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Papers by paulo fidalgo
GE - Portuguese Journal of Gastroenterology
Breast cancer · Invasive lobular carcinoma · Colonic metastases Envolvimento tardio do cólon por ... more Breast cancer · Invasive lobular carcinoma · Colonic metastases Envolvimento tardio do cólon por carcinoma lobular da mama: um diagnóstico a considerar!
The American Journal of Clinical Nutrition, Nov 1, 2008
Background: Polymorphisms located in genes involved in the metabolism of folate and some methyl-r... more Background: Polymorphisms located in genes involved in the metabolism of folate and some methyl-related nutrients are implicated in colorectal cancer (CRC). Objective: We evaluated the association of 3 genetic polymorphisms [C677T MTHFR (methylene tetrahydrofolate reductase), A2756G MTR (methionine synthase), and C1420T SHMT (serine hydroxymethyltransferase)] with the intake of methyl-donor nutrients in CRC risk. Design: Patients with CRC (n ҃ 196) and healthy controls (n ҃ 200) matched for age and sex were evaluated for intake of methyl-donor nutrients and the 3 polymorphisms. Results: Except for folate intake, which was significantly lower in patients (P ҃ 0.02), no differences were observed in the dietary intake of other methyl-donor nutrients between groups. High intake of folate (406.7 g/d) was associated with a significantly lower risk of CRC (odds ratio: 0.67; 95% CI: 0.45, 0.99). The A2756G MTR polymorphism was not associated with the risk of developing CRC. In contrast, homozygosity for the C677T MTHFR variant (TT) presented a 3.0-fold increased risk of CRC (95% CI: 1.3, 6.7). Similarly, homozygosity for the C1420T SHMT polymorphism also had a 2.6-fold increased risk (95% CI: 1.1, 5.9) of developing CRC. When interactions between variables were studied, low intake of all methyl-donor nutrients was associated with an increased risk of CRC in homozygous participants for the C677T MTHFR polymorphism, but a statistically significant interaction was only observed for folate (odds ratio: 14.0; 95% CI: 1.8, 108.5). No significant associations were seen for MTR or SHMT polymorphisms. Conclusion: These results show an association between the C677T MTHFR variant and different folate intakes on risk of CRC.
Revista Portuguesa De Cirurgia, 2009
Cancer, Nov 1, 1995
Studies using DNA technology have reported the presence of human papillomavirus (HPV) DNA in esop... more Studies using DNA technology have reported the presence of human papillomavirus (HPV) DNA in esophageal carcinomas, suggesting that it could play a role in the pathogenesis of this tumor. In the present study, in addition to DNA from neoplasms, normal mucosa was screened for viral DNA, assuming that this would increase HPV detection substantially. Seventeen patients with esophageal carcinoma and 10 control subjects were studied. In 8 of the patients, normal mucosa was also available. Polymerase chain reaction (PCR) was performed using primers for the E6 region of HPV-16 and HPV-18. Koilocytosis, a commonly accepted histopathologic marker of viral infection, was studied, and results were correlated with PCR findings. DNA from neoplastic lesions was positive for HPV-16 and HPV-18 in 8 of 16 (50%) and in 3 of 16 (18.8%), respectively. When tumor tissue and normal mucosa were available, PCR results were 3 of 8 (37.5%), 5 of 8 (62.5%), and 8 of 8 (100%) for HPV-16, in tumor, normal mucosa, and both. For HPV-18, results were 0 of 8 (0%), 5 of 8 (62.5%), and 5 of 8 (62.5%), respectively. In comparison with tumor samples, positivity in normal mucosa was increased for HPV-18 and for both viral genotypes (P = 0.01). No amplification was obtained in the control group. Koilocytosis was present in 33% of the cases. These results suggested a high prevalence of HPV in esophageal carcinoma. The detection rate is significantly higher in normal mucosa specimens, suggesting that infection probably antedates tumor development. Koilocytosis was substantially less sensitive than PCR.
Gene Chromosome Cancer, 1999
Germline mutations that give rise to premature termination codons in mRNAs have frequently been a... more Germline mutations that give rise to premature termination codons in mRNAs have frequently been associated with aberrant processing of the nascent transcripts. This can take the form either of nonsense-mediated mRNA decay or of aberrant splicing of the pre-mRNA. In a family affected by hereditary nonpolyposis colorectal cancer, a two-nucleotide deletion in codon 659, which introduces a frameshift and a new stop codon in exon 17 of the DNA mismatch repair gene MLH1, has been reported to lead to skipping of the exon. We now report that this phenomenon occurs also when there are missense or nonsense mutations in this codon. Our results thus suggest that in aberrant splicing the nature of the mutation may be less important than its position within the exon. These findings are of importance to mutation interpretation, as they imply that aberrant splicing could be associated even with silent mutations that do not lead to amino acid substitutions. Genes Chromosomes Cancer 26:372-375, 1999.
Gastroenterology, 2003
Background&Aim: Small intestinal Paneth cells contnbute to mucosal innate immunity by sensing bac... more Background&Aim: Small intestinal Paneth cells contnbute to mucosal innate immunity by sensing bactena and secreting microbicidaI peptides, particularly a-defensins (Nature Immunol l: 113, 2000). Our aims were to investigate the expression and function of Toll-like receptor (TLR)s and related molecules in crypts of human small intestine. Methods: Ileal mucosa were obtained from surgical specimens resected from patients with colon cancer with normal ileum under informed consent. Intact crypts were isolated by standard EDTA dissociation, and further collagenase dissociation was conducted to prepare crypt single cell s0spensions. RT-PCR experiments were performed on individual crypts or isolated Paneth cells to assay for TLRI-10, CD14, MD2 and MyD88 mRNAs. Specific TLRs were immunocolocalized in isolated crypts and in Paneth cells with a-defensin HD5 using anti-TLR-2 and TLR-4 antibodies and confocal microscopic analysis. Isolated intact crypts were exposed to I x l03 S. typhimurium CFU/crypt to induce Paneth cell secretion. Secretions were assayed for bactericidal activity against defensin sensitive S. typhimurium phoP-and for HD5 secretion by western blot analysis. Inhibition assay was performed using anti-TLR2 neutralizing antibody in the secretion assay system Results: TLR1-8, TLR10, CD14 and MyD88, but not M02 mRNAs were detected in single isolated crypts and isolated Paneth cells. TLR2 and ]-LR4 expression was restricted to Paneth cells in the isolated crypts. TLR4 staining in single Paneth cells was localized at the membrane surface and also near secretory granules, a-Defensin secretion by Paneth cells in response to bacteria was inhibited by TLR2 antibody pre-treatment as judged by the diminished bactencidal activity and reduced secretion of HD5 in western blots. Conclusion: Paneth cells in human small intestinal crypts express Toll-like receptors that appear to be implicated in ex vivo responses to bacterial exposure.
Revista De Investigacion Centro De Investigaciones Para La Regulacion De Poblaciones De Organismos Nocivos, 1990
Introdução: Em muitos Centros, a vigilância pós-operatória de doentes com carcinoma do cólon e re... more Introdução: Em muitos Centros, a vigilância pós-operatória de doentes com carcinoma do cólon e recto (CCR) foi desenvolvida na expectativa de se obter maior percentagem de diagnósticos pré-sintomáticos de recidiva, aumentar o número de doentes que podem beneficiar de uma nova tentativa de ressecção e prolongar a sobrevivência. Objectivos: Avaliar a sensibilidade da metodologia diagnósfica e a eficácia de um programa de vigilância na defecção e tratamento de recidiva de CCR. Métodos: Entre 1989-93, 218 doentes submetidos a ressecção curativa de CCR foram vigiados de acordo com um protocolo. Resultados: Registou-se recidiva em 54 (25 %) doentes, 61 % encontrando-se assintomáticos. A sensibilidade dos métodos de rasfreio ou diagnóstico foi: marcadores tumorais -85 % ; tomografia computorizada -91 %; ecografia/enzimologia hepática -75%/40%, respectivamente. A ressecção foi possível em 13 doentes (24%): anastomóticas -40%; metásfases hepáticas -29%. A probabilidade de ressecção não diferiu entre as recidivas sintomáticas e assintomáticas mas verificou-se maior sobrevivência dos doentes com recidivas ressecadas. Conclusões: Pelo seu baixo custo e elevada sensibilidade, os marcadores tumorais são o método de escolha para o rastreio de recidiva. A maioria das recidivas foram diagnosticadas em fase assintomática, mas este resultado não conduziu ao aumento da ressecabilidade. Contudo, um pequeno número de doentes beneficiou de nova ressecção com melhoria na sobrevivência.
INTRODUCTION: Bi-allelic germ-line mutations in the human homolog of MutY (MYH) gene cause the au... more INTRODUCTION: Bi-allelic germ-line mutations in the human homolog of MutY (MYH) gene cause the autosomal recessive inherited syndrome MYH associated polyposis (MAP). AIMS & METHODS: To access the phenotypic features of individuals presenting biallelic MYH germline mutations. We studied 21 patients (10M:11F, mean age of 43.5 years – 23–75) from 17 unrelated families. Patient's family history, number and histology of colonic lesions and extra-colonic manifestations were evaluated. RESULTS: 17 patients were homozygous or compound heterozygous for mutations in MYH hotspots Y165C and G382D. 1 patient was heterozygous for the Y165/int4 mutation and 3 patients were homozygous for other mutations (1103delC and R38X). 6 patients presented more than 100 adenomas and the others between 6 and 100 adenomas. 85.7% of patients presented more than 20 adenomas. CRC ocurred in 14/21 (66.6%) of and multiple cancers in 5 of patients at presentation. Age of CRC diagnosis was 47.5 years. 20/21 (95.2%...
United European Gastroenterology Journal, 2015
Introduction: Although colorectal cancer (CRC) has often been regarded as a single entity, differ... more Introduction: Although colorectal cancer (CRC) has often been regarded as a single entity, different pathways may lead to macroscopically similar cancers. These pathways may evolve into a patchy colonic field defect that we aimed to study in consecutive CRC patients. Methods: In a single-center, observational, prospective study, consecutive CRC patients were included if surgery and a perioperative colonoscopy were planned. Personal and familial history data were collected. Tumors were studied for microsatellite instability (MSI) status, DNA repair protein expression (DRPE) and presence of BRAF and/or APC mutations.
E se o fatalismo popular, expresso na ideia de destino quase inelutável, representasse -e antecip... more E se o fatalismo popular, expresso na ideia de destino quase inelutável, representasse -e antecipasse -afinal uma intuição daquilo que só agora começamos a descortinar? O que há de novo então na visão da carcinogénese que nos empurra, de forma surpreendente, para o fatalismo da alma lusitana? A questão põe-se agora em saber qual é o momento ou idade da sua iniciação e quais são os tempos de acumulação de eventos subsequentes. Os dados forçam-nos a admitir que a iniciação do cancro do cólon esporádico pode estar afinal inscrita de forma muito precoce na constituição do indivíduo, através de uma sementeira de variantes alélicas discretas, escondi-das numa grande massa de células estaminais do epitélio cólico. A expressão discreta tem aqui, evidentemente, uma conotação sobretudo de diferença binária, categóri-ca, radical, mesmo que de uma pequena amplitude de grau. De tal forma é discreta essa variação estrutural que o epitélio nos surge como entidade morfologicamente homogénea, mesmo ...
Acta médica portuguesa
The pattern of alcohol consumption has been studied among 92 males, workers in a factory of the L... more The pattern of alcohol consumption has been studied among 92 males, workers in a factory of the Lisbon area. In this population there were three groups of ethanol consumers: I--non consumers, 6%; II--medium, up to 80g/day, 68%; III--heavy consumers, more than 80g/day, 26%. Another group (IV) was considered, for reference, with 23 patients with heavy alcoholism in the outpatients of an alcoholic addicts clinic. Besides the clinical questionnaire and medical examination, the following methods have been used and analysed: brief MAST; Le Gô, Mean Corpuscular Volume (MCV), serum glutamic oxalacetic Trasaminase (SGOT), and gama-glutamyl transpepticlase (gamma GT). The mean ethanol consumption in group IV was significantly higher than in group III (p less than 0.005), and in group III higher than in group II (p less than 0.001). Group IV demarked itself form group III due to a higher prevalence of symptoms of physical dependence (p less than 0.001), and of consumption of tranquilizers (p l...
GE - Portuguese Journal of Gastroenterology
Breast cancer · Invasive lobular carcinoma · Colonic metastases Envolvimento tardio do cólon por ... more Breast cancer · Invasive lobular carcinoma · Colonic metastases Envolvimento tardio do cólon por carcinoma lobular da mama: um diagnóstico a considerar!
The American Journal of Clinical Nutrition, Nov 1, 2008
Background: Polymorphisms located in genes involved in the metabolism of folate and some methyl-r... more Background: Polymorphisms located in genes involved in the metabolism of folate and some methyl-related nutrients are implicated in colorectal cancer (CRC). Objective: We evaluated the association of 3 genetic polymorphisms [C677T MTHFR (methylene tetrahydrofolate reductase), A2756G MTR (methionine synthase), and C1420T SHMT (serine hydroxymethyltransferase)] with the intake of methyl-donor nutrients in CRC risk. Design: Patients with CRC (n ҃ 196) and healthy controls (n ҃ 200) matched for age and sex were evaluated for intake of methyl-donor nutrients and the 3 polymorphisms. Results: Except for folate intake, which was significantly lower in patients (P ҃ 0.02), no differences were observed in the dietary intake of other methyl-donor nutrients between groups. High intake of folate (406.7 g/d) was associated with a significantly lower risk of CRC (odds ratio: 0.67; 95% CI: 0.45, 0.99). The A2756G MTR polymorphism was not associated with the risk of developing CRC. In contrast, homozygosity for the C677T MTHFR variant (TT) presented a 3.0-fold increased risk of CRC (95% CI: 1.3, 6.7). Similarly, homozygosity for the C1420T SHMT polymorphism also had a 2.6-fold increased risk (95% CI: 1.1, 5.9) of developing CRC. When interactions between variables were studied, low intake of all methyl-donor nutrients was associated with an increased risk of CRC in homozygous participants for the C677T MTHFR polymorphism, but a statistically significant interaction was only observed for folate (odds ratio: 14.0; 95% CI: 1.8, 108.5). No significant associations were seen for MTR or SHMT polymorphisms. Conclusion: These results show an association between the C677T MTHFR variant and different folate intakes on risk of CRC.
Revista Portuguesa De Cirurgia, 2009
Cancer, Nov 1, 1995
Studies using DNA technology have reported the presence of human papillomavirus (HPV) DNA in esop... more Studies using DNA technology have reported the presence of human papillomavirus (HPV) DNA in esophageal carcinomas, suggesting that it could play a role in the pathogenesis of this tumor. In the present study, in addition to DNA from neoplasms, normal mucosa was screened for viral DNA, assuming that this would increase HPV detection substantially. Seventeen patients with esophageal carcinoma and 10 control subjects were studied. In 8 of the patients, normal mucosa was also available. Polymerase chain reaction (PCR) was performed using primers for the E6 region of HPV-16 and HPV-18. Koilocytosis, a commonly accepted histopathologic marker of viral infection, was studied, and results were correlated with PCR findings. DNA from neoplastic lesions was positive for HPV-16 and HPV-18 in 8 of 16 (50%) and in 3 of 16 (18.8%), respectively. When tumor tissue and normal mucosa were available, PCR results were 3 of 8 (37.5%), 5 of 8 (62.5%), and 8 of 8 (100%) for HPV-16, in tumor, normal mucosa, and both. For HPV-18, results were 0 of 8 (0%), 5 of 8 (62.5%), and 5 of 8 (62.5%), respectively. In comparison with tumor samples, positivity in normal mucosa was increased for HPV-18 and for both viral genotypes (P = 0.01). No amplification was obtained in the control group. Koilocytosis was present in 33% of the cases. These results suggested a high prevalence of HPV in esophageal carcinoma. The detection rate is significantly higher in normal mucosa specimens, suggesting that infection probably antedates tumor development. Koilocytosis was substantially less sensitive than PCR.
Gene Chromosome Cancer, 1999
Germline mutations that give rise to premature termination codons in mRNAs have frequently been a... more Germline mutations that give rise to premature termination codons in mRNAs have frequently been associated with aberrant processing of the nascent transcripts. This can take the form either of nonsense-mediated mRNA decay or of aberrant splicing of the pre-mRNA. In a family affected by hereditary nonpolyposis colorectal cancer, a two-nucleotide deletion in codon 659, which introduces a frameshift and a new stop codon in exon 17 of the DNA mismatch repair gene MLH1, has been reported to lead to skipping of the exon. We now report that this phenomenon occurs also when there are missense or nonsense mutations in this codon. Our results thus suggest that in aberrant splicing the nature of the mutation may be less important than its position within the exon. These findings are of importance to mutation interpretation, as they imply that aberrant splicing could be associated even with silent mutations that do not lead to amino acid substitutions. Genes Chromosomes Cancer 26:372-375, 1999.
Gastroenterology, 2003
Background&Aim: Small intestinal Paneth cells contnbute to mucosal innate immunity by sensing bac... more Background&Aim: Small intestinal Paneth cells contnbute to mucosal innate immunity by sensing bactena and secreting microbicidaI peptides, particularly a-defensins (Nature Immunol l: 113, 2000). Our aims were to investigate the expression and function of Toll-like receptor (TLR)s and related molecules in crypts of human small intestine. Methods: Ileal mucosa were obtained from surgical specimens resected from patients with colon cancer with normal ileum under informed consent. Intact crypts were isolated by standard EDTA dissociation, and further collagenase dissociation was conducted to prepare crypt single cell s0spensions. RT-PCR experiments were performed on individual crypts or isolated Paneth cells to assay for TLRI-10, CD14, MD2 and MyD88 mRNAs. Specific TLRs were immunocolocalized in isolated crypts and in Paneth cells with a-defensin HD5 using anti-TLR-2 and TLR-4 antibodies and confocal microscopic analysis. Isolated intact crypts were exposed to I x l03 S. typhimurium CFU/crypt to induce Paneth cell secretion. Secretions were assayed for bactericidal activity against defensin sensitive S. typhimurium phoP-and for HD5 secretion by western blot analysis. Inhibition assay was performed using anti-TLR2 neutralizing antibody in the secretion assay system Results: TLR1-8, TLR10, CD14 and MyD88, but not M02 mRNAs were detected in single isolated crypts and isolated Paneth cells. TLR2 and ]-LR4 expression was restricted to Paneth cells in the isolated crypts. TLR4 staining in single Paneth cells was localized at the membrane surface and also near secretory granules, a-Defensin secretion by Paneth cells in response to bacteria was inhibited by TLR2 antibody pre-treatment as judged by the diminished bactencidal activity and reduced secretion of HD5 in western blots. Conclusion: Paneth cells in human small intestinal crypts express Toll-like receptors that appear to be implicated in ex vivo responses to bacterial exposure.
Revista De Investigacion Centro De Investigaciones Para La Regulacion De Poblaciones De Organismos Nocivos, 1990
Introdução: Em muitos Centros, a vigilância pós-operatória de doentes com carcinoma do cólon e re... more Introdução: Em muitos Centros, a vigilância pós-operatória de doentes com carcinoma do cólon e recto (CCR) foi desenvolvida na expectativa de se obter maior percentagem de diagnósticos pré-sintomáticos de recidiva, aumentar o número de doentes que podem beneficiar de uma nova tentativa de ressecção e prolongar a sobrevivência. Objectivos: Avaliar a sensibilidade da metodologia diagnósfica e a eficácia de um programa de vigilância na defecção e tratamento de recidiva de CCR. Métodos: Entre 1989-93, 218 doentes submetidos a ressecção curativa de CCR foram vigiados de acordo com um protocolo. Resultados: Registou-se recidiva em 54 (25 %) doentes, 61 % encontrando-se assintomáticos. A sensibilidade dos métodos de rasfreio ou diagnóstico foi: marcadores tumorais -85 % ; tomografia computorizada -91 %; ecografia/enzimologia hepática -75%/40%, respectivamente. A ressecção foi possível em 13 doentes (24%): anastomóticas -40%; metásfases hepáticas -29%. A probabilidade de ressecção não diferiu entre as recidivas sintomáticas e assintomáticas mas verificou-se maior sobrevivência dos doentes com recidivas ressecadas. Conclusões: Pelo seu baixo custo e elevada sensibilidade, os marcadores tumorais são o método de escolha para o rastreio de recidiva. A maioria das recidivas foram diagnosticadas em fase assintomática, mas este resultado não conduziu ao aumento da ressecabilidade. Contudo, um pequeno número de doentes beneficiou de nova ressecção com melhoria na sobrevivência.
INTRODUCTION: Bi-allelic germ-line mutations in the human homolog of MutY (MYH) gene cause the au... more INTRODUCTION: Bi-allelic germ-line mutations in the human homolog of MutY (MYH) gene cause the autosomal recessive inherited syndrome MYH associated polyposis (MAP). AIMS & METHODS: To access the phenotypic features of individuals presenting biallelic MYH germline mutations. We studied 21 patients (10M:11F, mean age of 43.5 years – 23–75) from 17 unrelated families. Patient's family history, number and histology of colonic lesions and extra-colonic manifestations were evaluated. RESULTS: 17 patients were homozygous or compound heterozygous for mutations in MYH hotspots Y165C and G382D. 1 patient was heterozygous for the Y165/int4 mutation and 3 patients were homozygous for other mutations (1103delC and R38X). 6 patients presented more than 100 adenomas and the others between 6 and 100 adenomas. 85.7% of patients presented more than 20 adenomas. CRC ocurred in 14/21 (66.6%) of and multiple cancers in 5 of patients at presentation. Age of CRC diagnosis was 47.5 years. 20/21 (95.2%...
United European Gastroenterology Journal, 2015
Introduction: Although colorectal cancer (CRC) has often been regarded as a single entity, differ... more Introduction: Although colorectal cancer (CRC) has often been regarded as a single entity, different pathways may lead to macroscopically similar cancers. These pathways may evolve into a patchy colonic field defect that we aimed to study in consecutive CRC patients. Methods: In a single-center, observational, prospective study, consecutive CRC patients were included if surgery and a perioperative colonoscopy were planned. Personal and familial history data were collected. Tumors were studied for microsatellite instability (MSI) status, DNA repair protein expression (DRPE) and presence of BRAF and/or APC mutations.
E se o fatalismo popular, expresso na ideia de destino quase inelutável, representasse -e antecip... more E se o fatalismo popular, expresso na ideia de destino quase inelutável, representasse -e antecipasse -afinal uma intuição daquilo que só agora começamos a descortinar? O que há de novo então na visão da carcinogénese que nos empurra, de forma surpreendente, para o fatalismo da alma lusitana? A questão põe-se agora em saber qual é o momento ou idade da sua iniciação e quais são os tempos de acumulação de eventos subsequentes. Os dados forçam-nos a admitir que a iniciação do cancro do cólon esporádico pode estar afinal inscrita de forma muito precoce na constituição do indivíduo, através de uma sementeira de variantes alélicas discretas, escondi-das numa grande massa de células estaminais do epitélio cólico. A expressão discreta tem aqui, evidentemente, uma conotação sobretudo de diferença binária, categóri-ca, radical, mesmo que de uma pequena amplitude de grau. De tal forma é discreta essa variação estrutural que o epitélio nos surge como entidade morfologicamente homogénea, mesmo ...
Acta médica portuguesa
The pattern of alcohol consumption has been studied among 92 males, workers in a factory of the L... more The pattern of alcohol consumption has been studied among 92 males, workers in a factory of the Lisbon area. In this population there were three groups of ethanol consumers: I--non consumers, 6%; II--medium, up to 80g/day, 68%; III--heavy consumers, more than 80g/day, 26%. Another group (IV) was considered, for reference, with 23 patients with heavy alcoholism in the outpatients of an alcoholic addicts clinic. Besides the clinical questionnaire and medical examination, the following methods have been used and analysed: brief MAST; Le Gô, Mean Corpuscular Volume (MCV), serum glutamic oxalacetic Trasaminase (SGOT), and gama-glutamyl transpepticlase (gamma GT). The mean ethanol consumption in group IV was significantly higher than in group III (p less than 0.005), and in group III higher than in group II (p less than 0.001). Group IV demarked itself form group III due to a higher prevalence of symptoms of physical dependence (p less than 0.001), and of consumption of tranquilizers (p l...