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Obesity may increase the risk for non-Hodgkin's lymphoma (NHL) through an inflammatory pathway. We explored the relation of NHL with body size at different times in life within the Multiethnic Cohort that includes African Americans, Caucasians, Japanese, Latinos, and Native Hawaiians. Participants were 45 to 75 years old at recruitment in 1993 to 1996. This analysis included 87,079 men and 105,972 women with 461 male and 378 female NHL cases. We used Cox regression to model NHL risk with age as the time metric while adjusting for age at baseline, ethnicity, education, alcohol intake, and age at first live birth. Body weight and body mass index at age 21 were stronger predictors of NHL risk than anthropometric characteristics at baseline. For men, being in the highest quartile of body mass index and body weight at age 21 conferred a nonsignificant 86% and 41% higher NHL risk, respectively, whereas there was no association at baseline. For women, the risk associated with the highest quartile of weight at age 21 was 1.6 (P(trend) = 0.04), whereas women in the highest quartile at baseline had a nonsignificant risk of 27%. Height was positively related to NHL in men and women. Despite the small numbers, there was some consistency for risk estimates across ethnic groups and weak evidence for an association with NHL subtypes. These findings indicate that weight at age 21 may represent lifetime adiposity better than body weight at cohort entry. Alternatively, weight at age 21 may be more relevant for the etiology of NHL.

We investigate mechanisms of regression of liver hyperplasia which occurs after induction of growth by hepatomitogens and their subsequent withdrawal. We hypothesized that transforming growth factor beta 1 (TGF-beta 1) might be involved in the control of regression. Therefore we studied the effect of this agent on DNA synthesis and death of hepatocytes cultured in vitro. Both the low basal rate of DNA synthesis of untreated cells and its increase by epidermal growth factor (10 ng/ml) were suppressed by TGF-beta 1 at concentrations higher than 0.01-0.1 ng/ml. At the same range of concentrations of TGF-beta 1, the DNA content of the cultures declined significantly and numerous dead cells could be seen in the monolayer. Time course studies showed that TGF-beta 1 (1 ng/ml) decreased DNA content in the cultures linearly to 41 +/- 7% of controls during a period of 48 h. A similar decrease occurred with vital hepatocytes in hematoxylin and eosin stained monolayers. These changes were accompanied by an extensive release of lactate dehydrogenase which began at 20 h and was 70% of the total lactate dehydrogenase content of the cultures at 40-48 h. Little formation of guanidine hydrochloride resistant bodies and no fragmentation of DNA, indicators of apoptotic cell death, were detected after TGF-beta 1 (1 ng/ml) treatment. Time lapse cinematography revealed an active detachment of the cells from the underlying collagen gel. These studies show that inhibition of DNA synthesis by TGF-beta 1 is associated with enhanced cell death in cultured hepatocytes.

Parenchymal liver cells were isolated from human liver pieces of surgical waste as well as from rat livers. DNA synthetic activity was measured after different times in primary culture by [3H]thymidine incorporation and autoradiography. Labeling of control cultures of human hepatocytes at densities between 8,000 and 15,000 cells/cm2 was very low (0.4 to 1.3%). Human recombinant epidermal growth factor increased labeling 2- to 4-fold (P less than 0.01). Treatment with known inducers of liver growth in rats, namely, cyproterone acetate, alpha-hexachlorocyclohexane, nafenopin, phenobarbital, and rifampicin did not increase the number of labeled human liver cells. In some of the experiments, a 24-h exposure to the chemicals of rat or human hepatocytes was followed by a 24-h treatment with epidermal growth factor (EGF). In rat hepatocytes, incorporation rates were significantly increased. Cyproterone acetate and EGF acted in an additive manner, alpha-hexachlorocyclohexane and EGF were clearly overadditive, and phenobarbital had little effect. In human hepatocytes, little alteration in labeling indices was found; in some cases labeling was, rather, found to be lower than in cultures treated with EGF alone. These results show that human hepatocytes cultured in vitro are sensitive to stimulation of DNA synthesis by EGF; they differ from rat hepatocytes in their response to some drugs which show liver growth-promoting activity in rodents.