Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.     

p-Coumaric acid,Kaempferol, Astragalin and Tiliroside Influence the Expression of Glycoforms in AGS Gastric Cancer Cells

Abnormal glycosylation of cancer cells is considered a key factor of carcinogenesis related to growth, proliferation, migration and invasion of tumor cells. Many plant-based polyphenolic compounds reveal potential anti-cancer properties effecting cellular signaling systems. Herein, we assessed the effects of phenolic acid, p-coumaric acid and flavonoids such as kaempferol, astragalin or tiliroside on expression of selected cancer-related glycoforms and enzymes involved in their formation in AGS gastric cancer cells. The cells were treated with 80 and 160 µM of the compounds. RT-PCR, Western blotting and ELISA tests were performed to determine the influence of polyphenolics on analyzed factors. All the examined compounds inhibited the expression of MUC1, ST6GalNAcT2 and FUT4 mRNAs. C1GalT1, St3Gal-IV and FUT4 proteins as well as MUC1 domain, Tn and sialyl T antigen detected in cell lysates were also lowered. Both concentrations of kaempferol, astragalin and tiliroside also suppressed ppGalNAcT2 and C1GalT1 mRNAs. MUC1 cytoplasmic domain, sialyl Tn, T antigens in cell lysates and sialyl T in culture medium were inhibited only by kaempferol and tiliroside. Nuclear factor NF-κB mRNA expression decreased after treatment with both concentrations of kaempferol, astragalin and tiliroside. NF-κB protein expression was inhibited by kaempferol and tiliroside. The results indicate the rationality of application of examined polyphenolics as potential preventive agents against gastric cancer development.     

Single-Circulating Tumor Cell Whole Genome Amplification to Unravel Cancer Heterogeneity and Actionable Biomarkers

The field of single-cell analysis has advanced rapidly in the last decade and is providing new insights into the characterization of intercellular genetic heterogeneity and complexity, especially in human cancer. In this regard, analyzing single circulating tumor cells (CTCs) is becoming particularly attractive due to the easy access to CTCs from simple blood samples called “liquid biopsies”. Analysis of multiple single CTCs has the potential to allow the identification and characterization of cancer heterogeneity to guide best therapy and predict therapeutic response. However, single-CTC analysis is restricted by the low amounts of DNA in a single cell genome. Whole genome amplification (WGA) techniques have emerged as a key step, enabling single-cell downstream molecular analysis. Here, we provide an overview of recent advances in WGA and their applications in the genetic analysis of single CTCs, along with prospective views towards clinical applications. First, we focus on the technical challenges of isolating and recovering single CTCs and then explore different WGA methodologies and recent developments which have been utilized to amplify single cell genomes for further downstream analysis. Lastly, we list a portfolio of CTC studies which employ WGA and single-cell analysis for genetic heterogeneity and biomarker detection.     

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.     

Gene Variants Related to Cardiovascular and Pulmonary Diseases May Correlate with Severe Outcome of COVID-19

Background: Severe outcomes of COVID-19 account for up to 15% of all cases. The study aims to check if any gene variants related to cardiovascular (CVD) and pulmonary diseases (PD) are correlated with a severe outcome of COVID-19 in a Polish cohort of COVID-19 patients. Methods: In this study, a subset of 747 samples from unrelated individuals collected across Poland in 2020 and 2021 was used and whole-genome sequencing was performed. Results: The GWAS analysis of SNPs and short indels located in genes related to CVD identified one variant significant in COVID-19 severe outcome in the HADHA gene, while for the PD gene panel, we found two significant variants in the DRC1 gene. In this study, both potentially protective and risk variants were identified, of which variants in the HADHA gene deserve the most attention. Conclusions: This is the first study reporting the association between the HADHA and DRC1 genetic variants and COVID-19 severe outcome based on the cohort WGS analysis. Although all the identified variants are localised in introns, they may be correlated and therefore inherited along with other risk variants, potentially causative to severe outcome of COVID-19 but not discovered yet.     

Sanguinarine Inhibition of TNF-α-Induced CCL2, IKBKE/NF-κB/ERK1/2 Signaling Pathway,and Cell Migration in Human Triple-Negative Breast Cancer Cells

Angiogenesis is a process that drives breast cancer (BC) progression and metastasis, which is linked to the altered inflammatory process, particularly in triple-negative breast cancer (TNBC). In targeting inflammatory angiogenesis, natural compounds are a promising option for managing BC. Thus, this study was designed to determine the natural alkaloid sanguinarine (SANG) potential for its antiangiogenic and antimetastatic properties in triple-negative breast cancer (TNBC) cells. The cytotoxic effect of SANG was examined in MDA-MB-231 and MDA-MB-468 cell models at a low molecular level. In this study, SANG remarkably inhibited the inflammatory mediator chemokine CCL2 in MDA-MB-231 and MDA-MB-468 cells. Furthermore, qRT-PCR confirmed with Western analysis studies showed that mRNA CCL2 repression was concurrent with reducing its main regulator IKBKE and NF-κB signaling pathway proteins in both TNBC cell lines. The total ERK1/2 protein was inhibited in the more responsive MDA-MB-231 cells. SANG exhibited a higher potential to inhibit cell migration in MDA-MB-231 cells compared to MDA-MB-468 cells. Data obtained in this study suggest a unique antiangiogenic and antimetastatic effect of SANG in the MDA-MB-231 cell model. These effects are related to the compound’s ability to inhibit the angiogenic CCL2 and impact the ERK1/2 pathway. Therefore, SANG use may be recommended as a component of the therapeutic strategy for TNBC.     

考虑市场力风险约束的最优AGC控制模型

针对传统自动发电控制(AGC)优化模型中难以考虑市场力风险的问题,引入度量市场风险的价值模型,提出了以风险价值为限值的辅助服务成本约束混合整数非线性规划的AGC优化模型。为处理模型的非线性,引入两态辅助变量,将三态的机组状态变量进行等效转化,实现了模型的线性化,有效地降低了模型求解难度。以广西电网运行数据为例,对比不同风险置信水平下AGC控制性能,结果表明:置信水平越高,调节成本越大,控制效果越好,但无论置信水平高低,所提模型均能确保控制性能标准(CPS)合格,验证了模型的有效性,为电力市场环境下的AGC控制提供了有益参考。     

基于模糊层次分析法的自动化机房供电风险评估

针对电网调度自动化主站供电系统运行状态和潜在发生的风险,构建自动化机房供电评估指标体系,提出了一种基于模糊层次分析法的自动化机房供电风险评估方法,通过权重选择和分级评估,同时考虑各类影响因素间的相互作用,实现了对自动化机房供电的科学评估与判断,结合实例分析证明具有较强的科学性和实用性。     

面向未来的河北省南部电网智能化调度

介绍智能电网环境下调度侧的技术特征及河北省南部电网调度侧智能化的现状,分析河北省南部电网智能化调度存在的差距,并在此基础上提出开发励磁建模及参数辨识系统、进行基于ADPSS的在线数据快速安全风险分析、开发网损管理辅助分析系统、整合可实现电网自愈的关键技术、建设调度计划管理系统等提高河北南网调度智能化的措施.     

电网安全风险的调度应对体系研究

随着电力体制改革的不断深入以及近年来国内外相继出现的一系列大停电事故,电网安全已被上升到国家安全、社会稳定的战略高度,引起各方高度关注.电网企业将电网安全风险管理能力作为其立身之本、价值创造和赢得未来竞争的核心竞争力.基于此,重点从电网调度的角度,较为系统地探讨了电网安全风险的调度应对体系.