Immune checkpoint inhibitors combined with chemotherapy for the treatment of advanced pancreatic cancer patients.

Immune checkpoint inhibitors (ICIs) represent a major breakthrough for cancer treatment. However, evidence regarding the use of ICIs in pancreatic cancer (PC) remained scarce. To assess the efficacy and safety of ICIs plus chemotherapy, patients with advanced PC were retrospectively recruited and were treated with either chemotherapy alone or chemotherapy plus ICIs. Patients previously treated with any agents targeting T-cell co-stimulation or checkpoint pathways were excluded. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). The combination group showed a significantly longer OS than the chemotherapy group [median, 18.1 vs 6.1 months, hazard ratio (HR) 0.46 (0.23-0.90), P = 0.021]. The median PFSs were 3.2 months in the combination group and 2.0 months in the chemotherapy group [HR 0.57 (0.32-0.99), P = 0.041]. The combination group and the chemotherapy group had similar ORRs (18.2% vs 19.4%, P = 0.906). All patients who achieved a partial response received a doublet chemotherapy regimen regardless of co-treatment with ICIs. Grade 3 or higher adverse events occurred in 31.8% of the patients in the combination group and in 16.9% of those receiving chemotherapy. Although the incidence of serious treatment-related adverse events was higher in the combination group than in the chemotherapy group, the difference was not significant (P = 0.183). Our findings suggest that the combination of ICIs with chemotherapy is both effective and tolerable for advanced PC. ICIs combined with a doublet chemotherapy regimen might be a preferable choice.

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

BACKGROUND: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.

The Expression and Clinical Outcome of pCHK2-Thr68 and pCDC25C-Ser216 in Breast Cancer.

Checkpoint kinase 2 (CHK2) and cell division cycle 25C (CDC25C) are two proteins involved in the DNA damage response pathway, playing essential roles in maintaining genome integrity. As one of the major hallmarks of abnormal cellular division, genomic instability occurs in most cancers. In this study, we identified the functional expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer, as well as its association with breast cancer survival. Tissue microarray analysis using immunohistochemistry was constructed to identify the expression of pCHK2-Thr68 and pCDC25C-Ser216 in 292 female breast cancer patients. The relationship among protein expression, clinicopathological factors (e.g., human epidermal growth factor receptor 2 (HER 2), tumor size, tumor-node-metastasis (TNM) classification), and overall survival of the breast cancer tissues were analyzed using Pearson's χ-square (χ²) test, Fisher's exact test, multivariate logistic regression and Kaplan-Meier survival analysis. Significantly higher expressions of pCHK2-Thr68 and pCDC25C-Ser216 were observed in the nucleus of the breast cancer cells compared to the paracancerous tissue (pCHK2-Thr68, 20.38% vs. 0%; pCDC25C-Ser216, 82.26% vs. 24.24%). The expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer showed a positive linear correlation (p = 0.026). High expression of pCHK2-Thr68 was associated with decreased patient survival (p = 0.001), but was not an independent prognostic factor. Our results suggest that pCHK2-Thr68 and pCDC25C-Ser216 play important roles in breast cancer and may be potential treatment targets.

A novel pharmacological strategy by PTEN inhibition for improving metabolic resuscitation and survival after mouse cardiac arrest.

Sudden cardiac arrest (SCA) is a leading cause of death in the United States. Despite return of spontaneous circulation, patients die due to post-SCA syndrome that includes myocardial dysfunction, brain injury, impaired metabolism, and inflammation. No medications improve SCA survival. Our prior work suggests that optimal Akt activation is critical for cooling protection and SCA recovery. Here, we investigate a small inhibitor of PTEN, an Akt-related phosphatase present in heart and brain, as a potential therapy in improving cardiac and neurological recovery after SCA. Anesthetized adult female wild-type C57BL/6 mice were randomized to pretreatment of VO-OHpic (VO) 30 min before SCA or vehicle control. Mice underwent 8 min of KCl-induced asystolic arrest followed by CPR. Resuscitated animals were hemodynamically monitored for 2 h and observed for 72 h. Outcomes included heart pressure-volume loops, energetics (phosphocreatine and ATP from (31)P NMR), protein phosphorylation of Akt, GSK3ß, pyruvate dehydrogenase (PDH) and phospholamban, circulating inflammatory cytokines, plasma lactate, and glucose as measures of systemic metabolic recovery. VO reduced deterioration of left ventricular maximum pressure, maximum rate of change in the left ventricular pressure, and Petco2 and improved 72 h neurological intact survival (50% vs. 10%; P < 0.05). It reduced plasma lactate, glucose, IL-1ß, and Pre-B cell colony enhancing factor, while increasing IL-10. VO increased phosphorylation of Akt and GSK3ß in both heart and brain, and cardiac phospholamban phosphorylation while reducing p-PDH. Moreover, VO improved cardiac bioenergetic recovery. We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA. PTEN inhibitors may be a novel pharmacologic strategy for treating SCA.

[Association between serum homocysteine and in-hospital death in patients with acute pulmonary embolism].

OBJECTIVE: To explore the association between serum homocysteine (Hcy) level and in-hospital death in patients with acute pulmonary embolism. METHODS: A total of 186 acute pulmonary embolism patients [ (66.8 ± 12.7) years, 89 male] hospitalized in our department between June 2008 and June 2011 were included in this prospective study. Patients were divided into high Hcy group (Hcy ≥ 15.2 µmol/L, n = 95) and low Hcy group (Hcy < 15.2 µmol/L, n = 91). Patients were followed-up for 1 year for the incidence rate of early death associated with acute pulmonary embolism. The Cox proportional hazard model was used to analyze the relationship between serum Hcy level and early death in acute pulmonary embolism patients. RESULTS: Patients were hospitalized for 1-37 days [(10 ± 6) days]. In-hospital death rate was 14.5% (27/186) and was significantly higher in high Hcy group than in low Hcy group [25.3% (24/95) vs. 3.3% (3/91) , P = 0.001]. Univariate Cox regression analysis indicated that admission heart rate, oxygen saturation, enlargement of right ventricle, Hcy ≥ 15.2 µmol/L, serum creatinine level, peak TnT level and deep venous thrombosis (P < 0.05) were independent risk factors for in-hospital death. Multivariate Cox regression analysis showed that Hcy ≥ 15.2 µmol/L (HR = 4.10, 95%CI:3.00-4.98, P = 0.017), admission heart rate (HR = 1.10, 95%CI:1.01-1.20, P = 0.031) , deep venous thrombosis (HR = 1.65, 95%CI:1.45-1.76, P = 0.034) and age (HR = 1.10, 95%CI:1.02-1.19, P = 0.010) were independent predictors of in-hospital death for acute pulmonary embolism patients. One-year follow up was finished in 142 patients (89.3%). There were 19 deaths ( 5 due to repeat pulmonary embolism, 4 due to decompensated respiratory and /or cardiac diseases, 6 due to malignant tumors, 2 due to fatal bleeding and 2 due to pneumonia) . Death rate was similar between the two groups during follow up. CONCLUSION: Higher serum homocysteine is an independent for in-hospital death for patients with acute pulmonary embolism.

The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors.

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.

Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis.

BACKGROUND: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens. METHODS: Published articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata. RESULTS: A total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09-24.03), a median TTR of 2.05 months (m) (95%CI: 1.85-2.26), and a median DOR of 10.65 m (95%CI: 7.78-13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02-57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47-21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56-22.94]), while I+C (8.09 m [95%CI: 6.86-9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60-17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations. CONCLUSIONS: PD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.

[Vicissitude of antibiotic sensitivity of Gram negative bacilli in patients with infection in emergency departments in Beijing during 2005 to 2007].

OBJECTIVE: To investigate changes in antibiotic sensitivity of Gram negative bacilli infections among emergency patients in large hospitals in Beijing during 2005 to 2007. METHODS: Retrospective analysis of all the identified strains of Gram negative bacilli, and their sensitivity to antibiotic obtained in the emergency departments of 5 top first-class hospitals in Beijing for recent 3 years. RESULTS: Two thousand two hundred and eighty-five strains of Gram negative bacilli had taken 64.62% of all, the priority 5 of which were Pseudomonas aeruginosa (23.89%), Escherichia coli (19.91%), Acinetobacter baumanii (17.59%), Klebsiella pneumoniae (8.05%) and Staphylococcus maltophilia (3.94%). The sensitivity of commonly used antibiotics plummeted greatly in recent 3 years, especially carbapenems, cephalosporins and quinolones. The resistance of imipenem-resistant Pseudomonas aeruginosa was 17.30%, 22.53%, 31.92% respectively. The resistance of imipenem-resistant Acinetobacter baumanii was 13.87%, 12.09%, 23.56% respectively. CONCLUSION: Infectious bacteria in emergency departments in Beijing top first-class hospitals tend to show the characteristics of hospital infection. In recent years, the sensitivity of bacilli to antibiotic has dropped greatly. The situation of antibiotics resistance might be depressed.

Akt1-mediated CPR cooling protection targets regulators of metabolism, inflammation and contractile function in mouse cardiac arrest.

Therapeutic hypothermia initiated during cardiopulmonary resuscitation (CPR) in pre-clinical studies appears to be highly protective against sudden cardiac arrest injury. Given the challenges to implementing CPR cooling clinically, insights into its critical mechanisms of protection could guide development of new CPR drugs that mimic hypothermia effects without the need for physical cooling. Here, we used Akt1-deficient mice that lose CPR hypothermia protection to identify hypothermia targets. Adult female C57BL/6 mice (Akt1+/+ and Akt1+/-) underwent 8 min of KCl-induced asystolic arrest and were randomized to receive hypothermia (30 ± 0.5°C) or normothermia. Hypothermia was initiated during CPR and extended for 1 h after resuscitation. Neurologically scored survival was measured at 72 h. Other outcomes included mean arterial pressure and target measures in heart and brain related to contractile function, glucose utilization and inflammation. Compared to northothermia, hypothermia improved both 2h mean arterial pressure and 72h neurologically intact survival in Akt1+/+ mice but not in Akt1+/- mice. In Akt1+/+ mice, hypothermia increased Akt and GSK3ß phosphorylation, pyruvate dehydrogenase activation, and NAD+ and ATP production while decreasing IκBα degradation and NF-κB activity in both heart and brain at 30 min after CPR. It also increased phospholamban phosphorylation in heart tissue. Further, hypothermia reduced metabolic and inflammatory blood markers lactate and Pre-B cell Colony Enhancing Factor. Despite hypothermia treatment, all these effects were reversed in Akt1+/- mice. Taken together, drugs that target Akt1 and its effectors may have the potential to mimic hypothermia-like protection to improve sudden cardiac arrest survival when administered during CPR.

Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: A case-control study.

Immune checkpoint blockade-related pneumonitis is a rare but potentially life-threatening adverse effect, but its risk factors are not completely understood. This case-control study was conducted to identify pneumonitis risk factors in patients treated with anti-PD1 monoclonal antibodies (mAbs), including all the patients who developed pneumonitis after anti-PD-1 mAbs treatment in the Cancer Center of the Chinese People's Liberation Army from September 2015 to September 2017. Two controls per case were matched according to a propensity-score matching algorithm to account for confounding effects caused by individual baseline variables. Demographic and clinical information was obtained from medical records. In total, 55 cases and 110 controls were included in the study. No association was observed between smoking status or primary lung cancer and risk of pneumonitis. Significant risk factors for pneumonitis related to anti-PD-1 mAbs were prior thoracic radiotherapy, prior lung disease and combination therapy with odds ratios of 3.34 (1.51-7.39), 2.86 (1.45-5.64) and 2.73 (1.40-5.31), respectively. The associations remained significant in the multivariable logistic regression model. The risk of pneumonitis induced by anti-PD-1 mAbs is associated with prior thoracic radiotherapy, prior lung disease, and combination therapy. Clinicians should monitor these features in patients receiving anti-PD-1 therapy to optimize clinical safety and efficacy.

Echocardiographic and pathological characteristics of cardiac metastasis in patients with lymphoma.

The purposes of this study were to investigate the patterns of lymphoma involvement in the heart and to correlate pathologic findings in the heart at autopsy with echocardiographic presentation prior to death in patients with malignant lymphoma. Lymphoma patients with complete echocardiographic records prior to death and conformed cardiac metastasis at autopsy were included in the study. Echocardiographic records were reviewed retrospectively. Pathological diagnoses were compared with echocardiographic findings using Fisher's exact test. Twenty-nine patients aged 19-71 (mean +/- SD, 51.5+/-12.7) years were included in the study. Among them 17 (58.6%) were male. There were 6 cases (20.7%) with Hodgkin's disease and 23 (79.3%) cases with non-Hodgkin's lymphoma. Twenty-two (75.9%) cases were diagnosed with cardiac metastases at autopsy by gross appearance of their hearts. The most common (41.4%) site of metastatic involvement was the pericardium. The frequency of tumor on the valves was significantly lower than in the chambers and on other parts of the heart (6.9% versus 93.1%). Metastatic masses in right heart were found in 8 (8/23, 34.8%) non-Hodgkin's lymphoma cases, which was higher than that in Hodgkin's lymphoma cases (0/6, 0%; p=0.15). The frequency of high-grade non-Hodgkin's disease metastasizing to the right ventricle was significantly higher than that for the other kinds of lymphoma (3/7, 42.9% versus 0/22, 0%; p=0.01). Sensitivity of echocardiographic examination to detect cardiac metastasis was 75.9%. Echocardiography has been shown to be a sensitive method for the diagnosis of cardiac involvement in the patients with lymphoma. Patterns of cardiac involvement vary by the types of lymphoma, suggesting that different pathologic types of lymphoma may have different mechanisms of metastasis to the heart.

Echocardiographic and pathologic characteristics of primary cardiac tumors: a study of 149 cases.

To investigate the characteristics and pathological features of primary cardiac tumors and to evaluate the diagnostic sensitivity of echocardiography in primary cardiac tumors, all pathologic and echocardiographic records at the Chinese PLA general hospital and its satellite hospitals between January 1st, 1990 and January 1st, 2000 were reviewed to identify patients with a confirmed diagnosis of primary cardiac tumors. A total of 149 patients who had complete echocardiographic records and who were diagnosed with primary cardiac tumors were included in the study. Pathologic and echocardiographic records were reviewed retrospectively to evaluate the presence, location and histologic type of the tumors. The majority (n=118, 79.2%) of cases had been diagnosed with benign tumors. Myxoma was the most common histologic type accounting for 50.0% of total cardiac tumors. Lipoma was the second most common type of benign tumor. Among cases with malignant tumors (n=31, 20.8%), unclassified sarcoma (n=7), angiosarcoma (n=6) and rhabdomyosarcoma (n=6) were the common histologic types of primary malignant tumor. Non-myxomatous benign tumors were more likely to have occurred in the ventricle than myxomas (17/43, 39.5% vs. 7/75, 9.3%; P=0.00). The proportion of pericardium involvement in the malignant tumors (8/31, 25.8%) was significantly higher than that in the myxomas (0/75, 0%; P=0.00) and non-myxomas (2/43, 4.7%; P=0.01). The diagnostic sensitivity of transthoracic and transesophageal echocardiography was 93.3% (139/149) and 96.8% (30/31), respectively. The study, using a relatively large sample, confirms that myxoma was the most common primary cardiac tumor. The locations of tumor involvement varied by types of tumor. Echocardiography may be a useful tool for early diagnosis of primary cardiac tumors.

[Experimental study of the effects of mild hypothermia on the acute myocardial infarction size in the rabbits with coronary artery reperfusion].

OBJECTIVE: To study the effect of mild hypothermia on the acute myocardial infarction size in the rabbits with coronary artery reperfusion. METHODS: fourteen rabbits were randomly divided into two groups: mild hypothermia group and control group. Each group underwent 45 minutes of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Core temperatures were measured with thermistor. The mild hypothermia group received ice cooling around the body and the core temperature was dropped to 32-35 centigrade after occluded for 30 minutes, while the control group's body temperature were kept above 38 centigrade. The myocardial area at risk and the infarct area were determined with Evan's blue dye and triphenyl tetrazolium chloride (TTC). RESULTS: The total elevated amplitude of ST segment in chest leads V1, V3 and V5 in the mild hypothermia group was (25.8+/-8.5) mV, it was lower than that in the control group (37.7+/-6.5) Mv (P=0.021). The changes of serum MB isoenzyme of creatine kinase (CK-MB) activities in mild hypothermia group was (2646.9+/-1227.3) U/L, it was significantly lower than that in the control group (4787.8+/-1934.2) U/L(P=0.045). The weight of infarct myocardium of the mild hypothermia group was (0.23+/-0.05)g, it was lower than that in the control group (0.42+/-0.16)g (P=0.020). Myocardial infarct size as a percentage of the risk zone (0.214+/-0.044 vs. 0.357+/-0.066, P=0.001) and of the left ventricle weight (0.041+/-0.010 vs. 0.071+/-0.027, P=0.029) were smaller than those in the control group. The ratio of the survived myocardial area over the risk zone in the mild hypothermia group was significantly higher than that in the control group (0.786+/-0.044 vs. 0.643+/-0.066, P<0.001). CONCLUSION: Mild hypothermia may reduce infarct size in the rabbits with transient acute myocardial infarction, and increase survived myocardium in the risk zone.

Effect of initial temperature changes on myocardial enzyme levels and cardiac function in acute myocardial infarction.

In the present study, the effect of initial body temperature changes on myocardial enzyme levels and cardiac function in acute myocardial infarction (AMI) patients was investigated. A total of 315 AMI patients were enrolled and the mean temperature was calculated based on their body temperature within 24 h of admission to hospital. The patients were divided into four groups according to their normal body temperature: Group A, <36.5°C; group B, ≥36.5°C and <37.0°C; group C, ≥37.0°C and <37.5°C and group D, ≥37.5°C. The levels of percutaneous coronary intervention, myocardial enzymes and troponin T (TNT), as well as cardiac ultrasound images, were analyzed. Statistically significant differences in the quantity of creatine kinase at 12 and 24 h following admission were identified between group A and groups C and D (P<0.01). A significant difference in TNT at 12 h following admission was observed between groups A and D (P<0.05), however, this difference was not observed with groups B and C. The difference in TNT between the groups at 24 h following admission was not statistically significant (P>0.05). Significant differences in lactate dehydrogenase at 12 and 24 h following admission were observed between groups A and D (P<0.05), however, differences were not observed with groups B and C (P>0.05). Significant differences in glutamic-oxaloacetic transaminase at 12 and 24 h following admission were observed between groups A and D (P<0.05), however, differences were not observed in groups B and C (P>0.05). However, no significant differences were identified in cardiac function index between all the groups. Therefore, the results of the present study indicated that AMI patients with low initial body temperatures exhibited decreased levels of myocardial enzymes and TNT. Thus, the observation of an initially low body temperature may be used as a protective factor for AMI and may improve the existing clinical program.

5'-triphosphate-siRNA activates RIG-I-dependent type I interferon production and enhances inhibition of hepatitis B virus replication in HepG2.2.15 cells.

Hepatitis B virus (HBV) infection often results in acute or chronic viral hepatitis and other liver diseases including cirrhosis and hepatocellular carcinoma. Current therapies for HBV usually have severe side effects and can cause development of drug-resistant mutants. An alternative and safe immunotherapeutic approach for HBV infection is urgently needed for effective anti-HBV therapy. In this study, we propose a new strategy for anti-HBV therapy that activates type-I interferon (IFN) antiviral innate immunity through stimulating pattern-recognition receptors with RNA interference (RNAi) using a 5'-end triphosphate-modified small interfering RNA (3p-siRNA). We designed and generated a 3p-siRNA targeting overlapping region of S gene and P gene of the HBV genome at the 5'-end of pregenomic HBV RNA. Our results demonstrated that 3p-siRNA induced a RIG-I-dependent antiviral type-I IFN response when transfected into HepG2.2.15 cells that support HBV replication. The 3p-siRNA significantly inhibited HBsAg and HBeAg secretion from HepG2.2.15 cells in a RIG-I-dependent manner, and the antiviral effect of 3p-siRNA was superior to that of siRNA. Furthermore, 3p-siRNA had more pronounced inhibition effects on the replication of HBV DNA and the transcription of mRNA than that of siRNA. Finally, 3p-siRNA displayed antiviral activity with long-term suppression of HBV replication. In conclusion, our findings suggest that 3p-siRNA could act as a powerful bifunctional antiviral molecule with potential for developing a promising therapeutic against chronic HBV infection.

Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist.

A number of agents are now available for use in protecting against ionizing radiation. These radiation-protective agents, however, have many adverse effects. Efforts have been made to develop new radiation-protective agents for medical application. Here, we investigated whether a compound, polyethylenimine (PEI), which activates Toll-like receptor 5 (TLR5)-mediated NF-kB signaling pathways, could have an anti-radiation effect on a mouse model. First, a cell-based screening model for an agonist of TLR5-mediated NF-kB pathway was established and then validated by activation of TLR5-mediated NF-kB luciferase reporter activity with a known TLR5 agonist, flagellin. We found that PEI induced dose-dependent activation of the TLR5-mediated NF-kB pathway, indicating that PEI is indeed a TLR5 agonist. Furthermore, the anti-radiation effect of polyethylenimine was assessed using a γ-ray total body irradiation (TBI) mouse model. Compared with the irradiation control, both survival time and survival rate were significantly improved in mice that received either a low dose of polyethylenimine (P= 0.019) or a high dose of polyethylenimine (P< 0.001). We also observed a positive correlation between animal body weight and survival time in mice that received a low dose of polyethylenimine, a high dose of polyethylenimine and amifostine, over a period of 30 days, r= 0.42 (P< 0.02), 0.72 (P< 0.0001) and 0.95 (P< 0.0001), respectively, while a negative correlation between animal body weight and survival time was observed in the irradiation control (r= -0.89; P< 0.0001). These results indicate that polyethylenimine is a new TLR5 agonist with potential application in offering protection for patients receiving radiotherapy or in radiation-related accidents.

Novel ratiometric fluorescent sensor for silver ions.

Incorporating azacrown[N,S,O] into furoquinoline fluorophore yields a novel ratiometric fluorescent sensor FQ-crown for silver ions. UV-vis absorption and fluorescence emission investigations indicate that FQ-crown bears the features of a large Stokes shift, about 173 nm, and red-shift up to 50 nm in the emission spectra and high affinity for silver ions (log K = 7.21) in ethanol in comparison with other competitive d(10) metal ions.