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OBJECTIVE To investigate the regulatory effect of autophagy on the resistance of human liver cancer cell Huh7 to lenvatinib. METHODS Using human liver cancer cell Huh7 as subject， the lenvatinib-resist cell model （Huh7-LR） was generated by the low-dose gradient method combined with long-term administration. The sensitivity of parental cell Huh7 and drug-resistant cell Huh7-LR to lenvatinib was detected by using CCK-8 assay and flow cytometry. Western blot assay and GFP-mCherry-LC3 plasmid transfection were performed to detect the expression levels of autophagic protein Beclin-1， autophagic adapter protein sequestosome 1 （p62）， microtubule-associated protein 1 light chain 3 （LC3） and autophagic level. Furthermore， an autophagy activation model was constructed by cell starvation， the protein expression of p62 and autophagy level were detected by using Western blot assay and GFP-mCherry-LC3 plasmid transfection， and the effect of autophagy activation on the sensitivity of Huh7-LR cells to lenvatinib was detected by flow cytometry. RESULTS Compared with parental cells， the drug resistance index of Huh7-LR cells was 6.2； protein expression of p62 was increased significantly， while apoptotic rate， protein expression of Beclin-1 and LC3Ⅱ/ LC3Ⅰ ratio were all reduced significantly （P＜0.05 or P＜0.01）； the level of autophagy was decreased to some extent. Autophagy activation could significantly increase the protein expression of p62 in Huh7-LR cells （P＜0.05） and autophagy level， and significantly increase its apoptotic rate （P＜0.05）. CONCLUSIONS Autophagy is involved in lenvatinib resistance， and activating autophagy can reverse the resistance of liver cancer cells to lenvatinib to some extent.
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Tenofovir disoproxil fumarate （TDF） is a first-line treatment for chronic hepatitis B. With increasing use worldwide， the adverse events of renal injury caused by this drug have also attracted industry attention. This article reports a 61- year-old patient with liver cancer complicated with hepatitis B virus （HBV） infection. The patient started using TDF in mid-March 2022 and developed kidney injury after 2 months of treatment， during which he received 2 courses of donafenib combined with sintilimab chemotherapy and irregular administration of diclofenac for pain relief. In this paper， Naranjo’s assessment scale was used to evaluate the drugs that may be associated with renal injury， including TDF and sintilimab， and the drugs that are suspected to be associated with renal injury are donafenib and diclofenac. The renal injury caused by TDF can be judged according to the changes in the patient’s condition， the incidence of drug-induced renal injury， clinical manifestations， occurrence time， occurrence mechanism， drug combination， and high-risk factors. The changes of serum creatinine in patients with liver cancer complicated with HBV infection after TDF should be dynamically monitored in the clinic， and the dose of antiviral drugs should be adjusted if necessary and other antiviral drugs with less impact on renal function can be selected， to provide individualized medication recommendations for tumor patients， reduce the incidence of TDF-related renal injury.
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ObjectiveTo analyze the epidemiological distribution and temporal trends of liver cancer incidence among Luzhou residents from 2016‒2022， and to provide a theoretical basis for improving liver cancer prevention and treatment strategies in Luzhou. MethodsData on liver cancer incidence among Luzhou residents from 2016 to 2022 were collected， and the incidence rate， age-specific incidence rate， and annual percentage change （APC） were calculated. A Joinpoint regression model was used to fit a time series segment to the monthly number of new cases in each district and county of Luzhou to explore the trend of liver cancer incidence rate. ResultsThe incidence rate of liver cancer in Luzhou increased from 22.96/105 in 2016 to 32.31/105 in 2022. The incidence rate of liver cancer in men was higher than that in women in both 2016 and 2022， and the incidence rate of liver cancer in men increased from 34.83/105 in 2016 to 47.95/105 in 2022， with an APC of 3.3%； the incidence rate of liver cancer in women increased from 10.50/105 in 2016 to 15.95/105 in 2022， with an APC of 3.0%， and the differences in the change trends were not statistically significant （P>0.05）.The incidence of liver cancer was low in the age group of 0‒<40 years from 2016 to 2022 and increased with age； the incidence of liver cancer in the age group of 55 years and above was increasing at an average annual rate of 16.4%. ConclusionThe overall incidence of liver cancer in Luzhou is on the rise， and the incidence of liver cancer in men is higher than that in women. Middle-aged and elderly men are the key population for liver cancer prevention and treatment， and liver cancer prevention and treatment should be carried out in a targeted manner， taking into account regional development differences.
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Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.
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ObjectiveTo investigate the mechanism of Biejiajian Wan in the intervention of primary liver cancer based on long non-coding RNA SNHG5 （lncRNA SNHG5）/micro RNA-26a-5p （miRNA-26a-5p）/glycogen synthase kinase-3β （GSK-3β） signal axis. MethodDouble luciferase reporting assay was used to verify the targeted interaction between lncRNA SNHG5 and miRNA-26a-5p， miRNA-26a-5p， and GSK-3β in HepG2 cells. Nude-mouse transplanted tumor model of human HepG2 were established and randomly divided into model group， Biejiajian Wan low-dose group （0.5 g·kg-1）， medium-dose group （1.0 g·kg-1）， and high-dose group （2.0 g·kg-1）， and sorafenib group （100 mg·kg-1）， with 10 mice in each group. The mice were given intragastric administration of normal saline or drug for 28 days， and the tumor volume was measured at different time. Hematoxylin-eosin （HE） staining was used to observe the histological changes of tumors. The nucleic acid levels of lncRNA SNHG5， miRNA-26a-5p， GSK-3β， and β-catenin mPNA in tumor tissue were detected by real-time quantitative polymerase chain reaction （Real-time PCR）. The protein expression levels of GSK-3β and β-catenin in tumor tissue were detected by western blot. ResultCompared with the SNHG5-WT （wild type） + miRNA NC （negative control） group， the relative luciferase activities of the SNHG5-WT + miRNA-26a-5p mimic group were decreased （P<0.05）. Compared with the GSK-3β-WT + miRNA NC group， the relative luciferase activity of the GSK-3β-WT + miRNA-26a-5p mimic group was decreased （P<0.05）. Compared with the model group， the tumor volume of Biejiajian Wan low-dose， medium-dose， and high-dose groups was significantly decreased （P<0.05， P<0.01）. Compared with the model group， the cells in the tumor tissue of nude mice in each dose group of Biejiajian Wan were sparsely arranged with necrocytosis， which showed concentration-dependent changes. Compared with the model group， the expression levels of lncRNA SNHG5， GSK-3β， and β-catenin were decreased （P<0.05， P<0.01）， while the expression of miRNA-26a-5p was increased in each dose group of Biejiajian Wan （P<0.05， P<0.01）. Compared with the model group， the protein expression levels of GSK-3β and β-catenin were decreased in each dose group of Biejiajian Wan （P<0.05， P<0.01）. ConclusionBiejiajian Wan may affect the necrosis of liver cancer cells through lncRNA SNHG5/miRNA-26a-5p/GSK-3β signal axis and thus play an anti-tumor role. This research will provide more theoretical basis for the clinical application of Biejiajian Wan.
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ObjectiveTo investigate the effect of Ganoderma lucidum polysaccharides （GLP） on the proliferation， migration， cycle， and apoptosis of hepatocellular carcinoma SKHEP1 and Huh7 cells and to explore the underlying mechanism. MethodSK-HEP-1 and Huh-7 cells were classified into the blank group and low-， medium-， and high-dose GLP groups （3.5， 7， 14 g·L-1）. The proliferation of the cells was examined by cell counting kit-8 （CCK8） assay， and the migration by scratch assay. Cell cycle was measured by flow cytometry and apoptosis was detected based on Hoechst33258 staining. In addition， the expression of phosphatidylinositol 3-kinase （PI3K）， protein kinase B （Akt）， phosphorylated PI3K （pPI3K）， and phosphorylated Akt （pAkt） in the cells was determined by Western blot. ResultCompared with the blank group， the three doses of GLP reduced the proliferation and migration of SKHEP1 and Huh7 cells （P<0.05）， increased the percentage of cells in G1 phase （P<0.05）， and decreased percentage of cells in S and G2 phase （P<0.05）. In addition， the three doses can induce apoptosis of both SK-HEP-1 and Huh-7 cells， particularly the high dose. Moreover， the three doses of GLP lowered the levels of pPI3K and pAkt （P<0.05）. ConclusionGLP significantly inhibited the malignant phenotype of SK-HEP-1 and Huh-7 cells through the PI3K/Akt signaling pathway.
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Squalene epoxidase (SQLE) is a potential target for the treatment of liver cancer. Bioinformatics analysis indicated that the high expression of SQLE was closely related to the clinical stage and poor prognosis of patients with liver cancer. However, the existing inhibitors against SQLE 195 tyrosine residue (Y195) cannot be used clinically due to severe side effects. In this study, 35 small-molecule compounds targeting SQLE 335 tyrosine residue (Y335) were selected by computer virtual screening. Combined with MTT assay, 3 candidate compounds (19#, 31# and 35#) with significant inhibitory effects on the proliferation of Huh7 cell line were obtained. Further studies showed that these 3 compounds could inhibit the migration of Huh7 cells, reduce the contents of total and free cholesterol, up-regulate the expression of tumor suppressor gene PTEN, and down-regulate the expression of PI3K and AKT proteins. The results showed that the novel inhibitors 19#, 31# and 35# targeting SQLE Y335 could reduce cholesterol content, inhibit the proliferation and migration of Huh7, thus playing an anti-liver cancer role.
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Objective To summarize clinical experience of transabdominal pericardial anastomosis of suprahepatic vena cava of the donor and right atrium of the recipient in liver transplantation for Budd-Chiari syndrome (BCS) complicated with liver cancer. Methods Clinical data of a BCS patient complicated with liver cancer undergoing transabdominal pericardial anastomosis of suprahepatic vena cava and right atrium in liver transplantation were retrospectively analyzed. Results The hepatic vein and suprahepatic vena cava were partially occluded in the patient. Liver transplantation was completed by transabdominal pericardial anastomosis of suprahepatic vena cava and right atrium with beating-heart. In addition, due to pathological changes of the recipient's hepatic artery, splenic artery of the recipient was cut off, distal ligation was performed, and the proximal end was reversed and anastomosed with the common hepatic artery of the donor liver, and the reconstruction of hepatic artery was completed. The surgery was successfully performed. At approximately postoperative 1 week, the function of the liver allograft was gradually restored to normal, and no major complications occurred. The patient was discharged at postoperative 25 d. No signs of BCS recurrence was reported after 8-month follow-up. Conclusions It is safe and feasible to treat BCS by liver transplantation with transabdominal pericardial anastomosis of suprahepatic vena cava and right atrium. BCS patients complicated with liver cancer obtain favorable prognosis.
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ObjectiveTo investigate the inhibitory effects and mechanism of the compound Phyllanthus urinaria Ⅱ （CPU Ⅱ）on the growth of transplanted hepatocellular carcinoma Hep3B2.1-7 （Short for Hep3R） cells in nude mice. MethodAfter the establishment of a xenograft model of hepatocellular carcinoma Hep3B cells in mice， the model mice were randomly divided into a model group， a high-dose CPU Ⅱ group （57.5 g·kg-1）， a low-dose CPU Ⅱ group （28.75 g·kg-1）， and a 5-fluorouracil （5-FU） group （0.025 g·kg-1）， with eight mice in each group. The mice in the high- and low-dose CPU Ⅱ groups were treated with drugs by gavage， once per day， and those in the model group were treated with the same volume of normal saline. The mice in the 5-FU group were treated by 5-FU by intraperitoneal injection， once every other day. After 28 days of administration， mice were sacrificed， and transplanted tumors were collected. Immunohistochemistry （IHC） was used to detect the expression of proliferating cell nuclear antigen （PCNA） of tumor tissues. Terminal-deoxynucleotidyl transferase-mediated nick end labeling （TUNEL） was used to detect cell apoptosis of tumor tissues. The mRNA expression of miR-122 and insulin-like growth factor 1 receptor （IGF-1R） in tumor tissues was detected by Real-time quantitative PCR （Real-time PCR）. The protein expression of CCAAT/enhancer-binding protein α （C/EBPα）， hepatocyte nuclear factor-4α （HNF-4α）， and IGF-1R in tumor tissues was detected by Western blot. ResultThe tumor suppression rates of the high- and low-dose CPU Ⅱ groups and the 5-FU group were 74.90%， 63.62%， and 64.15%， respectively. Compared with the model group， the CPU Ⅱ groups and the 5-FU group showed reduced weight （P<0.01） and volume of tumors （P<0.01）， decreased PCNA positive cells， shallow staining， increased apoptosis cells of transplanted tumor tissues （P<0.05， P<0.01）， increased expression of mRNA expression of miR-122 （P<0.01）， down-regulated mRNA expression of IGF-1R （P<0.01）， and up-regulated protein expression of C/EBPα and HNF-4α in nude mouse transplanted tumor tissues （P<0.01）. The expression of IGF-1R protein in the high-dose CPU Ⅱ group was down-regulated （P<0.05）. Compared with the low-dose CPU Ⅱ group， the high-dose CPU Ⅱ group showed increased apoptotic cells （P<0.01）， up-regulated mRNA expression of miR-122 （P<0.01）， and increased expression of C/EBPα and HNF-4α proteins （P<0.01）. ConclusionCPU Ⅱ has an obvious inhibitory effect on the growth of transplanted hepatocellular carcinoma Hep3B cells in nude mice. The mechanism of action is related to enhancing the expression of transcription factors HNF-4α and C/EBPα， thereby promoting the expression of miR-122 and inhibiting the expression of its target gene IGF-1R.
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ObjectiveTo explore the anti-tumor effect and mechanism of Shenqi Yiliu prescription in the intervention of pyroptosis. MethodTen male BALB/c mice were randomly selected and assigned to the blank group. The remaining 40 mice underwent the induction of the liver cancer xenograft model. After 5 days of modeling， 40 surviving mice were randomly divided into model group， cisplatin group ［2.5×10-3 g·kg-1·（3 d）-1］， Shenqi Yiliu prescription group （27 g·kg-1·d-1）， and a combination group （Shenqi Yiliu prescription group + cisplatin）. The mice in the blank group and the model group were treated with an equal volume of normal saline for 10 days. The general conditions of mice in each group were observed. After the intervention， the tumor weight of the mice was weighed and the tumor inhibition rate was calculated. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in tumor tissues. The levels of mouse liver function indicators， including alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were detected. The TdT-mediated dUTP-biotin nick end labeling （TUNEL） assay was used to detect DNA damage in mouse tumor tissue cells. Immunohistochemistry （IHC）， immunofluorescence （IF）， and Western blot were used to detect the protein expression levels of NOD-like receptor protein 3 （NLRP3）， cysteinyl aspartate-specific protease-1 （Caspase-1）， and gasdermin D （GSDMD） in tumor tissues. The levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） in tumor tissues were detected by enzyme-linked immunosorbent assay （ELISA）. ResultCompared with the mice in the blank group， those in the model group were in a poor mental state， sleepy， and lazy， and their fur color was dull， with increased levels of serum ALT and AST in liver function tests （P<0.01）. Compared with the model group， the groups with drug intervention showed improved mental state， inhibited tumor growth to varying degrees， and decreased tumor weight， and the tumor inhibition rate in the combination group was the highest （P<0.01）. HE staining showed that the pathological and morphological lesions of the tumor tissues in the model group were significant， while those in all groups with drug intervention were improved to a certain extent. The karyolysis and nuclear rupture in the Shenqi Yiliu prescription group and the combination group were more significant. In the liver function test， the serum ALT and AST levels of mice in the Shenqi Yiliu prescription group and the combination group decreased （P<0.01）， and the inflammatory factors IL-1β and IL-18 in each group with drug intervention decreased （P<0.05， P<0.01）. Among them， the declining trend of IL-1β and IL-18 in the Shenqi Yiliu prescription group was the most significant （P<0.01）. TUNEL staining showed that the positive TUNEL staining in each group with drug intervention decreased after intervention （P<0.05， P<0.01）， especially the cisplatin group and Shenqi Yiliu prescription group （P<0.01）. Western blot， IHC， and IF found that the protein expression levels of NLRP3， Caspase-1， and GSDMD in each group with drug intervention decreased （P<0.05， P<0.01）. Compared with the mice in the cisplatin group， those in the Shenqi Yiliu prescription group and the combination group had better mental state and regular tumor morphology， and the tumor weight of the mice in the combination group decreased （P<0.05）. The levels of ALT and AST in the Shenqi Yiliu prescription group decreased （P<0.05）， and the levels of IL-1β and IL-18 in the Shenqi Yiliu prescription group and the combination group decreased （P<0.05， P<0.01）， especially in the combination group （P<0.01）. The results of IHC showed that the expression of GSDMD protein in the tumor tissues of mice in the combination group was reduced （P<0.01）. IF detection showed that the expression of NLRP3 in the tumor tissues of the Shenqi Yiliu prescription group was reduced （P<0.01）. The results of Western blot showed that the expression level of NLRP3 protein in the Shenqi Yiliu prescription group and the combination group decreased （P<0.01）， and the expression level of Caspase-1 protein in the combination group decreased （P<0.01）. The decrease in GSDMD protein expression was not significant， and the difference was not statistically significant. ConclusionShenqi Yiliu prescription combined with cisplatin has an obvious anti-tumor effect， which may be achieved by down-regulating the NLRP3/Caspase-1/GSDMD inflammatory pyroptosis pathway to inhibit cell pyroptosis， and relieve the inflammatory response in mice with liver cancer.
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@#Objective To investigate the effect of a multi-target protein tyrosine kinase inhibitor,Ponatinib,on proliferation,homogeneity adhesion and migration ability of human liver cancer cell line SK-Hep-1.Methods SK-Hep-1 cells were cultured routinely and added with 24 tyrosine kinase inhibitors such as Ponatinib respectively,and the effect of Ponatinib on the survival and proliferation of SK-Hep-1 cells was detected by MTT assay.SK-Hep-1 cells were cultured routinely until the fusion degree reached 90%,then added with 0.1,0.5 and 1.0 μmol/L Ponatinib respectively,and the control group(without Ponatinib) was set up.The effect of Ponatinib on adhesion ability of SK-Hep-1 cells was detected by cell slow aggregation assay and dissociation assay,while the effect on migration ability by scratch test,and the effect on E-cadherin protein expression in SK-Hep-1 cells by Western blot.Results All 24 tyrosine kinase inhibitors inhibited SK-Hep-1 cells,among which Ponatinib showed the strongest inhibitory effect with a IC_(50) of(0.288±0.044) μmol/L.Compared with the control group,the number of cell mass(t=16.143,44.002 and 44.853 respectively,each P <0.001) and N_(TC)/N_(TE) [ratio of single cell number(N) after digestion by trypsin containing EDTA(TE) and CaCl_2(TC)](t=4.276,10.625 and 27.571 respectively,each P <0.05) decreased significantly and E-cadherin protein expression increased significantly(t=-3.757,-4.561and-6.922 respectively,each P <0.05) in 0.1,0.5 and 1.0 μmol/L Ponatinib groups;Scratch migration rate significantly decreased in 0.5 and 1.0 μmol/L Ponatinib groups(t=6.272～16.733 respectively,each P <0.01),while there was no significant difference in 0.1 μmol/L Ponatinib group(t=0.473 and 0.872 respectively,each P> 0.05) after 24 h and 48 h of scratch.Conclusion Ponatinib inhibited proliferation and migration of SK-Hep-1 cells and promoted cell adhesion.
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Objective To describe and analyze the disease burden and its changing trend of liver cancer caused by nonalcoholic steatohepatitis (NASH) in China from 1990 to 2019, and to provide reference for reducing the morbidity and mortality of liver cancer in China. Methods Based on data from the Global Burden of Disease (GBD2019) study, different gender and age groups were selected. The morbidity, mortality, and disability adjusted life year (DALY) rate were used to analyze the disease burden of liver cancer caused by NASH in China from 1990 to 2019. The time trend was analyzed by using the Joinpoint regression model, and the annual percent of change (APC) and annual average percentage change (AAPC) of morbidity, mortality and DALY rate were calculated. Results Compared with 1990, the incidence rate, mortality rate and DALY rate of liver cancer caused by NASH in 2019 decreased by 4.05%, 12% and 25.79%, respectively. Age-standardized morbidity, standardized mortality and standardized DALY rates decreased by 49.50%, 54.72% and 58.45%, respectively. In 2019, the incidence rate, mortality data and DALY rate of liver cancer caused by NASH increased with age, and the highest mortality rate was among people over 85 years old. The average annual change percentage (AAPC) of age-standardized incidence rate, standardized mortality rate and standardized DALY rate of liver cancer caused by NASH from 1990 to 2019 were -2.65% ［95% CI（-3.09%，-2.21 %），P<0.001］, -2.86%［95% CI（-3.34%，-2.38 %），P<0.001］, and -2.91%［95% CI（-3.23%，-2.58%），P<0.001］，respectively. The AAPC of all indexes in males was higher than that in females. Conclusion From 1990 to 2019, the disease burden of liver cancer caused by NASH in China showed an overall downward trend. The AAPC of all indexes in males is higher than that in females, and the elderly population is a high-risk group.
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Liver cancer patients scheduled for liver transplantation (LT) are frequently accompanied by liver cirrhosis.Within a state of long-term malnutrition and inflammatory stress, they are prone to sarcopenia with a poor efficacy of LT.Influenced by such multiple factors as surgery, infections and metabolic disorders, there is an elevated risk of exacerbation or a new onset of sarcopenia after LT.Therefore meticulous managements of sarcopenia are required throughout all aspects and periods of LT.A refined recipient stratification system of sarcopenia can accurately predict the efficacy of LT and its evaluating system has been becoming more precise, diverse and intelligent.Currently basic researches of sarcopenia have remained in infancy and its interactions with the related organs have become a novel research field.Sarcopenia has become an emerging challenge of LT for liver cancer.Further mechanistic explorations of sarcopenia are warranted and clinical precision managements should be further optimized.
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Objective:To study the predictive value of Barcelona clinic liver cancer (BCLC) staging system combined with albumin-indocyanine green (ALICE) score (ALICE-BCLC) in hepatectomy for hepatocellular carcinoma, and compare it with BCLC staging system combined with Child-Pugh score (CP-BCLC).Methods:The clinical data of 311 patients with hepatocellular carcinoma who underwent hepatectomy at Jinhua Hospital Affiliated to Zhejiang University from April 2012 to June 2021 were analyzed retrospectively. There were 271 males and 40 females, with a median age of 59 years old (range 26 to 92 years old). These patients were divided into two groups based on the ALICE-BCLC: the ALICE-BCLC grade 0 group ( n=63) and the ALICE-BCLC grade A group ( n=248); and another two groups based on the CP-BCLC: the CP-BCLC grade 0 group ( n=58) and the CP-BCLC grade A group ( n=253). The clinical data, including indocyanine green retention rate at 15 min, and albumin were collected and the scores were calculated. Follow-up was conducted by combining outpatient visits with telephone calls. The survival rate was calculated by the life method, and survival curves were drawn by the Kaplan-Meier method. The multivariate Cox regression model was used to determine the main factors affecting prognosis. Weighted Kappa was used to compare consistency of the two staging systems. Results:Multivariate analysis showed that a maximum tumor diameter >5 cm, total bilirubin >18 μmol/L, major hepatectomy, CP-BCLC grade A and ALICE-BCLC grade A to be independent risk factors affecting overall survival of patients with hepatocellular carcinoma after liver resection with curative intent (all P<0.05). The median survival of patients in the CP-BCLC grade 0 group and the CP-BCLC grade A group were 43.0 and 28.0 months, respectively. There was a significant difference between the two groups ( P=0.017). The median survival of patients in the ALICE-BCLC grade 0 group and the ALICE-BCLC grade A group were 41.4 and 28.1 months, respectively. There was a significant difference between the two groups ( P=0.035). The weighted Kappa coefficient of ALICE-BCLC and CP-BCLC was 0.949, showing a strong consistency ( P<0.001). Conclusion:ALICE-BCLC showed a good predictive value for prognosis of hepatocellular carcinoma after liver resection, and it had a similar overall prognostic discrimination ability as CP-BCLC.
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Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a pep-tide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97-110 amino acids of apoptin(AP)(AA@G))was con-structed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced com-bination therapy.
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ObjectiveTo evaluate the efficacy and influencing factors of Biejiajianwan in the treatment of primary liver cancer based on real-world data of traditional Chinese medicine （TCM）. MethodClinical diagnosis and treatment data of patients with primary liver cancer admitted to five Grade-A tertiary hospitals in Henan Province from January 2015 to December 2020 were collected from the medical electronic database. The patients treated with Biejiajianwan for ≥30 days were assigned to the exposure group and those without treatment with Biejiajianwan or treated with Biejiajianwan for <30 days to the non-exposure group. The propensity score matching model was used to balance confounding factors between the two groups according to the 1∶1 genetic matching method. Kaplan-Meier method was used for survival analysis and survival curve plotting. Log-rank was used to test the difference in survival rate between the two groups. Univariate analysis of Biejiajianwan in the treatment of primary liver cancer was performed by Log-rank test combined with the Kaplan-Meier method. The factors with statistical significance （P<0.05） were combined with unbalanced factors by the propensity score matching model， and at the same time， clinical common sense and relevant prognostic factors by literature search were considered， which were subjected to multivariate analysis by Cox proportional hazards regression model. ResultA total of 2 207 electronic cases were collected，including 174 cases in the exposure group （Biejiajianwan group） and 2 033 cases in the non-exposure group. After propensity score matching， there were 174 cases in the exposure group and 174 cases in the non-exposure group. The Kaplan-Meier method was used for survival analysis on the matched data， and the Log-rank test results showed that the survival rate of patients with primary liver cancer in the Biejiajianwan group was higher than that in the control group （χ2=12.193， P<0.01）. Cox proportional hazards regression model analysis showed that the regression coefficient of Biejiajianwan was -0.916 4 with the hazard ratio （HR） ［95% confidence interval （CI）］=0.4 （0.239 5-0.668 0）， P<0.01， and the regression coefficient of radiofrequency ablation treatment was -0.976 5 with HR （95% CI）=0.376 6 （0.172 8-0.821 1， P<0.05）. Fibrinogen （FIB） abnormal regression coefficient was 0.481 4 with HR （95% CI）=1.618 4（1.022 0-2.562 9），P<0.05. ConclusionBiejiajianwan can prolong the survival period of patients with primary liver cancer. Radiofrequency ablation is an independent protective factor for Biejiajianwan in the treatment of primary liver cancer，while abnormal FIB are independent risk factors for Biejiajianwan in the treatment of primary liver cancer.
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[Abstract] Objective To explore the effect of serine protease inhibitor Kazal-type 1(SPINK1) on the proliferation of hepatocellular carcinoma cells RH-35 and its underling molecular mechanism. Methods Spink1 gene expression in liver cancer and rat liver cancer models were analyzed by Gene Expression Omnibus (GEO) data, RH-35 cells were treated with rrSPINK1 protein, the effect of rrSPINK1 on the proliferation and apoptosis of RH-35 cells was explored by MTT, 2’-deoxy-5-ethynyluridine(EdU) and flow cytometry, the molecular mechanism of SPINK1 regulating liver cancer were detected by Real-time PCR and Western blotting. Results The results showed that Spink1 gene was over-expressed significantly in liver cancer and rat liver cancer models, rrSPINK1-treated RH-35 cells showed increased viability, EdUpositive cell rate, and the proportion of cells in S phase and G
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AIM: To observe the clinical efficacy of Fuzheng Xiaoliu Granules in the treatment of stage II primary liver cancer and to explore its mechanism of action from the perspective of metabolomics. METHODS: Sixty patients with stage II primary liver cancer who achieved complete remission (CR) after comprehensive interventional therapy were randomly divided into treatment group and placebo group, with 30 patients in each group. They were treated for one year and observed for one year. The one-year recurrence rate, traditional chinese medicine (TCM) syndrome score, alpha-fetoprotein and child-pugh grade were compared between the two groups. The serum metabolites of the two groups before and after treatment were screened by ultra-high liquid chromatography-mass spectrometry technology, and the metabolic pathways and related biological pathways were analyzed. RESULTS: The one-year recurrence rate of the treatment group was significantly lower than that of the placebo group, and the overall improvement rate of TCM syndrome score was significantly better than that of the placebo group (P0.05). Metabolomics results showed that there were 39 and 33 different metabolites in the treatment group before and after treatment and in the two groups after treatment, respectively. After enrichment analysis and topological analysis of the different metabolites, it was found that Fuzheng Xiaoliu Granules could affect amino acid metabolism, fatty acid metabolism and purine metabolism and other metabolic pathways. Before and after treatment in the treatment group and after treatment in the two groups, there were the same differential metabolites and metabolic pathways in the two comparison results. The same differential metabolites with FOLD CHANGE>1 include Stearic acid, Hypoxanthine, Kynurenic acid, Arachidonic acid, and N-Arachidonoyl Dopamine. The same metabolic pathways with Impact>0.1 include Arachidonic acid metabolism and Histidine metabolism. CONCLUSION: Fuzheng xiaoliu granules can effectively reduce the recurrence rate of stage II liver cancer patients after comprehensive intervention and improve the TCM syndrome. It may inhibit the activation of PI3K/Akt and ERK signaling pathways by regulating the content of metabolites involved in metabolic pathways such as amino acids and fatty acids, thereby delaying tumor recurrence.
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Aim To observe the effect of Gupi Xiaoji Decoction (GPXJY) on the structure and function of mitochondria of human hepatoma cell HepG2 cells and explore its possible mechanism. Methods CCK8 was used to detect cell proliferation, Mito-Tracker Green fluorescence staining was used to observe the mitochondrial structure, flow cytometry was used to detect the membrane potential, Elisa was used to detect the ATP content, fluoroscopic electron microscopy was used to observe the microstructure changes, and high-content screening(HCS) was used to detect the related proteins. Results Fluorescence staining showed that GPXJY damaged the mitochondria of HepG2 cells and decreased the content of ATP. The results of flow cytometry showed that GPXJY could reduce the mitochondrial membrane potential of HepG2 cells. The results of electron microscope showed that GPXJY made the mitochondria of cancer cells swell and so on. HCS found that GPXJY significantly reduced the average fluorescence intensity of Bcl-2 in HepG2 cells, and significantly increased the average fluorescence intensity of apoptosis promoting proteins Bax, cytochrome-c, caspase-3 and cleaved-caspase-3, which was statistically significant. Conclusion GPXJY can regulate the structure and function of mitochondria in HepG2 cells.
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Circular RNAs are novel non-coding RNAs with multiple biological functions, which can participate in biological processes such as the occurrence, development, invasion, and metastasis of liver cancer, as well as drug resistance of liver cancer. This article reviews the roles and mechanisms of circR-NAs in chemotherapy resistance, targeted therapy resistance and immunotherapy resistance in liver cancer, in order to provide new ideas for solving liver cancer resistance.