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1.
Best Pract Res Clin Rheumatol ; 37(2): 101835, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37263807

RESUMO

Current treatment strategies in hip and knee osteoarthritis (OA) involve a combined approach that includes not only modification of risk factors and conservative treatment but also joint-preserving surgical therapy in the early stages, or joint replacement in late OA. With the recent development of new etiological concepts (i.e. hip dysplasia and femoroacetabular impingement as major risk factors for hip OA), treatment alternatives for joint preservation could be extended significantly. Satisfactory results of osteotomies and other reconstructive procedures around hip and knee joints can only be expected in early OA (Kellgren/Lawrence grade 0-II). If patients with advanced radiographic OA grades III-IV do not respond to conservative treatment over at least 3 months and express a relevant burden of disease, joint replacement might be considered. Prior to surgery, potential contraindications must be excluded, patient expectations need to be discussed, and modifiable risk factors, which may negatively influence the outcome, should be optimized.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Osteoartrite do Quadril , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/etiologia , Osteoartrite do Quadril/cirurgia , Articulação do Joelho/cirurgia
2.
Oncogene ; 38(30): 5873-5889, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31253871

RESUMO

Cutaneous melanoma is one of the most aggressive cancers characterized by a high plasticity, a propensity for metastasis, and drug resistance. Melanomas are composed of phenotypically diverse subpopulations of tumor cells with heterogeneous molecular profiles that reflect intrinsic invasive abilities. In an attempt to identify novel factors of the melanoma invasive cell state, we previously investigated the nature of the invasive secretome by using a comparative proteomic approach. Here, we have extended this analysis to show that PTX3, an acute phase inflammatory glycoprotein, is one such factor secreted by invasive melanoma to promote tumor cell invasiveness. Elevated PTX3 production was observed in the population of MITFlow invasive cells but not in the population of MITFhigh differentiated melanoma cells. Consistently, MITF knockdown increased PTX3 expression in MITFhigh proliferative and poorly invasive cells. High levels of PTX3 were found in tissues and blood of metastatic melanoma patients, and in BRAF inhibitor-resistant melanoma cells displaying a mesenchymal invasive MITFlow phenotype. Genetic silencing of PTX3 in invasive melanoma cells dramatically impaired migration and invasion in vitro and in experimental lung extravasation assay in xenografted mice. In contrast, addition of melanoma-derived or recombinant PTX3, or expression of PTX3 enhanced motility of low migratory cells. Mechanistically, autocrine production of PTX3 by melanoma cells triggered an IKK/NFκB signaling pathway that promotes migration, invasion, and expression of the EMT factor TWIST1. Finally, we found that TLR4 and MYD88 knockdown inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4-dependent pathway. Our work reveals that tumor-derived PTX3 contributes to melanoma cell invasion via targetable inflammation-related pathways. In addition to providing new insights into the biology of melanoma invasive behavior, this study underscores the notion that secreted PTX3 represents a potential biomarker and therapeutic target in a subpopulation of MITFlow invasive and/or refractory melanoma.


Assuntos
Proteína C-Reativa/fisiologia , Melanoma/metabolismo , NF-kappa B/metabolismo , Metástase Neoplásica/fisiopatologia , Componente Amiloide P Sérico/fisiologia , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Melanoma/patologia , Camundongos , Invasividade Neoplásica , Neoplasias Cutâneas/patologia , Regulação para Cima , Melanoma Maligno Cutâneo
3.
Br J Dermatol ; 178(4): e279-e285, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29441525

RESUMO

Results of clinical trials are the most important information source for generating external clinical evidence. The use of different outcomes across trials, which investigate similar interventions for similar patient groups, significantly limits the interpretation, comparability and clinical application of trial results. Core outcome sets (COSs) aim to overcome this limitation. A COS is an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. The Core Outcome Set Initiative within the Cochrane Skin Group (CSG-COUSIN) supports the development of core outcomes in dermatology. In the second CSG-COUSIN meeting held in 2017, 11 COS development groups working on skin diseases presented their current work. The presentations and discussions identified the following overarching methodological challenges for COS development in dermatology: it is not always easy to define the disease focus of a COS; the optimal method for outcome domain identification and level of detail needed to specify such domains is challenging to many; decision rules within Delphi surveys need to be improved; appropriate ways of patient involvement are not always clear. In addition, there appear to be outcome domains that may be relevant as potential core outcome domains for the majority of skin diseases. The close collaboration between methodologists in the Core Outcome Set Initiative and the international Cochrane Skin Group has major advantages for trialists, systematic reviewers and COS developers.


Assuntos
Ensaios Clínicos como Assunto/normas , Dermatologia/normas , Avaliação de Resultados em Cuidados de Saúde/normas , Tomada de Decisões , Humanos , Relações Interprofissionais
4.
Schmerz ; 31(6): 580-593, 2017 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-28660417

RESUMO

BACKGROUND: Pain intensity (PI) is a common outcome parameter in effectiveness studies on interdisciplinary multimodal pain therapy (IMPT), despite the fact that IMPT highlights dealing with rather than reducing chronic pain. Moreover, the measurement of pain intensity as a highly subjective experience is problematic. Patient participation is absolutely essential to examine the relevance of PI as a criterion of treatment success as well as to select/develop suitable measurement methods. METHOD: A qualitative multicenter study was conducted using focus groups with 69 patients (18-77 years; 80% female) at four different IMPT centers in Germany to discuss pain intensity as a therapy outcome parameter in IMPT, as well as the interpretability and feasibility of common measurement methods. RESULTS: The discussions emphasized that PI is a relevant, but not the primary, outcome in IMPT for patients. Patients' statements also demonstrate that there are some problems in measuring PI, for instance with regard to pain attacks. CONCLUSIONS: The focus group discussions suggested that, due to the highly subjective nature of PI, as well as (verbal) inaccuracies and a lack of standardization in common instruments, the measurement of pain intensity is a challenging task. These limitations should be taken into account in future studies.


Assuntos
Dor Crônica , Manejo da Dor , Medição da Dor , Adolescente , Adulto , Idoso , Dor Crônica/terapia , Terapia Combinada , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
5.
Schmerz ; 31(2): 139-148, 2017 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-27844156

RESUMO

BACKGROUND: To assess the efficacy of multimodal pain therapy for chronic pain patients it is necessary to use suitable outcome domains as well as reliable and valid measurement instruments. Using pain intensity as an example, however, it is shown that there are critical issues with respect to suitability for chronic pain patients and the quality (e.g. content validity, feasibility and interpretability) of commonly used measurement instruments. METHOD: A focus group concept was designed to discuss the construct of pain intensity and common measurement instruments with chronic pain patients who underwent multimodal pain therapy. The focus group concept was tested in two pilot groups (N = 10) where eight issues previously established in guidelines were discussed. RESULTS: The results of the pilot studies affirmed that the construct of pain intensity as well as the measurement instruments must be critically considered when applied to chronic pain patients and the effectiveness of multimodal pain therapy. The concept of patient focus groups proved to be a suitable method for patient participation. Integrating patients should be considered not only in discussions of existing pain scales but also in developing new measurement instruments.


Assuntos
Dor Crônica/reabilitação , Grupos Focais , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Medição da Dor/estatística & dados numéricos , Satisfação do Paciente , Dor Crônica/psicologia , Terapia Combinada/estatística & dados numéricos , Alemanha , Hospitais Universitários , Humanos , Clínicas de Dor , Projetos Piloto , Reprodutibilidade dos Testes , Resultado do Tratamento
6.
Eur J Pain ; 20(9): 1545-6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27633812
7.
Schmerz ; 30(6): 537-548, 2016 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-27349235

RESUMO

Decision making in evidence-based medicine is based on general data on therapy outcomes as well as the effectiveness and safety in specific patient populations. Typically, findings concerning therapy outcomes from different studies are aggregated for a final conclusion. In this context a comparison of results is hampered by studies in which therapy outcomes are heterogeneously measured. Such methodological challenges exist for almost all areas of medical treatment, as well as for multimodal pain therapy (MMPT). Through establishing core outcome sets (COS) the required standardization of measurement of therapy outcomes in clinical research can be achieved. A COS is an evidence-based and consented minimum set consisting of outcome domains (i.e. partial aspects of the medical condition to be investigated, which have to be measured in order to give the best possible demonstration of therapy outcome of an intervention) accomplished by valid, reliable and sensitive measurement instruments which should be applied in each clinical trial. No such COS has so far been found for MMPT. The aim of this article is to give an overview about currently recommended methodological approaches to develop a COS accompanied by a brief introduction about existing COS initiatives focusing on chronic pain. The existing COS recommendations are discussed and conclusions are drawn on whether existing recommendations could also be applied for MMPT. Finally, the impact of healthcare research in Germany on a standardized assessment of therapy outcome in MMPT is outlined.


Assuntos
Dor Crônica/terapia , Terapia Combinada/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Manejo da Dor/métodos , Medição da Dor/métodos , Dor Crônica/classificação , Dor Crônica/diagnóstico , Medicina Baseada em Evidências/métodos , Alemanha , Pesquisa sobre Serviços de Saúde/métodos , Humanos
8.
Br J Dermatol ; 174(2): 287-95, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26779929

RESUMO

A major obstacle of evidence-based clinical decision making is the use of nonstandardized, partly untested outcome measurement instruments. Core Outcome Sets (COSs) are currently developed in different medical fields to standardize and improve the selection of outcomes and outcome measurement instruments in clinical trials, in order to pool results of trials or to allow indirect comparison between interventions. A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The international, multidisciplinary Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN) aims to develop and implement COSs in dermatology, thus making trial evidence comparable and, herewith, more useful for clinical decision making. The inaugural meeting of CSG-COUSIN was held on 17-18 March 2015 in Dresden, Germany, as the exclusive theme of the Annual Cochrane Skin Group Meeting. In total, 29 individuals representing a broad mix of different stakeholder groups, professions, skills and perspectives attended. This report provides a description of existing COS initiatives in dermatology, highlights current methodological challenges in COS development, and presents the concept, aims and structure of CSG-COUSIN.


Assuntos
Ensaios Clínicos como Assunto/métodos , Dermatologia/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Ensaios Clínicos como Assunto/normas , Congressos como Assunto , Dermatologia/normas , Medicina Baseada em Evidências , Humanos , Cooperação Internacional , Relações Interprofissionais , Avaliação de Resultados em Cuidados de Saúde/normas , Garantia da Qualidade dos Cuidados de Saúde
9.
Allergy ; 71(3): 358-70, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26564008

RESUMO

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has identified quality of life (QoL) as a core outcome domain to be evaluated in every eczema trial. It is unclear which of the existing QoL instruments is most appropriate for this domain. Thus, the aim of this review was to systematically assess the measurement properties of existing measurement instruments developed and/or validated for the measurement of QoL in adult eczema. METHODS: We conducted a systematic literature search in PubMed and Embase identifying studies on measurement properties of adult eczema QoL instruments. For all eligible studies, we assessed the adequacy of the measurement properties and the methodological quality with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis summarizing findings from different studies was the basis to assign four degrees of recommendation (A-D). RESULTS: A total of 15 articles reporting on 17 instruments were included. No instrument fulfilled the criteria for category A. Six instruments were placed in category B, meaning that they have the potential to be recommended depending on the results of further validation studies. Three instruments had poor adequacy in at least one required adequacy criterion and were therefore put in category C. The remaining eight instruments were minimally validated and were thus placed in category D. CONCLUSIONS: Currently, no QoL instrument can be recommended for use in adult eczema. The Quality of Life Index for Atopic Dermatitis (QoLIAD) and the Dermatology Life Quality Index (DLQI) are recommended for further validation research.


Assuntos
Eczema/epidemiologia , Qualidade de Vida , Adulto , Dermatite Atópica/epidemiologia , Humanos , Vigilância da População , Reprodutibilidade dos Testes
10.
Eur J Pain ; 20(1): 51-63, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26031689

RESUMO

BACKGROUND AND OBJECTIVE: There are no recommendations provided for the outcome domains of chronic pain that should be explicitly considered in each clinical trial to describe the efficacy and effectiveness of multimodal pain therapy (MPT). Our aims were to summarize all reported outcome domains in studies assessing the effects of MPT for chronic pain, and to subsequently inform a consensus-based development of a core outcome set of domains in this field. DATABASE AND DATA TREATMENT: Medline, Embase and AMED were searched for studies reporting on chronic pain for at least 3 months that applied MPT and investigated outcome domains. All reported outcome domains were extracted from eligible articles. The patient-reported outcome measurement information system (PROMIS) was applied for conceptual classification. RESULTS: From 3626 potentially relevant titles, 70 studies were included. The median and maximal numbers of outcome domains were 8 and 34, respectively. Although most studies (n = 45/70) assessed a combination of all three core health areas, i.e. physical, mental and social health, there was great variation in the specific domains chosen to address these core health areas. No outcome domain was measured consistently in all studies. After selection of all outcome domains which were reported in at least 10% of all studies included, we identified 14 different outcome domains, mostly operationalized through the domains pain intensity (n = 56/70) and depressive symptoms (n = 42/70). CONCLUSIONS: The current lack of standardization of outcome domains in MPT studies hinders to readily compare interventions from different trials and is a barrier towards evidence-based decision making. Based on these results, the development of a core outcome set of domains for MPT has been initiated.


Assuntos
Dor Crônica/terapia , Terapia Combinada/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Manejo da Dor/métodos , Humanos
11.
Hautarzt ; 66(9): 699-711, 2015 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-26281899

RESUMO

In order to determine the appropriate therapy for dermatological diseases, numerous measurement instruments are available to measure disease severity. Due to the lack of laboratory parameters for some dermatological diseases to objectify the disease severity (e.g., atopic dermatitis, psoriasis), questionnaires are used. Laboratory as well as questionnaire-based measurements should be reliable, valid, and sensitive to change. In addition, measurement instruments should be feasible. Classifications of disease severity which are based on inadequate measurement properties result in incorrect clinical decisions and limit evidence-based healthcare. Therefore, systematically developed and evidence-based recommendations for the use of individual measurement instruments should be taken into consideration.


Assuntos
Dermatologia/normas , Anamnese/normas , Índice de Gravidade de Doença , Dermatopatias/classificação , Dermatopatias/diagnóstico , Inquéritos e Questionários/normas , Alemanha , Humanos
12.
Hautarzt ; 66(2): 103-7, 2015 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-25576146

RESUMO

BACKGROUND: Recognizing the whole spectrum of comorbidities related to atopic dermatitis (AD) is prerequisite for adequate, patient-centered care. OBJECTIVES: Based on systematic reviews (SRs) and published case-control studies, the current evidence on nonallergic comorbidities of AD is summarized. MATERIALS AND METHODS: A comprehensive systematic literature search was performed in Medline and Embase (Search period: through 15 November 2014). RESULTS: In total, nine systematic reviews were included. Six reviews investigating the association between AD and cancer suggested a decreased risk of glioma, meningioma, and acute lymphoblastic leukemia in patients with current or previous AD. One SR reported a consistent positive association of AD with attention deficit hyperactivity disorder. In comparison, two SRs focusing on the relationship between AD and diabetes mellitus type 1 and multiple sclerosis showed that there is no evidence supporting an association. A further screening of individual observational studies concerning immunological and psychiatric diseases pointed out that AD seems to be a significant risk factor for Crohn's disease, affective, schizophrenic, and behavior disorders. CONCLUSION: Further longitudinal studies are needed to verify the existence of causal relationships. Interdisciplinary working groups are desirable to investigate explanations for genetic and physiologic mechanisms of described associations between AD and nonallergic comorbidities.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Dermatite Atópica/epidemiologia , Doenças do Sistema Imunitário/epidemiologia , Transtornos Mentais/epidemiologia , Neoplasias/epidemiologia , Causalidade , Medicina Baseada em Evidências , Humanos , Incidência , Fatores de Risco
13.
Gesundheitswesen ; 76(12): 819-26, 2014 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-25531092

RESUMO

BACKGROUND: Assessment of the quality of medical care plays an increasingly important role in the German healthcare system. Requirements for quality indicators include validity, reliability, responsiveness, interpretability and feasibility. Because of the high impact of guidelines, quality indicators that are recommended in such guidelines are of special relevance. METHODS: We conducted a systematic review of all German S3 guidelines (actual as of November 30(th), 2013) to investigate the proportion of guidelines recommending quality indicators, which categories to classify quality indicators were used, and whether quality indicators in German S3 guidelines were developed following evidence-based methods. RESULTS: In 34 from 87 S3 guidelines (39%) a total of 394 quality indicators were defined. The vast majority of the recommended quality indicators focused on process quality. Outcome indicators were only recommended in 9 S3 guidelines (10%). None of the guidelines analysed reported the properties of the recommended quality indicators. CONCLUSION: Despite the increasing relevance of quality assessment for all stakeholders in the German healthcare system only approximately 40% of the S3 guidelines define indicators to measure the quality of care. Recommendations to assess outcome indicators are only provided in 10% of S3 guidelines. The process of the development and recommendation of quality indicators is heterogeneous and frequently not transparently reported. The current practice for the recommendation and validation of quality indicators in German S3 guidelines does not meet the requirements of evidence-based healthcare.


Assuntos
Atenção à Saúde/normas , Guias de Prática Clínica como Assunto , Garantia da Qualidade dos Cuidados de Saúde/normas , Indicadores de Qualidade em Assistência à Saúde/estatística & dados numéricos , Indicadores de Qualidade em Assistência à Saúde/normas , Terminologia como Assunto , Atenção à Saúde/estatística & dados numéricos , Alemanha
14.
Br J Dermatol ; 171(6): 1318-25, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24980543

RESUMO

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure.


Assuntos
Ensaios Clínicos como Assunto , Dermatite Atópica/terapia , Humanos , Assistência de Longa Duração , Avaliação de Resultados da Assistência ao Paciente , Qualidade de Vida , Resultado do Tratamento
15.
Allergy ; 69(1): 37-45, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24053642

RESUMO

The aims of this overview are to synthesize the current evidence of published systematic reviews (SRs) on nonallergic comorbidities of atopic eczema (AE). EMBASE and MEDLINE were searched for SRs published from inception to November 2012. SRs were selected independently based on predefined inclusion criteria. Methodological quality of SRs included was assessed by two independent reviewers using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) checklist. Nine SRs met all inclusion criteria. Six reviews addressing the association between AE and cancer suggest a decreased risk of glioma, meningioma, and acute lymphoblastic leukemia in patients with current or previous AE. One SR reported a consistent positive association of AE with attention-deficit hyperactivity disorder (ADHD). Diabetes mellitus type 1 and multiple sclerosis (MS) were not significantly related to AE in reviews based on cross-sectional and case-control studies. Patients with AE appear to be at decreased risk of brain tumors. The relationship of AE with Th1- and Th17-mediated (auto-)inflammatory conditions such as diabetes mellitus type 1 and MS should be clarified in prospective observational studies. Children with AE are at increased risk of ADHD. SRs on the risk of depression and Th17-mediated disorders such as inflammatory bowel disease of patients with AE are missing.


Assuntos
Dermatite Atópica/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comorbidade , Diabetes Mellitus Tipo 1/epidemiologia , Humanos , Esclerose Múltipla/epidemiologia , Neoplasias/epidemiologia
16.
Oncogene ; 31(19): 2461-70, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-21996743

RESUMO

Melanomas are very aggressive neoplasms with notorious resistance to therapeutics. It was recently proposed that the remarkable phenotypic plasticity of melanoma cells allows for the rapid development of both resistance to chemotherapeutic drugs and invasive properties. Indeed, the capacity of melanoma cells to form distant metastases is the main cause of mortality in melanoma patients. Therefore, the identification of the mechanism controlling melanoma phenotype is of paramount importance. In the present report, we show that deletion of microphthalmia-associated transcription factor (MITF), the master gene in melanocyte differentiation, is sufficient to increase the metastatic potential of mouse and human melanoma cells. MITF silencing also increases fibronectin and Snail, two mesenchymal markers that might explain the increased invasiveness in vitro and in vivo. Furthermore, ablation of this population by Forskolin-induced differentiation or MITF-forced expression significantly decreases tumour and metastasis formation, suggesting that eradication of low-MITF cells might improve melanoma treatment. Moreover, we demonstrate that a hypoxic microenvironment decreases MITF expression through an indirect, hypoxia-inducible factor 1 (HIF1)α-dependant transcriptional mechanism, and increases the tumourigenic and metastatic properties of melanoma cells. We identified Bhlhb2, a new factor in melanoma biology, as the mediator of hypoxia/HIF1α inhibitory effect on MITF expression. Our results reveal a hypoxia-HIF1α-BHLHB2-MITF cascade controlling the phenotypic plasticity in melanoma cells and favouring metastasis development. Targeting this pathway might be helpful in the design of new anti-melanoma therapies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Melanoma/secundário , Fator de Transcrição Associado à Microftalmia/metabolismo , Neoplasias Cutâneas/patologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular , Inativação Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Melanoma/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/secundário , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos , Fator de Transcrição Associado à Microftalmia/antagonistas & inibidores , Fator de Transcrição Associado à Microftalmia/genética , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Cutâneas/metabolismo
17.
Cell Death Dis ; 2: e199, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21881601

RESUMO

Metformin is the most widely used antidiabetic drug because of its proven efficacy and limited secondary effects. Interestingly, recent studies have reported that metformin can block the growth of different tumor types. Here, we show that metformin exerts antiproliferative effects on melanoma cells, whereas normal human melanocytes are resistant to these metformin-induced effects. To better understand the basis of this antiproliferative effect of metformin in melanoma, we characterized the sequence of events underlying metformin action. We showed that 24 h metformin treatment induced a cell cycle arrest in G0/G1 phases, while after 72 h, melanoma cells underwent autophagy as demonstrated by electron microscopy, immunochemistry, and by quantification of the autolysosome-associated LC3 and Beclin1 proteins. In addition, 96 h post metformin treatment we observed robust apoptosis of melanoma cells. Interestingly, inhibition of autophagy by knocking down LC3 or ATG5 decreased the extent of apoptosis, and suppressed the antiproliferative effect of metformin on melanoma cells, suggesting that apoptosis is a consequence of autophagy. The relevance of these observations were confirmed in vivo, as we showed that metformin treatment impaired the melanoma tumor growth in mice, and induced autophagy and apoptosis markers. Taken together, our data suggest that metformin has an important impact on melanoma growth, and may therefore be beneficial in patients with melanoma.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Metformina/farmacologia , Metformina/toxicidade , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 5 Relacionada à Autofagia , Proteína Beclina-1 , Linhagem Celular Tumoral , Fase G1 , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fase de Repouso do Ciclo Celular , Transplante Heterólogo
18.
Oncogene ; 30(49): 4887-900, 2011 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-21685937

RESUMO

Aberrant expression of Secreted Protein Acidic and Rich in Cysteine (SPARC)/osteonectin has been associated with an invasive tumor cell phenotype and poor outcome in human melanomas. Although it is known that SPARC controls melanoma tumorigenesis, the precise role of SPARC in melanoma cell survival is still unclear. Here, we show that SPARC has a cell-autonomous survival activity, which requires Akt-dependent regulation of p53. Suppression of SPARC by RNA interference in several human melanoma cells and xenografted A375 tumors triggers apoptotic cell death through the mitochondrial intrinsic pathway and activation of caspase-3. Cell death induced by depletion of SPARC is dependent on p53 and induction of Bax, and results in the generation of ROS. Stabilization of p53 in SPARC-depleted cells is associated with a decrease in Akt-mediated activating phosphorylation of MDM2. Inhibition of Akt signaling pathway is important for the observed changes as overexpression of constitutively active Akt protects cells against apoptosis induced by SPARC depletion. Conversely, increased expression of SPARC stimulates Akt and MDM2 phosphorylation, thus facilitating p53 degradation. Finally, we show that overexpression of SPARC renders cells more resistant to the p53-mediated cytotoxic effects of the DNA-damaging drug actinomycin-D. Our study indicates that SPARC functions through activation of Akt and MDM2 to limit p53 levels and that acquired expression of SPARC during melanoma development would confer survival advantages through suppression of p53-dependent apoptotic pathways.


Assuntos
Melanoma/patologia , Osteonectina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dactinomicina/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Melanoma/genética , Melanoma/metabolismo , Camundongos , Osteonectina/deficiência , Osteonectina/genética , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
19.
Cell Death Differ ; 18(1): 109-21, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20596077

RESUMO

We have previously demonstrated that the thiazolidinedione ciglitazone inhibited, independently of PPARγ activation, melanoma cell growth. Further investigations now show that ciglitazone effects are mediated through the regulation of secreted factors. Q-PCR screening of several genes involved in melanoma biology reveals that ciglitazone inhibits expression of the CXCL1 chemokine gene. CXCL1 is overexpressed in melanoma and contributes to tumorigenicity. We show that ciglitazone induces a diminution of CXCL1 level in different human melanoma cell lines. This effect is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Further, recombinant CXCL1 protein is sufficient to abrogate thiazolidinedione effects such as apoptosis induction, whereas extinction of the CXCL1 pathway mimics phenotypic changes observed in response to ciglitazone. Finally, inhibition of human melanoma tumor development in nude mice treated with ciglitazone is associated with a strong decrease in MITF and CXCL1 levels. Our results show that anti-melanoma effects of thiazolidinediones involve an inhibition of the MITF/CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy.


Assuntos
Antineoplásicos/uso terapêutico , Quimiocina CXCL1/metabolismo , Melanoma/tratamento farmacológico , Fator de Transcrição Associado à Microftalmia/metabolismo , Tiazolidinedionas/uso terapêutico , Animais , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Quimiocina CXCL1/genética , Quimiocina CXCL1/farmacologia , Regulação para Baixo , Humanos , Melanoma/metabolismo , Camundongos , Camundongos Nus , Fator de Transcrição Associado à Microftalmia/antagonistas & inibidores , Fator de Transcrição Associado à Microftalmia/fisiologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Transplante Heterólogo
20.
Oncogene ; 28(37): 3261-73, 2009 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-19581935

RESUMO

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5+ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of anti-apoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n=44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCdelta and a proteasome-dependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCdelta downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies.


Assuntos
Linfócitos B/patologia , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Quinase C-delta/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Ligantes , Proteína de Sequência 1 de Leucemia de Células Mieloides , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Quinase Syk
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