Synthesis,antitumor testing and molecular modeling study of some new 6-substituted amido,azo or thioureido-quinazolin-4(3H)-ones

A new series of 6-substituted amido, azo or thioureido-quinazolin-4(3H)-one was synthesized and tested for their in-vitro antitumor activity. Compounds 21, 53 and 60 showed broad spectrum antitumor activity with average IC₅₀ values of 6.7, 7.6 and 9.1 μM, respectively compared with methotrexate (1, IC₅₀ 19.26 μM). As an attempt to reveal the mechanism of the antitumor potency, cell cycle analysis and DHFR inhibition were performed. Compounds 59 and 61 induced their cytotoxicity in Hela (IC₅₀ 10.6 μM) and HCT-116 (IC₅₀ 15.5 μM) cell lines, respectively through Pre-G1 apoptosis, inhibiting cell growth at G2-M phase. Compounds 29, 33, 59 and 61 showed DHFR inhibitory potency at IC₅₀ 0.2, 0.2, 0.3 and 0.3 μM, respectively. The active DHFR inhibitors showed high affinity binding toward the amino acid residues Thr56, Ser59 and Ser118. The active compounds obeyed Lipinski’s rule of five and could be used as template model for further optimization.     

Assessment and Clinical Utility of a Non-Next-Generation Sequencing-Based Non-Invasive Prenatal Testing Technology

Background: Rolling-circle replication (RCR) is a novel technology that has not been applied to cell-free DNA (cfDNA) testing until recently. Given the cost and simplicity advantages of this technology compared to other platforms currently used in cfDNA analysis, an assessment of RCR in clinical laboratories was performed. Here, we present the first validation study from clinical laboratories utilizing RCR technology. Methods: 831 samples from spontaneously pregnant women carrying a singleton fetus, and 25 synthetic samples, were analyzed for the fetal risk of trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13), by three laboratories on three continents. All the screen-positive pregnancies were provided post-test genetic counseling and confirmatory diagnostic invasive testing (e.g., amniocentesis). The screen-negative pregnancies were routinely evaluated at birth for fetal aneuploidies, using newborn examinations, and any suspected aneuploidies would have been offered diagnostic testing or confirmed with karyotyping. Results: The study found rolling-circle replication to be a highly viable technology for the clinical assessment of fetal aneuploidies, with 100% sensitivity for T21 (95% CI: 82.35–100.00%); 100.00% sensitivity for T18 (71.51–100.00%); and 100.00% sensitivity for T13 analyses (66.37–100.00%). The specificities were >99% for each trisomy (99.7% (99.01–99.97%) for T21; 99.5% (98.62–99.85%) for T18; 99.7% (99.03–99.97%) for T13), along with a first-pass no-call rate of 0.93%. Conclusions: The study showed that using a rolling-circle replication-based cfDNA system for the evaluation of the common aneuploidies would provide greater accuracy and clinical utility compared to conventional biochemical screening, and it would provide comparable results to other reported cfDNA methodologies.     

A flexible summary statistics-based colocalization method with application to the mucin cystic fibrosis lung disease modifier locus

Mucus obstruction is a central feature in the cystic fibrosis (CF) airways. A genome-wide association study (GWAS) of lung disease by the CF Gene Modifier Consortium (CFGMC) identified a significant locus containing two mucin genes, MUC20 and MUC4. Expression quantitative trait locus (eQTL) analysis using human nasal epithelia (HNE) from 94 CF-affected Canadians in the CFGMC demonstrated MUC4 eQTLs that mirrored the lung association pattern in the region, suggesting that MUC4 expression may mediate CF lung disease. Complications arose, however, with colocalization testing using existing methods: the locus is complex and the associated SNPs span a 0.2 Mb region with high linkage disequilibrium (LD) and evidence of allelic heterogeneity. We previously developed the Simple Sum (SS), a powerful colocalization test in regions with allelic heterogeneity, but SS assumed eQTLs to be present to achieve type I error control. Here we propose a two-stage SS (SS2) colocalization test that avoids a priori eQTL assumptions, accounts for multiple hypothesis testing and the composite null hypothesis, and enables meta-analysis. We compare SS2 to published approaches through simulation and demonstrate type I error control for all settings with the greatest power in the presence of high LD and allelic heterogeneity. Applying SS2 to the MUC20/MUC4 CF lung disease locus with eQTLs from CF HNE revealed significant colocalization with MUC4 (p = 1.31 × 10^?5) rather than with MUC20. The SS2 is a powerful method to inform the responsible gene(s) at a locus and guide future functional studies. SS2 has been implemented in the application LocusFocus.     

影像设备电路板测试与故障诊断之系统实现

大型医学影像设备是医院中的贵重设备,其中不少进口设备的维护修理的技术难度较高,医院每年花费在医学影像设备上的维护修理费是非常之大。本文从建立国内的维修力量着眼,研讨医学影像设备维修方法。     

Monitoring clinical trials with multiple arms

In order to benefit from the substantial overhead expenses of a large group sequential clinical trial, the simultaneous investigation of several competing treatments becomes more popular. If at some interim analysis any treatment arm reveals itself to be inferior to any other treatment under investigation, this inferior arm may be or may even need to be dropped for ethical and/or economic reasons. Recently proposed methods for monitoring and analysis of group sequential clinical trials with multiple treatment arms are compared and discussed. The main focus of the article is on the application and extension of (adaptive) closed testing procedures in the group sequential setting that strongly control the familywise error rate. A numerical example is given for illustration.     

氚—烟酰苯胺在钉螺体内分布示踪的研究

本文应用氚－烟酰苯胺标记湖北钉螺，示踪观察不同时间烟酰苯胺进入螺体组织和脏器内的分布和进入途径。结果显示，钉螺接触药物从２２分钟开始检测出组织、脏器内氚含量，以后逐渐增高，至１４４０分钟达最高峰；合计不同时间各组织和脏器中药物含量由高至低排列次序为外套膜、胃肠、肝脏、肠内粪梗、睾丸、卵巢、鳃、神经节、心脏；转换氚含量为烟酰苯胺剂量，证实了烟酰苯胺杀螺的低用量与高效性；由单位重量组织和脏器中药物含量排位，反映出药物在螺体分布动态变化，以及药物通过消化系统、呼吸系统、外套膜表皮三条途径进入。     

Using pooled exposure assessment to improve efficiency in case-control studies

Assays can be so expensive that interesting hypotheses become impractical to study epidemiologically. One need not, however, perform an assay for everyone providing a biological specimen. We propose pooling equal-volume aliquots from randomly grouped sets of cases and randomly grouped sets of controls, and then assaying the smaller number of pooled samples. If an effect modifier is of concern, the pooling can be done within strata defined by that variable. For covariates assessed on individuals (e.g., questionnaire data), set-based counterparts are calculated by adding the values for the individuals in each set. The pooling set then becomes the unit of statistical analysis. We show that, with appropriate specification of a set-based logistic model, standard software yields a valid estimated exposure odds ratio, provided the multiplicative formulation is correct. Pooling minimizes the depletion of irreplaceable biological specimens and can enable additional exposures to be studied economically. Statistical power suffers very little compared with the usual, individual-based analysis. In settings where high assay costs constrain the number of people an investigator can afford to study, specimen pooling can make it possible to study more people and hence improve the study's statistical power with no increase in cost.