Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Associations of HLA and drug-metabolizing enzyme genes in co-trimoxazole-induced severe cutaneous adverse reactions

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B¹13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66–26.77, P = 2.94 × 10⁻⁴, Pc = 0.0126). Moreover, the HLA-C¹08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18–33.14, P = 8.60 × 10⁻⁴, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.     

Investigation of the mechanisms of Genkwa Flos hepatotoxicity by a cell metabolomics strategy combined with serum pharmacology in HL-7702 liver cells

1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study.

2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed. Besides, two signal molecules and four enzymes involved in biosynthesis pathway of lysophosphatidylcholine and the sphingosine kinase/sphingosine-1-phosphate pathway were determined to investigate the relationship between Genkwa Flos hepatotoxicity and these two classic pathways. Finally, the metabolic pathways related to specific biomarkers and two classic metabolic pathways were analyzed to explain the possible mechanism of Genkwa Flos hepatotoxicity.

3. Based on the results, lipid peroxidation and oxidative stress, phospholipase A₂/lysophosphatidylcholine pathway, the disturbance of sphingosine-1-phosphate metabolic profile centered on sphingosine kinase/sphingosine-1-phosphate pathway and fatty acid metabolism might be critical participators in the progression of liver injury induced by Genkwa Flos.     

液质联用技术鉴定清血八味片化学成分研究

目的:采用高效液相色谱-三重四级杆质谱(HPLC-MS/MS)测定清血八味片中的化学成分。方法:在负离子条件下采用Halo C_(18)色谱柱(2.1 mm×100 mm,2.7μm),以0.1%甲酸-10 mmol/L甲酸铵水和乙腈为流动相进行梯度洗脱,质谱采用Scan模式和MRM模式,检测清血八味片中的化学成分。结果:共鉴定出紫草中成分7种、土木香中成分3种、人工牛黄中成分4种、栀子中成分7种、瞿麦中成分7种、甘草中成分12种。结论:该方法快速可靠,操作简便,可用于清血八味片的质量控制研究,为临床药物使用提供一定的依据。     

鞘磷脂类信号通路与动脉粥样硬化的研究进展

动脉粥样硬化是临床常见的冠心病和脑梗死等缺血性心脑血管疾病的主要病理基础,其病因复杂,发病机制尚未完全阐明。近年来,越来越多的研究显示鞘磷脂类信号通路可通过调节脂代谢、炎症和血管内皮功能等影响动脉粥样硬化的发生发展。文章综述了鞘磷脂类信号通路关键分子鞘磷脂、神经酰胺和1-磷酸鞘氨醇与动脉粥样硬化的关系,旨在为防治疾病提供新思路。