SummaryBackgroundCancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival.MethodsData from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995–2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985–2005.FindingsRelative survival improved during 1995–2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2–6% at 1 year and by 2–3% at 5 years.InterpretationUp-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older.FundingDepartment of Health, England; and Cancer Research UK.

Background Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods In this longitudinal, population-based study, we collected patient-level data on 3•9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (

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This is the first questionnaire to measure lifetime physical activity by collecting data on each type of physical activity separately over lifetime and by measuring frequency, intensity, and duration of each activity. It is also the first physical activity questionnaire to be developed, refined, and administered using cognitive-based methods employed in survey research. Respondents were able to reliably recall their lifetime physical activity patterns. This instrument can be used for any disease outcome for which physical activity may be a risk factor.

Background and objective: Despite assumed similarities in Canadian and US dietary habits, some differences in food availability and nutrient fortification exist. Foodfrequency questionnaires designed for the USA may therefore not provide the most accurate estimates of dietary intake in Canadian populations. Hence, we undertook to evaluate and modify the National Cancer Institute's Diet History Questionnaire (DHQ) and nutrient database. Methods: Of the foods queried on the DHQ, those most likely to differ in nutrient composition were identified. Where possible these foods were matched to comparable foods in the Canadian Nutrient File. Nutrient values were examined and modified to reflect the Canadian content of minerals (calcium, iron, zinc) and vitamins (A, C, D, thiamin, riboflavin, niacin, B 6 , folate and B 12 ). DHQs completed by 13 181 Alberta Cohort Study participants aged 35 -69 years were analysed to estimate nutrient intakes using the original US and modified versions of the DHQ databases. Misclassification of intake for meeting the Dietary Reference Intake (DRI) was determined following analysis with the US nutrient database. Results: Twenty-five per cent of 2411 foods deemed most likely to differ in nutrient profile were subsequently modified for folate, 11% for vitamin D, 10% for calcium and riboflavin, and between 7 and 10% for the remaining nutrients of interest. Misclassification with respect to meeting the DRI varied but was highest for folate (7%) and vitamin A (7%) among men, and for vitamin D (7%) among women over 50 years of age. Conclusion: Errors in nutrient intake estimates owing to differences in food fortification between the USA and Canada can be reduced in Canadian populations by using nutrient databases that reflect Canadian fortification practices.

Herpes simplex virus type 1 (HSV-1), the prototype ␣-herpesvirus, causes several prominent diseases. The HSV-1 immediate early (IE) protein IE63 (ICP27) is the only regulatory gene with a homologue in every mammalian and avian herpesvirus sequenced so far. IE63 is a multifunctional protein affecting transcriptional and post-transcriptional processes, and it can shuttle from the nucleus to the cytoplasm. To identify interacting cellular proteins, a HeLa cDNA library was screened in the yeast two-hybrid system using IE63 as bait. Several interacting proteins were identified including heterogeneous nuclear ribonucleoprotein K (hnRNP K), a multifunctional protein like IE63, and the ␤ subunit of casein kinase 2 (CK2), a protein kinase, and interacting regions were mapped. Confirmation of interactions was provided by fusion protein binding assays, co-immunoprecipitation from infected cells, and CK2 activity assays. hnRNP K co-immunoprecipitated from infected cells with anti-IE63 serum was a more rapidly migrating subfraction than hnRNP K immunoprecipitated by antihnRNP K serum. Using anti-IE63 serum, both IE63 and hnRNP K were phosphorylated in vitro by CK2, while in immunoprecipitates using anti-hnRNP K serum, IE63 but not hnRNP K was phosphorylated by CK2. These data provide important new insights into how this key viral regulatory protein exerts its functions.The involvement of herpesviruses in a range of prominent medical or veterinary diseases makes them one of the most important virus families. Herpes simplex virus type 1 (HSV-1), 1 a common and effective human pathogen, is capable of establishing both lytic and latent infectious life cycles, and up to 80% of adults in the developed world are seropositive for this virus. HSV-1 is a nuclear replicating virus with a large doublestranded DNA genome that encodes some 80 gene products (1). During lytic infection, virus genes are expressed in a temporal cascade and are categorized as immediate early (IE, ␣), early (␤), or late (␥) based on the time postinfection of their expression (2). The five IE gene products, which do not require prior viral protein synthesis for their expression, regulate early and late gene expression and subvert the host cytotoxic T-lymphocyte response (3, 4). A key IE protein is the 63-kDa IE phosphoprotein IE63 also called ICP27 (5). IE63 is one of two HSV IE proteins essential for lytic virus replication (6) and is the only regulatory gene with a homologue in every herpesvirus of mammals and birds sequenced so far (7), suggesting that aspects of its regulatory role are maintained throughout the herpesvirus family.Studies of IE63 have shown that its expression is required for the switch from early to late virus gene expression (8) and have highlighted the multifunctional nature of this protein that acts both at the transcriptional and post-transcriptional levels (reviewed in Ref. 9). Acting post-transcriptionally, IE63 binds RNA in vivo with a reported specificity for intronless viral transcripts (10), enhances pre-mRNA 3Ј processing (11), in...

The multifunctional herpes simplex virus type 1 (HSV-1) protein IE63 (ICP27) interacts with the essential pre-mRNA splicing factor, spliceosome-associated protein 145 (SAP145), and in infected cells IE63 and SAP145 colocalize. This interaction was reduced or abrogated completely using extracts from cells infected with IE63 viral mutants, with mutations in IE63 KH and Sm homology domains, which do not exhibit host shutoff or inhibit splicing. In the presence of IE63, splicing in vitro was inhibited prior to the first catalytic step and the B/C complex formed during splicing was shifted up in mobility and reduced in intensity. With the use of splicing extracts, IE63 and SAP145 both comigrated with the B/C complex, suggesting that they interact within this complex to inhibit B/C complex formation or conversion. The inhibition of splicing may facilitate the export of viral or cellular transcripts, possibly via other protein partners of IE63. These data provide important new insights into how IE63 influences pre-mRNA processing during HSV-1 infection.Herpes simplex virus type 1 (HSV-1) is a nuclear replicating virus with a large double-stranded DNA genome that encodes some 80 gene products (30). During lytic infection, viral genes are expressed in a temporal manner (48) and are classified as immediate-early (IE), early, or late. The five IE genes do not require prior viral protein synthesis for their expression; four regulate early and late viral gene expression (11,13,15,29,37,50,51,54,67), while one subverts the host cytotoxic T-lymphocyte response (20).IE63 (ICP27), an HSV-1 RNA binding protein (21, 34, 52) essential throughout infection (50), promotes accumulation of a subset of viral early and late mRNAs and is necessary for the switch from early to late virus gene expression (29). IE63 is required for efficient viral DNA replication and stimulates the accumulation of certain viral early and late mRNAs (16,29,31,32,45,50,56,63,65). Itself not a transcriptional activator, IE63 is required for expression of viral early and late genes at both transcriptional and posttranscriptional levels. At the posttranscriptional level, IE63 has effects on the processing of pre-mRNA and mediates nucleocytoplasmic transport of transcripts from intronless viral genes which form the majority of viral RNAs (52). IE63 inhibits splicing of cellular pre-mRNAs to mediate host cell shutoff (18), redistributes splicing factors (39, 53), and increases RNA 3Ј processing at weak virus poly(A) sites (31). In addition, IE63 shuttles between the nucleus and the cytoplasm (35, 40, 52, 59).IE63 contains several functional domains (see Fig. 3B). The N terminus contains an acidic activation domain essential for enhancing early gene expression and hence viral DNA replication (46), a leucine-rich nuclear export signal which promotes nuclear shuttling (52), nuclear and nucleolar localization signals (33), and an RGG box involved in RNA binding (34). Along with a putative zinc finger (66), IE63 contains three KH-like domains homologous to RNA binding r...

The International Cancer Benchmarking Partnership (ICBP) was initiated by the Department of Health in England to study international variation in cancer survival, and to inform policy to improve cancer survival. It is a research collaboration between twelve jurisdictions in six countries: Australia (New South Wales, Victoria), Canada (Alberta, British Columbia, Manitoba, Ontario), Denmark, Norway, Sweden, and the United Kingdom (England, Northern Ireland, Wales). Leadership is provided by policymakers, with academics, clinicians and cancer registries forming an international network to conduct the research. The project currently has five modules examining: (1) cancer survival, (2) population awareness and beliefs about cancer, (3) attitudes, behaviours and systems in primary care, (4) delays in diagnosis and treatment, and their causes, and (5) treatment, co-morbidities and other factors. These modules employ a range of methodologies including epidemiological and statistical analyses, surveys and clinical record audit. The first publications have already been used to inform and develop cancer policies in participating countries, and a further series of publications is under way. The module design, governance structure, funding arrangements and management approach to the partnership provide a case study in conducting international comparisons of health systems that are both academically and clinically robust and of immediate relevance to policymakers.