RESUMO
BACKGROUND: Maculopapular cutaneous mastocytosis (MPCM) in children is classified in two variants: (i) monomorphic variant, presenting with the small macules or papules typically seen in adult patients; and (ii) polymorphic variant with larger lesions of variable size and shape, typically seen in children. The definition of polymorphic and monomorphic variants is mostly intuitive, and a validation of this classification has not been done. OBJECTIVE: To study interobserver variability in the classification of MPCM in two groups of observers: mastocytosis experts and general dermatologists. MATERIALS AND METHODS: Nineteen cases of childhood MPCM were shown blindly, for classification as monomorphic or polymorphic type, to 10 independent observers (eight dermatologists, one allergist and one haematologist) from Europe and North America with a vast experience in the management of paediatric mastocytosis. Also, the same cases were shown on a screen to 129 general dermatologists attending a meeting; their votes were registered by remote controls. The interobserver variability kappa coefficient (with 95% confidence interval) was calculated to measure the reliability of the correlation. RESULTS: The value of kappa interobserver variability coefficient for the group of 10 experts (95% confidence interval) was 0.39 (0.18-0.63), which is considered as 'fair'. The value of kappa interobserver variability coefficient for the group of 129 general dermatologists (95% confidence interval) was 0.17 (0.06-0.39), which is considered as 'slight'. A complete agreement of all 10 experts was achieved in only four of 19 cases (21.1%) The most voted choice was concordant between the two groups in only 11 of the 19 cases. CONCLUSIONS: We failed to validate the classification system of childhood MPCM in monomorphic and polymorphic types. While the rate of agreement was low for mastocytosis experts, it was nearly the agreement expected by chance in general dermatologists.
Assuntos
Urticaria Pigmentosa , Adulto , Criança , Europa (Continente) , Humanos , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
Haemangioma is a vascular tumour of infancy that is well known for its rapid growth during the first weeks to months of a child's life, followed by a spontaneous but slow involution. During the proliferative phase, the vessels are disorganized and composed of immature endothelial cells. When the tumour involutes, the vessels mature and enlarge but are reduced in number. Fat, fibroblasts and connective tissue replace the vascular tissue, with few, large, feeding and draining vessels evident. Both angiogenesis and vasculogenesis have been proposed as mechanisms contributing to the neovascularization in haemangioma tumours. In recent years, several of the 'building blocks', the cells comprising the haemangioma, have been isolated. Among them are haemangioma progenitor/stem cells, endothelial cells and pericytes. This review focuses on these cell types, and the molecular pathways within these cells that have been implicated in driving the pathogenesis of infantile haemangioma.
Assuntos
Hemangioma/etiologia , Neoplasias Cutâneas/etiologia , Corticosteroides/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Angiopoietinas/fisiologia , Células-Tronco Embrionárias/patologia , Endotélio Vascular/patologia , Hemangioma/tratamento farmacológico , Hemangioma/patologia , Humanos , Lactente , Mastócitos/patologia , Propranolol/uso terapêutico , Receptor TIE-2/fisiologia , Receptores Notch/fisiologia , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Serina-Treonina Quinases TOR/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
BACKGROUND: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. OBJECTIVES: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). RESULTS: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. CONCLUSIONS: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.
Assuntos
Carcinoma Pulmonar de Lewis/terapia , Endotelina-1/genética , Terapia Genética/métodos , Neovascularização Patológica/terapia , Regiões Promotoras Genéticas , Simplexvirus/enzimologia , Timidina Quinase/genética , Adenoviridae/genética , Animais , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Endotélio Vascular/metabolismo , Genes Virais/genética , Vetores Genéticos , Pulmão/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simplexvirus/genética , Timidina Quinase/metabolismoRESUMO
Ad-PPE-Fas-c is an adenovector that expresses Fas-c under the control of the modified pre-proendothelin-1 (PPE-1) promoter. Fas-c is a chimeric death receptor containing the extracellular portion of tumour necrosis factor 1 receptor (TNFR1) and the transmembrane and intracellular portion of Fas. We recently demonstrated that Ad-PPE-Fas-c induced Fas-receptor-mediated endothelial cell apoptosis. Previously, doxorubicin was shown to enhance Fas-receptor clustering and the induction of its cascade. Therefore, the goal of this work was to test whether doxorubicin augments the capacity of Ad-PPE-Fas-c to induce endothelial cell apoptosis and to elucidate whether either the death-receptor-mediated apoptotic cascade or the mitochondria-associated apoptotic cascade is involved in the combined treatment effect. We found that a combined treatment of Ad-PPE-Fas-c and doxorubicin synergistically induced a reduction in endothelial cell viability and apoptosis. z-IETD-FMK, a caspase-8 inhibitor, and z-LEHD-FMK, a caspase-9 inhibitor, significantly decreased apoptosis induced by the combined treatment. Systemically administered combined therapy significantly reduced the lung metastases burden (70%) in mice as compared to each treatment alone. Thus, a combined treatment of Ad-PPE-Fas-c gene therapy and chemotherapy may be effective in the treatment of metastatic diseases and both the Fas cascade and the mitochondria-associated cascade are essential for this effect.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Caspase 9/metabolismo , Doxorrubicina/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Terapia Genética , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/prevenção & controle , Adenoviridae/genética , Animais , Bovinos , Células Cultivadas , Endotélio Vascular/citologia , Vetores Genéticos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Currently, psoriasis is thought to be an inflammatory response to an antigenic stimulation, in which angiogenesis plays a fundamental role. Very late antigen-1 (VLA-1) is a beta(1) integrin collagen receptor that is up-regulated in many angiogenic processes. Data on its role in psoriasis are sparse. OBJECTIVE: In a prospective study, we evaluated the staining of VLA-1 in lesional skin from patients with psoriasis and atopic dermatitis. MATERIAL AND METHODS: Frozen sections from skin biopsies of patients with chronic plaque-type psoriasis (n = 18) and chronic atopic dermatitis (n = 7) were stained with a monoclonal antibody to VLA-1. The number of blood vessels stained with VLA-1 and the staining intensity were evaluated. These were correlated with the histologic features. RESULTS: The absolute number of blood vessels was found to be similar in the atopic and psoriatic samples. However, the number of vessels stained with anti-VLA-1, as well as the staining intensity, was shown to be significantly higher in the psoriasis group (P < 0.05). Differences between psoriatic lesions showing typical histological features of psoriasis and those showing features that overlap with dermatitis were found as well. CONCLUSIONS: Expression of VLA-1 was found significantly higher in lesional dermal blood vessels of psoriatic patients compared with atopic patients. These findings suggest a possible role for VLA-1 in the pathological angiogenesis of psoriasis. It may be an additional tool for establishing the diagnosis of psoriasis and provide a basis for new strategies in the treatment of psoriasis.