Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

术中同期韧带修复治疗踝关节骨折伴三角韧带断裂疗效及预后影响因素探讨

目的探讨术中同期韧带修复治疗踝关节骨折伴三角韧带断裂疗效及预后影响因素。方法回顾性分析溧阳市人民医院2016年1月至2018年12月收治踝关节骨折伴三角韧带断裂患者共183例临床资料,其中未行同期韧带修复者共48例设为A组,术中行同期韧带修复者135例设为B组,而B组根据修复方式分为浅层修复(54例),深层修复(48例)及完全修复(33例);比较不同组术中出血量、住院时间、美国足踝外科学会(AOFAS)评分、视觉模拟评分法(VAS)评分、术后并发症发生率及矢状面足跟着地角度,采用Logistic回归模型进行预后影响因素分析。结果B组住院时间、VAS评分、术后并发症发生率及矢状面足跟着地角度均少于A组(P<0.05);B组AOFAS评分高于A组(P<0.05);B组冠状面和水平面足跟着地角度则高于A组(P<0.05);深层组和完全组AOFAS评分少于浅层组(P<0.05);深层组和完全组VAS评分显著高于浅层组(P<0.05);完全组术后并发症发生率高于浅层组(P<0.05);Logistic回归模型单因素分析结果显示,年龄、合并其他损伤、受伤至手术时间、深层及浅层修复均是患者临床预后影响因素(P<0.05);而多因素分析结果则显示,浅层修复是患者临床预后独立保护因素(P<0.05)。结论踝关节骨折伴三角韧带断裂患者术中同期行韧带修复可有效提高临床疗效,改善关节生物力学指标;其中行浅层修复三角韧带更有助于增加临床获益。     

Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation – A single center retrospective efficacy analysis

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6–70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients’ characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p < 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.     

妊娠期高血压疾病危险因素及护理干预新进展

妊娠期高血压疾病是女性妊娠期间极为常见的一种妊娠并发症，亦为妇产科临床中极为常见的一种病症，该病症可产生 极大的危害性。目前临床主要站在流行病学角度上研究妊娠期高血压疾病，针对该病症的发病诱因、机制等尚未有统一认识形 成。本文主要分析和总结妊娠期高血压疾病的相关危险因素和护理干预措施，以供今后临床作参考。     

异牡荆素对非小细胞性肺癌细胞自我更新和凋亡的影响

目的研究异牡荆素(ISO)对非小细胞性肺癌(NSCLC)细胞的影响和潜在的机制。方法将A549和H1650细胞分别分为空白组、低剂量实验组(4μmol·L^-1 ISO)和高剂量实验组(16μmol·L^-1 ISO)。用噻唑蓝法检测NSCLC细胞活性,用肿瘤球形成实验检测NSCLC细胞的细胞球形成率,用Western blot法检测NSCLC细胞凋亡、自我更新、无翅型MMTV整合位点家族/β-连环蛋白(Wnt/β-catenin)信号通路相关蛋白的表达水平。结果与空白组比较,低、高剂量实验组中A549和H1650细胞在24,48和72 h的细胞活性均显著降低。低、高剂量实验组和空白组中A549细胞的细胞球形成率分别为(4.18±0.45)%,(2.01±0.67)%和(6.02±0.57)%,切割的半胱氨酸蛋白酶-3相对表达量分别为0.24±0.08,1.25±0.13和0.06±0.07,SRY相关高迁移率族盒蛋白-2相对表达量分别为0.49±0.04,0.25±0.03和1.00±0.09,Kruppel样因子4相对表达量分别为0.68±0.04,0.44±0.03和1.01±0.06,Wnt1相对表达量分别为0.63±0.06,0.28±0.04和1.00±0.06,β-catenin相对表达量分别为0.41±0.05,0.22±0.03和1.01±0.09;与空白组比较,低、高剂量实验组中A549细胞的上述指标的差异均有统计学意义(P<0.05,P<0.01)。上述3组中H1650细胞的上述指标也呈现一致的现象。结论ISO可能通过抑制Wnt/β-catenin信号通路来抑制NSCLC细胞活性和自我更新,并促进其凋亡。     

经聚乙烯亚胺钝化的荧光碳点负载阿霉素抑制非小细胞肺癌细胞增殖、迁移侵袭的治疗研究

目的研究利用经聚乙烯亚胺（PEI）钝化的荧光碳点（CD）装载阿霉素（DOX）进行药物递送，旨在增加DOX对非小细胞肺癌的治疗作用，减少DOX的心肌毒性。 方法通过一步微波加热法将甘油和PEI的混合物制备成CD-PEI，并通过静电效应将DOX装载至CD-PEI。采用CCK8实验检测CD-PEI-DOX对非小细胞肺癌细胞A549的增殖能力的影响；Transwell实验评估CD-PEI-DOX对A549细胞迁移侵袭能力的影响；最后通过体内动物实验评估CD-PEI-DOX的心肌毒性以及对非小细胞肺癌皮下肿瘤生长的抑制效果。 结果体外细胞实验证实，对比单纯的DOX处理组，CD-PEI-DOX对非小细胞肺癌A549细胞增殖、迁移侵袭能力的抑制作用更为显著。体内实验证实，CD-PEI-DOX纳米复合物治疗组小鼠心肌细胞结构完整，并且能有效抑制小鼠皮下肺癌肿瘤的生长。 结论经PEI钝化的荧光碳点负载阿霉素能显著提高DOX对非小细胞肺癌的治疗效果，并减少DOX对心脏的毒性作用。运用CD-PEI纳米颗粒改善化疗药物递送的治疗方案取得了初步证实，这可为肺癌化学治疗提供新思路，具有广大的临床应用前景。     

Growth and Nutritional Outcomes in Children Post-Haematopoietic Stem Cell Transplant without Exposure to Total Body Irradiation

AimsPoor growth in childhood cancer survivors who undergo haematopoietic stem cell transplant (HSCT) without exposure to radiation is reported anecdotally, although literature to support this is limited. The aims of this study were to assess the change in height standard deviation score (SDS) and the final adult height (FAH) in children who underwent chemotherapy-only conditioned HSCT and to identify predictors of poor growth.Materials and methodsWe conducted a retrospective hospital medical record review (1984–2010) of children (1–10 years) who underwent chemotherapy-only conditioned HSCT, noting anthropology measurements at cancer diagnosis, HSCT, 10 years old and FAH.ResultsThe median age at HSCT of the 53 patients was 4.5 years, 75% had a haematological malignancy and 25% a solid tumour. Half of the cohort underwent allogenic HSCT and most (89%) conditioned with busulphan. The mean change in height SDS from primary cancer diagnosis to FAH was –1.21 (±1.18 SD), equivalent to 7–8.5 cm loss, with a mean FAH of –0.91 SDS (±1.10 SD). The greatest height loss occurred between diagnosis and HSCT (–0.77 SDS, 95% confidence interval –1.42, –0.12, P = 0.01), with no catch-up growth seen by FAH. Patients with solid tumours had the greatest height loss. Overall body mass index SDS did not change significantly over time, or by cancer type.ConclusionsChemotherapy-only conditioned HSCT during childhood can impact FAH, with the greatest height loss occurring prior to HSCT and no catch-up growth after treatment finishes. Children transplanted for a solid tumour malignancy seem to be more at risk, possibly due to intensive treatment regimens, both pre-transplant and during conditioning.