다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Feature selection is an important problem for pattern classification systems. We study how to select good features according to the maximal statistical dependency criterion based on mutual information. Because of the difficulty in directly implementing the maximal dependency condition, we first derive an equivalent form, called minimal-redundancy-maximal-relevance criterion (mRMR), for first-order incremental feature selection. Then, we present a two-stage feature selection algorithm by combining mRMR and other more sophisticated feature selectors (e.g., wrappers). This allows us to select a compact set of superior features at very low cost. We perform extensive experimental comparison of our algorithm and other methods using three different classifiers (naive Bayes, support vector machine, and linear discriminate analysis) and four different data sets (handwritten digits, arrhythmia, NCI cancer cell lines, and lymphoma tissues). The results confirm that mRMR leads to promising improvement on feature selection and classification accuracy.

Feature selection based on mutual information criteria of max-dependency, max-relevance, and min-redundancy

The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combing the Earth for phytochemicals and “leads” which could be developed for treatment of infectious diseases. While 25 to 50% of current pharmaceuticals are derived from plants, none are used as antimicrobials. Traditional healers have long used plants to prevent or cure infectious conditions; Western medicine is trying to duplicate their successes. Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro to have antimicrobial properties. This review attempts to summarize the current status of botanical screening efforts, as well as in vivo studies of their effectiveness and toxicity. The structure and antimicrobial properties of phytochemicals are also addressed. Since many of these compounds are currently available as unregulated botanical preparations and their use by the public is increasing rapidly, clinicians need to consider the consequences of patients self-medicating with these preparations.

Plant Products as Antimicrobial Agents

Feature selection based on mutual information: criteria ofmax-dependency, max-relevance, and min-redundancy

Cellular Topoisomerase I Inhibition and Antiproliferative Activity

Candidate biomarker assessment for pharmacological response.

Currently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without treatment adherence concerns. Accordingly, it is important to continue to discover small molecules that have a novel mechanism of inhibition. In this work, HIV integrase inhibitors were selected by high-throughput screening. Chemical structure comparisons enabled the identification of stilbene disulfonic acids as a potential new chemotype. Biochemical characterization of the lead compound stilbenavir (NSC34931) and a few derivatives was performed. Stilbene disulfonic acid derivatives exhibit low to sub-micromolar antiviral activity, and they inhibit integrase through DNA-binding inhibition. They probably bind to the C-terminal domain of integrase, in the cavity normally occupied by the noncleaved strand of the viral DNA substrate. Because of this original mode of action compared to active site strand transfer inhibitors, they do not exhibit cross-resistance to the three main resistance pathways to integrase inhibitors (G140S-Q148H, N155H, and Y143R). Further structure-activity optimization should enable the development of more active and less toxic derivatives with potential clinical relevance.

https://www.mdpi.com/1420-3049/24/20/3675/pdf

Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening.

Interfacial inhibition is a general mode of inhibition for natural toxins and synthetic molecules to alter the dynamics of biological complexes. Interfacial inhibitors bind at the interface of two or more macromolecules while the multimeric complex undergoes conformational transition. The complex is therefore stabilized and locked in an intermediate conformational state. In this chapter, we describe the interfacial inhibition concept and how it was discovered from studies with DNA topoisomerase inhibitors.

Topoisomerases Inhibitors: A Paradigm for Interfacial Inhibition

Poly(ADP-ribose)polymerases (PARP) are DNA damage sensors and major repair factors for DNA single-strand breaks. Since the discovery of the synthetic lethality of PARP inhibitors in homologous recombination-deficient cells, the mechanism by which PARP inhibitors exert their cytotoxicity has been dominantly interpreted as an accumulation of unrepaired single-strand breaks resulting from catalytic PARP inhibition. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes (1). BMN 673 is the most potent PARP inhibitor to date in terms of cytotoxicity and PARP trapping potency (2). Nevertheless, the NCI60 data show that half of the 60 cell lines are tolerant to BMN 673. To elucidate the mechanisms of tolerance, we searched for genes with expression levels correlated to BMN 673 sensitivity, and found that Schlafen 11 (SLFN11) is one of the most positively correlated genes. Most cells without SLFN11 expression were tolerant to BMN 673. To examine the involvement of SLFN11 in BMN 673 sensitivity, we disrupted the SLFN11 gene in DU145 prostate cancer cells and EW8 Ewing9s sarcoma cells where SLFN11 expression levels and BMN 673 sensitivities are high. Knocking out SLFN11 in DU145 and EW8 did not affect their cell growth or cell cycle progression under normal conditions, but diminished their hypersensitivity to BMN 673 and another PARP inhibitor, olaparib. Cell cycle analyses revealed that SLFN11-proficient cells arrested at S phase while SLFN11 deficient cells were able to progress to G2 phase in the presence of BMN 673. Interestingly, arresting points at S phase in SLFN11 proficient cells were earlier when more PARP-DNA complexes were induced, suggesting that SLFN11 inhibits DNA replication under DNA damage. Differential kinetics of DNA repair and PARP-DNA complex formation were observed between SLFN11 proficient versus deficient cells. Our data suggest that the expression of SLFN11 may be a novel genomic biomarker for PARP inhibitor sensitivity. 1. Murai J, Huang S-yN, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Research. 2012;72:5588-99. 2. Murai J, Huang SN, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014; Submitted. Citation Format: Junko Murai, Rozenn Josse, James H. Doroshow, Yves Pommier. Schlafen 11 (SLFN11) is a critical determinant of cellular sensitivity to PARP inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1718. doi:10.1158/1538-7445.AM2014-1718

Yves Pommier

Papers

Cellular Topoisomerase I Inhibition and Antiproliferative Activity

Candidate biomarker assessment for pharmacological response.

Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening.

Topoisomerases Inhibitors: A Paradigm for Interfacial Inhibition

Abstract 1718: Schlafen 11 (SLFN11) is a critical determinant of cellular sensitivity to PARP inhibitors