Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

基于标准化患者法评价四川农村基层医生两种慢性病诊断准确性及其影响因素

目的 运用标准化患者法评估四川农村地区基层医生不稳定型心绞痛和2型糖尿病两种慢性病诊断准确性现状,探讨基层医生两种慢性病诊断准确性的主要影响因素,为提升基层医生两种慢性病诊断准确性提供科学依据。方法 采用多阶段随机整群抽样方法,抽取四川省自贡市5个区/县50个乡镇100个村为研究现场,以调查当日在岗的全科及内科医生作为研究对象。共进行两轮数据采集,第1轮采集样本乡镇卫生院和村卫生室医生的基本信息;第1轮调查完成1个月后,运用标准化患者法开展第2轮调查,收集农村基层医生对不稳定型心绞痛和2型糖尿病诊断结果信息。运用Logistic回归分析农村基层医生不稳定型心绞痛和2型糖尿病诊断准确性的影响因素。结果 共纳入172名农村基层医生,完成186次标准化患者访问,正确诊断率为48.39%。其中不稳定型心绞痛的正确诊断率为18.68%(17/91),2型糖尿病的正确诊断率为76.84%(73/95)。Logistic回归分析显示,具有执业医师资质的农村基层医生更有可能做出正确诊断(OR=4.857,95%CI=1.076~21.933,P=0.040)。农村基层医生在诊断过程中涉及的必要问诊和检查条目越多,做出正确诊断的概率越高(OR=1.627,95%CI=1.065~2.485,P=0.024)。与不稳定型心绞痛相比,农村基层医生对2型糖尿病做出正确诊断的可能性更高(OR=6.306,95%CI=3.611~11.013,P<0.001)。结论 四川农村基层医生不稳定型心绞痛和2型糖尿病诊断准确性整体较差,建议以基层医生慢性病诊断过程质量改善为突破口,提升基层医生执业水平,进而提高慢性病诊断准确性。     

Orientation and mobility outcome measures

Despite orientation and mobility (O&M) being a significant factor determining quality of life of people with low vision or blindness, there are no gold standard measures or agreement on how to measure O&M performance. In the first part of this systematic review, an inventory of O&M outcome measures used by recent studies to assess the performance of orientation and/or mobility of adults with vision impairment (low vision and blindness) is presented. A wide variety of O&M outcome measures have been implemented in different fields of study, such as epidemiologic research and interventional studies evaluating training, assistive technology, vision rehabilitation and vision restoration. The most frequent aspect of outcome measures is efficiency such as time, distance, speed and percentage of preferred walking speed, followed by obstacle contacts and avoidance, and dis/orientation and veering. Other less commonly used aspects are target identification, safety and social interaction and self-reported outcome measures. Some studies employ sophisticated equipment to capture and analyse O&M performance in a laboratory setting, while others carry out their assessment in real-world indoor or outdoor environments. In the second part of this review, the appropriateness of implementing the identified outcome measures to assess O&M performance in clinical and functional O&M practice is evaluated. Nearly a half of these outcome measures meet all four criteria of face validity (either clinical or functional), responsiveness, reliability and feasibility and have the potential to be implemented in clinical or functional O&M practice. The findings of this review confirm the complicated and dynamic nature of O&M. Multiple measures are required in any evaluation of O&M performance to facilitate holistic assessment of O&M abilities and limitations of each individual.     

骨形态发生蛋白2及碱性成纤维生长因子2对大鼠骨髓间充质干细胞膜片增殖和成骨分化的影响

文题释义： 细胞膜片技术：是在体外接种培养高密度的细胞，使其相互融合生长至100%而形成的透明致密膜状物。该技术不需要胰酶消化即可收集细胞，因此保留了大量的胞外基质、细胞间连接以及细胞-基质连接等结构。目前细胞膜片技术已成为组织工程领域的研究热点，已被推广应用于牙周膜、角膜、心脏、软骨、食管等多种组织器官修复。 成骨细胞：主要由内外骨膜和间充质始祖细胞分化而来，在复杂的骨形成过程中发挥着主要的功能，承担着骨基质的合成、分泌和矿化。骨髓间充质干细胞具有多向分化潜能，能定向分化为成骨细胞，其成骨分化过程可受多种因素的影响，如细胞因子的调控、遗传因素和激素水平等。背景：现阶段骨形态发生蛋白2和碱性成纤维生长因子2对骨髓间充质干细胞膜片增殖、成骨分化的影响和作用机制还尚未可知，如何将生长因子与组织工程细胞膜片技术相整合，最终将其用于骨缺损修复具有重要意义。 目的：探讨单独及联合应用骨形态发生蛋白2和碱性成纤维生长因子2对骨髓间充质干细胞膜片增殖和成骨分化的影响。 方法：体外分离培养鉴定SD大鼠骨髓间充质干细胞并构建细胞膜片，选用不同质量浓度的骨形态发生蛋白2和碱性成纤维生长因子2单独及联合诱导骨髓间充质干细胞膜片，CCK-8法结合碱性磷酸酶活性检测确定2种因子促进膜片增殖和成骨分化的最佳有效质量浓度；然后对骨髓间充质干细胞膜片进行成骨诱导，通过大体及显微镜观察、Vonkossa染色、茜素红染色、RT-PCR检测相关成骨标志物来评估诱导效果。 结果与结论：单独应用骨形态发生蛋白2可增强骨髓间充质干细胞膜片的碱性磷酸酶活性，最佳质量浓度为100 μg/L(P < 0.001)，单独应用碱性成纤维生长因子2能加速骨髓间充质干细胞膜片的增殖，最佳质量浓度为20 μg/L(P < 0.001)，而联合应用既可以促进膜片增殖又能提高其碱性磷酸酶活性(P < 0.001)；经成骨诱导后，4组膜片在形态学上无明显差异，均能诱导骨髓间充质干细胞膜片的成骨分化，其中联合组钙结节最明显(P < 0.001)，可显著促进膜片晚期成骨分化并抑制其早期成骨分化，具有明显的协同促进作用(P < 0.001)。结果表明，骨形态发生蛋白2和碱性成纤维生长因子2联合应用时具有协同作用，既可以促进骨髓间充质干细胞膜片增殖，又能显著增强其成骨诱导能力。ORCID: 0000-0003-1918-579X(何惠宇) 中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程     

Efeitos Terapêuticos da Tripla Antiagregação Plaquetária em Pacientes Femininas Idosas com Diabetes e Infarto Agudo do Miocárdio

BackgroundDual antiplatelet therapy (DAPT) is the cornerstone treatment of acute myocardial infarction (AMI).ObjectiveThe present study aimed to investigate the efficacy and safety of triple antiplatelet therapy (TAPT) in elderly female patients with diabetes and ST segment elevation myocardial infarction (STEMI), who had undergone percutaneous coronary intervention (PCI).MethodsWe designed a randomized, single-blind study. Control group A (97 elderly male patients with diabetes and STEMI, whose CRUSADE scores were < 30) received aspirin, ticagrelor, and tirofiban. A total of 162 elderly female patients with diabetes and STEMI were randomly divided into two groups according to CRUSADE score. Group B (69 patients with CRUSADE score > 31) received aspirin and ticagrelor. Group C (93 patients with CRUSADE score < 30) received aspirin, ticagrelor and tirofiban. P values < 0.05 were considered statistically significant.ResultsCompared to the findings in group A, post-PCI Thrombolysis in Myocardial Infarction (TIMI) grade 3 blood flow and TIMI myocardial perfusion grade 3 were significantly less prevalent in group B (p < 0.05). When compared to groups A and C, the incidence of major adverse complications was significantly higher in group B (p < 0.05).ConclusionTAPT could effectively reduce the incidence of major complications in elderly female patients with diabetes and STEMI. However, close attention should be paid to hemorrhage in patients receiving TAPT. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)