RESUMO
OBJECTIVE: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Efeito Fundador , Corpos de Mallory/patologia , Distrofias Musculares/genética , Mutação/genética , Miopatias Congênitas Estruturais/genética , Proteínas Nucleares/genética , Roma (Grupo Étnico)/genética , Escoliose/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Estudos de Coortes , Humanos , Corpos de Mallory/genética , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/etnologia , Miopatias Congênitas Estruturais/diagnóstico por imagem , Miopatias Congênitas Estruturais/etnologia , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Roma (Grupo Étnico)/etnologia , Escoliose/diagnóstico por imagem , Escoliose/etnologia , Espanha/etnologia , Adulto JovemRESUMO
Taxanes are being used for the treatment of breast cancer. However, cancer cells frequently develop resistance to these drugs with the subsequent recurrence of the tumor. MDA-MB-231 and T-47D breast cancer cell lines were used to assess the effect of paclitaxel treatment on apoptosis and cell cycle, the possible mechanisms of paclitaxel resistance as well as the enhancement of paclitaxel-induced apoptosis based on its combination with phenylethyl isothiocyanate (PEITC). T-47D cells undergo apoptosis in response to paclitaxel treatment. The induction of apoptosis was associated with a robust mitotic arrest and the disruption of Bcl-xL/Bak interaction. By contrary, MDA-MB-231 cells were insensitive to paclitaxel-induced apoptosis and this was associated with a high percentage of cells that slip out of paclitaxel-imposed mitotic arrest and also with the maintenance of Bcl-xL/Bak interaction. The sequential treatment of MDA-MB-231 cells with PEITC followed by paclitaxel inhibited the slippage induced by paclitaxel and increased the apoptosis induction achieved with any of the drugs alone. In breast cancer tissues, high Bcl-xL expression was correlated with a shorter time of disease-free survival in patients treated with a chemotherapeutic regimen that contains paclitaxel, in a statistically significant way. Thus, resistance to paclitaxel in MDA-MB-231 cells is related to the inability to disrupt the Bcl-xL/Bak interaction and increased slippage. In this context, the combination of a drug that induces a strong mitotic arrest, such as paclitaxel, with another that inhibits slippage, such as PEITC, translates into increased apoptotic induction.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Paclitaxel/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Feminino , Humanos , Isotiocianatos/farmacologia , Paclitaxel/uso terapêutico , Ligação ProteicaRESUMO
Immunomodulatory drugs have demonstrated efficacy in the therapy against autoimmune diseases such as rheumatoid arthritis, Crohn's disease or ulcerative colitis. Tumor necrosis factor-α (TNF-α) represents a target molecule for the treatment of these entities. Use of monoclonal antibodies can block the proinflammatory function of TNF-α. It has been shown that this action can reactivate quiescent chronic diseases as well as modify the immune response or potentiate carcinogens, thereby increasing the risk of secondary tumor development. In this context, different types of solid or hematological tumors have been documented. We present the case of a male with chronic ulcerative colitis who secondarily developed a cutaneous Hodgkin-type lymphoproliferative lesion associated with immunodeficiency. This secondary tumor developed after 6 months of treatment with anti-TNF-α.
