RESUMO
Vaccines are critical cost-effective tools to control the COVID-19 pandemic. The heterologous prime-boost vaccination has been used by many countries to overcome supply issues, so the effectiveness and safety of this strategy need to be better clarified. This study aims to verify the effect of heterologous prime-boost COVID-19 vaccination on healthcare professionals from Dante Pazzanese Hospital in Brazil. It was performed serological assays of vaccinated individuals after 2-dose of CoronaVac (Sinovac; n = 89) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca; n = 166) followed by a BNT162b2 booster (Pfizer-BioNTech; n = 255). The serum antibodies anti-S (spike), anti-N (nucleocapsid), and anti-RBD (receptor binding domain) were assessed by enzyme-linked immunosorbent assay. The heterologous booster dose induced a 10-fold higher anti-Spike antibody regardless of the 2-dose of a prime vaccine. It was strikingly observed that BNT162b2 enhanced levels of anti-spike antibodies, even in those individuals who did not previously respond to the 2-dose of CoronaVac. In conclusion, the heterologous scheme of vaccination using mRNA as a booster vaccine efficiently enhanced the antibody response against SARS-CoV-2, especially benefiting those elderly who were seronegative with a virus-inactivated vaccine.
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Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Idoso , Humanos , Anticorpos Antivirais/análise , Anticorpos Antivirais/imunologia , Vacina BNT162 , ChAdOx1 nCoV-19 , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Estudos Longitudinais , Pandemias , SARS-CoV-2 , VacinaçãoRESUMO
INTRODUCTION: The COVID-19 pandemic continues, with a late hyperinflammatory phase. The immunosuppressive therapy used in heart transplant patients, in theory, could reduce inflammation, thus benefitting patients with COVID-19. So far, however, there is still very little literature on this subject. METHODS: This is a single-center retrospective study. We described laboratory parameters and clinical outcomes from 11 heart transplant patients with COVID-19 assisted at Dante Pazzanese Institute of Cardiology between March and July 2020. RESULTS: Patients with ages of between 35 and 79 years were enrolled, and heart transplantation ranged from 3 to 264 months. The main comorbidities were diabetes mellitus (9/11; 81.8%), hypertension (10/11; 90.9%), and chronic renal disease (6/11; 54.5%). Cyclosporine A was used in 10 (90.9%) patients, mycophenolate mofetil in 9 (81.8%) patients, and mTOR inhibitor in 5 (45.5%) patients. Fever and cough were observed in 8 (72.7%) patients, and dyspnea and gastrointestinal symptoms in 5 (45.5%) patients. Lymphopenia was observed in 10 (90.9%) patients and thrombocytopenia in 5 (45.5%) patients. The higher level of troponin associated with chest tomography above 50% of bilateral pulmonary infiltrates with ground-glass opacity (GGO) was observed in those with the worst outcomes. Nine patients needed intensive care, and hospital stay ranged from 4 to 21 days, with 2 (18.2%) patients requiring vasopressor drugs and mechanical ventilation, and three (27.3%) patients dying due to COVID-19 complications. CONCLUSION: Heart transplant patients had similar symptoms and outcomes as the general population; immunosuppressive therapy seems not to have protected them. Patients who presented higher levels of troponin and D-dimer, associated with greater GGO pulmonary infiltrates, had worse outcomes. More studies with larger cohorts may clarify immunosuppressive effects on COVID-19 outcomes.
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COVID-19 , Transplante de Coração , Brasil , Transplante de Coração/efeitos adversos , Humanos , Pandemias , Estudos Retrospectivos , SARS-CoV-2RESUMO
INTRODUCTION: Primary graft failure (PGF) is an important contributor to early mortality, accounting for 41% of deaths within the first 30 days after heart transplantation (HT). Donor hypernatremia has been associated with PGF development. However, controversial data exist regarding the impact of sodium deregulation in patient survival after HT. This study aimed to assess the influence of donor hypernatremia on PGF development and to determine the serum sodium level threshold to assist in decision-making for organ procurement. METHODS: The medical record from 200 HT patients and organ donors were retrospectively assessed and categorized by PGF occurrence. Donor sodium levels were compared and cut-off points obtained by receiver operating characteristic (ROC) curve. A multiple logistic regression model was applied to assess the effects of factors and covariates that influence PGF development. RESULTS: Sodium levels of donors were significantly higher in recipients who developed PGF than those who did not develop PGF (162 vs. 153 mmol/L, P = .001). The sodium cut-off value determined by the ROC curve was 159 mmol/L. The group who received organs from donors with a serum sodium concentration ≥159 mmol/L had a higher incidence of PGF (63.3% vs 32.4%, P < .001). Furthermore, donor sodium levels ≥159 mmol/L increased the likelihood of recipients developing PGF by 3.4 times. It is also observed that the incidence of donor smoking addiction was significantly higher in the PGF group (28.6% vs. 11.5%, P = .004) and donor smoking addiction increased the risk of developing PGF by 2.8 times. CONCLUSION: Smoking addiction and the application of suboptimal organs from donors with hypernatremia contribute to primary graft failure in heart transplantation.
Assuntos
Rejeição de Enxerto/etiologia , Transplante de Coração/efeitos adversos , Hipernatremia/fisiopatologia , Complicações Pós-Operatórias/etiologia , Fumar/fisiopatologia , Doadores de Tecidos/provisão & distribuição , Adulto , Feminino , Seguimentos , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/patologia , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
INTRODUCTION: Vasculitis entails heterogeneous origins; it starts with an inflammatory process that leads to small vessels' necrosis, hemorrhage, and ischemic lesion, and may further result in occlusion of the vascular lumen. Vasculitis' contribution to allograft rejection is still unclear. This study aims to investigate the incidence of vasculitis in the early stages of heart transplantation as well as to assess the intragraft genes' expression associated with vascular function and subsequently to verify the way in which it affects the outcome of the allograft. METHODS: In this retrospective study, 300 archive paraffin-embedded endomyocardial biopsies from 63 heart allograft recipients were assessed. Cellular rejection and vasculitis were diagnosed through histological analysis, and antibody-mediated rejection was performed with immunohistochemical C4d staining. The transcripts of ICAM, VCAM, VEGF, CCL2, IFNG, TGFB, TNF, ADIPOR1, and ADIPOR2 genes were examined through quantitative polymerase chain reaction using B2M for normalization. RESULTS: We observed a higher prevalence of severe vasculitis in the early period of post-transplant, and recovery was observed to take place around 1 year post-transplant. Additionally, vasculitis was found to be directly associated with acute cellular rejection and antibody-mediated rejection. The intense C4d capillary positivity predicts higher long-term cardiovascular disease mortality. In comparison with the vasculitis-free group, the group with severe vasculitis displayed reduced left ventricular ejection fraction and an upregulation of VCAM and IFNG associated with the downregulation of VEGF, ADIPOR1, and ADIPOR2. CONCLUSION: The vasculitis associated with the presence of C4d and the change in intragraft gene expression profile may contribute to poor allograft outcomes.
Assuntos
Perfilação da Expressão Gênica , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/mortalidade , Transplante de Coração/mortalidade , Vasculite/diagnóstico , Vasculite/mortalidade , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Transplante de Coração/efeitos adversos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Vasculite/etiologiaRESUMO
Despite advances in immunosuppressive therapy, rejection still remains the main obstacle to a successful transplant. This study aims to explore the gene expression profile of the rejection process in order to decrease the number of unnecessary endomyocardial biopsies in stable patients. METHODS: A total of 300 formalin-fixed and paraffin-embedded (FFPE) endomyocardial biopsies sampled from 63 heart allograft recipients were included in this study. Acute cellular rejection (ACR) and antibody-mediated rejection (AMR) were diagnosed by histological analysis and immunohistochemical C4d staining, respectively. Analysis of gene expression was performed by quantitative real-time polymerase chain reaction. The samples were grouped according to the ISHLT rejection classification, aiming the statistical analysis. RESULTS: There was a significant decrease in the HMOX1, AIF1, and CCL2 transcript over the post-transplantation period in non-rejection group (P<.001). Furthermore, the ADIPOR1, ADIPOR2, BCL2L1, and VEGFA protective genes were significantly downregulated in the ACR group (P<.05). ADIPOR2, BCL2L1, IL6, and NOS2 genes were also significantly downregulated in the AMR group than in the non-rejection group (P<.05). CONCLUSION: The downregulations of the protective genes contribute to the allograft rejection, and the archived FFPE samples are useful for the gene expression analysis aiming the allograft rejection surveillance.
Assuntos
Biomarcadores/metabolismo , Rejeição de Enxerto/diagnóstico , Transplante de Coração/efeitos adversos , Isoanticorpos/efeitos adversos , Miocárdio/metabolismo , Complicações Pós-Operatórias , Substâncias Protetoras/metabolismo , Adulto , Biomarcadores/análise , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia , Miocárdio/patologia , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: Chagas cardiomyopathy (ChCM) is a severe form of Chagas disease and a major cause of cardiovascular morbidity and mortality. The dysregulation of the immune response leads to cardiac remodeling and functional disruptions, resulting in life-threatening complications. Conventional diagnostic methods have limitations, and therapeutic response evaluation is challenging. MicroRNAs (miRNAs), important regulators of gene expression, show potential as biomarkers for diagnosis and prognosis. AIM: This review aims to summarize experimental findings on miRNA expression in ChCM and explore the potential of these miRNAs as biomarkers of Chagas disease. METHODS: The search was conducted in the US National Library of Medicine MEDLINE/PubMed public database using the terms "Chagas cardiomyopathy" OR "Chagas disease" AND "microRNA" OR "miRNA" OR "miR." Additionally, bioinformatics analysis was performed to investigate miRNA-target interactions and explore enrichment pathways of gene ontology biological processes and molecular functions. RESULTS: The miR-21, miR-146b, miR-146a, and miR-155 consistently exhibited up-regulation, whereas miR-145 was down-regulated in ChCM. These specific miRNAs have been linked to fibrosis, immune response, and inflammatory processes in heart tissue. Moreover, the findings from various studies indicate that these miRNAs have the potential as biomarkers for the disease and could be targeted in therapeutic strategies for ChCM. CONCLUSION: In this review, we point out miR-21, miR-146b, miR-146a, miR-155, and miR-145-5p role in the complex mechanisms of ChCM. These miRNAs have been shown as potential biomarkers for precise diagnosis, reliable prognostic evaluation, and effective treatment strategies in the ChCM.
Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/metabolismo , Biomarcadores/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. METHODS: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. RESULTS: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. CONCLUSIONS: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.
Assuntos
Cardiomiopatia Chagásica/genética , Quimiocina CCL2/genética , Predisposição Genética para Doença , Imunidade Inata , Glicoproteínas de Membrana/genética , Receptores CCR5/genética , Receptores de Interleucina-1/genética , Trypanosoma cruzi/fisiologia , Adulto , Idoso , Brasil , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/prevenção & controle , Quimiocina CCL2/imunologia , Feminino , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores CCR5/imunologia , Receptores de Interleucina-1/imunologiaRESUMO
Chagas disease is a parasitic disease from South America, affecting around 7 million people worldwide. Decades after the infection, 30% of people develop chronic forms, including Chronic Chagas Cardiomyopathy (CCC), for which no treatment exists. Two stages characterized this form: the moderate form, characterized by a heart ejection fraction (EF) ≥ 0.4, and the severe form, associated to an EF < 0.4. We propose two sets of DNA methylation biomarkers which can predict in blood CCC occurrence, and CCC stage. This analysis, based on machine learning algorithms, makes predictions with more than 95% accuracy in a test cohort. Beyond their predictive capacity, these CpGs are located near genes involved in the immune response, the nervous system, ion transport or ATP synthesis, pathways known to be deregulated in CCCs. Among these genes, some are also differentially expressed in heart tissues. Interestingly, the CpGs of interest are tagged to genes mainly involved in nervous and ionic processes. Given the close link between methylation and gene expression, these lists of CpGs promise to be not only good biomarkers, but also good indicators of key elements in the development of this pathology.
Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Trifosfato de Adenosina/metabolismo , Biomarcadores/metabolismo , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/genética , Doença de Chagas/genética , Metilação de DNA , HumanosRESUMO
Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.
Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Trypanosoma cruzi , Doença de Chagas/genética , Epigênese Genética , Humanos , Fatores de Transcrição/genéticaRESUMO
Serological testing is a powerful tool in epidemiological studies for understanding viral circulation and assessing the effectiveness of virus control measures, as is the case of SARS-CoV-2, the pathogenic agent of COVID-19. Immunoassays can quantitatively reveal the concentration of antiviral antibodies. The assessment of antiviral antibody titers may provide information on virus exposure, and changes in IgG levels are also indicative of a reduction in viral circulation. In this work, we describe a serological study for the evaluation of antiviral IgG and IgM antibodies and their correlation with antiviral activity. The serological assay for IgG detection used two SARS-CoV-2 proteins as antigens, the nucleocapsid N protein and the 3CL protease. Cross-reactivity tests in animals have shown high selectivity for detection of antiviral antibodies, using both the N and 3CL antigens. Using samples of human serum from individuals previously diagnosed by PCR for COVID-19, we observed high sensitivity of the ELISA assay. Serological results with human samples also suggest that the combination of higher titers of antiviral IgG antibodies to different antigen targets may be associated with greater neutralization activity, which can be enhanced in the presence of antiviral IgM antibodies.
Assuntos
Anticorpos Antivirais/imunologia , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , COVID-19/prevenção & controle , Vigilância Imunológica , SARS-CoV-2/imunologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , Teste Sorológico para COVID-19/normas , Reações Cruzadas , Vírus da Dengue/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/normas , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Camundongos , Camundongos Endogâmicos BALB C , Sensibilidade e Especificidade , Zika virus/imunologiaRESUMO
BACKGROUND & AIMS: Diet is a modifiable risk factor, which may influence the gene expression and the concentration of inflammatory biomarkers related to obesity and atherosclerosis. In this substudy from Brazilian Cardioprotective Nutritional (BALANCE) Program, we hypothesized that a nutritional intervention based on the usual Brazilian diet modulates the expression of genes involved with atherosclerosis and inflammatory biomarkers in male patients, in the secondary prevention for cardiovascular disease. METHODS: Six male patients, aged 45 years or older, obese, were selected to follow a qualitative-quantitative food plan for 6 months. Glycemia, insulinemia, lipid profile, plasma concentration of inflammatory biomarkers (interleukin (IL) -1ß), IL-6, IL-8, IL-10, IL-12, tumor necrosis factor alpha, C-reactive protein and adiponectin, and expression of 84 atherosclerosis-related genes in total peripheral blood cells, were measured. RESULTS: After nutritional intervention, the participants reduced weight (p < 0.04), waist circumference (p < 0.04), Homeostasis Model Assessment index for insulin resistance (p = 0.046) and overall leukocyte count (p = 0.046) and neutrophils (p = 0.028). There was no significant modification in the plasma concentration of the inflammatory biomarkers, however, there was a significant increase in the expression of Apo A1 (p = 0.011), ELN (p = 0.017) and IL4 (p = 0.037) genes. CONCLUSIONS: The BALANCE Program, the qualitative-quantitative food plan composed of Brazilian usual foods, did not reduce the concentration of inflammatory biomarkers, but increased in total peripheral blood cells the expression of genes involved in reducing the risk of cardiometabolic in obese patients, in secondary prevention for cardiovascular disease. The clinical trial is registered at https://clinicaltrials.gov/ and the unique identifier is NCT01620398.
Assuntos
Doenças Cardiovasculares , Proteína C-Reativa/análise , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Expressão Gênica , Humanos , Masculino , Obesidade/genética , Prevenção SecundáriaRESUMO
BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide. OBJECTIVES: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH). METHODS: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients. SUMMARY: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.
Assuntos
Hiperlipoproteinemia Tipo II , Brasil , Epigenômica , Genômica , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Simulação de Acoplamento Molecular , FarmacogenéticaRESUMO
Several circulating miRNAs identified in the plasma of smokers have been implicated as promoters of nasopharyngeal and lung carcinoma. To investigate the plasma profile of miRNAs in subjects who reduces the number of smoked cigarettes and who quit after six months. We accompanied 28 individuals enrolled in a Smoking Cessation Program over 6 months. At Baseline, clinical characteristics, co-morbidities, and smoking history were similar among subjects. After 6 months, two groups were defined: who successfully quitted smoking (named "quitters", n = 18, mean age 57 years, 11 male) and who reduced the number of cigarettes smoked (20-90%) but failed to quit smoking (named "smokers", n = 10, mean age 52 years, 3 male). No significant clinical changes were observed between groups at baseline and after a 6-month period, however, quitters showed significant downregulations in seven miRNAs at baseline: miR-17 (- 2.90-fold, p = 0.029), miR-20a (- 3.80-fold, p = 0.021); miR-20b (- 4.71-fold, p = 0.027); miR-30a (- 3.95-fold, p = 0.024); miR-93 (- 3.63-fold, p = 0.022); miR-125a (- 1.70-fold, p = 0.038); and miR-195 (- 5.37-fold, p = 0.002), and after a 6-month period in 6 miRNAs: miR-17 (- 5.30-fold, p = 0.012), miR-20a (- 2.04-fold, p = 0.017), miR-20b (- 5.44-fold, p = 0.017), miR-93 (- 4.00-fold, p = 0.041), miR-101 (- 4.82-fold, p = 0.047) and miR-125b (- 3.65-fold, p = 0.025). Using time comparisons, only quitters had significant downregulation in miR-301b (- 2.29-fold, p = 0.038) after 6-month. Reductions in the number of smoked cigarettes was insufficient to change the plasma profile of miRNA after 6 months. Only quitting smoking (100% reduction) significantly downregulated miR-301b related to hypoxic conditions, promotion of cell proliferation, decreases in apoptosis, cancer development, and progression as increases in radiotherapy and chemotherapy resistance.
Assuntos
Regulação para Baixo/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Fumar/genética , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Abandono do Hábito de FumarRESUMO
[This corrects the article DOI: 10.3389/fimmu.2020.01386.].
RESUMO
Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of T. cruzi infection, while the others remain asymptomatic (ASY). IFN-γ and IFN-γ-producing Th1-type T cells are increased in peripheral blood and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN-γ-producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN-γ production by Th1-type T cells may be a key event for progression toward CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development. Methods: We studied a Brazilian population including 315 CCC cases and 118 ASY subjects. We assessed 35 Tag SNPs designed to represent all the genetic information contained in the IL12B, IL10, IFNG, and IL4 genes. Results: We found 2 IL12 SNPs (rs2546893, rs919766) and a trend of association for a IL10 SNP (rs3024496) to be significantly associated with the ASY group. these associations were confirmed by multivariate analysis and allele tests. The rs919766C, 12rs2546893G, and rs3024496C alleles were associated to an increase risk to CCC development. Conclusions: Our data show that novel polymorphisms affecting IL12B and IL10, but not IFNG or IL4 genes play a role in genetic susceptibility to CCC development. This might indicate that the increased Th1 differentiation and IFN-γ production associated with CCC is genetically controlled.
Assuntos
Cardiomiopatia Chagásica/genética , Interleucina-10/genética , Subunidade p40 da Interleucina-12/genética , Diferenciação Celular , Cardiomiopatia Chagásica/imunologia , Doença Crônica , Progressão da Doença , Predisposição Genética para Doença , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Células Th1/imunologiaRESUMO
BACKGROUND: Chagas cardiomyopathy (ChCM) is a severe form of Chagas disease and a major cause of cardiovascular morbidity and mortality. The dysregulation of the immune response leads to cardiac remodeling and functional disruptions, resulting in life-threatening complications. Conventional diagnostic methods have limitations, and therapeutic response evaluation is challenging. MicroRNAs (miRNAs), important regulators of gene expression, show potential as biomarkers for diagnosis and prognosis. AIM: This review aims to summarize experimental findings on miRNA expression in ChCM and explore the potential of these miRNAs as biomarkers of Chagas disease. METHODS: The search was conducted in the US National Library of Medicine MEDLINE/PubMed public database using the terms "Chagas cardiomyopathy" OR "Chagas disease" AND "microRNA" OR "miRNA" OR "miR." Additionally, bioinformatics analysis was performed to investigate miRNA-target interactions and explore enrichment pathways of gene ontology biological processes and molecular functions. RESULTS: The miR-21, miR-146b, miR-146a, and miR-155 consistently exhibited up-regulation, whereas miR-145 was down-regulated in ChCM. These specific miRNAs have been linked to fibrosis, immune response, and inflammatory processes in heart tissue. Moreover, the findings from various studies indicate that these miRNAs have the potential as biomarkers for the disease and could be targeted in therapeutic strategies for ChCM. CONCLUSION: In this review, we point out miR-21, miR-146b, miR-146a, miR-155, and miR-145-5p role in the complex mechanisms of ChCM. These miRNAs have been shown as potential biomarkers for precise diagnosis, reliable prognostic evaluation, and effective treatment strategies in the ChCM.
Assuntos
Humanos , Cardiomiopatia Chagásica/metabolismo , Doença de Chagas , Biomarcadores/metabolismo , Regulação para Cima , MicroRNAsRESUMO
BACKGROUND: Abdominal aortic aneurysm (AAA) is a pathological enlargement of infrarenal aorta close to the aortic bifurcation, and it is an important cause of mortality in the elderly. Therefore, the biomarker identification for early diagnosis is of great interest for clinical benefit. It is known that microRNAs (miRNAs) have important roles via target genes regulation in many diseases. This study aimed to identify miRNAs and their target genes involved in the pathogenesis of AAA. METHODS: Tissue samples were obtained from patients who underwent AAA surgery and from organ donors (control group). Quantitative PCR Array was applied to assess 84 genes and 384 miRNAs aiming to identify differentially expressed targets (AAA n = 6, control n = 6), followed by validation in a new cohort (AAA n = 18, control n = 6) by regular qPCR. The functional interaction between validated miRNAs and target genes was performed by the Ingenuity Pathway Analysis (IPA) software. RESULTS: The screening cohort assessed by PCR array identified 10 genes and 59 miRNAs differentially expressed (≥2-fold change, p<0.05). Among these, IPA identified 5 genes and 9 miRNAs with paired interaction. ALOX5, PTGIS, CX3CL1 genes, and miR-193a-3p, 125b-5p, 150-5p maintained a statistical significance in the validation cohort. IPA analysis based on the validated genes and miRNAs revealed that eicosanoid and metalloproteinase/TIMP synthesis are potentially involved in AAA. CONCLUSION: Paired interactions of differentially expressed ALOX5, PTGIS, CX3CL1 genes, and miR-193b-3p, 125b-5p, 150-5p revealed a potentially significant role of the eicosanoid synthesis and metalloproteinase/TIMP pathways in the AAA pathogenesis.
Assuntos
Aneurisma da Aorta Abdominal/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Adulto , Idoso , Aneurisma da Aorta Abdominal/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genéticaRESUMO
ABSTRACT: Vaccines are critical costeffective tools to control the COVID19 pandemic. The heterologous primeboost vaccination has been used by many countries to overcome supply issues, so the effectiveness and safety of this strategy need to be better clarified. This study aims to verify the effect of heterologous primeboost COVID19 vaccination on healthcare professionals from Dante Pazzanese Hospital in Brazil. It was performed serological assays of vaccinated individuals after 2dose of CoronaVac (Sinovac; n = 89) or ChAdOx1 nCoV19 (OxfordAstraZeneca; n = 166) followed by a BNT162b2 booster (PfizerBioNTech; n = 255). The serum antibodies antiS (spike), antiN (nucleocapsid), and antiRBD (receptor binding domain) were assessed by enzymelinked immunosorbent assay. The heterologous booster dose induced a 10fold higher antiSpike antibody regardless of the 2dose of a prime vaccine. It was strikingly observed that BNT162b2 enhanced levels of antispike antibodies, even in those individuals who did not previously respond to the 2dose of CoronaVac. In conclusion, the heterologous scheme of vaccination using mRNA as a booster vaccine efficiently enhanced the antibody response against SARSCoV2, especially benefiting those elderly who were seronegative with a virusinactivated vaccine.
Assuntos
Humanos , Imunoglobulina G , Nucleocapsídeo , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2RESUMO
INTRODUÇÃO: A varfarina é um anticoagulante utilizado na prevenção e tratamento de doenças tromboembólicas. Nos idosos, a principal indicação é fibrilação atrial. O exame mais utilizado para controle da anticoagulação é o tempo de protrombina, através do cálculo da razão normalizada internacional (RNI), na faixa 2-3, que requerem um monitoramento especial devido a idade, dificuldades na adesão, polimedicação ou comorbidades. Embora seja conhecido que os fatores genéticos influenciam na resposta terapêutica, na maioria dos hospitais a farmacogenética ainda não é considerada no cálculo de ajuste de dose. Portadores do genótipo rs9934438 AA requerem menor dose comparado com genótipo AG ou GG. O escore SAMe- -TT2R2 obtido por meio de algumas variáveis visa predizer quais os pacientes em uso de varfarina atingirão taxas de INR aceitáveis e, por consequência, um tempo na faixa terapêutica (TFT) adequado. Apostolakis, propuseram e validaram o escore SAMe-TT2R2 (S=sexo; A =idade OBJETIVO: Visando estabelecer uma conduta terapêutica personalizada, o presente estudo tem como objetivo avaliar correlação entre o polimorfismo rs9934438 do gene VKORC1 e correlaciona-lo com o escore SAME-TT2R2 na predição da qualidade da anticoagulação em uso de varfarina. MÉTODOS e RESULTADOS: Foram incluídos 29 pacientes, idade de 81,72 (±4,07), de ambos os sexos e em uso de varfarina. A análise do polimorfismofoi realizada através da PCR em tempo real utilizando os reagentes do kit TaqMan™ Sample-to-SNP™ e o sistema de detecção TaqMan® SNP Genotyping Assay. As análises estatísticas foram realizadas utilizando o pacote SPSS v. 16.0 e nível de significância adotado foi de 5% e o Escore SAME-TT2R2 foi calculado após entrevista. Os Escores Chadsvasc2 = 4,34 (±1,17), Hasbled = 2,24 (±0,68) e SAME-TT2R2 = 2,31(±1,28), a dose semanal variou de 10 a 55 mg. Apesar de ser um estudo piloto, com baixo amostra, a distribuição dos genótipos está em equilíbrio gênico, segundo Hardy-Weinberg (AA=24,3%, AG=41,3%, GG= 34,4%). Os portadores do genótipo AA necessitaram de menor dose para atingir a TFT quando comparados aos portadores do genótipo GG: 26,6 versus 39,7 mg/semana, corroborando o resultado do SAME-TT2R2 = 2 no grupo AA comparado ao GG que foi de 3. CONCLUSÃO: Os resultados mostram que o polimorfismo rs9934438 está associado com a dose semanal de varfarina administrada aos pacientes idosos de pelo menos 30% e com correspondência ao Escore SAME-TT2R2 que demostrou um índice menor.
Assuntos
AnticoagulantesRESUMO
Cardiomyopathies are major causes of heart failure. Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central and South America. Thirty percent of cases evolve into chronic chagas cardiomyopathy (CCC), which has worse prognosis as compared with other cardiomyopathies. In vivo bioenergetic analysis and ex vivo proteomic analysis of myocardial tissues highlighted worse mitochondrial dysfunction in CCC, and previous studies identified nuclear-encoded mitochondrial gene variants segregating with CCC. Here, we assessed the role of the mitochondrial genome through mtDNA copy number variations and mtDNA haplotyping and sequencing from heart or blood tissues of severe, moderate CCC and asymptomatic/indeterminate Chagas disease as well as healthy controls as an attempt to help decipher mitochondrial-intrinsic genetic involvement in Chagas disease development. We have found that the mtDNA copy number was significantly lower in CCC than in heart tissue from healthy individuals, while blood mtDNA content was similar among asymptomatic Chagas disease, moderate, and severe CCC patients. An MtDNA haplogrouping study has indicated that African haplogroups were over represented in the Chagas subject groups in comparison with healthy Brazilian individuals. The European lineage is associated with protection against cardiomyopathy and the macro haplogroup H is associated with increased risk towards CCC. Using mitochondria DNA sequencing, 84 mtDNA-encoded protein sequence pathogenic variants were associated with CCC. Among them, two variants were associated to left ventricular non-compaction and two to hypertrophic cardiomyopathy. The finding that mitochondrial protein-coding SNPs and mitochondrial haplogroups associate with risk of evolving to CCC is consistent with a key role of mitochondrial DNA in the development of chronic chagas disease cardiomyopathy.