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1.
J Eur Acad Dermatol Venereol ; 34(8): 1715-1721, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31838771

RESUMEN

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant skin cancer. One of the hallmarks of cancers, including EMPD, is an enhancement of aerobic glycolysis, which is also known as the Warburg effect. In the last step of glycolysis, the enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactic acid, the accumulation of which contributes to the creation of an acidic tumour microenvironment. This in turn results in immunosuppression in various types of cancers. However, the contribution of these pathways has not been well-studied in EMPD. OBJECTIVE: To investigate the significance of the Warburg effect and its contribution to the tumour immune microenvironment in EMPD. METHODS: The mRNA expression levels of molecules involved in glycolysis and immune-related cytokines were examined by ddPCR. The number of immune cells was assessed by immunohistochemistry (IHC). RESULTS: The levels of two glycolytic enzymes, HK2 and LDHA, in tumour tissues were significantly increased compared to those in paired-normal tissues. IHC analyses revealed increased numbers of PD-L1+ , PD-1+ , CD163+ M2 macrophages, Iba1+ macrophages and Foxp3+ Tregs that were associated with high LDHA levels in EMPD. ddPCR demonstrated that multiple cytokines including IL-4, IL-6, IL-10, TGF-ß and CCL-2 were upregulated and associated with high LDHA levels in EMPD. Statistical analyses showed that IL-6 mRNA expression correlated with the number of CD163+ , Iba-1+ and Foxp3+ cells. CONCLUSION: The Warburg effect contributes to immunomodulation in the tumour microenvironment and further elucidation may lead to better understanding of the pathogenesis of EMPD.


Asunto(s)
L-Lactato Deshidrogenasa/genética , Enfermedad de Paget Extramamaria/inmunología , Microambiente Tumoral , Humanos , Inmunohistoquímica , Enfermedad de Paget Extramamaria/genética
2.
Br J Dermatol ; 181(3): 505-511, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30706452

RESUMEN

BACKGROUND: Although carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) are useful markers for extramammary Paget disease (EMPD), serum CEA and CYFRA levels are not elevated in most patients with EMPD without metastasis. Cell-free (cf)DNA has attracted attention as an indicator of clinical conditions in several cancers. OBJECTIVES: To identify further useful biomarkers for the detection of EMPD, including early lesions, and to study the clinical implications of cfDNA in EMPD. METHODS: cfDNA were isolated from serum of patients with EMPD with and without metastasis, and from healthy volunteers. Serum extracts were amplified using polymerase chain reaction. RESULTS: Serum cfDNA levels were significantly elevated in patients with EMPD with or without metastasis compared with those in healthy controls. Serum cfDNA was a better diagnostic marker for the presence of EMPD than serum CYFRA. Moreover, the postoperative serum cfDNA levels were significantly lower than those from the preoperative samples, and the change in serum cfDNA levels reflected the clinical courses of patients with EMPD treated with chemotherapy. CONCLUSIONS: Taking the evidence together, serum cfDNA levels may be a useful marker for diagnosis and disease progression in EMPD. What's already known about this topic? Serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) are not elevated in most patients with extramammary Paget disease (EMPD) without metastasis. Cell-free (cf)DNA has attracted attention as an indicator of clinical conditions in several cancers. There are few reports of the clinical implications of cfDNA in dermatology. What does this study add? Serum cfDNA levels were significantly elevated in patients with EMPD with or without metastasis compared with those in healthy controls. Postoperative serum cfDNA levels were significantly lower than those from the preoperative samples. Changes in serum cfDNA levels reflected the clinical courses of patients with EMPD treated with chemotherapy. What is the translational message? Serum cfDNA levels in patients with EMPD are a useful marker for the detection of EMPD, including localized EMPD. Changes in serum cfDNA levels in an individual patient may reflect the clinical course of EMPD.


Asunto(s)
Biomarcadores de Tumor/sangre , Ácidos Nucleicos Libres de Células/sangre , Enfermedad de Paget Extramamaria/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Queratina-19/sangre , Masculino , Persona de Mediana Edad , Enfermedad de Paget Extramamaria/sangre , Enfermedad de Paget Extramamaria/genética , Enfermedad de Paget Extramamaria/cirugía , Periodo Posoperatorio , Periodo Preoperatorio , Piel/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/cirugía , Adulto Joven
3.
Q J Nucl Med Mol Imaging ; 62(1): 118-126, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26784940

RESUMEN

BACKGROUND: We investigated the relationship between 18F-FDG PET parameters and apparent diffusion coefficient (ADC) values obtained by diffusion weighted MRI (DWI) in patients with invasive ductal carcinoma (IDC). In addition, the prognostic utility of PET/MR mammography parameters was compared with that of known histologic prognostic factors. METHODS: Forty-six women aged 50.7±10.5 years underwent a preoperative PET/MR mammography assessment using an integrated PET/MR scanner. T1w, T2w, DWI (b value: 50, 400, and 800 s/mm2), dynamic contrast enhancement sequences, and 18F-FDG PET imaging were performed. IDCs were assessed using SUVmax values and intratumoral heterogeneities (IH) from the 18F-FDG PET images and mean (ADCmean) and minimum ADC (ADCmin) values were measured using the DWI images. Relationships between the PET parameters and ADC values were evaluated. Furthermore, SUVmax and ADC values were compared with histologic factors, tumor size, nodal status, lymphovascular invasion, Ki-67 expression and triple negative breast cancer (TNBC). RESULTS: In total 46 IDCs (2.1-7.5 cm in size) were analyzed. SUVmax (P=0.012) and elevated IH (P=0.041) were negatively correlated with ADCmin, then TNBC (P=0.013) and high Ki-67 expression (P=0.002) were associated with higher SUVmax. IDC with lymphovascular invasion had low ADCmin values (P=0.045). CONCLUSIONS: 18F-FDG PET metabolic parameters and ADCmin were negatively correlated. PET parameters and ADC values might reflect the expression of biological features of tumors and tumor invasiveness, respectively. Integrated PET/MR mammography seemed like to have potential of a one-stop method for evaluating and predicting the prognosis of IDC.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/patología , Imagen de Difusión por Resonancia Magnética , Mamografía , Tomografía de Emisión de Positrones , Adulto , Anciano , Femenino , Fluorodesoxiglucosa F18 , Humanos , Persona de Mediana Edad , Imagen Multimodal , Invasividad Neoplásica , Pronóstico
4.
Br J Dermatol ; 177(2): 456-469, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28078663

RESUMEN

BACKGROUND: Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies. OBJECTIVES: To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity. METHODS: The expression of HSP90 protein in angiosarcoma was examined using immunohistochemistry and immunoblotting. The effects of HSP90 inhibition were proven using proliferation, migration and invasion assay in angiosarcoma cells. The mechanism of antitumour effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA). RESULTS: The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared with those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose-dependent manner. HSP90 siRNA suppressed the proliferation, migration and invasion of angiosarcoma cells. Knock-down of HSP90 did not suppress vascular endothelial growth factor receptor 2 directly, but selectively suppressed several downstream targets of vascular endothelial growth factor signalling in angiosarcoma cells. CONCLUSIONS: HSP90 could be a novel therapeutic target for angiosarcoma.


Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Hemangiosarcoma/prevención & control , Transducción de Señal/fisiología , Neoplasias Cutáneas/prevención & control , Factor A de Crecimiento Endotelial Vascular/fisiología , Anticarcinógenos/farmacología , Antineoplásicos/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Estudios de Casos y Controles , Movimiento Celular/fisiología , Transformación Celular Neoplásica , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Taxoides/farmacología , Triazoles/farmacología , Células Tumorales Cultivadas
5.
Br J Dermatol ; 174(5): 1030-41, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26713607

RESUMEN

BACKGROUND: Dermatomyositis (DM) and systemic lupus erythematosus (SLE) have common skin features, including dermal mucin deposition and interferon signature, although their roles are unknown. OBJECTIVES: To identify common or specific molecular changes in DM and SLE skin. METHODS: Proteomic analysis was performed using DM and healthy skin. Glycosaminoglycans were analysed by high-performance liquid chromatography. RESULTS: The expression of 60 proteins was upregulated or downregulated in DM skin compared with healthy skin in the proteomic analysis. Among those proteins, PSMB9, an immunoproteasome subunit, was upregulated in the epidermis of DM and SLE, but not in other skin diseases. Furthermore, versican V1, a core protein for glycosaminoglycans, was upregulated, while type I collagen was downregulated in the dermis of DM and SLE skin. Interferon stimulated PSMB9 expression in cultured keratinocytes and reduced collagen expression in dermal fibroblasts, but did not affect versican expression. The PSMB9 knock-down in keratinocytes led to significant suppression of transforming growth factor (TGF)-ß2 and TGF-ß3, inducers of versican synthesis. TGF-ß3 expression was upregulated in both DM and SLE, while TGF-ß2 expression was increased only in the DM epidermis. ΔDiHS-diS1, a component of heparan sulfate, was significantly increased only in DM. TGF-ß2 expression significantly increased the ΔDiHS-diS1 expression in dermal fibroblasts in vitro. CONCLUSIONS: The interferon signature in DM and SLE skin reduces collagen in dermal fibroblasts, whereas overexpression of PSMB9 induced by interferon stimulates versican inducers in epidermal keratinocytes. In addition, the TGF-ß2-ΔDiHS-diS1 pathway may be responsible for the specific molecular change in DM skin.


Asunto(s)
Cisteína Endopeptidasas/fisiología , Fármacos Dermatológicos/farmacología , Dermatomiositis/etiología , Interferones/farmacología , Lupus Eritematoso Sistémico/etiología , Colágeno Tipo I/metabolismo , Dermatomiositis/metabolismo , Femenino , Expresión Génica , Humanos , Queratinocitos/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , Proteómica , Piel/metabolismo , Factores de Crecimiento Transformadores/metabolismo , Regulación hacia Arriba/fisiología , Versicanos/metabolismo
8.
Clin Exp Rheumatol ; 32(6 Suppl 86): S-4-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24959869

RESUMEN

OBJECTIVES: The toll-like receptor (TLR) family is thought to be expressed in many cell types in the skin and play a role in various diseases. The expression pattern and role of TLRs in systemic sclerosis (SSc) is to be clarified. We investigated the expression profiles of TLR-related genes in SSc fibroblasts, and tried to clarify their roles in the pathogenesis of this disease. METHODS: The expression profile of TLR-related genes was assessed by gene array. Real-time PCR was used to confirm the array result. The protein expression of TLRs and type I collagen was determined by immunoblotting and immunohistochemistry. RESULTS: PCR array revealed that several genes were up- or down-regulated in SSc fibroblasts compared to normal cells. Among them, both mRNA and protein levels of TLR5 and TLR10 were up-regulated in SSc fibroblasts. The transfection of Smad3 siRNA into SSc fibroblasts resulted in the down-regulation of TLR proteins. There was no significant difference in mRNA half-lives of TLR5 and TLR10 between normal and SSc fibroblasts. Immunohistochemical staining revealed that TLRs expression was strongly detected in SSc fibroblasts in vivo. The stimulation of TLR5 signal with flagellin reduced the expression of type I collagen in SSc fibroblasts, but not in normal fibroblasts. CONCLUSIONS: TLR5 and TLR10 expression is increased in SSc fibroblasts in vitro and in vivo, probably at transcript level via the TGF-ß/Smad3 activation. Furthermore, TLR5 itself may have suppressive effects on collagen expression, and its overexpression in SSc fibroblasts may be the negative feedback against tissue fibrosis.


Asunto(s)
Colágeno Tipo I/metabolismo , Citocinas/genética , Fibroblastos/metabolismo , ARN Mensajero/metabolismo , Esclerodermia Sistémica/genética , Receptores Toll-Like/genética , Western Blotting , Células Cultivadas , Citocinas/metabolismo , Dermis/citología , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esclerodermia Sistémica/metabolismo , Receptores Toll-Like/metabolismo , Transfección
9.
Dermatology ; 227(4): 295-8, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24281360

RESUMEN

Linear IgA bullous disease (LABD) has been reported in association with inflammatory bowel disease, in particular ulcerative colitis (UC). We reporting a 34-year-old female who developed LABD during a flare-up of UC. We administered infliximab, which has been approved for the treatment of UC; infliximab dramatically improved the cutaneous lesions and bowel symptoms. This is the first report showing a marked effect of infliximab on LABD. First, we hypothesize that infliximab works for UC and then calms down excessive production of inflammatory cytokines and autoantibodies, and so stricter control of UC by infliximab is beneficial against the skin condition of LABD. Second, we suggest that TNF-α production in the lesion of LABD is increased, so TNF-α plays an important role in developing cutaneous lesions. This case suggests that infliximab, a monoclonal antibody against TNF-α, is efficacious in the cutaneous symptoms of LABD.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Dermatosis Bullosa IgA Lineal/tratamiento farmacológico , Adulto , Colitis Ulcerosa/complicaciones , Femenino , Humanos , Infliximab , Dermatosis Bullosa IgA Lineal/complicaciones , Dermatosis Bullosa IgA Lineal/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo
10.
Clin Exp Dermatol ; 38(2): 172-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23397945

RESUMEN

BACKGROUND: Epidermal growth factor receptor (EGFR) is known to be abnormally expressed in many human carcinomas, suggesting that there may be an increase in serum EGFR levels in patients with malignant melanoma (MM) and that this might be a possible new tumour marker. AIM: To assess whether serum EGFR levels might be a marker of MM. METHODS: Serum samples were obtained from 66 patients with MM and 12 healthy controls, and EGFR levels were measured by double-determinant ELISA. RESULTS: Patients with in situ or stage I MM had significantly higher serum EGFR levels compared with healthy controls. Interestingly, serum EGFR levels decreased gradually with the stage of the tumour, being highest at stage I and lowest at stage IV. There was also a trend towards a reverse correlation between tumour thickness and serum EGFR levels. Moreover, a longitudinal study identified a trend for serum EGFR levels in patients with preoperative MM to decrease compared with patients with recurrent MM. CONCLUSIONS: To our knowledge, this is the first report investigating the serum EGFR levels of patients with MM, and gives new insight into the relationship between EGFR and MM. We found that serum EGFR levels were significantly increased in patients with early-stage MM such as in situ and stage I tumours. Measurements of serum EGFR levels might be of clinical value in the detection of early-stage MM.


Asunto(s)
Biomarcadores de Tumor/sangre , Receptores ErbB/sangre , Melanoma/sangre , Neoplasias Cutáneas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
11.
Clin Exp Dermatol ; 38(8): 890-6, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24252081

RESUMEN

BACKGROUND: The c-Jun N-terminal kinase (JNK) is thought to be involved in inflammation, proliferation and apoptosis. AIM: To examine the role of JNK isoforms in metastasis, proliferation, migration and invasion of the malignant melanoma (MM) cell lines SK-MEL-28, SK-MEL-3 and WM164, using a kinase-specific inhibitor or isoform-specific small interfering (si)RNAs. RESULTS: SK-MEL-3, a cell line established from metastatic MM, showed slightly increased phosphorylation of both JNK1 and JNK2, whereas WM164, a cell line derived from primary MM, showed significant phosphorylation of JNK1. A JNK inhibitor, SP600125, inhibited cell proliferation of SK-MEL-3 but not SK-MEL-28 or WM164. Transfection of JNK1-specific siRNA reduced the migratory activity of WM164 cells, while silencing of either JNK1 or JNK2 strongly suppressed the invasive activity of SK-MEL-3. CONCLUSIONS: Our study suggests that JNK isoforms have different roles in MM. Metastasis of MM may be regulated by JNK2, while invasion is regulated by both JNK1 and JNK2. JNK1 and JNK2 respectively mediate cell migration and cell proliferation. Further understanding of the specific roles of JNK isoforms in the pathogenesis of MM may lead to the development of therapies targeting specific isoforms.


Asunto(s)
Melanoma/enzimología , Proteína Quinasa 8 Activada por Mitógenos/fisiología , Proteína Quinasa 9 Activada por Mitógenos/fisiología , Neoplasias Cutáneas/enzimología , Antracenos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Immunoblotting , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Melanoma/patología , Invasividad Neoplásica , Isoformas de Proteínas/fisiología , Neoplasias Cutáneas/patología
12.
Clin Exp Dermatol ; 37(1): 34-9, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21883400

RESUMEN

BACKGROUND: Recently, increased evidence has shown that serum micro (mi)RNA levels are a useful biomarker for the diagnosis, prognosis and therapeutic value of various diseases. However, serum miRNA has not been investigated in patients with systemic sclerosis (SSc), to our knowledge. AIM: To investigate the possibility that serum levels of Homo sapiens miR-142 stem-loop (hsa-miR-142-3p), one of the miRNAs regulating the expression of integrin αV, could be a specific disease marker for SSc. METHODS: Serum samples were obtained from 61 patients with SSc and 20 healthy controls. Patients with systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma spectrum disorder (SSD), who did not fulfil American College of Rheumatology criteria for SSc but might develop SSc in the future, were included as disease controls in this study. miRNAs were purified from serum, and miR-142-3p levels were measured with a quantitative real-time PCR assay. RESULTS: Serum miR-142-3p levels in patients with SSc were significantly higher than in patients with SSD, SLE or DM, and healthy control groups. Patients with increased miR-142-3p levels tended to have a short sublingual frenulum. CONCLUSIONS: Our data indicate that serum levels of miR-142-3p may be elevated specifically in patients with SSc, correlating with the severity of this disease, and may be useful diagnostic markers for the presence of SSc and for the differentiation of SSc from SSD.


Asunto(s)
MicroARNs/sangre , Esclerodermia Sistémica/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa
13.
Br J Dermatol ; 165(5): 1003-10, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21711342

RESUMEN

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by intense proliferation and abnormal differentiation of keratinocytes, although the pathogenesis is still not completely clarified. OBJECTIVES: We investigated the mechanism of keratinocyte proliferation seen in psoriasis, focusing on microRNA (miRNA). MATERIALS AND METHODS: miRNAs were extracted from tissues and sera of psoriasis, atopic dermatitis and healthy control. To determine pathogenic miRNAs, we performed miRNA polymerase chain reaction (PCR) array analysis. The results were confirmed with quantitative real-time PCR, in situ hybridization, immunohistochemistry, transient transfection of siRNA and inhibitor in cultured keratinocytes and Western blotting. RESULTS: PCR array analysis using tissue miRNA demonstrated miR-424 level was markedly decreased in psoriasis skin in vivo. Protein expression of mitogen-activated protein kinase kinase 1 (MEK1) or cyclin E1, predicted target genes of miR-424, was increased in psoriatic skin, although their mRNA levels were not. The transfection of specific inhibitor of miR-424 in normal human keratinocytes led to upregulation of MEK1 or cyclin E1 protein, and resulted in increased cell proliferation. On the other hand, cell number was significantly decreased when cells were transfected with siRNA for MEK1 or cyclin E1. Furthermore, we first investigated serum miRNA levels in psoriasis. Although not significant, serum miR-424 concentration tended to be decreased in patients with psoriasis compared with healthy controls. CONCLUSIONS: Decreased miR-424 expression and subsequently increased MEK1 or cyclin E1 may play a key role in the pathogenesis of psoriasis. Investigation of the regulatory mechanisms of keratinocyte proliferation by miRNA may lead to new treatments and a disease activity marker.


Asunto(s)
Proliferación Celular , Queratinocitos/patología , MicroARNs/metabolismo , Psoriasis/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Células Cultivadas , Ciclina E/metabolismo , Femenino , Humanos , MAP Quinasa Quinasa 1/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Oncogénicas/metabolismo
14.
Skin Health Dis ; 1(3): e37, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35663139

RESUMEN

Background: Deficiency of DNA mismatch repair (MMR) induces microsatellite instability (MSI). Pembrolizumab, an antibody targeting PD-1 (an immune checkpoint inhibitor), is more effective against MMR-deficient tumours than against MMR-proficient tumours. The status of MMR is a useful biomarker for predicting the effectiveness of pembrolizumab administration. Although the status of MMR has attracted attention in skin tumours, there are few reports on MSI in extramammary Paget's disease (EMPD). Objectives: To evaluate the status of MMR in patients with EMPD. Materials & Methods: One hundred one patients with EMPD were included. MMR status of the genomic DNA of each subject was analysed using Promega panel (approved as a companion diagnostic agent for the administration of pembrolizumab). Results: MSI testing showed the occurrence rates of MSI-high (more than two markers are unstable), MSI-low (one marker is unstable) and MSS (all markers are stable) tumour tissues were 0% (0/101), 1.0% (1/101) and 99.0% (100/101), respectively. Conclusion: The status of MMR may not be useful for the potential therapeutic application of pembrolizumab.

15.
Br J Dermatol ; 162(4): 751-8, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19886888

RESUMEN

BACKGROUND: Although vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (KDR) signalling may play a major role in the microangiopathy of systemic sclerosis (SSc), serum levels of soluble KDR (sKDR) in this disease have not yet been determined. OBJECTIVES: To evaluate the possibility that serum sKDR levels can be a specific disease marker of SSc. METHODS: Serum sKDR levels of 42 patients with SSc, 10 patients with Raynaud's phenomenon (RP) and 22 healthy controls were measured with specific enzyme-linked immunosorbent assays. Quantitative real-time polymerase chain reaction (PCR) was performed to determine KDR mRNA levels. RESULTS: In females, the serum sKDR levels were significantly higher in patients with SSc, especially limited cutaneous SSc, than in patients with RP or healthy controls. Quantitative real-time PCR with RNA from skin sections revealed that KDR mRNA levels were also increased in the skin of patients with SSc with elevated serum sKDR levels. A significantly lower prevalence of pulmonary fibrosis, higher percentage vital capacity, and a higher incidence of telangiectasia were seen in female patients with SSc with elevated serum sKDR levels than those with normal levels. CONCLUSIONS: These results suggest that the skin can be one of the sources of elevated serum sKDR levels, and that serum sKDR levels are useful for diagnosis and may be a marker of microangiopathy in patients with SSc, especially females. The VEGF-A/KDR signalling system may be involved in the pathogenesis of the disease.


Asunto(s)
Enfermedades del Colágeno/sangre , Enfermedad de Raynaud/sangre , Esclerodermia Sistémica/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Enfermedades del Colágeno/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Enfermedad de Raynaud/patología , Esclerodermia Sistémica/patología , Índice de Severidad de la Enfermedad , Factores Sexuales , Estadística como Asunto , Adulto Joven
16.
Br J Dermatol ; 163(4): 776-80, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20491763

RESUMEN

BACKGROUND: Vascular abnormalities are one of the primary pathological components of systemic sclerosis (SSc). However, it has not been determined if there are also abnormalities in the formation of lymphatic vessels in SSc. OBJECTIVE: To evaluate lymphangiogenic activity in SSc skin. METHODS: The numbers of D2-40-positive lymphatic vessels in skin specimens from healthy control subjects and patients with SSc were counted and compared. Quantitative real-time polymerase chain reaction (PCR) was performed to determine mRNA levels of vascular endothelial growth factor (VEGF)-D and Flt-4 (fms-related tyrosine kinase 4, VEGFR-3, one of the receptors for VEGF-D) in the skin. Serum VEGF-D levels were measured with specific enzyme-linked immunosorbent assays. RESULTSZ: The number of lymphatic vessels in patients with SSc was significantly decreased compared with healthy control subjects. Mean relative transcript levels of FIGF (VEGF-D) and FLT4 (Flt-4) in skin tissue from patients with SSc were significantly increased compared with healthy control subjects. By the analysis of the association between serum VEGF-D levels and the clinical or laboratory features, we found that patients with SSc with higher serum VEGF-D levels more frequently have skin ulcers than those with normal VEGF-D levels. CONCLUSIONS: A systemic increase of VEGF-D, as well as local overexpression of FIGF and FLT4, may be the cause of disturbed lymphangiogenesis in SSc skin and play a role in the pathogenesis of SSc. We showed the possibility that regulation of VEGF-D/Flt-4 signalling could lead to new treatment of skin ulcers in SSc by controlling the formation of lymphatic vessels.


Asunto(s)
Linfangiogénesis/fisiología , Esclerodermia Sistémica/fisiopatología , Piel/metabolismo , Factor D de Crecimiento Endotelial Vascular/fisiología , Receptor 3 de Factores de Crecimiento Endotelial Vascular/fisiología , Femenino , Expresión Génica/fisiología , Humanos , Vasos Linfáticos/patología , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Transducción de Señal/fisiología , Piel/patología , Factor D de Crecimiento Endotelial Vascular/biosíntesis , Factor D de Crecimiento Endotelial Vascular/sangre , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesis
17.
Br J Dermatol ; 162(4): 717-23, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19995368

RESUMEN

BACKGROUND: Basic fibroblast growth factor (bFGF, FGF-2) has been described as a multipotent cytokine that regulates cell growth as well as differentiation, matrix composition, chemotaxis, cell adhesion and migration in numerous cell types. It is known that bFGF stimulates proliferation of cultured fibroblasts. However, the detailed mechanism of fibroblast proliferation induced by bFGF in vitro still remains to be elucidated. Objectives We investigated the precise effects of bFGF on fibroblast proliferation and the signalling pathways responsible for bFGF-induced proliferation in cultured human dermal fibroblasts (HDFs). METHODS: HDFs were cultured with bFGF in the presence or absence of specific inhibitors against MAPK signalling pathways including ERK, JNK and p38. The number of cells was counted and immunoblotting findings were examined for the activation of ERK1/2 and JNK. Furthermore, the inhibitory effects of ERK1, ERK2 and JNK1 were proven by the transfection of siRNA. RESULTS: bFGF increased the number of HDFs in a dose- and time-dependent manner. The bFGF-induced proliferation was suppressed by the MEK inhibitors PD98059 and U0126, and the JNK inhibitor SP600125. bFGF increased the phosphorylation levels of ERK1/2 and JNK1. Treatment with ERK1, ERK2 or JNK1 siRNA significantly inhibited bFGF-induced proliferation. CONCLUSIONS: This study indicates that ERK1/2 and JNK pathways play an important role in the bFGF-mediated effect in HDFs. This study also suggests that controlling ERK1/2 and/or JNK signalling may therefore be a new therapeutic approach for the treatment of chronic and untreatable skin ulcers.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Piel/citología
18.
Clin Exp Dermatol ; 35(3): 295-9, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19663837

RESUMEN

BACKGROUND: Genetic aberrations involving the platelet-derived growth factor-beta (PDGFB) gene and the collagen type 1 alpha1 (COL1A1) gene have been implicated in the pathogenesis of dermatofibrosarcoma protuberans (DFSP), a slow-growing and locally infiltrative dermal tumour. AIM: To investigate the genetic rearrangements in 10 patients who presented with a clinical diagnosis of DFSP. METHODS: Total RNA was obtained from frozen sections and sections embedded in paraffin wax, and used for direct sequencing of the cDNA produced from reverse transcription (RT) PCR. The expression of PDFGB mRNA in each of these cases was also examined. RESULTS: Of the 10 samples examined, 9 had the COL1A1/PDGFB fusion transcript by DNA sequencing. The sequenced products showed that there was a fusion between the end of exons 6, 8, 29 (two cases), 38, 25 or 47 (three cases) and the start of exon 2 of the PDGFB gene. Quantitative RT-PCR identified all samples as having significantly higher expression of the PDGFB gene compared with normal skin or dermatofibroma. CONCLUSIONS: Detection of the COL1A1/PDGFB fusion transcript may be important for the diagnosis of DFSP. Furthermore, relative PDGFB gene quantification by real-time PCR may also provide a good diagnostic tool when other methods fail to give conclusive results.


Asunto(s)
Biomarcadores de Tumor/genética , Colágeno Tipo I/genética , Dermatofibrosarcoma/genética , Factor de Crecimiento Derivado de Plaquetas/genética , Neoplasias Cutáneas/genética , Adulto , Niño , Mapeo Cromosómico , Dermatofibrosarcoma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Neoplasias Cutáneas/patología , Estadística como Asunto
20.
Clin Exp Dermatol ; 34(7): 781-3, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19508567

RESUMEN

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease characterized by sclerotic changes of the skin and internal organs. Telangiectasia is a frequent complication of patients with SSc. OBJECTIVE: To examine the prevalance of telangiectasia in patients with SSc and investigate the clinical and laboratory features of patients with SSc and telangiectasia. METHODS: In total, 211 patients with SSc who fulfilled the diagnostic criteria for SSc of the American College of Rheumatology were examined by laboratory and clinical methods. The average of disease duration time was 7.4 years. RESULTS: Telangiectasia was found in 119 of the 211 patients (56%) with SSc. The prevalence of oesophageal involvement, decreased diffusing capacity for carbon monoxide (DLCO), heart involvement, calcinosis, shortening of the sublingual frenulum, or pitting scars was significantly greater in patients with telangiectasia than in those without telangiectasia. CONCLUSION: Our study suggests that the presence of telangiectasia may be a marker of oesophageal involvement, decreased DLCO, and heart involvement.


Asunto(s)
Esclerodermia Sistémica/complicaciones , Telangiectasia/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Calcinosis/etiología , Niño , Enfermedades del Esófago/etiología , Femenino , Cardiopatías/etiología , Humanos , Masculino , Persona de Mediana Edad , Capacidad de Difusión Pulmonar/fisiología , Esclerodermia Sistémica/fisiopatología , Telangiectasia/fisiopatología , Adulto Joven
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