Role of site-directed mutagenesis and adjuvants in the stability and potency of anthrax protective antigen

Anthrax is a zoonotic infection caused by the gram-positive, aerobic, spore-forming bacterium Bacillus anthracis. Depending on the origin of the infection, serious health problems or mortality is possible. The virulence of B. anthracis is reliant on three pathogenic factors, which are secreted upon infection: protective antigen (PA), lethal factor (LF), and edema factor (EF). Systemic illness results from LF and EF entering cells through the formation of a complex with the heptameric form of PA, bound to the membrane of infected cells through its receptor. The currently available anthrax vaccines have multiple drawbacks, and recombinant PA is considered a promising second-generation vaccine candidate. However, the inherent chemical instability of PA through Asn deamidation at multiple sites prevents its use after long-term storage owing to loss of potency. Moreover, there is a distinct possibility of B. anthracis being used as a bioweapon; thus, the developed vaccine should remain efficacious and stable over the long-term. Second-generation anthrax vaccines with appropriate adjuvant formulations for enhanced immunogenicity and safety are desired. In this article, using protein engineering approaches, we have reviewed the stabilization of anthrax vaccine candidates that are currently licensed or under preclinical and clinical trials. We have also proposed a formulation to enhance recombinant PA vaccine potency via adjuvant formulation.     

产学研合作模式下长三角生物医药产业一体化协同创新发展研究——基于专利合作及基金项目合作

长三角一体化上升并发展为国家战略后，国内鲜有探讨长三角地区生物医药产业一体化协同发展的研究，长三角作为我国生物医药产业的重要地区，已初步形成产业集群的发展模式。本研究基于专利及基金项目合作的产学研模式，利用社会网络分析方法（SNA）对长三角地区生物医药产业中专利和国家自然科学基金重大项目合作进行分析研究。研究表明，长三角地区生物医药领域的产学研合作还处于发展阶段，一体化程度也有待提高；高校及科研院所更倾向于与企业合作开展发明专利，与高校合作开展基金项目研究。长三角地区三省一市间的生物医药产业发展也存在一定差距，建议长三角地区采取产学研深度融合模式，相关龙头科研机构建立开放式创新平台，医药类高校借助学科优势培养创新型人才，采取“揭榜挂帅”等方式进行关键核心技术攻关。     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

中药产业应对“一带一路”倡议的知识图谱分析

目的:分析"一带一路"倡议和中药产业的研究热点,为中药产业发展提供全新、系统的参考数据。方法:在中国知网以主题词的形式进行专业检索,使用CiteSpace软件绘制关键词网络图谱、聚类图谱、叠加图谱。结果:"一带一路"倡议研究现状以所涉及的区域经济、文化、社会协同发展等为主;中药产业研究现状以中药资源与种植、中药产业链、中药现代化、人才培养、中药产品研发和保护等为主;中药产业应对"一带一路"倡议的出路在于相关的政府机构对中药产业的政策支持、人才培养、中药产业相关的企业和个人要重视中药国际化和持续化发展、竞争力的培养等。结论:中药产业的良好、健康发展,需要党和各级政府适时出台各种有利于促进中药产业发展的政策和措施,社会各界要为中药产业的发展培养需要的人才、提供建议,中药企业要善于利用SWOT分析技术,坚持特色,重点培养核心竞争力。     

Randomized Crossover Trial of Phosphate-binding Medication on Serum Phosphate Levels in Patients With Aortic Stenosis

PurposeAortic stenosis is a common cause of valvular heart disease with no means of prevention. The recognized association between aortic stenosis and serum phosphate raises the possibility of preventing progression of the disorder by using phosphate-binding drugs, but there is uncertainty whether such treatment lowers serum phosphate levels in patients without diagnosed renal failure. This pilot study was conducted to answer this question in patients with aortic stenosis.MethodsA randomized, double-blind, crossover trial of the phosphate-binding drug sevelamer was conducted in 72 patients. Patients were prescribed sevelamer 0.8 g (low-dose), sevelamer 2.4 g (high-dose), and matching placebo, 3 times daily with food; each regimen lasted 6 weeks and was allocated at random. Serum phosphate levels were measured at the end of each treatment period, and within-person levels were compared.FindingsSixty-one patients completed the 3 treatment periods. There was no significant difference in the mean end-treatment phosphate levels across all patients (3.38, 3.36, and 3.31 mg/dL with placebo, low-dose sevelamer, and high-dose sevelamer, respectively). Post hoc analysis showed a reduction in phosphate levels with increasing sevelamer dose in the highest baseline phosphate quartile group; a 0.3 mg/dL reduction (mean, 4.09 mg/dL with placebo, 3.95 mg/dL with low-dose sevelamer, and 3.79 mg/dL with high-dose sevelamer; P_trend = 0.027).ImplicationsSevelamer had no overall statistically significant effect in lowering serum phosphate levels, but a reduction was observed in patients with phosphate levels in the highest quartile group of the population distribution. This hypothesis-generating result requires confirmation in an independent study. If confirmed, a trial of sevelamer in preventing the progression of aortic stenosis may be justified in patients with high phosphate levels. ISRCTN Registry identifier: ISRCTN17365679.     

Faster bone union progression and less sclerosis at the osteotomy margin after medial opening-wedge high tibial osteotomy using highly porous β-tricalcium phosphate granules versus allogeneic bone chips: A matched case–control study

BackgroundThis study compared bone union progression using highly porous (80% porosity) β-tricalcium phosphate (β-TCP) granules or allogeneic bone chips in the gap created by medial opening-wedge high tibial osteotomy (MOWHTO).MethodsThe study population consisted of 54 patients who received MOWHTO with locking plate fixation: 27 patients using highly porous β-TCP granules, and 27 age- and sex-matched patients using allogeneic bone chips. Bone union progression was evaluated 1, 3, 6, and 12 months postoperatively. The presence of radiographic sclerosis at the osteotomy margin was also assessed.ResultsAmong all patients, the highest degree of bone union observed 12 months postoperatively was grade 4. As postoperative time passed, bone union progression of highly porous β-TCP granules increased linearly and was statistically significant compared with that of cancellous allogeneic bone chips (P = 0.014). The presence of radiographic sclerosis at the osteotomy margin was significantly less common in the β-TCP group than in the allograft group (P = 0.003) and was the strongest predictor of delayed progress of bone union (odds ratio = 6.16, P = 0.006).ConclusionsPatients who underwent MOWHTO using highly porous β-TCP granules had faster new bone remodeling, less radiographic sclerosis at the osteotomy margin, and no inferior clinical outcome compared with allogeneic bone chips, as determined at the 1-year follow up. The presence of radiographic sclerosis at the osteotomy margin in patients undergoing MOWHTO using allogeneic bone or synthetic bone substitute may indicate delayed progress of bone union.