Assessing the value-adding impact of diagnostic-type tests on drug development and marketing

OBJECTIVE AND METHODS: We explore the cash value of the companion diagnostics opportunity from the perspective of the pharmaceutical partner. Cashflow-based modeling is used to demonstrate the potential financial benefits of key relationships between the pharmaceutical and diagnostics industries. RESULTS: In four scenarios, the uplift in the net present value (NPV) of a proprietary medicine can exceed $US1.8 billion. By simple extrapolation, the uplifted NPV calculations allow realistic and plausible estimates of the companion diagnostic opportunity to be in the region of $US40 billion to $US90 billion. CONCLUSION: It is expected that such market valuation could drive a macroeconomic change that shifts healthcare practice from reactionary disease-treatment to proactive health maintenance.     

Collective effects in traffic on bi-directional ant trails

Motivated by recent experimental work of Burd et al., we propose a model of bi-directional ant traffic on pre-existing ant trails. It captures in a simple way some of the generic collective features of movements of real ants on a trail. Analysing this model, we demonstrate that there are crucial qualitative differences between vehicular- and ant-traffics. In particular, we predict some unusual features of the flow rate that can be tested experimentally. As in the uni-directional model a non-monotonic density-dependence of the average velocity can be observed in certain parameter regimes. As a consequence of the interaction between oppositely moving ants the flow rate can become approximately constant over some density interval.     

Prediction of drug efficacy for cancer treatment based on comparative analysis of chemosensitivity and gene expression data

The NCI60 database is the largest available collection of compounds with measured anti-cancer activity. The strengths and limitations for using the NCI60 database as a source of new anti-cancer agents are explored and discussed in relation to previous studies. We selected a sub-set of 2333 compounds with reliable experimental half maximum growth inhibitions (GI(50)) values for 30 cell lines from the NCI60 data set and evaluated their growth inhibitory effect (chemosensitivity) with respect to tissue of origin. This was done by identifying natural clusters in the chemosensitivity data set and in a data set of expression profiles of 1901 genes for the corresponding tumor cell lines. Five clusters were identified based on the gene expression data using self-organizing maps (SOM), comprising leukemia, melanoma, ovarian and prostate, basal breast, and luminal breast cancer cells, respectively. The strong difference in gene expression between basal and luminal breast cancer cells was reflected clearly in the chemosensitivity data. Although most compounds in the data set were of low potency, high efficacy compounds that showed specificity with respect to tissue of origin could be found. Furthermore, eight potential topoisomerase II inhibitors were identified using a structural similarity search. Finally, a set of genes with expression profiles that were significantly correlated with anti-cancer drug activity was identified. Our study demonstrates that the combined data sets, which provide comprehensive information on drug activity and gene expression profiles of tumor cell lines studied, are useful for identifying potential new active compounds.     

Evidence supporting predicted metabolic pathways for Vibrio cholerae: gene expression data and clinical tests

Vibrio cholerae, the etiological agent of the diarrheal illness cholera, can kill an infected adult in 24 h. V.cholerae lives as an autochthonous microbe in estuaries, rivers and coastal waters. A better understanding of its metabolic pathways will assist the development of more effective treatments and will provide a deeper understanding of how this bacterium persists in natural aquatic habitats. Using the completed V.cholerae genome sequence and PathoLogic software, we created VchoCyc, a pathway-genome database that predicted 171 likely metabolic pathways in the bacterium. We report here experimental evidence supporting the computationally predicted pathways. The evidence comes from microarray gene expression studies of V.cholerae in the stools of three cholera patients [D. S. Merrell, S. M. Butler, F. Qadri, N. A. Dolganov, A. Alam, M. B. Cohen, S. B. Calderwood, G. K. Schoolnik and A. Camilli (2002) Nature, 417, 642-645.], from gene expression studies in minimal growth conditions and LB rich medium, and from clinical tests that identify V.cholerae. Expression data provide evidence supporting 92 (53%) of the 171 pathways. The clinical tests provide evidence supporting seven pathways, with six pathways supported by both methods. VchoCyc provides biologists with a useful tool for analyzing this organism's metabolic and genomic information, which could lead to potential insights into new anti-bacterial agents. VchoCyc is available in the BioCyc database collection (http://BioCyc.org).     

Comparative mycobactericidal efficacy of chemical disinfectants in suspension and carrier tests

The efficacy of nine disinfectants on Mycobacterium smegmatis was tested in the presence of sputum, using quantitative suspension and carrier tests. Glutaraldehyde, povidone iodine, and chlorhexidine gluconate produced at least a 6-log10 reduction in CFU in all tests. Four disinfectants (sodium dichloroisocyanurate, phenol, ethanol, and sodium hypochlorite) were not as effective in the carrier tests as in the suspension tests; this difference ranged from a 1- to a 5-log10 reduction in CFU. The efficacy of ethanol and sodium hypochlorite was further reduced (3- and 1-log10 reductions in CFU, respectively) in the presence of sputum. The quaternary ammonium compound and iodophor were ineffective in all tests. The findings of this study demonstrate the need for a quantitative carrier test such as the one presented here.     

Time-of-day effects on cognition in preadolescents: a trails study

Cognitive performance fluctuates during the day due to diurnal variations in alertness level. This study examined: (1) whether cognitive performance in school-aged children is affected by time-of-day; (2) which functional domains are particularly vulnerable to time-of-day effects; and (3) whether the effects are more pronounced for cognitively more demanding tasks or task conditions. Children, aged 10-12 yrs, were randomly assigned to a test session starting either at 08:30 (n?=?802), 10:00 (n?=?713), or 13:00?h (n?=?652). Speed and accuracy of information processing were evaluated by tasks that assess input-related cognitive processes (e.g., stimulus encoding), central cognitive processes (e.g., working memory, sustained attention), and output-related processes (e.g., response organization) using the Amsterdam Neuropsychological Tasks program. Time-of-day effects in children were identified in specific neurocognitive domains, such as visuospatial processing and working memory, but only under cognitively more demanding task conditions. Sustained attention showed a speed-accuracy tradeoff with increased slowness and lapses in the early morning, but with better feedback responsiveness and perceptual sensitivity than in the early afternoon. Furthermore, there was a significant interaction of time-on-task with time-of-day for tempo, with the afternoon group increasing in tempo with time-on-task, and the early-morning group first showing a slowing of tempo with time-on-task, followed at the end of the task by a speed increase towards the initial levels. To conclude, the authors found time-of-day effects in preadolescents, which were confined to cognitively more demanding tasks tapping input-related and central cognitive processes.     

硫普罗宁治疗慢性乙型肝炎的临床疗效对照研究

目的：评价硫普罗宁治疗慢性乙型肝炎的效果及安全性。方法：慢性乙型肝炎80例,随机分为两组。治疗组40例,以硫普罗宁0.2g加入5%葡萄糖溶液250ml中静滴,1次/日,连续治疗4周,对照组40例,以甘草酸二铵150mg加入5%葡萄糖溶液250ml中静滴,1次/日,连续治疗4周;同时分别监测肝功能指标：丙氨酸氨基转移酶（ALT）,天冬氨酸转移酶（AST）、总蛋白（TP）、总胆红素（TBi）、肝纤维化指标（HA、PCⅢ）及凝血酶原活动度（PTA）等,并进行比较分析。结果：硫普罗宁治疗组较对照组在肝功能复常方面显示良好的治疗效应,可使转氨酶及HA明显下降,两组显效率分别为50%（20/40）和25%（10/40）,总有效率为85%（34/40）和47.5%（19/40）,两组比较差异有显著性（p〈0.01）。结论：短期临床研究提示硫普罗宁治疗慢性乙型肝炎,可明显改善肝脏功能,有抗纤维化作用,且副作用少,疗效显著。     

金双歧治疗新生儿高胆红素血症的临床疗效研究

目的 探讨微生态制剂金双歧(双歧杆菌乳酸杆菌三联活菌片)对新生儿高胆红素血症的临床疗效,以找出能及早有效地纠正新生儿高胆红素血症,预防新生儿胆红素脑病发生的新方法.方法 通过随机抽样、收集青白江区人民医院2007年3月至2011年3月72例新生儿高胆红素血症患儿的临床资料并进行回顾性分析,将72例新生儿高胆红素血症患儿随机分为治疗组40例和对照组32例.对照组给予常规治疗,治疗组在常规治疗基础上,加用金双歧1片(0.5亿)/次,每天3次,温开水溶碎后喂服或经胃管注入,共7～10d.检测治疗前后两组血清胆红素水平、计算日平均经皮测胆红素下降值、平均住院时间和黄疸消退时间.结果 金双歧辅助治疗新生儿高胆红素血症,治疗后治疗组与对照组血清总胆红素水平分别为(58.21 +4.36) μmol/L和(64.16±5.29) μmol/L(P ＜0.01);治疗组和对照组日平均经皮测胆红素下降值、平均住院时间和黄疸退尽平均时间分别为( 10.35±2.46)、(7.68±1.35)μmol/L;( 6/54±2/59)、(9/05 +3/12)d; (6/38±1/38)、( 8/75±2/68)d;差异均有统计学意义(P＜0.01).结论 应用金双歧治疗新生儿高胆红素血症可迅速降低血胆红素水平,缩短治疗时间,预防胆红素脑病的发生疗效确切、安全,可作为治疗新生儿高胆红素血症的方法之一,值得临床应用推广.     

Comparative mycobactericidal efficacy of chemical disinfectants in suspension and carrier tests.

The efficacy of nine disinfectants on Mycobacterium smegmatis was tested in the presence of sputum, using quantitative suspension and carrier tests. Glutaraldehyde, povidone iodine, and chlorhexidine gluconate produced at least a 6-log10 reduction in CFU in all tests. Four disinfectants (sodium dichloroisocyanurate, phenol, ethanol, and sodium hypochlorite) were not as effective in the carrier tests as in the suspension tests; this difference ranged from a 1- to a 5-log10 reduction in CFU. The efficacy of ethanol and sodium hypochlorite was further reduced (3- and 1-log10 reductions in CFU, respectively) in the presence of sputum. The quaternary ammonium compound and iodophor were ineffective in all tests. The findings of this study demonstrate the need for a quantitative carrier test such as the one presented here.