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Background: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti-IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. Objective: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. Methods: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. Results: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. Conclusion: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.
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Eccrine sweat glands play an essential role in regulating body temperature. Sweat is produced in the coiled secretory portion of the gland, which is surrounded by obliquely aligned myoepithelial cells; the sweat is then peristaltically transported to the skin surface. Myoepithelial cells are contractile and have been implicated in sweat transport, but how myoepithelial cells contract and transport sweat remains unexplored. Here, we perform ex vivo live imaging of an isolated human eccrine gland and demonstrate that cholinergic stimulation induces dynamic contractile motion of the coiled secretory duct that is driven by gap junction-mediated contraction of myoepithelial cells. The contraction of the secretory duct occurs segmentally, and it is most prominent in the region surrounded by nerve fibers, followed by distension-contraction sequences of the excretory duct. Overall, our ex vivo live imaging approach provides evidence of the contractile function of myoepithelial cells in peristaltic sweat secretion from human eccrine glands.
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Glándulas Ecrinas , Sudor , Humanos , Glándulas Ecrinas/fisiología , Células Epiteliales , Uniones ComunicantesAsunto(s)
Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores , Resultado del Tratamiento , Índice de Severidad de la EnfermedadAsunto(s)
Implantación de Mama/efectos adversos , Implantes de Mama/efectos adversos , Dermatomiositis/etiología , Siliconas/efectos adversos , Adulto , Implantación de Mama/instrumentación , Dermatomiositis/diagnóstico , Dermatomiositis/cirugía , Remoción de Dispositivos , Femenino , Humanos , Resultado del TratamientoRESUMEN
Clear cell carcinoma (CCC) is a rare epithelial malignant tumor of the salivary glands. It is characterized by tumor cells with clear cytoplasm, hyalinized stroma, and most importantly the fusion genes EWSR1-ATF1, EWSR1-CREM, and EWSR1-PLAG1. Break-apart FISH has been performed for multiple CCC cases, but direct sequencing analysis has been performed in relatively few. Herein, we report an interesting case of CCC harboring three EWSR1-ATF1 translocations: EWSR1 exon 8-ATF1 exon 4, EWSR1 exon 7-ATF1 exon 4, and EWSR1 exon 7-ATF1 exon 5. This case indicates the possibility of independent EWSR1-ATF1 gene translocations, and could provide insight into CCC tumorgenesis.
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Adenocarcinoma de Células Claras , Proteínas de Fusión Oncogénica , Adenocarcinoma de Células Claras/genética , Exones , Humanos , Boca , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Factores de Transcripción/genéticaAsunto(s)
Autoanticuerpos/inmunología , Dermatomiositis/complicaciones , Regulación de la Expresión Génica , Helicasa Inducida por Interferón IFIH1/inmunología , Miocarditis/etiología , Proteínas de Resistencia a Mixovirus/genética , ARN/genética , Biopsia , Dermatomiositis/inmunología , Ecocardiografía , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Miocarditis/genética , Miocarditis/metabolismo , Miocardio/patología , Proteínas de Resistencia a Mixovirus/biosíntesisRESUMEN
Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.
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Anafilaxia/patología , Ejercicio Físico , Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DP/genética , Polimorfismo Genético , Hipersensibilidad al Trigo/patología , Adulto , Alelos , Anafilaxia/etiología , Anafilaxia/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipersensibilidad al Trigo/etiología , Hipersensibilidad al Trigo/metabolismoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab. METHODS: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18âblood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment." DISCUSSION: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/sangre , Dermatitis Atópica/tratamiento farmacológico , Humanos , Proyectos de Investigación , Índice de Severidad de la EnfermedadAsunto(s)
Bloqueadores de los Canales de Calcio/efectos adversos , Insuficiencia Respiratoria/complicaciones , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/etiología , Zonisamida/efectos adversos , Adulto , Biopsia , Bloqueadores de los Canales de Calcio/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas , Inmunohistoquímica , Masculino , Radiografía Torácica , Insuficiencia Respiratoria/tratamiento farmacológico , Piel/patología , Esteroides/administración & dosificación , Esteroides/uso terapéutico , Síndrome de Stevens-Johnson/terapia , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Zonisamida/uso terapéuticoAsunto(s)
Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Músculo Esquelético/patología , Dermatosis del Cuero Cabelludo/diagnóstico , Anciano , Biopsia , Fluorodesoxiglucosa F18/administración & dosificación , Humanos , Inmunoglobulina G/sangre , Enfermedad Relacionada con Inmunoglobulina G4/sangre , Enfermedad Relacionada con Inmunoglobulina G4/patología , Masculino , Músculo Esquelético/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Dermatosis del Cuero Cabelludo/sangre , Dermatosis del Cuero Cabelludo/patología , Piel/diagnóstico por imagen , Piel/patologíaAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Granuloma Anular/diagnóstico , Anciano , Biopsia , Femenino , Granuloma Anular/inducido químicamente , Granuloma Anular/inmunología , Granuloma Anular/patología , Humanos , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/inmunología , Piel/patologíaRESUMEN
Pediatric cutaneous mastocytosis (CM) is mainly attributed to gain-of-function mutations in KIT in mast cells. On the other hand, growing evidence suggests that CM patients exist without KIT mutations. To date, the association between the KIT mutation status and clinical phenotype has not been elucidated in pediatric CM, especially in patients with wild-type KIT. Nevertheless, genetic analysis has yet to be performed with whole KIT sequence of mast cells in Japanese patients with pediatric CM. In the present study, 11 Japanese patients with pediatric CM were analyzed to determine whether they had KIT mutations in their skin, and their clinical phenotypes were observed. The approximate frequency of patients with KIT mutation and that of wild-type KIT was almost consistent with the European analysis. The distribution of overall macules was similar between the patients with and without KIT mutations.