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Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a severe hyperinflammatory illness that affects adults and is caused by an EBV infection. Without allogeneic hematopoietic stem cell transplantation (allo-HSCT), the overall survival of adult patients with EBV-HLH is unsatisfactory, necessitating the development of innovative therapeutic approaches. The clinical records of twelve EBV-HLH patients who received sintilimab therapy combined with ruxolitinib on a compassionate basis at the First Affiliated Hospital of Soochow University were retrospectively examined in this investigation. All the patients responded without fever, but three patients relapsed within a week. Among the nine patients achieving complete response (CR), 55.6% (5/9) maintained CR for >4.5 months, and 33.3% (3/9) relapsed following CR. Neither patients with no response (NR) nor relapsed patients were fit for allo-HSCT, and all died soon after discharge. Six patients had clinical CR with a median follow-up of 5 (4.4-14.7) months. There were no documented severe negative effects. Additional information on this innovative treatment for adult EBV-HLH is provided in our report.
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Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Humanos , Adulto , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. METHODS: In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. RESULTS: We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. CONCLUSIONS: Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.
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This study aimed to assess the protective effect of nitroglycerin, a commonly used drug in cardiovascular diseases, on mice with acute liver injury induced by carbon tetrachloride (CCl4 ). The mice were randomly divided into three groups: control, CCl4 , and CCl4 + nitroglycerin. They were killed at 0, 6, 12, 24, and 48 h after treatment. Blood and liver tissue samples were collected for analysis. Analysis of the amounts of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hepatic glutathione (GSH), and malondialdehyde (MDA) showed that nitroglycerin protected against CCl4 -induced acute liver injury. Liver histological analysis provided further evidence of the protective effect of nitroglycerin. Furthermore, we found that nitroglycerin suppressed the increase of T helper 17 (Th17) cells in CCl4 -induced acute liver injury mice. The results indicate that nitroglycerin is a potential candidate for hepatic disease.
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Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Nitroglicerina/uso terapêutico , Células Th17/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glutationa/metabolismo , Interleucina-17/metabolismo , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos C57BL , Nitroglicerina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
Fibroblast-like synoviocytes (FLS), synovial tissue-specific cells, are key effector cells during the pathogenesis of rheumatoid arthritis (RA). Our previous study has shown that tripartite motif-containing protein 3 (TRIM3) overexpression inhibits the proliferation and cytokine secretion of RA FLS. Experiments with gene knockout mice have suggested the important roles of forkhead box o3a (Foxo3a) in RA pathogenesis. The present study aimed to investigate the correlation between Foxo3a and TRIM3 during RA pathogenesis. The expression of Foxo3a and TRIM3 was reduced in RA synovial tissues in comparison to healthy controls, and Foxo3a messenger RNA (mRNA) expression in RA synovial tissues correlated positively with TRIM3 mRNA expression. We found that stimulation with lipopolysaccharide (LPS) caused the downregulation of Foxo3a and TRIM3 in FLS. Foxo3a or TRIM3 overexpression significantly attenuated the promoting effects of LPS on cell proliferation and the release of tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1ß. In addition, Foxo3a suppressed the inhibitory effects of LPS on the mRNA and protein levels of TRIM3, as well as the activity of TRIM3 promoter. Foxo3a or TRIM3 overexpression attenuated collagen-induced arthritis in rats. Furthermore, knockdown of TRIM3 significantly suppressed the effects of Foxo3a overexpression on LPS-activated FLS. In summary, our findings suggested that Foxo3a exerted inhibitory effects on LPS-induced proliferation and inflammation through increasing TRIM3 transcription. The decreased expression of Foxo3a may contribute to the RA pathogenesis.
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Proteínas de Transporte/metabolismo , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Proteína Forkhead Box O3/metabolismo , Inflamação/metabolismo , Sinoviócitos/metabolismo , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Fibroblastos/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Sinoviócitos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. DESIGN: The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. RESULTS: Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. CONCLUSIONS: Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.
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Insuficiência Hepática Crônica Agudizada/diagnóstico , Hepatite B Crônica/diagnóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/microbiologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Adulto , Bilirrubina/sangue , Biomarcadores/sangue , China/epidemiologia , Feminino , Hepatite B Crônica/mortalidade , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Hepatitis B virus (HBV) causes acute and chronic hepatitis, and is one of the major causes of cirrhosis and hepatocellular carcinoma. Accumulating evidence suggests that inflammation is the key factor for liver cirrhosis and hepatocellular carcinoma. MicroRNAs play important roles in many biological processes. Here, we aim to explore the function of microRNAs in the HBX-induced inflammation. First, microarray experiment showed that HBV+ liver samples expressed higher level of miR-203a compared to HBV- liver samples. To verify these alterations, HBx-coding plasmid was transfected into HepG2 cells to overexpress HBx protein. The real-time PCR results suggested that over-expression of HBx could induce up-regulation of miR-203a. To define how up-regulation of miR-203a can induce liver cells inflammation, we over-expressed miR-203a in HepG2 cells. Annexin V staining and BrdU staining suggested that overexpression of miR-203a significantly increased the cell apoptosis and proliferation, meanwhile, over-expression of miR-203a could lead to a decrease in G0/G1 phase cells and an increase in G2/M phase cells. Some cytokines production including IL-6 and IL-8 were significantly increased, but TGFß and IFNγ were decreased in miR-203a over-expressed HepG2 cells. Luciferase reporter assay experiments, protein mass-spectrum assay and real-time PCR all together demonstrated that Rap1a was the target gene of miR-203a. Further experiments showed that these alterations were modulated through PI3K/ERK/p38/NFκB pathways. These data suggested that HBV-infection could up-regulate the expression of miR-203a, thus down regulated the expression of Rap1a and affected the PI3K/ERK/p38/NFκB pathways, finally induced the hepatitis inflammation.
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Inflamação/genética , MicroRNAs/metabolismo , Transativadores/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Apoptose/genética , Ciclo Celular , Proliferação de Células , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Hep G2 , Vírus da Hepatite B/fisiologia , Humanos , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Virais Reguladoras e AcessóriasRESUMO
BACKGROUND: The risk factors for recurrence and death after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) remain poorly known. This study was aimed to study the 10-year overall survival (OS) of HCC treated by ultrasound (US)-guided RFA and the risk factors for recurrence and death. METHODS: Between June 2005 and June 2016, 1000 patients with HCC treated by US-guided RFA at 4 hospitals in China; among them, 525 patients met the criteria for radical ablation and 410 had high AFP levels before RFA treatment. Clinical and biochemical factors were tested for association with recurrence and survival. Patients were divided into the recurrence (n = 348) and no recurrence groups (n = 62). RESULTS: The 5- and 10-year survival rates were 66 and 35%, respectively. Tumor size (HR = 1.36, 95% CI 1.12-1.65), albumin levels (HR = 0.76, 95% CI 0.65-0.91), prothrombin time (HR = 2.18, 95% CI 1.54-3.10), and α-fetoprotein levels (HR = 1.13, 95% CI 1.00-1.26) were independently associated with mortality after RFA for HCC. Tumor size (HR = 1.27, 95% CI: 1.15-1.40), HBV-DNA (HR = 7.70, 95% CI 3.57-16.63), AFP levels before treatment (HR = 2.172, 95% CI 1.256-3.756, P = 0.006), and AFP response (HR = 4.722, 95% CI 1.053-21.184, P = 0.0427) were independently associated with the risk of recurrence of HCC after RFA. The median survival of the patients with and without recurrence after RFA was 54 (95% CI 45-58) and 62 (95% CI 48-80) months, respectively (log-rank, P = 0.04). CONCLUSIONS: Tumor size, albumin, prothrombin time, and α-fetoprotein levels were independently associated with mortality after US-guided RFA for HCC, while tumor size and HBV-DNA were independently associated with recurrence. Patients with recurrence had a poorer survival compared with those without.
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Carcinoma Hepatocelular/mortalidade , Ablação por Cateter/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Cirurgia Assistida por Computador/métodos , Ultrassonografia/métodos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: During the spring of 2013, a novel avian-origin influenza A (H7N9) virus emerged and spread among humans in China. Data were lacking on the clinical characteristics of the infections caused by this virus. METHODS: Using medical charts, we collected data on 111 patients with laboratory-confirmed avian-origin influenza A (H7N9) infection through May 10, 2013. RESULTS: Of the 111 patients we studied, 76.6% were admitted to an intensive care unit (ICU), and 27.0% died. The median age was 61 years, and 42.3% were 65 years of age or older; 31.5% were female. A total of 61.3% of the patients had at least one underlying medical condition. Fever and cough were the most common presenting symptoms. On admission, 108 patients (97.3%) had findings consistent with pneumonia. Bilateral ground-glass opacities and consolidation were the typical radiologic findings. Lymphocytopenia was observed in 88.3% of patients, and thrombocytopenia in 73.0%. Treatment with antiviral drugs was initiated in 108 patients (97.3%) at a median of 7 days after the onset of illness. The median times from the onset of illness and from the initiation of antiviral therapy to a negative viral test result on real-time reverse-transcriptase-polymerase-chain-reaction assay were 11 days (interquartile range, 9 to 16) and 6 days (interquartile range, 4 to 7), respectively. Multivariate analysis revealed that the presence of a coexisting medical condition was the only independent risk factor for the acute respiratory distress syndrome (ARDS) (odds ratio, 3.42; 95% confidence interval, 1.21 to 9.70; P=0.02). CONCLUSIONS: During the evaluation period, the novel H7N9 virus caused severe illness, including pneumonia and ARDS, with high rates of ICU admission and death. (Funded by the National Natural Science Foundation of China and others.).
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Vírus da Influenza A , Influenza Humana , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aves , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Vírus da Influenza A/classificação , Influenza Aviária/transmissão , Influenza Humana/complicações , Influenza Humana/epidemiologia , Influenza Humana/mortalidade , Influenza Humana/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/etiologia , Estudos Retrospectivos , Carga Viral , Adulto JovemRESUMO
OBJECTIVE: To determine the impact of adjuvant corticosteroids administered to patients hospitalized with influenza A (H7N9) viral pneumonia. DESIGN: The effects of adjuvant corticosteroids on mortality were assessed using multivariate Cox regression and a propensity score-matched case-control study. Nosocomial infections and viral shedding were also compared. SETTING: Hospitals with influenza A (H7N9) viral pneumonia patient admission in 84 cities and 16 provinces of Mainland China. PATIENTS: Adolescent and Adult patients aged >14 yr with severe laboratory-confirmed influenza A (H7N9) virus infections were screened from April 2013 to March 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study population comprised 288 cases who were hospitalized with influenza A (H7N9) viral pneumonia. The median age of the study population was 58 years, 69.8% of the cohort comprised male patients, and 51.4% had at least one type of underlying diseases. The in-hospital mortality was 31.9%. Two hundred and four patients (70.8%) received adjuvant corticosteroids; among them, 193 had hypoxemia and lung infiltrates, 11 had chronic obstructive pulmonary disease, and 11 had pneumonia only. Corticosteroids were initiated within 7 days (interquartile range, 5.0-9.4 d) of the onset of illness and the maximum dose administered was equivalent to 80-mg methylprednisolone (interquartile range, 40-120 mg). The patients were treated with corticosteroids for a median duration of 7 days (interquartile range, 4.0-11.3 d). Cox regression analysis showed that compared with the patients who did not receive corticosteroid, those who received corticosteroid had a significantly higher 60-day mortality (adjusted hazards ratio, 1.98; 95% CI, 1.03-3.79; p = 0.04). Subgroup analysis showed that high-dose corticosteroid therapy (> 150 mg/d methylprednisolone or equivalent) significantly increased both 30-day and 60-day mortality, whereas no significant impact was observed for low-to-moderate doses of corticosteroids (25-150 mg/d methylprednisolone or equivalent). The propensity score-matched case-control analysis showed that the median viral shedding time was much longer in the group that received high-dose corticosteroids (15 d), compared with patients who did not receive corticosteroids (13 d; p = 0.039). CONCLUSIONS: High-dose corticosteroids were associated with increased mortality and longer viral shedding in patients with influenza A (H7N9) viral pneumonia.
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Corticosteroides/administração & dosagem , Subtipo H7N9 do Vírus da Influenza A , Influenza Humana/complicações , Influenza Humana/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Estudos de Casos e Controles , China/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/virologia , Pontuação de Propensão , Modelos de Riscos Proporcionais , Fatores de Tempo , Eliminação de Partículas Virais/efeitos dos fármacos , Adulto JovemRESUMO
Mesenchymal stem cells (MSCs) possess potent immunosuppression capacity and could exert strong therapeutic effects in many diseases, especially inflammatory disorders, in animal models and clinical settings. Although inflammatory cytokines are critical in inducing the immune modulatory properties of MSCs, detailed molecular mechanisms are yet to be fully understood. TGF-ß is a well-known anti-inflammatory cytokine and exists in various inflammatory processes; therefore, we investigated whether it could synergize with MSCs in suppressing immune responses. To our surprise, we found that TGF-ß actually reversed the immunosuppressive effect of MSCs on anti-CD3 activated splenocytes. Using TGF-ß unresponsive MSCs, we demonstrated that the TGF-ß directly acted on MSCs. Furthermore, we showed that the effect of TGF-ß is exerted through inhibiting inflammatory cytokines induced inducible NO synthase (iNOS) expression in a SMAD3-dependent manner. Interestingly, we found that TGF-ß produced by MSCs could act in an autocrine manner to reduce inflammatory cytokine-induced inducible NO synthase expression by MSCs themselves. Therefore, our study revealed a previously unrecognized property of TGF-ß in promoting immune responses in the presence of MSCs.
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Tolerância Imunológica/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Fator de Crescimento Transformador beta/farmacologia , Animais , Comunicação Autócrina/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Tolerância Imunológica/genética , Células-Tronco Mesenquimais/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Proteína Smad3/metabolismo , Transcrição GênicaRESUMO
BACKGROUND: Plasma exchange (PE)-centered artificial liver support system reduced the high mortality rate of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). But the data were diverse in different medical centers. The present prospective nationwide study was to evaluate the effects of PE on patients with HBV-ACLF at different stages. METHODS: From December 2009 to December 2011, we evaluated 250 patients at different stages of HBV-ACLF from 10 major medical centers in China. All the laboratory parameters were collected at admission, before and after PE. RESULTS: Among the 250 patients who underwent 661 rounds of PE, one-month survival rate was 61.6%; 141 (56.4%) showed improvement after PE. Variables such as age (P=0.000), levels of total bilirubin (TB, P=0.000), direct bilirubin (P=0.000), total triglycerides (P=0.000), low-density lipoprotein (P=0.022), Na+ (P=0.014), Cl- (P=0.038), creatinine (Cr, P=0.007), fibrinogen (P=0.000), prothrombin time (PT, P=0.000), white blood cell (P=0.000), platelet (P=0.003) and MELD (P=0.000) were significantly related to prognosis. Multivariate logistic regression analysis showed that age, disease stage, TB, Cr and PT levels were independent risk factors of mortality among HBV-ACLF patients. CONCLUSIONS: PE can improve the clinical outcome of patients with HBV-ACLF. Levels of TB, Cr and PT, age and disease stage help to predict prognosis.
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Insuficiência Hepática Crônica Agudizada/terapia , Hepatite B/complicações , Fígado Artificial , Troca Plasmática , Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/mortalidade , Insuficiência Hepática Crônica Agudizada/virologia , Adolescente , Adulto , Fatores Etários , Idoso , Bilirrubina/sangue , Biomarcadores/sangue , Distribuição de Qui-Quadrado , China , Creatinina/sangue , Feminino , Hepatite B/diagnóstico , Hepatite B/mortalidade , Humanos , Fígado Artificial/efeitos adversos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Troca Plasmática/efeitos adversos , Troca Plasmática/mortalidade , Estudos Prospectivos , Tempo de Protrombina , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To investigate the effect and clinical significance of glucocorticoid on CD4+CD25+ regulatory T cells (Tregs) in patients with hepatitis B virus (HBV)-related pre-liver failure. METHODS: The subjects of this study included 78 patients with pre-liver failure induced by HBV (cases) and 24 healthy individuals (controls). Among the 78 cases, 42 received glucocorticoid treatment and 36 did not. Between-group differences in Tregs (in peripheral blood) were evaluated by flow cytometry and statistical analysis. RESULTS: Two weeks of glucocorticoid treatment led to an increase in Treg level compared to baseline (before therapy: 2.76 ± 0.73 vs. 3.88 ± 1.60). In addition, after the two weeks of glucocorticoid treatment, the Treg level of improved patients was significantly higher than that measured at baseline (before therapy: 2.70 ± 0.77 vs 3.97 ± 1.59, P < 0.05). CONCLUSION: Glucocorticoids up-regulate the expression of Treg cells, which may contribute to the immunological mechanism that protects pre-liver failure patients from deterioration of their condition. Careful inspection and monitoring of Treg levels may help improve prognosis of these patients.
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Glucocorticoides/uso terapêutico , Falência Hepática/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Falência Hepática/virologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: The prognosis of hepatocellular carcinoma (HCC) is poor and there is no stable and reliable molecular biomarker for evaluation. This study attempted to find reliable prognostic markers from tumor mutational profiles. METHODS: A total of 362 HCC samples with whole-exome sequencing were collected as discovery datasets, and 200 samples with targeted sequencing were used for validation of the relevant results. All HCC samples were obtained from previously published studies. Bayesian non-negative matrix factorization was used to extract mutational signatures, and multivariate Cox regression models were utilized to identify the prognostic role of mutational factors. Gene set enrichment analysis was employed to discover potential signaling pathways associated with specific mutational groups. RESULTS: In the HCC discovery dataset, a total of four mutational signatures (i.e., signatures 4, 6, 16, and 22) were extracted, of which signature 16 characterized by T>C mutations was observed to be associated with favorable HCC prognosis, and this correlation was also found in the validation dataset. Further analysis showed that patients with ARID1A mutations exhibited inferior survival outcomes in both discovery and validation datasets. Mechanistic exploration revealed that the presence of signature 16 was associated with better immune infiltration and tumor immunogenicity, while patients with ARID1A mutations were away from these favorable immunological features. CONCLUSION: By integrating somatic mutation data and clinical information of HCC, this study identified that signature 16 and ARID1A mutations were associated with better and worse outcomes respectively, providing a basis for prognosis prediction and clinical treatment strategies of HCC.
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BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment. METHODS: This study utilized the TCGA dataset and a collection of oxidative stress genes to determine the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures. RESULTS: Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A significant correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines. CONCLUSION: The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as a model to evaluate the risk of oxidative stress in HCC. Furthermore, there is a notable correlation between the expression of these risk model genes and tumor immunity.
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Cuproptosis has been recently used to indicate unique biological processes triggered by Cu action as a new term. This study aimed to explore the relationship between cuproptosis-related lncRNA and hepatocellular carcinoma (HCC) with regard to immunity and prognosis. RNA sequencing and the clinical data were downloaded from the TCGA database. The cuproptosis-related genes were sorted out through literature study. The cuproptosis-related IncRNA signature was identified by Cox regression analysis and the least absolute shrinkage and selection operator analysis. The K-M survival analysis, receiver operating characteristic analysis, and C-index analysis were adopted to evaluate the prognostic prediction performance of the signature. The functional enrichment, immune infiltration and tumor mutation analysis were further analyzed. Subsequently, we predicted the differences in chemosensitivity from tumor gene expression levels for some chemotherapy drugs. The prognostic signature consisting of 5 overall survival-related CUPlncRNAs. It showed an extraordinary ability to predict the prognoses of patients with HCC. The signature can predict the abundance of immune cell infiltration, immune functions, expression of immune checkpoint inhibitors, m6A genes, which was supported by the GO biological process and KEGG analysis. And it may also have a guiding effect in the sensitivity of different chemotherapeutic drugs and tumor mutation burden. We constructed a new cuproptosis-related lncRNA signature for HCC patients. The model can be used for prognostic prediction and immune evaluation, providing a reference for immunotherapies and targeted therapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/genética , RNA Longo não Codificante/genética , Neoplasias Hepáticas/genética , Prognóstico , Imunidade , ApoptoseRESUMO
Oxidative stress (OS) is a condition in which the body has an unbalanced oxidative and antioxidant effect. Oxidative stress has emerged as a critical component in the onset and progression of numerous diseases, including liver cancer and chronic liver disease caused by the hepatitis C virus and hepatitis B virus. Reactive oxygen species (ROS) are the most prevalent reactive chemical species involved in the oxidative stress response during the progression of the disease. Oxidative stress has a unique role in the development of hepatocellular carcinoma (HCC), and excessive ROS production is a common occurrence in liver illnesses of various etiologies. In response to various deleterious stimuli, the liver shows manifestations of lipid accumulation, oxidative damage, inflammatory infiltration, and immune response, which interact with each other in a mutually reinforcing manner, collectively exacerbating liver damage and malignant transformation. The intracellular buildup of ROS is a two-edged sword for tumor advancement. ROS are tumorigenic, and low amounts of ROS can trigger different signaling pathways that promote proliferation, survival, and migration, among other aspects. However, excessive oxidative stress can induce tumor cell death. Understanding the mechanisms of oxidative stress in hepatocellular carcinogenesis is beneficial for the prevention and surveillance of hepatocellular carcinoma in humans. An improved knowledge of the impacts and potential implications of oxidative stress regulation in therapeutic strategies will likely allow us to find new therapeutic targets for cancer. Oxidative stress also plays a significant role in the treatment of hepatocellular carcinoma and the mechanisms of drug resistance involved. This paper reviews recent studies on oxidative stress in HCC that are more reliable and important, and provides a more comprehensive view of the development of the treatment of HCC based on the relevant summaries of the effect of oxidative stress on the treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , CarcinogêneseRESUMO
This study explored the predictive value of the monocyte-to-lymphocyte ratio (MLR) and platelet-lymphocyte ratio (PLR) in patients with acute-on-chronic liver failure (ACLF). A retrospective analysis was carried out on 40 patients with ACLF from January 2018 and August 2019 in our hospital. The patient's clinical information during hospitalization was collected, and their survivals were followed for 3 months. MLR and PLR values of patients were compared, and the correlation between liver function indicators and prognosis was analyzed. We observed that MLR levels in the survival and death groups were 0.521 (0.311, 0.827) and 0.741 (0.442, 1.121), respectively. MLR levels were markedly enhanced in the death group compared to the survival group (P = 0.021). The receiver operating characteristic curve (ROC) exhibited that the area under the ROC curve and 95% confidence interval for the survival group was 0.641 (0.528-0.757). Survival analysis demonstrated that the 3-month survival of the high MLR group was markedly lower than that of the low MLR group (P = 0.001). Multivariate regression exposed that MLR and PLR were independent prognostic factors for ACLF. MLR and PLR could be prospective prognosticative markers of ACLF.
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BACKGROUND/AIMS: To assess the incidence of gastric cancer development in gastric benign ulcer patients and to evaluate the value of biopsy by taking specimens from both the base and edges of ulcers in contrast to the traditional biopsy which takes specimens from the edges of ulcers only. METHODOLOGY: An endoscopic followup of more than 1 year was conducted on 456 gastric ulcer patients in our hospital for a duration over 8 years. We collected clinical, endoscopic and pathological data and obtained at least 6 biopsies from both the edges and the bases of ulcers healing or complete healing, respectively and assessed H. pylori infection. RESULTS: Gastric cancers developed in 11 (2.41%) of 456 GU patients. In the experimental group, 3 cases that were diagnosed by histology showed adenocarcinoma with specimens taken from the ulcer bases and in the other 5 cases the specimens were taken from the ulcer edges. The detection rate of gastric cancer from gastric ulcer between experimental group and control group was statistically significant (4.57% vs. 1.07%, p<0.05). CONCLUSIONS: Gastric ulcer may develop into gastric cancer over a certain period of time in patients infected with H. pylori. Biopsies from ulcer bases and edges at the second or subsequent endoscopies may lead to defection of gastric cancer earlier and more effectively than the biopsies which take specimens from the edges of ulcers only.
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Adenocarcinoma/patologia , Detecção Precoce de Câncer , Gastroscopia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia , Úlcera Gástrica/patologia , Cicatrização , Adenocarcinoma/epidemiologia , Adenocarcinoma/microbiologia , Idoso , Biópsia , China/epidemiologia , Seguimentos , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/epidemiologia , Lesões Pré-Cancerosas/microbiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/microbiologia , Úlcera Gástrica/epidemiologia , Úlcera Gástrica/microbiologia , Fatores de TempoRESUMO
Farnesoid X receptor (FXR) has been considered as a promising target for nonalcoholic steatohepatitis (NASH), while existing FXR agonists suffer from serious side effects. Thus, it is very necessary to identify novel FXR agonists with good safety. Auraptene (AUR) is a new FXR agonist with excellent safety and extensive pharmacological activities, while the lactone of AUR is vulnerable to esterolysis. In this study, the lactone of AUR was converted to metabolically stable amide moiety, and the obtained analog SU5 revealed comparable activity and better metabolic stability than that of AUR. In NASH model, SU5 showed stronger efficacy than AUR on fatty liver by upregulating gene expressions related to FXR in vivo. Moreover, SU5 improved lipid metabolism by downregulating the gene expressions of lipid synthesis, while upregulating the gene expressions of fatty acid ß-oxidation and triglyceride metabolism. Besides, the inflammation-related genes were significantly decreased in SU5-treated group. These positive results highlighted the pharmacological potential of SU5 for the treatment of NASH.
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Cumarínicos/uso terapêutico , Dieta , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Colina/metabolismo , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Dieta/veterinária , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Meia-Vida , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Metionina/metabolismo , Camundongos , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Objective: Studies have shown that cluster of differentiation (CD) 24 gene polymorphism is associated with several diseases. Among these, chronic hepatitis B (CHB) infection has not been investigated. This study aimed to assess the function of CD24 in CHB. Methods: The study included 478 cases of CHB and 318 cases without CHB from 230 families that underwent genotyping. Polymerase chain reaction-restriction fragment length polymorphism was performed to assess the single nucleotide polymorphism (SNP) P170 of the CD24 gene. The detected genotypes were TT, CT, and CC. Then, family based-association analysis was carried out to investigate the association between CD24 gene polymorphism and susceptibility to CHB. Results: In the 478 patients with CHB, the frequencies of CD24 P170 T and C alleles were 35.5% and 64.5%, respectively, and the frequencies of CD24 P170 CC, CT, and TT genotypes were 39.3%, 50.4% and 10.3%, respectively. In a CD24 single-locus analysis by a family-based association test of P170 polymorphisms, T and C were not significantly associated with CHB in the additive (Z = 0.169, P = 0.866; Z = -0.169, P = 0.866, respectively), dominant (Z = 0.522, P = 0.602; Z = 0.428, P = 0.669, respectively), or recessive (Z = -0.428, P = 0.669; Z = -0.522, P = 0.602, respectively) models. Transmission-disequilibrium (TD) and sib-transmission disequilibrium (STD) tests revealed no excess of T or C alleles from heterozygous parents to their children with the disease or higher frequencies of these alleles in patients compared with their normal siblings (χ 2 = 0.06, P = 0.897). Conclusion: The study findings suggest that the SNP P170 of CD24 has no significant association with susceptibility to the HB virus and related phenotypes in Chinese patients.