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.

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.

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.

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.

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.

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.

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.

Helicobacter pylori infection and atrophic gastritis in middle-aged Japanese residents of São Paulo and Lima.

BACKGROUND: Helicobacter pylori infection and atrophic gastritis (AG) are markedly more prevalent in Japan than in other industrialized countries, however, the reasons for such a high prevalence are not fully understood. To add to information on H. pylori infection and its association with AG, the authors studied Japanese living in less developed countries. METHODS: Cross-sectional surveys were conducted of randomly selected Japanese residents aged 40-59 years in São Paulo, Brazil and Lima, Peru. Serum IgG antibody to H. pylori and pepsinogen I (PGI) and II (PGII) were measured as markers of AG. RESULTS: The prevalence of H. pylori infection was similar in both populations, 77% (95% CI: 70-83) in São Paulo and 75% (95% CI: 65-82) in Lima, and was within the range of five populations in Japan from our previous study. However, the prevalence of AG, defined by PGI < 70 ng/ml and PGI/PGII < 3.0 was more prevalent among Japanese in São Paulo (39% [95% CI: 32-47]), than Japanese in Lima (18% [95% CI: 12-27]). This difference was not explained by sex, age, generation or H. pylori infection. CONCLUSIONS: Helicobacter pylori infection among Japanese in less developed countries was similar to Japanese in Japan, although prevalence of AG varied. Factors other than H. pylori infection are important in the development of AG among Japanese.

Estrogen and progesterone receptors in human papilloma virus-related cervical neoplasia.

Estrogen (ER) and progesterone (PR) receptors in the normal uterine cervix, cervical intraepithelial neoplasia and invasive carcinoma were studied in consecutive samples from Hospital do Cáncer, São Paulo, between 1996 and 1997. Tissue was collected by removing a fragment of the tumoral area using a 5-mm diameter biopsy punch, followed by removal of a macroscopically normal area as close as possible from the tumor. Histopathological confirmation was obtained for all specimens analyzed. A total of 24 normal tissues, 17 cases of cervical intraepithelial neoplasia and 7 of invasive carcinomas were studied. The ER/PR ratio was determined by immunohistochemistry using monoclonal antibodies specific for each receptor. Adjacent tissue slides were submitted to generic PCR for human papillomavirus (HPV) DNA detection followed by typing by dot blot hybridization. About half (45.8%) of the tumors were HPV DNA positive while 29.1% of the patients were also HPV positive in their respective normal tissue. ER was negative in the tumoral epithelium of 11 HPV-positive patients (P=0.04). There was a trend in the ER distribution in normal tissue that was opposite to that from lesions, but it was not statistically significant (P=0.069). No difference in ER distribution in stromal tissues was observed between HPV-positive and HPV-negative tissues. PR staining was negative in the epithelium of all cases studied. The results obtained from this small number of cases cannot be considered to be conclusive but do suggest that factors related to viral infection affect the expression of these ER/PR cervix receptors.

[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)

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.

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.

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.

Scanning electron microscopy of Leishmania major in Phlebotomus papatasi.

The morphology of Leishmania major parasites and their interactions with various regions of the alimentary canal of Phlebotomus papatasi were studied by scanning electron microscopy. Parasites were observed to undergo development initiated with the ingestion of amastigotes and culminating in a characteristic distribution of four distinct morphological forms in various parts of the alimentary canal: namely, large numbers of elongate nectomonads in the abdominal mid-gut, haptomonad forms attached to the cuticle of the stomodeal valve, small spherical forms attached to the esophagus and masses of short promastigotes, believed to be the infective forms, lying free in the anterior thoracic mid-gut and the esophagus.

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.