compared with BLM-treated wild-type mice, whereas the proportion of CD103-CD11b- dermal DCs, a major DC subset producing RALDH1 in response to BLM injection, was comparable between groups. Relevant to this finding, the proportion of regulatory T cells (Tregs) in the dermis was decreased in BLM-treated Fli1+/- mice relative to BLM-treated wild-type mice, while the proportions of Th1, Th2 and Th17 cells were unaltered. In the involved skin of SSc patients, Fli1 was downregulated in CD11c+ cells, including dermal DCs. CONCLUSIONS: Fli1 deficiency inhibits RALDH1 activity of CD103-CD11b- dermal DCs and related induction of Tregs in BLM-treated mice. Considering Fli1 reduction in SSc dermal DCs, Fli1deficiency may impair the dermal DC-Treg system, contributing to the development of skin fibrosis in SSc.
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Família Aldeído Desidrogenase 1/metabolismo , Retinal Desidrogenase/metabolismo , Escleroderma Sistêmico , Linfócitos T Reguladores , Animais , Células Dendríticas , Modelos Animais de Doenças , Fibrose , Humanos , Células de Langerhans , Camundongos , Proteína Proto-Oncogênica c-fli-1/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/patologiaRESUMO
Many features of extracellular matrices, e.g., self-healing, adhesiveness, viscoelasticity, and conductivity, are associated with the intricate networks composed of many different covalent and non-covalent chemical bonds. Whereas a reductionism approach would have the limitation to fully recapitulate various biological properties with simple chemical structures, mimicking such sophisticated networks by incorporating many different functional groups in a macromolecular system is synthetically challenging. Herein, we propose a strategy of convergent synthesis of complex polymer networks to produce biomimetic electroconductive liquid metal hydrogels. Four precursors could be individually synthesized in one to two reaction steps and characterized, then assembled to form hydrogel adhesives. The convergent synthesis allows us to combine materials of different natures to generate matrices with high adhesive strength, enhanced electroconductivity, good cytocompatibility in vitro and high biocompatibility in vivo. The reversible networks exhibit self-healing and shear-thinning properties, thus allowing for 3D printing and minimally invasive injection for in vivo experiments.