Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with BRCA1 :psi VBRCA1 recombination

Inherited susceptibility to breast cancer results from germline mutations in one of a number of genes including BRCA1. A significant number of BRCA1-linked familial breast cancer patients, however, have no detectable BRCA1 mutation. This could be due in part to the inability of commonly used mutation-detection techniques to identify mutations outside the BRCA1 coding region. This paper addresses the hypothesis that non coding region mutations, specifically in the BRCA1 promoter, account for some of these cases. We describe a new and detailed restriction map of the 5' region of the BRCA1 gene including the nearby NBR2, psiBRCA1, and NBR1 genes and the isolation of a number of new informative hybridization probes suitable for Southern analysis. Using this information we screened DNA from lymphoblastoid cell-lines made from 114 UK familial breast cancer patients and detected one large deletion in the 5' region of BRCA1. We show that the breakpoints for this deletion are in BRCA1 intron 2 and between NBR2 and exon 2 of psiBRCA1, raising the possibility that this deletion arose via a novel mechanism involving BRCA1:psiBRCA1 recombination. We have also screened 60 familial breast cancer patients from the Australian population, using an amplification refractory mutation system (ARMS) technique described previously by our group, and found one patient with a genotype consistent with a BRCA1 promoter deletion. These findings indicate that germline BRCA1 promoter deletions are a rare and yet significant mutation event and that they could arise via a novel genetic mechanism. Hum Mutat 19:435-442, 2002. (C) 2002 Wiley-Liss, Inc.

A cassette ligation strategy with thioether replacement of three Gly-Gly peptide bonds: Total chemical synthesis of the 101 residue protein early pregnancy factor [psi(CH2S)(28-29,56-57,76-77)]

The 101 residue protein early pregnancy factor (EPF), also known as human chaperonin 10, was synthesized from four functionalized, but unprotected, peptide segments by a sequential thioether ligation strategy. The approach exploits the differential reactivity of a peptide-NHCH2CH2SH thiolate with XCH2CO-peptides, where X = Cl or I/Br. Initial model studies with short functionalized (but unprotected) peptides showed a significantly faster reaction of a peptide-NHCH2CH2SH thiolate with a BrCH2CO-peptide than with a CICH2CO-peptide, where thiolate displacement of the halide leads to chemoselective formation of a thioether surrogate for the Gly-Gly peptide bond. This rate difference was used as the basis of a novel sequential ligation approach to the synthesis of large polypeptide chains. Thus, ligation of a model bifunctional N-alpha-chloroacetyl, C-terminal thiolated peptide with a second N-alpha-bromoacetyl peptide demonstrated chemoselective bromide displacement by the thiol group. Further investigations showed that the relatively unreactive N-alpha-chloroacetyl peptides could be activated by halide exchange using saturated KI solutions to yield the highly reactive No-iodoacetyl peptides. These findings were used to formulate a sequential thioether ligation strategy for the synthesis of EPF, a 101 amino acid protein containing three Gly-Gly sites approximately equidistantly spaced within the peptide chain. Four peptide segments or cassettes comprising the EPF protein sequence (BrAc-[EPF 78-101] 12, ClAc-[EPF 58-75]-[NHCH2CH2SH] 13, ClAc-[EPF 30-55]-[NHCH2CH2SH] 14, and Ac-[EPF 1-27]-[NHCH2CH2SH] 15) of EPF were synthesized in high yield and purity using Boc SPPS chemistry. In the stepwise sequential ligation strategy, reaction of peptides 12 and 13 was followed by conversion of the N-terminal chloroacetyl functional group to an iodoacetyl, thus activating the product peptide for further ligation with peptide 14. The process of ligation followed by iodoacetyl activation was repeated to yield an analogue of EPF (EPF psi(CH2S)(28-29,56-57,76-77)) 19 in 19% overall yield.

Chapter 16: Prophylactic Human Papillomavirus Vaccines

Candidate prophylactic vaccines based on papillomavirus L1 virus-like particles (VLPs) are currently in human clinical trials. The main long-term goal of the vaccine is to reduce the incidence of cervical cancer and its precursors. In animal papillomavirus models, systemic immunization with L1 VLPs can induce high titers of neutralizing antibodies that confer protection against high-dose experimental papillomavirus challenge. In humans, systemic vaccination with L1 VLPs has been well tolerated and induced high serum antibody titers (at least 40 times higher than titers seen following natural infection). A recent proof of principle HPV16 L1 VLP efficacy trial has shown excellent protection against persistent HPV16 infection and associated cytological abnormalities. Large scale efficacy trials of L1 VLPs from HPV16 and 18 (the HPV types found most frequently in cervical cancer), with or without HPV6 and 11 (the HPV types responsible for most genital warts), are planned. If the results of these large trials support the encouraging results of the early trials, they should lead to a commercial prophylactic HPV vaccine. Implementation issues may include how to make the vaccine available in the developing world, where the majority of cervical cancer cases occur, the appropriate age of vaccination, and the role of male vaccination. Because a VLP vaccine is likely to provide type-specific protection, increasing the number of cancer-associated HPV types in the vaccine is a likely approach to broadening the protection to additional types. There will probably also be efforts to develop alternative vaccine formulations better suited to implementation in developing countries as well as attempts to develop vaccines with a therapeutic activity against established HPV infection because a combined prophylactic/therapeutic vaccine may be expected to have an even greater impact than a purely prophylactic vaccine on HPV induced disease.

Atenção seletiva: PSI em crianças com distúrbio de aprendizagem

A atenção seletiva é importante para o aprendizado da leitura e escrita. OBJETIVO: Estudar os processos de atenção seletiva de crianças com e sem distúrbio de aprendizagem. MATERIAL E MÉTODO: O Grupo I foi constituído de quarenta indivíduos com idades entre nove anos e seis meses a dez anos e 11 meses, que apresentavam baixo risco para alteração no desenvolvimento das habilidades auditivas, linguagem e aprendizagem. O Grupo II foi constituído de 20 indivíduos com idades entre nove anos e cinco meses a 11 anos e dez meses, diagnosticados como portadores de distúrbio de aprendizagem. Foi realizado estudo prospectivo através do Teste Pediátrico de Inteligibilidade de Fala (PSI). RESULTADO: O teste PSI com mensagem competitiva ipsilateral, à orelha direita, na relação fala/ruído 0 e -10 foi apropriado para diferenciar o Grupo I e o Grupo II de forma estatisticamente significante. Atenção ao desempenho do Grupo II na performance da primeira orelha testada deve ser dada, por subsidiar características importantes de desempenho e reabilitação. CONCLUSÃO: O PSI foi adequado para diferenciar os grupos, havendo uma associação com o grupo com distúrbio de aprendizagem, que revelou alteração nos processos de atenção seletiva.

Factores determinantes do valor da empresa no mercado de capitais: evidência empírica para o PSI 20

El principal finalidad de la presente comunicación se traduce en el análisis del efecto de los indicadores de desempeño empresarial en la explicación del precio de las acciones que integran el principal índice bursátil de la Euronext Lisboa, el PSI 20. Para tal, recurrimos a un análisis fundamental, habiendo dividido los indicadores de desempeño empresarial en dos grupos, un con un cariz económico-financiero otro con un cariz bursátil. Utilizando una muestra de 17 empresas, los resultados son obtenidos a través de la aplicación del método OLS y reportan a 31 de Diciembre de 2007. Los resultados obtenidos sugieren que los indicadores de desempeño empresarial se presentan susceptibles de explicar el precio de mercado de las acciones de las empresas que integran el PSI 20. Se destaca el efecto significativamente positivo del resultado líquido y del valor contable y el efecto significativamente negativo del cash-flow. Los resultados obtenidos sugieren la existencia de una expectativa positiva relativamente al desempeño futuro de las empresas que integran el PSI 20.

Evidência empírica dos factores explicativos dos dividendos distribuídos pelas empresas do PSI 20

La presente comunicación tiene como objetivo central el análisis de los factores explicativos de la política de dividendos de las empresas que integran el principal índice bursátil del mercado de capitales portugués, el PSI 20. Con ese designio, utilizamos un conjunto de informaciones económicas y financieras de las empresas no financieras para explicar los dividendos por acción distribuidos en el período temporal comprendido por los años de 2005 a 2009. Los resultados logrados en el estudio empírico sugieren que el resultado líquido, los dividendos por acción distribuidos en el ejercicio económico anterior y el crecimiento de las ventas presentan un efecto positivo y estadísticamente significativo en la explicación de los dividendos por acción distribuidos en un determinado ejercicio económico. Sugieren todavía que el modelo desarrollado por Lintner (1956) se presenta válido para explicar la política de dividendos de las empresas de lo PSI 20.

Evidência empírica dos factores explicativos dos dividendos distribuidos pelas empresas do PSI 20

La presente comunicación tiene como objetivo central el análisis de los factores explicativos de la política de dividendos de las empresas que integran el principal índice bursátil del mercado de capitales portugués, el PSI 20. Con ese designio, utilizamos un conjunto de informaciones económicas y financieras de las empresas no financieras para explicar los dividendos por acción distribuidos en el período temporal comprendido por los años de 2005 a 2009. Los resultados logrados en el estudio empírico sugieren que el resultado líquido, los dividendos por acción distribuidos en el ejercicio económico anterior y el crecimiento de las ventas presentan un efecto positivo y estadísticamente significativo en la explicación de los dividendos por acción distribuidos en un determinado ejercicio económico. Sugieren todavía que el modelo desarrollado por Lintner (1956) se presenta válido para explicar la política de dividendos de las empresas de lo PSI 20.

A divulgação de informação sobre planos de benefícios de reforma em Portugal e a sua relação com o endividamento: Uma análise do PSI geral

Mestrado em Contabilidade e Gestão das Instituições Financeiras