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.     

对现代城乡规划制度建设的思考——《中华人民共和国城乡规划法》解读

<中华人民共和国城乡规划法>的颁布实施带来了我国城乡规划体系内外环境的革新,为制度的建设与完善提供了契机,但新规划法仍存在立法遗憾.在实施办法上,可将<土地法>约定的土地资源管制与<规划法>约定的使用性质管制分离,将平面集权式的用地管理体系调整为立体分权式的用地管理体系;建立包括城乡规划编制权,审批权、许可权、监督权,司法权在内的相互制约的五公权制衡制度.     

Development of a Multi-Epitope Vaccine for Mycoplasma hyopneumoniae and Evaluation of Its Immune Responses in Mice and Piglets

Mycoplasma hyopneumoniae (Mhp), the primary pathogen causing Mycoplasma pneumonia of swine (MPS), brings massive economic losses worldwide. Genomic variability and post-translational protein modification can enhance the immune evasion of Mhp, which makes MPS prone to recurrent outbreaks on farms, even with vaccination or other treatments. The reverse vaccinology pipeline has been developed as an attractive potential method for vaccine development due to its high efficiency and applicability. In this study, a multi-epitope vaccine for Mhp was developed, and its immune responses were evaluated in mice and piglets. Genomic core proteins of Mhp were retrieved through pan-genome analysis, and four immunodominant antigens were screened by host homologous protein removal, membrane protein screening, and virulence factor identification. One immunodominant antigen, {"type":"entrez-protein","attrs":{"text":"AAV27984.1","term_id":"53987783","term_text":"AAV27984.1"}}AAV27984.1 (membrane nuclease), was expressed by E. coli and named rMhp597. For epitope prioritization, 35 B-cell-derived epitopes were identified from the four immunodominant antigens, and 10 MHC-I and 6 MHC-II binding epitopes were further identified. The MHC-I/II binding epitopes were merged and combined to produce recombinant proteins MhpMEV and MhpMEVC6His, which were used for animal immunization and structural analysis, respectively. Immunization of mice and piglets demonstrated that MhpMEV could induce humoral and cellular immune responses. The mouse serum antibodies could detect all 11 synthetic epitopes, and the piglet antiserum suppressed the nuclease activity of rMhp597. Moreover, piglet serum antibodies could also detect cultured Mhp strain 168. In summary, this study provides immunoassay results for a multi-epitope vaccine derived from the reverse vaccinology pipeline, and offers an alternative vaccine for MPS.     

装配夹具的设计及应用

设计一种能够使工件按一定的技术要求准确定位和牢固夹紧的杠杆夹具,提高产品质量和生产效率。     

对抗震钢框架板件宽厚比限值与相应的地震作用设计取值的细化和完善

在文献[1]的基本思路和初步结果的基础上,对钢结构中按弹性准则设计的截面,根据腹板屈曲与否对其进行分级;改进、完善和细化了框架截面等级与地震作用取值的对应关系,使之更趋合理;给出了各等级截面的框架以众值烈度地震作用效应表达的地震组合设计式,使实际应用更为方便。     

凯氏定氮仪在复混肥料总氮含量测定中的运用

我国是一个农业大国。农业的发展是国民经济和社会发展的重要因素。复混肥料在农业中的运用也日益广泛。文章研究的凯氏定氮仪法的检测方法与国标方法GB/T8572-2001的原理相同。与国标法比较,总氮含量的绝对误差在0.01%～0.29%之间,极差在0.07%～0.18%之间,检测准确度和精密度都符合国家标准的要求。此方法操作简便快速高效、安全可靠,效果令人满意。     

磷酸酯化淀粉的高效湿法合成研究

本研究选用磷酸盐组合物,进行在低温下的淀粉高效磷酸酯化反应。结果表明,在湿法的低温条件下,采用适当的复合磷酸盐及反应促进体系,体系中淀粉浓度在40%～42%,磷酸氢二钠和磷酸二氢钠的比例为0.5,复合盐用量15%,pH保持在5～6之间,50℃反应5 h,Gx16在1%～5%的用量,可以显著提高淀粉的磷酸酯化程度(以结合磷含量表示),同时由于反应效率的提高,使湿法的反应均匀性,残留磷酸盐含量可控性,流程简洁、方便等优势得以突出,对比现实的生产工艺,该方法在稳定质量、节能降耗、减少污染排放等方面都极具优势,有重要的推广价值。