贝叶斯方法在肿瘤新药早期临床研发中的发展与应用

贝叶斯学派是通过综合未知参数的先验信息与样本信息,依据贝叶斯定理,求出后验分布,根据后验分布推断未知参数的统计方法。相比频率派,贝叶斯学派更加灵活、高效。肿瘤新药是全球研发的热点,但同时也存在高失败率的风险。在肿瘤新药早期研发中,高效寻找最佳剂量、优势人群、估计疗效和成功率是医药企业和研究者的共同需求。近年来,肿瘤新药研发呈现化学药物生物制品转变、单药治疗向联合治疗转变、传统设计向创新设计转变等新趋势;伴随出现的各种挑战,包括无法找到最高耐受剂量、延迟毒性、延迟反应、剂量疗效关系变化、剂量组合众多等。基于贝叶斯方法,恰当借用先验信息,能有效帮助企业在肿瘤早期研发中,实现从传统研发模式(高投入、长周期、低效率)向现代研发模式(低投入、短周期、高效率)的转变。研究还进行了贝叶斯方法在肿瘤新药早期研发的进展阐述,与频率派的理念、应用场景的比较分析,可为医药研发的所有从业人员提供宏观、系统的参考。

Biodiversity of Duckweeds in Eastern China and Their Potential for Bioremediation of Municipal and Industrial Wastewater

Duckweed is a group of aquatic plants with the potential of wastewater remediation and fast accumulation of biomass. The accumulated biomass, rich in cellulose, starch and protein, can be used for biofuel, bio-fertilizer, animal feed and human food. Characterization of natural biodiversity of duckweed species is essential for the germplasm preservation and various practical applications. We have collected samples of duckweed in eastern China and characterized species biodiversity by genotyping, using chloroplast (atpF-atpH and psbK-psbI spacers). Spirodela polyrhiza was revealed as a clear dominant duckweed species in all locations of the area. Other duckweed species were identified as Landoltia punctata, Lemna aequinoctialis and Lemna turionifera. Selected isolates of these four species were used in the experiments to estimate their potential in removing nitrogen and phosphorus nutrients from municipal and industrial wastewater sampled at the local sewage plants. Duckweed was able to reduce the concentration of nitrogen up to 98% and phosphorus up to 96%. The presented data demonstrates high efficiency of the local duckweed isolates for bioremediation of different types of wastewater and the great potential of duckweed for wastewater treatment when incorporated into the purification chain.

Optically-excited simultaneous photoacoustic and ultrasound imaging based on aflexible gold-PDMS film

We constructed a flexible gold-polydimethylsiloxane(gold-PDMS)nanocomposites film with controllable thickness and light transmittance,to realize optically-excited simultaneous photo-acoustic(PA)and ultrasound(US)imaging under a single laser pulse irradiation.Benefiting from the excellent thermoelastic properties,the gold-PDMS film absorbs part of the incident laser energy and produces a high-intensity US,which is used to realize US imaging.Meanwhile,the partly transmitted light is used to excite samples for PA imaging.By controlling the thickness of the gold-PDMS,we can control the center frequency in the US imaging.We experimentally analyzed the frequency of the produced US signal by the gold-PDMSfilm and compared it with the finite element analysis(FEA)method,where the experiments agree with the FEA results.This method is demonstrated by the experiments on phantoms and a mouse model.Our work provides a cost-effective methodology for simultaneous PA and US imaging.

Bus frequency optimization in a large-scale multi-modal transportation system:integrating 3D-MFD and dynamic traffic assignment

A properly designed public transport system is expected to improve traffic efficiency.A high-frequency bus service would decrease the waiting time for passengers,but the interaction between buses and cars might result in more serious congestion.On the other hand,a low-frequency bus service would increase the waiting time for passengers and would not reduce the use of private cars.It is important to strike a balance between high and low frequencies in order to minimize the total delays for all road users.It is critical to formulate the impacts of bus frequency on congestion dynamics and mode choices.However,as far as the authors know,most proposed bus frequency optimization formulations are based on static demand and the Bureau of Public Roads function,and do not properly consider the congestion dynamics and their impacts on mode choices.To fill this gap,this paper proposes a bi-level optimization model.A three-dimensional Macroscopic Fundamental Diagram based modeling approach is developed to capture the bi-modal congestion dynamics.A variational inequality model for the user equilibrium in mode choices is presented and solved using a double projection algorithm.A surrogate model-based algorithm is used to solve the bi-level programming problem.

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Angiogenesis,a process by which the preexisting blood vasculature gives rise to new capillary vessels,is associated with a variety of physiologic and pathologic conditions.However,the molecular mechanism underlying this important process remains poorly understood.Here we show that histone deacetylase 6(HDAC6),a microtubule-associated enzyme critical for cell motility,contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells.Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice.The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting.Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization.In addition,microtubule end binding protein 1(EB1)is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures.These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.

Potassium 2-(l-hydroxypentyl)-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice

A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate(PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer's disease(AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal(i.p.) injection of lipopolysaccharide(LPS). Levels of i NOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1(HO-1) in the cortex and hippocampus. PHPB reduced the levels of i NOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.

Ru(bpy)_(3)^(2+)-sensitized{001}facets LiCoO_(2) nanosheets catalyzed CO_(2) reduction reaction with 100% carbonaceous products

Photosensitized heterogeneous CO_(2) reduction(PHCR)has emerged as a promising means to convert CO_(2) into valuable chemicals,however,challenged by the relatively low carbonaceous product selectivity caused by the competing hydrogen evolution reaction(HER).Here,we report a PHCR system that couples Ru(bpy)32+photosensitizer with{001}faceted LiCoO_(2) nanosheets photocatalyst to simultaneously yield 21.2 and 722μmol·g^(-1)·h^(-1) of CO,and 4.42 and 108μmol·g^(-1)·h^(-1) of CH4 under the visible light and the simulated sunlight irradiations,respectively,with completely suppressed HER.The experimental and theoretical studies reveal that the favored CO_(2) adsorption on the exposed Li sites on{001}faceted LiCoO_(2) surface is responsible for the completely suppressed HER.

Collagen fiber anisotropy characterization by polarized photoacoustic imaging for just-in-time quantitative evaluation of burn severity

Just-in-time burn severity assessment plays a vital role in burn treatment and care.However,it is still difficult to quantitatively and promptly evaluate burn severity by existing medical imaging methods via initial burn depth measurement since burn wounds are usually dynamically developed.As an elastic skeleton of skin,the degree of conformational changes of collagen fibers caused by overheating can reflect the burn severity in a timelier manner.Herein,the polarized photoacoustic technique(PPAT)for just-in-time quantitative evaluation of burn severity via collagen fiber anisotropy assessment is proposed.First,phantom experiments demonstrate the ability of PPAT for deep imaging in a transport mean free path and accurately quantify changes in microstructural order by thermal damage.Then,the Pearson correlation coefficient of the PPAT in assessing burn severity is shown to be up to 0.95,validated by burn skin samples.The PPAT provides a just-in-time quantitative strategy for burn severity evaluation.

Microbulbifer sp.SH-1依赖褐藻胶裂解酶AlgSH6、AlgSH7和AlgSH17协同增效降解褐藻

褐藻是多糖、多酚、萜类等天然活性化合物的重要来源.然而,如何高效提取藻体内的活性物质是褐藻资源高值化利用的瓶颈问题.本文报道了一株高效降解褐藻的海洋细菌Microbulbifer sp.SH-1.该菌株在36 h内对海带、马尾藻、泡叶藻等褐藻的降解率达76.21%~96.31%.全基因组测序及基因注释结果发现, Microbulbifer sp.SH-1的基因组大小为4.68 Mbp,共编码3788个基因,包含3个对褐藻降解起关键作用的褐藻胶裂解酶基因algsh6、algsh7和algsh17.异源表达结果显示,重组酶AlgSH6、AlgSH7和AlgSH17对褐藻胶的降解活性分别为1577.29、15608.53和1709.18 U/mg.分子对接、薄层色谱(thin layer chromatography, TLC)及电喷雾质谱(electrospray ionization mass spectrometry, ESI-MS)分析表明, AlgSH7为内切型褐藻胶裂解酶,降解产物为聚合度(degree of polymerization, DP) 2~5的不饱和寡糖;AlgSH6与AlgSH17兼具内切活性和外切活性,二者单一降解产物均包含褐藻胶单糖及DP 2~5的寡糖.值得注意的是, AlgSH6与AlgSH17酶组合能够完全降解褐藻胶为单糖.此外, 3种酶两两组合的酶活性比单酶活性提高了20.51%~61.55%,三酶组合的活性提高了136.41%.以上结果表明,菌株Microbulbifer sp.SH-1通过褐藻胶裂解酶AlgSH6、AlgSH7及AlgSH17共同作用实现褐藻的高效降解,这为褐藻资源的开发利用提供了科学依据.

Design and experiment of seed furrow cleaning device based on throwing and sliding for no-till maize seeding

In order to solve the serious problems of seeds are covered by residual film and overhead by straw during no-till seeding,a seed furrow cleaning device for no-till maize seeding was developed,which adopted a collaborative cleaning method of rotating spring teeth and curved sliding shovel.The movement process and motion trajectory of throwing residual film and straw were constructed.The maximum distance of throwing to one side in horizontal and maximum height in vertical were obtained.The motion trajectory of adjacent spring teeth was analyzed by Matlab,the motion trajectories of adjacent spring teeth at different speeds of 120 r/min,150 r/min and 180 r/min were achieved,the theoretical analysis results showed that the area of omitted area decreased with the increase of rotation speed.Based on theoretical and simulation analysis of critical parameters,the forward speed of machine,rotation speed of spring teeth,and dip angle between spring teeth and rotary disc were selected as the influencing factor.Straw cleaning rate(SCR)and residual film cleaning rate(RFCR)were selected as the response values for three factors and three levels of orthogonal experiment design.The optimal combination of the selected parameters was obtained,and the field test verification was also conducted.The results showed that the rotation speed of spring teeth,forward speed and dip angle of spring teeth significantly affect SCR and RFCR were in decreasing order.The field test results indicated that when forward speed was 6 km/h,rotation speed of spring teeth was 180 r/min and dip angle of spring teeth was 40°,SCR and RFCR were 88.27%and 84.31%,respectively.This study provides a reference for the development of no-till seeder in Xinjiang and the northwestern regions of China.

Operando reconstruction-induced CO_(2)reduction activity and selectivity for cobalt-based photocatalysis

The oxygen atom coordination inducing the structure reconstruction of the catalytic site is identified and recognized ambiguously,which is related to accurately declare the mechanism in a dynamic catalytic process.Herein,we demonstrated that the reconstructed catalytic sites would lead to a remarkable performance for photocatalytic CO_(2)reduction.At the initial 4-cycles testing,the in-situ formation of CoOx active sites on the Co(CoP)surface performed an increasing transient activity and selectivity toward CO evolution.The formation of reconstructive Co-O bond and the appearance of intermediate specie CO were simultaneously observed by the pre-operando Raman,revealing the dynamic relationship between catalytic site structure and the photocatalytic properties.Moreover,density functional theory calculations showed that the electronic structure of the reconstructive surface sites could modulate the ability of CO_(2)adsorption and CO desorption.The reduced barrier energy for the rate-determining step finally improved the activity and selectivity of CO_(2)reduction.

Rare tumors: a blue ocean of investigation

Advances in novel drugs,therapies,and genetic techniques have revolutionized the diagnosis and treatment of cancers,substantially improving cancer patients’prognosis.Although rare tumors account for a non-negligible number,the practice of precision medicine and development of novel therapies are largely hampered by many obstacles.Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping.Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines,insufficient biomarkers for prognosis/efficacy,and inability to identify potential novel therapies in clinical trials.Herein,by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas,we proposed a definition of rare tumor in China,including 515 tumor types with incidences of less than 2.5/100000 per year.We also summarized the current diagnosis process,treatment recommendations,and global developmental progress of targeted drugs and immunotherapy agents on the status quo.Lastly,we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN.With this informative report,we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.