5 research outputs found
Correlação entre o padrão de expressão tecidual e os valores séricos do antígeno carcinoembrionário em doentes com câncer colorretal
A correlação entre diferentes padrões de expressão celular do CEA e a quantificação sérica do antígeno é assunto controvertido. OBJETIVO: O objetivo do presente estudo foi verificar se o padrão de distribuição tecidual do CEA no carcinoma colorretal, se correlaciona com seus níveis séricos. MÉTODO: Estudaram-se 24 pacientes portadores de adenocarcinoma colorretal, com média de idade de 62,6 anos. A mensuração sérica foi realizada por quimioluminescência. No estudo do padrão de distribuição tecidual empregou-se método imunoistoquímico com a técnica da estreptavidina-biotina peroxidase, utilizando anticorpos monoclonais anti-CEA. O padrão de expressão tecidual foi classificado em apical, citoplasmático e estromal, segundo a localização predominante do CEA. A intensidade da imunoexpressão foi classificada em leve, moderada e forte. Empregou-se o teste de Mann-Whitney na comparação dos níveis de CEA sérico, segundo o padrão de distribuição tecidual e o grau histológico do tumor, o teste de Kruskal-Wallis para análise de variância e o teste de Spearman para avaliação da correlação entre as variáveis estudadas, adotando-se nível de significância de 5% (p<0,05). RESULTADOS: Dois (8,3%) doentes foram classificados no estádio A de Dukes, 12 (50,0%) no B e 10 (41,6%) no C. Os valores médios do CEA sérico nos doentes com tumores restritos à parede intestinal (A e B de Dukes) foram significativamente menores que os dos doentes com comprometimento linfonodal (p = 0,0139). Nos 14 (58,3%) enfermos com padrão apical de distribuição o valor médio de CEA sérico era de 4,0 ng/ml, enquanto nos 10 (41,6%) em que havia expressão do tipo citoplasmática o valor médio do CEA sérico era de 31,0 ng/ml (p = 0,0002). Independente da graduação histológica, tumores com expressão tecidual do tipo apical apresentavam valores séricos do CEA significativamente menores do que tumores com padrão citoplasmático (p<0.05) Não se encontrou padrão estromal de distribuição. Houve correlação estatisticamente significante entre o padrão de distribuição tecidual, valores séricos do CEA e a classificação de Dukes. CONCLUSÃO: Os resultados do presente estudo permitem concluir que tumores com padrão de distribuição tecidual citoplasmática cursam com valores séricos de CEA significativamente mais elevados que tumores com padrão de distribuição apical. Existe correlação positiva e estatisticamente significante, entre os diferentes padrões de distribuição celular do CEA, seus níveis séricos e o estadiamento da doença.<br>The correlation between different cell expression patterns of CEA and the quantities of this antigen in serum is still a controversial subject. OBJECTIVE: The objective of the present study was to verify whether there is a correlation between the distribution pattern of CEA in the neoplastic tissue and CEA levels in serum. METHOD: Twenty-four patients with colorectal cancer were studied. Their mean age was 62.6 years. The measurement of CEA in serum was done by quimioluminiscence technique. To study the tissue expression pattern, the immunohistochemical method with the streptavidin-biotin peroxidase technique was utilized with the use of anti-CEA monoclonal antibodies. The tissue expression pattern was classified as apical, cytoplasmic or stromal, according to the predominant localization of the CEA distribution in the neoplastic tissue. The intensity of the immunoexpression of CEA in the neoplastic tissue was classified as slight, moderate or strong. The Mann-Whitney test was used to compare the CEA levels in serum with the tissue distribution pattern and histological tumor grade. The Kruskal-Wallis test was used to variance analysis and Spearman test was used to analyze the correlation among the studied variables. The significance level of 5% (p<0.05) was adopted. RESULTS: Two patients (8.3%) were classified in Dukes stage A, 12 (50.0%) in B and 10 (41.6%) in C. The mean CEA values in serum in patients with tumors restricted to the intestinal wall (Dukes A + B) were significantly lower than did the tumors with lymph node involvement (p=0.0139). In the 14 patients (58.3%) who presented an apical tissue expression pattern, the mean CEA value in serum was 4.0 ng/ml, while in the 10 patients (41.6%) with expression of cytoplasmic type, the mean CEA value in serum was 31.0 ng/ml (p=0.0002). Independent of the histological grade, the tumors with tissue expression of apical type presented CEA values in serum that were significantly lower than did the tumors with the cytoplasmic pattern (p<0.05). No patients were found to have the stromal pattern of CEA distribution. There was a statistically significant correlation between the tissue expression pattern, CEA values in serum and the Dukes classification. CONCLUSION: The results from the present study allow concluding that tumors with the cytoplasmic pattern of CEA distribution presented serum values of the antigen significantly higher than apical pattern. There is a positive and statistically significant correlation between the different cell distribution patterns of CEA, its levels in serum and the staging of the disease
Proposta para estadiamento do câncer colorretal baseada em critérios morfofuncionais: correlação com níveis séricos do antígeno carcinoembrionário Proposal for colorectal cancer stages based on morphofunctional criteria: correlation with carcinoembryonic antigen levels
A análise de características morfofuncionais pode ser útil na predição evolutiva do câncer colorretal, especialmente se relacionadas aos níveis séricos de antígeno carcinoembrionário. A pesquisa de instabilidades de cromossomos e genes e alterações da expressão tecidual de proteínas por eles codificadas, tornam atraente a possibilidade do emprego de fatores funcionais como variáveis potencialmente válidas na compreensão do prognóstico do carcinoma colorretal.¹ OBJETIVO: Propor estadiamento baseado nas características morfológicas e funcionais do carcinoma colorretal, valorizando o poder prognóstico do antígeno carcinoembrionário. MÉTODO: Acompanhou-se 35 pacientes em estágios diferentes da evolução do adenocarcinoma colorretal no período de 2001 a 2007. A medida sérica do antígeno carcinoembrionário foi executada pela técnica de quimioluminescência. Realizou-se estudo anatomopatológico para determinação do grau histológico e estádio TNM, e análise imunohistoquímica para determinação da polarização tecidual do antígeno carcinoembrionário. A classificação morfofuncional foi determinada pela combinação entre grau histológico e polarização do antígeno. O estadiamento morfofuncional baseou-se na associação entre classificação morfofuncional e estadiamento TNM, por pontuação atribuída a cada uma das classificações. As variáveis estudadas foram: CEA sérico, classificação morfofuncional, estadiamento TNM e morfofuncional. Os resultados foram analisados por análise variância, teste de correlação e análise de sobrevivência (Kaplan-Meier e Modelo de Regressão de Cox), adotando-se p>0,05% para rejeição da hipótese de nulidade. RESULTADOS: A curva de sobrevida no estadiamento morfofuncional apresentou resultados semelhantes aos encontrados no estadiamento TNM. Houve relação entre a nova proposta de estadiamento e o tempo de sobrevida do paciente. Observou-se relação entre o tempo de sobrevida, a classificação morfofuncional e o nível sérico de antígeno carcinoembrionário. CONCLUSÃO: O estadiamento morfofuncional é válido para a avaliação prognóstica dos pacientes com adenocarcinoma colorretal, e relaciona-se com os níveis séricos do CEA.<br>The analysis of morphofunctions characteristics can be useful in the colorectal cancer evolution, especially if related to the serum carcinoembryonic antigen levels. The research of chromosomes and genes instability, as well as the alterations of tissue protein codified, makes attractive the possibility to use potentially valid functional factors as variables for the understanding of colorectal carcinoma prognosis. OBJECTIVE: To consider classes based on morphologic and functional colorectal carcinoma characteristics, valuing serum carcinoembryonic antigen levels prognostic power. METHOD: Third-five patients in different stages of colorectal carcinoma underwent operations from 2001 to 2007. Serum CEA levels, histological grade, tissue CEA cell polarization capacity were analyzed. Colorectal carcinoma was classified according to TNM stages. The morphofunctional classification was determined by the combination between histological grade and antigen polarization, morphofunctional stages have been based in association between morphofunctional classification and stages TNM, by punctuation attributed to each one classification. The results had been analyzed by variance analysis, correlation test and survival analysis (Kaplan-Meier and Cox Model Regression), adopting p<0.05. RESULTS: Morphofunctional stages survival curve resulted similar to the joined ones in stages TNM. It had relation between new classification proposed and patient survival time. They had observed relation among survival time, morphofunctional classification and serum carcinoembryonic antigen. CONCLUSION: Morphofunctional classification is valid for colorectal cancer patient's prognostic evaluation and is related with the serum CEA levels
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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability:
Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)