Therapeutic Targeting of DNA Damage Response in Cancer

DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.     

Application of ATR-FTIR for a rapid and simultaneous determination of sugars and organic acids in apricot fruit

A simple, fast and accurate Fourier transform mid-infrared spectroscopy method was developed for simultaneously determining sugar and organic acid contents in apricot fruit slurries using the attenuated total reflectance. The potential of this method coupled with chemometric techniques based on partial least squares was assessed by comparison with currently used enzymatic determination of sucrose, glucose, fructose, malic acid and citric acid. Fruits of eight contrasted cultivars harvested at different ripening stages were used in this study and randomly divided in a calibration set (505 apricots) and in a validation set (252 apricots). The most suitable region was found in the range between 1500 and 900 cm⁻¹. Good prediction performances were obtained (R² ? 0.74 and RMSEP ? 18%). Results concerning the prediction of other quality traits such as firmness, skin colour, ethylene production, soluble solids content and titratable acidity were discussed.     

硅橡胶泡沫伽马辐照后结构和元素分布研究

在密闭的氮气气氛下,用伽马射线辐照聚二甲基硅橡胶泡沫,采用全反射红外光谱(ATR)和X射线光电子能谱(XPS)对辐照后的化学结构和元素含量变化进行了表征.结果表明:化学结构单元Si-CH3最容易受到伽马射线的影响,在低的辐照剂量下表面Si-CH3成分随着辐照剂量增加而减小;高剂量下材料的元素分布发生了变化,近表面C元素含量要比泡沫体中部的C元素含量高.因此,在密闭环境下辐照老化后的硅橡胶泡沫的表面性能和体内性能存在差异.     

Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis

DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)—triggered by radiation-induced double strand breaks—is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO₂-enrichment and nano-liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells.     

Orthogonal ligation to spherical polymeric microparticles: Modular approaches for surface tailoring

Modular ligation strategies for the functionalization of polymeric microspheres provide new perspectives for their applications in material science. In the current trend article we highlight variable synthetic procedures for generating functional microspheres via orthogonal modular conjugation chemistries. An overview of the different surface chemistries available is provided, followed by surface-sensitive characterization techniques relevant for the microparticles. Finally, we explore future trends in modular orthogonal modification approaches on microparticles and provide an outlook on the perspectives that the field of surface-modification of polymeric microparticles holds.     

Linking Simultaneous In Situ WAXS/SAXS/Raman with Raman/ATR/UV–vis Spectroscopy: Comprehensive Insight into the Synthesis of Molybdate Catalyst Precursors

A new setup is presented which enables simultaneous wide- and small-angle X-ray scattering (WAXS/SAXS) and Raman spectroscopic experiments during the synthesis of Mo-based mixed oxide catalyst precursors at the μ-spot beamline at the Berliner Elektronenspeicherring-Gesellschaft für Synchrotronstrahlung (BESSY). Furthermore, we report about the separate monitoring of the same reactions under comparable conditions by simultaneous combined ATR/UV–vis/Raman spectroscopic measurements. For testing the performance of both experimental setups two syntheses were described comprising the precipitation of metal molybdates by mixing solutions of metal nitrates and ammonium heptamolybdate. Additionally, the effect of H₃PO₄ admixture on precipitation was investigated. The combined evaluation of spectroscopic and WAXS/SAXS data allows the discrimination between different molybdate species appearing in solution and precipitate. Furthermore, these molybdate species could be assigned to separate phases of different crystallinity.     

测量机器人视场内多目标问题的研究

利用Leica TCA1800对测量机器人视场内出现多目标的问题进行了实验研究,其结论有助于在工程监测时,作为选择监测站的位置和布设监测点的参考,以便有效地避免出错信息.同时给出了在编写自动监测程序时的处理方法,可以使得程序能够顺利运行并在监测过程中找到正确的观测点.     

2D HRR Radar Data Modeling and Processing

High Range Resolution (HRR) -based Automatic Target Recognition (ATR) has attracted increasing attention due to a number of potential advantages over alternative radar techniques in moving target identification. Most current HRR-based ATR studies have been conducted using 1D HRR signatures. However, these 1D HRR signatures are generally plagued by scintillation effects, and thus demonstrate highly irregular behavior that dramatically degrades the performance and robustness of algorithms based on these signatures. In order to circumvent this difficulty, an alternative HRR radar data representation and processing technique is presented in this paper. This technique models and extracts the target characteristics directly, based on the 2D HRR raw data. In this paper, we first derive a general, but complex HRR radar model, and then simplify this model by instantiating a set of real-world radar and target parameters for the model. This simplification process produces two HRR radar models with different degrees of simplicity. After establishing this set of models, the typical HRR data processes, such as feature extraction and clutter suppression, are reduced to one problem, which is model-parameter estimation. Based upon the most simplified HRR model we proposed, we devise two model- parameter estimation algorithms. One is a scatterer extraction algorithm based on available 1D Parameter Estimation (1DPE), while the other is based on 2D discrete Fourier Transform (2DFT). In order to examine the performance of these two algorithms a set of simulations are conducted. The experimental results are presented, and the performance comparison between 1DPE and 2DFT is presented.     

Surface modification of polyacrylonitrile staple fibers via alkaline hydrolysis for superabsorbent applications

The alkaline hydrolysis of polyacrylonitrile staple fibers was investigated for evaluation as superabsorbent materials. Studies were performed to analyze the hydrolysis of fibers and the quantification of the developed functional groups, such as carboxyl and amide groups as well as changes in the nitrile content by means of Micro‐ATR. Dyeing of the samples with methylene blue was carried out to monitor the carboxyl groups formed during the hydrolysis. A gradual decrease in the nitrile groups and built up of the carboxyl and the amide groups was observed during the hydrolysis. Microscopic investigation carried out to investigate the surface structure of hydrolyzed fibers. Hydrolysis led to surface nonhomogeneity and erosion that was dependent on the hydrolysis conditions. The fibers showed good water retention behavior, making them superabsorbent materials. The dyeing showed more intense coloration in the surface region of the modified fibers. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 91: 3127–3133, 2004