Sorafenib is a new standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, the survival benefit of this treatment is modest, partly owing to drug resistance. Recent evidence has demonstrated the existence of tumor-initiating cells (T-ICs) as the culprit for treatment resistance. To examine whether sorafenib resistance was a result of the presence of liver T-ICs, we developed sorafenib-resistant HCC cells both in vitro and in vivo through continuous exposure to sorafenib. Using these models, we found that sorafenibresistant clones demonstrated enhanced T-IC properties, including tumorigenicity, selfrenewal, and invasiveness. In addition, several T-IC markers were found to be up-regulated, among which CD47 was found to be most significant. Using chromatin immunoprecipitation assays and expression analyses, CD47 expression was found to be regulated by nuclear factor kappa B (NF-jB) through a specific response element in the promoter of CD47, and the site occupancy and expression were increased and decreased upon stimulation and inhibition of NF-jB, respectively. Consistently, NF-jB was activated in sorafenib-resistant HCC cells, and this finding was confirmed in clinical HCC samples, which showed a positive correlation between NF-jB and CD47 expression. Functional characterization of CD47 in sorafenib-resistant HCC cells was evaluated using a lentivirus-based knockdown approach and showed increased sensitization to sorafenib upon CD47 knockdown. Furthermore, blockade of CD47 using anti-CD47 antibody (Ab) showed a similar effect. Using a patientderived HCC xenograft mouse model, we found that anti-CD47 Ab (500 lg/mouse) in combination with sorafenib (100 mg/kg, orally) exerted synergistic effects on tumor suppression, as compared with sorafenib and anti-CD47 Ab alone. Conclusions: NF-jB-mediated CD47 up-regulation promotes sorafenib resistance, and targeting CD47 in combination with sorafenib is an attractive therapeutic regimen for the treatment of HCC patients. (HEPATOLOGY 2015;62:534-545) L iver cancer (hepatocellular carcinoma; HCC) is a major malignancy worldwide, 1 and the front-line treatment for this disease is liver transplantation and surgical resection. However, most HCCs are inoperable, given that patients typically present at advanced stages, and even after surgical resection, the long-term prognosis of HCC remains unsatisfactory owing to its high recurrence rate. For advanced-staged HCC

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Emergence of SARS-CoV-2 variants of concern (VOC) with progressively increased transmissibility between humans is a threat to global public health. Omicron variant also evades immunity from natural infection or vaccines1. It is unclear whether its exceptional transmissibility is due to immune evasion or inherent virological properties.We compared the replication competence and cellular tropism of the wild type (WT) virus, D614G, Alpha, Beta, Delta and Omicron variants in ex vivo explant cultures of human bronchus and lung. Dependence on TMPRSS2 for infection was also evaluated. We show that Omicron replicated faster than all other SARS-CoV-2 in the bronchus but less efficiently in the lung parenchyma. All VOCs had similar cellular tropism as the WT. Delta was more dependent on serine protease than other VOCs tested.Our findings demonstrate that Omicron is inherently able to replicate faster than other variants known to date and this likely contributes to its inherently higher transmissibility, irrespective of its ability to evade antibody immunity. The lower replication competence of Omicron in human lung may be compatible with reduced severity but the determinants of severe disease are multifactorial. These findings provide important biological clues to the transmissibility and pathogenesis of SARS-CoV-2 VOCs.

Anti-CD47 antibody treatment could complement chemotherapy which may be a promising therapeutic strategy for the treatment of HCC patients.