Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.     

Sinensetin attenuates oxygen–glucose deprivation/reperfusion-induced neurotoxicity by MAPK pathway in human cerebral microvascular endothelial cells

Sinensetin is a polymethoxylated flavone with anti-inflammatory and anti-oxidative activities. This work aimed to explore the function and mechanism of sinensetin in oxygen and glucose deprivation/reperfusion (OGD/R)-induced neurotoxicity. The overlapping target genes of cerebral stroke and sinensetin were determined according to GeneCards and ParmMapper tools and were subjected to Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Human cerebral microvascular endothelial cells (HCMECs) were stimulated with OGD/R. Neurotoxicity was investigated by Cell Counting Kit-8, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) level, qRT-PCR, and TUNEL analysis. The proteins (p38, JNK, and ERK) in mitogen-activated protein kinase (MAPK) signaling were measured using Western blotting. Total of 50 overlapping target genes of cerebral stroke and sinensetin were predicted. Pathway analysis showed they might be involved in the MAPK pathway. Sinensetin attenuated OGD/R-induced neurotoxicity by mitigating viability reduction, LDH release, ROS generation, inflammatory response, and apoptosis in HCMECs. Sinensetin weakened OGD/R-induced activation of the MAPK pathway via decreasing the phosphorylation of p38, JNK, and ERK. The pathway inhibitors mitigated the activation of the MAPK signaling, and sinensetin exacerbated this effect. The inhibitors reversed OGD/R-induced neurotoxicity in HCMECs, and sinensetin contributed to this role. Overall, sinensetin prevents OGD/R-induced neurotoxicity through decreasing the activation of MAPK pathway.     

Unmasking antibiotic-associated neurological disorders: The underminer in Intensive Care Unit

Psychosis is a common and intractable disorder of hospitalization, especially in patients hospitalized in Intensive Care Unit (ICU). Along with the widely use of multiple antibiotics in community-acquired infection and hospital-acquired infection, the occurrence of antibiotic-associated neurological disorders has become more frequently. However, antibiotic neurotoxicity is often overlooked or misinterpreted. In this review, we summarized the neurological disorders caused by antibacterial agent usage and firstly systematically formulated the pathogenesis of antibiotic-associated neurotoxic reactions. Precautions of the complications are critical in preventing serious clinical outcome as the inducement is curable. Regular neurological physical examination, electroencephalogram (EEG) examination, lumbar puncture and therapeutic drug monitoring closely are essential for early diagnosis and differential diagnosis.     

Association between R1 resection and oncological outcome in resectable gastrointestinal stromal tumors without tumor rupture: A systematic review and meta-analysis

BackgroundThe influence of positive microscopic margin (R1) resection on the prognosis of gastrointestinal stromal tumors (GISTs) is controversial. Tumor rupture is significantly associated with the occurrence of R1 resection and may be a confounder of R1 resection in GISTs. The present meta-analysis evaluated the real influence of R1 resection on the prognosis of GISTs by excluding the confounding effect of tumor rupture.MethodsThe PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases were searched. Studies that compared R1 with negative microscopic margin (R0) resection in GIST patients and reported the time-to-event data of recurrence-free survival (RFS) or disease-free survival (DFS) were eligible for inclusion. The quality of the observational studies was assessed using the Newcastle–Ottawa scale.ResultsOf the 4896 records screened, 23 retrospective studies with 6248 participants were selected. In the overall analysis, R1 resection resulted in a significantly shorter RFS/DFS than R0 resection for GISTs (HR = 1.80, 95% CI = 1.54–2.10, P < 0.001, I² = 14%). However, the inferior RFS/DFS vanished when tumor rupture cases were excluded (HR = 1.34, 95% CI = 0.98–1.83, P = 0.07, I² = 33%). Sensitivity analysis by high-quality studies brought about a more robust HR of 1.15 (95% CI = 0.88–1.50, P = 0.29), with low heterogeneity (I² = 0%). The qualities of evidence for the outcomes were high.ConclusionsThis meta-analysis shows that R1 resection did not influence the survival outcome of GISTs. Reresection may not be necessary when positive microscopic margins exist. This analysis could provide high-quality evidence for the development of guidelines.     

注射用核糖核酸Ⅱ改善晚期胰腺癌化疗患者整体获益可能性的真实世界研究北大核心

目的:评价注射用核糖核酸Ⅱ联合化疗在真实世界中治疗晚期胰腺癌的疗效和安全性。方法:基于LinkDoc数据库纳入2012年至2018年就诊于河南省肿瘤医院等10家研究中心且确诊为局部进展期和晚期胰腺癌的患者923例,试验组采用化疗联合注射用核糖核酸Ⅱ治疗,对照组采用单纯化疗治疗。采用倾向性评分匹配的方法均衡两组的基线信息,比较两组间的总生存期(overall survival,OS)、无进展生存期(progression-free survival,PFS)及不良事件和化疗相关不良反应的发生率。结果:试验组和对照组的中位OS分别为7.5个月和6.7个月,中位PFS分别为3.7个月和3.3个月,差异均无统计学意义(P>0.05)。试验组不良事件发生率略低于对照组(88.7%vs 92.1%),试验组化疗相关不良反应发生率略高于对照组(64.1%vs 57.1%),差异均无统计学意义(P>0.05)。结论:注射用核糖核酸Ⅱ联合化疗治疗晚期胰腺癌具有生存获益趋势,无肝转移患者是潜在的优势人群,该结论尚需前瞻性研究进一步确证。     

LINC00649通过miR-424-5p/IGF1R轴调控内质网应激介导的宫颈癌细胞凋亡

目的探讨LINC00649/miR-424-5p/IGF1R对内质网应激(ERs)介导的宫颈癌(CC)细胞凋亡的影响。方法从GEO数据库中获取CC相关的数据,并分析差异表达的miRNAs。利用生物信息学数据库预测miR-424-5p的上、下游靶点,将LINC00649和IGF1R纳入研究,随后双荧光素酶实验进一步验证靶向关系。qRT-PCR检测LINC00649、miR-424-5p和IGF1R在CC组织和细胞中的表达水平。CCK-8和流式细胞术分别评估CC细胞增殖和凋亡变化。Western blot检测ERs相关蛋白GRP78、CHOP和Caspase-12的表达。结果与癌旁组织和H8细胞相比,LINC00649和IGF1R在CC组织和细胞中表达上调,而miR-424-5p下调(均P<0.05)。LINC00649的异常高表达与CC患者的预后不良有关,敲减LINC00649可通过促进ERs来抑制CC细胞活力,诱导细胞凋亡(均P<0.05)。LINC00649吸附miR-424-5p上调IGF1R的表达。miR-424-5p抑制剂或过表达IGF1R均可部分逆转敲减LINC00649对CC细胞的影响(均P<0.05)。结论 LINC00649能够通过miR-424-5p/IGF1R抑制CC细胞的ERs过程进而减少细胞凋亡,提高细胞活力。