Higher levels of antibodies to the tumour-associated antigen cyclin B1 in cancer-free individuals than in patients with breast cancer.

Cyclin B1 is a checkpoint protein that regulates cell division from G2 to the M phase. Studies in mice have shown that cyclin B1 vaccine-induced immunity significantly delayed or prevented the spontaneous cancer development later in life. We hypothesized that if these results showing a protective effect of anti-cyclin B1 antibodies could be extrapolated to the human condition, cancer-free individuals should have higher levels of endogenous antibodies than patients with cancers characterized by the over-expression of this tumour-associated antigen. To test this hypothesis, we characterized a large (1739 subjects) number of multi-ethnic patients with breast cancer (which over-expresses cyclin B1) and matched controls for anti-cyclin B1 immunoglobulin (Ig)G antibodies. Multivariate analyses, after adjusting for the covariates, showed that cancer-free individuals had significantly higher levels of naturally occurring IgG antibodies to cyclin B1 than patients with breast cancer (mean ± standard deviation: 148·0 ± 73·6 versus 126·1 ± 67·8 arbitrary units per ml; P < 0·0001). These findings may have important implications for cyclin B1-based immunotherapy against breast cancer and many other cyclin B1-over-expressing malignancies.

Racially restricted contribution of immunoglobulin Fcγ and Fcγ receptor genotypes to humoral immunity to human epidermal growth factor receptor 2 in breast cancer.

Tumour-associated antigen human epidermal growth factor receptor 2 (HER2) is over-expressed in 25-30% of breast cancer patients and is associated with poor prognosis. Naturally occurring anti-HER2 antibody responses have been described in patients with HER2 over-expressing tumours. There is significant interindividual variability in antibody responsiveness, but the host genetic factors responsible for this variability are poorly understood. The aim of the present investigation was to determine whether immunoglobulin genetic markers [GM (genetic determinants of γ chains)] and Fcγ receptor (FcγR) alleles contribute to the magnitude of natural antibody responsiveness to HER2 in patients with breast cancer. A total of 855 breast cancer patients from Japan and Brazil were genotyped for several GM and FcγR alleles. They were also characterized for immunoglobulin (Ig)G antibodies to HER2. In white subjects (n = 263), GM 23-carriers had higher levels of anti-HER2 antibodies than non-carriers of this allele (p = 0·004). At the GM 5/21 locus, the homozygotes for the GM 5 allele had higher levels of anti-HER2 antibodies than the other two genotypes (P = 0·0067). In black subjects (n = 42), FcγRIIa-histidine/histidine homozygotes and FcγRIIIa-phenylalanine/valine heterozygotes were associated with high antibody responses (P = 0·0071 and 0·0275, respectively). FcγR genotypes in white subjects and GM genotypes in black subjects were not associated with anti-HER2 antibody responses. No significant associations were found in other study groups. These racially restricted contributions of GM and FcγR genotypes to humoral immunity to HER2 have potential implications for immunotherapy of breast cancer.

Elderly Japanese emigrants to Brazil before World War II: II. Prevalence of senile dementia.

BACKGROUND: We previously showed the prevalence of dementia in the town of Tajiri (Miyagi Prefecture, Japan), and found it to be 8.0%. The first population-based study on dementia in Brazil (Catanduva) disclosed the prevalence as being 7.1%. To evaluate the effects of environment on development of dementia, elderly Japanese immigrants living in Brazil were examined. Brazil is the country with the largest number of Japanese immigrants. METHODS: All immigrants aged 65 years and over from Miyagi Prefecture, living in the four cities of the São Paulo Metropolitan area were targeted (n = 192). We were able to examine 166 subjects (86.5%). The diagnosis of dementia was based on the DSM-IV with the severity assessed by the CDR (clinical dementia rating) scales. The cognitive ability screening instrument (CASI) was used for neuropsychological assessment. RESULTS: Thirteen subjects were diagnosed with dementia, CDR 1-3, the prevalence being 7.8%. Older subjects suffered more from dementia, and, paradoxically, the more highly educated subjects also suffered more. All the CASI items, except for long-term memory and visual construction, significantly deteriorated in the CDR 0.5 group compared with the CDR 0 group. COMMENTS: The prevalence of dementia was not thought to be affected by environmental factors. A paradoxically higher rate of dementia in the more educated subjects was probably due to the historical problems of the immigrants. Intact CASI item long-term memory in the CDR 0.5 group indicated that suspected dementia patients could maintain this function. This is the first epidemiological study on dementia in elderly Japanese immigrants in Brazil.

Epstein-Barr virus-associated gastric carcinoma in Japanese Brazilians and non-Japanese Brazilians in São Paulo.

The proportion of Epstein-Barr virus-associated gastric carcinoma (EBV-GC) was examined in 149 Japanese-Brazilian and 151 non-Japanese-Brazilian gastric-carcinoma cases using in situ hybridization (ISH) assay to detect EBV-encoded small RNA (EBER), and the results were compared with our referent Japanese data. We found that 4.7% of cases in Japanese Brazilians were EBER-positive. This frequency was slightly lower than that of the referent Japanese, among whom 6.2% of 2038 gastric-carcinoma cases were EBER-positive. On the other hand, the non-Japanese-Brazilian series showed a significantly higher proportion of EBV-GC (11.2%) than the referent group did (P = 0.01). Although EBV-GC was predominant in males among non-Japanese Brazilians (M / F = 3.6, P = 0.047), as was the case in Japanese (M / F = 2.7), Japanese Brazilians did not show such a male predominance. The sex-ratio difference between the Japanese Brazilians and Japanese was statistically significant (P = 0.005). In conclusion, the present study in Japanese Brazilians and Japanese yielded no evidence suggesting any change in the frequency of EBV-GC caused by migration, except the absence of male predominance, which was observed both in Japanese and non-Japanese Brazilians.

Serological Immunoglobulin G antibody titers to Helicobacter pylori in Japanese Brazilian and Non-Japanese Brazilian gastric cancer patients and controls in São Paulo.

Helicobacter pylori (H. pylori) infection is considered a cause of gastric cancer (GC), though evidence for this association is scarce in high-risk areas. Possible case control and/or ethnic differences were investigated as to the presence of H. pylori and its immunogloblin G antibody titer in the multi-ethnic city of São Paulo, where the incidence of GC is relatively high. We performed a cross-sectional comparison of antibody titers to H. pylori in Japanese Brazilian, and non-Japanese Brazilian GC patients and their controls. Japanese Brazilian patients were matched by age, sex and ethnicity with two controls, while non-Japanese Brazilian patients were matched as above with one control. Among Japanese Brazilians, 59 of 93 (63.4%) patients with GC and 127 of 186 (68.3%) controls were positive for H. pylori-specific antibody (odds ratio (OR) = 0.80, 95% confidence interval (CI) = 0.47 - 1.36), while among non-Japanese Brazilians, 171 of 228 patients with GC (75.7%) and 178 of 226 controls (78.8%) were positive (OR = 0.84, 95% CI = 0.54 - 1.30). The median serum antibody titer was lower in cases than in controls in both ethnic groups. A high titer (H. pylori titer > or = 50) was associated with less likelihood of GC for both ethnic groups (for Japanese Brazilians, OR = 0.39, 95% CI = 0.16 - 0.92; for non-Japanese Brazilians, OR = 0.56, 95% CI = 0.31 - 1.02). The high titer can be regarded as a sign of the necessity of eradication, and low titer is regarded as a sign of the necessity of close screening for GC in both ethnic groups, because extended atrophy may cause spontaneous disappearance of H. pylori from the stomach.

hOGG1 exon7 polymorphism and gastric cancer in case-control studies of Japanese Brazilians and non-Japanese Brazilians.

Polymorphism of hOGG1 may be capable of serving as a genetic marker for individual susceptibility to various cancers because of its role in the repair of oxyradical DNA damage. We examined the distribution of the hOGG1 Ser326Cys polymorphism and its presumed correlation with gastric cancer risk in two case-control studies of different ethnic groups in São Paulo, Brazil. Potentially eligible Japanese (JB) and non-Japanese Brazilian (NJB) case subjects were defined as patients with newly diagnosed malignant neoplasms of the stomach in 13 hospitals in São Paulo. Ninety-six JBs and 236 NJBs were adopted as subjects. Two controls were matched for each JB case, and one control for each NJB case. The subjects were interviewed using a questionnaire and their blood samples were collected. A significant difference in the distribution of this polymorphism between the two ethnic groups was observed (chi(2)=58.3, P<0.01). The mutant type (Ser/Cys or Cys/Cys) was predominant (approximately 65%) in the JBs, but was only present in approximately 40% of the NJBs. Logistic regression analysis showed no significant increased risk for either the Ser/Cys or Cys/Cys type in either group. The odds ratios of the Cys allele for gastric cancer were 1.01 (95% confidence interval (CI): 0.52-1.93) in the JBs and 0.85 (95% CI: 0.57-1.26) in the NJBs. In the NJBs, a significant increased risk of smoking was shown only in the Ser/Ser type, and no increased risk was shown in the genotypes with the Cys allele. However, no statistically significant interactions were observed with smoking or other possible confounding factors. No statistically significant difference in the distribution of the polymorphism was observed between the intestinal type and diffuse type of gastric cancer in either the JBs or the NJBs. The ethnic difference in hOGG1 Ser326Cys polymorphism was much greater than the case-control difference, and this polymorphism is unlikely to be associated with gastric cancer.

Genomic structure and loss of heterozygosity of EPHB2 in colorectal cancer.

EphB2, a member of the Eph receptor protein-tyrosine kinase family, is overexpressed in several human gastrointestinal tumors. Furthermore, the EphB2 gene is localized at 1p35-p36.1, a frequently deleted region in colon and other cancers. So, despite its overexpression in some kind of tumors, we decided to study the possibility of involvement in the EphB2 gene (EPHB2) mutation in colon cancers, because some of the well known tumor suppressor genes (e.g. p53) is overexpressed (really accumulated) in tumors. Fifty colon tumor samples of matched with their respective normal tissues, were studied for mutation of the EPHB2. Analysis of the genomic structure of EphB2 and survey of all 16 exons revealed an infrequent polymorphism (intron 2) and mutation (intron 8). Another polymorphism in exon 6, localized at nucleotide 1359 (A-->G) was found to be rather frequent in Japanese and Chinese subjects, but very rare in Caucasians. Taking advantage of this polymorphism within EPHB2, we surveyed the loss of heterozygosity (LOH) status of this gene in Japanese colorectal tumors. Among the 50 samples analyzed, 24 were informative, and LOH was found in five of the15 (33.3%) informative rectal cancer cases. Mutation analysis covering all 16 exons in the remaining allele did not reveal any mutations. Thus, EPHB2 is not a classical tumor suppressor gene.

Cytochrome P450 2E1 polymorphism in gastric cancer in Brazil: case-control studies of Japanese Brazilians and non-Japanese Brazilians.

Cytochrome P450 2E1 (Cyp2E1) is involved in the metabolic oxidation of carcinogenic nitroso compounds, including N-nitrosoamines. There is an RsaI polymorphism in the transcriptional regulatory region of this gene, and in vitro evidence suggests that the variant type of this polymorphic site has higher transcriptional activity but less chlorzoxazone-metabolizing activity. Interindividual differences in the metabolic capacity of Cyp2E1 are assumed to be associated with cancer susceptibility, but the results of the previous studies on the relation between Cyp2E1 RsaI polymorphism and cancer susceptibility have been inconsistent. Two case-control studies of gastric cancer in Japanese Brazilians (96 cases, 192 controls) and Brazilians not of Japanese ancestry (non-Japanese Brazilians; 236 cases, 236 controls) in São Paulo were designed to clarify the role of the Cyp2E1 RsaI genotype in susceptibility to gastric cancer after considering multifactorial environmental influences. The subjects with variant RsaI genotypes amounted to 47% (28 of 59) and 48% (64 of 133), respectively, of the Japanese cases and controls, and 6% (11 of 187) and 10% (19 of 192), respectively, of the non-Japanese cases and controls. As expected, a difference in the distributions of the two groups was observed. The odds ratio of the RsaI variant genotype of Cyp2E1 was 0.46 (95% confidence interval, 0.21-1.04) in the non-Japanese Brazilian population and 0.98 (95% confidence interval, 0.50-1.90) in the Japanese Brazilian population after adjusting for sex, age, tobacco use, and meat consumption. Additional adjustment for potential confounding factors did not change the odds ratio substantially. No significant interactions were observed between the polymorphism and environmental factors. In regard to the histological type of gastric cancer, the variant genotype was significantly more prevalent than the common genotype in Japanese subjects with diffuse type gastric cancer. Our study suggests that the Cyp2E1 RsaI polymorphism is associated with a reduced risk of gastric cancer, although how the assumed increase in Cyp2E1 expression produced by this polymorphism is related to a reduced risk of cancer remains unclear. The observations in this study are consistent with the recent observations of esophageal cancer in endemic areas of China.

Ethnic differences in serum pepsinogen levels among Japanese and non-Japanese Brazilian gastric cancer patients and controls.

A low level of serum pepsinogen I (Pg I) is a risk factor for gastric cancer (GC); low levels of Pg I and the pepsinogen ratio (Pg I:Pg II) are correlated with chronic atrophic gastritis. We report serum Pg levels and compare the degree of association with GC among Japanese and non-Japanese Brazilians. Sera were cross-sectionally ascertained from 93 Japanese Brazilian patients category matched by age and sex with 110 controls, and 228 non-Japanese Brazilian patients individually matched by age and sex with one control. Among non-Japanese Brazilians, GC was associated with a Pg I level <30 ng/ml (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7-3.8) and a Pg I:Pg II ratio < 3.0 (OR, 3.4; 95% CI, 2.2-5.3). However, among Japanese Brazilians, the association was present with a level of Pg I < 30 ng/ml (OR, 3.5; 95% CI, 1.9-6.3), and was weak with a Pg I:Pg II ratio < 3.0 (OR, 1.3; 95% CI, 0.73-2.4). Serum Pg I may be preferred to the Pg I:Pg II ratio to study the association between Pg and GC among Japanese Brazilians.

Serum n-3 fatty acids, fish consumption and cancer mortality in six Japanese populations in Japan and Brazil.

Japanese people consume significant amounts of long chain n-3 polyunsaturated fatty acids (PUFAs) derived from fish, but the association of PUFAs with cancer mortality has not been fully investigated. To study geographic differences in n-3 PUFAs intake, we compared serum fatty acid and dietary fish intake among various Japanese populations having different rates of cancer mortality. The subjects were 50 men from each of five regions in Japan and 47 Japanese men from Sao Paulo, Brazil. All were randomly selected and aged 40 to 49 years. Serum fatty acids were measured by gas chromatography and the frequency of fish intake was obtained by a food frequency questionnaire. Significant geographic differences in serum fatty acid levels (% of total fatty acids) and fish intake (days/4 weeks) were observed. The percentages of serum total PUFA were similar in the six regions, though there was an almost three-fold difference in n-3 PUFAs content between Brazil (3.9%) and Akita (10.9%). The frequency of total fish intake corresponded to serum n-3 PUFAs composition. The relationship between cancer mortality and serum n-3 PUFAs levels was not clear, though an inverse association between prostate cancer and serum n-3 PUFAs levels appeared to exist. The results suggest that although serum n-3 PUFAs varied significantly, the observed geographic difference did not account for the different cancer risks at the population level.

CYP1A1 and CYP2E1 polymorphism and lung cancer, case-control study in Rio de Janeiro, Brazil.

Msp I polymorphism and exon 7 Ile-Val polymorphism of CYP1A1, and Rsa I polymorphism of CYP2E1 were studied in lung cancer patients and controls in Rio de Janeiro, Brazil. Of the three polymorphisms studied, only the exon 7 polymorphism of CYP1A1 (Val-containing genotypes) had a distribution which was statistically significant in the patients and controls. The contribution of Val containing genotypes of CYP1A1 exon 7 was greater in the subpopulation of squamous cell carcinoma patients with a lower life-time smoking consumption (OR, 2.92 vs 1.97). This association is consistent with the previous findings by Kawajiri et al. and the first observation of the positive association of this locus with lung cancer in a Western population (Kawajiri K, Nakachi K, Imai K, Yoshii A, Shimada N, Watanabe J. FEBS Let 1990; 263, 131-133). Furthermore, together with the lack of association of Msp I polymorphism in the non-coding region of CYP1A1, the locus truly responsible for lung cancer risk among pleural polymorphisms of CYP1A1 appeared to be exon 7 Ile-Val polymorphism. In the future, investigations of multiple markers in different ethnic populations may reveal cancer risk markers common to all mankind.

The heme-binding region polymorphism of cytochrome P450IA1 (CypIA1), rather than the RsaI polymorphism of IIE1 (CypIIE1), is associated with lung cancer in Rio de Janeiro.

Ile-Val polymorphism in exon 7 of cytochrome P450IA1 (CypIA1) and RsaI polymorphism of cytochrome P450IIE1 (CypIIE1) were examined in a case-control study of lung cancer in Rio de Janeiro, Brazil. The Val-containing genotype in exon 7 of CypIA1 was found to be associated with lung cancer in this population (odds ratio, 2.26; 95% confidence interval, 1.14-4.47 for 99 cases versus 108 controls of 123 matched pairs), whereas RsaI polymorphism in CypIIE1 was not associated with lung cancer susceptibility. In squamous cell carcinoma, the degree of association of Val-containing genotype was greater in those with fewer pack-years of smoking. The RsaI polymorphism of CypIIE1 has a different distribution from the Japanese pattern and is not associated with lung cancer. When we analyzed the association of Ile-Val polymorphism to MspI polymorphism of CypIA1, the Val/Val homozygote was found only in the subpopulation with the MspI site-present homozygote. The apparent lack of association of CypIA1 MspI polymorphism with lung cancer in this area reported in our previous study and the results of the present study indicate that the "true" responsible site for lung cancer susceptibility should be the Ile-Val polymorphism in the catalytic site of CypIA1.

Risk factors for lung cancer in Rio de Janeiro, Brazil: a case-control study.

The association between the risk of lung cancer and tobacco smoking, dietary factors and occupational exposures was examined in a hospital-based case-control study. The study involved 123 consecutive cases and 123 controls, matched by age (+/- 3), sex, and race. In this first study of lung cancer risk in Brazil, we found that tobacco smoking is the strongest risk factor with an odds ratio (OR) for current and former smokers of 22 (CI, 6.5-76) and 7.7 (CI, 2.2-27), respectively. An OR of 2.8 (CI, 1.0-7.7) was found for users of black tobacco in the form of hand-rolled cigarettes) in combination with conventional cigarettes, after adjustment for life-time consumption of any kind of tobacco; users of conventional cigarettes only were considered as a reference group. Cessation of smoking had an important influence in reducing the lung cancer risk, whereas early initiation of smoking increased the risk. Among dietary factors, frequent consumption of meat (P < 0.01) and pasta (P = 0.02) were positively associated with lung cancer risk after adjusting for smoking and income. No association was found with green/yellow vegetables or fruits. We were unable to detect any significant association related to occupational exposures. This study confirmed the association of lung cancer with smoking as the most important predictor of risk. It also indicates the increase in risk associated with the use of black tobacco in combination with conventional cigarettes.

Cytochrome P-450 lA1 genotype in lung cancer patients and controls in Rio de Janeiro, Brazil.

Mspl restriction fragment length polymorphism in cytochrome P-450 IA1 (CypIA1) gene, which has been associated with lung cancer susceptibility in Japanese, was studied in persons from Rio de Janeiro, in the framework of a hospital-based, age, race (black or nonblack), and gender-matched case-control study (n = 222; 110 cases and 112 controls). Contrary to the hypothesis, there was no difference in the frequency of the C genotype (Mspl site-present homozygous), even after racial breakdown. There were no significant differences between cases and controls when categorized according to tobacco consumption. The lifetime quantity of tobacco smoked was not different among lung cancer patients with three different genotypes (A, Mspl site-absent, homozygous; B, heterozygote; and C). The background frequency of the Mspl polymorphism C genotype is a little less than 10%, similar to that of the Japanese healthy population. The CyplA1 Mspl polymorphism itself does not seem to be related to susceptibility to bronchial carcinogenesis in this area.

Wood stove effects on indoor air quality in Brazilian homes: carcinogens, suspended particulate matter, and nitrogen dioxide analysis.

The effects of wood burning stoves on indoor air quality was investigated in a rural community of southern Brazil, during the winter season of 1991. The concentrations of polycyclic aromatic hydrocarbons (PAHs), nitrogen dioxide (NO2) and suspended particulate matter (SPM) were assessed in houses with wood stoves and the results compared with levels found in houses with gas stoves. Strikingly higher (p < 0.01) levels of PAHs, and much higher (p = 0.07) levels of SPM were found in the kitchens with wood stoves. In contrast, NO2 concentrations in the kitchen as well in personal exposure, were found to be slightly higher in houses with gas stoves. All these differences were minimally affected by smoking, outdoor air pollution or other emissions from indoor combustion products. These findings appear to support the hypothesis that domestic wood burning stoves are risk factors for some upper digestive and respiratory tract cancers in Brazil.

Comparative epidemiology of oral cancer in Brazil and India.

A comparison of the risk factors and occurrence of oral cancer in Brazil and India is presented. These two countries have among the highest incidence rates for such cancer in the world. A distinct pattern of risk factors was observed for each country: in India, tobacco chewing was the predominant risk factor: in Brazil, the major risk factor was the combination of tobacco smoking and alcohol consumption. Observations by descriptive epidemiology reveal high age-standardized incidence rates of oral cancer along with some distinctive differences associated with age distribution, sex ratios, and trends in each country. The desirability of additional oral cancer prevention research is also emphasized.

[Current status of air pollution in Sao Paulo, Brazil: effects and problems associated with the introduction of ethanol-fueled motor vehicles].

Recently suggestions have been advanced that alternative fuels including ethanol, methanol or methane instead of so called "fossil fuels" may help improve the current conditions of air pollution. According to results of general survey in Sao Paulo, since their introduction in 1978, ethanol-fueled cars have increased their share to almost 50% of all light vehicles in 1983. The current status of air pollution in Sao Paulo metropolitan area (SPMA) is described in relation to the use of such alternative fuel. The average concentrations in air of SO2 and lead have been decreasing drastically during the period of 1982-88, whereas non-methane hydrocarbon, NO2 and O3 levels have been increasing to attain the worst levels in the world as indicated in Fig. 2. The use of ethanol-fuel, which contains less sulphate and lead, is thought to have contributed more or less to the above reductions of SO2 and lead in the air. However, the pollutants that have increased may derive mainly from diesel and gasoline exhausts of heavy vehicles. The general state of air pollutions appears not to have been improved, suggesting the difficulty in resolving air pollution issues. On the other hand, a current problem specific to ethanol-fuel is the aldehydes or other carcinogenic components in exhaust. Peak formaldehyde concentration, for example, have been reported to have reached 159 ppb in SPMA, which may be one of the highest levels shown in ambient air.(ABSTRACT TRUNCATED AT 250 WORDS)

Macrophage-nematode interaction in vivo: Nippostrongylus brasiliensis infective larvae in the peritoneum of unsensitized rats.

Infective larvae of Nippostrongylus brasiliensis injected into the peritoneum of non-immune rats become coated with several layers of host macrophages. Cell-coated larvae remain free in the peritoneum or attach to the omentum, while other larvae attach to the omentum without becoming coated. All larvae, whether coated or not, die, become pigmented and break into fragments. Ultrastructural observations revealed a progressive disintegration of the soft tissues of the immobilized larvae, characterized by autolytic changes and accumulation of pigment with histochemical characteristics of lipofuscin. The cuticle remains intact and excludes Trypan blue during the entire autolytic process, thus demonstrating that macrophage secretions do not participate in the disintegration process. When larval enzymes are inactivated by heat treatment and the larvae are injected i.p., no autolysis occurs and the internal organs remain recognizable. These larvae become coated over their entire length with several layers of macrophages and are progressively phagocytized by macrophages clustering at both ends. Different modes of nematode disintegration within the rodent host involving macrophages are discussed.