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M Soares

Publications and source records attributed to M Soares.

At least 19 recordsLinked to original sources
PubMed2006

CDH1/E-cadherin germline mutations in early-onset gastric cancer.

BACKGROUND: Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear. AIMS: To examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC <50 years old). METHODS: 211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry. RESULTS: 1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer. CONCLUSION: This is the first population-based study, in a low-incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2-3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.

Adult↗
PubMed2005

Hyperglycemia induced by pharmacological activation of central serotonergic pathways depends on the functional integrity of brain CRH system and 5-HT3 receptors.

In the present study, we investigated the effect of central serotonergic pathway activation achieved through third ventricle injections of quipazine, a serotonergic agonist, on plasma glucose levels of fasted and fed adult Wistar male rats, whose third ventricles were canulated 7 days before the experiments. Central quipazine administration induced a significant increase in plasma glucose levels in fasted animals, but was unable to modify plasma glucose concentrations in fed rats. Pretreatment with alpha-helical CRH, a CRH antagonist, significantly attenuated quipazine-induced hyperglycemia. Pretreatment with two different 5-HT3 receptor antagonists, LY-278,584 and ondansetron, was also able to produce a significant reduction in the hyperglycemic response evoked by central administration of quipazine. None of the antagonists used was capable of modifying plasma glucose concentrations when injected alone into the third ventricle. Quipazine-treated, hyperglycemic animals did not show any increase in plasma insulin levels. We conclude that acute pharmacological serotonergic stimulation by quipazine produces hyperglycemia by mechanisms that require the functional integrity of both CRH and 5-HT3 receptors, and that impairment in insulin secretion and/or activity may explain hyperglycemia induced by third ventricle injections of quipazine.

Animals↗
PubMed2004

Prospective evaluation of the epidemiology, microbiology, and outcome of bloodstream infections in adult surgical cancer patients.

The aim of this study was to describe the epidemiology and microbiology of bloodstream infections (BSIs) among adult surgical cancer patients and to determine independent factors that influence in-hospital mortality. The study enrolled 112 consecutive episodes of BSIs in adult surgical cancer patients during a 26-month period. The median age of the patients was 64.5 years, and crude in-hospital mortality was 19.6%. The median time from surgery to the index blood culture was 11 days and from index blood culture to death was 4.5 days. Seventy-five percent of the patients had an advanced tumor disease, 36.6% were under intensive care, and 68.7% had a central venous catheter in place at the time the bloodstream infection was diagnosed. Associated infected sites were present in 57.1% of the episodes. There were 328 noninfectious co-morbid conditions. Poor performance status, weight loss, hypoalbuminemia, and ventilatory support accounted for 67.4% of them. There was a predominance of aerobic gram-negative bacilli (62%), followed by gram-positive cocci (26.6%) and fungi (9.3%). The observed mortality rates associated with these organism groups were similar (23.6% vs 15% vs 28.6%, respectively; P=0.44). The most frequent organisms were Enterobacter spp., coagulase-negative staphylococci, Klebsiella spp., Acinetobacter spp., and fungi. Nonfermentative strains predominated in patients with catheters. Thirty-five (30.2%) pathogens were considered resistant. There was no significant difference in the mortality rate between patients with resistant and those with nonresistant organisms (20% vs 26%, respectively; P=0.49). Logistic regression analysis showed > or = 4 co-morbid conditions, advanced tumor, thoracic surgery, catheter retention, and pulmonary infiltrates as independent predictors of mortality. Medical and infection control measures addressing certain variables amenable to intervention might reduce the negative impact of postoperative infectious morbidity and mortality of BSIs in adult surgical cancer patients.

Aged↗
PubMed2001

The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers.

Mutations in the extracellular domain of the 55-kD tumor-necrosis factor (TNF) receptor (TNFRSF1A), a key regulator of inflammation, define a periodic-fever syndrome, TRAPS (TNF receptor-associated periodic syndrome [MIM 142680]), which is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and/or conjunctivitis; some patients also develop systemic amyloidosis. Elsewhere we have described six disease-associated TNFRSF1A mutations, five of which disrupt extracellular cysteines involved in disulfide bonds; four other mutations have subsequently been reported. Among 150 additional patients with unexplained periodic fevers, we have identified four novel TNFRSF1A mutations (H22Y, C33G, S86P, and c.193-14 G-->A), one mutation (C30S) described by another group, and two substitutions (P46L and R92Q) present in approximately 1% of control chromosomes. The increased frequency of P46L and R92Q among patients with periodic fever, as well as functional studies of TNFRSF1A, argue that these are low-penetrance mutations rather than benign polymorphisms. The c.193-14 G-->A mutation creates a splice-acceptor site upstream of exon 3, resulting in a transcript encoding four additional extracellular amino acids. T50M and c.193-14 G-->A occur at CpG hotspots, and haplotype analysis is consistent with recurrent mutations at these sites. In contrast, although R92Q also arises at a CpG motif, we identified a common founder chromosome in unrelated individuals with this substitution. Genotype-phenotype studies identified, as carriers of cysteine mutations, 13 of 14 patients with TRAPS and amyloidosis and indicated a lower penetrance of TRAPS symptoms in individuals with noncysteine mutations. In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes.

Alternative Splicing↗
PubMed2001

Recombinant human tumor antigen MUC1 expressed in insect cells: structure and immunogenicity.

MUC1, a member of the mucin family of molecules, is a transmembrane glycoprotein abundantly expressed on human ductal epithelial cells and tumors originating from those cells. MUC1 expressed by malignant cells is aberrantly O-glycosylated. Differences in O-glycosylation of the tandem repeat region of MUC1 make tumor and normal forms of this antigen immunologically distinct. The tumor-specific glycoform is, therefore, expected to be a good target for immunotherapy and a good immunogen for generation of antitumor immune responses. We have generated a renewable source of this glycoform by expressing MUC1 cDNA in Sf-9 insect cells using a baculovirus vector. This form of MUC1 (BV-MUC1) is O-glycosylated at a very low level, approximately 0.3% (w/w), and this is not due to the lack of appropriate glycosylotransferases in insect cells. Peptidyl GalNAc-transferases isolated from Sf-9 cells were able to glycosylate in vitro a synthetic MUC1 peptide as efficiently as the transferases isolated from human milk. Neither preparation of peptidyl GalNAc-transferases, however, was able to glycosylate BV-MUC1. This underglycosylated recombinant MUC1 mimics underglycosylated MUC1 on human tumor cells and could serve as an immunogen to stimulate responses that would recognize MUC1 on tumor cells. To test this we immunized mice with Sf-9 cells expressing BV-MUC1. Sera from immunized mice recognized MUC1 on human tumor cells. We also generated MUC1-specific T cells that proliferated in response to synthetic MUC1 peptide.

Amino Acid Sequence↗
PubMed2001

Appropriateness of emergency department visits in a Portuguese university hospital.

STUDY OBJECTIVE: There are no studies in Portugal supporting a common claim that most emergency department visits are inappropriate. The aim of this study was to determine the prevalence of and to evaluate factors associated with an appropriate ED visit in a major public hospital. METHODS: A cross-sectional prospective study was performed at a public university hospital ED. Data for demographic variables, duration of complaint, transfer from other medical sources, and previous medical care for the same complaints were collected by interviewing all patients who arrived at the ED within a consecutive period of at least 24 hours. Data for diagnostic tests, treatment performed, and final patient destination were collected by triage records review. An appropriate ED visit was defined by explicit criteria: interhospital transfer, patient death at the ED, hospitalization, and diagnostic tests or treatments performed. RESULTS: The study included 5,818 adult patients. The prevalence of an appropriate ED visit, by use of our criteria, was 68.7%. Sex was an effect modifier. According to this study, determinants of an appropriate visit for men and women were age 60 years or older and complaints of 24 hours or less and in women but not in men, retired from work and with arrival between midnight and 8 AM. CONCLUSIONS: In a university hospital in Oporto, the majority of ED visits were appropriate according to explicit criteria. Some variables may be associated with appropriateness of ED visits. A duration of the complaint 24 hours or less along with an arrival between midnight and 8 AM in women and age 60 years or older in men were the most important determinants.

Adult↗
PubMed2000

Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.

The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress. The anti-inflammatory properties of heme oxygenase-1 may serve as a basis for this cytoprotection. We demonstrate here that carbon monoxide, a by-product of heme catabolism by heme oxygenase, mediates potent anti-inflammatory effects. Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10. Carbon monoxide mediated these anti-inflammatory effects not through a guanylyl cyclase-cGMP or nitric oxide pathway, but instead through a pathway involving the mitogen-activated protein kinases. These data indicate the possibility that carbon monoxide may have an important protective function in inflammatory disease states and thus has potential therapeutic uses.

Animals↗
PubMed1999

Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions.

Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant type of amyloidosis resulting from the deposition of transthyretin (ATTR) variants in the peripheral and autonomic nervous systems. ATTR V30M-associated FAP exhibits marked genetic anticipation in some families, with clinical symptoms developing at an earlier age in successive generations. The genetic basis of this phenomenon in FAP is unknown. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. We have used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the ten possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the ten trinucleotide repeats analyzed. The distribution of the maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. The present data do not support a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP.

Adolescent↗
PubMed1999

An encyclopedia of mouse genes.

The laboratory mouse is the premier model system for studies of mammalian development due to the powerful classical genetic analysis possible (see also the Jackson Laboratory web site, http://www.jax.org/) and the ever-expanding collection of molecular tools. To enhance the utility of the mouse system, we initiated a program to generate a large database of expressed sequence tags (ESTs) that can provide rapid access to genes. Of particular significance was the possibility that cDNA libraries could be prepared from very early stages of development, a situation unrealized in human EST projects. We report here the development of a comprehensive database of ESTs for the mouse. The project, initiated in March 1996, has focused on 5' end sequences from directionally cloned, oligo-dT primed cDNA libraries. As of 23 October 1998, 352,040 sequences had been generated, annotated and deposited in dbEST, where they comprised 93% of the total ESTs available for mouse. EST data are versatile and have been applied to gene identification, comparative sequence analysis, comparative gene mapping and candidate disease gene identification, genome sequence annotation, microarray development and the development of gene-based map resources.

Animals↗
PubMed1999

Frequencies of platelet-specific alloantigen systems 1-5 in three distinct ethnic groups in Brazil.

The human platelet antigen (HPA) systems are related to immune platelet disorders as well as to the development of occlusive vascular disease. Several distinct biallelic HPA systems are known, and a heterogeneous distribution of HPA alleles has been described among distinct ethnic groups. In this study we genotyped 320 carefully selected individuals from three distinct ethnic groups in Brazil (Caucasians, Blacks and Amazonian Indians) for the HPA-1, -2, -3, -4 and -5 systems. A similar prevalence for all HPA alleles was found in Brazilians of Caucasian and Black descent. These data contrast with those reported for similar ethnic groups in other countries. Among the Amazonian Indians, no b allele of the HPA-1, -4 and -5 systems was identified. The data presented here could be useful in the diagnosis of alloimmune platelet disease, in genetic counselling and in the development of screening programmes for HPA-related diseases.

Adolescent↗
PubMed1999

Variation in the salivary peptide, maxadilan, from species in the Lutzomyia longipalpis complex.

Maxadilan is an approximately 7kDa peptide that occurs in the saliva of the sand fly Lutzomyia longipalpis. This peptide is a potent vasodilator and may also have immunomodulatory effects related to the pathogenesis of leishmanial infections. Variation in the primary DNA and inferred amino acid sequence of maxadilan is reported. Differences were found within and among natural field populations as well as among sibling species. Extensive amino acid sequence differentiation, up to 23%, was observed among maxadilan from different populations. This is a remarkable degree of polymorphism considering the small size of this peptide. The vasodilatory activity of maxadilan was equivalent among recombinant maxadilan variants. All maxadilan variants induce interleukin-6. Predicted secondary structure and hydrophobicity plots suggest that these characteristics are conserved among variant peptides. However, profiles based on the antigenic index do differ among peptides.

Animals↗
PubMed1999

Distinct human immunodeficiency virus strains in the bone marrow are associated with the development of thrombocytopenia.

We analyzed bone marrow and blood from human immunodeficiency virus type 1 (HIV-1)-infected individuals and described the HIV-1 quasispecies in these cellular compartments. HIV-1 isolates from the bone marrow of thrombocytopenic patients contained distinct amino acids in the V3 loop and infected T-cell lines, implicating this virus in the development of thrombocytopenia.

Amino Acid Sequence↗
PubMed1999

[The Institutional Program for Health and Environment in the development process of the Oswaldo Cruz foundation].

The objective of this paper is to show the development program about health and environment in an institution of academic research and teaching, technological development and services. We analyse data from the register of projects in health and environment in the development process as the thematic axis for this program. We show the sectors which the projects are related, the key words of research and teaching, the construction of thematic axis that should guide and the different approach of interdisciplinary. At the end we show the challenges and perspectives for an interdisciplinar work about health and environment in an academic research and teaching institution.

Brazil↗
PubMed1998

Detection of clonal Hodgkin and Reed-Sternberg cells with identical somatically mutated and rearranged VH genes in different biopsies in relapsed Hodgkin's disease.

Hodgkin's disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg (H-RS) cells are rare and surrounded by abundant reactive cells. Single-cell analyses showed that H-RS cells regularly bear clonal Ig gene rearrangements. However, there is little information on the clinical evolution of HD in a given patient. In this study, we used the single-cell polymerase chain reaction (PCR) to identify H-RS cells with clonal Ig gene rearrangements in biopsy specimens of patients with relapsed HD. The obtained clonal variable region heavy-chain (VH) gene rearrangements were used to construct tumor-clone-specific oligonucleotides spanning the complementarity determining region (CDR) III and somatically mutated areas in the rearranged VH gene. A number of biopsies were obtained during a period of 3 years from two HD patients. H-RS cells with identical VH rearrangements were detected in two separate infiltrated lymph nodes from one patient with nodular sclerosis HD. In a second patient with mixed cellularity HD subtype, clonal VH rearrangements with identical sequences were detected in infiltrated spleen and two lymph node biopsies. Despite the high sensitivity of the PCR method used (one clonal cell in 10(5) mononuclear cells), residual H-RS cells were not found in peripheral blood, leukapheresis material, purified CD34(+) stem cells or bone marrow. The results show that different specimens from relapsed patients suffering from classical HD carry the same clonotypic IgH rearrangements with identical somatic mutations, demonstrating the persistence and the dissemination of a clonal tumor cell population. Thus, PCR assays with CDRIII-specific probes derived from clonal H-RS cells are of clinical importance in monitoring the dissemination of HD and tumor progression and could be useful for analysis of minimal residual disease after autologous stem cell transplantation.

Adult↗
PubMed1998

Differential inhibition of B-cell development and xenoreactive natural antibody production by administration of anti-mu or anti-delta monoclonal antibodies in adult rats.

BACKGROUND: Given the role of xenoreactive natural antibodies (XNA) in the pathogenesis of xenograft rejection, we tested whether the administration of anti-mu or anti-delta monoclonal antibodies (mAbs) in adult rats would suppress the generation of XNA. METHODS: Adult LOU/C (Igkappa-1a) rats were treated with anti-mu or anti-delta mAbs after nonlethal total body irradiation and bone marrow transplantation from congenic LOU/C (Igkappa-1b) rats. The differentiation of donor bone marrow (BM)-driven Igkappa-1b+ B cells and XNA production were analyzed. RESULTS: Both anti-mu and anti-delta mAbs arrested B-cell differentiation in the BM. In anti-mu-treated rats, there was a total depletion of donor-driven, peripheral Igkappa-1b+ B cells, secreting cells, and circulating XNA of the Igkappa-1b allotype. In anti-delta-treated rats, a significant number of Igkappa-1b+ B cells, which did not express membrane IgD, "escaped" deletion and partially repopulated peripheral lymphoid organs. This B-cell population was active in the production of XNA, as revealed by the high serum levels of XNA in these animals. CONCLUSIONS: Anti-mu administration resulted in arrest of B-cell differentiation and in down-regulation of IgM and IgG XNA production in adult rats. These data suggest that the use of anti-mu mAbs may be a useful approach to suppress the production of XNA and prevent xenograft rejection. Furthermore, we suggest that the B-cell population responsible for the production of XNA in adult rats belongs to a B-cell lineage expressing low levels of membrane IgD and "escaping" deletion in the BM upon anti-delta treatment.

Animals↗
PubMed1998

A20 inhibits NF-kappaB activation in endothelial cells without sensitizing to tumor necrosis factor-mediated apoptosis.

Expression of the NF-kappaB-dependent gene A20 in endothelial cells (EC) inhibits tumor necrosis factor (TNF)-mediated apoptosis in the presence of cycloheximide and acts upstream of IkappaBalpha degradation to block activation of NF-kappaB. Although inhibition of NF-kappaB by IkappaBalpha renders cells susceptible to TNF-induced apoptosis, we show that when A20 and IkappaBalpha are coexpressed, the effect of A20 predominates in that EC are rescued from TNF-mediated apoptosis. These findings place A20 in the category of "protective" genes that are induced in response to inflammatory stimuli to protect EC from unfettered activation and from undergoing apoptosis even when NF-kappaB is blocked. From a therapeutic perspective, genetic engineering of EC to express an NF-kappaB inhibitor such as A20 offers the mean of achieving an anti-inflammatory effect without sensitizing the cells to TNF-mediated apoptosis.

Adenoviridae↗
PubMed1998

Retroviral expression of MUC-1 human tumor antigen with intact repeat structure and capacity to elicit immunity in vivo.

MUC-1 mucin is an epithelial cell antigen whose aberrant expression plays a role in autoimmunity and tumor immunity and is thus an attractive candidate for immunotherapy of gene therapy. Because the MUC-1 cDNA is composed almost entirely of 60-bp tandem repeats and is susceptible to homologous recombination, it presents a special challenge to cloning and expression in viral vectors. Nevertheless, we have been successful in constructing a retroviral vector (MFG-MUC-1) with a 22-tandem repeat MUC-1 cDNA. Both stable and transient packaging cell lines are capable of producing high-titer retroviruses that can transfer the expression of MUC-1 to murine 3T3 cells. Transduced cells express uniformly high levels of MUC-1 on their surface, and western blot analysis reveals that the molecule expressed is of full length and extensively glycosylated. We have used the MFG-MUC-1 vector to stably transduce an immortalized murine dendritic cell line and show that immunization of mice with transduced cells elicits specific immune responses to mucin. The ability of this vector to transfer expression of the MUC-1 tumor antigen to potent antigen-presenting cells is expected to be of use in the immunotherapy of epithelial cancers.

3T3 Cells↗