脊髓小脑共济失调2型家系ATXN2基因中间重复病例表型与分子遗传学特征

目的探讨脊髓小脑共济失调2型(SCA2)致病基因ATXN2异常等位基因中间重复个体的表型和分子遗传学特点。方法针对2005—2018年中日友好医院神经科运动障碍与神经遗传病研究中心收集的1383个常染色体显性遗传共济失调家系的先证者和部分家系成员,采用荧光标记毛细管电泳片段分析方法进行动态突变检测,对携带ATXN2基因中间重复的个体进行临床表型和遗传特征分析。结果共检出163个家系(包含先证者和家系成员共203人)携带异常扩展的ATXN2基因CAG重复序列,其中93个家系中有107例的异常扩展等位基因重复次数在29~34次之间。在其中的20个亲子对中,父系遗传16个,异常等位基因的代间扩展增加0~28次,母系遗传4个,异常等位基因的代间扩展增加0~4次。结论对于临床拟诊SCA2家系患者,需对其亲代或成年子代个体进行ATXN2基因检测,以免漏诊。动态突变基因检测有助于识别中间重复的个体,对明确家系致病基因和遗传咨询至关重要。     

Troubled-Cell Indicator Based on Mean Value Property for Hybrid WENO Schemes

In this paper, we introduce a new type of troubled-cell indicator to improve hybrid weighted essentially non-oscillatory (WENO) schemes for solving the hyperbolic conservation laws. The hybrid WENO schemes selectively adopt the high-order linear upwind scheme or the WENO scheme to avoid the local characteristic decompositions and calculations of the nonlinear weights in smooth regions. Therefore, they can reduce computational cost while maintaining non-oscillatory properties in non-smooth regions. Reliable troubled-cell indicators are essential for efficient hybrid WENO methods. Most of troubled-cell indicators require proper parameters to detect discontinuities precisely, but it is very difficult to determine the parameters automatically. We develop a new troubled-cell indicator derived from the mean value theorem that does not require any variable parameters. Additionally, we investigate the characteristics of indicator variable; one of the conserved properties or the entropy is considered as indicator variable. Detailed numerical tests for 1D and 2D Euler equations are conducted to demonstrate the performance of the proposed indicator. The results with the proposed troubled-cell indicator are in good agreement with pure WENO schemes. Also the new indicator has advantages in the computational cost compared with the other indicators.     

A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

以专培学员为主导的CBL教学对心血管专培学员自身综合能力提升的影响

心血管专科医师规范化培训目标要求高于住院医师培训，完成心血管专培的医生应能在医疗、教学、科研能力上明显提高，达到心血管专科主治医师水平。如何提高心血管专培学员教学能力是专培中的难点。将专培学员随机分为两组,分别采用案例教学法（case-based learning, CBL）和传统教学法进行带教,课程结束后通过测验和调查问卷两种方式对教学效果进行考察。旨在探讨由心血管专培学员主导CBL教学法在实施过程中是否对其自身综合能力有所提升。结果显示，CBL教学法组学生临床理论及病例分析考试分数均高于对照组；心血管专培学员通过主导CBL教学，在教学能力、组织能力和学科协调均有提升；相较传统教学法,CBL教学法的教学效果更佳,有利于心血管专培学员自身综合能力提升。