Epstein-Barr virus-positive gastric cancer: a distinct molecular subtype of the disease?

Abstract: Approximately 90% of the world population is infected by Epstein-Barr virus (EBV). Usually, it infects B lymphocytes, predisposing them to malignant transformation. Infection of epithelial cells occurs rarely, and it is estimated that about to 10% of gastric cancer patients harbor EBV in their malignant cells. Given that gastric cancer is the third leading cause of cancer-related mortality worldwide, with a global annual incidence of over 950,000 cases, EBV-positive gastric cancer is the largest group of EBV-associated malignancies. Based on gene expression profile studies, gastric cancer was recently categorized into four subtypes; EBV-positive, microsatellite unstable, genomically stable and chromosomal instability. Together with previous studies, this report provided a more detailed molecular characterization of gastric cancer, demonstrating that EBV-positive gastric cancer is a distinct molecular subtype of the disease, with unique genetic and epigenetic abnormalities, reflected in a specific phenotype. The recognition of characteristic molecular alterations in gastric cancer allows the identification of molecular pathways involved in cell proliferation and survival, with the potential to identify therapeutic targets. These findings highlight the enormous heterogeneity of gastric cancer, and the complex interplay between genetic and epigenetic alterations in the disease, and provide a roadmap to implementation of genome-guided personalized therapy in gastric cancer. The present review discusses the initial studies describing EBV-positive gastric cancer as a distinct clinical entity, presents recently described genetic and epigenetic alterations, and considers potential therapeutic insights derived from the recognition of this new molecular subtype of gastric adenocarcinoma.

Chagas' disease: selective affinity and cytotoxicity of Trypanosoma cruzi-immune lymphocytes to parasympathetic ganglion cells

The megaesophagus and megacolon endemic in South America are related , to Chagas' disease. These mega conditions are found in patients with chronic Chagas's infection, when the parasite is not demonstrable in the lesions. These are characterized by depopulation of parasympathetic ganglion cells, dilation and hypertrophy of the viscera. In the experiments described here we deminstrate a selective affinity and adherence of Trypanosoma cruzi-immune lymphocytes to myenteric, parasympathetic ganglion cells, leading to neuronolysis. None of these features are observed when non-immune lymphocytes from control rabbits are used, or when the immune lymphocytes are allowed to react with CNS neurons. This demonstration is an indication of the high degree of specificity of the destruction of parasympathetic neurons in Chagas' disease. We postulate that the T. cruzi-immune lymphocyte rejection of parasympathetic neurons, but not of CNS neurons, might be related to recognition of a cross-reacting antigenic determinant secreted only by the target neurons. In favor of this interpretation is the observation of lymphocytic infiltrates and parasympathetic ganglion cell destruction in chronic Chagas' infection in the absence of encephalitis.

Methodology in structural determination and synthesis of insect pheromone

By means of ethereal washing of insect pheromone glands of female moths, GC-MS detection along with microchemical reactions and electroantennogram (EAG) survey, six economically important insect species were targeted for pheromone identification. The discovery of a natural pheromone inhibitor, chemo-selectivity and species isolation by pheromone will be described. The modified triple bond migration and triethylamine liganded vinyl cuprate were applied for achiral pheromone synthesis in double bond formation. Some optically active pheromones and their stereoisomers were synthesized through chiral pool or asymmetric synthesis. Some examples of chiral recognition of insects towards their chiral pheromones will be discussed. A CaH2 and silica gel catalyzed Sharpless Expoxidation Reaction was found in shortening the reaction time.

Epidemiological risk sratification of malaria in the Américas

During the last years, malaria had a significant increase in Latin America, emerging again as one critical health problem in the Region of the Americas. More than 1.04 million new cases were reported in 1990. This resurgence of malaria needed a comprehensive strategy for its prevention and control. National malaria control programs recognized the epidemiological stratification of malaria as a valuable method to assist them in the recognition of local variations and factors that specifically contribute to the level and intensity of transmission in critical malarious areas. Also it serves as a useful instrument for the selection of needed malaria prevention and control activities. The principal feature of this approach is to provide a dynamic and ongoing process for assessing in the epidemiological importance of different risk factors (socio-economic, ecological, organizatuion of health services) in malaria transmission. health interventions are based on this assesment and are aimed directly at the reduction or elimination of the identified risk factors operating at the local level. Intersectorial co-participation and the integration of malaria programs in local health services are also important aspects of this public health approach.

The level of infestation with the vector of cattle babesiosis in Argentina

Studies were carried out to determine the differential aptitude to sustain the only vector of cattle babesiosis in Argentina, the tick Boophilus microplus, throughout the infested region of this country. Tick counts on Bos taurus cattle were used as the main criterion to classify favourable (F), intermediate (I) and unfavourable (U) areas for its development. The geographical limits of each area set up using data of non-parasitic tick stages, temperature, water balance and map recognition of flooded and unflooded zones. The F area contained 16.5 x 10 (elevado a sexta potência) ha with a cattle population of 6 x 10 (elevado a sexta potência); the I and U areas had 25 x 10 (elevado a sexta potência ha with 2.7 x 10 (elevado a sexta potência) cattle and 198 x 10 (elevado a sexta potência) with population of 2.4 x 10(elevado a sexta potência) cattle, respectively. Research on the relationship amongst Babesia-Boophilus-cattle is needed in the F area for tick development which coincides with the best region for cattle breeding.

Development of an immunoenzymatic assay using a monoclonal antibody against a 50-kDa catabolite from the P126 Plasmodium falciparum protein to the diagnosis of malaria infection

The WHO criterion of defering any donation of blood by a confirmed case of malaria for three years after cessation of therapy can not be applied in areas where malaria in endemic. For this reason we developed an immunoenzymatic assay for the detection of plasmodial antigens for blood screening in malararial endemic areas. So, we tested sera from 191 individuals. Among patients with active disease 100% of the cases of Plasmodium falciparum or mixed infections and 91.7% of those with P. vivax were positive for the presence of plasmodial antigens. The lower parasitaemia detected was 0.0003% for P. vivax malária. When the frequency of positive circulating malarial antigens was evaluated among asymptomatic and symptomatic individuals with negative TBS, positive results were found in respectively 38.7% and 17.7% of the individuals studied in the 30 days after confirmed malaria attack. Data provide by these assays have shown that ELISA seemed to be more sensitive than parasitological examination for malaria diagnosis. This test by virtue of its high sensivity and the facilities in processing a large number of specimens, can prove to be useful in endemic areas for the recognition of asymptomatic malaria and screening of blood donors.

Hepatitis B and C prevalences among blood donors in the south region of Brazil

The prevalence of hepatitis B and C infection has been determined in a seroepidemiological survey among blood donors from the south of Brazil (Florianópolis, State of Santa Catarina). These markers has also been correlated with the levels of alanine aminotransferase (ALT), a surrogate marker to prevent post-transfusion hepatitis. Sera from 5000 donors were randomly collected in the period of April to November 1991. The prevalences of HBsAg, anti-HBs and anti-HBc were respectively 0.78, 7.02 and 13.98. The anti-HCV prevalence after confirmation testing with line immunoassay (LIA), was 1.14. Normal values of ALT ( < = 32 U/ml) were found in 59.78, values slightly above the mean (ALT between 32-70 U/ml) in 37.74 and high values of ALT ( > = 70 U/ml) in 2.48. The positivity of anti-HCV antibodies increased with the elevation of ALT levels. This correlation was not observed in relation to HBsAg. There exists a diversity in the recognition of HCV epitopes among HCV positive donors. Via the confirmation test used, we could observe that 94.7 of donors recognize the structural core antigen. Besides that, we observed that 5.26 of the HCV reactive sera recognized only epitopes located in the NS4 and/or NS5 region, indicating the importance of these epitopes for the improvement of assays.

Acute respiratory infections in children living in two low income communities of Rio de Janeiro, Brazil

Community studies of non-hospitalized children are essential to obtain a more thorough understanding of acute respiratory infections (ARI) and provide important information for public health authorities. This study identified a total ARI incidence rate (IR) of 4.5 per 100 child-weeks at risk and 0.78 for lower respiratory tract infections (LRI). Disease duration averaged less than one week and produced a total time ill with ARI of 5.8% and for LRI 1.2%. No clear seasonal variation was observed, the sex-specific IR showed a higher proportion of boys becoming ill with ARI and LRI and the peak age-specific IR occurred in infants of 6-11 months. Correlation with risk factors of the child (breastfeeding, vaccination, diarrheal disease, undernourishment) and the environment (crowding, living conditions, maternal age and education) showed marginal increases in the rate ratios, making it difficult to propose clear-cuts targets for action to lower the ARI and LRI morbidity. The importance of an integral maternal-child health care program and public education in the early recognition of LRI is discussed.

The Changing Face of the Epidemiology of Tuberculosis due to Molecular Strain Typing: A Review

About one third of the world population is infected with tubercle bacilli, causing eight million new cases of tuberculosis (TB) and three million deaths each year. After years of lack of interest in the disease, World Health Organization recently declared TB a global emergency and it is clear that there is need for more efficient national TB programs and newly defined research priorities. A more complete epidemiology of tuberculosis will lead to a better identification of index cases and to a more efficient treatment of the disease. Recently, new molecular tools became available for the identification of strains of Mycobacterium tuberculosis (M. tuberculosis), allowing a better recognition of transmission routes of defined strains. Both a standardized restriction-fragment-length-polymorphism-based methodology for epidemiological studies on a large scale and deoxyribonucleic acids (DNA) amplification-based methods that allow rapid detection of outbreaks with multidrug-resistant (MDR) strains, often characterized by high mortality rates, have been developed. This review comments on the existing methods of DNA-based recognition of M. tuberculosis strains and their peculiarities. It also summarizes literature data on the application of molecular fingerprinting for detection of outbreaks of M. tuberculosis, for identification of index cases, for study of interaction between TB and infection with the human immunodeficiency virus, for analysis of the behavior of MDR strains, for a better understanding of risk factors for transmission of TB within communities and for population-based studies of TB transmission within and between countries

The Role of Protein Kinases in Antigen-activation of Peripheral Blood Mononuclear Cells of Schistosoma mansoni Infected Individuals

T cell recognition of antigens displayed on the surface of antigen presenting cell results in rapid activation of protein tyrosine kinases and kinase C. This process leads to second messengers, such as inositol phosphates and diacylgycerol, and phosphorylation of multiple proteins. The role of different protein kinases in the activation of peripheral blood mononuclear cells (PBMC) from Schistosoma mansoni infected individuals was evaluated using genistein and H-7, specific inhibitors of protein tyrosine kinase and kinase C, respectively. Our results showed that proliferation in response to soluble egg antigen or adult worm antigen preparation of S. mansoni was reduced when PBMC were cultured in presence of protein kinase inhibitors. Using these inhibitors on in vitro granuloma reaction, we also observed a marked reduction of granuloma index. Taken together, our results suggest that S. mansoni antigen activation of PBMC involves protein kinases activity

Evolution of the clinical and epidemiological knowledge about Chagas disease 90 years after its discovery

Three different periods may be considered in the evolution of knowledge about the clinical and epidemiological aspects of Chagas disease since its discovery: (a) early period concerning the studies carried out by Carlos Chagas in Lassance with the collaboration of other investigators of the Manguinhos School. At that time the disease was described and the parasite, transmitters and reservoirs were studied. The coexistence of endemic goiter in the same region generated some confusion about the clinical forms of the disease; (b) second period involving uncertainty and the description of isolated cases, which lasted until the 1940 decade. Many acute cases were described during this period and the disease was recognized in many Latin American countries. Particularly important were the studies of the Argentine Mission of Regional Pathology Studies, which culminated with the description of the Romaña sign in the 1930 decade, facilitating the diagnosis of the early phase of the disease. However, the chronic phase, which was the most important, continued to be difficult to recognize; (c) period of consolidation of knowledge and recognition of the importance of Chagas disease. Studies conducted by Laranja, Dias and Nóbrega in Bambuí updated the description of Chagas heart disease made by Carlos Chagas and Eurico Villela. From then on, the disease was more easily recognized, especially with the emphasis on the use of a serologic diagnosis; (d) period of enlargement of knowledges on the disease. The studies on denervation conducted in Ribeirão Preto by Fritz Köberle starting in the 1950 decade led to a better understanding of the relations between Chagas disease and megaesophagus and other visceral megas detected in endemic areas.

Antigenic community between Schistosoma mansoni and Biomphalaria glabrata: on the search of candidate antigens for vaccines

We have previously confirmed the presence of common antigens between Schistosoma mansoni and its vector, Biomphalaria glabrata. Cross-reactive antigens may be important as possible candidates for vaccine and diagnosis of schistosomiasis. Sera from outbred mice immunized with a soluble Biomphalaria glabrata antigen (SBgA) of non-infected B. glabrata snails recognized molecules of SBgA itself and S. mansoni AWA by Western blot. Recognition of several molecules of the SBgA were inhibited by pre-incubation with AWA (16, 30, 36, 60 and 155 kDa). The only specific molecule of AWA, inhibited by SBgA, was a 120 kDa protein. In order to determine which epitopes of SBgA were glycoproteins, the antigen was treated with sodium metaperiodate and compared with non-treated antigen. Molecules of 140, 60 and 24 kDa in the SBgA appear to be glycoproteins. Possible protective effects of the SBgA were evaluated immunizing outbred mice in two different experiments using Freund's Adjuvant. In the first one (12 mice/group), we obtained a significant level of protection (46%) in the total worm load, with a high variability in worm recovery. In the second experiment (22 mice/group), no significant protection was observed, neither in worm load nor in egg production per female. Our results suggest that SBgA constitutes a rich source of candidate antigens for diagnosis and prophylactic studies.

Identification of immunodominant epitopes of Schistosoma mansoni vaccine candidate antigens using human T cells

Paramyosin and Sm14 are two of the six antigens selected by the World Health Organization as candidates to compose a subunit vaccine against schistosomiasis. Both antigens are recognized by individuals naturally resistant to Schistosoma mansoni infection and induced protective immunity in the murine model. Three Sm14 epitopes and eleven paramyosin epitopes were selected by their ability to bind to different HLA-DR molecules using the TEPITOPE computer program, and these peptides were synthetically produced. The cellular recognition of Sm14 and paramyosin epitopes by peripheral blood mononuclear cells of individuals living in endemic area for schistosomiasis was tested by T cell proliferation assay. Among all Sm14 and paramyosin epitopes studied, Sm14-3 was preferentially recognized by individuals naturally resistant to S. mansoni infection while Para-5 was preferentially recognized by individuals resistant to reinfection. These two peptides represent promising antigens to be used in an experimental vaccine against schistosomiasis, since their preferential recognition by resistant individuals suggest their involvement in the induction of protective immunity.

Serological evidence of hepatitis E virus infection in different animal species from the Southeast of Brazil

Serological evidence of hepatitis E virus infection (HEV) has been observed in both humans and different animal species living in non-endemic areas, suggesting that animals could be important reservoir for virus transmission to man. Antibodies to HEV have been detected in some Brazilian population groups. Nevertheless, sporadic cases of acute HEV infection have never been reported. We collected 271 serum samples from several domestic animals and also from pig handlers from Southeast of Brazil in order to investigate the seroprevalence of HEV infection. Anti-HEV IgG was detected in cows (1.42%), dogs (6.97%), chickens (20%), swines (24.3%), and rodents (50%), as well as in pig handlers (6.3%). The recognition of swine HEV infections in pigs in many countries of the world led us to investigate a larger sample of pigs (n = 357) from the same Brazilian region with ages ranging from 1 to > 25 weeks. IgG anti-HEV was detected in 100% of 7-day old pigs. Following a gradual decline between weeks 2 and 8 (probably due to loss of maternal IgG), the prevalence then steady increased until it reached 97.3% of animals older than 25 weeks. Besides the detection of anti-HEV antibodies in different animal species, the results showed that swine HEV infection seems to be almost universal within this Brazilian pig population. This is the first report that shows evidences of HEV circulation in Brazilian animal species and pig handlers.

Virulence attenuation and phenotypic variation of Paracoccidioides brasiliensis isolates obtained from armadillos and patients

Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, the most important systemic mycosis in Latin America. The virulence profiles of five isolates of P. brasiliensis were studied in two different moments and correlated with some colonial phenotypic aspects. We observed a significant decrease in the virulence and an intense phenotypic variation in the mycelial colony. The recognition of all ranges of phenotypic and virulence variation of P. brasiliensis, as well as its physiological and genetic basis, will be important for a better comprehension of its pathogenic and epidemiological features.