Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Objective:To investigate the effects of sclerostin (SOST) and WNT/CTNNB1 signaling pathway on the cell cycle, migration and invasion of human uveal melanoma (UM) cells and its related mechanism.Methods:UM tissues from 20 cases of epithelioid UM and 16 cases of spindle cell type UM were collected.The contents of SOST, Wnt-1 and Catenin beta-1 proteins in the collected tissues were detected by immunohistochemical staining.Three human UM tissue derived cell lines OCM-1 (primary spindle cell type), Mum-2B (metastatic epithelioid) and Mum-2C (metastatic spindle cell type) were selected and divided into three groups, blank control group not transfected, empty vector group transfected with SOST negative control vector and SOST siRNA group transfected with SOST siRNA.After 24-hour transfection, the mRNA and protein expression levels of SOST, CTNNB1, WNT protein family 1 (WNT1), CCND1, matrix metalloproteinase (MMP)2 and MMP9 were detected by real-time fluorescence quantitative PCR and Western blot, respectively.The invasion and migration ability of the transfected cells were measured by transwell method, and the cell cycle distribution was detected by flow cytometry.Another 9 female BALB/c nude mice were selected and randomized into OCM-1 group, OCM-1 empty vector group and SOST shRNA group, inoculated with OCM-1 without lentivirus infection, OCM-1 with blank lentivirus infection and OCM-1 with SOST shRNA lentivirus infection, respectively.Six weeks after inoculation, the in situ formation of tumor was observed.The interaction between SOST and low density lipoprotein receptor related protein(LRP)-5/6 in OCM-1 cells was explored by co-immunoprecipitation assay.The study protocol was approved by the Ethics Committee of Tianjin Medical University Eye Hospital (2018KY[L]-20).Results:Immunohistochemical staining results showed that the SOST expression level was higher and the expression levels of Wnt-1 and Catenin beta-1 were lower in spindle cell type UM tissues than in epithelioid UM tissues, and the differences were all statistically significant (all at P<0.01). The real-time fluorescence quantitative PCR results showed that the relative expression of SOST mRNA was significantly lower and the relative expressions of CCND1, WNT1 and MMP9 mRNA were significantly higher in SOST siRNA groups than in corresponding empty vector groups in the three cell lines (all at P<0.05). In OCM-1 and Mum-2C cell lines, the relative expressions of CTNNB1 mRNA were significantly higher in SOST siRNA groups than in empty vector groups (all at P<0.01). Western blot results showed that the relative expression of SOST protein was significantly lower and the relative expressions of Wnt-1, Catenin beta-1, cyclin-D1, MMP2 and MMP9 proteins were significantly higher in SOST siRNA groups than in empty vector groups (all at P<0.01). Transwell assay showed that the cell invasion and migration ability of SOST siRNA group was significantly higher than that of blank control group and empty vector group in the three cell lines (all at P<0.01). Flow cytometry showed that the proportion of G1-phase cells and the G1/S-phase ratio were significantly lower in SOST siRNA group than in blank control groups and empty vector groups (all at P<0.01). The eyeball volume of OCM-1 group, OCM-1 empty vector group and SOST shRNA group was (42.7±4.6), (49.0±22.9) and (135.2±32.7)mm 3, respectively, showing a significant overall difference ( F=19.963, P<0.01). The eyeball volume of SOST shRNA group was larger than that of OCM-1 group and OCM-1 empty vector group, and the differences were statistically significant (both at P<0.05). Co-immunoprecipitation results showed that SOST could interact with LRP-5 and LRP-6 by binding to them, respectively. Conclusions:Silencing SOST can promote the invasion and migration of UM cells, and increase the proportion of UM cells in the division phase.Silencing SOST can promote tumor growth in eyes of nude mice.SOST may play this function by interacting with the membrane receptor LRP-5/LRP-6 and then regulating the WNT/CTNNB1 signal pathway.

Objective To provide nutritional supportive scheme for patients with radiation injury through the treatment of the one exposed to Nanjing 192Ir source accident.Methods The reasonable nutrition treatment scheme was made on the basis of dietary survey and nutritional index monitoring during clinical stages of the patient,including body weight,body mass index(BMI),biochemical indexes,electrolyte,etc.,as well as metabolic cart determination of resting energy expenditure (REE).Results Patient on admission (days 5 post-irradiated) weighing 42.5 kg,172 days after the first irradiated (the first skin grafting) fell to a minimum of 36 kg,then gradually rise,hen rose back to normal range on days 383 before discharge.Normal admission hemoglobin was 135 g/L,172 d after irradiated to a minimum of 54 g/L,normal discharge;when lymphocytes admission low as 0.5 × 109/L,58 days back to normal after exposure,172 days after irradiated down to 0.4 × 109/L.Serum albumin was normal admission 41.2 g/L,172 days after irradiated down to 25.3 g/L.The normal level of serum prealbumin was 0.22 g/L,248 days to a minimum of 0.04 g/L,the basic return to normal at discharge was 0.17 g/L.Admission normal liver function,bilirubin index slightly higher,the all in one parenteral nutrition after about 2.5 months later,bilirubin and liver function indicators were gradually increased,the adjusted treatment and nutrition liver and gallbladder and other gradually returned to normal after treatment.REE and the body weight were determined by metabolic cart on days 294,308 and 342 for the energy requirements.Conclusions For patient with radiation injury,appropriate nutrition therapy is a key method for the clinical treatment and rehabilitation,which can maintain the nutritional status of patients and improve clinical treatment.

Objective To retrospectively study the relationship between several risk factors such as cirrhosis,Child-Pugh classification,tumor size,portal vein tumor thrombus,intraoperative transfusion,hepatic portal occlusion time and the prognosis of hepatic cellular cancer( HCC ) patients after hepatic resection. Methods The clinical data of 123 patients who received hepatic resection for HCC at Tongji Hospital between 2007 and 2009 were retrospectively analyzed. Log-Rank test and Cox proportional hazard model were used in the univariate and multivariate analyses of risk factors. Results 1,2,3,5 year recurrence and survival rates were 54. 17%,66. 67%,81. 40%,87. 50% and 93. 50%,73. 17%,58. 54%,27. 64%,respectively. The mean recurrence time and survival time were 19. 5 months and 42. 9 months. In univariate analysis,presence of cirrhosis(χ2 =11. 159,P=0. 005),Child-Pugh classification(χ2 =7. 715,P=0. 028),tumor size(≥5cm)(χ2 =11. 483,P=0. 004),presence of portal vein invasion(χ2 =22. 271,P=0. 001)were risk factors affecting HCC recurrence. In multivariate analysis,presence of cirrhosis(χ2 =8. 993,P=0. 003),tumor size (≥5cm)(χ2 =4. 022,P=0. 039),presence of portal vein invasion(χ2 =5. 023,P=0. 027)were inde-pendent risk factors affecting HCC recurrence. In univariate analysis,presence of cirrhosis(χ2 =7. 339,P=0. 025),AFP﹥400 ng/ml(χ2 =5. 431,P=0. 042),Child-Pugh classification(χ2 =13. 389,P=0. 002), tumor size(≥5cm)(χ2 =11. 342,P=0. 003),presence of portal vein invasion(χ2 =52. 167,P﹤0. 001), hepatic portal occlusion(χ2 =5. 801,P=0. 037),intraoperative blood transfusion(χ2 =14. 959,P=0. 001) were risk factors affecting a shorter overall survival. In multivariate analysis,presence of cirrhosis(χ2 =9. 133, P=0. 003),Child-Pugh classification(χ2 =4. 799,P=0. 028),tumor size(≥5 cm)(χ2 =9. 101,P=0. 004),presence of portal vein invasion(χ2 =11. 126,P=0. 001),hepatic portal occlusion(χ2 =3. 985, P=0. 046)were independent prognostic factors affecting shorter overall survival. Conclusion Cirrhosis, Child-Pugh classification,tumor size(≥5 cm),presence of portal vein invasion,and hepatic portal occlusion were independent prognostic factors for HCC patients after hepatic resection.