Efficacy and safety of lenvatinib combined with PD­1/PD­L1 inhibitors in the treatment of hepatocellular carcinoma: A meta­analysis and systematic review.

A meta-analysis of the clinical survival indicators, adverse reactions and safety of lenvatinib combined with programmed death-1 (PD-1) inhibitors in treating liver cancer was conducted, providing objective and effective evidence for clinical use. The present study is anticipated to guide the clinical application of lenvatinib. In the current meta-analysis, the PubMed, Embase and Cochrane Library databases were searched from inception to September 2023. Randomized controlled trials (RCTs), non-RCTs and single-arm trial studies related to the combined treatment of lenvatinib and PD-1/PD-ligand 1 (L1) inhibitors for hepatocellular carcinoma (HCC) were included, while published and unpublished literature on other study types, literature with incomplete or inadequate information, animal experiments, literature reviews and systematic studies were excluded. Data were processed using STATA 15.1. The pooled results showed that the objective response rate [ORR; odds ratio (OR), 3.36; 95% confidence interval (CI), 2.13-5.30; P<0.001], disease control rate (DCR; OR, 1.62; 95% CI, 1.03-2.57; P=0.038) and partial response (PR; OR, 3.81; 95% CI, 2.17-6.70; P<0.001) of combined lenvatinib and PD-1/PD-L1 inhibitor therapy were significantly higher than those of lenvatinib monotherapy. Additionally, subgroup analysis results showed that the DCR of combination therapy using lenvatinib and nivolumab was significantly higher than that of lenvatinib monotherapy (OR, 2.20; 95% CI; 1.07-4.51; P=0.032). The difference between combination therapy using lenvatinib and camrelizumab, and lenvatinib monotherapy was not significant. However, the complete response, stable disease, progression disease and incidence rate of adverse events between combination therapy and lenvatinib monotherapy were not significantly different. Compared with lenvatinib alone, lenvatinib combined with PD-1/PD-L1 inhibitors significantly improved ORR, mainly PR, and DCR in patients with HCC. At present, lenvatinib is mainly combined with nivolumab to increase the DCR of lenvatinib monotherapy for HCC. In addition, the incidence rate of adverse reactions between combination therapy and lenvatinib monotherapy was not significantly different for HCC.

Exosomes derived from Baicalin-pretreated bone mesenchymal stem cells improve Th17/Treg imbalance after hepatic ischemia-reperfusion via FGF21 and the JAK2/STAT3 pathway.

Baicalin is an active compound extracted from Scutellaria baicalensis with antioxidant and anti-inflammatory properties. Bone mesenchymal stem cells (BMSCs)-derived exosomes have shown promise for the treatment of hepatic ischemia-reperfusion (I/R) injury. This study aims to investigate the role of Baicalin-pretreated BMSCs-derived exosomes in hepatic I/R injury and its mechanisms. BMSCs were pretreated with or without Baicalin, and their exosomes (Ba-Exo and Exo) were collected and characterized. These exosomes were administered to mice via tail vein injection. Treatment with Exo and Ba-Exo significantly suppressed the elevation of ALT and AST induced by hepatic injury. Additionally, both Exo and Ba-Exo treatments resulted in a reduction in the liver weight-to-body weight ratio. RT-PCR results revealed a significant downregulation of pro-inflammatory cytokines with Exo and Ba-Exo treatment. Both Exo and Ba-Exo treatment improved the Th17/Treg cell imbalance induced by I/R and reduced hepatic injury. Additionally, exosomes were cocultured with normal liver cells, and the expression of fibroblast growth factor 21 (FGF21) in liver cells was elevated through Ba-Exo treatment. After treatment, the JAK2/STAT3 pathway was inhibited, and FOXO1 expression was upregulated. Finally, recombinant FGF21 was injected into mouse tail veins to assess its effects. Recombinant FGF21 injection further inhibited the JAK2/STAT3 pathway, increased FOXO1 expression, and improved the Th17/Treg cell imbalance. In conclusion, this study confirms the protective effects of Exo and Ba-Exo against hepatic I/R injury. Ba-Exo mitigates hepatic I/R injury, achieved through inducing FGF21 expression in liver cells, inhibiting the JAK2/STAT3 pathway, and activating FOXO1 expression. Therefore, baicalin pretreatment emerges as a promising strategy to enhance the therapeutic capability of BMSCs-derived exosomes for hepatic I/R.

Expression of lncRNA DLX6-AS1 in patients with hepatic carcinoma and its prognostic value.

Hepatic carcinoma (HCC) is one of the most common malignant tumors worldwide, and the prognosis of HCC patients is often poor. Long-chain non-coding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) has been shown to be involved in the pathogenesis of various cancers. This study aims to investigate the expression of DLX6-AS1 in HCC patients and its prognostic value. The serum DLX6-AS1 was quantified using a reverse transcription-polymerase chain reaction (RT-PCR) assay in both HCC patients and healthy individuals, and the correlation of DLX6-AS1 with clinicopathological features of HCC patients, as well as the diagnostic and prognostic value of DLX6-AS1 for HCC patients, were analyzed. The results showed that the expression of serum DLX6-AS1 in HCC patients was significantly higher than that of healthy individuals (P < 0.05), and DLX6-AS1 was related to tumor differentiation, pathological staging, and lymph node metastasis (all P < 0.05). Patients with high DLX6-AS1 expression showed significantly higher mortality than those with low DLX6-AS1 expression, and the DLX6-AS1 expression in dead patients was significantly higher than that in living patients. Furthermore, the AUC of DLX6-AS1 for poor prognosis of HCC patients was larger than 0.8. The univariate analysis revealed that the poor prognosis of HCC patients was related to pathological staging, lymph node metastasis, differentiation, and DLX6-AS1 expression (all P < 0.05), and the Cox multivariate analysis revealed that pathological staging, lymph node metastasis, differentiation, and DLX6-AS1 expression were independent risk factors for poor prognosis of HCC patients (all P < 0.05). These findings suggest that DLX6-AS1 may be a promising target for diagnosis, treatment, and prognosis prediction of HCC patients.

circRERE regulates the expression of GBX2 through miR-1299 and ZC3H13/N6-methyladenosine (m6A) to promote growth and invasion of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours in the world. Current studies have shown that circular RNAs (circRNAs) and N6-methyladenosine (m6A) methylation play important roles in the progression of HCC, but further studies are needed to confirm the underlying mechanisms. The expression of circRERE was significantly upregulated in HCC cells, and its downregulation reduced HCC cell viability and invasion while increasing apoptosis. Further study showed that circRERE bound directly to miR- 1299. After downregulating the expression of circRERE, miR-1299 expression was significantly enhanced, while the expression of its downstream target gene GBX2 was suppressed, indicating that circRERE promoted the expression of GBX2 through miR-1299. In addition, downregulation of circRERE expression significantly increased the m6A level of GBX2 and promoted the expression of methyltransferase ZC3H13, while overexpression of ZC3H13 significantly inhibited the expression of GBX2 but increased its m6A methylation. circRERE could regulate the m6A modification of GBX2 through ZC3H13, thus promoting the expression of GBX2.GBX2 was upregulated in HCC tissues, while miR-1299 and ZC3H13 were downregulated. MiR-1299 mimics, ZC3H13 overexpression or GBX2 siRNA significantly inhibited HCC cell viability, promoted apoptosis and reduced invasion; GBX2 exerted the opposite effects and could reverse the regulatory effects of miR-1299 or ZC3H13 on HCC cells. Therefore, circRERE promotes the growth and invasion of HCC cells by regulating the expression of GBX2 through miR-1299 and ZC3H13/m6A, indicating that it is a key circRNA in the progression of HCC.

Comparison of the efficacy and safety of repeated hepatectomy and radiofrequency ablation in the treatment of primary recurrent liver cancer: a meta-analysis.

BACKGROUND: Since there is still controversy about the comparison of the efficacy and safety of RH and RFA in the treatment of recurrent liver cancer, we conducted a meta-analysis to compare the efficacy and safety, in order to provide evidence-based evidence for future research and clinical treatment. METHODS: We searched PubMed, Embase, and Cochrane Library from the establishment of the database to Feb 2021. We included studies that reported liver cancer patients underwent repeated hepatectomy (RH) or radiofrequency ablation (RFA), and we excluded duplicate publications, research without full text, incomplete information, or inability to conduct data extraction, animal experiments, reviews, and systematic reviews. The STATA 15.1 was used to analyze the data. RESULTS: The pooled results show that the 3-year and 5-year overall survival (OS) rate of the repeated hepatectomy group was significantly higher than the radiofrequency ablation group (odds ratio (OR) = 1.95, 95% confidence interval (CI):1.47-2.60, P ≤ 0.001; OR = 1.65, 95% CI: 1.12-2.43, P = 0.012). Similarly, the pooled results show that the 3-year and 5-year disease-free survival (DFS) rate of the repeated hepatectomy group was significantly higher than the radiofrequency ablation group (OR = 1.73, 95% CI: 1.30-2.31, P ≤ 0.001; OR = 1.84, 95% CI: 1.38-2.49, P ≤ 0.001). However, there is no significant difference in the 1-year OS and DFS rate of repeated hepatectomy group and radiofrequency ablation group. Additionally, the pooled results show that the postoperative Clavien-Dindo (CD) grade II or higher complication rate of the repeated hepatectomy group was significantly higher than the radiofrequency ablation group (OR = 2.80, 95% CI: 1.37-5.75, P = 0.005). CONCLUSION: Based on the pooled results of 8 existing retrospective studies, RH has a higher OS rate and DFS rate in the treatment of recurrent liver cancer, while the postoperative complication rate of RFA is lower. When survival is the primary goal, RH should be the first choice for recurrent liver cancer.

Effect and molecular mechanism of Lin28 on 5-Fu sensitivity of hepatocellular carcinoma HepG2 cells / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect and mechanism of RNA binding protein Lin28 on the 5-fluorouracil (5-Fu) sensitivity of HepG2 cells. Methods: HepG2 cells were transfected with plasmid pcDNA3.1-Lin28 or si-Lin28 (small interfering RNA of Lin28). qPCR and Western blotting were used to detect the expression of Lin28 in HepG2 cells after transfection. Changes of cell proliferation in transfected cells after 5-Fu treatment was detected by CCK8 assay and the 50% inhibitory concentration (IC50) was calculated. Flow cytometry was used to detect apoptotic rate after 5-Fu treatment and the expression of apoptosis-related protein was assayed by Western blotting. The mRNA expressions of drug-resistant miRNAs (let-7a and let-7b), as well as cancer stem cell markers (Oct4, Nanog and Sox2) after transfection were detected by qPCR. Results: As compared to the HepG2/Vector cells, the mRNA and protein expressions of Lin28 were significantly up-regulated in HepG2/Lin28 cells (P<0.05 or P<0.01). Over-expression of Lin28 significantly suppressed the sensitivity of HepG2 cells to 5-Fu (IC50elevated obviously, P<0.05) and significantly increased cell proliferation while decreased apoptotic rate and expression of apoptotic-related protein caspase-3 (all P<0.01). As compared to si-control group, expression of Lin28 in HepG2/si-Lin28 cells was significantly down-regulated (P<0.01). Lin28 knockdown significantly reduced cell proliferation and IC50 of 5-Fu (all P<0.01) but increased apoptotic rate and expression of apoptosis-related protein (P<0.01). Compared with HepG2/Vector group, expressions of let-7a and let-7b, as well as cancer stem cell markers (Oct4, Nanog and Sox2) were significantly increased in HepG2/Lin28 cells (all P<0.01); while these molecules were significantly decreased in HepG2/si-Lin28 cells as comparing to si-control group (all P<0.01). Conclusion: Lin28 can modulate the chemosensitivity of HepG2 cells by regulating the expression of miRNAs and the formation of cancer stem cells. Targeting Lin28 might be a promising approach to improve the chemotherapy efficacy in HCC.

Luteolin suppresses tumor progression through lncRNA BANCR and its downstream TSHR/CCND1 signaling in thyroid carcinoma.

The flavonoid luteolin is a natural antioxidant that usually occurs in its glycosylated form in many green vegetables, and has shown anticancer effects against various cancers. However, the potential tumor-suppressive role of luteolin in thyroid carcinoma and its underlying mechanism remain largely unknown. In current study, SBR assay, clone formation assay were employed to evaluate the effects of luteolin on thyroid cancer. We found that luteolin significantly inhibits thyroid cancer growth. The further mechanisms of its anticancer activity were analyzed by flow cytometry, quantitative real-time PCR, and Western blotting. We found that luteolin decreased the expression of BRAF-activated long noncoding RNA (BANCR), which further led to downregulation of TSHR and downstream oncogenic signaling. Moreover, overexpression of BANCR/TSHR signaling can largely abolish the anti-tumor effects of luteolin on thyroid carcinoma in vitro and in vivo. In conclusion, luteolin may serve as a potential important anticancer agent for thyroid carcinoma by blocking the BANCR/TSHR signaling.

Interstitial chemotherapy with ricin-loaded thermosensitive hydrogel in pancreatic cancer xenograft.

BACKGROUND: Pancreatic cancer is one of the most aggressive malignancies, and has a poor prognosis. Despite efforts made in multiple fields, there has been little success in improving the disease-free survival rate of patients. This study was undertaken to investigate the effectiveness and feasibility of using intra-tumoral injection of ricin-loaded thermosensitive hydrogel for treatment of pancreatic cancer xenografts, attempting to develop a new treatment for human pancreatic cancer. METHODS: BALB/c-(nu/nu) nude mice were inoculated subcutaneously in the right flank with the human pancreatic cancer cells, SW1990. Fourteen days after inoculation, 32 mice, bearing tumors of volume 1.5-2.0 cm3, were randomly assigned to one of four groups, and given an intra-tumoral injection of: (1) saline; (2) 23% w/w thermosensitive hydrogel alone; (3) ricin, 10 microg/kg; or (4) 10 microg/kg ricin loaded in thermosensitive hydrogel. On day 14 after administration, the tumors were excised to calculate the inhibition rate of tumor growth and perform histopathological examination. Tumor cell apoptosis was detected by flow cytometry, and RT-PCR was performed to evaluate the mRNA expression levels of Bcl2 and Bax. RESULTS: Intra-tumoral injection of ricin-loaded thermosensitive hydrogel resulted in remarkable control of tumor growth. The tumor became necrotic by day 14 after administration. The histological results clearly confirmed that the tumor cells were lysed. The percentage of apoptotic cells detected by flow cytometry was higher in the ricin hydrogel group than in the other groups. Semi-quantitative RT-PCR revealed that the mRNA expression level of Bcl2 was down-regulated whereas Bax was upregulated. CONCLUSIONS: Intra-tumoral injection of ricin-loaded thermosensitive hydrogel may provide an effective approach for interstitial chemotherapy in pancreatic cancer. Inducing apoptosis by downregulating Bcl2 expression and upregulating Bax expression may be a key molecular mechanism.

An omnidirectional M-mode echocardiography system and its clinical application.

This paper introduces the omnidirectional M-mode echocardiography (OME), which can detect dynamic information from sequential echocardiography images. The method for detecting dynamic information is based on the rebuilding of their "gray (position)-time" function [Qiang L, Wenjing J, Li Z. A method for detecting dynamic information of sequential images--omnidirectional gray-time waveform and its applications in echocardiography images. In: Proceedings of CISST' 2001. 2001. p. 760-3; Qiang L, Wenjing J, Xiuzhi Y. A method for mining data of sequetial images-rebuilding of gray (position)-time function on arbitrary direction lines. In: Proceeding of CISST' 2002, vol. 3-6. 2002; Qiang L, Li Z, Wenjing J. The realization of omnidirectional gray-time waveform system and its application on echocardiography. J Electron Meas Instrum, 2002;16(1):70-5] on direction lines. The system can obtain motion and inherent dynamic information of a certain part of the cardiac structure at a certain moment. The system also shows a group of omnidirectional M-mode echocardiography images with synchronous ECG, which is rebuilt from 2D echocardiography images. The ECG supplies a standard time for the omnidirectional M-mode echocardiography images. The system has been applied in clinical application for 3 years and the results are good.

Synthesis, properties and X-ray crystal structure of a new heteropolyacid supermolecular charge-transfer complex [(VB1)2DMFHPMo12O40.5DMF].

The title complex [(VB(1))(2)DMFHPMo(12)O(40).5DMF, VB(1) = vitamin B(1) (thiamine chloride), DMF = N,N-dimethylformamide] has been synthesized and characterized by elemental analysis, IR, UV-Vis, electron spin resonance, X-ray photoelectron spectroscopy and cyclic voltammetry methods. The X-ray crystal structure revealed that there is one independent molecule in the unit cell of the title complex that contains one mixed-valence heteropolyanion, two VB(1)(+) cations and six DMF molecules. The title complex possesses a centrosymmetrical arrangement in the unit cell, with the P atom at the symmetry center of the heteropolyanion and with eight O atoms surrounding the central P atom, such that two sets of PO(4) tetrahedra are formed. The PO(4) tetrahedra and MoO(6)(6-(7-)) octahedra are disordered in the heteropolyanion. The bond distances of P-O(a) and Mo=O(d) are in the ranges 1.57 (4)-1.70 (4) A and 1.61 (2)-1.67 (2) A, respectively.