Higher mass meningococcal group C-tetanus toxoid vaccines conjugated with carbodiimide correlate with greater immunogenicity

To examine the link between meningococcal C (MenC) vaccine size and immunogenic response, a panel of MenC glycoconjugate vaccines were prepared differing in chain length, molar mass and hydrodynamic volume. The preparations consisted of different lengths of MenC polysaccharide (PS) covalently linked to monomeric purified tetanus toxoid (TT) carrier protein using the coupling reagent ethylcarbodiimide hydrochloride (EDC). Size exclusion chromatography with multi-angle light scattering (SEC-MALS) and viscometry analysis confirmed that the panel of MenC-TT conjugates spanned masses of 191,500 to 2,348,000 g/mol, and hydrodynamic radii ranging from 12.1 to 47.9 nm. The two largest conjugates were elliptical in shape, whereas the two smallest conjugates were more spherical. The larger conjugates appeared to fit a model described by multiple TTs with cross-linked PS, typical of lattice-like networks described previously for TT conjugates, while the smaller conjugates were found to fit a monomeric or dimeric TT configuration. The effect of vaccine conjugate size on immune responses was determined using a two-dose murine immunization. The two larger panel vaccine conjugates produced higher anti-MenC IgG1 and IgG2b titres after the second dose. Larger vaccine conjugate size also stimulated greater T-cell proliferative responses in an in vitro recall assay, although cytokines indicative of a T-helper response were not measurable. In conclusion, larger MenC-TT conjugates up to 2,348,000 g/mol produced by EDC chemistry correlate with greater humoral and cellular murine immune responses. These observations suggest that conjugate size can be an important modulator of immune response.     

健脾疏肝降脂方干预非酒精性脂肪肝病肥胖小鼠肝功能、游离脂肪酸机制探讨

目的:观察健脾疏肝降脂方治疗非酒精性脂肪肝(NAFLD)肥胖小鼠ALT、AST、FFA及光镜下病理组织学改变,并与壳脂胶囊治疗组比较,观察其疗效。方法:将72只小鼠随机分为模型组、健脾疏肝降脂方高、中、低剂量组、壳脂胶囊对照组和空白组。采用饲养高脂饲料及皮下注射5%CCl₄复制NAFLD肥胖小鼠模型,分别以相应药物灌胃6周,检测血清中ALT、AST及FFA的含量,光镜下观察肝组织的脂肪变程度。结果:①各个用药组相比模型组,血清ALT、AST均降低有统计学意义(P<0.01),且中药各浓度组较壳脂胶囊组血清ALT、AST降低,差异有统计学意义(P<0.05); 中药高、中剂量组相比模型组FFA降低,比较有统计学意义(P<0.05); 但与壳脂胶囊组相比,中药各剂量组改善FFA,差异无明显统计学意义(P>0.05)。②光镜可见:各用药组光镜下病理组织改变均较模型组明显,以中、高剂量组较低剂量组小鼠肝细胞脂肪变程度减轻较明显。结论:健脾疏肝降脂方能有效降低NAFLD肥胖小鼠的肝功能、其与浓度无关; 可以降低FFA及改善光镜下肝脏的脂肪变,其有效程度与浓度有一定的关系。     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.     

Design,synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase

BackgroundAcetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer’s disease.MethodsColorimetric Ellman’s method was used for determination of IC₅₀ value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action.Result and discussionA new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC₅₀ = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC₅₀ = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM.ConclusionIt is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstractOpen in a separate windowA new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.Electronic supplementary materialThe online version of this article (10.1007/s40199-020-00346-9) contains supplementary material, which is available to authorized users.     

Pediatric bowel preparation: Sodium picosulfate,magnesium oxide,citric acid vs polyethylene glycol,a randomized trial

BACKGROUND Bowel preparation in children can be challenging.AIM To describe the efficacy, safety, and tolerability of sodium picosulfate, magnesium oxide, and citric acid(SPMC) bowel preparation in children.METHODS Phase 3, randomized, assessor-blinded, multicenter study of low-volume, divided dose SPMC enrolled children 9-16 years undergoing elective colonoscopy. Participants 9-12 years were randomized 1:1:1 to SPMC ? dose × 2, SPMC 1 dose × 2, or polyethylene glycol(PEG). Participants 13-16 years were randomized 1:1 to SPMC 1 dose × 2 or PEG. PEG-based bowel preparations were administered per local protocol. Primary efficacy endpoint for quality of bowel preparation was responders(rating of ‘excellent' or ‘good') by modified Aronchick Scale. Secondary efficacy endpoint was participant's tolerability and satisfaction from a 7-item questionnaire. Safety assessments included adverse events(AEs) and laboratory evaluations.RESULTS 78 participants were randomized, 48 were 9-12 years, 30 were 13-16 years. For the primary efficacy endpoint in 9-12 years, 50.0%, 87.5%, and 81.3% were responders for SPMC ? dose × 2, SPMC 1 dose × 2, and PEG groups, respectively. Responder rates for 13-16 years were 81.3% for SPMC 1 dose × 2 and 85.7% for PEG. Overall, 43.8% of participants receiving SPMC 1 dose × 2 reported it was ‘very easy' or ‘easy' to drink, compared with 20.0% receiving PEG. Treatment-emergent AEs were reported by 45.5% of participants receiving SPMC 1 dose × 2 and 63.0% receiving PEG.CONCLUSION SPMC was an efficacious and safe for bowel preparation in children 9-16 years, with comparable efficacy to PEG. Tolerability for SPMC was higher compared to PEG.     

唑来膦酸联合椎体后凸成形治疗骨质疏松性压缩骨折：提高骨密度、预防椎体再骨折、远期疗效评价的Meta分析

文题释义：椎体后凸成形：采用椎体内置入气囊的方法通过扩张使椎体复位，在椎体内部形成空隙，减小骨水泥注入所需的推力，使骨水泥在椎体内不易流动，可有效解除或缓解疼痛、恢复病椎高度，但临床发现仍存在骨水泥渗漏等风险。 唑来膦酸：椎体后凸成形已被广泛应用于骨质疏松性压缩骨折的治疗，临床疗效显著，然而如何有效改善骨质疏松状况成为临床面临的重要问题。唑来膦酸是双膦酸盐类药物，可有效抑制骨吸收，降低再发骨折风险，改善骨折患者的功能评分。 背景：临床应用唑来膦酸治疗骨质疏松症缺乏系统的科学评价和循证学依据，因此目前对于唑来膦酸联合椎体后凸成形治疗骨质疏松性椎体压缩骨折的临床疗效尚无明确定论。 目的：系统评价唑来膦酸联合椎体后凸成形治疗骨质疏松性椎体压缩骨折的临床疗效。 方法：应用计算机检索公开发表在CNKI、万方、维普等中文数据库及CBM、PubMed、Cochrane等英文数据库中，有关唑来膦酸联合椎体后凸成形治疗骨质疏松性椎体压缩骨折的随机对照试验，试验组治疗方式为唑来膦酸联合椎体后凸成形，对照组治疗方式为椎体后凸成形，时间截止至2019年9月。由2位研究员独立进行文献筛选、数据提取，按Cochrane协作网标准对纳入随机对照试验逐个进行质量评价，采用RevMan 5.3软件对符合纳入标准的研究进行统计分析。 结果与结论：①最终纳入5篇文献，均为随机对照研究，试验组患者175例，对照组患者184例；②统计分析结果显示：试验组治疗后12个月的骨密度高于对照组[MD=0.12，95%CI(0.08，0.17)，P < 0.000 01]，治疗后6，12个月的目测类比评分低于对照组[MD=0.46，95%CI(0.18，0.75)，P=0.002；MD=0.85，95%CI(0.20，1.50)，P=0.01]，治疗后1年的Oswestry功能障碍指数评分低于对照组[MD=6.59，95%CI(4.77，8.41)，P < 0.000 01]，骨水泥渗漏率、椎体骨折再发率低于对照组[OR=0.22，95%CI(0.08，0.59)，P=0.003；OR=0.18，95%CI(0.07，0.50)，P=0.000 8]；两组椎体高度恢复、椎体后凸Cobb角比较差异无显著性意义[MD=0.65，95%CI(-0.27，1.56)，P=0.16；MD=-0.60，95%CI(-2.45，1.25)，P=0.53]；③结果表明与单独应用椎体后凸成形相比，唑来膦酸联合椎体后凸成形在提高骨密度值、减少椎体骨折再发率、改善患者远期临床症状、预防骨水泥骨水泥渗漏等并发症方面具有显著优势，但后期仍需大量高质量的多中心随机对照研究提供更充足的证据。 ORCID: 0000-0001-8871-3539(李凯明) 中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程     

Repurposing fallen leaves to bio-based reaction medium for hydration,hydroxylation, carbon-carbon and carbon-nitrogen bond formation reactions

A green reaction medium has been developed from the Water Extract of Teak leaf (Tectona grandis) ash (WET). The alkaline nature of the WET was successfully applied towards hydration of nitriles, conversion of arylboronic acids to phenols with 30% aqueous H₂O₂, Knoevenagel condensation for benzylidenemalononitrile derivatives formation and Chan-Lam reaction of arylboronic acids with imidazole derivatives. In current protocols dual role of WET as reaction medium as well as base has been explored. A wide range of substrates with varying electronic natures is compatible under these WET mediated reaction conditions with excellent yields.     

HPLC同时测定归芍疏肝散中芍药苷阿魏酸和甘草酸铵的含量

目的:建立同时测定归芍疏肝散中芍药苷、阿魏酸和甘草酸铵含量的高效液相色谱法。方法:采用Amethyst C18色谱柱(200 mm×4.6 mm,5μm),乙腈-0.1%磷酸为流动相,梯度洗脱,流速为1.0 mL·min-1,检测波长为237 nm,柱温为30℃。结果:在线性范围内3种成分线性良好(r≥0.9998),精密度RSD均<2%;重复性RSD均<3%;平均回收率98.81%~100.25%,RSD均<2%。结论:该方法快捷,操作简便,结果可靠,可用于归芍疏肝散的质量控制。