Preparation of 177Lu‐labeled Nimotuzumab for radioimmunotherapy of EGFR‐positive cancers: Comparison of DOTA and CHX‐A″‐DTPA as bifunctional chelators

This study was aimed at evaluating the role of bifunctional chelators DOTA‐NCS and CHX‐A″‐DTPA‐NCS used for conjugating ¹⁷⁷Lu with Nimotuzumab on the radiochemical yields, purity, in vitro stability, and specificity of the radioimmunoconjugates to EGFR. Two immunoconjugates were prepared wherein Nimotuzumab was conjugated with the acyclic ligand p‐NCS‐Bn‐CHX‐A″‐DTPA and macrocyclic ligand p‐NCS‐Bn‐DOTA. These were radiolabeled with ¹⁷⁷Lu, purified on PD‐10 column, and characterized by SE‐HPLC. In vitro stability was determined up to 4 days post preparation. Specificity of the radioimmunoconjugates was ascertained by in vitro studies in A431 cells while the biodistribution patterns were studied in normal Swiss mice up to 96 hours post injection. Four to five molecules of CHX‐A″‐DTPA/DOTA were attached to one molecule of Nimotuzumab. Radiochemical purity of both ¹⁷⁷Lu‐CHX‐A″‐DTPA‐Nimotuzumab and ¹⁷⁷Lu‐DOTA‐Nimotuzumab was determined to be greater than 98%. Both the radioimmunoconjugates exhibited good in vitro stability at 37°C up to 4 days post preparation in saline, and their clearance was largely by the hepatobiliary route. The DOTA‐ and CHX‐A″‐DTPA‐based radioimmunoconjugates could be prepared with good radiochemical purity, in vitro stability, and specificity to EGFR. Further studies in EGFR‐positive cancers would pave way for them for use in the clinics.     

陆为民运用乌梅丸临床经验撷菁

陆为民教授是国医大师、著名脾胃病专家徐景藩教授的学术继承人,以擅用经方治疗临床诸证尤其是消化系统疾病而颇负盛名,其对于仲景经典名方"乌梅丸"的运用尤广。他认为,《伤寒杂病论》原文所栽乌梅丸虽为"寒热错杂、阴阳气不相顺接"之厥阴病主方,但因其"酸苦相合、寒温并用、攻补兼施"的组方特点,在临床实践过程中只要紧紧抓住其"寒热并存、虚实错杂"的病机,同时结合下半夜为"厥阴欲解时"的发病特点,根据病证表现灵活化裁,其可运用的病证范围十分广泛。陆为民教授在乌梅丸的临床运用过程中,始终把握"辨其病机而用、研其药性而选、衡其病证而调"的原则,同时不拘泥于原方药物及剂量,随证变化,疗效颇佳。     

Preparation,evaluation, and first clinical use of 177Lu‐labeled hydroxyapatite (HA) particles in the treatment of rheumatoid arthritis: utility of cold kits for convenient dose formulation at hospital radiopharmacy

While radiation synovectomy (RSV) constitutes a successful paradigm for the treatment of arthritis, a major cornerstone of its success resides in the selection of appropriate radiolabeled agent. Among the radionuclide used for RSV, the scope of using ¹⁷⁷Lu [T_1/2 = 6.65 d, E_β(max) = 497 keV, E_γ = 113 KeV (6.4%), 208 KeV (11%)] seemed to be attractive owing to its suitable decay characteristics, easy availability, and cost‐effective production route. The present article describes a formulation of ¹⁷⁷Lu‐labeled hydroxyapatite (HA) using ready‐to‐use kits of HA particles of 1–10 µm size range. The developed kits enable convenient one‐step preparation of ¹⁷⁷Lu‐HA (400 ± 30 MBq doses) in high radiochemical purity (>99%) and stability at hospital radiopharmacy. The preparation showed promising results in pre‐clinical studies carried out in Wistar rats bearing arthritis in knee joints. In preliminary clinical investigation, significant improvement in the disease conditions was reported in 10 patients with rheumatoid arthritis of knee joints treated with 333 ± 46 MBq doses of ¹⁷⁷Lu‐HA. The studies reveal that while ¹⁷⁷Lu labeled HA particles holds considerable promise as a cost‐effective agent for RSV, the adopted strategy of using HA kits could be a potential step toward wider clinical utilization of radiolanthanide‐labeled HA particles. Copyright © 2014 John Wiley & Sons, Ltd.     

传为陆探微作《洛神赋图》弗利尔馆藏卷的探讨

现存《洛神赋图》尚有七种 ,今藏美国华盛顿弗利尔美术馆传为陆探微作的《洛神赋图》是其中唯一的白描本 ,而且首尾最为完备。该卷虽疑点较多 ,但将其与其他数种画迹及相关著录进行比较、考证 ,尚可看出其流传有序 ,所据母本依稀可辨。从该卷题跋也可以看出与唐人《洛神赋图》粉本的某些联系。由此可以推断唐人粉本、李公麟临本、《东图玄览》著录之白描绢本、传仇英仿本皆在明代社会流传。此卷系临仿唐人粉本或他本 ,故而命题为“唐陆探微九歌图” ,这是有可能的。如果此说成立的话 ,那么唐代是存在过题为陆探微所作《洛神图》的 ,此卷亦即唐本陆探微《洛神图》的再摹本。文中附图三幅均系国内外首次发表 ,弥足珍贵     

Evaluation of Blood-Brain Barrier Passage of a Muscarine M1 Agonist and a Series of Analogous Tetrahydropyridines Measured by In Vivo Microdialysis

Purpose. To investigate the blood-brain barrier (BBB) passage of theM1 muscarine agonist Lu 25-109(5-(2-Ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-methylpyridine) and potential metabolites using in vivomicrodialysis. Methods. Anesthetized rats were administered an intravenous infusionof one of seven analogs with a Log D_7.4 ranging from 0.35 to –2.4.Microdialysis probes were implanted in the brain and the jugular vein.The integrity of the BBB was evaluated using2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA), a compound notexpected to penetrate the BBB. The data was corrected for in vitrorecovery. Results. Lu 25-109, Lu 24-165 (demethylated Lu 25-109) and Lu25-077 (N-demethylated Lu 25-109) entered the brain in a 1:1 ratio withthe blood. Although Lu 29-081 (hydroxylated Lu 25-109) presented asimilar Log D_7.4 to Lu 25-109 and Lu 24-164, it entered the brain witha lower brain:blood ratio of 0.5. Lu 32-181 (Lu 25-109 N-oxide), Lu35-026 (deethylated and oxidized Lu 25-109) and Lu 31-126(deethylated Lu 25-109) were not detected in the brain samples, indicating nopenetration. Infusion of Lu 25-109 resulted in a time perspective ofthe formation and distribution of the two metabolites Lu 25-077 andLu 32-181. Although the hydroxylated compound (Lu 29-081) had aLog D_7.4 of –0.6, within the range 0.35 to –0.83 of the compoundspenetrating the BBB, it showed a brain: blood ratio of 0.5. Lu 35-026showed an unusual infusion profile with a t_max of 100–150 min and asubsequent decrease in blood concentration. Conclusions. Compounds with Log D_7.4 above –0.83 penetrated theBBB, whereas compounds below –1.5 did not. Knowledge of LogD_7.4 values is not sufficient to evaluate BBB passage because the valuedoes not predict the influence of active transport processes.     

Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49

Purpose Lutetium-177 (¹⁷⁷Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both and radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the ¹⁷⁷Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo.Methods Conjugation and labeling conditions of multivalent scFv with ¹⁷⁷Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)₂; tetramer, [sc(Fv)₂]₂} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with ¹⁷⁷Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of ¹⁷⁷Lu-labeled tetravalent [sc(Fv)₂]₂ construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts.Results Approximately, 90% of ¹⁷⁷Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t_1/2) of ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t_1/2) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4±1.3 and 8.9±0.6 for ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0±0.6 and 8.4±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv)₂]₂ was significantly (p<0.005) reduced in the presence of l-lysine.Conclusion The results of this study demonstrate that the ITCB-DTPA conjugation and ¹⁷⁷Lu-labeling of scFvs are feasible without influencing the antibody characteristics. ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of l-lysine. Therefore, ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ may be a potential radiopharmaceutical for the treatment of cancer.     

改良生津汤与开塞露治疗产后便秘100例临床对照

目的：比较改良生津汤与开塞露治疗产后便秘的作用。资料：收集本院阴道产后便秘100例．分为两组，每组50例。方法：Ⅰ组病人服用生津汤通便，Ⅱ组病人使用开塞露通便。结果：Ⅰ组病人全部于6小时内排出软便，Ⅱ组病人46例排便，有4人无效。结论：改良生津汤治疗产后便秘方法简便，效果肯定。不影响哺乳。值得临床推广。     

基于CiteSpace和VOSviewer可视化分析药食同源中药罗汉果的发展态势

目的 罗汉果Siraitia grosvenorii为药食同源中药,具有较高营养价值、药用价值。随着居民饮食消费观念改变,天然甜味剂市场需求增加,而罗汉果作为天然代糖,热度日趋增强。分析罗汉果的研究现状和发展态势,为未来研究拓展提供参考。方法 以罗汉果为关键词,从中国知网（CNKI）数据库与Web of Science（WOS）数据库核心集检索并导出相关文献,并导入Endnote软件进行查重、筛选和格式转换后导出题录。最后使用CiteSpace、VOSviewer、Excel软件分别对罗汉果中英文文献的整体产出、研究主体及合作网络、高被引文献、关键词等进行分析。结果 共纳入文献551篇,其中中文文献458篇,英文文献93篇。罗汉果的年发文量大体呈现增长趋势,共有14个国家参与罗汉果的研究,其中以中国为主。中英文文献居发文量榜首的机构分别为广西壮族自治区药用植物园、Chinese Academy of Sciences（中国科学院）。中英文文献发文量最多的作者均为马小军。研究领域内各机构和团队之间的交流合作有待加强。被引频次前10的中英文文献主要研究方向为罗汉果的化学成分、植物培养及药理作用研究等。罗汉果苷V作为罗汉果中备受关注的活性物质是该领域的研究热点。中英文关键词共现、聚类显示研究热点集中于罗汉果的栽培、提取分离、工艺优化、药理作用、应用等方面。结论 罗汉果研究目前仍处于上升阶段,未来罗汉果领域的研究重点应关注罗汉果苷V的高含量品种选育、提取工艺等方面,另罗汉果多糖结构与活性的关联性也是罗汉果发展的重要趋势。     

Negative pressure wound therapy for surgical site infections: a systematic review and meta-analysis of randomized controlled trials

ObjectivesPrevious studies showed the effectiveness of negative pressure wound therapy (NPWT) in preventing surgical site infections (SSIs), but current guidelines do not recommend its routine use for surgical wounds. The aim was to compare the effectiveness and safety of NPWT with standard surgical dressing or conventional therapy for preventing SSIs.MethodsPubmed, Embase and the Cochrane Library were systematically searched on 10 April 2019. Also, we searched clinicaltrials.gov and references of relevant studies. Eligibility criteria were randomized controlled trials (RCTs) and adult surgical patients were included. The effectiveness of NPWT versus standard surgical dressing or conventional therapy was investigated. Relative risks (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to estimate the pooled effect of dichotomous outcomes and continuous outcomes respectively. The primary outcome was surgical site infections. The quality of included studies and the certainty of the evidence were assessed using the risk of bias tool and the GRADE approach.ResultsA total of 45 RCTs with 6624 surgical patients were included. NPWT reduced SSIs (RR 0.58; 95% CI 0.49–0.69) and wound dehiscence(17 RCTs; RR 0.80; 95% CI 0.65–1.00). NPWT did not increase the risk of hematoma (9 RCTs; RR 0.91; 95% CI 0.40–2.07) and hospital readmission(9 RCTs; RR 0.77; 95% CI 0.52–1.12) or prolong length of hospital stay(15 RCTs; MD –0.38; 95% CI, –0.78 to 0.02). NPWT significantly increased the risk of all adverse event-related outcomes (10 RCTs; RR 3.21; 95% CI, 1.17–8.78). The level of certainty was identified as low for the primary outcome and very low for all the secondary outcomes.ConclusionsCompared with standard wound care, NPWT may reduce the risk of SSIs. We are uncertain whether NPWT reduces or increases the risk of wound dehiscence, haematoma, hospital readmission and all adverse event-related outcomes or if it shortens or prolongs length of hospital stay.     

鲁沃夫牌除锈剂的使用体会

鲁沃夫牌除锈剂的使用体会目的：探讨我院病案存在的主要问题,分析原因,制定对策. 方法：查找我院2010年3月21日-9月30日终末病案书写质量主要缺陷,并进行统计分析.结果：病案质量存在多方面问题.缺陷最多的依次是病程记录、病案首页、入院记录、出院记录.结论：杜绝病案缺陷的发生,提高病案质量,是一项系统的工程,需要全体医务人员共同努力.