Publications

Various aspects of the Mediterranean diet were analyzed in a series of studies conducted in Northern Italy on over 20,000 cases of several major cancers and 18,000 controls. For most digestive tract cancers, the risk decreased with increasing vegetable and fruit consumption, with relative risks between 0.3 and 0.7 for the highest level of intake, and the population attributable risks for low intake of vegetables and fruit ranged between 15 and 40%. Less strong inverse relations were observed for other (epithelial) cancers, too. A number of micronutrients contained in vegetables and fruit showed an inverse relation with cancer risk. In particular, flavones, flavonols and resveratrol were inversely related to breast cancer risk. Olive oil, which is the main common denominator of the Mediterranean diet, has also been inversely related to cancers of the colorectum and breast, and mainly of the upper digestive and respiratory tract.

Data from a multicenter case-control study on breast cancer conducted in Italy were used to analyze the relationship between various types of fibers and breast cancer risk. Cases were 2,569 women with histologically confirmed, incident breast cancer; controls were 2,588 women admitted to the same network of hospitals for acute, nonneoplastic, non-hormone-related diseases. Cases and controls were interviewed between 1991 and 1994 using a validated food frequency questionnaire. The data were modeled through multiple logistic regression, controlling for demographic and reproductive breast cancer risk factors. The continuous odds ratios for the difference between the upper cut point of the fourth and the first quintile of intake were 0.90 [95% confidence interval = 0.82-0.98, p (for trend) < 0.05] for cellulose and 0.94 (95% confidence interval = 0.86-1.02) for soluble fibers. The protection tended to be stronger in premenopausal women. No material association was found for noncellulose polysaccharides and lignin. This study, based on a large data set from various Italian regions, suggests that fiber intake may confer some protection against breast cancer, particularly for cellulose and also for soluble fibers, i.e., those of vegetable origin. This possible protection has been related to an influence of fibers on levels and availability of estrogens and other steroid hormones in breast carcinogenesis.

Germinal centers (GCs) represent the main sites for the generation of high-affinity, class-switched antibodies during T cell-dependent antibody responses. To study gene function specifically in GC B cells, we generated Cγ1-cre mice in which the expression of Cre recombinase is induced by transcription of the Ig γ1 constant region gene segment (Cγ1). In these mice, Cre-mediated recombination at the fas , Ig β, IgH , and Rosa26 loci occurred in GC B cells as early as 4 days after immunization with T cell-dependent antigens and involved &gt;85% of GC B cells at the peak of the GC reaction. Less than 2% of IgM + B cells showed Cre-mediated recombination. These cells carried few Ig somatic mutations, expressed germ-line Cγ1- and activation-induced cytidine deaminase-specific transcripts and likely include GC B cell founders and/or plasma cell precursors. Cre-mediated recombination involved most IgG1, but also a fraction of IgG3-, IgG2a-, IgG2b-, and IgA-expressing GC and post-GC B cells. This result indicates that a GC B cell can transcribe more than one downstream C H gene before undergoing class switch recombination. The efficient induction of Cre expression in GC B cells makes the Cγ1-cre allele a powerful tool for the genetic analysis of these cells, as well as, in combination with a suitable marker for Cre-mediated recombination, the tracking of class-switched memory B and plasma cells in vivo . To expedite the genetic analysis of GC B cells, we have established Cγ1-cre F 1 embryonic stem cells, allowing further rounds of gene targeting and the cloning of compound mutants by tetraploid embryo complementation.

The role of ovarian function is reviewed with reference to breast, female genital tract neoplasms, and ischaemic heart disease. The risk of breast cancer is increased by early menarche, late menopause and regular menstrual cycles. The associations observed are modest, but are still consistent with an unfavourable effect of ovarian function on breast cancer risk. Ovarian cancer is possibly related to early menarche and associated with late menopause. A protective effect has been observed with irregular menstrual cycles and oral contraceptive use. Ovulation has been related to ovarian cancer risk in terms of the multistage model of carcinogenesis, although the biological process appears more complex. Endometrial cancer risk is increased by early menarche, late menopause, nulliparity, and — in premenopausal women — obesity. The risk of endometrial cancer is increased by oestrogens and decreased by progestins. Thus, anovulation increases endometrial cancer risk. Ischaemic heart disease is not related to age at menarche, but is associated with early menopause. Irregular menstrual cycles may also increase the risk. The impact of ovulation on cardiovascular disease should be viewed with reference to the different role of oestrogens (protective) and progestins (possible adverse). Other hormone imbalances (e.g., hyperandrogenaemia) may also be related to ischaemic heart diseases.

National trends in death certification rates from cancer of the stomach in Italy over the period 1955 to 1979 were analyzed using a standard cross-sectional approach and a log-linear Poisson model to isolate the effects of birth cohort, calendar period, and age. Overall, age-standardized death certification rates decreased from 47.04 to 30.74/100,000 males (average annual rate of change, assuming that the decrease has been constant, -1.8%) and from 34.55 to 19.27/100,000 females (average annual rate of change -2.4%). The decreases were even larger in middle age for both sexes. Both cohort and period of death curves were markedly downwards. However, cohort values did not decrease for generations born around the second world war (1935-1945), thus indirectly confirming the importance of (dietary) habits in childhood on subsequent gastric cancer risk. Further, the geographic distribution of certified mortality from gastric cancer in the 95 Italian provinces over the period 1975 to 1977 was analyzed. Death certification rates were about 10% lower for both sexes in the 14 provinces including the largest urban concentrations (over 250,000 inhabitants) than in the remaining areas. This finding might be related to earlier availability of modern food processing and storage in urban areas. It is, however, more difficult to explain the lower mortality rates (about 50% in both sexes) in the southern compared with the central and northern areas, since southern Italy is the less developed part of the country. Likewise, there appears to be at present little satisfactory explanation for the several clusters of exceedingly high mortality areas scattered in northern and central Italy, since some of these areas are several hundred kilometers apart, and there is no obvious common denominator in diet or other environmental factors that may explain their higher gastric cancer mortality rates.

Epidemiological studies on coffee, alcohol and bladder cancer risk published up to 2007 were reviewed. Coffee drinkers have a moderately higher relative risk of bladder cancer compared to non-drinkers. The association may partly be due to residual confounding by smoking or dietary factors, but the interpretation remains open to discussion, although the absence of dose and duration-risk relations weighs against the presence of a causal association. Most studies of alcohol and bladder cancer found no association, with some studies finding a direct and other an inverse one. This again may be due to differential confounding effect of tobacco smoking--the major risk factor for bladder cancer--in various populations. Thus, epidemiological findings on the relation between alcohol drinking and bladder cancer exclude any meaningful association.