Safety and immunogenicity of a skin- and neuro-attenuated live vaccine for varicella: a randomized, double-blind, controlled, dose-escalation and age de-escalation phase 1 clinical trial.

Background: Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin- and neuro-attenuated varicella vaccine candidate (v7D). Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay. Findings: Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3). Interpretation: The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine. Funding: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, and Beijing Wantai CO., LTD.

Efficacy, safety, and immunogenicity of an Escherichia coli-produced Human Papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial.

BACKGROUND: This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. METHODS: This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18-45 years, with intact cervix and 1-4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18-26 and 27-45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. FINDINGS: Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2-100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9-99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. INTERPRETATION: The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Safety and immunogenicity of an Escherichia coli-produced bivalent human papillomavirus type 6/11 vaccine: A dose-escalation, randomized, double-blind, placebo-controlled phase 1 trial.

A dose-escalation, randomized, double-blind, placebo-controlled phase 1 clinical trial enrolled 145 eligible participants aged 18-55 years in March 2015 in Liuzhou, China. Stratified by age and sex, the participants were randomly assigned to receive either 30, 60, or 90 µg of the HPV-6/11 vaccine (n = 41/40/40) or the parallel placebo vaccine (n = 8/8/8) with a 0/1/6-month dose-escalation schedule. Participants were actively followed-up to record local and systemic AEs occurring within 30 days after each vaccination, and SAEs occurred in 7 months. Blood and urine samples of each participant were collected before and 2 days after the first and third vaccination to determine changes in routine blood, serum biochemical, and urine indexes. Serum HPV-6/11-specific IgG and neutralizing antibody levels at month 7 were analyzed. A total of 79 adverse events were reported, and no SAEs occurred. The incidences of total adverse reactions in the 30 µg, 60 µg, and 90 µg HPV vaccine groups and the control group were 31.7%, 50.0%, 42.5%, and 62.5%, respectively. All but one of the adverse reactions was mild or moderate with grade 1 or 2. No vaccine-related changes with clinical significance were found in paired blood and urine indexes before and after vaccinations. All the participants in the per-protocol set seroconverted at month 7 for both IgG and neutralizing antibodies. The candidate novel Escherichia-coli-produced bivalent HPV-6/11 vaccine has been preliminarily proven to be well tolerated and with robust immunogenicity in a phase 1 clinical study, supporting further trials with larger sample size. The study has been registered at ClinicalTrials.gov (NCT02405520).

Atomic-scale probing of heterointerface phonon bridges in nitride semiconductor.

Interface phonon modes that are generated by several atomic layers at the heterointerface play a major role in the interface thermal conductance for nanoscale high-power devices such as nitride-based high-electron-mobility transistors and light-emitting diodes. Here we measure the local phonon spectra across AlN/Si and AlN/Al interfaces using atomically resolved vibrational electron energy-loss spectroscopy in a scanning transmission electron microscope. At the AlN/Si interface, we observe various interface phonon modes, of which the extended and localized modes act as bridges to connect the bulk AlN modes and bulk Si modes and are expected to boost the phonon transport, thus substantially contributing to interface thermal conductance. In comparison, no such phonon bridge is observed at the AlN/Al interface, for which partially extended modes dominate the interface thermal conductivity. This work provides valuable insights into understanding the interfacial thermal transport in nitride semiconductors and useful guidance for thermal management via interface engineering.

Nicotinamide mononucleotide-elicited NAMPT signaling activation aggravated adjuvant-induced arthritis in rats by affecting peripheral immune cells differentiation.

Supplement of nicotinamide mononucleotide (NMN), the direct precursor of nicotinamide adenine dinucleotide (NAD+) has gained prominence due to the significant anti-aging potentials of nicotinamide phosphoribosyltransferas (NAMPT)/NAD+ signaling. Because over-expression of NAMPT is deeply implicated in inflammatory arthritis, we investigated the effects of NMN supplement on rats with adjuvant-induced arthritis (AIA). Tested rats were given oral treatment of NMN at 200 mg/kg/day for 25 days. Arthritis score and body weight were periodically recorded. Clinical outcomes were evaluated based on arthritic manifestations, ELISA analysis and histological examination. T cells subsets were analyzed by flow cytometry. Expressions of protein and mRNA were assessed by immunoblotting and PCR methods, respectively. Levels of CD172a, CD43, and NAMPT in peripheral blood mononuclear cells (PBMCs) were investigated by immunofluorescence approach. Obtained results were further validated by experiments in vitro. Generally, NMN exacerbated AIA severity in rats. It deteriorated MMP3-controlled tissues damages, and altered immune profile by increasing Th17/Treg cells ratio. The up-regulation of NAMPT in PBMCs from NMN-treated rats was confirmed by both immunofluorescence and PCR experiments, which was synchronized with significant increase in iNOS, MCP-1, IL-1ß expression. NMN-primed AIA PBMCs were potent in up-regulating MCP-1, IL-1ß, MMP3 and p-JNK expression in synovioblast. NMN stimulus barely affected Th17 cells count in in vitro cultured splenocytes, but it greatly potentiated the capability of AIA monocytes in inducing IL-17α secretion and Th17 cells differentiation in the co-cultured splenocytes. It suggested that long-term NMN supplement could exacerbate inflammatory arthritis by reshaping the immune milieu through the up-regulation of NAMPT.

EEG signal classification based on SVM with improved squirrel search algorithm.

Electroencephalography (EEG) is a complex bioelectrical signal. Analysis of which can provide researchers with useful physiological information. In order to recognize and classify EEG signals, a pattern recognition method for optimizing the support vector machine (SVM) by using improved squirrel search algorithm (ISSA) is proposed. The EEG signal is preprocessed, with its time domain features being extracted and directed to the SVM as feature vectors for classification and identification. In this paper, the method of good point set is used to initialize the population position, chaos and reverse learning mechanism are introduced into the algorithm. The performance test of the improved squirrel algorithm (ISSA) is carried out by using the benchmark function. As can be seen from the statistical analysis of the results, the exploration ability and convergence speed of the algorithm are improved. This is then used to optimize SVM parameters. ISSA-SVM model is established and built for classification of EEG signals, compared with other common SVM parameter optimization models. For data sets, the average classification accuracy of this method is 85.9%. This result is an improvement of 2-5% over the comparison method.

[Acupuncture at Ciliao (BL 32) for prevention of postpartum urinary retention in elderly parturient women: a randomized controlled trial].

OBJECTIVE: To explore the preventive effect of acupuncture at Ciliao (BL 32) on postpartum urinary retention as well as the time and volume of the first urination after delivery in elderly parturient women undergoing vaginal delivery. METHODS: A total of 180 elderly parturient women (≥35 years old) undergoing vaginal delivery were randomly divided into a blank control group, a conditional control group and an observation group, 60 cases in each group. The patients in the blank control group were treated with routine nursing plan; based on the treatment of the blank control group, the patients in the conditional control group were treated with additional intervention measures such as applying hot towel on the bladder and fingers pressing to stimulate urination; based on the treatment of the blank control group, the patients in the observation group were treated with acupuncture at bilateral Ciliao (BL 32) one hour after delivery for 20 min (the acupuncture was given only once). The incidence rate of postpartum urinary retention as well as the time and volume of the first urination among the women without urinary retention were observed; the satisfaction rate of the 3 groups was recorded. RESULTS: The incidence rate of postpartum urinary retention in the observation group was 5.0% (3/60), which was significantly lower than 26.7% (16/60) in the blank control group (P<0.01) and 16.7% (10/60) in the conditional control group (P<0.05); the incidence rate of postpartum urinary retention in the conditional control group was significantly lower than that in the blank control group [16.7% (10/60) vs 26.7%(16/60), P<0.05]. In the elderly women without urinary retention, the first urination time in the observation group was significantly earlier than that in the blank control group and conditional control group (P<0.01), and the first urination time in the conditional control group was earlier than that in the blank control group (P<0.01). The volume of first urination in the observation group was higher than that in the blank control group and the conditional control group (P<0.05, P<0.01). The satisfaction rates in the observation group and conditional control group were higher than that in the blank control group (P<0.01). CONCLUSION: Acupuncture at Ciliao (BL 32) could effectively prevent the postpartum urinary retention, improve the time and volume of the first urination in elderly parturient women undergoing vaginal delivery.

HIV Prevalence and Factors Influencing the Uptake of Voluntary HIV Counseling and Testing among Older Clients of Female Sex Workers in Liuzhou and Fuyang Cities, China, 2016-2017: A Cross-Sectional Study.

OBJECTIVE: To compare the prevalence of HIV and associated factors for participating HIV voluntary counseling and testing (VCT) among older clients of female sex workers (CFSWs) in Liuzhou City and Fuyang City in China. METHODS: A cross-sectional study was conducted and the study employed 978 male CFSWs, aged 50 years and above from October 2016 to December 2017. All participants were required to complete a questionnaire and provide blood samples for HIV testing. Multivariate logistic regression analysis was used to analyze the influential factors of using VCT program and tested for HIV. RESULTS: The HIV infection prevalence rate was 1.2% and 0.5%, while 52.3% and 54.6% participants had ever utilized VCT service and tested for HIV in Liuzhou City and Fuyang City, respectively. The older CFSWs who ever heard of VCT program were more likely to uptake VCT program in both cities (ORLiuzhou = 2.224, ORFuyang = 2.421). Participants, whose marital status was married or cohabiting (ORLiuzhou = 0.548, ORFuyang = 0.495), who have stigma against individuals who are living with HIV/AIDS (ORLiuzhou = 0.273, ORFuyang = 0.371), whose monthly income is more than 500 yuan (ORLiuzhou = 0.622, ORFuyang = 0.600), and whose age is more than 60 years old (ORLiuzhou = 0.639, ORFuyang = 0.554), were less likely to visit VCT clinics. Those who are worried about HIV-infected participants were more likely to utilize VCT services in Fuyang City (AOR = 1.838, 95%CI : 1.146-2.948). CONCLUSION: Combine strategy will be needed to promote the utilization of VCT service, based on the socioeconomic characteristics of older male CFSWs in different cities of China.

Efficacy, Safety, and Immunogenicity of an Escherichia coli-Produced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial.

BACKGROUND: The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. METHODS: A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission. RESULTS: In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. CONCLUSIONS: The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18-associated high-grade genital lesions and persistent infection in women.

Quantitative Structure Activity Relationship Studies and Molecular Dynamics Simulations of 2-(Aryloxyacetyl)cyclohexane-1,3-Diones Derivatives as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a significant enzyme in the biosynthesis of plastoquinone and tocopherol. Moreover, it is also a potential target to develop new herbicide. The technology of computer-aided drug design (CADD) is a useful tool in the efficient discovery of new HPPD inhibitors. Forty-three compounds with known activities were used to generate comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models based on common framework and molecular docking. The structural contribution to the activity was determined, which provided further information for the design of novel inhibitors. Molecular docking was used to explain the changes in activity caused by the binding mode between ligand and protein. The molecular dynamics (MD) results indicated that the electrostatic energy was the major driving force for ligand-protein interaction and the Phe403 made the greatest contribution to the binding. The present work has provided useful information for the rational design of novel HPPD inhibitors with improved activity.

A dual-function probe based on naphthalene for fluorescent turn-on recognition of Cu2+ and colorimetric detection of Fe3+ in neat H2O.

A simple naphthalene derivative, 6-hydroxy-2-naphthohydrazide (NAH), was designed and synthesized through two facile steps reactions with the 6-hydroxy-2-naphthoic acid (NCA) as the starting material. In neat H2O (10% 0.01 M HEPES buffer, v/v, pH = 7.4), probe NAH showed a highly selective and sensitive response towards Fe3+ via perceptible color change and displayed "turn-on" dual-emission fluorescence response for Cu2+. The binding stoichiometry ratio of NAH/Cu2+ and NAH/Fe3+ were all confirmed as 1:1 by the method of fluorescence job's plot and UV-Vis job's plot, respectively. Probe NAH can be used over a wide pH range for the determination of Fe3+ (2.0-10.0) and Cu2+ (6.0-10.0) without interference from other co-existing metal ions. A possible detection mechanism was the hydrolysis of NAH upon the addition of Fe3+ or Cu2+, thereby leading to the formation of 6-hydroxy-naphthalene-2-carboxylic acid (NCA) which was further confirmed by the various spectroscopic techniques including FT-IR, 1H NMR titration and HRMS. Moreover, NAH was successfully applied to the detection of Cu2+ and Fe3+ in tap water, ultrapure water and BSA.

A naphthalene-quinoline based chemosensor for fluorescent "turn-on" and absorbance-ratiometric detection of Al3+ and its application in cells imaging.

A new naphthalene-quinoline based chemosensor L was prepared and structurally characterized. L exhibited excellent selectivity and sensitivity to Al3+ through distinct fluorescence enhancement (335-fold) and ratiometric detection in DMF/H2O (v/v, 1/9) based on the combined mechanisms of ESIPT and CHEF. The recognizing behavior of L toward Al3+ had been investigated in detail through Job's Plot, FT-IR, HNMR, and HRMS analysis. The limit of detection (LOD) for Al3+ was as low as and 3.67 × 10-8 M. L was successfully applied in real sample detection and construction of molecular logic gate. Moreover, L was verified to be of low cytotoxicity and good imaging characteristics for the detection of Al3+ in cells HSC.

Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potent new bleaching herbicide target. Therefore, in silico structure-based virtual screening was performed in order to speed up the identification of promising HPPD inhibitors. In this study, an integrated virtual screening protocol by combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases. 3D-pharmacophore Hypo1 model was applied to efficiently narrow potential hits. The hit compounds were subsequently submitted to molecular docking studies, showing four compounds as potent inhibitor with the mechanism of the Fe(II) coordination and interaction with Phe360, Phe403, and Phe398. MD result demonstrated that nonpolar term of compound 3881 made great contributions to binding affinities. It showed an IC50 being 2.49 µM against AtHPPD in vitro. The results provided useful information for developing novel HPPD inhibitors, leading to further understanding of the interaction mechanism of HPPD inhibitors.

A Highly Selective Naphthalimide-Based Chemosensor: "Naked-Eye" Colorimetric and Fluorescent Turn-On Recognition of Al3+ and Its Application in Practical Samples, Test Paper and Logic Gate.

A novel naphthalimide-based colorimetric and fluorescent turn-on chemosensor for Al3+ was synthesized and characterized with spectroscopic techniques. In MeOH solution, BPAM showed high selectivity and sensitivity to Al3+ by a 60-fold fluorescence enhancement and blue-shift absorption with visible color changes attributed to the contribution of chelation enhanced fluorescence (CHEF) and inhibition of intramolecular charge transfer (ICT). A 1:1 BPAM-Al3+ complex confirmed by job's plot and HRMS with a binding constant of 6.37 × 104 M- 1, and the detection limit for Al3+ was as low as 1.59 × 10- 7 M. BPAM was successfully applied in real sample detection and assessing the existence of Al3+ by a colorimetric method on filter paper. Furthermore, the fluorescent signals of BPAM were designed to construct an INHIBIT molecular logic gate.

A Highly Selective and Sensitive Fluorescent Turn-Off Probe for Cu2+ Based on a Guanidine Derivative.

A new highly selective and sensitive fluorescent probe for Cu2+, N-n-butyl-4-(1'-cyclooctene-1',3',6'-triazole)-1,8-naphthalimide (L), was synthesized and evaluated. The structure of compound L was characterized via IR, ¹H-NMR, 13C-NMR and HRMS. The fluorescent probe was quenched by Cu2+ with a 1:1 binding ratio and behaved as a "turn-off" sensor. An efficient and sensitive spectrofluorometric method was developed for detecting and estimating trace levels of Cu2+ in EtOH/H2O. The ligand exhibited excitation and emission maxima at 447 and 518 nm, respectively. The equilibrium binding constant of the ligand with Cu2+ was 1.57 × 104 M-1, as calculated using the Stern.

3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors.

p-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking-based virtual screening were performed to identify novel potential HPPD inhibitors. The complex-based pharmacophore model (CBP) with 0.721 of ROC used for screening compounds showed remarkable ability to retrieve known active ligands from among decoy molecules. The ChemDiv database was screened using CBP-Hypo2 as a 3D query, and the best-fit hits subjected to molecular docking with two methods of LibDock and CDOCKER in Accelrys Discovery Studio 2.5 (DS 2.5) to discern interactions with key residues at the active site of HPPD. Four compounds with top rankings in the HipHop model and well-known binding model were finally chosen as lead compounds with potential inhibitory effects on the active site of target. The results provided powerful insight into the development of novel HPPD inhibitors herbicides using computational techniques.

Janus silver mesoporous silica nanobullets with synergistic antibacterial functions.

In this study, we exploited a one-pot method to fabricate cetyltrimethylammonium bromide (CTAB)-loaded Janus silver mesoporous silica nanoparticles (Janus Ag-MSNs@CTAB). These bullet-like nanoparticles had a silver head (80nm in diameter) attached to a mesoporous silica stick (200-300nm in length). The CTAB-loaded nanobullets exhibited a marked affinity for the bacterial cell surface and the simultaneously sustained release behavior of CTAB and silver ions. The minimum inhibitory concentrations (MIC) of Janus Ag-MSNs@CTAB were determined to be 10µg/mL and 20µg/mL for E. coli and S. Aureus, respectively. Importantly, Janus Ag-MSNs@CTAB provided a single-particle nanoplatform with a synergistic effect against both Gram-positive and Gram-negative bacteria. A thorough investigation indicated that CTAB induces a dramatic loss of bacterial membrane integrity, which facilitated the internalization of silver. This report described an efficient and convenient method of synthesizing Janus silver mesoporous silica nanoparticles, and these nanobullets show promising potential in biomedical applications.

Short-term Pharmacological Inhibition of MyD88 Homodimerization by a Novel Inhibitor Promotes Robust Allograft Tolerance in Mouse Cardiac and Skin Transplantation.

BACKGROUND: Most strategies for antirejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models. RESULTS: TJ-M2010-5 directly and indirectly interacted with the Toll/IL-1R domain of MyD88, inhibiting MyD88 homodimerization. In vitro, TJ-M2010-5 inhibited maturation of dendritic cells, which suppressed nuclear translocation of NF-κB and T cell activation. In vivo, short-term (10 days) monotherapy of TJ-M2010-5 resulted in long time survival of 50% of the cardiac allografts, and longer-term (14 days) combination treatment of TJ-M2010-5 with CD154 mAb resulted in survival of 29% of skin allografts, which outperformed far more than CsA did and stimulated the proliferation of CD4CD25FoxP3 Regulatory T cells in recipient mice. CONCLUSIONS: Pharmacological inhibition of MyD88 signaling by this novel inhibitor TJ-M2010-5 shows a powerful anti-rejection effect, which may have therapeutic potential in clinical transplantation. The inhibition of both innate and adaptive immunity may be necessary for tolerance induction in nonsolid organs.

Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro.

The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT.

Comparative immunogenicity of hepatitis B vaccine with different dosages and schedules in healthy young adults in China.

OBJECTIVES: To compare immunogenicity of hepatitis B vaccine between the standard 3-dose (20 µg) and 2-dose with higher-dosage (60 µg) regimens in healthy young adults and evaluate the safety profile. METHODS: A randomized, parallel-group clinical trial was conducted among healthy young adults aged 18-25 years. Subjects were randomly assigned to three groups. One group was administered hepatitis B vaccine with the standard regimen of 0-1-6 month (20 µg) and other groups were immunized with regimens of 0-1 or 0-2 month (60 µg) respectively. Serum samples were collected at 1 month after a series vaccination and 12 months after the first-dose inoculation for anti-HBs antibody measurement with a Chemiluminescent Microparticle ImmunoAssay (CMIA). RESULTS: The seroprotection rates in 20 µg (0-1-6 month), 60 µg (0-1 month) and 60 µg (0-2 month) groups were 100, 93.64 and 99.19% at month 7/2/3, and 100, 96.04 and 95.90% at month 12, respectively. There were no significant differences among three vaccine groups (p>0.05). The geometric mean concentration (GMC) of anti-HBs was significantly higher in 20 µg (0-1-6 month) group than that in 60 µg (0-1 month) group at month 7/2 (1847.99 vs. 839.27 mIU/ml, p=0.004), but was similar to that in 60µg (0-2 month) group at month 7/3 (1847.99 vs. 1244.80 mIU/ml, p=0.138). At month 12, the GMC in 20 µg (0-1-6 month) group was significantly higher than those of other groups (1456.63 vs. 256.30, 235.15 mIU/ml, respectively, p<0.001). The total incidence of injection-site or systemic adverse reactions was <3%. CONCLUSIONS: A 2-dose with higher-dosage hepatitis B vaccine regimens are comparable to the standard 3-dose regimen in terms of immunogenicity except a relatively rapid decline in GMC levels which are associated with the longevity of protection. All formulations of hepatitis B vaccine were well tolerated. CLINICALTRIALS.GOV IDENTIfiER: NCT02203357.