Variance-based sensitivity analysis of biological uncertainties in carbon ion therapy

PurposeBiological models to estimate the relative biological effectiveness (RBE) or the equivalent dose in 2 Gy fractions (EQD2) are needed for treatment planning and plan evaluation in carbon ion therapy. We present a model-independent, Monte Carlo based sensitivity analysis (SA) approach to quantify the impact of different uncertainties on the biological models.Methods and materialsThe Monte Carlo based SA is used for the evaluation of variations in biological parameters. The key property of this SA is the high number of simulation runs, each with randomized input parameters, allowing for a statistical variance-based ranking of the input variations. The potential of this SA is shown in a simplified one-dimensional treatment plan optimization. Physical properties of carbon ion beams (e.g. fragmentation) are simulated using the Monte Carlo code FLUKA. To estimate biological effects of ion beams compared to X-rays, we use the Local Effect Model (LEM) in the framework of the linear-quadratic (LQ) model. Currently, only uncertainties in the output of the biological models are taken into account.Results/conclusionsThe presented SA is suitable for evaluation of the impact of variations in biological parameters. Major advantages are the possibility to access and display the sensitivity of the evaluated quantity on several parameter variations at the same time. Main challenges for later use in three-dimensional treatment plan evaluation are computational time and memory usage. The presented SA can be performed with any analytical or numerical function and hence be applied to any biological model used in carbon ion therapy.     

基于DPSEEA模型构建生物安全评价体系：以深圳市为例

由于生物安全内涵外延和基本要素的模糊性、评价指标及评价方法的多元性等因素的限制, 我国至今尚未形成全面有效的生物安全评价指标体系。为构建生物安全评价体系, 研判生物安全现状, 本文首先运用规范分析法剖析《生物安全法》中有关“生物安全”定义的特点及不足, 从国家安全角度认为生物安全是指国家有效防范和应对危险生物因子及相关因素的威胁, 维护和保障自身安全与利益的能力和状态。明晰了生物安全的外延, 即只有对国家安全利益、民众健康、生态环境保护产生威胁的生物风险, 才是生物安全所规制的对象。其次, 生物安全基本要素包括自然生物安全和社会经济生物安全。自然生物安全主要指民众健康和生态环境保护方面, 包括生物个体安全和生物多样性安全。社会经济生物安全的关注点在国家安全利益, 即社会稳定和国家经济利益, 包括生物技术安全、生物实验室安全。第三, 以生物安全基本要素为管理对象的尺度, 将国家安全利益、民众健康和生态环境保护作为评价主体, 以生物法治为理念, 运用模型构建法, 将定性指标和定量指标相结合, 基于驱动力‒压力‒状态‒接触‒影响‒行动模型(driving force-pressure-state-exposure-effect-action, DPSEEA)构建了一套具有生物法治特色的生物安全评价指标体系, 包括生物安全法律法规体系健全水平、生物安全所涉违法犯罪行为的打击力度、生物安全各部门机构协调机制的建立和完善程度、符合规定标准的生物实验室数量和百分比、生物安全人才数量及密度、对生物产业和基本卫生部门的官方援助及其他途径投资总额、疫苗覆盖的目标人群比例、生物安全的宣传教育普及率8项评价指标在内共32项生物安全评价指标。最后, 基于实地调研及数据统计分析, 以2019年和2020年深圳生物安全工作为例对评价体系进行验证。结果显示, 深圳生物安全工作在农业生物安全、动植物防疫、防范外来物种入侵方面成果显著; 但仍在法律法规体系、生物安全人才培养和资金投入、生物安全普及率方面存在不足。针对上述问题提出完善生物安全法律法规体系并注重法律协调衔接、“一个健康”实现多元协同生物治理、加强人才培养和资金投入、加强生物安全宣传教育等建议。     

Bis(tBuSATE) phosphotriester prodrugs of 8-azaguanosine and 6-methylpurine riboside; bis(pom) phosphotriester prodrugs of 2'-deoxy-4'-thioadenosine and its corresponding 9alpha anomer

As an extension of previous work with bis(POM) nucleotide prodrugs, we report the synthesis and biological evaluation in tumor cell culture of the bis(pivaloyloxymethyl) phosphotriester prodrug of slightly cytotoxic 2'-deoxy-4'-thioadenosine and its alpha-anomer. We have experienced need for an alternative phosphate masking group, particularly with purine nucleosides. Accordingly, we report synthesis and biological evaluation of the bis(tBuSA TE) phosphotriester prodrugs of 8-azaguanosine and 6-methylpurine riboside, nucleoside analogs with moderate to significant cytotoxicity. All four prodrugs were examined in tumor cell culture in parallel with the parent nucleosides. Synthetic routes and biological data are presented.     

New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central alpha 2-antagonistic activity as potential antidepressants

The synthesis and biological activity of a series of benzofuro[3,2-c]pyridines and a benzothieno[3,2-c]pyridine are described. These compounds exhibit high affinity for the alpha 2-adrenoceptor, with high selectivity versus the alpha 1-receptor. Compound 1 also shows potent in vivo central activity and has been selected for further biological and clinical evaluation.     

Carboxylic acid isosteres improve the activity of ring-fused 2-pyridones that inhibit pilus biogenesis in E. coli

Ring-fused 2-pyridones, termed pilicides, are small synthetic compounds that inhibit pilus assembly in uropathogenic Escherichia coli. Their biological activity is clearly dependent upon a carboxylic acid functionality. Here, we present the synthesis and biological evaluation of carboxylic acid isosteres, including, for example, tetrazoles, acyl sulfonamides, and hydroxamic acids of two lead 2-pyridones. Two independent biological evaluations show that acyl sulfonamides and tetrazoles significantly improve pilicide activity against uropathogenic E. coli.     

Synthesis and biological evaluation of cepharadiones A and B and related dioxoaporphines

Described herein is the first total synthesis and structural confirmation of cepharadione A, a naturally occurring DNA damaging agent. Also reported is the synthesis of cepharadione B, a closely related natural product, as well as the biological evaluation of both natural products. Finally, the preparation and biological evaluation of novel dioxoaporphine analogues is described.     

Ecological considerations for biological control of aphids in protected culture

Several braconid and aphelinid parasitoids, midges, lacewings, and ladybird beetles are used to control aphids in greenhouses. Here, I review three topics as ecological bases for the biological control of aphids in a protected culture: the preliminary evaluation of biological control agents, natural enemy release strategies, and the effects of intraguild predation (IGP) on biological control. A comparison of several parasitoid species was conducted to select agents for the biological control of aphids; the intrinsic rate of natural increase was a useful criterion in the preliminary evaluation. To compare predators as biological control agents, the aphid-killing rate must be considered as a critical criterion, rather than reproductive criteria. The banker plant system (open rearing system) is used as a release method for Aphidius colemani and other natural enemies of aphids. Continuous release of parasitoid adults, which is the important characteristic of this method, has a stabilizing effect on population fluctuation in the aphid–parasitoid system. Two species of natural enemies can be used to control aphids in greenhouses. When one parasitoid and one predator are used simultaneously in a greenhouse, IGP of the parasitoid by the predator can occur, but the effect of IGP is less important in greenhouses than in the field.     

Design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors

The design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors, which possess new templates instead of a cyclohexane ring, are described. The mode of interaction with the enzyme is discussed based on the structure-activity relationship (SAR) data obtained for the synthesized inhibitors. Furthermore, the roles of three pharmacophores, a catechol moiety, a nitrile moiety, and acidic moieties, are discussed using in silico docking studies. More detailed biological evaluations of selected compounds are also presented.     

Solution-phase combinatorial synthesis and evaluation of piperazine-2,5-dione derivatives

An efficient one-pot synthesis of a 61-membered combinatorial chemistry library of piperazine-2,5-diones was accomplished. Results of combinatorial synthesis, purification, analysis, and biological evaluation are described.     

bis(tBuSATE) PHOSPHOTRIESTER PRODRUGS OF 8-AZAGUANOSINE AND 6-METHYLPURINE RIBOSIDE; bis(POM) PHOSPHOTRIESTER PRODRUGS OF 2′-DEOXY-4′-THIOADENOSINE AND ITS CORRESPONDING 9α ANOMER

As an extension of previous work with bis(POM) nucleotide prodrugs, we report the synthesis and biological evaluation in tumor cell culture of the bis(pivaloyloxymethyl) phosphotriester prodrug of slightly cytotoxic 2′-deoxy-4′-thioadenosine and its α-anomer. We have experienced need for an alternative phosphate masking group, particularly with purine nucleosides. Accordingly, we report synthesis and biological evaluation of the bis(tBuSATE) phosphotriester prodrugs of 8-azaguanosine and 6-methylpurine riboside, nucleoside analogs with moderate to significant cytotoxicity. All four prodrugs were examined in tumor cell culture in parallel with the parent nucleosides. Synthetic routes and biological data are presented.     

1,4-Diazepane-2,5-diones as novel inhibitors of LFA-1

1,4-Diazepane-2,5-diones (2) are found to be a new class of potent LFA-1 inhibitors. The synthesis, structure, and biological evaluation of these 1,4-diazepine-2,5-diones and related derivatives are described.     

Synthesis and biological evaluation of novel small non-peptidic HIV-1 PIs: the benzothiophene ring as an effective moiety

Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC(50)=60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.     

Synthesis and evaluation of vancomycin and vancomycin aglycon analogues that bear modifications in the residue 3 asparagine

The synthesis and biological evaluation of a set of residue 3 analogues of vancomycin and its aglycon are described. These investigations follow from the promising biological activity of a protected and synthetically modified vancomycin aglycon analogue in which the asparagine side chain was modified to possess a nitrile, rather than a carboxamide. Although this modification typically was detrimental to antimicrobial activity, hydrophobic vancomycin aglycon analogues that lack a lipid anchor as well as the disaccharide are detailed that exhibit unusual potency against VanB, but not VanA, resistant bacteria.     

Synthesis of chiral phosphorus mustards derived from serine

The synthesis and biological evaluation of chiral, diastereomeric phosphorus mustards derived from natural and unnatural serine are reported herein.     

Synthesis, solution structure, and bioactivity of six new simplified analogues of the natural cyclodepsipeptide jaspamide

Recently, we described the synthesis and the biological evaluation of three modified analogues of jaspamide (1), a natural cyclodepsipeptide possessing a potent antitumor activity as a consequence of its ability to interfere with actin cytoskeleton. To obtain additional information on the potential pharmacophoric core of the target molecule, which is of fundamental importance to discover new and more effective anticancer products, we decided to explore the biological effects of further structural modifications carried out on the parent molecule. The synthesis and the chemical characterization of six jaspamide analogues (2-7) are reported and their conformational and biological properties are described.     

Preclinical and pharmacology and toxicology of hematopoietic growth factors

Initial evaluation of the safety of biological products, whether manufactured by biotechnology or not, is dictated by the extent of knowledge of the biological effects in vitro, in animals, and in man at the proposed dose and duration of administration. The quantity of useful information that will be gained from an animal study is considered for each product on a case-by-case basis. This requires consideration of the availability of a relevant species. Relevance is determined by presence and relative affinity and distribution of receptors for the biological product, relative potency in induction of biological activity related to the putative mechanism of action and pharmacokinetic considerations. The impurities and immunogenic potential of the product are also considered in designing the preclinical studies. After evaluating all these factors, the residual lack of knowledge is FDA's basis for recommending specific preclinical testing. The considerations inherent in the preclinical evaluation of factors acting primarily on hematopoietic cells, erythropoietin (EPO), interleukins (IL's) and colony stimulating factors (CSF) (1) will be discussed using case examples.     

New orally active PDE4 inhibitors with therapeutic potential

The design, synthesis, and biological evaluation of a series of pyrazolopyridines was carried out. Structural optimization of the aniline moiety of 4-anilinopyrazolopyridine derivative 3a, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was performed successfully. The details of the discovery of new orally active PDE4 inhibitors, which are expected to show therapeutic potential, are presented and their structure-activity relationships are discussed. Pharmacological evaluation and pharmacokinetic data for representative compounds are also presented.     

N-substituted-3-arylpyrrolidines: potent and selective ligands at serotonin 1A receptor.

3-Arylpyrrolidines are synthesized through the coupling of N-benzyl-3-(methanesulfonyloxy)pyrrolidine with diarylcuprates. Pharmacological evaluation of a series of N-substituted-3-arylpyrrolidines toward several neurotransmitter receptors indicated that some of them are good ligands for serotonin 1A receptor. Particularly, N-[(N-saccharino)butyl]pyrrolidines were found to be potent and selective ligands. A preliminary biological evaluation for several selected compounds indicated that they are potentially effective antianxiety and antidepressant agents.     

Quantitative estimation combined chemical and radioactive exposure on biological objects

We summarized the researches to estimate the methods of combined (chemical and/or radioactive nature) factor action on biological objects. The data examined indicate that methods commonly used need a revision and adaptation in case of analyzing data on biological effects in natural plant and animal populations. Basic principles of evaluation of man-caused factor contribution into variation level observed in natural population are discussed.