Influenza and COVID-19 co-infection and vaccine effectiveness against severe cases: a mathematical modeling study.

Background: Influenza A virus have a distinctive ability to exacerbate SARS-CoV-2 infection proven by in vitro studies. Furthermore, clinical evidence suggests that co-infection with COVID-19 and influenza not only increases mortality but also prolongs the hospitalization of patients. COVID-19 is in a small-scale recurrent epidemic, increasing the likelihood of co-epidemic with seasonal influenza. The impact of co-infection with influenza virus and SARS-CoV-2 on the population remains unstudied. Method: Here, we developed an age-specific compartmental model to simulate the co-circulation of COVID-19 and influenza and estimate the number of co-infected patients under different scenarios of prevalent virus type and vaccine coverage. To decrease the risk of the population developing severity, we investigated the minimum coverage required for the COVID-19 vaccine in conjunction with the influenza vaccine, particularly during co-epidemic seasons. Result: Compared to the single epidemic, the transmission of the SARS-CoV-2 exhibits a lower trend and a delayed peak when co-epidemic with influenza. Number of co-infection cases is higher when SARS-CoV-2 co-epidemic with Influenza A virus than that with Influenza B virus. The number of co-infected cases increases as SARS-CoV-2 becomes more transmissible. As the proportion of individuals vaccinated with the COVID-19 vaccine and influenza vaccines increases, the peak number of co-infected severe illnesses and the number of severe illness cases decreases and the peak time is delayed, especially for those >60 years old. Conclusion: To minimize the number of severe illnesses arising from co-infection of influenza and COVID-19, in conjunction vaccinations in the population are important, especially priority for the elderly.

Looking through the imaging perspective: the importance of imaging necrosis in glioma diagnosis and prognostic prediction - single centre experience.

BACKGROUND: The aim of the study was to investigate the diagnostic value of imaging necrosis (Imnecrosis) in grading, predict the genotype and prognosis of gliomas, and further assess tumor necrosis by dynamic contrast-enhanced MR perfusion imaging (DCE-MRI). PATIENTS AND METHODS: We retrospectively included 150 patients (104 males, mean age: 46 years old) pathologically proved as adult diffuse gliomas and all diagnosis was based on the 2021 WHO central nervous system (CNS) classification. The pathological necrosis (Panecrosis) and gene mutation information were collected. All patients underwent conventional and DCE-MRI examinations and had been followed until May 31, 2021. The Imnecrosis was determined by two experienced neuroradiologists. DCE-MRI derived metric maps have been post-processed, and the mean value of each metric in the tumor parenchyma, peritumoral and contralateral area were recorded. RESULTS: There was a strong degree of inter-observer agreement in defining Imnecrosis (Kappa = 0.668, p < 0.001) and a strong degree of agreement between Imnecrosis and Panecrosis (Kappa = 0.767, p < 0.001). Compared to low-grade gliomas, high-grade gliomas had more Imnecrosis (85.37%, p < 0.001), and Imnecrosis significantly increased with the grade of gliomas increasing. And Imnecrosis was significantly more identified in IDH-wildtype, 1p19q-non-codeletion, and CDKN2A/B-homozygous-deletion gliomas. Using multivariate Cox regression analysis, Imnecrosis was an independent and unfavorable prognosis factor (Hazard Ratio = 2.113, p = 0.046) in gliomas. Additionally, extravascular extracellular volume fraction (ve) in tumor parenchyma derived from DCE-MRI demonstrated the highest diagnostic efficiency in identifying Panecrosis and Imnecrosis with high specificity (83.3% and 91.9%, respectively). CONCLUSIONS: Imnecrosis can provide supplementary evidence beyond Panecrosis in grading, predicting the genotype and prognosis of gliomas, and ve in tumor parenchyma can help to predict tumor necrosis with high specificity.

Temporary impact on medical system and effectiveness of mitigation strategies after COVID-19 policy adjustment in China: a modeling study.

Background: As China amends its "zero COVID" strategy, a sudden increase in the number of infections may overwhelm medical resources and its impact has not been quantified. Specific mitigation strategies are needed to minimize disruption to the healthcare system and to prepare for the next possible epidemic in advance. Method: We develop a stochastic compartmental model to project the burden on the medical system (that is, the number of fever clinic visits and admission beds) of China after adjustment to COVID-19 policy, which considers the epidemiological characteristics of the Omicron variant, age composition of the population, and vaccine effectiveness against infection and severe COVD-19. We also estimate the effect of four-dose vaccinations (heterologous and homologous), antipyretic drug supply, non-pharmacological interventions (NPIs), and triage treatment on mitigating the domestic infection peak. Result: As to the impact on the medical system, this epidemic is projected to result in 398.02 million fever clinic visits and 16.58 million hospitalizations, and the disruption period on the healthcare system is 18 and 30 days, respectively. Antipyretic drug supply and booster vaccination could reduce the burden on emergency visits and hospitalization, respectively, while neither of them could not reduce to the current capacity. The synergy of several different strategies suggests that increasing the heterologous booster vaccination rate for older adult to over 90% is a key measure to alleviate the bed burden for respiratory diseases on the basis of expanded healthcare resource allocation. Conclusion: The Omicron epidemic followed the adjustment to COVID-19 policy overloading many local health systems across the country at the end of 2022. The combined effect of vaccination, antipyretic drug supply, triage treatment, and PHSMs could prevent overwhelming medical resources.

Analysis and hierarchical clustering of infratentorial morphological MRI identifies SCAs phenogroups.

BACKGROUND: Clinical decision-making in spinocerebellar ataxia spectrum diseases (SCAs) has mainly been based on genetic tests, not considering the SCAs' imaging and clinical heterogenicity. OBJECTIVE: To identify SCAs phenogroups by analysis and hierarchical clustering of infratentorial morphological MRI for unveiling pathophysiological differences among common SCA subtypes. METHODS: We prospectively enrolled 119 (62 women; mean age 37 years) genetically diagnosed SCAs (SCA1 n = 21, SCA2 n = 10, symptomatic SCA3 n = 59, presymptomatic SCA3 n = 22, SCA6 n = 7) and 35 healthy controls (HCs). All patients underwent MRI and detailed neurological and neuropsychology examinations. The width of each cerebellar peduncle (CP) and anteroposterior diameter of the spinal cord and pontine were measured. Twenty-five SCAs patients (15 women; mean age 35 years) were followed for at least a year (17 (15, 24) months), whose MRI and the Scale for the Assessment and Rating of Ataxia (SARA) were collected. RESULTS: Infratentorial morphological MRI measurements could significantly discriminate SCAs from HCs, even among SCA subtypes. Two mutually exclusive and clinically distinct phenogroups were identified. Despite similar (CAG)n, phenogroup 1 (n = 66, 55.5%) presented more atrophied infratentorial brain structures and more severe clinical symptoms with older age and earlier age of onset when compared with phenogroup 2. More importantly, all SCA2, most of SCA1 (76%), and symptomatic SCA3 (68%) were classified into phenogroup 1, whereas all SCA6 and all presymptomatic SCA3 were in phenogroup 2. The right middle CP had the highest diagnostic value in predicting phenogroup 2 (AUC = 0.99; P < 0.01) with high specificity (95%). Consistent with the significantly increased SARA (7.5 vs 10, P = 0.021), the bilateral inferior CP, spinal cord, and pontine tegmentum were more atrophy during the follow-up (P < 0.05). CONCLUSION: SCAs were with significant infratentorial brain atrophy than HCs. We identified two different SCAs phenogroups associated with substantial differences in infratentorial brain atrophy, clinical presentation, and may reflect the underlying molecular profiles to some extent, paving the way for a more personalized diagnostic and treatment approach.

Molecular networks reveal complex interactions with MSM in heterosexual women living with HIV-1 who play peripheral roles in Guangzhou, China.

BACKGROUND: With the number of newly diagnosed HIV-positive heterosexual women increasing yearly, it is urgent to understand HIV-1 transmission among heterosexual women in Guangzhou, China. METHODS: HIV-1 pol sequences were obtained from people living with HIV-1 during 2008 to 2017 in Guangzhou, China. A molecular network was constructed using HIV-1 TRAnsmission Cluster Engine with 1.5% genetic distance. Potential linkage and centrality metric were measured with Cytoscape. Transmission pathways between heterosexual women and men who have sex with men (MSM) were determined using Bayesian phylogenetic analysis. RESULTS: In the network, 1799 (62.6%) MSM, 692 (24.1%) heterosexual men and 141 (4.9%) heterosexual women formed 259 clusters. Molecular clusters including MSM and heterosexuals were more likely to form larger networks (P<0.001). Nearly half of the heterosexual women (45.4%) were linked to heterosexual men and 17.7% to MSM, but only 0.9% of MSM were linked to heterosexual women. Thirty-three (23.4%) heterosexual women linked to at least one MSM node and were in peripheral role. Compared to general heterosexual women, the proportion of heterosexual women linked to MSM infected with CRF55_01B (P<0.001) and CRF07_BC (P<0.001) was higher than that of other subtypes, and the proportion diagnosed between 2012 and 2017 (P = 0.001) was higher than that in 2008-2012. In MCC trees, 63.6% (21/33) of the heterosexual women differentiated from the heterosexual evolutionary branch, while 36.4% (12/33) differentiated from the MSM evolutionary branch. CONCLUSION: Heterosexual women living with HIV-1 were mainly linked to heterosexual men and were in peripheral positions in the molecular network. The role of heterosexual women in HIV-1 transmission was limited, but the interaction between MSM and heterosexual women were complex. Awareness of the HIV-1 infection status of sexual partners and active HIV-1 detection are needed for women.

Quantitative susceptibility mapping evaluation of glioma.

OBJECTIVES: To comprehensively evaluate the glioma using quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: Forty-two patients (18 women; mean age, 45 years) with pathologically confirmed gliomas were retrospectively included. All the patients underwent conventional and advanced MRI examinations (QSM, DWI, MRS, etc.). Five patients underwent paired QSM (pre- and post-enhancement). Four Visually Accessible Rembrandt Image (VASARI) features and intratumoural susceptibility signal (ITSS) were observed. Three ROIs each were manually drawn separately in the tumour parenchyma with relatively high and low magnetic susceptibility. The association between the tumour's magnetic susceptibility and other MRI parameters was also analysed. RESULTS: Morphologically, gliomas with heterogeneous ITSS were more similar to high-grade gliomas (p = 0.006, AUC: 0.72, sensitivity: 70%, and specificity: 73%). Heterogeneous ITSS was significantly associated with tumour haemorrhage, necrosis, diffusion restriction, and avid enhancement but did not change between pre- and post-enhanced QSM. Quantitatively, tumour parenchyma magnetic susceptibility had limited value in grading gliomas and identifying IDH mutation status, whereas the relatively low magnetic susceptibility of the tumour parenchyma helped identify oligodendrogliomas in IDH mutated gliomas (AUC = 0.78) with high specificity (100%). The relatively high tumour magnetic susceptibility significantly increased after enhancement (p = 0.039). Additionally, we found that the magnetic susceptibility of the tumour parenchyma was significantly correlated with ADC (r = 0.61) and Cho/NAA (r = 0.40). CONCLUSIONS: QSM is a promising candidate for the comprehensive evaluation of gliomas, except for IDH mutation status. The magnetic susceptibility of tumour parenchyma may be affected by tumour cell proliferation. KEY POINTS: • Morphologically, gliomas with a heterogeneous intratumoural susceptibility signal (ITSS) are more similar to high-grade gliomas (p = 0.006; AUC, 0.72; sensitivity, 70%; and specificity, 73%). Heterogeneous ITSS was significantly associated with tumour haemorrhage, necrosis, diffusion restriction, and avid enhancement but did not change between pre- and post-enhanced QSM. • Tumour parenchyma's relatively low magnetic susceptibility helped identify oligodendroglioma with high specificity. • Tumour parenchyma magnetic susceptibility was significantly correlated with ADC (r = 0.61) and Cho/NAA (r = 0.40).

Development of a tongue image-based machine learning tool for the diagnosis of gastric cancer: a prospective multicentre clinical cohort study.

Background: Tongue images (the colour, size and shape of the tongue and the colour, thickness and moisture content of the tongue coating), reflecting the health state of the whole body according to the theory of traditional Chinese medicine (TCM), have been widely used in China for thousands of years. Herein, we investigated the value of tongue images and the tongue coating microbiome in the diagnosis of gastric cancer (GC). Methods: From May 2020 to January 2021, we simultaneously collected tongue images and tongue coating samples from 328 patients with GC (all newly diagnosed with GC) and 304 non-gastric cancer (NGC) participants in China, and 16 S rDNA was used to characterize the microbiome of the tongue coating samples. Then, artificial intelligence (AI) deep learning models were established to evaluate the value of tongue images and the tongue coating microbiome in the diagnosis of GC. Considering that tongue imaging is more convenient and economical as a diagnostic tool, we further conducted a prospective multicentre clinical study from May 2020 to March 2022 in China and recruited 937 patients with GC and 1911 participants with NGC from 10 centres across China to further evaluate the role of tongue images in the diagnosis of GC. Moreover, we verified this approach in another independent external validation cohort that included 294 patients with GC and 521 participants with NGC from 7 centres. This study is registered at ClinicalTrials.gov, NCT01090362. Findings: For the first time, we found that both tongue images and the tongue coating microbiome can be used as tools for the diagnosis of GC, and the area under the curve (AUC) value of the tongue image-based diagnostic model was 0.89. The AUC values of the tongue coating microbiome-based model reached 0.94 using genus data and 0.95 using species data. The results of the prospective multicentre clinical study showed that the AUC values of the three tongue image-based models for GCs reached 0.88-0.92 in the internal verification and 0.83-0.88 in the independent external verification, which were significantly superior to the combination of eight blood biomarkers. Interpretation: Our results suggest that tongue images can be used as a stable method for GC diagnosis and are significantly superior to conventional blood biomarkers. The three kinds of tongue image-based AI deep learning diagnostic models that we developed can be used to adequately distinguish patients with GC from participants with NGC, even early GC and precancerous lesions, such as atrophic gastritis (AG). Funding: The National Key R&D Program of China (2021YFA0910100), Program of Zhejiang Provincial TCM Sci-tech Plan (2018ZY006), Medical Science and Technology Project of Zhejiang Province (2022KY114, WKJ-ZJ-2104), Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer (JBZX-202006), Natural Science Foundation of Zhejiang Province (HDMY22H160008), Science and Technology Projects of Zhejiang Province (2019C03049), National Natural Science Foundation of China (82074245, 81973634, 82204828), and Chinese Postdoctoral Science Foundation (2022M713203).

An empirical research on China's policy for ICT integration in Basic Education from 1988 to 2021.

This paper presents a comprehensive review of China's policy for the integration of ICT in basic education from 1988 to 2021 through a mixed-methods research on 179 policy documents. I identified three phases of China's evolving policy system for the integration of ICT in basic education. The policy focuses on the innovation of teaching, the construction of infrastructure, and the cultivation of ICT competence to promote education reform and modernization, which finally contributes to education equity and quality. To achieve these targets, in recent 10 years, joint efforts and open communication have been stressed in the policy. This study provides a quantitative foundation for understanding policy change for the integration of ICT in basic education in China.

Frequent fragility of randomized controlled trials for HCC treatment.

BACKGROUND: The fragility index (FI) of trial results can provide a measure of confidence in the positive effects reported in randomized controlled trials (RCTs). The aim of this study was to calculate the FI of RCTs supporting HCC treatments. METHODS: A methodological systematic review of RCTs in HCC treatments was conducted. Two-arm studies with randomized and positive results for a time-to-event outcome were eligible for the FI calculation. RESULTS: A total of 6 trails were included in this analysis. The median FI was 0.5 (IQR 0-10). FI was ≤7 in 4 (66.7%) of 6 trials; in those trials the fragility quotient was ≤1%. CONCLUSION: Many phase 3 RCTs supporting HCC treatments have a low FI, which challenges the confidence in concluding the superiority of these drugs over control treatments.

A novel predictor of severe dengue: The aspartate aminotransferase/platelet count ratio index (APRI).

To evaluate risk factors for the development of dengue into severe dengue in Guangdong. A retrospective analysis of clinical data from 212 dengue patients between June and October 2014. A total of 174 (82.1%) patients in our study had classic dengue, of which 38 (17.9%) had severe diseases. The frequencies of jaundice, pleural effusion, ascites, and vaginal bleeding were significantly different between the two groups (P < 0.05). The routine laboratory test results for alanine aminotransferase, aspertate aminotransferase, albumin, leukocyte count, platelet count, activated partial prothrombin time, prothrombin time, and aspartate aminotransferase/platelet count ratio index showed a significant association with severe dengue (P < 0.01). The areas under the receiver operating characteristic curves (AUC) were 0.727 (95% CI 0.662-0.78), 0.699 (95%CI 0.632-0.760), 0.634 (95%CI 0.565-0.698), 0.757 (95%CI 0.694-0.813), 0.775 (95%CI 0.713-0.829), 0.713 (95%CI 0.647-0.773), 0.719 (95%CI 0.730-0.843), and 0.785 (95%CI 0.724-0.893), respectively. The logistic regression analysis identified three factors, including high WBC (OR 1.52), prolonged PT (OR 1.745). and high APRI (OR 1.05) may be associated with the discrimination criteria to identify patients with and without severe diseases. The combination of the three factors (WBC, PT, and APRI) showed better AUC (0.877) and OR (1.52) scores. Our study indicates that laboratory tests such as WBC, PT, and APRI, helped identify patients at risk of developing severe dengue. The APRI was identified as a valuable predictor of patients with severe dengue. Combining the WBC, PT, and APRI scores allowed a better prediction of severe dengue.

Roles of Interferons in Pregnant Women with Dengue Infection: Protective or Dangerous Factors.

Dengue infection is a serious public health problem in tropical and subtropical areas. With the recent outbreaks of Zika disease and its reported correlation with microcephaly, the large number of pregnancies with dengue infection has become a serious concern. This review describes the epidemiological characteristics of pregnancy with dengue and the initial immune response to dengue infection, especially in IFNs production in this group of patients. Dengue is much more prevalent in pregnant women compared with other populations. The severity of dengue is correlated with the level of IFNs, while the serum IFN level must be sufficiently high to maintain the pregnancy and to inhibit virus replication.

Toxicologic evaluations of recombinant liver-targeting interferon IFN-CSP: Genotoxicity and tegenicratoity.

Interferon alpha as the one of FDA recommended drugs for Hepatitis B virus (HBV) infection has many side effects. Targeting IFNα to the liver may be a strategy to increase its efficacy locally and may increase efficacy of IFNα-based therapy of HBV infection. We have prepared a novel liver-targeting fusion interferon (IFN-CSP) combining IFN α2b with plasmodium region I peptide and have revealed it may be an excellent candidate as a liver-targeting anti-HBV agent. In this study, we investigated the genotoxic and teratogenic effects of IFN-CSP. The genotoxicity of IFN-CSP was evaluated by using a standard battery of tests (bacterial reverse mutation assay, mouse bone marrow micronucleus assay, and mouse sperm malformation assay). The results showed that IFN-CSP did not increase the number of revertant colonies in the plates of four strains, had no marked effect on the incidence of mouse bone marrow micronucleus and did not affect sperm deformity proportion at doses up to 8.8 × 108IU/kg, which was 1128.2 folds of the maximum' clinical equivalent dosage. Meanwhile, for teratogenicity test of IFN-CSP in female SD rats at the dosage of 6.3 × 107 IU/kg, no toxicological signs were observed. These results indicated that IFN-CSP has no genotoxicity and teratogenicity under the testing conditions.

HBV Infection Status and the Risk of Cholangiocarcinoma in Asia: A Meta-Analysis.

Background. The inconsistent finding was between hepatitis B virus (HBV) infections and cholangiocarcinoma (CCA). This meta-analysis is to explore this relationship in Asia. Methods. A literature search was performed using PubMed, Web of Science, and Cochrane Library to October 30, 2015. Pooled incidence rate and OR with 95% CI were calculated using STATA 11.0. Results. Thirty-nine studies were included. The pooled incidence rate of CCA patients with HBV infection was 31% (95% CI 22%-39%). The pooled OR showed increased risk of CCA incidence with HBV infection (OR = 2.72, 95% CI 1.90-3.88), especially in ICC (OR = 3.184, 95% CI 2.356-4.302), while it showed no risk in ECC (OR = 1.407, 95% CI 0.925-2.141). Also, the pooled OR showed increased risk of ICC and ECC incidence (OR = 6.857, 95% CI 4.421-10.633 and OR = 1.740, 95% CI 1.260-2.404) in patients with HBsAg+/HBcAb+. The pooled OR showed increased risk of ICC incidence (OR = 1.410, 95% CI 1.095-1.816) in patients with HBsAg-/HBcAb+. Conclusion. It is suggested that HBV infection is associated with an increased risk of CCA in Asia. Two HBV infection models (HBsAg+/HBcAb+ and HBsAg-/HBcAb+) increase the risk of CCA, and patients with HBsAg-/HBcAb+ also had a risk of ICC. This trial is registered with PROSPERO CRD42015029264.

Targeting Mechanism of a Novel Liver-targeting Interferon IFN-CSP Involves Liver Heparan Sulfate Proteoglycan.

BACKGROUND: In our previous study, a novel liver-targeting interferon (IFN-CSP) combining IFN α2b with plasmodium region I-plus peptide was successfully designed and prepared with Escherichia coli expression systems. The purified IFN-CSP showed anti-HBV activity and liver-targeting potentiality. The present investigation was designed to investigate the molecular mechanisms responsible for liver-targeting of IFN-CSP. METHODS: The binding site of IFN-CSP in hepatocytes was assayed by immunofluorescent staining. The correspondence of HSPG distribution and the pattern of IFN-CSP binding in liver tissue were determined using a confocal laser scanning microscope. Both the hepatocytes and liver tissue were using as model to investigate the effect of enzyme and soluble glycosaminoglycan on IFN-CSP binding using flow cytometry and fluorescence microscope. RESULTS: Studies of hepatocytes demonstrated that the localization of IFN-CSP in hepatocytes was the plasma membrane. Studies of liver tissue slices showed that IFN-CSP bound to liver tissue in a pattern similar to the distribution of heparan sulfate proteoglycan (HSPG) immunoreactivity. Pretreatment of hepatocytes and liver slices with heparinase reduced the binding of IFN-CSP to HepG2.2.15 cells and liver slices. Coincubation of IFN-CSP with heparin markedly inhibited IFNCSP binding to HepG2.2.15 cells and liver slices. CONCLUSION: These results indicate that the molecular mechanisms responsible for IFN-CSP targeting involve binding to HSPG of hepatocytes and liver.

Comparative Pharmacokinetics, Tissue Distribution, Excretion of Recombinant Liver-Targeting Interferon with IFN α2b Administered Intramuscular in Rats.

Interferon α2b (IFN α2b) is the first cytokine, which has been approved by FDA to treat chronic hepatitis B. However, it has no organ or tissue selectivity effect, and will be rapidly cleared out in the liver after the administration treatment. In our previous study, a novel liver-targeting fusion interferon (IFN-CSP) was constructed by recombining human IFN α2b with a CSP region I-plus peptide. The purpose of this study is to compare pharmacokinetics, tissue distribution, excretion of recombinant liver-targeting interferon IFN-CSP with IFN α2b following intramuscular administration in rats and estimate whether the fusion protein recombinant liver-targeting interferon has liver-targeting effect. Serum, tissue, urinary, fecal, and biliary concentrations of the drug were measured at various time points after administration using ELISA test. The pharmacokinetic character of IFN-CSP and IFNα2b was described using a non-compartmental model after a single intramuscular administration. Our results showed that there were no significant differences between these two drugs in pharmacokinetic and elimination. However, drug concentration of recombinant liver-targeting IFN was higher than IFN α2b in the liver after intramuscular administration in rats at different time points. It was increased in the spleen but not apparently, and decreased in the heart, lung and kidney. In conclusion, compared with traditional IFN α2b, the novel recombinant liver-targeting IFN will be more accumulated in the liver tissue. With this excellent property, IFN-CSP shows a great application prospect in clinical treatment, although further investigation is still needed.

Comparative Pharmacokinetics, Tissue Distribution, Excretion of Recombinant LiverTargeting Interferon with IFN α2b Administered Intramuscular in Rats.

Interferon α2b (IFN α2b) is the first cytokine, which has been approved by FDA to treat chronic hepatitis B. However, it has no organ or tissue selectivity effect, and will be rapidly cleared out in the liver after the administration treatment. In our previous study, a novel liver-targeting fusion interferon (IFN-CSP) was constructed by recombining human IFN α2b with a CSP region I-plus peptide. The purpose of this study is to compare pharmacokinetics, tissue distribution, excretion of recombinant liver-targeting interferon IFN-CSP with IFN α2b following intramuscular administration in rats and estimate whether the fusion protein recombinant liver-targeting interferon has liver-targeting effect. Serum, tissue, urinary, fecal, and biliary concentrations of the drug were measured at various time points after administration using ELISA test. The pharmacokinetic character of IFN-CSP and IFNα2b was described using a non-compartmental model after a single intramuscular administration. Our results showed that there were no significant differences between these two drugs in pharmacokinetic and elimination. However, drug concentration of recombinant liver-targeting IFN was higher than IFN α2b in the liver after intramuscular administration in rats at different time points. It was increased in the spleen but not apparently, and decreased in the heart, lung and kidney. In conclusion, compared with traditional IFN 2b, the novel recombinant liver-targeting IFN will be more accumulated in the liver tissue. With this excellent property, IFN-CSP shows a great application prospect in clinical treatment, although further investigation is still needed.

IFN-CSP inhibiting hepatitis B virus in HepG2.2.15 cells involves JAK-STAT signal pathway.

Frequent and high-dose administration of interferon to patients with viral hepatitis results in various side effects. In our previous study, a novel liver-targeting interferon (IFN-CSP) combining Plasmodium region I peptide with IFNα2b was successfully designed and expressed in the Escherichia coli expression systems. This targeting would target the IFNα2b specifically to the liver, thus reducing the adverse events. In the present study, we further investigated the anti-HBV effects and molecular mechanisms of recombinant IFN-CSP in HepG2.2.15 cell line. Hepatitis B surface antigen (HBsAg) and HBe antigen (HBeAg) in the culture supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA). HBV-DNA was measured by real-time quantitative PCR. HBV core protein was assayed by immunofluorescent and western blot analysis. The expressions of signal transducers and transactivator 1 (STAT1), STAT2, IFN regulatory factor 9 (IRF-9), and 2'-5'-oligoadenylate synthetase 1 (OAS1) were investigated by the reverse transcription PCR and western blot analysis. Results indicate IFN-CSP efficiently inhibited HBsAg and HBeAg secretion, HBV-DNA replication, and HBV core protein expression in HepG2.2.15 cells. The anti-HBV mechanisms involve activation of JAK-STAT signaling and increase of the anti-HBV protein OAS expression. IFN-CSP could be a good substitute for IFNα2b for anti-HBV treatment.

Research on hepatitis C virus entry inhibitor / 病毒学报

Hepatitis c virus (HCV) infection has become one of the global public health problem,while there is no vaccine to prevent HCV infection, the so-called "cocktail" therapy that use a combination of drugs targeting multiple steps in the HCV infection cycle could achieve better curative effect. the process of HCV entering into host cell is the important step of drug intervention, in which HCV envelope protein El and E2, Host cell factors including Heparan sulfate(HS), CD81, scavenger receptor class B type I (SR-BI), Occludin (OCLD), Claudin (CLDN), low densitity lipoprotein receptor (LDLR), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), Liver/lymph node specific ICAM-3-grabbing integrin(L-SIGN), trans- ferrin receptor 1 (TfR1) and so on play a important role. The virus and the host factors can be used as targets of hcv entry inhibitors many studies have shown that as novel and promising compounds, HCV entry inhibitors combinating with other drugs can be more effective in the treatment of HCV, this paper have re- viewed targets and inhibitors of HCV enterring into host cell since 1990s.