Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age ∼13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m−2/150 mg m−2 day−1, 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1–7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin–temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m−2 cisplatin and 150 mg m−2 × 5 temozolomide in heavily treated, and 200 mg m−2 × 5 temozolomide in less-heavily pretreated children

ACGT and vicilin core sequences in a promoter domain required for seed-specific expression of a 2S storage protein gene are recognized by the opaque-2 regulatory protein

The expression of Brazil nut storage albumin genes is highly regulated during seed development. Several sequences in the promoter of one of these genes show homologies with the target sites of the maize O2 bZIP regulatory protein. We therefore asked whether the O2 protein would recognize these promoter sequences. We show that the O2 protein binds to three different sequences (F1, F2 and F3). F1 and F3 are hybrid C/G and A/G boxes, respectively, that are homologous to the O2-binding site of a maize cr-zein gene. F2 is a new O2-binding sequence related to the O2 target sites of the Coix alpha-coxin, the maize b-32 genes and the AP-1 pseudopalindrome. Molecular modelling showed that an Asn and a Ser in the O2 DNA binding domain make different base-specific contacts with each operator. 5' Promoter deletions of the be2S1 gene showed that the domain containing the O2 target sites F1 and F2 is required for detectable reporter gene expression in transgenic tobacco seeds. Moreover, the homologous coir O2 protein was shown to in situ transactivate the promoter region encompassing the three O2-binding sites F1, F2 and F3. Thus, these sites may be in vivo regulatory sequences mediating activation by bZIP regulatory proteins.34687988

Influência do capital intelectual na avaliação de desempenho aplicada ao setor hospitalar The influence of intellectual capital in performance evaluation: a case-study in the hospital sector

Este estudo contribui com a adaptação, para as entidades públicas, de uma ferramenta de avaliação de desempenho sedimentada nas empresas privadas. O objetivo é demonstrar como pode ser mensurado o impacto da atividade de ensino no valor econômico agregado por um hospital universitário público à sociedade. Para tanto, o texto foi dividido em quatro partes, além dos aspectos introdutórios, metodológicos e das considerações finais. Inicialmente, será contextualizado o setor hospitalar, mais especificamente os hospitais universitários públicos. Logo após, serão apresentadas as definições, a natureza e mensuração do capital intelectual, seguidas da demonstração dos principais modelos avaliação de desempenho econômico. Finalmente, será apresentado um modelo adaptado, sob o enfoque da gestão baseada no valor, propondo ajuste nos indicadores de retorno e do respectivo investimento, demonstrando os impactos da gestão do capital intelectual e da atividade de ensino no resultado econômico de tais instituições. O estudo foi elaborado por intermédio de uma metodologia consubstanciada em uma pesquisa bibliográfica, sob o prisma do método de procedimento comparativo descritivo. Ressalta-se, por fim, a importância da prestação de contas para a sociedade quanto ao uso do recurso público.<br>This paper contributes to public institutions with the adaptation of a performance evaluation tool based on private companies. The objective is to demonstrate how the impact of an educational activity might be measured in the economic value added for the society of a public university hospital. The paper was divided in four parts, despite the introductory and methodological aspects and the final remarks. First, the hospital sector is explained, specifically in the context of the public university hospitals. Then, the definitions, the nature and measure of the intellectual capital are presented, followed by the disclosure of the main economic performance evaluation models. Finally, an adapted model is presented, under the approach of the value based management, considering adjustments of the return and the respective investment measures, showing the impacts of the intellectual capital management and the education activity on the economic result of those institutions. The study was developed based on a methodology supported by a bibliographical research, using a comparative method procedure in the descriptive modality. At last, it is highlighted the importance of accountability for the society regarding the use of public resources and how this study can help in this way