The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging ...single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common minor allele frequency (MAF) >= 5% variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P-adj = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P-trend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study ...and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (
P
=4.0 ×10
−8
to
P
=2.7 ×10
−24
). We also identified a SNP in
TERT
more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New ...potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC
values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.
Surgical lung biopsy has been studied in distinct populations, mostly going beyond clinical issues to impinge upon routine histopathological diagnostic information in diffuse infiltrates; however, ...detailed tissue analyses have rarely been performed. The present study was designed to investigate the prognostic contribution provided by detailed tissue analysis in diffuse infiltrates.
Medical records and surgical lung biopsies from the period of 1982 to 2003 of 63 patients older than 18 years with diffuse infiltrates were retrospectively examined. Lung parenchyma was histologically divided into 4 anatomical compartments: interstitium, airways, vessels, and alveolar spaces. Histological changes throughout these anatomical compartments were then evaluated according to their acute or chronic evolutional character. A semiquantitative scoring system was applied to histologic findings to evaluate the intensity and extent of the pathological process. We applied logistic regression to predict the risk of death associated with acute and chronic histological changes and to estimate the odds ratios for each of the independent variables in the model.
Impact on survival was found for male gender (P = 0.03), presence of diffuse alveolar damage (P = 0.001), and chronic histological changes (P = 0.0004) on biopsy. Thus, being male was associated with a slightly lower risk (O.R. = 0.18; P=0.03) of dying than being female. Death risk was increased 17 times in the presence of acute histological changes such as diffuse alveolar damage and 2.5 times in the presence of chronic histological changes.
Detailed analysis of histological specimens can provide more than a nosological diagnosis: this approach can provide valuable information concerning prognosis.
A biópsia pulmonar cirúrgica tem sido estudada em populações distintas, geralmente abordando aspectos histopatológicos puramente diagnósticos em infiltrados pulmonares difusos, além de dados clínicos. Contudo, análises teciduais detalhadas em tais casos têm sido pouco exploradas. O presente estudo foi delineado com o intuito de se investigar a contribuição prognóstica fornecida pela análise histológica detalhada em infiltrados difusos.
Foram examinados retrospectivamente os prontuários e biópsias pulmonares cirúrgicas de 63 pacientes maiores de 18 anos, com infiltrados difusos, de 1982 a 2003. O parênquima pulmonar foi dividido em 4 compartimentos histológicos: interstício, vias aéreas, vasos e espaços alveolares. Alterações histológicas de cada compartimento histológico foram então avaliadas de acordo com seu caráter evolutivo agudo ou crônico. Um escore semiquantitativo foi aplicado a achados histopatológicos com o intuito de se avaliar a intensidade e a extensão do processo patológico. Aplicamos regressão logística para predizer o risco de morte para alterações histológicas agudas e crônicas e para estimar a razão de probabilidades para cada uma das variáveis independentes do modelo.
O impacto sobre a sobrevida foi observado para o gênero masculino (p=0.03), para a presença de dano alveolar difuso (p=0.001) e para alterações histológicas crônicas (p=0.0004) em biópsias. Assim, homens apresentariam menor chance (O.R. = 0.18; P=0.03) de morrer do que mulheres. O risco de morte foi 17 vezes maior na presença de alterações histológicas agudas como dano alveolar difuso e 2,5 vezes na presença de alterações histológicas crônicas.
A análise detalhada de espécimes histológicos pode proporcionar maiores e mais valiosas informações de valor prognóstico do que o simples diagnóstico nosológico.
Surgical lung biopsy is an invasive procedure performed when other procedures have failed to provide an urgent and specific diagnosis, but there may be reluctance to perform it in critically ill ...patients with diffuse pulmonary infiltrates.
To evaluate the diagnostic accuracy, the changes in therapy and survival of patients with diffuse lung infiltrates, mostly presenting acute respiratory failure, who underwent surgical biopsy.
We retrospectively examined medical records and surgical lung biopsies from 1982 to 2003 of 63 patients older than 18 years with diffuse infiltrates. Clinical diagnoses were compared to histopathological ones, from biopsies and autopsies. Laboratory and epidemiological data were evaluated, and their relationship to hospital survival was analyzed.
All histological specimens exhibited abnormalities, mostly presenting benign/inflammatory etiologies. Fifteen patients had an etiologic factor determined in biopsy, most commonly Mycobacterium tuberculosis. The preoperative diagnosis was rectified in 37 patients. Autopsies were obtained in 25 patients and confirmed biopsy results in 72% of cases. Therapy was changed for 65% of patients based on biopsy results. Forty-nine percent of patients survived to be discharged from the hospital. Characteristics that differed significantly between survivors and nonsurvivors included sex (P = 0.05), presence of comorbidity (P = 0.05), SpO2 (P = 0.05), and presence of diffuse alveolar damage in the biopsy (P = 0.004).
Surgical lung biopsy provided a specific, accurate etiologic diagnosis in many patients with diffuse pulmonary infiltrates when clinical improvement did not occur after standard treatment. Surgical lung biopsy may reveal a specific diagnosis that requires distinct treatment, and it would probably have an impact in lowering the mortality of these patients.
A biópsia pulmonar cirúrgica é um procedimento invasivo executado quando outros procedimentos não forneceram um diagnóstico urgente e específico; no entanto, pode haver relutância em sua execução em pacientes críticos, que apresentam infiltrados pulmonares difusos.
Avaliar a acurácia diagnóstica, mudanças na terapêutica e a sobrevida de pacientes com infiltrado pulmonar difuso, em sua maior parte apresentando a insuficiência respiratória aguda, submetidos a biópsia cirúrgica.
Foram examinados retrospectivamente registros médicos e biópsias pulmonares cirúrgicas de 63 pacientes maiores de 18 anos de idade, com infiltrados difusos, entre 1982 a 2003. Os diagnósticos clínicos foram comparados aos histopatológicos, de biópsias e de autópsias. Dados laboratoriais e epidemiológicos foram avaliados e sua correlação com a sobrevida hospitalar analisada.
Todos os espécimes histológicos exibiram alterações, em sua maior parte de natureza benigna/inflamatória. Em quinze casos o fator etiológico pôde ser determinado na biópsia, sendo o Mycobacterium tuberculosis o mais freqüente. O diagnóstico pré-operatório foi mudado em 37 pacientes. Autópsias foram realizadas em 25 pacientes e confirmaram resultados da biópsia em 72%. A terapêutica foi alterada em 65% dos pacientes com base nos resultados da biópsia. Quarenta e nove por cento dos pacientes sobreviveram ao final do período de hospitalização. Características que diferiram significativamente entre sobreviventes versus não sobreviventes incluíram sexo (p=0.05), a presença de comorbidade (p=0.05), a SatO2 (p=0.05), e a presença de dano alveolar difuso na biópsia (p=0.004).
A biópsia pulmonar cirúrgica forneceu um diagnóstico etiológico específico e exato em muitos pacientes com infiltrados pulmonares difusos quando a melhora clínica não ocorreu após o tratamento padrão. A biópsia pulmonar cirúrgica pode fornecer diagnósticos que requerem tratamentos específicos, com provável impacto na redução do índice de mortalidade destes pacientes.
PURPOSE: Surgical lung biopsy has been studied in distinct populations, mostly going beyond clinical issues to impinge upon routine histopathological diagnostic information in diffuse infiltrates; ...however, detailed tissue analyses have rarely been performed. The present study was designed to investigate the prognostic contribution provided by detailed tissue analysis in diffuse infiltrates. METHODS: Medical records and surgical lung biopsies from the period of 1982 to 2003 of 63 patients older than 18 years with diffuse infiltrates were retrospectively examined. Lung parenchyma was histologically divided into 4 anatomical compartments: interstitium, airways, vessels, and alveolar spaces. Histological changes throughout these anatomical compartments were then evaluated according to their acute or chronic evolutional character. A semiquantitative scoring system was applied to histologic findings to evaluate the intensity and extent of the pathological process. We applied logistic regression to predict the risk of death associated with acute and chronic histological changes and to estimate the odds ratios for each of the independent variables in the model. RESULTS: Impact on survival was found for male gender (P = 0.03), presence of diffuse alveolar damage (P = 0.001), and chronic histological changes (P = 0.0004) on biopsy. Thus, being male was associated with a slightly lower risk (O.R. = 0.18; P=0.03) of dying than being female. Death risk was increased 17 times in the presence of acute histological changes such as diffuse alveolar damage and 2.5 times in the presence of chronic histological changes. CONCLUSION: Detailed analysis of histological specimens can provide more than a nosological diagnosis: this approach can provide valuable information concerning prognosis.PROPOSIÇÃO: A biópsia pulmonar cirúrgica tem sido estudada em populações distintas, geralmente abordando aspectos histopatológicos puramente diagnósticos em infiltrados pulmonares difusos, além de dados clínicos. Contudo, análises teciduais detalhadas em tais casos têm sido pouco exploradas. O presente estudo foi delineado com o intuito de se investigar a contribuição prognóstica fornecida pela análise histológica detalhada em infiltrados difusos. MÉTODOS: Foram examinados retrospectivamente os prontuários e biópsias pulmonares cirúrgicas de 63 pacientes maiores de 18 anos, com infiltrados difusos, de 1982 a 2003. O parênquima pulmonar foi dividido em 4 compartimentos histológicos: interstício, vias aéreas, vasos e espaços alveolares. Alterações histológicas de cada compartimento histológico foram então avaliadas de acordo com seu caráter evolutivo agudo ou crônico. Um escore semiquantitativo foi aplicado a achados histopatológicos com o intuito de se avaliar a intensidade e a extensão do processo patológico. Aplicamos regressão logística para predizer o risco de morte para alterações histológicas agudas e crônicas e para estimar a razão de probabilidades para cada uma das variáveis independentes do modelo. RESULTADOS: O impacto sobre a sobrevida foi observado para o gênero masculino (p=0.03), para a presença de dano alveolar difuso (p=0.001) e para alterações histológicas crônicas (p=0.0004) em biópsias. Assim, homens apresentariam menor chance (O.R. = 0.18; P=0.03) de morrer do que mulheres. O risco de morte foi 17 vezes maior na presença de alterações histológicas agudas como dano alveolar difuso e 2,5 vezes na presença de alterações histológicas crônicas. CONCLUSÃO: A análise detalhada de espécimes histológicos pode proporcionar maiores e mais valiosas informações de valor prognóstico do que o simples diagnóstico nosológico.
INTRODUCTION: Surgical lung biopsy is an invasive procedure performed when other procedures have failed to provide an urgent and specific diagnosis, but there may be reluctance to perform it in ...critically ill patients with diffuse pulmonary infiltrates. PURPOSE: To evaluate the diagnostic accuracy, the changes in therapy and survival of patients with diffuse lung infiltrates, mostly presenting acute respiratory failure, who underwent surgical biopsy. METHODS: We retrospectively examined medical records and surgical lung biopsies from 1982 to 2003 of 63 patients older than 18 years with diffuse infiltrates. Clinical diagnoses were compared to histopathological ones, from biopsies and autopsies. Laboratory and epidemiological data were evaluated, and their relationship to hospital survival was analyzed. RESULTS: All histological specimens exhibited abnormalities, mostly presenting benign/inflammatory etiologies. Fifteen patients had an etiologic factor determined in biopsy, most commonly Mycobacterium tuberculosis. The preoperative diagnosis was rectified in 37 patients. Autopsies were obtained in 25 patients and confirmed biopsy results in 72% of cases. Therapy was changed for 65% of patients based on biopsy results. Forty-nine percent of patients survived to be discharged from the hospital. Characteristics that differed significantly between survivors and nonsurvivors included sex (P = 0.05), presence of comorbidity (P = 0.05), SpO2 (P = 0.05), and presence of diffuse alveolar damage in the biopsy (P = 0.004). CONCLUSION: Surgical lung biopsy provided a specific, accurate etiologic diagnosis in many patients with diffuse pulmonary infiltrates when clinical improvement did not occur after standard treatment. Surgical lung biopsy may reveal a specific diagnosis that requires distinct treatment, and it would probably have an impact in lowering the mortality of these patients.INTRODUÇÃO: A biópsia pulmonar cirúrgica é um procedimento invasivo executado quando outros procedimentos não forneceram um diagnóstico urgente e específico; no entanto, pode haver relutância em sua execução em pacientes críticos, que apresentam infiltrados pulmonares difusos. OBJETIVO: Avaliar a acurácia diagnóstica, mudanças na terapêutica e a sobrevida de pacientes com infiltrado pulmonar difuso, em sua maior parte apresentando a insuficiência respiratória aguda, submetidos a biópsia cirúrgica. MÉTODO: Foram examinados retrospectivamente registros médicos e biópsias pulmonares cirúrgicas de 63 pacientes maiores de 18 anos de idade, com infiltrados difusos, entre 1982 a 2003. Os diagnósticos clínicos foram comparados aos histopatológicos, de biópsias e de autópsias. Dados laboratoriais e epidemiológicos foram avaliados e sua correlação com a sobrevida hospitalar analisada. RESULTADOS: Todos os espécimes histológicos exibiram alterações, em sua maior parte de natureza benigna/inflamatória. Em quinze casos o fator etiológico pôde ser determinado na biópsia, sendo o Mycobacterium tuberculosis o mais freqüente. O diagnóstico pré-operatório foi mudado em 37 pacientes. Autópsias foram realizadas em 25 pacientes e confirmaram resultados da biópsia em 72%. A terapêutica foi alterada em 65% dos pacientes com base nos resultados da biópsia. Quarenta e nove por cento dos pacientes sobreviveram ao final do período de hospitalização. Características que diferiram significativamente entre sobreviventes versus não sobreviventes incluíram sexo (p=0.05), a presença de comorbidade (p=0.05), a SatO2 (p=0.05), e a presença de dano alveolar difuso na biópsia (p=0.004). CONCLUSÃO: A biópsia pulmonar cirúrgica forneceu um diagnóstico etiológico específico e exato em muitos pacientes com infiltrados pulmonares difusos quando a melhora clínica não ocorreu após o tratamento padrão. A biópsia pulmonar cirúrgica pode fornecer diagnósticos que requerem tratamentos específicos, com provável impacto na redução do índice de mortalidade destes pacientes.