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.     

Single-dose combination nanovaccine induces both rapid and durable humoral immunity and toxin neutralizing antibody responses against Bacillus anthracis

Bacillus anthracis, the causative agent of anthrax, continues to be a prominent biological warfare and bioterrorism threat. Vaccination is likely to remain the most effective and user-friendly public health measure to counter this threat in the foreseeable future. The commercially available AVA BioThrax vaccine has a number of shortcomings where improvement would lead to a more practical and effective vaccine for use in the case of an exposure event. Identification of more effective adjuvants and novel delivery platforms is necessary to improve not only the effectiveness of the anthrax vaccine, but also enhance its shelf stability and ease-of-use. Polyanhydride particles have proven to be an effective platform at adjuvanting the vaccine-associated adaptive immune response as well as enhancing stability of encapsulated antigens. Another class of adjuvants, the STING pathway-targeting cyclic dinucleotides, have proven to be uniquely effective at inducing a beneficial inflammatory response that leads to the rapid induction of high titer antibodies post-vaccination capable of providing protection against bacterial pathogens. In this work, we evaluate the individual contributions of cyclic di-GMP (CDG), polyanhydride nanoparticles, and a combination thereof towards inducing neutralizing antibody (nAb) against the secreted protective antigen (PA) from B. anthracis. Our results show that the combination nanovaccine elicited rapid, high titer, and neutralizing IgG anti-PA antibody following single dose immunization that persisted for at least 108 DPI.     

The Prognostic Role of Peritumoral Edema in Patients with Newly Diagnosed Glioblastoma: A Retrospective Analysis

ObjectivePrevious studies on glioblastomas (GBMs) have not reached a consensus on peritumoral edema (PTE)’s influence on survival. This study evaluated the PTE index’s prognostic role in newly diagnosed GBMs using a well-designed method.MethodsSelected patients were reviewed after a rigorous screening process. Their general information was obtained from electronic medical records. The imaging metrics (MTD, TTM, TTE) representing tumor diameter, laterality, and PTE extent were obtained by manual measurement in Syngo FastView software. The PTE index was a ratio of TTE to MTD. Multiple variables were evaluated using analysis of variance and Cox regression model.ResultsOf 143 patients, 62 were included in this study. MGMT promoter methylation and tumor laterality were both independent prognostic factors (p = 0.020, 0.042; HR = 0.272, 2.630). The lateral tumors’ index was higher than that of the medial tumors (57.7% vs. 42.6%, p = 0.027). Low-index tumors were located in relatively medial positions compared with high-index tumors (TTM, 4.9 vs. 12.8, p = 0.032). This finding indicated that the PTE index tended to increase with tumor laterality. Moreover, the patients with low-index tumors had a significant survival disadvantage in the univariate analysis but not in the multivariate analysis (p = 0.023, 0.220). However, further analysis found that the combination of tumor laterality and PTE statistically stratified the survival outcome. The patients with lateral high-index tumors survived significantly longer (p = 0.022, HR = 1.927).ConclusionsIn contrast with the previous studies, this study recommends combining PTE and tumor laterality for survival stratification in newly diagnosed GBMs.     

Respuesta a antiangiogénicos en el edema macular secundario a necrosis retiniana aguda

A 55 year-old female patient with unilateral Acute Retinal Necrosis (ARN) developed macular oedema (MO) after the resolution of her necrosis. The macular oedema (MO) was managed and controlled for four years with intravitreal anti-VEGF injections. Anti-VEGF therapy could be useful for the treatment of MO secondary to ARN, the same as for treating MO resulting from panuveitis, where its efficacy has been already demonstrated.     

水通道蛋白4与脑血管病

水通道蛋白4（aquaporin4,AQP4）是水通道蛋白家族成员，在中枢神经系统主要表达于星形胶质细胞终足。大量实验研究显示，AQP4表达对不同类型卒中后脑水肿的发生、发展和消退起着重要作用。此外，AQP4表达还可通过影响血脑屏障完整性以及促进星形胶质细胞迁移、神经再生、神经炎性反应等机制影响脑血管病的发展过程。探讨AQ P4在脑内物质跨膜转运和细胞内外环境平衡中的调节机制及其在脑血管病模型中的表达，对于理解临床脑血管病的发生、发展、保护和治疗具有重要的意义。     

Systematic analysis of post-treatment soft-tissue edema and seroma on MRI in 177 sarcoma patients

PurposeTo assess post-treatment subcutaneous edema, muscle edema, and seroma in MRI after soft-tissue sarcoma (STS) resection with regard to muscle involvement of STS and therapy.MethodsIn all, 177 patients were included and received 1.5-T MRI follow-up examinations after treatment. Post-treatment changes were classified according to type of therapy (therapy 1-surgery; therapy 2-surgery with radiation therapy) and primary tumor localization in soft tissue (localization 1, subcutaneous tissue; localization 2, muscle involvement).Subcutaneous and muscle edema were divided into three grades: grade 0, absence of edema; grade 1, low-to-moderate edema; and grade 2, high-grade edema.ResultsThe mean age of the patients was 55.7 ± 18.2 years and the mean volume of the resected primary STS was 321.5 cm³. After therapy 1 of a sarcoma in localization 1, patients significantly more often showed low-grade subcutaneous tissue edema and an absence of muscle edema (p < 0.001) than high-grade edema. The risk for grade 2 subcutaneous tissue and muscle edema significantly increased with a tumor in localization 2 (RR = 2.58, p = 0.016 and RR = 15, p = 0.0065/RR = 2.05 , p = 0.021, respectively) and after therapy 2 (RR = 15, p = 0.0087 and RR = 2.05, p < 0.0001, respectively). Of the patients with sarcoma in localization 2, 88% developed grade 2 muscle edema after therapy 2; 40% of the patients developed post-treatment seroma. The risk for seroma is significantly higher after surgery and radiation therapy than after surgery alone (p < 0.001).ConclusionHigh-grade postoperative subcutaneous and muscle edema are significantly associated with muscle involvement of primary STS both in patients with and without radiation therapy. The risk for seroma is significantly higher after surgery with additional radiation therapy than after surgery alone.     

桃核承气汤治疗老年患者骨折术后肢体水肿并发腹胀、便秘的临床疗效观察

目的探讨桃核承气汤治疗老年患者骨折术后肢体水肿并发腹胀、便秘的临床疗效。方法选取2016年5月—2018年10月收治的112例骨折术后肢体水肿并发腹胀、便秘的老年患者,使用随机数字表法将其随机分为观察组(56例)与对照组(56例)。两组均给予常规对症治疗,观察组在此基础上联合桃核承气汤内服治疗,所有患者均治疗7 d。比较两组治疗后临床疗效,治疗前后患肢肿胀程度、疼痛视觉模拟评分法(VAS)评分、血清疼痛介质[前列腺素E₂(PGE₂)、一氧化氮(NO)、5-羟色胺(5-HT)]水平及血流变学参数[全血黏度(WBV)、红细胞比容(HCT)、纤维蛋白原(FIB)]值变化不良反应发生情况。结果观察组治疗后总有效率高于对照组(P<0.05)。两组治疗后患肢肿胀程度、疼痛VAS评分均较本组治疗前显著降低(P<0.05),且观察组下降更显著(P<0.05)。两组治疗后各项疼痛介质(PGE₂、NO、5-HT)血清浓度均较本组治疗前显著下降(P<0.05),且观察组降低更显著(P<0.05)。两组治疗后血流变学各项参数(WBV、HCT、FIB)值亦均较本组治疗前显著减少(P<0.05),且观察组降低更显著(P<0.05)。结论桃核承气汤治疗老年患者骨折术后肢体水肿并发腹胀、便秘,能有效促进患肢肿胀、疼痛及腹胀、便秘症状的缓解,可能与其下调体内疼痛介质表达有关。     

系统性毛细血管渗漏综合征的临床研究进展

系统性毛细血管渗漏综合征为一组反复发作的低容量性低血压、血液浓缩、非蛋白尿性低蛋白血症 ,全身水肿、多数情况下伴有异型球蛋白血症的临床综合征。其原因由于毛细血管通透性增加 ,目前具体发病机理尚不明确。近年发现特布他林和茶碱对预防发作有效。临床医生应对该病提高警惕性。     

基于气血津液理论谈糖尿病肾脏疾病水肿的治疗思路

气血津液是构成人体生命活动的基础物质,生理情况下津血同源、气血互根,病理状态下津液成水、气血水交阻而为病。糖尿病肾脏疾病水肿发生发展过程中,常常气血津液同时病变。气化不利、水湿内停是糖尿病肾脏疾病水肿的重要环节,微型癥瘕、络脉瘀结是其重要的病理基础,治疗应该在辨证的基础上,补气利水、行气利水及活血利水。其中补气需重用黄芪,调气需通利三焦,活血需重视通络,权衡气血水相关各种因素的盛衰缓急,抓住病机的关键辨证论治。