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BACKGROUND: Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported. MATERIALS AND METHODS: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. RESULTS: We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations. CONCLUSIONS: High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.
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PURPOSE: To assess the Consultation And Relational Empathy (CARE) measure as a tool for examiners to assess medical students' empathy during Objective and Structured Clinical Examinations (OSCEs), as the best tool for assessing empathy during OSCEs remains unknown. METHODS: We first assessed the psychometric properties of the CARE measure, completed simultaneously by examiners and standardized patients (SP, either teachers - SPteacher - or civil society members - SPcivil society), for each student, at the end of an OSCE station. We then assessed the qualitative/quantitative agreement between examiners and SP. RESULTS: We included 129 students, distributed in eight groups, four groups for each SP type. The CARE measure showed satisfactory psychometric properties in the context of the study but moderate, and even poor inter-rater reliability for some items. Considering paired observations, examiners scored lower than SPs (p < 0.001) regardless of the SP type. However, the difference in score was greater when the SP was a SPteacher rather than a SPcivil society (p < 0.01). CONCLUSION: Despite acceptable psychometric properties, inter-rater reliability of the CARE measure between examiners and SP was unsatisfactory. The choice of examiner as well as the type of SP seems critical to ensure a fair measure of empathy during OSCEs.
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Avaliação Educacional , Empatia , Simulação de Paciente , Psicometria , Estudantes de Medicina , Humanos , Estudantes de Medicina/psicologia , Reprodutibilidade dos Testes , Masculino , Feminino , Avaliação Educacional/métodos , Avaliação Educacional/normas , Relações Médico-Paciente , Competência Clínica/normas , Educação de Graduação em MedicinaRESUMO
Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a ß-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.
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Fator de Transcrição GATA6/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/fisiologia , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias Cutâneas/patologia , Células-Tronco/patologia , Animais , Proliferação de Células , Dano ao DNA , Feminino , Folículo Piloso/metabolismo , Folículo Piloso/patologia , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Camundongos , Camundongos Knockout , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutação , Neoplasias das Glândulas Sebáceas/genética , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Células-Tronco/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
The accurate diagnosis of skin adnexal neoplasms is sometimes challenging but is necessary because medical management and follow-up may differ between tumors. GATA6 transcription factor has been identified as a new marker of the upper folliculosebaceous compartment (lower infundibulum, junctional zone and isthmus, and upper sebaceous gland) in the human skin. We aimed to determine the diagnostic accuracy of GATA6 immunostaining to diagnose sebaceous tumors compared with that to diagnose other adnexal and nonadnexal cutaneous neoplasms. We conducted a retrospective, evaluator-nonblinded study comparing the reference standard (diagnosis by an expert dermatopathologist) with GATA6 immunostaining to identify sebaceous tumors in a cohort containing 234 different tumors. The GATA6 expression score was significatively higher in sebaceous than that in nonsebaceous tumors. In addition, tumors originating from the upper hair follicle showed positive results for GATA6 staining; however, they showed lower GATA6 expression scores. Detection of sebaceous tumors using GATA6 positivity had a sensitivity of 95.7% (95% CI, 85.8-99.2), specificity of 80.8% (95% CI, 74.5-85.8), positive predictive value of 55.6% (95% CI, 44.7-65.9), and negative predictive value of 98.7% (95% CI, 95.4-99.8). GATA6 showed similar sensitivity to adipophilin, the reference marker; however, the specificity of GATA6 was higher, as observed in a cohort of 106 tumors enriched in squamous cell carcinomas with clear-cell histology. In addition, GATA6 positivity was assessed in 39 sebaceous carcinomas and compared with epithelial membrane antigen (EMA), CK7, and androgen receptor (AR) staining results. Although CK7 staining displayed lower diagnostic performances, GATA6 staining showed comparable results as EMA and AR. Finally, we found GATA6 expression in skin metastases of gastrointestinal origin, whereas GATA6 was absent in metastases originating from breast or lung cancers. Overall, our work identified GATA6 immunostaining as a new diagnostic tool for sebaceous tumors.
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Neoplasias das Glândulas Sebáceas , Neoplasias Cutâneas , Humanos , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/diagnóstico , Pele/patologia , Neoplasias Cutâneas/patologia , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/patologia , Fator de Transcrição GATA6RESUMO
Leg ulcers are a major complication of sickle cell disease (SCD). They are particularly challenging to treat and innovative therapies are needed. We previously showed that the healing of SCD ulcers is delayed because of decreased angiogenesis. During pregnancy, fetal microchimeric cells (FMC) transferred to the mother are recruited to maternal wounds and improve angiogenesis. After delivery, FMC persist in maternal bone marrow for decades. Here, we investigated whether fetal cells could also improve SCD ulcers in the post-partum setting. We found that skin healing was similarly improved in post-partum mice and in pregnant mice, through increased proliferation and angiogenesis. In a SCD mouse model that recapitulates refractory SCD ulcers, we showed that the ulcers of post-partum SCD mice healed more quickly than those of virgin mice. This was associated with the recruitment of fetal cells in maternal wounds where they harbored markers of leukocytes and endothelial cells. In a retrospective cohort of SCD patients, using several parameters we found that SCD women who had ever had a baby had less of a burden related to leg ulcers compared to nulliparous women. Taken together, these results indicate that healing capacities of FMC are maintained long after delivery and may be exploited to promote wound healing in post-partum SCD patients.
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Anemia Falciforme , Úlcera da Perna , Gravidez , Feminino , Camundongos , Animais , Úlcera/complicações , Células Endoteliais , Estudos Retrospectivos , Cicatrização , Úlcera da Perna/complicações , Úlcera da Perna/terapia , Anemia Falciforme/complicaçõesRESUMO
Preventing brain cell loss and enhancing tissue repair are crucial objectives to improve the outcome of stroke. Fetal microchimerism has been implicated in brain repair following ischemic stroke in mice. CCL2/CCR2 signaling pathway triggers fetal progenitors trafficking to cutaneous wounds. Therefore, we sought to evaluate whether CCL2 could dampen brain damage in a model of excitotoxic lesion in post-partum mice. Virgin or post-partum mice were subjected to an intracerebral injection of ibotenate to induce excitotoxic lesions. Low doses of CCL2 or its vehicle were concomitantly injected. Morphological and molecular analyses were performed 1 and 5 days following the procedure. Intracerebral treatment with low doses of CCL2 was able to limit brain excitotoxic damage induced by ibotenate in post-partum mice, through an enhanced recruitment of fetal microchimeric cells to the damaged hemisphere. At day 1 post-injection, we observed a decreased cortical apoptosis associated with a reduced reactive astrocytosis. At day 5, we found an increased proportion of mature neurons and oligodendrocytes correlating with an increase in GAP43 growth cones. At this stage, immune microglial cells were reduced, while angiogenesis was enhanced. Importantly, CCL2 did not have beneficial effects in virgin mice therefore ruling out a specific role of CCL2 independently from fetal microchimeric cells mobilization. CCL2 treatment efficiently enhances fetal cell mobilization to improve the outcome of a brain excitotoxic challenge in post-partum mice. This study paves the way for a "natural stem cell therapy" based on the selective recruitment of fetal progenitors to repair maternal brain injury.
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Lesões Encefálicas , Humanos , Feminino , Animais , Camundongos , Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Período Pós-Parto , Quimiocina CCL2/metabolismo , Quimiocina CCL2/farmacologiaRESUMO
The two clinico-pathological patterns are 'Sweet-like syndrome' and 'Multiple COVID-Arm'. 'Sweet-like syndrome' presents clinically as erythematous and oedematous papules or plaques, sometimes developing vesiculation or bullae. Histology shows classical Sweet syndrome with a diffuse dermal neutrophilic infiltrate, or an infiltrate of histiocyte-like immature myeloid cells consistent with a histiocytoid Sweet syndrome. 'Multiple COVID-arm' is characterized by multiple large inflammatory plaques with histological analyses showing a perivascular and interstitial inflammatory infiltrate with eosinophils.
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COVID-19 , Síndrome de Sweet , Braço/patologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Histiócitos/patologia , Humanos , Síndrome de Sweet/diagnóstico , Síndrome de Sweet/etiologia , Síndrome de Sweet/patologiaAssuntos
COVID-19 , Pérnio , Interferon Tipo I , Vacinas contra COVID-19 , Humanos , RNA Mensageiro/genética , SARS-CoV-2RESUMO
Among the new players at the endoplasmic reticulum (ER)-mitochondria interface regulating interorganelle calcium signaling, those specifically involved during ER stress are not known at present. We report here that the truncated variant of the sarcoendoplasmic reticulum Ca(2+)-ATPase 1 (S1T) amplifies ER stress through the PERK-eIF2alpha-ATF4-CHOP pathway. S1T, which is localized in the ER-mitochondria microdomains, determines ER Ca(2+) depletion due to increased Ca(2+) leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements. This leads to increased Ca(2+) transfer to mitochondria in both resting and stimulated conditions and activation of the mitochondrial apoptotic pathway. Interestingly, S1T knockdown was shown to prevent ER stress, mitochondrial Ca(2+) overload, and subsequent apoptosis. Thus, by bridging ER stress to apoptosis through increased ER-mitochondria Ca(2+) transfer, S1T acts as an essential determinant of cellular fate.
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Apoptose , Cálcio/metabolismo , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/patologia , Mitocôndrias/enzimologia , Mutação/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Apoptose/efeitos dos fármacos , Sequência de Bases , Brefeldina A/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Indução Enzimática/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Células HeLa , Homeostase/efeitos dos fármacos , Humanos , Isoenzimas/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/enzimologia , Dados de Sequência Molecular , Elementos de Resposta/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , eIF-2 Quinase/metabolismoRESUMO
Psoriasis is a multifactorial, chronic inflammatory skin disease with unresolved questions on its primary events. Iron overload has been described in the epidermis of psoriasis patients, but its relevance remains unknown. We found that the key iron regulatory hormone hepcidin was highly expressed in the epidermis of psoriasis patients, especially the pustular variants resistant to treatments. In a murine model of acute skin inflammation, keratinocyte-derived hepcidin was required for iron retention in keratinocytes, leading to hyperproliferation of the epidermal layer and neutrophil recruitment, two main features of psoriatic skin lesions. Keratinocytes overexpressing hepcidin were sufficient to elicit these psoriasiform features in a transgenic mouse model. Furthermore, transcriptome analysis of these keratinocytes revealed canonical pathways found in human psoriasis, pointing to a causal role for hepcidin in the pathogenesis of the disease. Altogether, our data suggest that hepcidin could be an actionable target for skin psoriasis treatment, in addition to current therapeutics, or targeted as maintenance therapy during remission to prevent recurrence.
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Proliferação de Células , Hepcidinas , Ferro , Queratinócitos , Camundongos Transgênicos , Infiltração de Neutrófilos , Psoríase , Pele , Hepcidinas/metabolismo , Hepcidinas/genética , Psoríase/metabolismo , Psoríase/patologia , Animais , Queratinócitos/metabolismo , Humanos , Ferro/metabolismo , Camundongos , Pele/metabolismo , Pele/patologia , Modelos Animais de Doenças , Masculino , Feminino , Epiderme/metabolismo , Epiderme/patologia , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Inflamação/patologiaRESUMO
Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.
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Inflamassomos , Monócitos , Síndromes Mielodisplásicas , Dermatopatias Genéticas , Adulto , Humanos , Inflamassomos/genética , Estudos Prospectivos , Células Mieloides , MutaçãoRESUMO
In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca²âº) homeostasis has been linked to presenilins, the catalytic core in γ-secretase complexes cleaving the amyloid precursor protein (APP), thereby generating amyloid-ß (Aß) peptides. Here we investigate whether APP contributes to ER Ca²âº homeostasis and whether ER Ca²âº could in turn influence Aß production. We show that overexpression of wild-type human APP (APP(695)), or APP harboring the Swedish double mutation (APP(swe)) triggers increased ryanodine receptor (RyR) expression and enhances RyR-mediated ER Ca²âº release in SH-SY5Y neuroblastoma cells and in APP(swe)-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca²âº release leads to the reduction of both intracellular and extracellular Aß load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This Aß reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and ß- and γ-secretases activities. Importantly, dantrolene diminishes Aß load, reduces Aß-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in Aß production and learning and memory performances, and delineate RyR-mediated control of Ca²âº homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches.
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Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Doença de Alzheimer/genética , Aminofenóis/uso terapêutico , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Análise de Variância , Animais , Encéfalo/citologia , Cafeína/farmacologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Células Cultivadas , Citosol/efeitos dos fármacos , Citosol/metabolismo , Dantroleno/farmacologia , Modelos Animais de Doenças , Embrião de Mamíferos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Inibidores Enzimáticos/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Maleimidas/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Proteínas de Membrana/metabolismo , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Relaxantes Musculares Centrais/farmacologia , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Purinas/uso terapêutico , RNA Mensageiro/metabolismoRESUMO
Importance: A new treatment for cystic fibrosis combining 3 CFTR modulators-elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature. Objective: To describe the clinicopathological features and treatment response of ELX-TEZ-IVA-associated acneiform eruptions in patients with cystic fibrosis. Design, Setting, and Participants: This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included. Exposures: Treatment with ELX-TEZ-IVA. Main Outcomes and Measures: Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed. Results: This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated). Conclusions and Relevance: This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA-associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.
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Acne Vulgar , Erupções Acneiformes , Fibrose Cística , Exantema , Foliculite , Adulto , Feminino , Humanos , Acne Vulgar/tratamento farmacológico , Acne Vulgar/induzido quimicamente , Erupções Acneiformes/induzido quimicamente , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos adversos , Combinação de Medicamentos , Exantema/induzido quimicamente , Foliculite/induzido quimicamente , Isotretinoína , Mutação , Masculino , Adulto JovemRESUMO
BACKGROUND: Pregnant women and their fetuses are particularly susceptible to respiratory pathogens. How they respond to SARS-CoV-2 infection is still under investigation. METHODS: We studied the transcriptome and phenotype of umbilical cord blood cells in pregnant women infected or not with SARS-CoV-2. RESULTS: Here we show that symptomatic maternal COVID-19 is associated with a transcriptional erythroid cell signature as compared with asymptomatic and uninfected mothers. We observe an expansion of fetal hematopoietic multipotent progenitors skewed towards erythroid differentiation that display increased clonogenicity. There was no difference in inflammatory cytokines levels in the cord blood upon maternal SARS-CoV-2 infection. Interestingly, we show an activation of hypoxia pathway in cord blood cells from symptomatic COVID-19 mothers, suggesting that maternal hypoxia may be triggering this fetal stress hematopoiesis. CONCLUSIONS: Overall, these results show a fetal hematopoietic response to symptomatic COVID-19 in pregnant mothers in the absence of vertically transmitted SARS-CoV-2 infection which is likely to be a mechanism of fetal adaptation to the maternal infection and reduced oxygen supply.
During pregnancy, women are more prone to respiratory infectious diseases. It is not known if COVID-19 infection has an adverse effect on the growing fetus. Here, we aimed to identify any potential effects of COVID-19 infection on the fetus by taking measurements from the umbilical cord blood cells. In mothers who displayed symptomatic COVID-19 infection, we observed an increased production of hematopoietic progenitor cells, especially the ones that are responsible for producing red blood cells. We think this might be a coping mechanism for the fetus, as the mother's body deals with the infection. Therefore, our work shows that growing fetuses do respond to maternal COVID-19 symptoms, even when they are protected in the womb from the infection and may never get infected by the mother.
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Sarcoidosis is a systemic disease that affects the skin in about 25% of patients. The treatment of cutaneous sarcoidosis is guided by the extent of lesions, associated symptoms and organ involvement. To evaluate rates of response to various potential first-line treatments for cutaneous sarcoidosis during the year following treatment initiation. This retrospective multicentre study included 120 patients with cutaneous sarcoidosis. Treatment response was assessed retrospectively from the patients' medical records. Univariate logistic regression analysis, with an estimation of unadjusted odds ratios (OR) and their 95% CI ,was performed to identify factors associated with complete cutaneous remission (CR), followed by multivariate logistic regression analysis. At one year, 43 of the 120 (36%) included patients had CR. The best response rates were obtained with oral corticosteroids (12/21, 57%), followed by a combination of hydroxychloroquine and topical steroids (6/13, 46%). In multivariate analysis, lupus pernio was the only predictor of a poor cutaneous response. We suggest the use of a combination of hydroxychloroquine and topical steroids as an optimal first-line treatment for cutaneous sarcoidosis, given the known adverse effects of systemic corticosteroids.
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Sarcoidose , Dermatopatias , Humanos , Estudos Retrospectivos , Hidroxicloroquina/uso terapêutico , Dermatopatias/patologia , Sarcoidose/patologia , Corticosteroides/uso terapêutico , EsteroidesRESUMO
Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5' UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.
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Doenças do Desenvolvimento Ósseo/genética , Cálcio/metabolismo , Mutação , Nucleotidases/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Arginina/metabolismo , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Células Cultivadas , Pré-Escolar , Condrócitos/metabolismo , Cromossomos Humanos Par 17 , Códon sem Sentido , Consanguinidade , Retículo Endoplasmático Rugoso/ultraestrutura , Éxons , Evolução Fatal , Feminino , Fibroblastos/ultraestrutura , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Núcleo Familiar , RNA Mensageiro/metabolismo , RadiografiaRESUMO
Wnt/ß-catenin signaling plays crucial roles in melanocyte biology and may be implicated in melanoma progression. In this study, we retrospectively examined a real-life cohort of melanomas mutated for ß-catenin (CTNNB1), in association or not with a MAPK mutation (of BRAF or NRAS), and analyzed their clinical, histopathological, and molecular characteristics. Our results indicate that, regardless of the presence of a concurrent MAPK mutation, CTNNB1mut cutaneous primary melanomas display more proliferative hallmarks (increased Breslow thickness, mitotic index, and ulceration) than their CTNNB1 wild-type counterparts. Accordingly, they often progress to the metastatic stage. Furthermore, concurrent CTNNB1 and MAPK mutations do not necessarily confer a deep penetrating nevi phenotype. Altogether, this study provides evidence that CTNNB1 mutations in melanomas are associated with specific clinical and pathological features.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/patologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , beta Catenina/genética , Melanoma Maligno CutâneoRESUMO
Although human dermis contains distinct fibroblast subpopulations, the functional heterogeneity of fibroblast lines from different donors is under-appreciated. We identified one commercially sourced fibroblast line (c64a) that failed to express α-smooth muscle actin (α-SMA), a marker linked to fibroblast contractility, even when treated with transforming growth factor-ß1 (TGF-ß1). Gene expression profiling identified insulin-like growth factor 1 (IGF1) as being expressed more highly, and Asporin (ASPN) and Wnt family member 4 (WNT4) expressed at lower levels, in c64a fibroblasts compared to three fibroblast lines that had been generated in-house, independent of TGF-ß1 treatment. TGF-ß1 increased expression of C-X-C motif chemokine ligand 1 (CXCL1) in c64a cells to a greater extent than in the other lines. The c64a gene expression profile did not correspond to any dermal fibroblast subpopulation identified by single-cell RNAseq of freshly isolated human skin cells. In skin reconstitution assays, c64a fibroblasts did not support epidermal stratification as effectively as other lines tested. In fibroblast lines generated in-house, shRNA-mediated knockdown of IGF1 increased α-SMA expression without affecting epidermal stratification. Conversely, WNT4 knockdown had no consistent effect on α-SMA expression, but increased the ability of fibroblasts to support epidermal stratification. Thus, by comparing the properties of different lines of cultured dermal fibroblasts, we have identified IGF1 and WNT4 as candidate mediators of two distinct dermal functions: myofibroblast formation and epidermal maintenance.
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Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFß signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.