The chromosome region 17p13.3 is thought to encode a tumour suppressor gene involved in sporadic breast cancer and other malignancies. Physical ordering of markers has been carried out by a series of multicolour fluorescent in situ hybridisation (FISH) experiments, using isolated yeast artificial chromosomes (YACs) and cosmids. Eight polymorphic markers ordered within this new physical map and one external marker were used to investigate the pattern of loss of heterozygosity in a panel of 40 sporadic breast tumour patients. The data revealed a region of high loss (60%) within distal 17p13.3, defined by markers D17S926, D17S695 and D17S849 which mapped close together. A contig of YACs was constructed physically linking these three markers.
Summary A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2′-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.
This paper explores the question of whether it is possible to arrange sustainable flood insurance coverage for domestic properties in Canada and elsewhere and whether it should be public or private insurance . It considers the essential requirements for a sustainable insurance market, including the importance of adverse selection and the vicious circle, with particular regard to flood risks. Based on a critical overview of the different private and public insurance solutions to flood risks around the world, the conclusion is drawn that the "bundled" system of private insurance would have the best prospects of success and would provide the best value for money for the community. However, for private flood insurance to be sustainable, the State would need to make a conscious decision not to provide any further compensation to flood victims. Instead it should concentrate on renewing infrastructure and working in partnership with insurers on issues such as building codes and planning matters. Some suggestions are made about how such a private insurance system might be established. Support for a private insurance system could be a potentially sensitive political risk for the government, if its citizens regard the provision of flood compensation as a social duty. Some consideration is therefore given to ways in which the insurance industry has demonstrated social responsibility in connection with other issues, such as climate change and the United Nations Environment Program. Insurers can bring data, expertise on risk management, risk transfer, and claims handling expertise to the table. The State can establish the conditions for a sustainable market in the face of a growing risk. The key to success is partnerships.
This paper examines climate change mitigation and adaptation from an insurance industry perspective, with particular reference to London and the USA. It illustrates how British insurers are increasingly shaping public policy and using new technology to manage the risks from climate change impacts and makes a plea for society to make more use of insurance expertise in future decision making. In particular, more dialogue is needed between architects, planners and insurers to adapt our buildings and cities for climate change impacts. The paper is an abbreviated and updated version of the paper presented by the author in Houston, Texas, in 2005. 1. Explanatory note: Great Britain Great Britain is a collection of over 400 islands off the coast of the continent of Europe. According to the CIA website, it is about the size of the State of Oregon in the USA. Despite its size, it is the fourth largest economy in the world. Some of the examples in this paper relate to insurance activities in Great Britain (GB), and it may be useful to explain that Britain is made up of the two kingdoms of England and Scotland together with the Principality of Wales. Therefore, it is wrong therefore to say 'England' when referring to Britain as a whole. Indeed, Scotland accounts for 40% of the land area of Britain and 9% of the population. One county in Scotland is bigger than Belgium, while another has a longer coastline than France. Scotland has its own established church, and separate legal and educational systems. It also has its own banknotes and language (Gaelic) although this is spoken only by a minority. The Shetland Islands, while within Scotland politically, have a separate legal system and language, and a measure of local autonomy. Since devolution in April 1999, Scotland has had its own elected parliament, which has legislative powers over internal affairs. Wales has its own language, church and elected assembly, but this has no legislative powers so in terms of legal and political organization that is similar to England. For some of the issues considered below, it is necessary to distinguish between England and Wales on the one hand and Scotland on the other, because
Binding of 125I-iodohydroxybenzylpindolol to beta-adrenoceptors has been examined in lymphoblastoid cell lines from members of 5 families affected by manic-depressive disorder. Cell lines from 6 manic-depressives, 7 unaffected relatives and 11 non-psychiatric controls were examined. Binding was reduced to less than half of control values in cell lines from 4 out of 6 manic-depressives and only 1 out of 18 unaffected relatives or controls. All the cell lines with reduced beta-adrenoceptor binding came from 3 families; members of the remaining 2 families showed normal binding. These findings suggest that genetic heterogeneity is present in manic-depressive disorder and that a beta-adrenoceptor defect may influence genetic susceptibility to the disorder.
Summary Molecular and immunohistochemical studies of genetic events on chromosome 17p were prospectively compared with conventional clinical and pathological parameters and disease behaviour at a minimum of 72 months follow-up. In a series of 91 patients with primary operable breast cancer, 37 out of 91 (41 %) patients had disease relapse and 23 out of 91 (25%) had died during the follow-up period. Allelic imbalance at the YNZ22 locus (1 7p1 3.3), demonstrated in 33 out of 63 (52%) informative patients, was significantly associated with disease recurrence (P < 0.01, 2 d.f. Cox analysis) and showed a trend towards impaired survival (P = 0.08, 2 d.f. Cox analysis) after a mean follow-up of 84 months for survivors. By contrast, p53 mutation (in 10 out of 60, 17% of cancers), p53 allelic imbalance (in 23 out of 56, 41% informative patients), p53 mRNA expression (in 47 out of 87, 54% patients), p53 mRNA overexpression (in 24 out of 87, 28%) or p53 protein expression (detected in 25/76, 32%) were not associated with disease behaviour. There was no significant association between allelic imbalance at YNZ22 and any abnormality of p53 DNA, RNA or protein. Allelic imbalance at 17p13.3 (YNZ22) serves as a marker of poor prognosis in breast cancer. As yet unidentified genes on 17p13.3, distinct from and telomeric to p53, are therefore likely to be of clinical importance in breast cancer.
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