Le test urinaire PCA3 : quelles perspectives ?

Since its introduction 10 years ago, the urinary PCA3 test was evaluated in several studies that allowed demonstration of its diagnostic value when predicting prostate biopsy outcome. Its good specificity, notably when compared to seric PSA, offers to the urologist the opportunity to better evaluate whether prostate biopsies are warranted, especially in patients with at least one set of previous negative biopsies. Several points remain to be determined such as its true influence on prostate decision making in clinical practice and the resulting medico-economic benefit. The place of the urinary PCA3 test among other developing prostate cancer biomarkers, notably PHI index and urinary TMPRSS2:ERG fusions, has also to be defined.     

Association between misalignment of circadian rhythm and obesity in Korean men: Sixth Korea National Health and Nutrition Examination Survey

ABSTRACT

Background: The disruption of circadian rhythm has been found to associate with obesity in vivo and in vitro. Sleep duration, eating habits, total feeding time, and nightshift work can also affect circadian rhythms. This study investigated the association between misalignment of circadian rhythm and obesity in Korean men, using a cross-sectional database.

Methods: This study used data from the Korean National Health and Nutrition Examination Survey (KNHANES), whose study population was 3,658 men aged 18 to 60 years. General and abdominal obesity was defined as a body mass index (BMI) ≥ 25 kg/m² and waist circumference ≥ 90 cm, respectively. Circadian rhythm factors were determined with a self-report questionnaire and included breakfast frequency, sleep duration, and work time. Frequency of breakfast was divided into regular breakfast (five to seven times a week) and irregular breakfast (less than five times a week). Sleep duration was divided into less than 7 hours, 7–9 hours, and over 9 hours. Working time was defined as day/evening, night shift, and other type. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for general and abdominal obesity were calculated using multivariable logistic regression according to the number of factors that disturb the circadian rhythm.

Results: Participants with 1 (aOR 1.34, 95% Cl 1.10–1.61) and ≥2 (aOR 1.62, 95% Cl 1.29–2.05) factors disturbing circadian rhythms were associated with elevated risk for general obesity. Similarly, those with 1 (aOR 1.33, 95% Cl 1.09–1.63) and ≥2 (aOR 1.70, 95% Cl 1.32–2.20) factors had elevated risk for abdominal obesity.

Conclusions: Factors disturbing the circadian rhythm were associated with general and abdominal obesity. Additional studies are needed, and associations with metabolic diseases should be investigated.     

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor–water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.     

DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.     

Difference of two dependent sensitivities and specificities: Comparison of various approaches

In diagnostic studies, a new diagnostic test is often compared with a standard test and both tests are applied on the same patients, called paired design. The true disease state is in general given by the so‐called gold standard (most reliable method for classification), which has to be known for all patients. The benefit of the new diagnostic test can be evaluated by sensitivity and specificity, which are in fact proportions. This means, for the comparison of two diagnostic tests, confidence intervals for the difference of the dependent estimated sensitivities and specificities are calculated. In the literature, many comparisons of different approaches can be found, but none explicitly for diagnostic studies. For this reason we compare 13 approaches for a set of scenarios that represent data of diagnostic studies (e.g., with sensitivity and specificity ?0.8). With simulation studies, we show that the nonparametric interval with normal approximation can be recommended for the difference of two dependent sensitivities or specificities without restriction, the Wald interval with the limitation of slightly anti‐conservative results for small sample sizes, and the nonparametric intervals with t‐approximation, and the Tango interval with the limitation of conservative results for high correlations.     

大型煤电基地开发生态累积效应及定量分析方法研究

大型煤电基地(CEBs)是我国煤基能源和材料集中开发区域和国家能源战略安全重要支撑，合理评价CEBs开发生态影响是CEBs可持续协调开发、科学管理中的难点问题。研究将CEBs开发视为系统工程，与自然生态系统(NES)相关联，深入研究大型煤电基地生态系统(CEBES)的驱动行为、内在结构及主要关系、生态影响途径、生态累积过程和生态累积效应及阈值分析方法。基于CEBs空间和功能定位提出CEBs的概念、内涵和特点，融合构建的CEBES涵盖到自然资源、能源开发行为(煤、电等)、其他人类活动(农、牧、城)和大气、水、土壤及生物域；研究表明CEBES的生态累积状态受三种行为驱动和影响(自然行为、能源开发行为和其他人类活动),通过融合、传导和辐射耦合作用，表现为生态要素损伤、系统结构变化和系统状态失衡三级状态，生态累积具有影响多态性、空间多尺度和过程渐变性特点；明确了生态累积过程、累积效应和阈值及其相互关系，引入反映生态影响累积程度的生态损伤系数，提出四类生态阈值(生态要素、内部结构、系统状态和行为调控);基于系统性和实用性筛选反映生态累积相对状态的60项指标，构建具有“三力”驱动、分区要素耦合和系...     

1991-2017年叶尔羌河流域冰川景观格局时空演变

冰川景观变化是全球环境和气候变化的共同"指示器"。随着全球气候变化加剧，干旱和半干旱地区的冰川景观将进一步变化。科学评估冰川景观格局时空演变特征，为应对冰川景观变化及其影响提供科学参考。基于1991-2017年Landsat TM/ETM+/OLI遥感影像，采用监督分类方法获取叶尔羌河流域冰川景观时空格局及变化数据，利用景观格局指数、质心迁移模型、分形维数等方法分析近26年叶尔羌河流域冰川景观格局时空演变特征。结果表明：（1）1991-2017年叶尔羌河流域冰川斑块面积呈消减趋势，但有所减缓，共减少799.50 km²（-13.09%）。冰川斑块面积消减主要集中在海拔5400-5800 m之间，相较之下，海拔4400 m以下的区域冰川斑块面积消减率最高，达63.68%；不同坡度冰川景观消减率存在差异，陡坡冰川斑块面积消减率最高（15.98%），急陡坡消减率最低（2.87%）；阴阳两坡冰川景观均呈消减趋势，阳坡冰川斑块面积消减速率显著高于阴坡。（2）近26年来，叶尔羌河流域冰川斑块数量、最大斑块指数均减小，而平均形状指数、平均周长面积比、分裂指数均增加，表明冰川景观不断消减，破碎化程度增加。（3）研究期间，叶尔羌河流域冰川景观质心发生迁移，整体呈现东北偏移趋势。（4）通过分形理论对叶尔羌河流域冰川景观空间结构特征进行分析表明，该流域冰川景观消减率略微降低，但仍然处于持续消融状态。     

基于可持续发展目标的资源型城市可持续发展评价技术及应用——以湖南省郴州市为例

资源型城市作为我国重要战略保障基地，面临较为突出的不可持续问题，定量化开展可持续发展水平监测评估是推动其绿色转型发展、激活再生动力的重要途径。基于联合国可持续发展目标体系(SDGs),结合行星边界理论，从资源型城市可持续发展特征出发，建立了由2个系统、4个支柱、12个领域和48项指标组成的资源型城市可持续发展评价指标体系。借鉴全球SDGs监测评估实践经验，考虑指标属性，综合确定各指标的阈值，并采用改进的离差标准化、障碍度分析及耦合协调度分析等方法建立综合评价技术体系。以拥有“有色金属之乡”称号的郴州市国家可持续发展议程创新示范区为评价对象，对其2005—2019年连续15年的可持续发展水平进行实证分析。结果表明：(1)郴州市可持续发展水平整体上呈现稳步上升趋势，得分由0.398上升到0.610。(2)4个支柱中，自然资源支柱的得分进步幅度最大，高达71.3%,说明郴州市已经逐步提高对资源利用效率的重视，同时意识到挖掘替代资源的重要性，资源保障与利用能力不断提升；而发展动力支柱得分始终处于较弱或中等水平，已成为制约郴州市可持续发展和绿色转型的主要因素，其中科技创新驱动是该支柱发展关键障碍...     

Uncertainty associated with river health assessment in a varying environment: The case of a predictive fish-based index in France

Sensitive biological measures of river ecosystem quality are needed to assess, maintain or restore ecological conditions of water bodies. Since our understanding of these complex systems is imperfect, decision-making requires recognizing uncertainty. In this study, a new predictive multi-metric index based on fish functional traits was developed to assess French rivers. Information on fish assemblage structure, local environment and human-induced disturbances of 1654 French river sites was compiled. A Bayesian framework was used to predict theoretical metric values in absence of human pressure and to estimate the uncertainty associated with these predictions. The uncertainty associated with the index score gives the confidence associated with the evaluation of site ecological conditions.Among the 228 potential metrics tested, only 11 were retained for the index computation. The final index is independent from natural variability and sensitive to human-induced disturbances. In particular, it is affected by the accumulation of different degradations and specific degradations including hydrological perturbations. Predictive uncertainty is globally lower for IPR+ than for underlying metrics.This new methodology seems appropriate to develop bio-indication tools accounting for uncertainty related to reference condition definition and could be extended to other biological groups and areas. Our results support the use of multi-metric indexes to assess rivers and strengthen the idea that examination of uncertainty could contribute greatly to the improvement of the assessment power of bio-indicators.     

Three-dimensional model on thermal response of skin subject to laser heating

A three-dimensional (3D) multilayer model based on the skin physical structure is developed to investigate the transient thermal response of human skin subject to laser heating. The temperature distribution of the skin is modeled by the bioheat transfer equation, and the influence of laser heating is expressed as a source term where the strength of the source is a product of a Gaussian shaped incident irradiance, an exponentially shaped axial attenuation, and a time function. The water evaporation and diffusion is included in the model by adding two terms regarding the heat loss due to the evaporation and diffusion, where the rate of water evaporation is determined based on the theory of laminar boundary layer. Cryogen spray cooling (CSC) in laser therapy is studied, as well as its effect on the skin thermal response. The time-dependent equation is discretized using the finite difference method with the Crank–Nicholson scheme and the stability of the numerical method is analyzed. The large sparse linear system resulted from discretizing the governing partial differential equation is solved by a GMRES solver and the expected simulation results are obtained.