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1.
Chem Biol Interact ; 325: 109131, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417163

RESUMO

We have previously demonstrated promotion of diethylnitrosamine (DEN) initiated liver tumorigenesis after feeding diets high in fat or ethanol (EtOH) to male mice. This was accompanied by hepatic induction of the proto-oncogene PIKE (Agap2). Switch of dietary protein from casein to soy protein isolate (SPI) significantly reduced tumor formation in these models. We have linked EtOH consumption in mice to microbial dysbiosis. Adoptive transfer studies demonstrate that microbiota from mice fed ethanol can induce hepatic steatosis in the absence of ethanol suggesting that microbiota or the microbial metabolome play key roles in development of fatty liver disease. Feeding SPI significantly changed gut bacteria in mice increasing alpha diversity (P < 0.05) and levels of Clostidiales spp. Feeding soy formula to piglets also resulted in significant changes in microbiota, the pattern of bile acid metabolites and in inhibition of the intestinal-hepatic FXR/FGF19-SHP pathway which has been linked to both steatosis and hepatocyte proliferation. Moreover, feeding SPI also resulted in induction of hepatic PPARα signaling and inhibition of PIKE mRNA expression coincident with inhibition of steatosis and cancer prevention. Feeding studies in the DEN model with differing dietary fats demonstrated tumor promotion specific to the saturated fat, cocoa butter relative to diets containing olive oil or corn oil associated with microbial dysbiosis including dramatic increases in Lachnospiraceae particularly from the genus Coprococcus. Immunohistochemical analysis demonstrated that tumors from EtOH-fed mice and patients with alcohol-associated HCC also expressed high levels of a novel cytochrome P450 enzyme CYP2W1. Additional adoptive transfer experiments and studies in knockout mice are required to determine the exact relationship between soy effects on the microbiota, expression of PIKE, CYP2W1, PPARα activation and prevention of tumorigenesis.


Assuntos
Família 2 do Citocromo P450/metabolismo , Microbioma Gastrointestinal , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/prevenção & controle , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Proteínas de Soja/farmacologia , Animais , Carcinogênese/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Cancer Immunol Immunother ; 69(10): 2021-2031, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32405793

RESUMO

Following excision of colorectal tumors, metastatic disease is prevalent, primarily occurs in the liver, and is highly predictive of poor prognosis. The perioperative period is now recognized as critical in determining the incidence of postoperative metastases and long-term cancer outcomes. Thus, various perioperative prophylactic interventions are currently studied during this time frame. However, immune stimulation during the perioperative period has rarely been attempted due to specific contraindications to surgery and various adverse effects. Here, to prevent liver metastases, we perioperatively employed a TLR-9 agonist, CpG-C, which exhibits minimal pyrogenic and other adverse effects in patients. We found that marginating-hepatic (MH) cells in BALB/c mice contained high percentage of NK cells, but exhibited negligible NK cytotoxicity, as previously reported in humans. However, a single CpG-C administration (25-100 µg/mouse) doubled MH-NK cell numbers, increased NK cell activation and maturation markers (NKp46, CD11b), decreased the inhibitory NKG2A ligand, and dramatically increased MH-NK-cell cytotoxicity against the syngeneic CT26 colon cancer line. Moreover, in operated mice, this innocuous intervention also markedly improved resistance to CT26 and MC38 hepatic metastases in BALB/c and C57BL/6 mice, respectively. Beneficial effects of CpG-C were mediated through activation of MH-NK cells, as indicated by an in vivo NK depletion study. Last, CpG-C protected against surgery-induced suppression of MH-NK cytotoxicity and improved their activation indices. Thus, we suggest that systemic perioperative CpG-C treatment should be considered and studied as a novel therapeutic approach to improve long-term cancer outcomes in colorectal cancer patients.


Assuntos
Neoplasias do Colo/prevenção & controle , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Oligodesoxirribonucleotídeos/administração & dosagem , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Período Perioperatório , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G1055-G1069, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363891

RESUMO

Liver cancer is a worldwide disease, and, currently, due to the poor prognostic and therapeutic options of liver cancer, we investigated the T cell epitopes as potential therapeutic vaccine candidates to get the benefit of experimental processes and utilize the complete ability of the immune system compared with other artificial ex vivo proliferation of T cells. Activation of T cells targets and kills several tumors, developing a strong rationale for the improvement of immunotherapeutic strategies to cancer therapy. To predict T cell epitopes for liver cancer, we designed a comprehensive immunoinformatics framework involving data mining, immunogenicity prediction, functional proteomic analysis, conservation studies, molecular modeling, and in vivo validation analysis. We found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) I molecules to control the cancerous activity. Five extracellular antigenic proteins, including complement protein (C6), serotransferrin, coagulation factor XIII B, serum albumin (ALB), and prothrombin, were identified. We predicted and synthesized T cell epitopes to human leukocytes antigen-A*01:01 allele of MHC class I molecule. The hematological assay and IgG ELISA showed that C6 and ALB epitopes induced the production of lymphocytes, granulocytes, and peptide-specific IgG in immunized rats. We observed substantial high levels of granzymes B in serum samples of C6 and ALB compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.NEW & NOTEWORTHY We observed substantial high levels of granzymes B in serum samples of component C6 (C6) and albumin (ALB) compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Neoplasias Hepáticas/prevenção & controle , Proteínas de Neoplasias/imunologia , Animais , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Proteômica , Ratos
4.
Gastroenterol Clin North Am ; 49(2): 201-214, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389359

RESUMO

Enhancing host immunity by vaccination to prevent hepatitis B virus (HBV) infection remains the most important strategy for global control of hepatitis B. Currently, 187 countries have in place infant hepatitis B vaccination programs. Hepatitis B surface antigen prevalence has decreased to less than 1% in children after successful implementation of universal HBV vaccination in newborns. The incidence of primary liver cancer in children, adolescents, and young adults has drastically decreased to near zero in birth cohorts receiving hepatitis B vaccination. Elimination of chronic hepatitis B by 2030 is not a mission impossible.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hepatite B/complicações , Hepatite B/diagnóstico , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B , Humanos , Incidência , Lactente , Recém-Nascido , Neoplasias Hepáticas/etiologia , Masculino , Prevalência , Adulto Jovem
5.
Gastroenterol Clin North Am ; 49(2): 215-238, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389360

RESUMO

Despite the availability of a protective vaccine for over 3 decades, the number of persons with chronic hepatitis B virus (HBV) infection remains high. These persons are at risk for cirrhosis and hepatocellular carcinoma. Current treatment is effective at inhibiting viral replication and reducing complications of chronic HBV infection, but is not curative. There is a need for novel, finite therapy that can cure chronic HBV infection. Several agents are in early-phase development and can be broadly viewed as agents that target the virus directly or indirectly or the host immune response. This article highlights key developments in antiviral/immunomodulatory therapy, the rationale for these approaches, and possible therapeutic regimens.


Assuntos
Antivirais/administração & dosagem , Hepatite B/terapia , Imunomodulação , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Feminino , Hepatite B/complicações , Hepatite B/prevenção & controle , Hepatite B/virologia , Vírus da Hepatite B , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Prevalência
6.
Gastroenterol Clin North Am ; 49(2): 301-314, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389364

RESUMO

The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Qualidade de Vida , Resposta Viral Sustentada , Antivirais/administração & dosagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Doenças Cardiovasculares , Crioglobulinemia , Diabetes Mellitus , Quimioterapia Combinada , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Linfoma não Hodgkin
7.
Intern Med ; 59(7): 901-907, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238660

RESUMO

Objective The influence of interferon (IFN)-free direct-acting antiviral (DAA) on hepatocellular carcinoma (HCC) recurrence remains unclear. Previous retrospective analyses revealed that the time interval between HCC curative treatment and IFN-free DAA induction is the critical factor affecting HCC recurrence. Thus, this study aimed to examine the influence of DAA therapy on HCC recurrence considering this interval. Methods Factors contributing to HCC recurrence were retrospectively analyzed using a landmark time analysis and time-dependent extended Cox proportional hazards model. Patients After screening 620 patients who were diagnosed with primary HCC from January 2001 to December 2016, 76 patients with early-stage (primary and solitary) disease who received curative treatment and were positive for serum hepatitis C virus RNA were included. Results HCC recurrence was observed in 8 of 17 (47.1%) patients who had received IFN-free DAA therapy and 45 of 59 (76.3%) who had not. No significant difference was seen between the IFN-free DAA (-) and IFN-free DAA (+) groups in the landmark time and time-dependent Cox proportional hazards model analyses. However, IFN-free DAA therapy tended to decrease the HCC recurrence rate after curative treatment for primary HCC in patients with chronic hepatitis. In addition, IFN-free DAA therapy tended to decrease the second HCC recurrence rate after treatment for the first HCC recurrence. Conclusion Our results, with a consideration of the time interval between HCC curative treatment and IFN-free DAA induction, showed that IFN-free DAA therapy was not associated with early-stage HCC recurrence after curative treatment.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Feminino , Hepatite C Crônica/complicações , Humanos , Imunoterapia , Interferons/uso terapêutico , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Prevenção Secundária/métodos
8.
Metabolism ; 107: 154220, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32243868

RESUMO

BACKGROUND AND AIMS: Obesity, diabetes and associated non-alcoholic steatohepatitis (NASH) are rising risk factors for hepatocellular carcinoma (HCC). Macrophages are important immune cells involved in inflammation and tumour development. Macrophage inositol-requiring enzyme 1 alpha (IRE1α), an ER-stress protein, has been shown to be involved in macrophage cytokine production, and myeloid-specific IRE1α knock-out (myeloid IRE1α-KO) mice showed reduced weight gain during high-fat diet feeding. However, the effect of myeloid IRE1α on NASH and subsequent HCC development has not been examined. Here, we characterized the transcriptional profile of the hepatic macrophage population in a diabetes-NASH-HCC mouse model, and investigated the effect of myeloid-specific IRE1α deletion on the phenotype of hepatic macrophage subsets and experimental NASH-HCC development. METHODS: Mice with non-functional myeloid IRE1α were created by crossing Ire1a floxed mice with Lysm-Cre mice. Two-day old myeloid IRE1α-KO and wild type (WT) mice were subcutaneously injected with streptozotocin (STZ), and male mice were fed a high-fat, -sucrose, -cholesterol diet (Western diet, WD) from the age of 4 weeks until 21 weeks. Control myeloid IRE1α-KO and WT mice received a PBS injection and were fed a matched control diet. These mice were evaluated for obesity, diabetes, NASH and HCC. The hepatic macrophage population was evaluated by flow cytometry and RNA sequencing on FACS-isolated macrophage subsets. RESULTS: STZ-injection and WD feeding resulted in an impaired glucose tolerance, advanced NASH with fibrosis, and HCC development. Myeloid IRE1α-KO STZ mice showed lower fasting glucose levels at the start of WD feeding, and an improved glucose tolerance and attenuated HCC development after 17 weeks of WD feeding despite a similar degree of liver steatosis and inflammation compared to WT mice. Transcriptomic analysis of WT liver Kupffer cells, macrophages and monocytes revealed phenotypical changes in those cell subsets during NASH-HCC development. Isolated liver Kupffer cells and macrophages from mice with a myeloid IRE1α deletion showed downregulated pathways involved in immune system activation and metabolic pathways (only in Kupffer cells), whereas pathways involved in cell division and metabolism were upregulated in monocytes. These transcriptional differences were attenuated during NASH-HCC development. CONCLUSION: Our results show that myeloid-specific IRE1α deletion results in an altered transcriptional profile of hepatic macrophages and dampens diabetes-induced NASH-HCC development, possibly by attenuated diabetes induction.


Assuntos
Diabetes Mellitus Experimental/complicações , Endorribonucleases/genética , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Proteínas Serina-Treonina Quinases/genética , Animais , Glicemia/metabolismo , Dieta Ocidental , Intolerância à Glucose/prevenção & controle , Macrófagos do Fígado/patologia , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas Experimentais/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ativação Transcricional
9.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 183-187, 2020 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-32164075

RESUMO

Hepatocellular carcinoma (HCC) is the fifth world's largest malignant tumor, which seriously endangers human health. The commonly used treatment effects are not satisfactory and the mortality rate is still high. Therefore, there is an urgent need for effective adjuvant treatment to improve patient survival. Alpha-fetoprotein (AFP) acts as the most common tumor marker used for HCC diagnosis. Studies have shown that alpha-fetoprotein can self-induce T cells in patients with hepatocellular carcinoma, and its immunogenic antigenic epitopes provide new ideas for the study of AFP vaccine. Presently, a variety of AFP vaccines have been developed, such as DC vaccine, DNA vaccine, and peptide vaccine, which have been successfully applied to HCC mouse model and phase I /II clinical trials, with evident results. This article discusses the molecular mechanism, categories and application prospects of AFP vaccine in HCC.


Assuntos
Vacinas Anticâncer , Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , alfa-Fetoproteínas/administração & dosagem , Animais , Biomarcadores Tumorais , Humanos , Camundongos
10.
Cochrane Database Syst Rev ; 3: CD005004, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32118296

RESUMO

BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009, Issue 3).Tea is one of the most commonly consumed beverages worldwide. Teas from the plant Camellia sinensis can be grouped into green, black and oolong tea, and drinking habits vary cross-culturally. C sinensis contains polyphenols, one subgroup being catechins. Catechins are powerful antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Some experimental and nonexperimental epidemiological studies have suggested that green tea may have cancer-preventative effects. OBJECTIVES: To assess possible associations between green tea consumption and the risk of cancer incidence and mortality as primary outcomes, and safety data and quality of life as secondary outcomes. SEARCH METHODS: We searched eligible studies up to January 2019 in CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and reference lists of previous reviews and included studies. SELECTION CRITERIA: We included all epidemiological studies, experimental (i.e. randomised controlled trials (RCTs)) and nonexperimental (non-randomised studies, i.e. observational studies with both cohort and case-control design) that investigated the association of green tea consumption with cancer risk or quality of life, or both. DATA COLLECTION AND ANALYSIS: Two or more review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. We summarised the results according to diagnosis of cancer type. MAIN RESULTS: In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review. Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea-supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low-certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low-certainty evidence). No evidence of effect of non-melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low-certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies. In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case-control studies, which were on average of intermediate to high methodological quality based on Newcastle-Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low-certainty evidence). Conversely, we found no association between green tea consumption and cancer-related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low-certainty evidence). For most of the site-specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case-control studies. AUTHORS' CONCLUSIONS: Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites. Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case-control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk.


Assuntos
Camellia sinensis , Neoplasias/prevenção & controle , Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , Chá , Neoplasias da Mama/prevenção & controle , Camellia sinensis/química , Estudos de Casos e Controles , Feminino , Flavonoides/farmacologia , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/prevenção & controle , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/prevenção & controle , Masculino , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/prevenção & controle , Neoplasias/epidemiologia , Neoplasias/mortalidade , Fenóis/farmacologia , Extratos Vegetais/efeitos adversos , Polifenóis , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Chá/efeitos adversos , Neoplasias Urogenitais/epidemiologia , Neoplasias Urogenitais/prevenção & controle
11.
Medicine (Baltimore) ; 99(9): e19008, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118712

RESUMO

Aspirin therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether aspirin therapy lowers the risk of HCC in patients with alcoholic cirrhosis.A retrospective analysis of data from 949 consecutive patients with alcoholic cirrhosis who abstained from alcoholic drinking was performed. The primary and secondary outcomes were development of HCC and gastrointestinal bleeding events, respectively. Risk was compared between patients with aspirin treatment and patients who were not treated (non-aspirin group) using a time-varying Cox proportional hazards model for total population and propensity score-matching analysis.The aspirin group included 224 patients and the non-aspirin group had 725 patients. During the study period of median duration of 3.1 years, 133 patients (13.6%) developed HCC. In time-varying Cox proportional analyses, the aspirin group showed a significantly lower risk of HCC (adjusted hazard ratio [aHR]: 0.13; 95% confidence interval [CI]: 0.08-0.21; P < .001). In propensity score-matched pairs, aspirin therapy significantly reduced the risk of HCC (aHR: 0.14; 95% CI: 0.09-0.22; P < .001). In bleeding risk, treatment with aspirin alone was not significantly associated with a higher bleeding risk (aHR: 0.81; 95% CI: 0.45-1.44; P = .46).Aspirin therapy was associated with the lower risk of HCC in patients with alcoholic cirrhosis.


Assuntos
Aspirina/uso terapêutico , Carcinoma Hepatocelular/etiologia , Cirrose Hepática Alcoólica/complicações , Neoplasias Hepáticas/etiologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/prevenção & controle , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos
12.
Medicine (Baltimore) ; 99(6): e18948, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028404

RESUMO

The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection is ascertained. However, some authors raised the issue of an increased incidence of de novo hepatocellular carcinoma (HCC) in patients treated with DAAs. Aim of the study was to evaluate the rate of HCC occurrence in a real-life cohort of patients who received anti-HCV treatment with DAAs.A prospective multicentre study was conducted. All adult patients with HCV infection who received treatment between March 2015 and December 2017 in 4 hospital of Campania region (South Italy) with at least 6 months of follow-up were enrolled.A total of 323 patients were included in the study. Most patients had HCV genotype 1b (61.8%). The overall SVR12 rate was 95.5%. Median time of observation was 10 months. The incidence rate of HCC was 0.2 per 100 person-months (crude incidence rate 3.4%, 95 confidence interval: 1.5%-5.3%). The median time for HCC occurrence was 11 months. HCC occurrence rate was significantly higher among patients who did not achieve SVR12 compared with patients who did (28.6% vs 2.8%, P < 0.05). No patient with F0-F3 fibrosis developed HCC. Among patients with cirrhosis, at the multivariate time-to-event analysis, no covariates were independently associated with the risk of HCC occurrence.Treatment with DAAs did not increase the risk of HCC occurrence. Patients who achieved SVR12 had a lower rate of HCC occurrence. Further studies are needed to estimate the incidence and the risk for HCC in the long-term follow-up among patients undergoing treatment with DAAs.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/prevenção & controle , Estudos de Coortes , Feminino , Humanos , Incidência , Itália/epidemiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida
13.
Toxicol Appl Pharmacol ; 392: 114918, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045588

RESUMO

Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro. Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro, impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/metabolismo , Orlistate/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/farmacologia
14.
Am J Gastroenterol ; 115(3): 406-414, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31895708

RESUMO

OBJECTIVES: It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB. METHODS: We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as ≤35 U/L (men) and ≤25 U/L (women) and VR as serum hepatitis B virus DNA <15 IU/mL. RESULTS: During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P < 0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P < 0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6-12, 12-24, and >24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P < 0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P = 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P = 0.31) was associated with a significantly lower HCC risk. DISCUSSION: In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR.


Assuntos
Alanina Transaminase/sangue , Antivirais/uso terapêutico , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/virologia , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/virologia , Adulto , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Feminino , Seguimentos , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Masculino , Risco , Tenofovir/uso terapêutico , Resultado do Tratamento
15.
Am J Gastroenterol ; 115(2): 271-280, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31634265

RESUMO

INTRODUCTION: It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: This retrospective cohort study analyzed an international consortium that encompassed 19 centers from 6 countries or regions composed of previously untreated CHB patients then treated with either ETV or TDF monotherapy. Those who developed HCC before antiviral treatment or within 1 year of therapy were excluded. The association between antiviral regimen and HCC risk was evaluated using competing-risk survival regression. We also applied propensity score matching (PSM) to 1:1 balance the 2 treatment cohorts. A total of 5,537 patients were eligible (n = 4,837 received ETV and n = 700 received TDF) and observed for HCC occurrence until December 23, 2018. Before PSM, the TDF cohort was significantly younger and had generally less advanced diseases. RESULTS: In the unadjusted analysis, TDF was associated with a lower risk of HCC (subdistribution hazard ratio [SHR], 0.45; 95% confidence interval [CI], 0.26-0.79; P = 0.005). The multivariable analysis, however, found that the association between TDF and HCC no longer existed (SHR, 0.81; 95% CI, 0.42-1.56; P = 0.52) after adjustment for age, sex, country, albumin, platelet, α-fetoprotein, cirrhosis, and diabetes mellitus. Furthermore, the PSM analysis (n = 1,040) found no between-cohort differences in HCC incidences (P = 0.51) and no association between regimens (TDF or ETV) and HCC risk in the multivariable-adjusted analysis (adjusted SHR, 0.89; 95% CI, 0.41-1.92; P = 0.77). DISCUSSION: TDF and ETV did not significantly differ in the prevention of HCC in patients with CHB.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/prevenção & controle , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Tenofovir/uso terapêutico , Adulto , Carcinoma Hepatocelular/etiologia , China , Estudos de Coortes , Progressão da Doença , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hong Kong , Humanos , Cooperação Internacional , Japão , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , República da Coreia , Estudos Retrospectivos , Taiwan , Resultado do Tratamento , Estados Unidos
16.
Gastroenterology ; 158(1): 215-225.e6, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574268

RESUMO

BACKGROUND & AIMS: There have been conflicting results from studies comparing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with tenofovir disoproxil fumarate (TDF) vs those treated with entecavir. We compared the effects of TDF vs entecavir on HCC risk in a large cohort of patients with chronic HBV infection in China. METHODS: We performed a retrospective study of consecutive adults with chronic HBV infection who initially received treatment with entecavir or TDF, for at least 6 months, from January 2008 through June 2018. Patients who had cancers or liver transplantation before or within the first 6 months of treatment were excluded. Propensity score weighting and 1:5 matching were used to balance the clinical characteristics between the 2 groups. Fine-Gray model was used to adjust for competing risk of death and liver transplantation. RESULTS: We analyzed data from 29,350 patients (mean age, 52.9 ± 13.2 years; 18,685 men [63.7%]); 1309 were first treated with TDF (4.5%) and 28,041 were first treated with entecavir (95.5%). TDF-treated patients were younger (mean age, 43.2 years vs 53.4 years) and a lower proportion had cirrhosis (38 patients [2.9%] vs 3822 patients treated with entecavir [13.6%]). At a median follow-up time of 3.6 years after treatment began (interquartile range, 1.7-5.0 years), 8 TDF-treated patients (0.6%) and 1386 entecavir-treated patients (4.9%) developed HCC. Patients' clinical characteristics were comparable after propensity score weighting. TDF treatment was associated with a lower risk of HCC than entecavir treatment after propensity score weighting (weighted subdistribution hazard ratio, 0.36; 95% confidence interval 0.16-0.80; P = .013) and 1:5 matching (weighted subdistribution hazard ratio, 0.39; 95% confidence interval 0.18-0.84; P = .016). CONCLUSIONS: In a retrospective analysis of 29,350 patients with chronic HBV infection in China, treatment with TDF was associated with a lower risk of HCC than treatment with entecavir, over a median follow-up time of 3.6 years.


Assuntos
Antivirais/administração & dosagem , Carcinoma Hepatocelular/prevenção & controle , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Tenofovir/administração & dosagem , Adulto , Assistência ao Convalescente , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , China/epidemiologia , Progressão da Doença , Feminino , Guanina/administração & dosagem , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Incidência , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
17.
J Nutr ; 150(4): 775-783, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851339

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. Choline deficiency has been well studied in the context of liver disease; however, less is known about the effects of choline supplementation in HCC. OBJECTIVE: The objective of this study was to test whether choline supplementation could influence the progression of HCC in a high-fat-diet (HFD)-driven mouse model. METHODS: Four-day-old male C57BL/6J mice were treated with the chemical carcinogen, 7,12-dimethylbenz[a]anthracene, and were randomly assigned at weaning to a cohort fed an HFD (60% kcal fat) or an HFD with supplemental choline (60% kcal fat, 1.2% choline; HFD+C) for 30 wk. Blood was isolated at 15 and 30 wk to measure immune cells by flow cytometry, and glucose-tolerance tests were performed 2 wk prior to killing. Overall tumor burden was quantified, hepatic lipids were measured enzymatically, and phosphatidylcholine species were measured by targeted MS methods. Gene expression and mitochondrial DNA were quantified by quantitative PCR. RESULTS: HFD+C mice exhibited a 50-90% increase in both circulating choline and betaine concentrations in the fed state (P ≤ 0.05). Choline supplementation resulted in a 55% decrease in total tumor numbers, a 67% decrease in tumor surface area, and a 50% decrease in hepatic steatosis after 30 wk of diet (P ≤ 0.05). Choline supplementation increased the abundance of mitochondria and the relative expression of ß-oxidation genes by 21% and ∼75-100%, respectively, in the liver. HFD+C attenuated circulating myeloid-derived suppressor cells at 15 wk of feeding (P ≤ 0.05). CONCLUSIONS: Choline supplementation attenuated HFD-induced HCC and hepatic steatosis in male C57BL/6J mice. These results suggest a therapeutic benefit of choline supplementation in blunting HCC progression.


Assuntos
Colina/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Animais , Betaína/sangue , Colina/sangue , DNA Mitocondrial/análise , Suplementos Nutricionais , Fígado Gorduroso/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/química , Fígado/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/patologia , Tamanho do Órgão/efeitos dos fármacos
18.
Nat Commun ; 10(1): 5745, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848339

RESUMO

Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.


Assuntos
Estrogênios/metabolismo , Neoplasias Hepáticas/secundário , Fígado/patologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral/transplante , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Estradiol/administração & dosagem , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/imunologia , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Ovariectomia , Neoplasias Pancreáticas/patologia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Fatores Sexuais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
19.
PLoS One ; 14(11): e0224773, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31751366

RESUMO

OBJECTIVE: To compare the efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B. METHODS: The Web of Science, PubMed, Cochrane Library, EMBASE, Clinical Trials and China National Knowledge Infrastructure(CNKI) databases were electronically searched to collect randomized controlled trials (RCTs) regarding the comparison between tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B (CHB) since the date of database inception to July 2019. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used for the meta-analysis. RESULTS: Early on, tenofovir had a greater ability to inhibit the hepatitis B virus, I2 = 0% [RR = 1.08, 95% CI (1.03, 1.13), P<0.01] (96 weeks). Entecavir can normalize the ALT levels earlier, I2 = 0% [RR = 0.87, 95% CI (0.77, 0.98), P = 0.02] (48 weeks). However, there was no statistically significant difference between TDF and ETV at 144 weeks. Tenofovir was as effective as entecavir in terms of HBeAg clearance and HBeAg seroconversion, I2 = 0% [RR = 1.05, 95% CI (0.68, 1.62), P = 0.82]; I2 = 69% [RR = 0.93, 95% CI (0.54, 1.61), P = 0.80]. The difference in the incidence of elevated creatine kinase levels was not statistically significant I2 = 0% [RR = 0.66, 95% CI (0.27, 1.60), P = 0.35]. CONCLUSIONS: Tenofovir and entecavir were equally effective in the treatment of patients with nucleos(t)ide analogue-naive chronic hepatitis B. In addition, TDF has an advantage in the incidence of hepatocellular carcinoma. Additional RCTs and a large-sample prospective cohort study should be performed.


Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/prevenção & controle , Carcinoma Hepatocelular/virologia , Guanina/uso terapêutico , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
20.
Hepatol Int ; 13(6): 688-694, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31701393

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder worldwide, affecting 25.2% of the general population. In fact, NAFLD is among the most common etiologies for hepatocellular carcinoma (HCC). The burden of NAFLD is primarily driven by the epidemic of obesity and type 2 diabetes which are expected to worsen throughout the world. In this context, the burden of NAFLD and associated HCC and cirrhosis are also expected to increase. Despite its growing disease burden, diagnostic tools and treatment modalities remain very limited. This conundrum of increasing prevalence and limited treatment options will be reflected as increasing number of NAFLD-related cirrhosis and HCC cases. This article reviews the most updated information about NAFLD-related HCC and provides some insight into strategies that must be considered to reduce its potential disease burden.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Saúde Global , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle
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