The Molecular Mechanisms of Actions,Effects, and Clinical Implications of PARP Inhibitors in Epithelial Ovarian Cancers: A Systematic Review

Ovarian cancer is the most lethal gynecologic malignancy in the United States. Some patients affected by ovarian cancers often present genome instability with one or more of the defects in DNA repair pathways, particularly in homologous recombination (HR), which is strictly linked to mutations in breast cancer susceptibility gene 1 (BRCA 1) or breast cancer susceptibility gene 2 (BRCA 2). The treatment of ovarian cancer remains a challenge, and the majority of patients with advanced-stage ovarian cancers experience relapse and require additional treatment despite initial therapy, including optimal cytoreductive surgery (CRS) and platinum-based chemotherapy. Targeted therapy at DNA repair genes has become a unique strategy to combat homologous recombination-deficient (HRD) cancers in recent years. Poly (ADP-ribose) polymerase (PARP), a family of proteins, plays an important role in DNA damage repair, genome stability, and apoptosis of cancer cells, especially in HRD cancers. PARP inhibitors (PARPi) have been reported to be highly effective and low-toxicity drugs that will tremendously benefit patients with HRD (i.e., BRCA 1/2 mutated) epithelial ovarian cancer (EOC) by blocking the DNA repair pathways and inducing apoptosis of cancer cells. PARP inhibitors compete with NAD⁺ at the catalytic domain (CAT) of PARP to block PARP catalytic activity and the formation of PAR polymers. These effects compromise the cellular ability to overcome DNA SSB damage. The process of HR, an essential error-free pathway to repair DNA DSBs during cell replication, will be blocked in the condition of BRCA 1/2 mutations. The PARP-associated HR pathway can also be partially interrupted by using PARP inhibitors. Grossly, PARP inhibitors have demonstrated some therapeutic benefits in many randomized phase II and III trials when combined with the standard CRS for advanced EOCs. However, similar to other chemotherapy agents, PARP inhibitors have different clinical indications and toxicity profiles and also face drug resistance, which has become a major challenge. In high-grade epithelial ovarian cancers, the cancer cells under hypoxia- or drug-induced stress have the capacity to become polyploidy giant cancer cells (PGCCs), which can survive the attack of chemotherapeutic agents and start endoreplication. These stem-like, self-renewing PGCCs generate mutations to alter the expression/function of kinases, p53, and stem cell markers, and diploid daughter cells can exhibit drug resistance and facilitate tumor growth and metastasis. In this review, we discuss the underlying molecular mechanisms of PARP inhibitors and the results from the clinical studies that investigated the effects of the FDA-approved PARP inhibitors olaparib, rucaparib, and niraparib. We also review the current research progress on PARP inhibitors, their safety, and their combined usage with antiangiogenic agents. Nevertheless, many unknown aspects of PARP inhibitors, including detailed mechanisms of actions, along with the effectiveness and safety of the treatment of EOCs, warrant further investigation.     

VSculpt : a distributed virtual sculpting environment for collaborative design

A collaborative virtual sculpting system supports a team of geographically separated designers/engineers connected by networks to participate in designing three-dimensional (3D) virtual engineering tools or sculptures. It encourages international collaboration at a minimal cost. However, in order for the system to be useful, two factors need to be addressed: intuitiveness and real-time interaction. Although a lot of effort has been put into developing virtual sculpting environments, only limited work addresses collaborative virtual sculpting. This is because in order to support real-time collaborative virtual sculpting, many challenging issues need to be addressed. We propose a collaborative virtual sculpting framework, called VSculpt. Through adapting some techniques we developed earlier and integrating them with some techniques developed here, the proposed framework provides a real-time intuitive environment for collaborative design. In particular, it addresses issues on efficient rendering and transmission of deformable objects, intuitive object deformation using the CyberGlove and concurrent object deformation by multiple clients. We demonstrate and evaluate the performance of the proposed framework through a number of experiments.     

Determination of perchlorate in infant formula by isotope dilution ion chromatography/tandem mass spectrometry

A sensitive and selective isotope dilution ion chromatography/tandem mass spectrometry (ID IC-MS/MS) method was developed and validated for the determination of perchlorate in infant formula. The perchlorate was extracted from infant formula by using 20 ml of methanol and 5 ml of 1% acetic acid. All samples were spiked with (18)O(4) isotope-labelled perchlorate internal standard prior to extraction. After purification on a graphitised carbon solid-phase extraction column, the extracts were injected into an ion chromatography system equipped with an Ionpac AS20 column for separation of perchlorate from other anions. The presence of perchlorate in samples was quantified by isotope dilution mass spectrometry. Analysis of both perchlorate and its isotope-labelled internal standard was carried out on a Waters Quattro Ultima triple quadrupole mass spectrometer operating in a multiple reaction monitoring (MRM) negative ionisation mode. The method was validated for linearity and range, accuracy, precision, sensitivity, and matrix effects. The limit of quantification (LOQ) was 0.4 μg l(-1) for liquid infant formula and 0.95 μg kg(-1) for powdered infant formula. The recovery ranged from 94% to 110% with an average of 98%. This method was used to analyse 39 infant formula, and perchlorate concentrations ranging from 相似文献   

Attenuation of iNOS and COX2 by blueberry polyphenols is mediated through the suppression of NF-κB activation

Treatment of BV2 microglial cells with blueberry extracts has been shown to be effective in reducing lipopolysaccharide (LPS)-induced proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), inducible NO synthase (iNOS), and cyclooxygenase 2 (COX2). The current study explored the possibility that the down-regulation of iNOS and COX2 by blueberry extracts was mediated through NF-κB signaling pathway. A column-purified fraction of polyphenol-enriched blueberry extract (PC18) was used to treat LPS-activated BV2 cells. The results thus far showed that blueberry polyphenols significantly suppressed iNOS and COX2 promoter activities. In addition, blueberry polyphenols inhibited NF-κB nuclear translocation in LPS-activated BV2 cells. These findings suggested that the beneficial effects of blueberries may involve direct modulation of oxidative stress and/or inflammatory signaling cascades.     

A monolithic InP/SOI platform for integrated photonics

The deployment of photonic integrated circuits (PICs) necessitates an integration platform that is scalable, high-throughput, cost-effective, and power-efficien...     

浅谈IEC电线及电缆标准

1引言 电线及电缆制造商在拓展全球市场时,都面临一项高难度的挑战,就是要同时符合不同市场的国家标准要求。即使是同一款的线型,制造商通常也因应不同国家的要求,生产不同的电线型号。这些电线在推向市场之前,必须通过多项测试和认证,而这些测试及认证,有时需要在全球各地的实验室和认证机构内进行。     

Molecular design of nanohybrid gas separation membranes for optimal CO2 separation

Organic-inorganic materials comprising CO₂-philic components may yield superior CO₂ transport properties and good CO₂/H₂ gas selectivity. We report that a fine balance in size heterogeneity in the silicon-based structures is essential and a mixture of sizes up to 50 nm surrounded by 5–15 nm silicon-based nanostructures is the preferred inorganic phase morphology that yields optimal nanohybrid membranes. The combination of optimal synthesis conditions i.e. water/silicon ratio, condensation and ozone pre-treatment durations yields a nanohybrid membrane with a CO₂ permeability of 2000 Barrer while achieving a CO₂/H₂ selectivity of 11. The findings of this work are important for the design of gas separation membranes using green materials.     

Residualisation and resilience: public housing in Hong Kong

Public housing has been an important element in the welfare state and a substantial literature has analysed its origins and growth in different places. However, as it has matured and been redefined by privatisation and regeneration, debates have changed and increasingly been concerned with residualisation and decline. This paper outlines considerations affecting comparative analysis of public housing and presents new material related to explanations for the resilience of public housing in Hong Kong.