BackgroundsFusobacterium nucleatum (F. nucleatum) has been shown to be associated with immunotherapy in colorectal cancer (CRC), but its exact mechanism needs to be further explored.MethodsWe first analyzed the correlation between F. nucleatum abundance and mismatch repair (MMR) protein deficiency in CRC tissues from 567 patients. We then treated CRC cells and tissues with F. nucleatum and its metabolites. RNA sequencing was used to evaluate the involved pathways, and non-targeted metabolomics was employed to analyze the metabolites regulating MLH1. CRC cells were treated with butyrate, a metabolite of F. nucleatum, with or without the autophagy-lysosome pathway inhibitor chloroquine or mTOR activator MHY1485. Finally, subcutaneous tumors of BALB/C mice were treated with PD-L1 blockade, butyrate, or their combination.ResultsThe results showed that the abundance of F. nucleatum in CRC tissues is correlated with MSI and MLH1 deficiency. F. nucleatum, its culture supernatant, and its metabolite butyrate cause the downregulation of MLH1 protein via autophagy-lysosome pathway. Subcutaneous tumors in mice received the combined treatment of PD-L1 blockade and butyrate shrink more evidently than those disposed by single therapy.ConclusionsF. nucleatum reduces MLH1 expression via the lysosomal pathway by butyrate, leading to deficient mismatch repair (dMMR), which may yield therapeutic benefits in CRC patients with microsatellite stability (MSS).

MSS/pMMR patients are unresponsive to PD-1/PD-L1 blockade in colorectal cancer (CRC), but the mechanisms are unclear. A better understanding of immunotherapy resistance in CRC may lead to more precise treatment and expand the benefit of immunotherapy to patients. In this study, we constructed mouse model of subcutaneous CRC tumor received anti-PD-L1 treatment with or without fusobacterium nucleatum (F. nucleatum) infection. Then we used single-cell RNA sequencing (scRNA-seq) to explore the comprehensive landscape of the tumor microenvironment (TME). Our data delineated the composition, subclonal diversity and putative function of distinct cells, tracked the developmental trajectory of tumor cells and highlighted cell-cell interactions. We found different compositions and functions of both tumor cells and immune cells. Single anti-PD-L1 monoclonal antibody (mAb) treated tumor exhibited two specific clusters which might be resistant to PD-L1 blockade. The accumulation of immune cells, including T cell, NK cell and pro-inflammatory macrophage subset in tumors infected with F. nucleatum may be one of the reasons for the increased sensitivity to PD-L1 blockade. Thus, targeting F. nucleatum to change the composition of tumor cell subclusters and enliven the immune response might help to overcome immune checkpoint blockade (ICB) resistance.

Cardiac hypertrophy, worldwide known as an adaptive functional compensatory state of myocardial stress, is mainly believed to proceed to severe heart diseases, even to sudden death. Emerging studies have explored the microRNA alteration during hypertrophy. However, the mechanisms of microRNAs involved in cardiac hypertrophy are still uncertain. We studied young rats to establish abdominal aorta coarctation (AAC) for 4 weeks. With the significant downregulated cardiac function and upregulated hypertrophic biomarkers, AAC-induced rats showed enlarged myocardiocytes and alterations in microRNAs, especially downregulated miR-31-5p. miR-31-5p targets the 3'UTR of Nfatc2ip and inhibits myocardial hypertrophy in vitro and in vivo. Furthermore, we verified that Nfatc2ip is necessary and sufficient for cardiac hypertrophy in neonatal rat cardiomyocytes. Moreover, we found miR-31-5p inhibited the colocalization of Nfatc2ip and hypertrophic gene β-Mhc. Luciferase assay and ChiP-qPCR test demonstrated that Nfatc2ip binded to the core-promoter of β-Mhc and enhanced its transcriptional activity. Above all, our study found a new pathway, mir-31-5p/Nfatc2ip/β-Mhc, which is involved in cardiac hypertrophy, suggesting a potential target for intervention of cardiac hypertrophy.

Background: Dysregulation of RNA N6-methyladenosine (m6A) modification is indispensable in tumorigenesis. However, in muscle-invasive bladder cancer (MIBC), the key regulators and mechanisms involved in this process remain largely unknown. This study aimed to screen the key m6A regulators and explore its possible role in MIBC. Methods: Aberrantly expressed m6A regulator genes were screened in The Cancer Genome Atlas (TCGA) MIBC cohort (n = 408) and validated using fresh-frozen and formalin-fixed paraffin-embedded (FFPE) specimens collected during this study. Clinicopathological relevance and association with tumor immune infiltration was further assessed. Results: We identified that the expression of YT521-B homology-domain-containing protein 1 (YTHDC1), an m6A RNA-binding protein, was downregulated in tumor tissues compared with adjacent noncancerous tissues in the TCGA MIBC cohort and our clinical samples. Low YTHDC1 expression correlated with short patient survival, advanced pathologic stage, lymph node metastasis, basal-squamous molecular subtype, non-papillary histological type, and certain genetic mutations important to MIBC. Remarkably, YTHDC1 expression exhibited negative association with tumor-infiltrating M2 macrophage abundance in MIBC. Conclusion: Among m6A regulators, we identified that YTHDC1 was downregulated in MIBC and might play an important role in the pathological process in MIBC, especially tumor microenvironment regulation.

目的:评价R-R差异能否预测房颤射频消融术后左心收缩功能的改善.方法:回顾研究2019年7月～2021年7月在阜阳市第五人民医院行射频消融成功的房颤患者.术后左室射血分数升高＞7.5％定义为心功能改善.根据心功能变化将患者分为改善组和非改善组.对比分析2组的临床特点、心电图及超声心动图.采用多变量回归分析,筛选心功能改善的相关因素.结果:在纳入的80例患者中,改善组患者46例(57.5％).2组在高血压及睡眠呼吸暂停综合征合并症率、心电图的R-R差异、超声心动图的左室舒张末及收缩末内径上差异均有统计学意义(P＜0.05).多变量回归分析显示,R-R差异度越高的患者,心功能改善可能性更高(OR=2.12,95％CI 1.82～2.71).结论:高R-R差异与房颤射频消融术后左心收缩功能改善可能相关.

血管生成是肿瘤生长、复发、转移的关键环节.近年来,抗血管生成治疗作为一种有效的抗肿瘤策略,日益受到重视,并显著改善多种实体瘤的预后.本文就晚期非小细胞肺癌(non-small cell lung caner,NSCLC)VEGF/VEGFR通路抗血管生成治疗的研究进展作一综述.

目的:利用Meta分析比较表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)与单药二线治疗晚期非小细胞肺癌(NSCLC)的临床疗效.方法:在PubMed、EMBASE、中国生物医学文献、CNKI、维普、万方等数据库中检索1965年1月至2014年4月发表的相关文献.制定纳入标准对文献进行筛选以保证纳入研究的同质性.由2名评价者独立评价所纳入研究的质量,提取资料并交叉核对.符合标准的研究采用Stata 12.0软件进行Meta分析.以客观缓解率(ORR)选择比值比(OR)作为效应尺度指标,计算无进展生存时间(PFS)和总生存时间(OS)风险比(HR),同时计算95％可信区间(CI).结果:17个随机对照实验符合全部纳入标准,含4514例NSCLC患者.Meta分析显示,接受靶向治疗和化疗组的PFS(HR 0.94,95％CI =0.79-1.12,P=0.511)、OS(HR 0.98,95％ CI =0.89-1.08,P=0.699)无显著统计学差异.在EGFR基因状态未知人群中,靶向治疗ORR好于化疗(OR 1.53,95％CI=1.02-2.31,P=0.040).同时对于EGFR基因状态的野生人群,靶向治疗OS好于化疗(HR 0.75,95％CI =0.57-0.99,P=0.044).结论:对于EGFR基因状态未知人群,靶向治疗和化疗组的PFS、OS无显著统计学差异,而靶向治疗缓解率ORR好于化疗.

Objective To evaluate the efficacy and safety of gefitinib maintenance therapy in advanced non-small-cell lung cancer(NSCLC)patients without disease progression after first-line che-motherapy.Methods Forty-six NSCLC patients without disease progression after first-line chemo-therapy were given the best support therapy (control group, n=18) or in combination with gefitinib maintenance therapy (observation group, n=28). Clinical efficacy and adverse reactions were compared between the two groups. Results The overall response rate was 28.6% in observation group and 5.6%in control group. The disease control rate was 82.1% in observation group and 62.1% in control group. There were no significant differences in the overall response rate and disease control rate between the two groups (P>0.05).Compared with control group, the median progression-free survival was significantly prolonged in observation group (11.07 months vs 3.77 months, P=0.006). However, the difference in the overall survival was not significant between observation group and control group (30.07 months vs 18.17 months, P=0.24). In observation group, the common adverse events included rash (15/28, 53.6%) , ALT increased (7/28, 25.0%) and diarrhea (6/28, 21.4%). Conclusion Gefitinib maintenance therapy is effective and safe and can prolong survival in patients with NSCLC.