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Abstract Eliminating primary tumor (“roots”) and inhibiting associated‐circulating tumor cells (associated‐CTCs, “seeds”) are vital issues that need to be urgently addressed in cancer therapy. Associated‐CTCs, which include single CTCs, CTC clusters, and CTC–neutrophil clusters, are essential executors in metastasis and the cause of metastasis‐related death in cancer patients. Herein, a “roots and seeds” multipoint costriking nanodevice (GV‐Lipo/sorafenib (SF)/digitoxin (DT)) is developed to eliminate primary tumors and inhibit the spread of associated‐CTCs for enhancing metastasis inhibition and the therapeutic effect on hepatocellular carcinoma (HCC). GV‐Lipo/SF/DT eliminates primary tumor cells by the action of SF, thus reducing CTC production at the roots and improving the therapeutic effect on HCC. GV‐Lipo/SF/DT inhibits associated‐CTCs effectively via the enhanced identification and capture effects of glypican‐3 and/or vascular cell adhesion molecule 1 (VCAM1) targeting, dissociating CTC clusters using DT, blocking the formation of CTC–neutrophil clusters using anti‐VCAM1 monoclonal antibody, and killing CTCs with SF. It is successfully verified that GV‐Lipo/SF/DT increases the CTC elimination efficiency in vivo, thus effectively preventing metastasis, and shows enhanced antitumor efficacy in both an H22‐bearing tumor model and orthotopic HCC models. Overall, the “roots and seeds” multipoint costriking strategy may open a new cancer treatment model for the clinic.

Superenhancers drive abnormal gene expression in tumors and promote malignancy. However, the relationship between superenhancer‐associated long noncoding RNA (lncRNA) and abnormal metabolism is unknown. This study identifies a novel lncRNA, fatty acid synthesis‐related lncRNA (FASRL), whose expression is driven by upstream stimulatory factor 1 (USF1) through its superenhancer. FASRL promotes hepatocellular carcinoma (HCC) cell proliferation in vitro and in vivo. Furthermore, FASRL binds to acetyl‐CoA carboxylase 1 (ACACA), a fatty acid synthesis rate‐limiting enzyme, increasing fatty acid synthesis via the fatty acid metabolism pathway. Moreover, the expression of FASRL, USF1, and ACACA is increased, and their high expression indicates a worse prognosis in HCC patients. In summary, USF1 drives FASRL transcription via a superenhancer. FASRL binding to ACACA increases fatty acid synthesis and lipid accumulation to mechanistically exacerbate HCC. FASRL may serve as a novel prognostic marker and treatment target in HCC. [ABSTRACT FROM AUTHOR]

Summary: Background: It is unknown whether patients with chronic hepatitis B (CHB) who achieved hepatitis B surface antigen (HBsAg) seroclearance spontaneously or following anti‐viral therapy have similar clinical outcomes. Aim: To compare the risk of hepatocellular carcinoma (HCC) in patients with CHB who either cleared HBsAg spontaneously or following anti‐viral therapy Methods: Adult CHB‐monoinfected patients who cleared HBsAg between January 2000 and March 2019 were identified from a territory‐wide database in Hong Kong. Patients with liver transplantation and/or HCC before HBsAg loss were excluded. Patients' demographics, comorbidities, anti‐viral treatment, laboratory parameters and HCC development were analysed. Results: Of 7,124 identified patients with CHB who cleared HBsAg, mean age was 58.1 ± 13.8 years; 4,340 (60.9%) were male; 451 (6.3%) had cirrhosis; 5,917 (83.1%) and 1,207 (16.9%) had spontaneous and nucleos(t)ide analogue (NA)‐induced HBsAg seroclearance, respectively. Most patients had normal liver function at HBsAg loss. Patients with NA‐induced HBsAg seroclearance were younger, and more likely to be male and cirrhotic than patients with spontaneous HBsAg loss. At a median (interquartile range) follow‐up of 4.3 (2.2‐7.6) years, 97 (1.6%) and 16 (1.3%) patients with spontaneous and NA‐induced HBsAg loss developed HCC, respectively. Patients who achieved NA‐induced HBsAg loss had comparable HCC risk as those with spontaneous HBsAg loss (adjusted subdistribution hazard ratio 0.75, 95% CI 0.43‐1.32, P = 0.323). The results remained robust in propensity score weighting and matching analyses. Conclusion: The HCC risk was similarly low after either spontaneous or NA‐induced HBsAg seroclearance in a territory‐wide cohort of patients with CHB who had cleared HBsAg. [ABSTRACT FROM AUTHOR]

Abstract: To construct an improved biological missile, an immunoconjugate ADM–Dex–ScFv-SA3 was synthesized, which was composed of a hepatocellular carcinoma-specific, single-chain Fv antibody (ScFv-SA3) and a highly potent cytotoxic drug, adriamycin (ADM), as the warhead. Oxidized Dextran T10 (Dex-T10) was used as a linker to connect these two moieties. The 40 KD soluble anti-hepatoma human Trx-ScFv-SA3 protein was expressed in E. coli BL21 (DE3), using a prokaryotic expression vector, pET21a (+)-Trx-ScFv-SA3-His. It was purified using a His-Tag Ni-Agarose column and identified by western blot. The activity of Trx-ScFv-SA3 was verified by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry to confirm that it specifically binds to the hepatocellular carcinoma cell line HepG2. To prepare ADM–Dex–ScFv-SA3, ADM was conjugated to the antibody at a molar ratio of 14.21:1. The antitumor effect of the conjugate was tested by MTT assay, plate colony formation assay and xenografts in a nude mice experimental model. In vitro experiments revealed that ADM–Dex–ScFv-SA3 could bind to tumor cells selectively and inhibit the proliferation and the colony formation ability of HepG2 cells. In vivo experiments showed that ADM–Dex–ScFv-SA3 suppressed the tumor growth and prolonged the median survival time in tumor-bearing mice. Tumor histology slides indicated a significantly slower tumor tissue proliferation in the ADM–Dex–ScFv-SA3 group. These data indicate that the targeted drug, ADM–Dex–ScFv-SA3, may be a highly potent and selective therapy for the treatment of hepatoma. [Copyright &y& Elsevier]