Modeling amyotrophic lateral sclerosis in hSOD1 transgenic swine.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that occurs in two clinically indistinguishable forms: sporadic (SALS) and familial (FALS), the latter linked to several gene mutations, mostly inheritable in a dominant manner. Nearly 20% of FALS forms are linked to mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Research on ALS relies on transgenic models and particularly on mice carrying a glycine-to-alanine conversion at the 93rd codon (G93A) of the hSOD1 gene. Although G93A transgenic mice have been widely employed in clinical trials and basic research, doubts have been recently raised from numerous reliable sources about their suitability to faithfully reproduce human disease. Besides, the scientific community has already foreseen swine as an attractive and alternative model to nonhuman primates for modeling human diseases due to closer anatomical, physiological and biochemical features of swine rather than rodents to humans. On this basis, we have produced the first swine ALS model by in vitro transfection of cultured somatic cells combined with somatic cell nuclear transfer (SCNT). To achieve this goal we developed a SOD1(G93A) (superoxide dismutase 1 mutated in Gly93-Ala) vector, capable of promoting a high and stable transgene expression in primary porcine adult male fibroblasts (PAF). After transfection, clonal selection and transgene expression level assessment, selected SOD1(G93A) PAF colonies were used as nuclei donors in SCNT procedures. SOD1(G93A) embryos were transferred in recipient sows, and pregnancies developed to term. A total of 5 piglets survived artificial hand raising and weaning and developed normally, reaching adulthood. Preliminary analysis revealed transgene integration and hSOD1(G93A) expression in swine tissues and 360° phenotypical characterization is ongoing. We believe that our SOD1(G93A) swine would provide an essential bridge between the fundamental work done in rodent models and the reality of treating ALS.

Somatic cell nuclear transfer and transgenesis in large animals: current and future insights.

Somatic cell nuclear transfer (SCNT) was first developed in livestock for the purpose of accelerating the widespread use of superior genotypes. Although many problems still exist now after fifteen years of research owing to the limited understanding of genome reprogramming, SCNT has provided a powerful tool to make copies of selected individuals in different species, to study genome pluripotency and differentiation, opening new avenues of research in regenerative medicine and representing the main route for making transgenic livestock. Besides well-established methods to deliver transgenes, recent development in enzymatic engineering to edit the genome provides more precise and reproducible tools to target-specific genomic loci especially for producing knockout animals. The interest in generating transgenic livestock lies in the agricultural and biomedical areas and it is, in most cases, at the stage of research and development, with few exceptions that are making the way into practical applications.

Cancer mortality in Europe, 2000-2004, and an overview of trends since 1975.

BACKGROUND: To update the pattern of cancer mortality in Europe. MATERIALS AND METHODS: We analysed cancer mortality in 34 European countries during 2000-2004, with an overview of trends in 1975-2004 using data from the World Health Organization. RESULTS: From 1990-1994 to 2000-2004, overall cancer mortality in the European Union declined from 185.2 to 168.0/100 000 (world standard, -9%) in men and from 104.8 to 96.9 (-8%) in women, with larger falls in middle age. Total cancer mortality trends were favourable, though to a variable degree, in all major European countries, including Russia, but not in Romania. The major determinants of these favourable trends were the decline of lung (-16%) and other tobacco-related cancers in men, together with the persistent falls in gastric cancer, and the recent appreciable falls in colorectal cancer. In women, relevant contributions came from the persistent decline in cervical cancer and the recent falls in breast cancer mortality, particularly in northern and western Europe. Favourable trends were also observed for testicular cancer, Hodgkin lymphomas, leukaemias, and other neoplasms amenable to treatment, though the reductions were still appreciably smaller in eastern Europe. CONCLUSION: This updated analysis of cancer mortality in Europe showed a persistent favourable trend over the last years.

The recent decline in mortality from Hodgkin lymphomas in central and eastern Europe.

BACKGROUND: Hodgkin lymphoma (HL) is a largely curable disease and its mortality had steadily declined in western Europe since the late 1960s. Only modest declines were, however, observed in central/eastern Europe. MATERIALS AND METHODS: We updated trends in mortality from HL in various European areas up to 2004 and analyzed patterns in incidence for selected European countries providing national data. RESULTS: In most western European countries, HL mortality continued to steadily decline up to the mid 2000s. More recent reductions were also observed in eastern European countries. Overall, mortality from HL declined from 1.17/100,000 (age-standardized, world population) in 1980-1989 to 1.42/100,000 in 2000-2004 in men from the 15 member states of the European Union (EU) from western and northern Europe. In the EU 10 accession countries of central and eastern Europe, male mortality from HL was 1.42/100,000 in 1980-1984, 1.32 in 1990-1994, and declined to 0.76 in 2000-2004. Similar trends were observed in women. No consistent patterns were found for HL incidence. CONCLUSIONS: The present work confirms the persistent declines in HL mortality in western European countries, and shows favorable patterns over more recent calendar years in central/eastern ones, where rates, however, are still at levels observed in western Europe in the early 1990s.

Cancer mortality in the European Union, 1970-2003, with a joinpoint analysis.

BACKGROUND: Cancer mortality peaked in the European Union (EU) in the late 1980s and declined thereafter. MATERIALS AND METHODS: We analyzed EU cancer mortality data provided by the World Health Organization in 1970-2003, using join point analysis. RESULTS: Overall, cancer mortality levelled off in men since 1988 and declined in 1993-2003 (annual percent change, APC = -1.3%). In women, a steady decline has been observed since the early 1970s. The decline in male cancer mortality has been driven by lung cancer, which levelled off since the late 1980s and declined thereafter (APC = 2.7% in 1997-2003). Recent decreases were also observed for other tobacco-related cancers, as oral cavity/pharynx, esophagus, larynx and bladder, as well as for colorectal (APC = -0.9% in 1992-2003) and prostate cancers (APC = -1.0% in 1994-2003). In women, breast cancer mortality levelled off since the early 1990s and declined thereafter (APC = -1.0% in 1998-2003). Female mortality declined through the period 1970-2003 for colorectal and uterine cancer, while it increased over the last three decades for lung cancer (APC = 4.6% in 2001-2003). In both sexes, mortality declined in 1970-2003 for stomach cancer and for a few cancers amenable to treatment. CONCLUSION: This update analysis of the mortality from cancer in the EU shows favorable patterns over recent years in both sexes.

Continuing declines in cancer mortality in the European Union.

BACKGROUND: From 1988 to 1997 age-standardised total cancer mortality rates in the European Union (EU) fell by around 9% in both sexes. Available cancer mortality data in Europe up to 2002 allow a first check of the forecast of further declines in cancer mortality. PATIENTS AND METHODS: We considered trends in age-standardised mortality from major cancer sites in the EU during the period 1980-2002. RESULTS: For men, total cancer mortality, after a peak of 191.1/100,000 in 1987 declined to 177.8 in 1997 (-7%), and to 166.5 in 2002. Corresponding figures for females were 107.9/100,000, 100.5 and 95.2, corresponding to falls of 7% from 1987 to 1997, and to 5% from 1997 to 2002. Over the last 5 years, lung cancer declined by 1.9% per year in men, to reach 44.4/100,000, but increased by 1.7% in women, to reach 11.4. In 2002, for the first year, lung cancer mortality in women was higher than that for intestinal cancer (11.1/100,000), and lung cancer became the second site of cancer deaths in women after breast (17.9/100,000). From 1997 to 2002, appreciable declines were observed in mortality from intestinal cancer in men (-1.6% per year, to reach 18.8/100,000), and in women (-2.5%), as well as for breast (-1.7% per year) and prostate cancer (-1.4%). CONCLUSIONS: Despite the persisting rises in female lung cancer, the recent trends in cancer mortality in the EU are encouraging and indicate that an 11% reduction in total cancer mortality from 2000 to 2015 is realistic and possible.

Lung cancer mortality in European women: recent trends and perspectives.

BACKGROUND: Lung cancer mortality in men has been declining since the late 1980s in most European countries. In women, although rates are still appreciably lower than those for men, steady upward trends have been observed in most countries. To quantify the current and future lung cancer epidemic in European women, trends in lung cancer mortality in women over the last four decades were analyzed, with specific focus on the young. PATIENTS AND METHODS: Age-standardized (world standard) lung cancer mortality rates per 100,000 women-at all ages, and truncated 35--64 and 20--44 years-were derived from the WHO for the European Union (EU) as a whole and for 33 separate European countries. Joinpoint regression analysis was used to identify points where a significant change in trends occurred. RESULTS: In the EU overall, female lung cancer mortality rates rose by 23.8% between 1980--1981 and 1990--1991 (from 7.8 to 9.6/100,000), and by 16.1% thereafter, to reach the value of 11.2/100,000 in 2000--2001. Increases were smaller in the last decade in several countries. Only in England and Wales, Latvia, Lithuania, Russia and Ukraine did female lung cancer mortality show a decrease over the last decade. In several European countries, a decline in lung cancer mortality in young women (20--44 years) was observed over the last decade. CONCLUSIONS: Although female lung cancer mortality is still increasing in most European countries, the more favorable trends in young women over recent calendar years suggest that if effective interventions to control tobacco smoking in women are implemented, the lung cancer epidemic in European women will not reach the levels observed in the USA.

Resveratrol and breast cancer risk.

Resveratrol is a non-flavonoid polyphenol that has attracted attention as a potential anticancer agent in vitro and in vivo, but scanty epidemiological data are available. We have therefore analysed the relation between dietary intake of resveratrol and breast cancer risk using data from a case-control study conducted between 1993 and 2003 in the Swiss Canton of Vaud on 369 cases and 602 controls. Compared with the lowest tertile of total resveratrol intake, the multivariate odds ratios (OR) were 0.50 for the intermediate and 0.39 for the highest tertile, and the trend in risk was significant. A significant inverse association was observed for resveratrol from grapes (OR = 0.64 and 0.55), but not for wine. The inverse relation between resveratrol and breast cancer risk was not explained by several potential confounding factors, including detailed allowance for alcohol intake, nor attributable to a non-specific favourable effect of fruit on breast cancer risk.

Trends in cancer mortality in the European Union and accession countries, 1980-2000.

Cancer mortality rates and trends over the period 1980-2000 for accession countries to the European Union (EU) in May 2004, which include a total of 75 million inhabitants, were abstracted from the World Health Organization (WHO) database, together with, for comparative purposes, those of the current EU. Total cancer mortality for men was 166/100,000 in the EU, but ranged between 195 (Lithuania) and 269/100,000 (Hungary) in central and eastern European accession countries. This excess related to most cancer sites, including lung and other tobacco-related neoplasms, but also stomach, intestines and liver, and a few neoplasms amenable to treatment, such as testis, Hodgkin's disease and leukaemias. Overall cancer mortality for women was 95/100,000 in the EU, and ranged between 100 and 110/100,000 in several central and eastern European countries, and up to 120/100,000 in the Czech Republic and 138/100,000 in Hungary. The latter two countries had a substantial excess in female mortality for lung cancer, but also for several other sites. Furthermore, for stomach and especially (cervix) uteri, female rates were substantially higher in central and eastern European accession countries. Over the last two decades, trends in mortality were systematically less favourable in accession countries than in the EU. Most of the unfavourable patterns and trends in cancer mortality in accession countries are due to recognised, and hence potentially avoidable, causes of cancer, including tobacco, alcohol, dietary habits, pollution and hepatitis B, plus inadequate screening, diagnosis and treatment. Consequently, the application of available knowledge on cancer prevention, diagnosis and treatment may substantially reduce the disadvantage now registered in the cancer mortality of central and eastern European accession countries.

Declining mortality from kidney cancer in Europe.

Mortality rates from kidney cancer increased throughout Europe up until the late 1980s or early 1990s. Trends in western European countries, the European Union (EU) and selected central and eastern European countries have been updated using official death certification data for kidney cancer abstracted from the World Health Organisation (WHO) database over the period 1980-1999. In EU men, death rates increased from 3.92 per 100,000 (age standardised, world standard) in 1980-81 to 4.63 in 1994-95, and levelled off at 4.15 thereafter. In women, corresponding values were 1.86 in 1980-81, 2.04 in 1994-95 and 1.80 in 1998-99. Thus, the fall in kidney cancer mortality over the last 5 years was over 10% for both sexes in the EU. The largest falls were in countries with highest mortality in the early 1990s, such as Germany, Denmark and the Netherlands. Kidney cancer rates levelled off, but remained very high, in the Czech Republic, Baltic countries, Hungary, Poland and other central European countries. Thus, in the late 1990s, a greater than three-fold difference in kidney cancer mortality was observed between the highest rates in the Czech Republic, the Baltic Republics and Hungary, and the lowest ones in Romania, Portugal and Greece. Tobacco smoking is the best recognised risk factor for kidney cancer, and the recent trends in men, mainly in western Europe, can be related to a reduced prevalence of smoking among men. Tobacco, however, cannot account for the recent trends registered in women.

Monitoring falls in gastric cancer mortality in Europe.

We have considered trends in age-standardized mortality from gastric cancer in 25 individual European countries, as well as in the European Union (EU) as a whole, in six selected central-eastern European countries and in the Russian Federation over the period 1950-1999. Steady and persisting falls in rates were observed, and the fall between 1980 and 1999 was approximately 50% in the EU, 45% in eastern Europe and 40% in Russia. However, the declines were greater in Russia and eastern Europe, since rates were much higher, in absolute terms. Joinpoint regression analysis indicated that the falls were proportionally greater in the last decade for men (-3.83% per year in the EU) and in the last 25 years for women (-3.67% per year in the EU) than in previous calendar years. Moreover, steady declines in gastric cancer mortality were observed in the middle-aged and the young population as well, suggesting that they are likely to persist in the near future. In terms of number of deaths avoided, however, the impact of the decline in gastric cancer mortality will be smaller, particularly in the EU.

Processed meat and the risk of selected digestive tract and laryngeal neoplasms in Switzerland.

BACKGROUND: Processed meat has been related to the risk of digestive tract neoplasms but the evidence remains inconclusive. We examined data from a network of case-control studies conducted between 1992 and 2002 in the Swiss Canton of Vaud. PATIENTS AND METHODS: We studied 316 patients with incident, histologically confirmed oral and pharyngeal cancer, 138 patients with oesophageal cancer, 91 patients with laryngeal cancer and 323 patients with colorectal cancer. Controls were 1271 subjects admitted to the same hospital for a wide spectrum of acute non-neoplastic conditions, unrelated to long-term modification of diet. RESULTS: There were strong direct trends in risk between consumption of processed meat and the various neoplasms considered: the multivariate odds ratios for the highest quartile of intake compared to the lowest were 4.7 for oral and pharyngeal cancer, 4.5 for oesophageal cancer, 3.4 for laryngeal cancer and 2.5 for colorectal cancer. The association was stronger in younger subjects, in moderate drinkers and in non-smokers. CONCLUSION: Processed meat represents a strong indicator of unfavourable diet for digestive tract and laryngeal cancer risk in this population.

Trends in cancer mortality at age 15 to 24 years in Europe.

Trends in death certification rates from all cancers and seven selected cancer sites (bone sarcoma, soft-tissue sarcoma, ovary, testis, non-Hodgkin's lymphomas, Hodgkin's disease, leukaemias) were analysed for the population aged 15-24 years in Europe and, for comparative purposes, in the United States of America (USA) and Japan over the period of 1965-1998. Overall, there was a decrease in total cancer mortality of approximately 40% for both sexes. The declined mortality is largely attributable to better treatments and inclusion in multicentre clinical trials. The degree of improvement was similar in Japan and the USA, but was less in Eastern European countries, reflecting delays in the application of effective treatments, and limited involvement in large, well-designed clinical trials for these curable cancers in Eastern Europe.

Trends in mortality from suicide, 1965-99.

OBJECTIVE: To analyse trends in mortality from suicide over the period 1965-99. METHOD: Data were derived from the WHO database, including data for 47 countries. RESULTS: In the European Union (EU), all age suicide mortality peaked at 16.1/100,000 in men in 1980-84, and declined thereafter to 14.4/100,000 in 1995-98. In females, the fall was 29% to reach 4.6/100,000. A similar pattern of trends was observed in several eastern European countries. In contrast, mortality from suicide rose substantially in the Russian Federation, from 37.7/100,000 in males in 1985-89 to 58.3/100,000 in 1995-98 (+55%), and to 9.5/100,000 (+12%) in females. In the USA and most other American countries providing data, no consistent pattern was evident for males, but falls were observed in females. Steady declines were registered for Japan, starting from the highest suicide rates worldwide in the late 1950s. Suicide rates were upwards in Ireland, Italy, Spain, the UK, Cuba, Australia and New Zealand. Substantial rises were observed in a few countries (Ireland, Cuba, Mexico, Australia and New Zealand) for young males. CONCLUSION: In spite of mixed trends, suicide remains a significant public health problem worldwide.

The recent decline in gallbladder cancer mortality in Europe.

Mortality from gallbladder cancer has been traditionally high in Eastern Europe, and lower in northern countries. Trends in 18 European countries, including the European Union (EU) and selected Eastern European countries, have been updated using official death certification data abstracted from the WHO database over the period 1980-1999. In the EU, age-standardized rates declined by about 30% between the late 1980s and 1999 to reach 1.8/100 000 for women, and by about 10% to reach 1.4/100 000 for men. In the Czech Republic and Hungary, rates for women were over 6/100 000 until the early 1990s, and declined by about 25% thereafter. For males, gallbladder cancer mortality showed no consistent trend, with rates over 3/100 000. Thus, a high mortality area from gallbladder cancer is still evident for both sexes in Central and Eastern Europe. The trends in mortality from gallbladder cancer are probably influenced by changes in risk factor exposure, such as diet, nutrition or tobacco, but essentially reflect more widespread and earlier adoption of cholecystectomy in the EU, since gallstones are the major risk factor for gallbladder cancer. The data also indicate the scope for further improvement of the management of gallbladder disease in Eastern Europe.

Oral contraceptives and colorectal cancer.

BACKGROUND: Only limited information and understanding are available on the potential relation between oral contraceptive use and the risk of colorectal cancer. Further data on the issue are therefore useful and may help informed choice of contraception. METHODS AND RESULTS: Data were derived from a case-control study of colorectal cancer conducted between 1992 and 2001 in the Swiss Canton of Vaud, including 131 women with colorectal cancer and 373 controls admitted in the same hospital as the cases with diagnosis of acute, non-neoplastic disease, unrelated to long-term modification of diet. Oral contraceptive use was reported by 11% of cases versus 17% of controls, corresponding to multivariate odds ratio of 0.8 (95% CI: 0.4-1.7). The odds ratio was non-significantly below unity across strata of duration, time since first and last oral contraceptive use. CONCLUSION: These findings add further evidence on a possible inverse relation between oral contraceptive and colorectal cancer risk.

Mortality from major cancer sites in the European Union, 1955-1998.

After long-term rises, over the last decade age-standardised mortality from most common cancer sites has fallen in the European Union (EU). For males, the fall was 11% for lung and intestines, 12% for bladder, 6% for oral cavity and pharynx, and 5% for oesophagus. For females, the fall was 7% for breast and 21% for intestines. There were also persisting declines in stomach cancer (30% in both sexes), uterus (mainly cervix, -26%) and leukaemias (-10%). Mortality rates for other common neoplasms, including pancreas for both sexes, prostate and ovary, tended to stabilise. The only unfavourable trends were observed for female lung cancer (+15%). Lung cancer rates in women from the EU are approximately one-third of those in the USA, and 50% lower than breast cancer rates in the EU. Lung cancer rates in European women have also tended to stabilise below the age of 75 years. Thus, effective interventions on tobacco control could, in principle, avoid a major lung cancer epidemic in European women.

Lung cancer mortality in European regions (1955-1997).

BACKGROUND: The different spread of tobacco smoking across European countries has caused a substantial variability in lung cancer mortality. The objective of this investigation was to analyse the trends in lung cancer mortality rates in three broad European regions (Northern and Western countries, Eastern countries, and Mediterranean countries) during the second half of the 20th century. PATIENTS AND METHODS: Mortality data were obtained from the World Health Organisation database. Lung cancer mortality rates were age-standardised by the direct method to the world standard population. Trends from 1955 to 1997 were assessed by means of joinpoint regression analysis. RESULTS: In men, rates in Eastern Europe increased to reach in the 1990s the highest values ever registered, while downward trends were observed in Northern and Western Europe since 1979, and in Mediterranean countries since the 1990s. In women, upward trends were observed in the three regions considered for the whole period. CONCLUSIONS: Different smoking prevalences over time explain the shift of almost one decade in the trends in Mediterranean men as compared with Northern and other Western European men. The persisting upward trends in women in the three regions are of concern.