The mechanisms leading to the life-threatening dengue hemorrhagic fever (DHF) remain elusive. DHF preferentially occurs during secondary dengue infections, suggesting that aberrant immune responses are involved in its development. We previously demonstrated that the autoantibodies elicited by dengue virus (DENV) nonstructural protein 1 (NS1; anti–NS1 Igs) induce plasma leakage and mortality in mice with warfarinized anticoagulant suppression. However, the involved pathogenic Ig fractions of anti–NS1 Igs remain unclear. In this study, the autoreactive Igs in patients with DHF and in NS1-immunized rabbits crossreacted with TNF-related apoptosis-inducing ligand receptor 1 (death receptor [DR]4). Challenges with the DENV in a subcytotoxic dose sensitized endothelial cells to apoptosis. Treatments with the autoantibodies induced proapoptotic activities and suppressed the surface expression of endothelial anticoagulant thrombomodulin. Combined treatments comprising the DENV and DR4 affinity-purified fractions of anti–NS1 IgGs (anti–NS1-DR4 Ig), but not preimmune control IgGs, in subcytotoxic doses led to apoptosis in endothelial cells. Treatments with the anti–NS1-DR4 Ig led to plasma leakage, coagulopathy, and morality in mice with warfarinized anticoagulant suppression. These results suggest that DR4-induced endothelial cell sensitization through NS1-elicited autoantibodies exacerbates anticoagulant suppression, vascular injury, and plasma leakage. Detecting and blocking anti–DR Igs in patients may be novel strategies for managing severe DENV infection.

Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a sequence-specific RNA-binding protein and translational regulator, with expression associated with tumor progression. Nevertheless, CPEB4 seems to play paradoxical roles in cancers–an oncogenic promoter in pancreatic ductal adenocarcinoma (PDA) and glioblastomas but a tumor suppressor in hepatocellular carcinoma (HCC). To assess whether CPEB4-regulated carcinogenesis is tissue-specific, we reevaluated the role of CPEB4 in HCC. Although proliferation of hepatocytes appeared normal in CPEB4-knockout (KO) mice after partial hepatectomy, knockdown (KD) of CPEB4 in HepG2 liver cancer cells promoted colony formation in vitro. Moreover, the growth of CPEB4-KD cells was accelerated in an in vivo xenograft mouse model. In tumorous and adjacent non-tumorous paired liver specimens from 49 HCC patients, the protein level of CPEB4 was significantly upregulated in early-stage HCC but decreased toward late-stage HCC. This finding agrees with changes in CPEB4 mRNA level from analysis of two sets of HCC microarray data from the Gene Expression Omnibus (GEO) database. Taken together, downregulation of CPEB4 likely occurs at the late cancer stage to facilitate HCC progression. Biphasic alteration of CPEB4 expression during HCC progression suggests its complicated role in tumorigenesis.

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Background: Stereotactic body radiation therapy (SBRT) is a non-invasive treatment option for metastatic cancer. The purpose of our study was to investigate the efficacy and safety of SBRT for patients with pulmonary or hepatic metastases. Methods:We retrospectively reviewed patients treated with SBRT between 2013 and 2019. Previous local or systemic treatments were allowed. Our end points were the outcomes in terms of local control (LC) of treated metastases, overall survival (OS), and treatment toxicities. The significance of each prognostic factor was estimated using survival analysis.Results: Fifty-one patients and 181 metastatic lesions were analyzed. The median follow-up time was 18 months and the median patient age was 60 years old. The predominant origins of primary cancers include hepatocellular carcinoma (HCC) (21.6%) and colorectal cancer (19.6%), followed by breast cancer (15.7%), nonsmall cell lung cancer (NSCLC) (7.8%), nasopharyngeal cancer (NPC) (7.8%), and others (21.6%). The most common prescribed doses were 50 Gy in 5 fractions (62.4%) and 60 Gy in 5 fractions (31.5%). The 1-and 2-year LC rates were 95.4% and 85.8%. The 1-and 2-year OS rate were 72.9% and 45.1% while the median OS was 24 months. The HCC origin group had worse LC (HR 3.12, P=0.039) and more than 3 treated lesions (HR 3.28, P=0.008) was negatively impacting the OS. In no events the acute or late toxicities were more than grade 3. Conclusions:The results of our study suggest that SBRT offers a feasible treatment with low toxicities and achieves high rates of LC for pulmonary or hepatic metastases.