Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics.The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

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Background Real-time adherence monitoring is now possible through medication storage devices equipped with cellular technology. We assessed the effect of triggered cell phone reminders and counseling utilizing objective adherence data on antiretroviral (ART) adherence among Chinese HIV-infected patients. Methods We provided ART patients in Nanning, China, with a medication device (“Wisepill”) to monitor their ART adherence electronically. After 3 months, we randomized subjects within optimal (≥95%) and suboptimal (<95%) adherence strata to intervention vs. control arms. In months 4–9, intervention subjects received individualized reminders triggered by late dose-taking (no device-opening by 30 minutes past dose time), and counseling using device-generated data. Controls received no reminders or data-informed counseling. We compared post-intervention proportions achieving optimal adherence, mean adherence, and clinical outcomes. Results Of 120 subjects enrolled, 116 (96.7%) completed the trial. Pre-intervention, optimal adherence was similar in intervention vs. control arms (63.5% vs. 58.9%, respectively; p=0.60). In the last intervention month, 87.3% vs. 51.8% achieved optimal adherence (risk ratio (RR) 1.7, 95% Confidence Interval (CI) 1.3–2.2); mean adherence was 96.2% vs. 89.1% (p=0.003). Among pre-intervention suboptimal adherers, 78.3% vs. 33.3% (RR 2.4, CI 1.2–4.5) achieved optimal adherence; mean adherence was 93.3% vs. 84.7% (p=0.039). Proportions were 92.5% and 62.9% among optimal adherers, respectively (RR 1.5, CI 1.1–1.9); mean adherence was 97.8% vs. 91.7% (p=0.028). Post-intervention differences in clinical outcomes were not significant. Conclusion Real-time reminders significantly improved ART adherence in this population. This approach appears promising for managing HIV and other chronic diseases and warrants further investigation and adaptation in other settings.

Objective. Coronavirus disease 2019 (COVID-19) outbreak is a major challenge all over the world, without acknowledged treatment. Intravenous immunoglobulin (IVIG) has been recommended to treat critical coronavirus disease 2019 (COVID-19) patients in a few reviews, but the clinical study evidence on its efficacy in COVID-19 patients was lacking. Methods. 325 patients with laboratory-confirmed critical COVID-19 were enrolled from 4 government-designated COVID-19 treatment centres in southern China from December 2019 to March 2020. The primary outcomes were 28-and 60-day mortality, and the secondary outcomes were the total length of in-hospital and the total duration of the disease. Subgroup analysis was carried out according to clinical classification of COVID-19, IVIG dosage and timing. Results. In the enrolled 325 patients, 174 cases used IVIG and 151 cases did not. The 28-day mortality was improved with IVIG after adjusting confounding in overall cohort (P = 0.0014), and the in-hospital and the total duration of disease were longer in the IVIG group (P < 0.001). Subgroup analysis showed that only in patients with critical type, IVIG could significantly reduce the 28-day mortality, decrease the inflammatory response and improve some organ functions (all P < 0.05); the application of IVIG in the early stage (admission ≤ 7 days) with a high dose (> 15 g per day) exhibited significant reduction in 60-day mortality in the critical-type patients. Conclusion. Early administration of IVIG with high dose

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Purpose: Aspirin has recently been reported to reduce both the incidence and the risk of metastasis in colon cancer. However, there is no evidence at the cellular levels or in the animal models for such an effect of aspirin on cancer metastasis.Experimental Design: MTT assay, colony formation assay, and apoptosis assay were employed to analyze the effects of aspirin on the osteosarcoma cell viability in vitro. The NF-kB activity was measured by the NF-kB p65 luciferase reporter. Western blotting was used to analyze the proteins in cells. The migration and invasion abilities of osteosarcoma cells in vitro were measured by the Transwell assay. Xenograft-bearing mice were used to assess the roles of aspirin in both tumor growth and metastasis of osteosarcoma in vivo (n ¼ 5-8 mice/group). An unpaired Student t test or ANOVA with the Bonferroni post hoc test were used for the statistical comparisons.Results: Aspirin reduced cell viability in a dose-and timedependent manner in osteosarcoma cell lines, and aspirin synergistically sensitized osteosarcoma cells to cisplatin (DDP) in vitro and in vivo (P < 0.001). Moreover, aspirin markedly repressed the migration and invasion of osteosarcoma cells in vitro (P < 0.001), and dramatically diminished the occurrence of osteosarcoma xenograft metastases to the lungs in vivo (P < 0.001). Mechanistically, aspirin diminishes osteosarcoma migration, invasion, and metastasis through the NF-kB pathway.Conclusions: Aspirin suppresses both the growth and metastasis of osteosarcoma through the NF-kB pathway at the cellular level and in the animal models.

Induced pluripotent stem cells (iPSCs) hold great potential for cell therapy and tissue engineering. Neural crest stem cells (NCSCs) are multipotent that are capable of differentiating into mesenchymal lineages. In this study, we investigated whether iPSC-derived NCSCs (iPSC-NCSCs) have potential for tendon repair. Human iPSCNCSCs were suspended in fibrin gel and transplanted into a rat patellar tendon window defect. At 4 weeks posttransplantation, macroscopical observation showed that the repair of iPSC-NCSC-treated tendons was superior to that of non-iPSC-NCSC-treated tendons. Histological and mechanical examinations revealed that iPSCNCSCs treatment significantly enhanced tendon healing as indicated by the improvement in matrix synthesis and mechanical properties. Furthermore, transplanted iPSC-NCSCs produced fetal tendon-related matrix proteins, stem cell recruitment factors, and tenogenic differentiation factors, and accelerated the host endogenous repair process. This study demonstrates a potential strategy of employing iPSC-derived NCSCs for tendon tissue engineering.

Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally upregulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.