Anthropometric and behavioral correlates of insulin-like growth factor I and insulin-like growth factor binding protein 3 in middle-aged Japanese men

High levels of plasma insulin-like growth factor I (IGF-I) and low levels of insulin-like growth factor binding protein 3 (IGFBP-3) have been related to increased risk of several cancers. Little is known about the behavioral determinants of these biologic markers. The authors examined the relation of anthropometric and behavioral factors to plasma concentrations of IGF-I and IGFBP-3 in a cross-sectional study of 616 Japanese men aged 45-55 years in 1995-1996. In univariate analyses, body mass index was strongly, positively associated with both IGF-I and IGFBP-3. The waist/hip ratio was also linearly related to IGF-I and IGFBP-3 up to the third quartile level. Height was weakly, positively associated with IGF-I and IGFBP-3. Smoking was inversely associated with IGF-I and IGFBP-3. Alcohol use was associated inversely with IGF-I and positively with IGFBP-3. Neither IGF-I nor IGFBP-3 was related to physical activity. Results of the multivariate analysis were essentially the same as those of the univariate analyses. The findings regarding body mass index are in contrast to those of previous studies showing null or inverse associations, and they suggest that the relation of body mass index to IGF-I or IGFBP-3 may vary among populations. The study also indicates that smoking and alcohol use might affect plasma IGF-I and IGFBP-3.     

Fish consumption and breast cancer risk

The omega-3 fatty acids, especially long-chain eicosapentaenoic acid (20:5n-3) and docosahexaenoic (22:6n-3) contained in "fatty" fish, have consistently been shown to retard the growth of breast cancer in vitro and in animal experiments. In contrast, studies of the association between fish consumption and breast cancer risk in human populations have not consistently shown inverse associations. However, previous studies have not considered the specific types of fish consumed. Using data from a large, nationwide case-control study conducted in Sweden, we examined the association between consumption of fatty and lean fish and breast cancer risk. Odds ratios (OR) and 95% confidence intervals were computed from unconditional logistic regression models. High consumption of fish was weakly associated with reduced breast cancer risk, and the association was not statistically significant. With multivariate adjustment, the OR for women with the highest consumption (> or =3.5 servings/wk) compared with women with the lowest (virtually none) was 0.88 (95% confidence interval = 0.60-1.29, P for trend = 0.15). When type of fish was examined separately, the association was similar for fatty and lean fish.     

Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients

OBJECTIVE: Pharmacological, clinical, and postmortem studies suggest altered gamma-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects. METHOD: Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase. RESULTS: Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged. CONCLUSIONS: Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.     

Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16(INK4A) protein.

Dysfunction of proteins involved in the G1 to S transition of the cell cycle, such as p16(INK4A) and RB1, is common in many cancer types. A screen of p16 protein expression was performed in benign, borderline, and invasive ovarian tumors, together with endometrial cancers, aligned on a tissue microarray. We observed frequent p16 overexpression in serous papillary carcinomas of ovarian and endometrial origin. An extended cohort of ovarian serous papillary carcinomas was examined to further evaluate the frequency of p16 overexpression. Strong, uniform staining in the majority of cancer cells occurred commonly in invasive serous papillary ovarian cancers, particularly in grade 3 carcinomas. RB1 protein expression abnormalities were rare. Our data indicate that abnormalities in the retinoblastoma pathway, as determined by p16 overexpression, are common in serous papillary carcinomas and are probably an early event.     

p53 Alterations and protein accumulation in benign breast tissue and breast cancer risk: a cohort study.

Disruption of p53 gene function seems to have a pivotal role in carcinogenesis. p53 gene changes occur before the development of breast cancer and therefore might influence breast cancer risk. We investigated the association between p53 protein accumulation and p53 mutations detected in benign breast tissue and risk of subsequent breast cancer. We conducted a case-control study nested within the cohort of 4,888 women in the Canadian National Breast Screening Study who were diagnosed with biopsy-confirmed benign breast disease during active follow-up. Cases were women with benign breast disease who subsequently developed breast cancer; five controls were matched to each case. p53 protein accumulation was assessed immunohistochemically using sections of paraffin-embedded benign breast tissue from 104 cases and 385 controls; for 82 of these cases and 327 of the controls, DNA was successfully extracted from the breast tissue for p53 gene analysis using PCR-single-strand conformation polymorphism/direct sequencing. p53 protein accumulation was associated with a 2-fold increase in risk of progression to breast cancer [adjusted odds ratio (OR), 2.16; 95% confidence interval (95% CI), 1.08-4.30], whereas p53 nucleotide changes overall were not associated with altered risk (adjusted OR, 1.22; 95% CI, 0.68-2.19); those with both p53 immunopositivity and a p53 nucleotide change had an OR (95% CI) of 3.20 (1.21-8.50). Nonpolymorphic intronic changes were associated with a 2.8-fold increase in risk (OR, 2.84; 95% CI, 1.09-7.41). The results of this study suggest that p53 protein accumulation and nonpolymorphic intronic changes in p53 are associated with increased risk of progression to breast cancer in women with benign breast disease.     

Human papillomavirus infections with multiple types and risk of cervical neoplasia.

BACKGROUND: Besides an established role for certain human papillomavirus (HPV) genotypes in the etiology of cervical cancer, little is known about the influence of multiple-type HPV infections on cervical lesion risk. We studied the association between multiple HPV types and cervical lesions among 2,462 Brazilian women participating in the Ludwig-McGill study group investigation of the natural history of HPVs and cervical neoplasia. METHODS: Cervical specimens were typed by a PCR protocol. The cohort's repeated-measurement design permitted the assessment of the relation between the cumulative and concurrent number of HPV types and any-grade squamous intraepithelial lesions (SIL) and high-grade SIL (HSIL). RESULT: At individual visits, 1.9% to 3.2% of the women were infected with multiple HPVs. Cumulatively during the first year and the first 4 years of follow-up, 12.3% and 22.3% were infected with multiple types, respectively. HSIL risk markedly increased with the number of types [odds ratio (OR), 41.5; 95% confidence interval (95% CI), 5.3-323.2 for single-type infections; OR, 91.7; 95% CI, 11.6-728.1 for two to three types; and OR, 424.0; 95% CI, 31.8-5651.8 for four to six types, relative to women consistently HPV-negative during the first year of follow-up]. The excess risks for multiple-type infections remained after exclusion of women infected with HPV-16, with high-risk HPV types, or persistent infections, particularly for any-grade SIL. Coinfections involving HPV-16 and HPV-58 seemed particularly prone to increase risk. CONCLUSION: Infections with multiple HPV types seem to act synergistically in cervical carcinogenesis. These findings have implications for the management of cervical lesions and prediction of the outcome of HPV infections.     

Insulin-like Growth Factor (IGF)-I, IGF-binding Protein-3 and Colorectal Adenomas in Japanese Men

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0–4.5, trend P =0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (≥5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.