Preparation of Ternary Lanthanide Complexes with Unsaturated Acid and 1,10-Phenanthroline, and Their Anti-Inflammatory Action

Four ternary lanthanide complexes with unsaturated acid and 1,10-phenanthroline are prepared in methanol and characterized by elemental analysis, molar conductance, UV, IR, (()~1H) NMR and XPS. The results from this paper show that the complexes Ln(phen)(SA)_3·2H_2O or Ln(phen)(CA)_3·H_2O (Ln=Ce(Ⅲ), Sm(Ⅲ) and Eu(Ⅲ), (phen=1,10-)phenanthroline, SA=Sorbate and CA=Cinnamate) has better anti-inflammatory effect than cerium nitrate and their gremores are steadier than cerium nitrate gremor. And there is a kind of medicament which can replace the cerium nitrate gremor completely in treating burn.

New evidence-based adaptive clinical trial methods for optimally integrating predictive biomarkers into oncology clinical development programs

Predictive biomarkers are important to the future of oncology; they can be used to identify patient populations who will benefit from therapy, increase the value of cancer medicines, and decrease the size and cost of clinical trials while increasing their chance of success. But predictive biomarkers do not always work. When unsuccessful, they add cost, complexity, and time to drug development. This perspective describes phases 2 and 3 development methods that efficiently and adaptively check the ability of a biomarker to predict clinical outcomes. In the end, the biomarker is emphasized to the extent that it can actually predict.

Simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation by ultra-high performance liquid chromatography coupled with nano quantity analyte detector

A novel method for simultaneous determination of kolliphor HS15 and miglyol 812 in microemulsion formulation was developed using ultra-high performance liquid chromatography coupled with a nano quantitation analytical detector （UHPLC-NQAD）. All components in kolliphor HS15 and miglyo1812 were well separated on an Acquity BEH C18 column. Mobile phase A was 0.1% trifluoroacetic acid （TFA） in water and mobile phase B was acetonitrile. A gradient elution sequence was programed initially with 60% organic solvent, slowly increased to 100% within 8 min. The flow rate was 0.7 mL/min. Good linearity （r 〉 0.95） was obtained in the range of 27.6-1381.1 μg/mL for polyoxyl 15 hydroxystearate in kolliphor HS15, 0.8-202.0 μg/mL for caprylic acid triglyceride and 2.7-221.9μg/mL for capric acid triglyceride in miglyol 812. The relative standard deviations （RSD） ranged from 0.6% to 1.7% for intra-day precision and from 0.4% to 2.7% for inter-day precision. The overall recoveries （accuracy） were 99.7%-101.4% for polyoxyl 15 hydroxystearate in kolliphor HS15, 96.7%-99.6% for caprylic acid triglyceride, and 94.1%- 103.3% for capric acid triglyceride in miglyol 812. Quantification limits （QL） were determined as 27.6 μg/ mL for polyoxy115 hydroxystearate in kolliphor HS15, 0.8 μg/mL for caprylic acid triglyceride, and 2.7 μg/ mL for capric acid triglyceride in miglyol 812. No interferences were observed in the retention time ranges of kolliphor HSI5 and miglyol 812. The method was validated in terms of specificity, linearity, precision, accuracy, QL, and robustness. The proposed method has been applied to microemulsion for- mulation analyses with good recoveries （82.2%-103.4%）.

Polyethylene glycol 3350 in occasional constipation: A one-week, randomized, placebo-controlled, double-blind trial

AIM:to evaluate the efficacy and safety of polyethylene glycol(PEG)3350 in subjects with self-reported occasional constipation.METHODS:Eligible subjects≥17 years of age were randomized to receive either placebo or PEG 335017 g once daily in this multicenter,double-blind trial.Evaluations were conducted before(baseline)and after a 7-d treatment period.The primary efficacy variable was the proportion of subjects reporting complete resolution of straining and hard or lumpy stools.Secondary efficacy variables assessed the severity of the subjects’daily bowel movement(BM)symptoms,and preference of laxatives based on diary entries,visual analog scale scores,and questionnaires.RESULTS:Of the 203 subjects enrolled in the study,11had major protocol violations.Complete resolution was noted by 36/98(36.7%)subjects in the PEG 3350 group and 23/94(24.5%)in the placebo group(P=0.0595).The number of complete BMs without straining or lumpy stools was similar between both groups.Subjects receiving PEG 3350 experienced significant relief in straining and reduction in hardness of stools over a7-d period(P<0.0001).Subjects reported that PEG3350 had a better effect on their daily lives,provided better control over a BM,better relief from constipation,cramping,and bloating,and was their preferred laxative.Adverse events(AEs)were balanced between the PEG3350 and the placebo groups.No deaths,serious AEs,or discontinuations due to AEs were reported.This trial is registered at clinicaltrials.gov as NCT00770432.CONCLUSION:Oral administration of 17 g PEG3350 once daily for a week is effective,safe,and well tolerated in subjects with occasional constipation.

A Direct Droplet Digital PCR Method for <i>E. coli</i>Host Residual DNA Quantification

Injectable drugs manufactured in E. coli must be tested for host residual DNA (hr DNA) impurity in ensuring drug purity and safety. Because of low allowable hr DNA as impurity, highly sensitive methods are needed. Droplet digital PCR (ddPCR) is a new method where the reaction is partitioned into about 20,000 nanoliter-sized droplets and each droplet acts as individual PCR reaction. After completion of end-point PCR, droplets are analyzed for fluorescence and categorized as positive or negative and DNA quantified using Poisson statistics. Here we describe development of a direct E. coli hr DNA dd PCR method where the drug is directly added to the ddPCR reaction. We show that the ddPCR method has acceptable precision and high accuracy, works with different biologic drugs, and compared to qPCR shows higher tolerance of drug matrices. The method does not require DNA extraction or standard curves for quantification of hr DNA in unknown samples.

Evaluation of the Effect of Aspirin on Platelet Aggregation: Methodological Recommendations for Aspirin-Drug Interaction Studies

Given the broad application of aspirin as antiplatelet drug, availability of standardized methodology to assess potential interaction with any co-medication on platelet aggregation is desired. We characterized the effect of aspirin (ASA) therapy on collagen-induced platelet aggregation in whole blood to define such methodology. Collagen-induced platelet whole blood aggregation was assessed in 6 healthy male volunteers on 2 occasions (Day 1, Day 7) using the Chronolog aggregometer. From Day 2 up to Day 7, subjects received a daily oral dose of 75 mg ASA. The relationship between collagen dose and platelet aggregation response was assessed. On Day 1, maximal aggregation was observed at 1 μg/mL collagen (15.3 ± 4.6 Ω) and higher. Reproducible results were obtained without any indication of intra-subject fluctuations. ASA treatment decreased maximal aggregation by 80% and 38% at 0.5 and 2.0 μg/mL collagen, respectively. Power calculations were performed based on the observed intra-subject variability and demonstrated minimal sample sizes of 9 - 11 subjects for future cross-over ASA-drug interaction studies exploring effects on platelet aggregation, which demonstrates that the proposed collagen-induced ex vivo whole blood platelet aggregation is a feasible methodology to evaluate ASA-drug interactions in healthy volunteers.

Evaluating Methods for Dealing with Missing Outcomes in Discrete-Time Event History Analysis: A Simulation Study

Background: In discrete-time event history analysis, subjects are measured once each time period until they experience the event, prematurely drop out, or when the study concludes. This implies measuring event status of a subject in each time period determines whether (s)he should be measured in subsequent time periods. For that reason, intermittent missing event status causes a problem because, unlike other repeated measurement designs, it does not make sense to simply ignore the corresponding missing event status from the analysis (as long as the dropout is ignorable). Method: We used Monte Carlo simulation to evaluate and compare various alternatives, including event occurrence recall, event (non-)occurrence, case deletion, period deletion, and single and multiple imputation methods, to deal with missing event status. Moreover, we showed the methods’ performance in the analysis of an empirical example on relapse to drug use. Result: The strategies assuming event (non-)occurrence and the recall strategy had the worst performance because of a substantial parameter bias and a sharp decrease in coverage rate. Deletion methods suffered from either loss of power or undercoverage issues resulting from a biased standard error. Single imputation recovered the bias issue but showed an undercoverage estimate. Multiple imputations performed reasonably with a negligible standard error bias leading to a gradual decrease in power. Conclusion: On the basis of the simulation results and real example, we provide practical guidance to researches in terms of the best ways to deal with missing event history data.

真实世界数据和证据在我国临床决策中的应用现状

传统上,循证医学理念下的临床决策通常以随机对照试验作为最佳临床证据。快速发展的真实世界数据和真实世界证据领域结合了真实临床环境的复杂性,为临床医生提供了补充性证据,并丰富了证据类别,以辅助临床医生做出更好的循证临床决策。本研究旨在梳理我国用于循证临床决策的真实世界数据和证据的范围和适用性,并总结潜在障碍和可行建议,以期进一步推进高质量真实世界数据和证据在循证临床决策中的可接受性。

樟叶胡椒中新木脂素成分的研究

自胡椒科胡椒属植物樟叶胡椒(Piper polysyphorum C. DC)中分离到六个新木脂素(neolignans)类化合物,经光谱(UV,IR,MS,~1H-NMR,^(13)C-NMR,2D-NMR,CD)分析及衍生物制备,确定Ⅱ为新化合物,即threo-△~7-7-羟基-3,4,5,3′,5′-五甲氧基-8-O-4′-新木脂素,为一对对映体,命名为樟叶素(polysyphorin),Ⅰ,Ⅲ,Ⅳ为新的对映体,分別为(+)-virolongin,(+)-grandisin及(+)-lancifolin D.化合物Ⅴ为南藤素(wallichinine),Ⅵ为山蒟素D(hancinone D)。血小板活化因子(PAF)受体结合实验及PAF引起的血小板聚集实验证明化合物Ⅰ～Ⅴ具有明显的抑制活性。

异型南五昧子(Kadsura heteroclita)中的具有血小板活化因子(PAF)拮抗活性的联苯环辛烯类木脂素

自异型南五味子（Kadsure heteroclita）首次分得7个已知的联苯环辛烯类木脂素，tigloylgomisin P(1),angeloylgomisin P(2),gomisin A(3),五味子素（4），angeloylgomisin H (5)，gomisin B(6)，R（＋）－gomisin M (7)。tigloylgomisin P(1)的构型以二维核磁共振光谱技术确定。应用[^3H]血小板活化因子（PAF）结合人血小板膜的分析方法测定，证明化合物（1），（2）和（7）有PAF受体拮抗活性。

帕博利珠单抗联合以铂类为基础的化疗治疗非小细胞肺癌合并稳定性脑转移患者的结局:KEYNOTE-021、-189和-407研究的汇总分析

背景与目的此项探索性分析回顾评价了晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的结局,旨在确定基线时合并脑转移是否会影响一线应用帕博利珠单抗联合化疗(pembrolizumab plus chemotherapy,PC)比对单用化疗的疗效。患者和方法对KEYNOTE-021队列G(非鳞癌)、KEYNOTE-189(非鳞癌)和KEYNOTE-407(鳞癌)三项研究晚期NSCLC患者的数据进行汇总分析。患者接受含铂两药化疗和/或35个周期帕博利珠单抗治疗(每3周200 mg)。所有研究均纳入了经治或初治的稳定性脑转移患者(KEYNOTE-189与KEYNOTE-407研究纳入初治脑转移患者)。经治的脑转移患者已处于病情稳定的状态≥2周(KEYNOTE-021队列G患者≥4周),无新发或脑转移病灶扩大的证据且入组前至少3天以上未使用激素。初治的无症状脑转移患者需定期接受脑部影像学检查。结果共纳入1298例患者,其中171例有基线脑转移,1127例无脑转移。两组的中位随访时间(范围)在数据截止时分别为10.9(0.1-35.1)个月和11.0(0.1-34.9)个月。合并脑转移和无脑转移患者的总生存期[0.48(95%CI:0.32-0.70)和0.63(95%CI:0.53-0.75)]和无进展生存期[0.44(95%CI:0.31-0.62)和0.55(95%CI:0.48-0.63)]的风险比(PC/化疗)相似。合并脑转移的患者中,PC组和单用化疗组患者的中位总生存期分别为18.8个月和7.6个月,中位无进展生存期分别为6.9个月和4.1个月。无论是否合并脑转移,PC组患者的客观缓解率都高于单用化疗组,且缓解持续时间有显著延长。合并脑转移的患者中,PC组与单用化疗组的治疗相关不良事件发生率分别为88.2%和82.8%;而无脑转移的患者中,两组治疗相关不良事件的发生率分别为94.5%和90.6%。结论无论是否合并脑转移,与单用化疗相比,帕博利珠单抗联合以铂类为基础的组织学特异性化疗可改善所有PD-L1亚组的临床结局,其中包括PD-L1肿瘤比例评分<1%的患者,并且在晚期NSCLC患者中安全性良好。该方案是晚期NSCLC初治患者的标准方案,并可用于合并稳定性脑转移的患者。

骨密度测量中精密度的重要性

骨密度测定 ,不论采取何特殊技术 ,即使严格地按照厂家建议的操作程序 ,也常常不能达到完美的重复性。必须确定每台骨密度仪不同骨骼部位的精确度。精密度 ,如标准差平均方根或变异系数平均方根 ,被用来确定骨密度的变化 ,即精密度决定最小显著性变化值和随访需要的至少时间间隔。除非确定了精密度 ,否则就不能确定任何水平的统计可信度最小显著性变化值 。

社区中老年居民高血压的流行病学调查及危险因素分析

目的了解南充市顺庆区中老年居民高血压患病情况和危险因素,为高血压的防治提供依据。方法选择南充市顺庆区45岁及以上的社区居民,进行生活习惯、慢性病史、慢性病家族史等问卷调查,同时行体格检查和相关生物化学指标检查。结果南充市居民高血压患病率、知晓率、治疗率及控制率分别为37.8%、48.1%、42%和18%,新发病率为24%,按2017年美国新指南标准的新发病率为69.59%。年龄（OR=1.047）、超重（OR=1.5）、肥胖（OR=1.911）、中心型肥胖（OR=1.208）、吸烟（OR=1.238）、睡眠过短（OR=1.105）、睡眠过长（OR=1.261）、糖尿病（OR=1.341）、血脂异常（OR=1.268）、冠心病（OR=1.57）、脑卒中（OR=3.33）、高血压家族史（OR=2.155）及脑卒中家族史（OR=1.367）与高血压的患病密切相关。结论南充市社区45岁及以上居民高血压患病率较高;知晓率、治疗率、控制率较低,年龄、超重、肥胖、中心型肥胖、吸烟、睡眠过短、睡眠过长、糖尿病、血脂异常、冠心病、脑卒中、高血压家族史、脑卒中家族史是高血压患病的独立危险因素。针对危险因素加强社区居民高血压防治工作意义重大。

Targeting the PI3K-AKT-mTOR signaling network in cancer

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumour types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.

Development of a physiologically relevant dripping analytical method using simulated nasal mucus for nasal spray formulation analysis

Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types of mucus depending on the indication or diseased state. This research investigated the effects of nasal mucus on the dripping behavior of nasal formulations and focused on developing an improved in vitro analytical test method that is more physiologically relevant in characterizing nasal formulation dripping behavior. Method development was performed using simulated nasal mucus preparations for both healthy and diseased states as coatings for the dripping experiment representing a wide range of viscosity. Factors evaluated during development of this in vitro test method included amount of mucus, application of mucus, drying times, and compatibility of the mucus on a C18 Thin Layer Chromatography(TLC) substrate. The dripping behavior of nasal formulations containing a range of 1%Avicel to 3.5% Avicel was assessed by actuating the nasal spray on a perpendicular TLC plate coated with either healthy or diseased simulated nasal mucus. After actuation of the nasal spray, the dripping of the formulation on the coated TLC plate was measured after the plate was repositioned vertically. The method that was developed generated reproducible results on the dripping behavior of nasal formulations and provided critical information about the compatibility of the formulation with the nasal mucus for different diseased states, aiding in nasal spray formulation development and physical characterization of the nasal spray.

狭义相对论的逻辑不自洽问题和新伽利略时空观

科学理论需要在逻辑上自洽。分析了狭义相对论对高速运动的不稳定微观粒子寿命延长的解释,发现狭义相对论的解释否定了光速不变原理或相对论性时空观。进一步分析发现,在狭义相对论“时间膨胀”和“长度收缩”的推导过程中,观察系和被观察系的指定完全相反。这一现象说明“时间膨胀”和“长度收缩”不是狭义相对论的逻辑结果,狭义相对论的逻辑结论应该是“时间收缩”和“长度收缩”(或“时间膨胀”和“长度膨胀”)。在狭义相对论的理论框架内不能正确地推导出运动物体的横质量,在狭义相对论的框架内得出正确横质量公式的推导都存在逻辑或物理错误。因此,狭义相对论在逻辑上是不自洽的,相对论性时空观没有实验证据。现代物理学应该建立在以局部优势引力场为相对优越参照系的新伽利略时空观的基础上。从光传播媒介对应于局部优势引力场这一原则出发,解释了迈克尔逊-莫雷实验、菲索流水光速实验和光行差现象。“运动质量”可由运动物体在受电磁场或引力场作用时受力的大小与该物体的运动速度有关得到解释。不稳定粒子寿命和物理时钟受各自的运动状态影响,也可以分别由粒子衰变和物理时钟依赖的具体物理过程受其相对于局部优势引力场的运动状态的影响来解释。

Development and validation of a GC–FID method for quantitative analysis of oleic acid and related fatty acids

Oleic acid is a common pharmaceutical excipient that has been widely used in various dosage forms. Gas chromatography （GC） has often been used as the quantitation method for fatty acids normally requiring a derivatization step. The aim of this study was to develop a simple, robust, and derivatization-free GC method that is suitable for routine analysis of all the major components in oleic acid USP-NF （United States Pharmacopeia-National Formulary） material. A gas chromatography-flame ionization detection （GC-FID） method was developed for direct quantitative analysis of oleic acid and related fatty acids in oleic acid USP-NF material. Fifteen fatty acids were separated using a DB-FFAP （nitroterephthalic acid modified polyethylene glycol） capillary GC column （30 m × 0.32 mm i.d.） with a total run time of 20 rain. The method was validated in terms of specificity, linearity, precision, accuracy, sensitivity, and robust- ness. The method can be routinely used for the purpose of oleic acid USP-NF material analysis.

Molecular targeted agents—where we are and where we are going

A total of 23 new cancer medicines or indication expansions were approved by the U. S. Food and Drug Administration in 2012. Among these, 12 are new molecular entities (NMEs)-new chemical or biological drugs approved for the first time for oncologic use-and 10 of these NMEs are molecular targeted agents. Among the 10 targeted agents, 4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors, targeting well established targets validated by previously approved agents such as bevacizumab (Avastin) or imatinib (Gleevec). Despite this progress, several questions remain: Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic? Where will the next wave of new cancer drugs come from? Where should R&D efforts be invested to continue improve cancer treatment and management, especially for tumor types uniquely prevalent in China? This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies, as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.

选择性雄激素受体调节子的开发及其治疗应用

雄激素控制着广泛的生理学功能.雄激素受体作为调节雄激素多种生物学作用的甾体类受体,是一种配基诱导的转录因子.雄激素信号系统的异常导致了从性别确定和性征发育到精神和情感失常的许多紊乱.雄激素替代治疗能改善许多临床症状,包括性腺机能低下与骨质疏松,但由于疗效不高和缺少方便给药的安全制剂而受到限制.最近甾体类受体和选择性受体调节子的基因调控技术,为选择性雄激素受体调节子能否解答现行雄激素治疗中存在的问题,提供了验证的机会.配基化的雄激素受体转录引发复合物的组成决定了基因调控的特异性,设计用于引发组织和启动子特异基因转录的合成配基提供了开发更有效的雄激素治疗的希望.建立能预测合成配基活性的测试方法是选择性雄激素受体调节子开发的关键.化合物筛选的高效率和基因指纹技术的进步,如微阵列技术和蛋白质组学,将加速有效的选择性受体调节子鉴定.