A general synthetic approach to hydroquinone meroterpenoids: stereoselective synthesis of (+)-(S)-metachromin V and alliodorol.

A new general synthetic approach to hydroquinone meroterpenoids is here described. The framework of the aforementioned natural compounds was built up through the Li2CuCl4 catalysed cross coupling reaction of the 4-substituted-( E)-prenyl acetates 9 with 2,5-bis(benzyloxy)phenyl magnesium bromide 8 as a key step. The latter sp3-sp2 coupling affords the products in good chemical yields and in very high stereoisomeric purity. A further key step of the present synthetic method consists of the removal of the benzylic protecting groups by a very mild procedure based on the use of lithium naphthalenide. The latter reagent, in combination with aliphatic dialkylamines, is able to cleave all the benzylic protecting groups leaving unaffected the polyenic moieties. By these means, we devised a new synthesis of the natural hydroquinone geranylhydroquinone, farnesylhydroquinone, metachromin V and alliodorol. In addition, the marine meroterpenoid, (+)-( S)-metachromin V, was synthesized for the first time; its chemical structure was confirmed and its absolute configuration was unambiguously assigned

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. Patients and methods: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 μg/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. Results: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. Conclusions: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosup-pression should be accepted in order to obtain a high anti-tumor activity of this regimen and a potential improvement in surviva

EVOLUÇÃO DA PESQUISA BRASILEIRA EM RESOURCE-BASED VIEW (RBV): ESTUDO DOS ENANPAD NA ÃREA DE ESTRATÉGIA ENTRE 1997 - 2006

O objetivo do presente trabalho foi verificar a contribuição brasileira nos estudos de estratégia o enfoque na RESOURCE-BASED VIEW ? RBV. O estudo visou expor e analisar a evolução da pesquisa em RBV no Brasil, a partir dos trabalhos selecionados e apresentados no ENANPAD. No levantamento preliminar para a análise dos artigos, considerando 10 anos de ENANPAD (1997 ? 2006), foram selecionados 57 artigos. A identificação e seleção dos artigos envolveram os seguintes critérios: avaliação dos títulos e resumos dos artigos apresentados na área de estratégia entre 1997 e 2006; busca complementar por palavras-chave tais como RBV, VBR, recursos, capacidades, competências, visão baseada em recursos e resource-based view, core competence e de dynamic capabilitiess na base de dados do ENANPAD. Procedemos também à análise das referências utilizadas nos artigos. Na primeira parte revemos brevemente aspectos fundamentais da RBV. Na segunda parte apresentamos a metodologia seguida na coleta dos dados e fazemos à análise dos resultados. Concluímos com uma discussão geral, propondo a partir da evolução dos trabalhos nacionais uma agenda que possa orientar pesquisas futuras.RBV, estratégia, ENANPAD.

Cranial ultrasound screening in term and late preterm neonates born by vacuum-assisted delivery: Is itworthwhile?

Background: Vacuum extraction is the most common choice to assist vaginal delivery, but there are still concerns regarding the neonatal injuries it may cause. This study aimed to evaluate the rate of intracranial injuries assessed by cranial ultrasound (cUS) among infants born by vacuum extraction, and the relationship with maternal and perinatal factors. Methods: This was a single-center retrospective study carried out in a level-3 neonatal unit. A total of 593 term and late preterm infants born by vacuum-assisted delivery were examined with a cUS scan within 3 days after birth. Results: Major head injuries were clinically silent and occurred in 2% of the infants, with a rate of intracranial haemorrhage of 1.7%. Regardless of obstetric factors, the risk of cranial injury was increased in infants requiring resuscitation at birth (p = 0.04, OR 4.1), admitted to NICU (p = 0.01, OR 5.5) or with perinatal asphyxia (p < 0.01, OR 21.3). Maternal age ≥40 years correlated both with adverse perinatal outcomes (p < 0.05) and the occurrence of major injury (p = 0.02, OR 4.6). Conclusion: Overall, vacuum extraction is a safe procedure for neonates. Head injuries are usually mild and asymptomatic, and with spontaneous recovery. However, the rate of major cranial injuries in our cohort warrants further investigation to support a cUS screening, particularly for infants requiring respiratory support at birth. Also, maternal age might be taken into account when evaluating the risk for neonatal complications after vacuum application