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2.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375194

RESUMO

Infectious diseases represent a relevant issue in lung cancer patients. Bacterial and viral infections might influence the patients' prognosis, both directly affecting the immune system and indirectly impairing the outcome of anticancer treatments, mainly immunotherapy. In this analysis, we aimed to review the current evidence in order to clarify the complex correlation between infections and lung cancer. In detail, we mainly explored the potential impact on immunotherapy outcome/safety of (1) bacterial infections, with a detailed focus on antibiotics; and (2) viral infections, discriminating among (a) human immune-deficiency virus (HIV), (b) hepatitis B/C virus (HBV-HCV), and (c) Sars-Cov-2. A series of studies suggested the prognostic impact of antibiotic therapy administration, timing, and exposure ratio in patients treated with immune checkpoint inhibitors, probably through an antibiotic-related microbiota dysbiosis. Although cancer patients with HIV, HBV, and HCV were usually excluded from clinical trials evaluating immunotherapy, some retrospective and prospective trials performed in these patient subgroups reported similar results compared to those described in not-infected patients, with a favorable safety profile. Moreover, patients with thoracic cancers are particularly at risk of COVID-19 severe outcomes and mortality. Few reports speculated about the prognostic implications of anticancer therapy, including immunotherapy, in lung cancer patients with concomitant Sars-Cov-2 infection, showing, to date, inconsistent results. The correlation between infectious diseases and immunotherapy remains to be further explored and clarified in the context of dedicated trials. In clinical practice, the accurate and prompt multidisciplinary management of lung cancer patients with infections should be encouraged in order to select the best treatment options for these patients, avoiding unexpected toxicities, while maintaining the anticancer effect.


Assuntos
Infecções Bacterianas/complicações , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Viroses/complicações , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/imunologia , Síndrome de Imunodeficiência Adquirida/patologia , Síndrome de Imunodeficiência Adquirida/terapia , Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/patologia , /patologia , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/virologia , HIV/efeitos dos fármacos , Hepatite B/complicações , Hepatite B/imunologia , Hepatite B/patologia , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Humanos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/virologia , Microbiota/efeitos dos fármacos , Microbiota/imunologia
3.
J Exp Med ; 217(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33002101

RESUMO

Eliminating the burden of disease caused by hepatitis C virus infection is proving difficult, despite the availability of curative drug treatments. Progress will require innovations in healthcare delivery and a deeper understanding of how the liver and other vital organs survive damage caused by chronic injury.


Assuntos
Hepatite C/patologia , Cirrose Hepática/patologia , Fígado/patologia , Progressão da Doença , Hepatite C/tratamento farmacológico , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico
4.
J Cancer Res Ther ; 16(3): 619-623, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719277

RESUMO

Introduction: Patients receiving treatment for head-and-neck squamous cell carcinoma (HNSCC) also may have coexisting viral infections caused by HIV, HBV, and HCV (seropositive). There is scarce literature regarding the clinical presentation and treatment outcomes for these patients with coexisting viral infections (seropositive HNSCC). We conducted this study to assess the clinical presentation and treatment outcomes (overall survival [OS] and disease-specific survival [DSS]) of seropositive HNSCC patients. Methodology: This was a retrospective cohort study on seropositive HNSCC patients registered at our center from 2012 to 2014. The viral infections were identified by the presence of the antibodies to these viruses in the patient's blood samples. Results: Out of the 19,137 HNSCC patients registered, 156 patients had HBV, HCV, and/or HIV infection. Among these, HBV infection was the most common (n = 86/156, 55.1%) followed by HIV infection (n = 36/156, 23.1%) and HCV infection (n = 29/156, 18.6%). The oral cavity was the most common subsite involved. Majority of these patients presented at an advanced stage (advanced T stage - 71.8% and node positive - 62.2%). The majority of the patients received curative-intent treatment (65.4%). The OS at 3 years for these HNSCC patients with coexisting HIV, HBV, and HCV infection was 60%, 62.6%, and 57.5%, respectively, and their DSS at 3 years was 58.8%, 78.6%, and 53.8%, respectively. Conclusions: Seropositive patients with HNSCC often present in the advanced stage but have a good survival if treated appropriately.


Assuntos
Soropositividade para HIV/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Anticorpos Anti-HIV/sangue , Soropositividade para HIV/imunologia , Soropositividade para HIV/patologia , Soropositividade para HIV/virologia , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Hepatite B/imunologia , Hepatite B/patologia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Índia/epidemiologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Taxa de Sobrevida
5.
Anticancer Res ; 40(7): 3983-3990, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620641

RESUMO

BACKGROUND/AIM: Few studies have studied micro hepatic vein invasion in hepatocellular carcinoma (HCC). We explored the correlation between hepatic vein invasion and hepatitis B/C virus infection. PATIENTS AND METHODS: Between April 2000 and February 2018, 869 patients underwent liver resection for HCC at a single center. The patients were divided into two groups: those with micro hepatic vein invasion (VV+) and those without (VV-). The clinical data, overall survival (OS) and correlations with the presence of hepatitis B and C viruses were investigated. RESULTS: There were 817 VV- patients and 43 VV+ patients. OS was 66.2 months for VV- patients and 9.9 months for VV+ patients (p=0.0010). VV+ patients had significantly higher levels of serum HBV DNA (p=0.016). CONCLUSION: HCC patients with micro hepatic vein invasion showed significantly shorter OS. A higher level of HBV DNA appears to be a risk factor for micro hepatic vein invasion.


Assuntos
Carcinoma Hepatocelular/patologia , Veias Hepáticas/patologia , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , DNA Viral/sangue , Feminino , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite C/patologia , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
PLoS One ; 15(5): e0233702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442221

RESUMO

Liver fibrosis is a manifestation of chronic liver injury. It leads to hepatic dysfunction and is a critical element in the pathogenesis of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSC) plays a central role in liver fibrogenesis of different etiologies. To elucidate the molecular mechanism of this phenomenon, it is important to analyze the changes in gene expression that accompany the HSC activation process. In this study, we isolated quiescent and activated HSCs from control mice and mice with CCl4-induced liver fibrosis, respectively, and performed RNA sequencing to compare the differences in gene expression patterns between the two types of HSCs. We also reanalyzed public gene expression data for fibrotic liver tissues isolated from patients with HBV infection, HCV infection, and nonalcoholic fatty liver disease to investigate the gene expression changes during liver fibrosis of these three etiologies. We detected 146 upregulated and 18 downregulated genes in activated HSCs, which were implicated in liver fibrosis as well. Among the overlapping genes, seven transcription factor-encoding genes, ARID5B, GATA6, MITF, PBX1, PLAGL1, SOX4, and SOX9, were upregulated, while one, RXRA, was downregulated. These genes were suggested to play a critical role in HSC activation, and subsequently, in the promotion of liver fibrosis. We undertook the RNA sequencing of quiescent and activated HSCs and analyzed the expression profiles of genes associated with HSC activation in liver fibrotic tissues from different liver diseases, and also aimed to elucidate the changes in gene expression patterns associated with HSC activation and liver fibrosis.


Assuntos
Hepacivirus/metabolismo , Células Estreladas do Fígado/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Hepatite C/metabolismo , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/virologia , Hepatite B/patologia , Hepatite C/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de Transcrição/biossíntese
7.
Transplantation ; 104(6): e164-e173, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32150036

RESUMO

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) are waitlisted at older ages than individuals with other liver diseases, but the effect of age on liver transplantation (LT) outcomes in this population and whether it differs from other etiologies is not known. We aimed to evaluate the impact of age on LT outcomes in NASH. METHODS: The United Network for Organ Sharing database was used to identify adults with NASH, hepatitis C virus (HCV) infection, and alcohol-related liver disease (ALD) listed for LT during 2004-2017. Patients were split into age groups (18-49, 50-54, 55-59, 60-64, 65-69, ≥70), and their outcomes were compared. RESULTS: From 2004 to 2017, 14 197 adults with NASH were waitlisted, and the proportion ≥65 increased from 15.8% to 28.9%. NASH patients ages 65-69 had an increased risk of waitlist and posttransplant mortality compared to younger groups, whereas the outcomes in ages 60-64 and 55-59 were similar. The outcomes of individuals with NASH were similar to patients of the same age group with ALD or HCV. Functional status and dialysis were predictors of posttransplant mortality in individuals ≥65 with NASH, and cardiovascular disease was the leading cause of death. CONCLUSIONS: Older NASH patients (≥65) have an increased risk of waitlist and posttransplant mortality compared to younger individuals, although outcomes were similar to patients with ALD or HCV of corresponding age. These individuals should be carefully evaluated prior to LT, considering their functional status, renal function, and cardiovascular risk. Further studies are needed to optimize outcomes in this growing population of transplant candidates.


Assuntos
Doença Hepática Terminal/cirurgia , Fígado Gorduroso Alcoólico/cirurgia , Hepatite C/cirurgia , Transplante de Fígado/estatística & dados numéricos , Hepatopatia Gordurosa não Alcoólica/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Causas de Morte , Progressão da Doença , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Fígado Gorduroso Alcoólico/mortalidade , Fígado Gorduroso Alcoólico/patologia , Feminino , Hepatite C/mortalidade , Hepatite C/patologia , Humanos , Transplante de Fígado/normas , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/patologia , Seleção de Pacientes , Período Pós-Operatório , Estados Unidos/epidemiologia , Listas de Espera/mortalidade , Adulto Jovem
9.
Cancer Epidemiol ; 65: 101691, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32088651

RESUMO

BACKGROUND: A growing body of evidence has suggested an association between Hepatitis C virus (HCV) infection and risk of pancreatic cancer (PAC). Herein, we conducted a meta-analysis of available evidence to explore this association. METHODS: We systematically retrieved studies that investigated the association between HCV infection and risk of PAC. Pooled odds ratio (OR) with corresponding 95 % confidence interval (CI) of PAC for patients with HCV infection was calculated using the fixed- or random-effects model. RESULTS: A total of 16 studies (8 cohort and 8 case-control) were included in this meta-analysis. Combined, patients with HCV infection were more likely to develop PAC than people without it (pooled OR = 1.51, 95 % CI: 1.31, 1.74; I2 = 63.49 %, p-value for heterogeneity< 0.001). Studies that adjusted their results for diabetes, chronic pancreatitis, alcohol intake, and smoking showed lower ORs than studies that did not adjust for them. CONCLUSION: HCV infection was associated with increased risk of PAC, but this association was attenuated among studies that adjusted their results for potential risk factors for PAC. Future prospective cohort studies are needed to confirm this association.


Assuntos
Hepatite C/epidemiologia , Hepatite C/patologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/virologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Fatores de Risco
10.
Clin Exp Rheumatol ; 38 Suppl 124(2): 139-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31969220

RESUMO

OBJECTIVES: Essential mixed cryoglobulinaemia (EMC) is a disorder of B-cells producing rheumatoid factor (RF), and is clinically and immunologically similar to mixed cryoglobulinaemia (MC) related to hepatitis C virus (HCV-MC). We report here the first comprehensive analysis of B-cell clonality, phenotype and function in EMC. METHODS: The study population included 16 patients with EMC and 24 patients with HCV-MC. Molecular analysis was done for the detection of circulating clonal B cells and for B cell receptor sequencing. B-cell phenotype, proliferative response, apoptosis and ERK signaling were analysed by flow cytometry. RESULTS: Molecular analysis of immunoglobulin genes rearrangements revealed circulating B-cell clones in about half of patients, on average of smaller size than those found in HCV-MC patients. Sequence analysis showed usage of the same stereotyped RF-encoding B-cell receptors frequently expressed in HCV-MC and in primary Sjögren's syndrome. B-cells with low expression of CD21 (CD21low) and unusual homing and inhibitory receptors were increased in EMC and in HCV-MC, but at a significantly lower extent in the former. The CD21low B-cells of EMC and HCV-MC patients shared functional features of exhaustion and anergy, namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis. CONCLUSIONS: Our findings suggest a common pathogenetic mechanism in EMC, HCV-MC and primary Sjögren's syndrome, consisting of autoantigen-driven clonal expansion and exhaustion of selected RF-producing B-cells. The more massive clonal expansion in HCV-MC may be due to co-stimulatory signals provided by the virus.


Assuntos
Autoantígenos/imunologia , Linfócitos B/imunologia , Crioglobulinemia/patologia , Hepatite C/patologia , Fator Reumatoide , Linfócitos B/patologia , Crioglobulinemia/virologia , Hepacivirus , Humanos
11.
J Biol Chem ; 295(7): 1843-1856, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31929110

RESUMO

Viruses depend on the host cell translation machinery for their replication, and one common strategy is the presence of internal ribosome entry sites (IRESs) in the viral RNAs, using different sets of host translation initiation factors. The hepatitis C virus (HCV) IRES binds eukaryotic translation initiation factor 3 (eIF3), but the exact functional role of the eIF3 complex and of its subunits remains to be precisely defined. Toward this goal, here we focused on eIF3 subunit e. We used an in vitro assay combining a ribosome-depleted rabbit reticulocyte lysate and ribosomes prepared from HeLa or Huh-7.5 cells transfected with either control or eIF3e siRNAs. eIF3e silencing reduced translation mediated by the 5'UTR of various cellular genes and HCV-like IRESs. However, this effect was not observed with the bona fide HCV IRES. Silencing of eIF3e reduced the intracellular levels of the c, d, and l subunits of eIF3 and their association with the eIF3 core subunit a. A pulldown analysis of eIF3 subunits associated with the HCV IRES disclosed similar effects and that the a subunit is critical for binding to the HCV IRES. Carrying out HCV infections of control and eIF3e-silenced Huh-7.5 cells, we found that in agreement with the in vitro findings, eIF3e silencing does not reduce HCV replication and viral protein expression. We conclude that unlike for host cellular mRNAs, the entire eIF3 is not required for HCV RNA translation, favoring viral expression under conditions of low eIF3e levels.


Assuntos
Fator de Iniciação 3 em Eucariotos/genética , Hepacivirus/genética , Hepatite C/genética , Sítios Internos de Entrada Ribossomal/genética , Animais , Linhagem Celular , Hepacivirus/patogenicidade , Hepatite C/patologia , Hepatite C/virologia , Humanos , Ligação Proteica/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , RNA Viral/química , RNA Viral/genética , Coelhos , Ribossomos/química , Ribossomos/genética , Proteínas Virais/química , Proteínas Virais/genética
12.
J Clin Invest ; 130(2): 768-773, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904582

RESUMO

CD4+ T cell failure is a hallmark of chronic hepatitis C virus (HCV) infection. However, the mechanisms underlying the impairment and loss of virus-specific CD4+ T cells in persisting HCV infection remain unclear. Here we examined HCV-specific CD4+ T cells longitudinally during acute infection with different infection outcomes. We found that HCV-specific CD4+ T cells are characterized by expression of a narrower range of T cell inhibitory receptors compared with CD8+ T cells, with initially high expression levels of PD-1 and CTLA-4 that were associated with negative regulation of proliferation in all patients, irrespective of outcome. In addition, HCV-specific CD4+ T cells were phenotypically similar during early resolving and persistent infection and secreted similar levels of cytokines. However, upon viral control, CD4+ T cells quickly downregulated inhibitory receptors and differentiated into long-lived memory cells. In contrast, persisting viremia continued to drive T cell activation and PD-1 and CTLA-4 expression, and blocked T cell differentiation, until the cells quickly disappeared from the circulation. Our data support an important and physiological role for inhibitory receptor-mediated regulation of CD4+ T cells in early HCV infection, irrespective of outcome, with persistent HCV viremia leading to sustained upregulation of PD-1 and CTLA-4.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Hepatite C/patologia , Humanos , Masculino , Pessoa de Meia-Idade
13.
Gastroenterol. hepatol. (Ed. impr.) ; 43(1): 14-21, ene. 2020. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-188286

RESUMO

Introduction: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. Aim: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). Patients and methods: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. Results: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). Discussion: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH


Introducción: El diagnóstico de la recurrencia grave de la hepatitis C se basa en criterios histológicos y analíticos. Sin embargo, existe poca información respecto su correlación. Objetivo: Evaluar la precisión de los criterios analíticos el diagnóstico de la hepatitis colestásica fibrosante (HCF). Pacientes y métodos: Análisis retrospectivo de pacientes con una recidiva grave precoz del virus de la hepatitis C (VHC) tras el trasplante hepático (TH) en 2 hospitales universitarios europeos entre 2000-2014. Los pacientes se clasificaron según criterios analíticos en HCF, hepatitis colestásica (HC) y hepatitis aguda no colestásica (HANC). Las características histológicas también fueron evaluadas. Resultados: Se incluyeron 70 pacientes que desarrollaron una recurrencia grave del VHC en el primer año tras TH con una biopsia hepática disponible. La mayoría eran varones (70%) con mediana de edad de 58 años (50-64) y genotipo 1b (71,4%). La mediana de tiempo desde el TH hasta el diagnóstico de la recurrencia fue de 2,96 meses (2,1-5,3). Treinta y nueve pacientes fueron clasificados como HCF, 21 como HC y 10 como HANC. La balonización intensa y reacción ductular se asociaron con HCF con una OR de 4,66 (p=0,047) y 20,58 (p=0,025), respectivamente. Considerando la biopsia hepática como gold standard, la sensibilidad, especificidad y valores predictivos positivo y negativo de los criterios analíticos fueron 0,8, 0,5, 0,3 y 0,9, respectivamente. Sin embargo, la correlación entre ambos fue escasa (k=0,033). Discusión: Los criterios analíticos podrían utilizarse para descartar la presencia de HCF, pero la biopsia sigue siendo obligatoria para el diagnóstico. La reacción ductular y la balonización son predictores de HCF


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Hepatite C/patologia , Transplante de Fígado/efeitos adversos , Hepatócitos/patologia , Hepatite C/diagnóstico , Hepatite C/etiologia , Estudos Retrospectivos , Recidiva , Biópsia , Fígado/patologia , Sensibilidade e Especificidade , Análise Multivariada
14.
Clin Exp Immunol ; 199(2): 163-171, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31618438

RESUMO

Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)-related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti-phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still-unknown pathways.


Assuntos
Doenças Autoimunes/sangue , Crioglobulinemia/sangue , Hepacivirus , Hepatite C/sangue , Cadeias kappa de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Doenças Reumáticas/sangue , Idoso , Doenças Autoimunes/imunologia , Crioglobulinemia/imunologia , Feminino , Hepatite C/imunologia , Hepatite C/patologia , Humanos , Cadeias kappa de Imunoglobulina/imunologia , Cadeias lambda de Imunoglobulina/imunologia , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/imunologia
15.
Gastroenterol Hepatol ; 43(1): 14-21, 2020 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31495536

RESUMO

INTRODUCTION: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. AIM: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). PATIENTS AND METHODS: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. RESULTS: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). DISCUSSION: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH.


Assuntos
Ductos Biliares/patologia , Colestase/patologia , Hepatite C/patologia , Hepatócitos/patologia , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/patologia , Ductos Biliares/diagnóstico por imagem , Biópsia , Colestase/classificação , Colestase/diagnóstico , Colestase/cirurgia , Feminino , Hepatite C/classificação , Hepatite C/diagnóstico , Hepatite C/cirurgia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/diagnóstico , Recidiva , Estudos Retrospectivos , Fatores de Tempo
16.
Carcinogenesis ; 41(2): 159-170, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31300810

RESUMO

Excess consumption of trans-fatty acid (TFA), an unsaturated fatty acid containing trans double bonds, is a major risk factor for cardiovascular disease and metabolic syndrome. However, little is known about the link between TFA and hepatocellular carcinoma (HCC) despite it being a frequent form of cancer in humans. In this study, the impact of excessive dietary TFA on hepatic tumorigenesis was assessed using hepatitis C virus (HCV) core gene transgenic mice that spontaneously developed HCC. Male transgenic mice were treated for 5 months with either a control diet or an isocaloric TFA-rich diet that replaced the majority of soybean oil with shortening. The prevalence of liver tumors was significantly higher in TFA-rich diet-fed transgenic mice compared with control diet-fed transgenic mice. The TFA-rich diet significantly increased the expression of pro-inflammatory cytokines, as well as oxidative and endoplasmic reticulum stress, and activated nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), leading to high p62/sequestosome 1 (SQSTM1) expression. Furthermore, the TFA diet activated extracellular signal-regulated kinase (ERK) and stimulated the Wnt/ß-catenin signaling pathway, synergistically upregulating cyclin D1 and c-Myc, driving cell proliferation. Excess TFA intake also promoted fibrogenesis and ductular reaction, presumably contributing to accelerated liver tumorigenesis. In conclusion, these results demonstrate that a TFA-rich diet promotes hepatic tumorigenesis, mainly due to persistent activation of NF-κB and NRF2-p62/SQSTM1 signaling, ERK and Wnt/ß-catenin pathways and fibrogenesis. Therefore, HCV-infected patients should avoid a TFA-rich diet to prevent liver tumor development.


Assuntos
Carcinoma Hepatocelular/patologia , Gorduras na Dieta/efeitos adversos , Hepatite C/patologia , Neoplasias Hepáticas/patologia , Ácidos Graxos Trans/efeitos adversos , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/virologia , Proliferação de Células , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Fibrose , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/genética , Hepatite C/virologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/virologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Transgênicos , Fatores de Risco , Ácidos Graxos Trans/administração & dosagem , Regulação para Cima , Proteínas do Core Viral/genética , Via de Sinalização Wnt
17.
Rev. Ciênc. Plur ; 6(3): 35-52, 2020. tab
Artigo em Português | LILACS, BBO - Odontologia | ID: biblio-1128058

RESUMO

Introdução:Considerado um grave problema de saúde pública, a Hepatite é uma doença que se destaca por ser silenciosa e nem sempre apresentar sinais e sintomas, favorecendo assim o atraso no seu diagnóstico.Objetivo:Diante de um crescimento contínuo no estado do Rio Grande do Norte (RN) de casos de Hepatite B e C, o presentetrabalho objetivouidentificar o perfil epidemiológico da população do RN diagnosticada e notificada com hepatites B e/ou C entre os anos de 2007 a 2015, segundo as regionais de saúde. Método:Trata-se de um estudo observacional, descritivo, do tipo transversal, que utilizou uma consulta ao DATASUS para a obtenção dos dados. Resultados:Verificou-se que houve predominância do sexo masculino dentre os casos de hepatite B e C, assim como a faixa etária de 20 a 39 anos, considerando-se hepatite B e 40 a 59 para a hepatite C. Ademais, a raça parda foi a predominante em ambos os tipos virais; a 7ª região de saúde foi a regional que mais possuiu notificação e houve uma maior prevalência dos casos de hepatite B e C em pessoas com menores níveis de escolaridade. Conclusões:Concluiu-se que o perfil das hepatites B e C no estado do Rio Grande do Norte tem se mostrado semelhante aos dados do Brasil, com uma alta prevalência, sugerindo assim a necessidade de se ter uma maior articulação entre os setores e departamentos responsáveis pelo registro e controle das hepatites virais do tipo B e C e a importância do gestor em saúde frente a essas situações para a realização de medidas preventivas (AU).


Introduction:Considered a serious public health problem, Hepatitis is a disease that stands out for being silent and not always showing signs and symptoms, thus favoring the delay in its diagnosis.Objective:Faced with a continuous growth in the state of Rio Grande do Norte (RN) of cases of Hepatitis B and C, the present study aimed to identify the epidemiological profile of the population of the RN diagnosed and notified with hepatitis B and / or C between the years 2007 to 2015, according to regional health.Methods:This is an observational, descriptive, cross-sectional study that used a consultation with DATASUS to obtain the data.Results:It was found that there was a male predominance among the cases of hepatitis B and C, as well as the age group of 20 to 39 years, considering hepatitis B and 40 to 59 for hepatitis C. Furthermore, the brown race was the predominant in both viral types; the 7th health region was the region with the most reports and there was a higher prevalence of cases of hepatitis B and C in people with lower levels of education.Conclusions:It was concluded that the profile of hepatitis B and C in the state of Rio Grande do Norte has shown to be similar to the data from Brazil, with a high prevalence, thus suggesting the need to have a greater articulation between the sectors and departments responsible for the registry and control of type B and C viral hepatitis and the importance of the health manager in face of these situations for carrying out preventive measures (AU).


Introducción:considerada como un grave problema de salud pública, la hepatitis es una enfermedad que destaca por ser silenciosa y no siempre muestra signos y síntomas, favoreciendo así el retraso en su diagnóstico. Objetivo:Frente aun crecimiento continuo en el estado de Rio Grande do Norte (RN) de casos de hepatitis B y C, el presente estudio tuvo como objetivo identificar el perfil epidemiológico de la población de NB diagnosticada y notificada con hepatitis B y / o C entre los años de 2007 a 2015, según la salud regional. Método:Este es un estudio observacional, descriptivo, transversal que utilizó una consulta con DATASUS para obtener los datos. Resultados:se encontró que había un predominio de hombres entre los casos de hepatitis B y C, así como el grupo de edad de 20 a 39 años, considerando la hepatitis B y 40 a 59 para la hepatitis C. Además, la raza marrón predominaba en ambos tipos virales; la séptima región de salud fue la región con más informes y hubo una mayor prevalencia de casos de hepatitis B y C en personas con niveles más bajos de educación. Conclusiones:Se concluyó que el perfil de hepatitis B y C en el estado de Rio Grande do Norte ha demostrado ser similar a los datos de Brasil, con una alta prevalencia, lo que sugiere la necesidad de una mayor articulación entre los sectores y departamentos responsables. para el registro y control de la hepatitis viral tipo B y C y la importancia del gerente de salud ante estas situaciones para llevar a cabo medidas preventivas (AU).


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Política Pública , Brasil/epidemiologia , Epidemiologia , Hepatite C/patologia , Hepatite B/patologia , Estudos Transversais/métodos , Estudos Observacionais como Assunto/métodos
18.
Cells ; 8(11)2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694343

RESUMO

Hepatocellular carcinoma (HCC) represents the fifth most common cancer worldwide and the third cause of cancer-related mortality. Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis, and eventually HCC. HCV is the most common risk factor for HCC in western countries and leads to a more aggressive and invasive disease with poorer patient survival rates. However, the mechanism by which the virus induces the metastatic spread of HCC tumor cells through the regulation of invadopodia, the key features of invasive cancer, is still unknown. Here, the integration of transcriptome with functional kinome screen revealed that HCV infection induced invasion and invadopodia-related gene expression combined with activation of host cell tyrosine kinases, leading to invadopodia formation and maturation and consequent cell invasiveness in vitro and in vivo. The promotion of invadopodia following HCV infection was mediated by the sustained stimulation of epidermal growth factor receptor (EGFR) via the viral NS3/4A protease that inactivates the T-cell protein tyrosine phosphatase (TC-PTP), which inhibits EGFR signaling. Characterization of an invadopodia-associated gene signature in HCV-mediated HCC tumors correlated with the invasiveness of HCC and poor patient prognosis. These findings might lead to new prognostic and therapeutic strategies for virus-mediated invasive cancer.


Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Hepacivirus/patogenicidade , Hepatite C/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Invasividade Neoplásica/patologia , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Receptores ErbB/genética , Expressão Gênica/genética , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Podossomos/genética , Podossomos/virologia , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Transdução de Sinais/genética
19.
Cells ; 8(10)2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652598

RESUMO

BACKGROUND: The role of regulatory T cells (Tregs) is now well established in the progression of hepatocellular carcinoma (HCC) linked to Hepatitis C virus (HCV) infection. However, nothing is known about the potential interplay between Tregs and HCV. In this pilot study, we have investigated the ability of Tregs to hang HCV on and the subsequent effect on their suppressive function and phenotype. Moreover, we have evaluated how HCV could promote the recruitment of Tregs by infected primary human hepatocytes. METHODS: Tregs of healthy donors were incubated with JFH-1/HCVcc. Viral inoculation was assessed using adapted assays (RT-qPCR, Flow Citometry (FACS) and Western Blot (WB). Expression of Tregs phenotypic (CD4, CD25, CD127 and Foxp3) and functional (IL-10, GZMB, TGF-ß1 and IL-2) markers was monitored by RT-qPCR, FACS and ELISA. Suppressive activity was validated by suppressive assays. Tregs recruitment by infected primary hepatic cells was evaluated using Boyden Chamber. RESULTS: Tregs express the classical HCV receptors (CD81, CLDN1 and LDLR) and some co-receptors (CD5). HCV inoculation significantly increases the suppressive phenotype and activity of Tregs, and raises their anergy by inducing an unexpected IL-2 production. Moreover, HCV infection induces the expression of chemokines (CCL17, CXCL16, and CCL20) by primary hepatic human hepatocytes and chemokine receptors (CCR4, CXCR6 and CCR6) by Tregs. Finally, infected hepatocytes have a significantly higher potential to recruit Tregs in a seemingly CCL20-dependent manner. CONCLUSIONS: Direct interaction between HCV and Tregs represents a newly defined mechanism that could potentiate HCV immune evasion and favor intratumoral recruitment contributing to HCC progression.


Assuntos
Hepacivirus/imunologia , Hepatite C/imunologia , Evasão da Resposta Imune , Fígado/imunologia , Linfócitos T Reguladores/imunologia , Antígenos de Diferenciação/imunologia , Regulação da Expressão Gênica/imunologia , Hepatite C/patologia , Humanos , Fígado/patologia , Fígado/virologia , Linfócitos T Reguladores/patologia
20.
Cells ; 8(11)2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652893

RESUMO

Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.


Assuntos
Autofagia Mediada por Chaperonas/fisiologia , Hepatite C/metabolismo , Fígado/metabolismo , Autofagia/fisiologia , Carcinoma Hepatocelular/patologia , Sobrevivência Celular , Diabetes Mellitus Tipo 2 , Estresse do Retículo Endoplasmático , Hepacivirus/metabolismo , Hepacivirus/patogenicidade , Hepatite C/patologia , Hepatite C Crônica/metabolismo , Hepatócitos/metabolismo , Humanos , Interferon-alfa/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Lisossomos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Microambiente Tumoral , Replicação Viral
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