Formalin-Inactivated EV71 Vaccine Candidate Induced Cross-Neutralizing Antibody against Subgenotypes B1, B4, B5 and C4A in Adult Volunteers

Background

Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia. No effective EV71 vaccine is available. A randomized and open-label phase I clinical study registered with ClinicalTrials.gov #NCT01268787, aims to evaluate the safety, reactogenicity and immunogenicity of a formalin-inactivated EV71 vaccine candidate (EV71vac) at 5- and 10-µg doses. In this study we report the cross-neutralizing antibody responses from each volunteer against different subgenotypes of EV71 and CVA16.

Methods

Sixty eligible healthy adults were recruited and vaccinated. Blood samples were obtained on day 0, 21 and 42 and tested against B1, B4, B5, C2, C4A, C4B and CVA16 for cross-neutralizing antibody responses.

Results

The immunogenicity of both 5- and 10- µg doses were found to be very similar. Approximately 45% of the participants had <8 pre-vaccination neutralization titers (Nt) against the B4 vaccine strain. After the first EV71vac immunization, 95% of vaccinees have >4-fold increase in Nt, but there was no further increase in Nt after the second dose. EV71vac induced very strong cross-neutralizing antibody responses in >85% of volunteers without pre-existing Nt against subgenotype B1, B5 and C4A. EV71vac elicited weak cross-neutralizing antibody responses (∼20% of participants) against a C4B and Coxsackie virus A16. Over 90% of vaccinated volunteers did not develop cross-neutralizing antibody responses (Nt<8) against a C2 strain. EV71vac can boost and significantly enhance the neutralizing antibody responses in volunteers who already had pre-vaccination antibodies against EV71 and/or CVA16.

Conclusion

EV71vac is efficient in eliciting cross-neutralizing antibody responses against EV71 subgenotypes B1, B4, B5, and C4A, and provides the rationale for its evaluation in phase II clinical trials.

Trial Registration

ClinicalTrials.gov __NCT01268787     

The Power of Ground User in Recommender Systems

Accuracy and diversity are two important aspects to evaluate the performance of recommender systems. Two diffusion-based methods were proposed respectively inspired by the mass diffusion (MD) and heat conduction (HC) processes on networks. It has been pointed out that MD has high recommendation accuracy yet low diversity, while HC succeeds in seeking out novel or niche items but with relatively low accuracy. The accuracy-diversity dilemma is a long-term challenge in recommender systems. To solve this problem, we introduced a background temperature by adding a ground user who connects to all the items in the user-item bipartite network. Performing the HC algorithm on the network with ground user (GHC), it showed that the accuracy can be largely improved while keeping the diversity. Furthermore, we proposed a weighted form of the ground user (WGHC) by assigning some weights to the newly added links between the ground user and the items. By turning the weight as a free parameter, an optimal value subject to the highest accuracy is obtained. Experimental results on three benchmark data sets showed that the WGHC outperforms the state-of-the-art method MD for both accuracy and diversity.     

Seasonal Distribution and Diversity of Ground Arthropods in Microhabitats Following a Shrub Plantation Age Sequence in Desertified Steppe

In desertified regions, shrub-dominated patches are important microhabitats for ground arthropod assemblages. As shrub age increases, soil, vegetation and microbiological properties can change remarkably and spontaneously across seasons. However, relatively few studies have analyzed how ground arthropods respond to the microhabitats created by shrubs of different plantation ages across seasons. Using 6, 15, 24 and 36 year-old plantations of re-vegetated shrubs (Caragana koushinskii) in the desert steppe of northwestern China as a model system, we sampled ground arthropod communities using a pitfall trapping method in the microhabitats under shrubs and in the open areas between shrubs, during the spring, summer and autumn. The total ground arthropod assemblage was dominated by Carabidae, Melolonthidae, Curculionidae, Tenebrionidae and Formicidae that were affected by plantation age, seasonal changes, or the interaction between these factors, with the later two groups also influenced by microhabitat. Overall, a facilitative effect was observed, with more arthropods and a greater diversity found under shrubs as compared to open areas, but this was markedly affected by seasonal changes. There was a high degree of similarity in arthropod assemblages and diversity between microhabitats in summer and autumn. Shrub plantation age significantly influenced the distribution of the most abundant groups, and also the diversity indices of the ground arthropods. However, there was not an overall positive relationship between shrub age and arthropod abundance, richness or diversity index. The influence of plantation age on arthropod communities was also affected by seasonal changes. From spring through summer to autumn, community indices of ground arthropods tended to decline, and a high degree of similarity in these indices (with fluctuation) was observed among different ages of shrub plantation in autumn. Altogether the recovery of arthropod communities was markedly affected by seasonal variability, and they demonstrated distinctive communal fingerprints in different microhabitats for each plantation age stage.     

Insulin Promotes Glucose Consumption via Regulation of miR-99a/mTOR/PKM2 Pathway

Insulin is known to regulate multiple cellular functions and is used for the treatment of diabetes. MicroRNAs have been demonstrated to be involved in many human diseases, including Type 2 diabetes. In this study, we showed that insulin decreased miR-99a expression levels, but induced glucose consumption and lactate production, and increased the expression of mTOR, HIF-1α and PKM2 in HepG2 and HL7702 cells. Forced expression of miR-99a or rapamycin treatment blocked insulin-induced PKM2 and HIF-1α expression, and glucose consumption and lactate production. Meanwhile, knockdown of HIF-1α inhibited PKM2 expression and insulin-induced glucose consumption. Taken together, these findings will reveal the role and mechanism ofinsulin in regulating glycolytic activities via miR-99a/mTOR.     

Endothelin Receptor A Blockade Is an Ineffective Treatment for Adriamycin Nephropathy

Endothelin is a vasoconstricting peptide that plays a key role in vascular homeostasis, exerting its biologic effects via two receptors, the endothelin receptor A (ETA) and endothelin receptor B (ETB). Activation of ETA and ETB has opposing actions, in which hyperactive ETA is generally vasoconstrictive and pathologic. Selective ETA blockade has been shown to be beneficial in renal injuries such as diabetic nephropathy and can improve proteinuria. Atrasentan is a selective pharmacologic ETA blocker that preferentially inhibits ETA activation. In this study, we evaluated the efficacy of ETA blockade by atrasentan in ameliorating proteinuria and kidney injury in murine adriamycin nephropathy, a model of human focal segmental glomerulosclerosis. We found that ETA expression was unaltered during the course of adriamycin nephropathy. Whether initiated prior to injury in a prevention protocol (5 mg/kg/day, i.p.) or after injury onset in a therapeutic protocol (7 mg/kg or 20 mg/kg three times a week, i.p.), atrasentan did not significantly affect the initiation and progression of adriamycin-induced albuminuria (as measured by urinary albumin-to-creatinine ratios). Indices of glomerular damage were also not improved in atrasentan-treated groups, in either the prevention or therapeutic protocols. Atrasentan also failed to improve kidney function as determined by serum creatinine, histologic damage, and mRNA expression of numerous fibrosis-related genes such as collagen-I and TGF-β1. Therefore, we conclude that selective blockade of ETA by atrasentan has no effect on preventing or ameliorating proteinuria and kidney injury in adriamycin nephropathy.     

P16 and P53 Play Distinct Roles in Different Subtypes of Breast Cancer

Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16^INK4a and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple-negative breast cancers in DCIS and IDC.     

Oxaliplatin and Its Enantiomer Induce Different Condensation Dynamics of Single DNA Molecules

The interactions of DNA with oxaliplatin (Pt(R,R-DACH)) or its enantiomer (Pt(S,S-DACH)) were investigated using magnetic tweezers and atomic force microscope. In the process of DNA condensation induced by Pt-DACH, only diadducts and micro-loops are formed at low Pt-DACH concentrations, while at high Pt-DACH concentrations, besides the diadducts and micro-loops, long-range cross-links are also formed. The diadduct formation rate of Pt(R,R-DACH) is higher than that of Pt(S,S-DACH). However, the proportions of micro-loops and long-range cross-links for Pt(S,S-DACH) are higher than those for Pt(R,R-DACH). We propose a model to explain these differences between the effect of Pt(R,R-DACH) and that of Pt(S,S-DACH) on DNA condensation. The study has strong implications for the understanding of the effect of chirality on the interaction between Pt-DACH and DNA and the kinetics of DNA condensation induced by platinum complexes.