Transarterial chemoembolization (TACE) is commonly used to treat patients with unresectable hepatocellular carcinoma (HCC); however, TACE alone has demonstrated unsatisfactory survival benefits. Our previous studies suggested that TACE plus oral medication of thalidomide, carmofur and compound mylabris capsule (TCC cocktail) may be a better therapeutic option. In this randomized, open-label, multicenter clinical trial, 72 treatment-naive HCC patients were randomly assigned to receive cTACE alone or cTACE plus oral TCC cocktail between July 2018 and October 2019. The primary endpoint of this trial was the 1-, 2- and 3-year overall survival (OS) rates. The second endpoints of this trial included 1-, 2- and 3-year progression-free survival (PFS) rates, objective response rates (ORR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety with adverse events (AEs). The 1-, 2- and 3-year OS rates were significantly higher in the cTACE plus TCC group than in the cTACE group (83.2 https://www.chictr.org.cn/showproj.html?proj=27493 as ChiCTR1800016335 on 25th May 2018 named an open-label, multicenter, randomized, prospective clinical trial of thalidomide based triple oral regimen for low-dose maintenance therapy after TACE in advanced hepatocellular carcinoma.

Despite ferroptosis induction being a promising strategy for hepatocellular carcinoma (HCC), its clinical application is limited by intrinsic resistance mechanisms. Through CRISPR-Cas9 screening of epigenetic regulators, we identified JMJD6 as a critical mediator of ferroptosis resistance in HCC. JMJD6 knockdown or pharmacological inhibition (iJMJD6) enhanced ferroptosis induced by ferroptosis inducers (erastin and RSL3), as indicated by decreased cell viability, reduced intracellular glutathione levels, increased lipid peroxidation, and disrupted mitochondrial cristae morphology, thereby promoting the susceptibility of HCC to ferroptosis. Clinically, JMJD6 was highly expressed in HCC, and its elevated expression was correlated with a poor prognosis in HCC. Mechanistically, JMJD6 interacts with BRD4, forming a transcriptional complex that binds to the PPARγ promoter. Through its demethylase activity, JMJD6 reduces H4R3me2s levels at the promoter, thereby promoting PPARγ transcription, activating the PPARγ-GPX4 axis to enhance lipid peroxidation scavenging and ferroptosis resistance. Given the role of ferroptosis in resistance mechanisms of molecular-targeted therapies, we combined iJMJD6 with sorafenib or lenvatinib, demonstrating enhanced ferroptosis and potent suppression of HCC proliferation in vitro and in vivo. Our findings revealed the JMJD6/PPARγ/GPX4 axis as a key driver of ferroptosis resistance and established JMJD6 targeting as a novel strategy to improve ferroptosis-based HCC therapies.

Objective: Protein convertase subtilisin/Kexin type 9 (PCSK9) has been found to be closely associated with the occurrence and development of numerous tumors. However, the precise role of PCSK9 and its relationship to the development of hepatocellular carcinoma (HCC) remain largely unknown. This study aimed to clarify these issues. Methods: The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by the quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemical analyses, and the effects of PCSK9 expression on HCC cell biological traits were investigated by overexpressing and downregulating PCSK9 expression in vivo and in vitro. Additionally, the mechanism by which PCSK9 mediated dissociation of glutathione S-transferase Pi 1 (GSTP1) dimers and phosphorylation of the Jun N-terminal kinase (JNK) pathway components were investigated. Results: PCSK9 expression levels were significantly lower in HCC tissues than in adjacent non-tumor samples. In vivo and in vitro experiments suggested that PCSK9 inhibited HCC cell proliferation and metastasis. Further analysis showed that PCSK9 interacted with GSTP1 and promoted GSTP1 dimer dissociation and JNK signaling pathway inactivation in HCC cells. Moreover, the relationships between PCSK9 protein expressions and clinical outcomes were investigated. The PCSK9-lo group displayed a significantly shorter overall survival (OS; median OS: 64.2 months vs. 83.2 months; log-rank statistic: 4.237; P = 0.04) and recurrence-free survival (RFS; median RFS: 26.5 months vs. 46.6 months; log-rank statistic: 10.498; P = 0.001) time than the PCSK9-hi group. Conclusions: PCSK9 inhibited HCC cell proliferation, cell cycle progression, and apoptosis by interacting with GSTP1 and suppressing JNK signaling, suggesting that PCSK9 might act as a tumor suppressor and be a therapeutic target in HCC patients.

Liver cancer is an extraordinarily heterogeneous malignant disease. The tumor microenvironment (TME) and tumor-associated macrophages (TAMs) are the major drivers of liver cancer initiation and progression. It is critical to have a better understanding of the complicated interactions between liver cancer and the immune system for the development of cancer immunotherapy. Based on the gene expression profiles of tumor immune infiltration cells (TIICs), upregulated genes in TAMs and downregulated genes in other types of immune cells were identified as macrophage-specific genes (MSG). In this study, we combined MSG, immune subtypes, and clinical information on liver cancer to develop a tumor immune infiltration macrophage signature (TIMSig). A four-gene signature (S100A9, SLC22A15, TRIM54, and PPARGC1A) was identified as the TAM-related prognostic genes for liver cancer, independent of multiple clinicopathological parameters. Survival analyses showed that patients with low TIMSig had a superior survival rate than those with high TIMSig. Additionally, clinical immunotherapy response and TIMSig was observed as highly relevant. In addition, TIMSig could predict the response to chemotherapy. Collectively, the TIMSig could be a potential tool for risk-stratification, clinical decision making, treatment planning, and oncology immunotherapeutic drug development.

Abstract Background PCSK9 has been found to be closely related to the occurrence and development of a variety of tumors. However, the concrete role of PCSK9 and its relationship with HCC development is largely unknown. Methods The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry assays. The effects of PCSK9 expression on HCC biological traits were investigated by overexpressing and downregulating PCSK9 protein in vivo and in vitro. The mechanism by which PCSK9 mediates the depolymerization of the GSTP1 dimer and the phosphorylation of the JNK signaling pathway was further investigated. Results PCSK9 is downregulated in human HCC tissues. HCC cell proliferation, cell cycle phase distribution and apoptosis were inhibited by PCSK9 in vitro. PCSK9 suppresses tumor growth and metastasis of HCC in vivo. PCSK9 interacts with GSTP1 and promotes the depolymerization of the GSTP1 dimer and inactivation of the JNK signaling pathway. Furthermore, low PCSK9 protein expression in primary HCC tissues correlated with worse clinical outcomes. Conclusions PCSK9 inhibits HCC cell proliferation, cell cycle phase distribution and apoptosis by interacting with GSTP1 and suppressing the JNK signaling pathway, suggesting that PCSK9 might act as a tumor suppressor and may serve as a therapeutic target for the treatment of HCC.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in nonmalignant pathological processes. However, TREM2's function in malignant diseases, especially in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that TREM2 is a novel tumor suppressor in HCC. TREM2 expression was obviously decreased in hepatoma cells (especially metastatic HCC cells), and in most human HCC tissues (especially extrahepatic metastatic tumors). Reduced tumor TREM2 expression was correlated with poor prognosis of HCC patients, and with aggressive pathological features (BCLC stage, tumor size, tumor encapsulation, vascular invasion, and tumor differentiation). TREM2 knockdown substantially promoted cell growth, migration, and invasion in vitro and in vivo, while TREM2 overexpression produced the opposite effect. TREM2 suppressed HCC metastasis by inhibiting epithelial-mesenchymal transition, accompanied by abnormal expression of epithelial and mesenchymal markers. Further study revealed that downregulation of TREM2 in HCC was regulated by miR-31-5p. Moreover, by directly interacting with β-catenin, TREM2 attenuated oncogenic and metastatic behaviors by inhibiting Akt and GSK3β phosphorylation, and activating β-catenin. TREM2 suppressed carcinogenesis and metastasis in HCC by targeting the PI3K/Akt/β-catenin pathway. Thus, we propose that TREM2 may be a candidate prognostic biomarker in malignant diseases and TREM2 restoration might be a prospective strategy for HCC therapy.

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. Methods: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. Results: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. Conclusions: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression.

Hepatocellular carcinoma (HCC) develops in a complex microenvironment characterized by chronic inflammation. In recent years, cholesterol metabolic abnormalities have been implicated the importance in cancer cell physiology. This study was designed to investigate the relationship between inflammation and cholesterol accumulation in HCC cells.

We discovered that entecavir (ETV), nucleos(t)ide analogue against hepatitis B virus (HBV), possessed liver cancer stem cell suppression function in addition to its antiviral function. However, its molecular mechanisms underlying the antitumor effect on hepatocellular carcinoma (HCC) have not been clarified. First of all, the experiments of ETV effect on tumor cells were performed. Cell counts kit 8 (CCK8) was applied to detect the ETV inhibitory effect with different concentrations on Huh7 cells which is a human hepatocellular carcinoma cell line in vitro. Besides, the tumorigenic potential of the cells in vivo were investigated by assessing growth of xenograft tumors in nude mice. Metastatic features of Huh7 were assessed in Matrigel invasion assays and wound healing analyses. Cell apoptosis and cell cycle profile were detected by flow cytometry (FCM). Western blot was used to analyze the expression of p21, caspase 8, caspase 9, and pAKT in the cells. ETV inhibited the growth of hepatic cancer cells in a concentration-dependent and a time-dependent manner. ETV activated caspase cleavage in a concentration-dependent manner to induce apoptosis. Also, we found that ETV can promote G1/S phase arresting accompanied with the upregulation of p21. The ability of migration, invasion and tumorigenesis of ETV treated huh7 cells were decreased. More importantly, the effect of ETV on cell proliferation was confirmed to be associated with AKT phosphorylation inhibition. In summary, ETV reduces the malignant transformation of HCC by promoting p21 at least partially through the AKT inhibition in addition to its antiviral effect.

OBJECTIVE This study aimed to determine whether the human immunodeficiency virus (HIV) exists in giant idiopathic esophageal ulcers in the patients with acquired immune deficiency syndrome (AIDS). METHODS 16 AIDS patients with a primary complaint of epigastric discomfort were examined by gastroscopy. Multiple and giant esophageal ulcers were biopsied and analyzed with pathology staining and reverse transcription-polymerase chain reaction (RT-PCR) to determine the potential pathogenic microorganisms, including HIV, cytomegalovirus (CMV) and herpes simplex viruses (HSV). RESULTS HIV was detected in ulcer samples from 12 out of these 16 patients. Ulcers in 2 patients were infected with CMV and ulcers in another 2 patients were found HSV positive. No obvious cancerous pathological changes were found in these multiple giant esophageal ulcer specimens. CONCLUSION HIV may be one of the major causative agents of multiple benign giant esophageal ulcers in AIDS patients.

Objective: Esophageal varices (EV) and gastric varices (GV) rupture hemorrhage in advanced cirrhotic patients is a serious medical condition and requires immediate treatment. This clinical study aims to find out a more efficient way of using endoscopic variceal ligation (EVL) in treating variceal bleeding and hypotension caused by upper gastrointestinal hemorrhage, and to compare the long-term therapeutic effect of single-band and multiband ligation techniques. Methods: Sixty-seven patients with clinical diagnosed cirrhosis and massive hematemesis were admitted to hospital through emergency room visits. The blood pressure (Bp) of these patients was between 60-82/30-55 mmHg, and their hemoglobin (Hb) levels were in the range of 50-87 g/L. All patients were given fluid resuscitation and somatostatin or terlipressin to reduce portal vein pressure. Patients with Hb level lower than 60 g/L were also given blood transfusion. When patients' Bp stabilized at 78-86/50-55 mmHg and Hb reached 55-60 g/L, endoscopic variceal ligation techniques were immediately applied to stop bleeding. Patients were randomly divided into single-band and multi-band ring ligation groups, while some patients accompanying with GV was treated by injecting in the bleeding gastric varices with sequential sclerosing agent, tissue adhesive and sclerosing agent (named as "sandwich" injection therapy). In the multi-bands treatment group, two to four bands were applied on the varices. The number of bands used for varices were dependent on the severity of EV. In another group of patients (single-band group), only one band was used on varices. Results: All sixty-seven patients were found to have EV by gastroscopic examination, and fifty-three of them had accompanying GV. Sixty-six of these sixty-seven cases were rescued successfully by using immediate endoscopic variceal ligation treatment within 24 hours after bleeding. One exception is a patient who still had bleeding even after EVL and sclerotherapy because he had been treated with Sengtaken-Blakemore tube for three days and that might cause erosion and ulcers in his esophagus. Among the thirty-five multi-band ligation treated patients, eight patients' EV were completely eradicated, and twenty-one patients' EV were mostly eradicated. Varicose veins disappeared in 82.8% of the multi-band treated patients. In singleband ligation treated group which comprises of thirty two patients, EV were completely eradicated in five patients and EV were mostly eradicated in fourteen patients. Varicose veins disappeared in 59.4% of these single-band treated patients. One-year follow-up results showed that the EV recurrence rate in the multi-bands ligation group was 5.7%, which was significantly lower than the rate of 18.7% in the single-band ligation group. No esophageal stenosis was observed in either groups. Conclusion: Patients with EV and/or GV rupture hemorrhage can be rescued successfully by endoscopic variceal ligation therapy. The long-term efficacy of the multi-band ligation technique is superior to single-band ligation.

Objective To explore the feasibility of early diagnosis of cirrhosis by Fibroscan and serum liver fibrosis markers.Methods Thirty-four cases of chronic hepatitis B (CHB) patients were recruited.Each of them was exami-nated by Fibroscan , serum hepatic fibrosis markers , abdominal ultrasonography , and hepatic biopsy .Then 4 samples taken randomly from them were performed gastroscopy .The non-invasive methods were compared with their pathological diagnosis .SPSS V17 .0 LSD-t test was applied to analyze the values of Fibroscan and serum liver fibrosis markers , in the patients’ pathology diagnosises S2, S3, S4 period, respectively.The match rate was calculated that Fibroscan , abdomi-nal B ultrasound and Fibroscan combined with serum liver fibrosis markers matched the pathological diagnosis .Results The values of Fibroscan and HA in the pathological stage S 2, S3, S4 respectively were 9.45 ±4.36, 15.27 ±4.15, 23.50 ±7.69 and 96.49 ±49.93, 180.76 ±67.40, 396.08 ±97.30 (P<0.05).There were no significant differ-ences in the values of the other serum liver fibrosis markers ( CG, LN, PⅢP, CⅣ) between the pathological stage of S 2 and S3 (P>0.05), however, there were significant differences between the values of the stages S 2, S4 or S3, S4, re-spectively (P <0.01).The match rates of Fibroscan values and histology of S0-1, S2, S3, S4 were 33.33%, 81 .82%, 37 .50%, 67 .67%, respectively .The match rates of almost normal , chronic hepatitis , cirrhosis tested by ab-dominal ultrasonography and pathological stages S 0-1, S2-3, S4 were 16.67%, 67.7%, 16.67%.The match rates of Fibroscan values combining with serum liver fibrosis markers and 4 pathological stages were 57 .14%, 91 .67%, 57.14%, 87.50%;the patients with esophageal and (or) gastric varices were found by gastroscopy , which their hepat-ic pathological examination showed stage S 4; but the gastroscopy hinted the patients with chronic superficial gastritis whose hepatic pathology exhibited S2.Conclusion Fibroscan combining serum liver fibrosis markers (especially HA)&nbsp;can improve the detection of early liver fibrosis or cirrhosis in clinic , and uniting abdominal ultrasonography will be more advantageous to the clinical diagnosis and prognosis .

乙型肝炎病毒（HBV）感染仍然是危害全球的公共卫生问题。据报道，全球约20亿人过去或现在感染过 HBV，超过3．5亿人是慢性病毒携带者，其中大部分人为严重进展性肝病，并有转化为肝癌的高风险。肝癌在常见肿瘤中排第五位，在全世界肿瘤相关死因中排第三位，最近的流行病学数据表明，其发病率在世界范围内不断增加，慢性 HBV 感染导致世界上55％～60％肝癌的发生。临床上广泛应用的 HBV 血清学标志物是HBV 感染的常见指标，但曾被认为是 HBV 感染唯一标记的乙型肝炎表面抗原（HBsAg），并不能真正代表有无 HBV 感染。随着现代医学科学技术的发展，临床发现 HBsAg 阴性肝病患者发展为肝癌的病例，也不再是偶然事件。

BACKGROUND/AIMS:Anoikis resistance is a prerequisite for hepatocellular carcinoma (HCC) metastasis. The role of Caveolin-1 (CAV1) in anoikis resistance of HCC remains unclear.METHODS:The oncogenic effect of CAV1 on anchor-independent growth and anoikis resistance was investigated by overexpression and knockdown of CAV1 in hepatoma cells. IGF-1 pathway and its downstream signals were detected by immunoblot analysis. Caveolae invagination and IGF-1R internalization was studied by electron microscopy and (125)I-IGF1 internalization assay, respectively. The role of IGF-1R and tyrosine-14 residue (Y-14) of CAV1 was explored by deletion experiment and mutation experiment, respectively. The correlation of CAV1 and IGF-1R was further examined by immunochemical analysis in 120 HCC specimens.RESULTS:CAV1 could promote anchor-independent growth and anoikis resistance in hepatoma cells. CAV1-overexpression increased the expression of IGF-1R and subsequently activated PI3K/Akt and RAF/MEK/ERK pathway, while CAV1 knockdown showed the opposite effect. The mechanism study revealed that CAV1 facilitated caveolae invagination and (125)I-IGF1 internalization. IGF-1R deletion or Y-14 mutation reversed CAV1 mediated anchor-independent growth and anoikis resistance. In addition, CAV1 expression was positively related to IGF-1R expression in human HCC tissues.CONCLUSION:CAV1 confers resistance of hepatoma cells to anoikis by activating IGF-1 pathway, providing a potential therapeutic target for HCC metastasis.

目的:观察多环与单环套扎在肝硬化食管静脉曲张(EV)出血急诊内镜治疗后临床疗效的异同.方法:75例急诊内镜诊断为EV或合并胃底静脉曲张上消化道出血患者随机采用多环或单环橡皮圈套扎治疗,分为多环套扎治疗组和单环套扎治疗组.多环套扎治疗组40例,根据EV程度给予单位点2环、3环或4环套扎治疗;单环套扎治疗组35例.合并胃底静脉曲张须先给予硬化剂聚桂醇+组织胶+硬化剂方法注射治疗.单环套扎治疗再出血患者改用多环套扎治疗.结果:多环套扎治疗组治疗后胃镜复查EV完全消失8例,基本消失26例,EV消失率85％;单环套扎治疗组治疗后胃镜复查EV完全消失5例,基本消失15例,EV消失率57％;2组比较存在显著性差异(P＜0.05).1年再出血率多环套扎治疗组为5％,明显低于单环套扎治疗组的23％ (P＜0.05).改用多环套扎治疗的再出血患者曲张静脉明显消失.结论:多环套扎治疗EV效果优于单环套扎治疗.

Entecavir (ETV) has been used for more than 2 decades in treating hepatitis B virus (HBV) infections. It has shown significant anti-HBV effect and has led to histological improvement in the liver of chronic hepatitis B (CHB) patients. In patients treated with ETV for over two years, reversal of cirrhosis to normal tissue has also been observed. However, the mechanisms of these tissue repairing or recovery processes are not yet clear. In order to determine the roles that bone marrow and liver stem/progenitor cells play in these processes, we evaluated the CD34⁺ and CD133⁺ stem/progenitor cells in peripheral blood from 292 patients and liver tissues from 43 patients who had received therapies with and without ETV. A significant increase in both CD34⁺ and CD133⁺ cells was found in CHB and cirrhosis patients compared to the healthy controls. In patients treated with ETV, CD34⁺ cells increased 2 and 4 fold in peripheral blood and liver tissues, respectively, while their CD4⁺ and CD8⁺ cells remained the same. On the other hand, CD133⁺ cells did not change or even slightly decreased with ETV treatment. Results from immunohistochemistry staining, real time RT-PCR, and the enzyme-linked immunosorbent assay also revealed the same level of CD34⁺ cell increase and CD133⁺ cell decrease (or no change) in ETV treated patients, compared to patients without ETV therapies. Liver functions in patients with ETV treatment improved in general, but one liver cirrhosis patient with high expression of CD133 in liver tissue developed hepatocellular carcinoma (HCC). In summary, ETV may have differential effects on various stem cell subtypes. ETV-activated stem cells in bone marrow and liver tissues may contribute to the recovery from injuries caused by HBV infection. They also contribute to the regeneration of normal tissue and the recovery of normal liver function. Meanwhile, ETV does not activate stem cells that may participate in the initiation of HCC.

>食管溃疡是由不同病因引起的食管各段黏膜层、黏膜下层甚至肌层破坏而形成的炎性病变。目前,有关人免疫缺陷病毒(HIV)合并胃、十二指肠溃疡的报道已有不少,然而与HIV相关的食管溃疡的报道仍为数不多。近期我院收治了1例HIV感染致食管多发巨大溃疡患者,现结合国内外相关文献报道如下。患者女,34岁,因进食胸骨后疼痛伴反酸、嗳气2个月于2011年7月收治入院。患者曾于当地医院接受对症治