Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel

Background: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments. Aim: The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel. Methods: DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT-PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting. Results: The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel. Conclusion: The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.7 page(s

Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure

BACKGROUND: DNA Ligase IV deficiency syndrome is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV gene (LIG4). The clinical phenotype shows overlap with a number of other rare syndromes, including Seckel syndrome, Nijmegen breakage syndrome, and Fanconi anemia. Thus the clinical diagnosis is often delayed and established by exclusion. METHODS: We describe a patient with pre- and postnatal growth retardation and dysmorphic facial features in whom the diagnoses of Seckel-, Dubowitz-, and Nijmegen breakage syndrome were variably considered. Cellular radiosensitivity in the absence of clinical manifestations of Ataxia telangiectasia lead to the diagnosis of DNA ligase IV (LIG4) deficiency syndrome, confirmed by compound heterozygous mutations in the LIG4 gene. At age 11, after a six year history of progressive bone marrow failure and increasing transfusion dependency the patient was treated with matched sibling donor hematopoetic stem cell transplantation (HSCT) using a fludarabine-based conditioning regimen without irradiation. RESULTS: The post-transplantation course was uneventful with rapid engraftment leading to complete and stable chimerism. Now at age 16, the patient has gained weight and is in good clinical condition. CONCLUSION: HSCT using mild conditioning without irradiation qualifies as treatment of choice in LIG4-deficient patients who have a matched sibling donor

Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms

Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50(s) allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef(−/−)Rad50(s/s) mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50(s) and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation

Reposição hormonal e exercício físico no tratamento da insuficiência cardíaca: revisão sistemática

FUNDAMENTAÇÃO: A despeito do pleno uso da terapia farmacológica e não farmacológica, persistem as expressivas morbidade e mortalidade decorrentes da insuficiência cardíaca (IC). No contexto terapêutico é relevante a inibição das inadequadas adaptações neuro-hormonais e metabólicas, sendo bem conhecida a deficiência anabólica que se instala na IC. Mas somente recentemente surgiram alguns estudos sobre os benefícios que adviriam da terapia de reposição ou suplementação de testosterona (TRT). OBJETIVOS: Pesquisar estudos que abordem a TRT na insuficiência cardíaca (IC), em especial os desenvolvidos no cenário ideal de tratamento clínico, que inclui programa de exercício físico. MÉTODOS: Foram consultadas as bases de dados SciELO e PubMed, a base de dados Cochrane de Revisões Sistemáticas e o Registro de Ensaios Controlados da Colaboração Cochrane. RESULTADOS: Os poucos estudos sobre TRT em pacientes com IC evidenciaram melhora da função hemodinâmica, da resistência à insulina, da capacidade funcional e das respostas neuro-hormonal e neuromuscular, evidenciaram as controvérsias quanto à influência sobre o perfil inflamatório, e não constataram mudanças na função e na estrutura cardiovascular central. Entretanto, não foi encontrado nenhum estudo sobre TRT concomitante ao programa de exercícios físicos. CONCLUSÕES: O estágio atual de conhecimento, embora baseado em poucos estudos, permite considerar a TRT no tratamento de pacientes com IC. Não está bem definida a forma ideal da TRT, no que diz respeito à duração do tratamento, critérios de inclusão e exclusão etc. Existe uma grande lacuna na literatura, chamando atenção à inexistência de estudos sobre a TRT concomitante ao tratamento clínico pleno, que inclui um programa de exercícios físicos