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1.
Gene ; 806: 145935, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34478821

RESUMO

Soluble molecules of programmed death ligand 1 (sPD-L1) are known to modulate T-cell depletion, an important mechanism of hepatitis B virus (HBV) persistence and liver disease progression. In addition, PD-L1 polymorphisms in the 3'-UTR can influence PD-L1 expression and have been associated with cancer risk, although not definitively. The purpose of this study was to investigate the association of PD-L1 polymorphisms and circulating levels of sPD-L1 in HBV infection and live disease progression. In this study, five hundred fifty-one HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 186), liver cirrhosis (LC, n = 142) and hepatocellular carcinoma (HCC, n = 223) and 240 healthy individuals (HC) were enrolled. PD-L1 polymorphisms (rs2297136 and rs4143815) were genotyped by in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of PD-L1 polymorphisms with HBV infection as well as with progression of related liver diseases. Plasma sPD-L1 levels were quantified by ELISA assays. The PD-L1 rs2297136 AA genotype was associated with HBV infection susceptibility (HBV vs. HC: OR = 1.6; 95%CI = 1.1-2.3; p = 0.0087) and disease progression (LC vs. CHB: OR = 1.8; 95%CI = 1.1-2.9; p = 0.018). Whereas, the rs2297136 GG genotype was a protective factor for HCC development. Plasma sPD-L1 levels were significantly high in HBV patients (p < 0.0001) and higher in the LC followed by CHB and HCC groups. High sPD-L1 levels correlated with increased liver enzymes and with advanced liver disease progression (Child-pugh C > B > A, p < 0.0001) and BCLC classification (BCLC D > C > B > A, p = 0.031). We could, for the first time, conclude that PD-L1 rs2297136 polymorphism and plasma sPD-L1 protein levels associate with HBV infection and HBV-related liver disease progression.


Assuntos
Antígeno B7-H1/genética , Carcinoma Hepatocelular/genética , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Polimorfismo Genético , Regiões 3' não Traduzidas , Adulto , Idoso , Antígeno B7-H1/sangue , Biomarcadores/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Expressão Gênica , Predisposição Genética para Doença , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/virologia , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
2.
J Hazard Mater ; 421: 126777, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34364209

RESUMO

Microplastics are an emerging environmental issue as a result of their ubiquity, persistence, and intrinsic toxic potential. In addition, their ability to sorb and transport a wide variety of environmental pollutants (i.e. "Trojan Horse" effect) exerts significant adverse impacts upon ecosystems. The toxicological evaluation of the single and combined effects produced by polyethylene microplastics and two polychlorinated biphenyl congeners was performed on the human hepatoma cell line HepG2 by cell viability assessment and an untargeted lipidomic study. The cell lethality evaluation evinced that MPs did not induce relevant cell lethality at any of the concentration range tested, while both PCBs presented a hormetic behavior. The lipidomic analysis suggested that both single PCB exposures induced significant lipidomic changes, especially for glycerophospholipids and glycerolipids. In contrast, for MPs single exposure, the most remarkable change was the substantial enhancement of triglyceride content. Regarding combined exposures, results showed that MPs could induce even more harmful effects than those produced intrinsically as a result of desorbing previously sorbed toxic pollutants. To the best of our knowledge, this is the first study assessing the toxicity of microplastics and their possible "Trojan Horse" effect by applying an untargeted lipidomic methodology.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Bifenilos Policlorados , Ecossistema , Humanos , Lipidômica , Microplásticos , Plásticos/toxicidade , Bifenilos Policlorados/análise , Bifenilos Policlorados/toxicidade , Polietileno/toxicidade
3.
J Colloid Interface Sci ; 607(Pt 2): 1516-1526, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34592546

RESUMO

Sorafenib-mediated chemotherapy is currently the first choice for hepatocellular carcinoma (HCC) that cannot be surgically excised, and can significantly improve the survival of patients. However, its poor water solubility restricts its bioavailability, and long-term single use of it does not achieve satisfactory HCC therapy effects. Herein, we report a novel cascaded copper-based metal-organic framework (MOF) therapeutic nanocatalyst using HKUST-1 by integrating cyclooxygenase-2 (COX-2) inhibitor meloxicam (Mel) and chemotherapeutic agent sorafenib (Sol) to amplify HCC therapy. This HKUST-1 nanocatalyst can be degraded by glutathione (GSH) into a Fenton-like agent to trigger chemodynamic therapy (CDT). CDT-mediated cytotoxic reactive oxygen species (ROS) can activate ferroptosis by accumulating lipid peroxides (LPO). Alternatively, GSH depletion not only deactivates glutathione peroxidase 4 (GPX4) to trigger ferroptosis, but also leads to oxidative stress amplification. Moreover, Sol can also activate ferroptosis by inhibiting system XC-, resulting in cascade-amplified ferroptosis mediated HCC therapy. Furthermore, the down-regulation of COX-2 can induce PINK1/Parkin-mediated mitophagy to further act synergistically with Sol-mediated chemotherapy. Therefore, this HKUST-1 nanocatalyst provides a novel strategy to regulate GSH and COX-2 levels for amplified chemo/chemodynamic and ferroptosis-mediated HCC therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Cobre , Ciclo-Oxigenase 2 , Glutationa , Humanos , Neoplasias Hepáticas/tratamento farmacológico
4.
Biol Trace Elem Res ; 200(1): 134-146, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33634364

RESUMO

Boron has an important potential for facilitating biological activity and for use in pharmaceutical drug design. Boron glycine monoester (BGM) and boron glycine diester (BGD) compounds containing boron atoms were synthesized and investigated their cytotoxic, oxidative stress, and antimicrobial activities on the HepG2 cancer cell line. The cytotoxic activity of newly synthesized boron compounds on hepatocellular carcinoma was determined by the MTT method for 48 h. Antioxidant (CAT, GSH), lipid peroxidation (MDA), and enzyme activity (ACP, ALP) analyses were determined by spectrophotometric methods in HepG2 cells. Antimicrobial activity was determined by the disk diffusion method. After 48 h of BGM and BGD application to HepG2 cells, we found the IC50 values as 9.9 mM and 24 mM, respectively. While CAT and ACP enzyme activities decreased in all groups compared to the control, ALP enzyme activity did not change in the BGM group but increased in the BGD group. It was determined that the GSH level did not change in all groups, while the MDA level increased. It has been stated that these IC50 doses of BGM and BGD have antibacterial effects on Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922. Newly synthesized boron compounds, particularly BGM, with their cytotoxic, oxidative stress, and antimicrobial effects, could provide a new therapeutic approach for the treatment of hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Antioxidantes , Boro/farmacologia , Compostos de Boro/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Glicina , Humanos , Neoplasias Hepáticas/tratamento farmacológico
5.
Gene ; 807: 145964, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34530087

RESUMO

AIMS: We aimed to investigate the role of G protein subunit alpha Z(GNAZ) in the progression and prognosis of patients with hepatocellular carcinoma (HCC). METHODS: Oncomine, GEO, TCGA, GEPIA2, Kaplan-Meier Plotter, TIMER2, Metascape, CCLE, LinkedOmics, and UALCAN databases were used to analyze the differential expression of GNAZ in HCC and normal liver tissues, relationship between GNAZ expression and prognosis of patients with HCC, and expression of GNAZ in common human HCC cell lines. Western blotting was performed to analyze GNAZ expression, while the Cell Counting Kit 8 assay was used to determine cell proliferation, and flow cytometry was used to evaluate the cell cycle and apoptosis. Wound healing and transwell invasion assays were used to investigate cell metastasis and invasion. RESULTS: Using Oncomine, Gene Expression Omnibus (GEO), and GEPIA2 databases, GNAZ was found to be overexpressed in HCC tissues compared with that in adjacent normal liver tissues, and western blotting analysis showed GNAZ overexpression in seven patients with HCC who underwent surgical resection of HCC and para-cancerous tissues (p < 0.01). Survival analysis revealed that high GNAZ expression was negatively associated with overall survival (OS), recurrence-free survival, progression-free survival, and disease-specific survival in patients with HCC (p < 0.05). GNAZ overexpression was associated with worse 4- month, 6- month, 12- month, 24- month, 36- month, 48- month, and 60-month OS, as well as with different clinicopathological characteristics of patients with HCC, including hepatitis virus infection state; alcohol consumption state; male; female; Asian; microvascular invasion, Stage I-II, Stage II-III, and Stage III-IV; and grade II (Cox regression, p < 0.05). KEGG/GO biological process enrichment indicated that the genes similar to GNAZ in HCC were mainly enriched in the cell cycle, cell cycle phase transition, DNA replication checkpoint, and regulation of G0 to G1 transition. siRNA-GNAZ significantly reduced the viability of JHH-2 and SNU-761 cells from 12 to 96 h; increased the percentage of cells in the G0/G1 phase and decreased that of cells in the S and G2/M phases (p < 0.05); and markedly downregulated the expression of cyclin D, cyclin E, and CDK2 protein. siRNA-GNAZ also significantly increased the percentage of JHH-2 and SNU-761 cell apoptosis at late stages, while the number of surviving cells decreased (p < 0.05), and upregulated the expression of apoptosis-related proteins Bax and caspase 3 protein. Furthermore, siRNA-GNAZ remarkably reduced the healing of scratch wounds in JHH-2 and SNU-761 cells and the number of invasive cells compared with that in the control group (p < 0.001). CONCLUSION: Our study demonstrated that GNAZ plays a pivotal role as a potential oncogene and predicts poor prognosis in patients with HCC. It promotes tumor proliferation via cell cycle arrest, apoptosis, migration, and invasion. Thus, GNAZ may be a potential candidate biomarker providing useful insight into hepatocarcinogenesis and aggressiveness.


Assuntos
Carcinoma Hepatocelular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Idoso , Apoptose/genética , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transcriptoma/genética
6.
Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med ; 29(Special Issue): 1287-1291, 2021 Aug.
Artigo em Russo | MEDLINE | ID: mdl-34792879

RESUMO

INTRODUCTION: Liver cirrhosis is a major but preventable cause of health loss worldwide. The era of «big data¼ allows us to evaluate this nosology in a new format. PURPOSE: Evaluation of the registered population of patients with cirrhosis of the liver of cirrhosis of various etiology in Moscow. Moscow. MATERIALS AND METHODS: Based on the data of the Moscow Department of Healthcare for the drug provision for the period from 2017 to 2019. Тhe population of patients with an established diagnosis of liver (other etiology) was characterized according to ICD-10 code K.74 (K74.0-74.6) according to the International Statistical Classification of Diseases and Related Health Problems of the 10th revision. RESULTS: Over a 4-year period, more than 2 thousand patients with established diagnosis of liver cirrhosis received preferential drug provision in Moscow. The largest part of the population of patients with liver cirrhosis receiving preferential drug provision in Moscow is represented by the patients of age groups 40-59 years old and 60-79 years old, the groups 30-39 years old and 80-99 years old were comparable annually. There was a decrease in the number of patients with liver cirrhosis in the age groups of 30-39 and 18-19 years compared with the base year (2017) by 37% and 57%, respectively. At the same time, in pediatric patients (from the neonatal period to 17 years), there was an intensive increase in patients from 52 to 550% compared to the baseline year (2017).


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Criança , Humanos , Recém-Nascido , Classificação Internacional de Doenças , Cirrose Hepática/epidemiologia , Pessoa de Meia-Idade , Moscou/epidemiologia
7.
Zhonghua Zhong Liu Za Zhi ; 43(11): 1143-1147, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34794215

RESUMO

Liver cancer is one of the malignant tumors with the highest fatality rate in China and the 5-years survival rate is only 12.5%. Early detection to undertake early treatment can improve the survival rate of patients with liver cancer. Nowadays, the unsatisfactory performance of serum Alpha-fetoprotein (AFP) test, and the problems of insensitive to small lesions for ultrasound and exposure to nuclear radiation for CT, necessitate the urgency to explore novel diagnostic biomarkers of liver cancer. It has been demonstrated the presence of autoantibodies targeting tumor-associated antigens prior to clinic symptoms implied underlying early diagnostic value of malignancies. High specificity but low sensitivity of single autoantibodies such as the most reported anti-p53, anti-insulin like growth factor-Ⅱ mRNA binding protein, and anti-glucose regulated protein can be solved by combining different autoantibodies. However, the autoantibodies of different combinations vary in studies. Simultaneously, autoantibodies in combination with AFP facilitate further improving the detection rate of liver cancer. Nevertheless, the autoantibodies related to prognosis of liver cancer needs to be more studied in the near future.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Autoanticorpos , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Prognóstico , alfa-Fetoproteínas
8.
Zhonghua Zhong Liu Za Zhi ; 43(11): 1148-1155, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34794216

RESUMO

Objective: To investigate the effects of lncRNA LINC00839 on the proliferation, migration and invasion of hepatocellular carcinoma cells and its mechanism. Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of LINC00839 and miR-3666 in hepatocellular carcinoma tissues and adjacent tissues. Pearson correlation was used to analyze the correlation between LINC00839 and miR-3666 expression in liver cancer tissues. Hepatocellular carcinoma cells MHCC97H were cultured in vitro and divided into si-NC group, si-LINC00839 group, miR-NC group, miR-3666 group, si-LINC00839+ anti-miR-NC group, and si-LINC00839+ anti-miR-3666 group. Methylthiazoletrazolium (MTT) method and clone formation experiment were used to detect cell proliferation. Transwell array was used to detect the cell migration and invasion. Western blot was used to detect the protein expressions of p21, E-cadherin and MMP-2. The double luciferase reporter gene experiment was used to verify the regulatory relationship between LINC00839 and miR-3666. Results: Compared with adjacent tissues, the expression level of LINC00839 in hepatocellular carcinoma tissues increased (2.82±0.27 vs. 0.96±0.10, P<0.001), but the expression level of miR-3666 decreased (0.23±0.02 vs. 1.01±0.10, P<0.001). The expression levels of LINC00839 and miR-3666 in liver cancer tissue were negatively correlated (r=-0.658, P<0.001). The survival rate of MHCC97H cells in the si-LINC00839 group [(53.91±5.41)% vs. (100.53±10.22)%], the number of clones formed (92.0±8.0 vs. 164.0±14.3), the number of migration (131.0±12.7 vs. 247.0±22.4), the number of invasion (66.0±6.4 vs. 120.0±11.6) and the protein level of MMP-2 (0.20±0.02 vs. 0.67±0.06) were lower than those in the si-NC group (P<0.001). However, the protein levels of p21 (0.76±0.07 vs. 0.25±0.02) and E-cadherin (0.78±0.08 vs. 0.14±0.01) were higher than those in the si-NC group (P<0.001). LINC00839 targeted and negatively regulated the expression of miR-3666. The survival rate of MHCC97-H cells in the miR-3666 group [(47.93±4.86)% vs. (100.11±10.21)%], the number of clone formation (78.0±7.7 vs. 166.0±15.9), the number of migration (117.0±12.1 vs. 250.0±25.0), the number of invasion (57.0±5.7 vs. 121.0±12.3) and the protein level of MMP-2 (0.16±0.01 vs. 0.69±0.07) were lower than those in the miR-NC group (all P<0.001). However, the protein levels of p21 (0.83±0.08 vs. 0.24±0.02) and E-cadherin (0.87±0.09 vs. 0.13±0.01)were higher than those in the miR-NC group (all P<0.001). The survival rate of MHCC97-H cells in the si-LINC00839+ anti-miR-3666 group [(89.94±9.05)% vs. (54.12±5.39)%], the number of clones (143.0±13.8 vs. 94.0±9.4), the number of migration (208.0±19.8 vs. 129.0±12.6), the number of invasion (108.0±10.1 vs. 65.0±6.4) and the protein level of MMP-2 (0.31±0.03 vs 0.66±0.06) were higher than those in the si-LINC00839+ anti-miR-NC group (P<0.001). However, the protein levels of p21 (0.31±0.03 vs. 0.74±0.07) and E-cadherin (0.28±0.03 vs. 0.80±0.08) were lower than those int the si-LINC00839+ anti-miR-NC group (P<0.001). Conclusion: Inhibition of LINC00839 expression may inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells by targeting up-regulation of miR-3666 expression.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética
9.
Zhonghua Zhong Liu Za Zhi ; 43(11): 1156-1163, 2021 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-34794217

RESUMO

Objective: To investigate the effect of miR-369-3p targeting ACTN4 expression on proliferation and apoptosis of hepatocellular carcinoma cells. Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect the expression levels of miR-369-3p and ACTN4 in hepatocarcinoma tissues and adjacent tissues. MiR-369-3p mimics, miR-negative control (NC), si-ACTN4, and si-NC were transfected into hepatocellular carcinoma MHCC97H cells by liposome method. Cell proliferation was detected by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-dipheny-ltetrazolium bromide (MTT) assay. Flow cytometry was used to detect cell cycle and apoptotic rates. The dual luciferase reporter assay was used to verify the targeted regulation of ACTN4 by miR-369-3p. Western blot was used to detect the expressions of cyclin D1, p21, Bcl-2 and Bax. Results: The expression level of miR-369-3p in liver cancer tissue was lower than that in adjacent tissues [(0.46±0.04) vs (1.00±0.08), P<0.001)], while the expression level of ACTN4 was higher than that in adjacent tissues [mRNA (3.12±0.29) vs (1.01±0.09); protein (0.61±0.06) vs (0.25±0.03), P<0.001]. Overexpression of miR-369-3p significantly decreased the cell viability[(0.71±0.06) vs (1.26±0.11), P<0.001)], increased cell apoptosis rate [(20.16±2.11)% vs (6.25±0.64)%, P<0.001], increased the proportion of cells in G(1) phase [(31.14±3.36)% vs (51.56±5.23)%, P<0.001], decreased the proportion of cells in S phase [(32.44±3.56)% vs (14.33) ±1.45)%, P<0.001], increased the levels of p21 and Bax protein (P<0.001), and decreased the levels of cyclin D1 and Bcl-2 protein (P<0.001). Inhibition of the expression of ACTN4 significantly reduced the cell viability [(0.78±0.07) vs (1.24±0.12), P<0.001], increased the apoptosis rate [(6.58±0.66)% vs (18.32±1.82)%, P<0.001], increased the proportion of cells in G(1) phase [(48.69±4.21)% vs (30.33±3.01)%, P<0.001], decreased the proportion of cells in S phase [(36.21±3.42)% vs (18.54±1.61)%, P<0.001], increased the protein levels of p21 and Bax (P<0.001), and decreased the levels of cyclin D1 and Bcl-2 protein (P<0.001). Compared with the miR-369-3p+ pcDNA group, overexpression of ACTN4 increased the proliferation ability of hepatocellular carcinoma MHCC97H cells at 72 hours of culture[(1.12±0.11) vs (0.68±0.06), P<0.001], significantly reduced the proportion of cells in G(1) stage [(38.81±3.24)% vs (51.80±4.57)%, P<0.001], significantly increased the proportion of S-phase cells [(31.65±3.11)% vs (15.69±1.44)%, P<0.001], decreased cell apoptosis rate [(13.86±1.37)% vs (22.69±2.24)%, P<0.001], increased protein expressions of cyclin D1 and Bcl-2 (P<0.001), decreased the protein expressions of p21 and Bax (P<0.001). Conclusion: MiR-369-3p can induce cell cycle arrest in G(1) phase, inhibit the proliferation and promote apoptosis of liver cancer cells by regulating the expression of ACTN4.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Actinina/genética , Apoptose , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética
10.
Gan To Kagaku Ryoho ; 48(11): 1389-1392, 2021 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-34795132

RESUMO

The successful treatment of 2 cases of portal vein tumor thrombus caused by hepatocellular carcinoma was reported. It is difficult to manage portal vein tumor thrombi by conventional transarterial chemoembolization(c-TACE)using lipiodol and a gelatin sponge. On the other hand, drug-eluting-microsphere TACE(DEM-TACE)can preserve hepatic function by maintaining the capillary circulation of sinusoids and the peribiliary arterial plexus. Even in cases of portal vein tumor thrombus, DEM-TACE could be safely performed without hepatic infarction. Bevacizumab, anti-VGEF monoclonal antibody, was injected into hepatic arteries with anti-neoplastic agents, followed by the epirubicin-loaded superabsorbent polymer microsphere( HepaSphere). The tumor thrombi in 2 cases were successfully eliminated after treatment for more than 2 years without deterioration of the hepatic function.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Trombose , Bevacizumab , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Microesferas , Veia Porta , Estudos Retrospectivos , Trombose/terapia , Resultado do Tratamento
11.
BMC Gastroenterol ; 21(1): 416, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724892

RESUMO

BACKGROUND: MKI67 plays a vital role in the tumour microenvironment (TME) and congenital immunity. The present work focuses on exploring the prognosis prediction performance of MKI67 and its associations with T cell activity and immune infiltration within numerous cancers, especially hepatocellular liver carcinoma (LIHC). METHODS: Oncomine, GEPIA2, and HPA were adopted to analyse MKI67 levels in different types of cancers. The prognostic prediction performance of MKI67 was evaluated through the TCGA portal, GEPIA2, LOGpc, and Kaplan-Meier Plotter databases. The associations of MKI67 with related gene marker sets and immune infiltration were inspected through TISIDB, GEPIA2, and TIMER. We chose MKI67 to analyse biological processes (BPs) and KEGG pathways related to the coexpressed genes. Furthermore, the gene-miRNA interaction network for MKI67 in liver cancer was also examined based on the miRWalk database. RESULTS: MKI67 expression decreased in many cancers related to the dismal prognostic outcome of LIHC. We found that MKI67 significantly affected the prognosis of LIHC in terms of histology and grade. Increased MKI67 levels were directly proportional to the increased immune infiltration degrees of numerous immune cells and functional T cells, such as exhausted T cells. In addition, several critical genes related to exhausted T cells, including TIM-3, TIGIT, PD-1, LAG3, and CXCL13, were strongly related to MKI67. Further analyses showed that MKI67 was associated with adaptive immunity, cell adhesion molecules (CAMs), and chemokine/immune response signal transduction pathways. CONCLUSION: MKI67 acts as a prognostic prediction biomarker in several cancers, particularly LIHC. Upregulation of MKI67 elevates the degree of immune infiltration of many immune cell subtypes, including functional T cells, CD4+ T cells, and CD8+ T cells. Furthermore, MKI67 shows a close correlation with T cell exhaustion, which plays a vital role in promoting T cell exhaustion within LIHC. Detection of the MKI67 level contributes to prognosis prediction and MKI67 modulation within exhausted T cells, thus providing a new method to optimize the efficacy of anti-LIHC immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos , Humanos , Prognóstico , Microambiente Tumoral
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(10): 1509-1518, 2021 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-34755666

RESUMO

OBJECTIVE: To identify the key genes involved in the transformation of hepatitis B virus (HBV) into hepatocellular carcinoma (HCC) and explore the underlying molecular mechanisms. METHODS: We analyzed the mRNA microarray data of 119 HBV-related HCC tissues and 252 HBV-related non-tumor tissues in GSE55092, GSE84044 and GSE121248 from the GEO database, and the "sva" R package was used to remove the batch effects. Integration analysis was performed to identify the differentially expressed genes (DEGs) in HBV-related liver cancer and liver tissues with HBV infection. The significant DEGs were functionally annotated using GO and KEGG analyses, and the most important modules and hub genes were explored with STRING analysis. Kaplan-Meier and Oncomine databases were used to verify the HCC gene expression data in the TCGA database to explore the correlations of the hub genes with the occurrence, progression and prognosis of HCC. We also examined the expressions of the hub genes in 17 pairs of surgical specimens of HCC and adjacent tissues using RT-qPCR. RESULTS: We identified a total of 121 DEGs and 3 genetic markers in HCC (P < 0.01). These DEGs included cyclin1 (CDK1), cyclin B1 (CCNB1), and nuclear division cycle 80 (NDC80), which participated in cell cycle, pyrimidine metabolism and DNA replication and were highly correlated (P < 0.05). Analysis of the UALCAN database confirmed high expressions of these 3 genes in HCC tissues, which were correlated with a low survival rate of the patients, as shown by Kaplan-Meier analysis of the prognostic data from the UALCAN database. CDK1, CCNB1 and NDC80 were all correlated with the clinical grading of HCC (P < 0.05). The results of RT-qPCR on the surgical specimens verified significantly higher expressions of CDK1, CCNB1 and NDC80 mRNA in HCC tissues than in the adjacent tissues. CONCLUSION: CDK1, CCNB1 and NDC80 genes can be used as prognostic markers of HBV-related HCC and may serve as potential targets in preclinical studies and clinical treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína Quinase CDC2/genética , Carcinoma Hepatocelular/genética , Divisão do Núcleo Celular , Biologia Computacional , Ciclina B1/genética , Proteínas do Citoesqueleto , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/genética , Prognóstico
13.
BMC Genomics ; 22(1): 814, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34763675

RESUMO

BACKGROUND: Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3' end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results. RESULTS: We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients. CONCLUSIONS: Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Carcinogênese , Carcinoma Hepatocelular/genética , Dependovirus/genética , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/genética , Tailândia , Integração Viral/genética
14.
World J Gastroenterol ; 27(40): 6737-6749, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34790004

RESUMO

Hepatitis C virus (HCV) chronic infection is associated with fibrosis progression, end-stage liver complications and HCC. Not surprisingly, HCV infection is a leading cause of liver-related morbidity and mortality worldwide. After sustained virological response (SVR), the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis. Therefore, lifelong surveillance is currently recommended. This strategy is likely not universally cost-effective and harmless, considering that not all patients with advanced fibrosis have the same risk of developing HCC. Factors related to the severity of liver disease and its potential to improve after SVR, the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR. Efforts to develop predictive models and risk calculators, biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era, when thousands of patients with advanced fibrosis and cirrhosis have reached SVR. These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified. In this review, factors affecting the probability of HCC development after SVR, the benefits and risks of surveillance, suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Fatores de Risco , Resposta Viral Sustentada
15.
Diagn Interv Radiol ; 27(6): 732-739, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34792027

RESUMO

PURPOSE: Clinical studies conducted in different geographic regions using different methods to compare transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) have demonstrated discordant results. Meta-analyses in this field indicate comparable overall survival (OS) with TACE and TARE, while reporting a longer time to progression and a higher downstaging effect with TARE treatment. In terms of isolated procedure costs, treatment with TARE is 2 to 3 times more, and in some countries even more, expensive than TACE. However, relevant literature indicates that TARE is more advantageous compared to TACE regarding the need for repeat procedures, costs of complication management, total hospital stay and quality of life. Heterogeneity of hepatocellular carcinoma (HCC) patients as well as the shortcomings of clinical classifications, randomized clinical trials and cost-effectiveness studies make it difficult to choose between treatment alternatives in this field. As in other countries, these challenges lead to differences in treatment choice across different centers in Turkey. METHODS: The present expert panel used two round modified Delphi method to investigate the resources and clinical parameters referenced while selecting patients for drug-eluting beads (DEB)-TACE and TARE treatment modalities in Turkish clinical practice. The cost-effectiveness parameters and comparisons of these treatments have also been evaluated at a prediction level. RESULTS: The panelists stated that they most commonly use the BCLC staging system for the management of HCC patients in Turkey. However, they did not find any of the staging systems or treatment guidelines sufficient enough for their clinical practice in terms of covering the down-staging intent of treatments. Since living donor transplant preference is higher in Turkey than the rest of the Western countries, down-staging treatments are thought to be more prioritized in Turkey than that in other Western countries. The panelists reached a consensus that TARE may provide improved OS and reduce the number of repeat procedures compared to DEB-TACE in intermediate-stage patients with a single tumor spanning a diameter above 5 cm who experience recurrence after previous treatment with TACE and most TACE-naïve patient groups in intermediate stage. CONCLUSION: Based on the consensus on OS and the number of procedures, the panelists assumed that TARE would be more cost-effective than DEB-TACE in most groups of TACE-naïve patients in intermediate stage and in those with a single tumor spanning a diameter above 5 cm. It was also stated that the predicted cost-effectiveness advantage of TARE could be more pronounced in patients with a tumor diameter greater than 7 cm.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Preparações Farmacêuticas , Carcinoma Hepatocelular/terapia , Consenso , Humanos , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia , Qualidade de Vida , Resultado do Tratamento , Turquia , Radioisótopos de Ítrio
16.
Diagn Interv Radiol ; 27(6): 746-753, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34792029

RESUMO

PURPOSE: We aimed to evaluate the usefulness of guidewire-catheter induced hydrodissection (GIH) to assist radiofrequency ablation (RFA) for subcapsular hepatocellular carcinoma (HCC) with iodized oil retention in patients with failed artificial ascites due to perihepatic adhesion. METHODS: This retrospective study included 17 patients with small subcapsular HCC ineligible for ultrasonography-guided RFA who received RFA under guidance of fluoroscopy and cone-beam computed tomography immediately after iodized oil transarterial chemoembolization (TACE) between April 2011 and January 2016. In the study patients, creation of artificial ascites to protect the perihepatic structures failed due to perihepatic adhesion and GIH was attempted to separate the perihepatic structures from the ablation zone. The technical success rate of GIH, technique efficacy of RFA with GIH, local tumor progression (LTP), peritoneal seeding, and complications were evaluated. RESULTS: The technical success rate of GIH was 88.24% (15 of 17 patients). Technique efficacy was achieved in all 15 patients receiving RFA with GIH. During an average follow-up period of 48.1 months, LTP developed in three patients. Cumulative LTP rates at 1, 2, 3, and 5 years were 13.3%, 20.6%, 20.6%, and 20.6%, respectively. No patient had peritoneal seeding. Two of the 15 patients receiving RFA with GIH had a CIRSE grade 3 liver abscess, but none had complications associated with thermal injury to the diaphragm or abdominal wall near the ablation zone. CONCLUSION: GIH can be a useful method to assist RFA for subcapsular HCC with iodized oil retention in patients with failed artificial ascites due to perihepatic adhesion.


Assuntos
Carcinoma Hepatocelular , Ablação por Cateter , Quimioembolização Terapêutica , Neoplasias Hepáticas , Ablação por Radiofrequência , Ascite/terapia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Cateteres , Terapia Combinada , Humanos , Óleo Iodado , Neoplasias Hepáticas/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
17.
Diagn Interv Radiol ; 27(6): 768-773, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34792032

RESUMO

PURPOSE: We aimed to determine whether antireflux (ARC) catheter may result in better tumor targeting in liver radioembolization using 90Y-resin microspheres. METHODS: Patients treated with resin microspheres for hepatocellular carcinoma (HCC) and secondary liver malignancies were retrospectively analyzed. All patients underwent a 99mTc-macroaggregated albumin (99mTc-MAA) single photon emission computed tomography (SPECT) following the planning arteriography with a conventional end-hole catheter. For 90Y-microspheres injection, two groups were defined depending on the type of catheter used: an ARC group (n=38) and a control group treated with a conventional end-hole catheter (n=23). 90Y positron emission tomography computed tomography (PET/CT) was performed after the therapeutic arteriography. The choice of the catheter was not randomized, but left to the choice of the interventional radiologist. 99mTc-MAA SPECT and 90Y PET/CT were co-registered with the baseline imaging to determine a tumor to normal liver ratio (T/NL[MAA or 90Y]) and tumor dose (TD[MAA or 90Y]) for the planning and therapy. RESULTS: Overall, 38 patients (115 lesions) and 23 patients (75 lesions) were analyzed in the ARC and control groups, respectively. In the ARC group, T/NL90Y and TD90Y were significantly higher than T/NLMAA and TDMAA. Median (IQR) T/NL90Y was 2.16 (2.15) versus 1.74 (1.43) for T/NLMAA (p < 0.001). Median (IQR) TD90Y was 90.96 Gy (98.31 Gy) versus 73.72 Gy (63.82 Gy) for TDMAA (p < 0.001). In this group, the differences were highly significant for neuroendocrine metastases (NEM) and HCC and less significant for colorectal metastases (CRM). In the control group, no significant differences were demonstrated. CONCLUSION: The use of an ARC significantly improves tumor deposition in liver radioembolization with resin microspheres.


Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/radioterapia , Cateteres , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Microesferas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Agregado de Albumina Marcado com Tecnécio Tc 99m , Tomografia Computadorizada de Emissão de Fóton Único , Radioisótopos de Ítrio/uso terapêutico
18.
Diagn Interv Radiol ; 27(6): 789-791, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34792035

RESUMO

A 46-year-old man with a history of hepatitis B cirrhosis and hepatocellular carcinoma (HCC) status post liver transplantation two years ago complicated by HCC recurrence and biliary stenosis presented with hypovolemic shock and melena one month after endoscopic exchange of plastic biliary stents. During endoscopic retrograde cholangiopancreatography, patient was found to have hemobilia and developed uncontrollable bleeding after a common bile duct (CBD) sweep managed by insertion of a stent-graft across major papilla into presumed CBD. The bleeding continued with subsequent negative angiography, and a computed tomography angiography showed malpositioned stent-graft between major papilla and inferior vena cava (IVC). This was successfully managed by the deployment of a vascular plug inside the stent graft and excluding it by deploying a stent across the affected area in IVC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hematemese/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Stents
19.
BMC Gastroenterol ; 21(1): 419, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749658

RESUMO

BACKGROUND: Inoperable hepatocellular carcinoma (HCC) is treated by conventional transarterial chemoembolization (cTACE) using cone-beam computed tomography (CBCT) or digital subtraction angiography (DSA). We compared patient survival outcomes between CBCT-cTACE with automated tumor-feeder detection (AFD) software and DSA-cTACE alone in inoperable HCC patients. METHODS: We reviewed the data of 337 HCC patients treated by CBCT-cTACE or DSA-cTACE between January 2015 and December 2019. Treatment response, progression-free survival (PFS), overall survival (OS), and complications between the CBCT-cTACE and DSA-cTACE groups were compared. Univariate and multivariate logistic regression analyses examined the potential prognostic factors affecting survival after chemoembolization. RESULTS: Tumor response rates in complete response, partial response, and stable disease at 1 month were 67%, 28%, and 4% in the CBCT-cTACE group and 22%, 48%, and 9% in the DSA-cTACE group, respectively. OS rates of patients in the CBCT-cTACE versus DSA-cTACE groups were 87% versus 54%, 44% versus 15%, and 34% versus 7% at 1, 3, and 5 years, respectively. The CBCT-cTACE group had significantly improved PFS (p < 0.001) and OS (p < 0.001). Multivariate analysis showed that CBCT with AFD software was an independent factor associated with longer OS (hazard ratio, 0.38; p < 0.001). CONCLUSIONS: Compared with conventional DSA, combining selective cTACE with CBCT and AFD software leads to better tumor response and prolongs OS in patients with inoperable HCC.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Tomografia Computadorizada de Feixe Cônico , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Estudos Retrospectivos , Software , Resultado do Tratamento
20.
BMC Gastroenterol ; 21(1): 418, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749663

RESUMO

BACKGROUND: The detection rate of Barcelona Clinic Liver Cancer (BCLC) very-early-stage hepatocellular carcinoma (HCC) is increasing because of advances in surveillance and improved imaging technologies for high-risk populations. Surgical resection (SR) and radiofrequency ablation (RFA) are both first-line treatments for very-early-stage HCC, but the differences in clinical outcomes between patients treated with SR and RFA remain unclear. This study investigated the prognosis of SR and RFA for very-early-stage HCC patients with long-term follow-up. METHODS: This study was retrospectively collected data on the clinicopathological characteristics, overall survival (OS), and disease-free survival (DFS) of 188 very-early-stage HCC patients (≤ 2 cm single HCC). OS and DFS were analyzed using the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. RESULTS: Of the 188 HCC patients, 103 received SR and 85 received RFA. The median follow-up time was 56 months. The SR group had significantly higher OS than the RFA group (10-year cumulative OS: 55.2% and 31.3% in the SR and RFA groups, respectively). No statistically significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 45.9% and 32.6% in the SR and RFA groups, respectively). After PSM, the OS in the SR group remained significantly higher than that in the RFA group (10-year cumulative OS: 54.7% and 42.2% in the SR and RFA groups, respectively). No significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 43.0% and 35.4% in the SR and RFA groups, respectively). Furthermore, in the multivariate Cox regression analysis, treatment type (hazard ratio (HR): 0.54, 95% confidence interval (CI): 0.31-0.95; P = 0.032) and total bilirubin (HR: 1.92; 95% CI: 1.09-3.41; P = 0.025) were highly associated with OS. In addition, age (HR: 2.14, 95% CI: 1.36-3.36; P = 0.001) and cirrhosis (HR: 1.79; 95% CI: 1.11-2.89; P = 0.018) were strongly associated with DFS. CONCLUSION: For patients with very-early-stage HCC, SR was associated with significantly higher OS rates than RFA. However, no significant difference was observed in DFS between the SR and RFA groups.


Assuntos
Carcinoma Hepatocelular , Ablação por Cateter , Neoplasias Hepáticas , Ablação por Radiofrequência , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Pontuação de Propensão , Ablação por Radiofrequência/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
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