The m6A Reader YTHDF1 Promotes Lung Carcinoma Progression via Regulating Ferritin Mediate Ferroptosis in an m6A-Dependent Manner.

N6-methyladenosine (m6A) plays a significant role as an epigenetic mechanism, which is involved in various cancers' progress via regulating mRNA modification. As a crucial m6A "reader", YTHDF1 is able to alter m6A-modified mRNA and promote the protein translation process in multiple cancers. However, the role of YTHDF1 in lung cancer has not been fully investigated. This study focuses on elucidating the function of YTHDF1 in the development of lung cancer and its underlying mechanism. We demonstrated that YTHDF1 was highly expressed in lung carcinoma progression; then, the loss of function experiments in lung cell lines confirmed that knockdown of YTHDF1 suppressed cell proliferation, migration and invasion and induced ferroptosis of lung cancer cells. Further functional assays showed that ferritin (FTH) was identified as the key target of YTHDF1 in lung cancer cells. Furthermore, the overexpression of ferritin in YTHDF1-depleted cells partially restored lung cancer cell suppression. Collectively, our data suggested that the upregulation of YTHDF1 promotes lung cancer carcinogenesis by accelerating ferritin translation in an m6A-dependent manner. We hope that our findings may provide a new target for lung cancer diagnosis and treatment.

Effectiveness of no drainage after elective day-case laparoscopic cholecystectomy, even with intraoperative gallbladder perforation: a randomized controlled trial.

BACKGROUND: Laparoscopic cholecystectomy (LC) has been carried out as day-case surgery. Current guidelines do not mention the role of drainage after LC. In particular, data stay blank with no prospective study on drainage management when gallbladder perforation (GP) accidentally occurs intraoperatively. METHODS: A randomized controlled trial was conducted to compare clinical outcomes of drainage and no drainage after elective day-case LC. Intraoperative GP was recorded. The primary and secondary outcomes were major and minor complications, respectively. RESULTS: Two hundred patients were randomized. No major complications occurred in either group. In secondary outcomes, nausea/vomiting, pain, hospital stay, and cost were similar in the drainage group and no drainage group; postoperative fever, WBC, and CRP levels were significantly lower in the no drainage group. GP occurred in 32 patients. Male patients with higher BMI and CRP and abdominal pain within 1 month were more likely to occur GP. Subgroup analysis of GP, primary outcomes, and most secondary outcomes had no difference. Postoperative WBC and CRP were higher in the drainage group. Postoperative fever occurred in 63 patients. Univariate analysis of fever showed that blood loss, drainage, postoperative WBC, CRP, and hospital stay were significant. Multivariable logistic regression analysis demonstrated that drainage was an independent risk factor for fever after LC (OR 3.418, 95% CI 1.392-8.390; p = 0.007). CONCLUSIONS: No drainage after elective day-case LC is safe and associated with fewer complications, even in intraoperative GP. The trial proves that drainage is an independent risk factor for postoperative fever. The use of a drain after LC may lead to an unsuccessful day-case procedure by causing fever, elevated CRP, and extended hospital stay (NCT03909360).

Fu Fang Zhen Zhu Tiao Zhi Capsules Protect against Myocardial Ischemia by Inhibiting Cardiomyocyte Pyroptosis.

Background: Fu Fang Zhen Zhu Tiao Zhi (FTZ) is a traditional Chinese herbal prescription widely used to treat dyslipidemia, metabolic diseases, and diabetic coronary disorders. Cardiomyocyte death and loss of regenerative ability cause cardiac dysfunction and heart failure. FTZ can effectively treat diabetic cardiomyopathy and macrovascular diseases; however, the mechanism behind the phenomenon is still unclear. Here, we determined the mechanism of action of FTZ in treating myocardial infarction. Methods: Male C57BL/6 mice were treated with 2.4 or 1.2 g/kg FTZ, or administered saline by oral gavage daily for four weeks, and a 24-hour ligation was administered to the artery. Echocardiography was used to evaluate cardiac function. Hematoxylin and eosin and Evans blue/triphenyltetrazolium chloride staining were carried out by staining the cardiac tissue, used to evaluate cardiac function and infarct size. Using western blotting and reverse transcriptase-polymerase chain reaction, we determined the relative levels of NOD-like receptor protein (NLRP) 3, ASC, cleaved caspase-l (C-Caspase-1), GSDMD, and GSDMD-N. TUNEL, immunohistochemical, and immunofluorescence staining were used to determine cell death and NLRP3 expression. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)-1ß and IL-18. Results: FTZ reduced ischemia-induced cardiomyocyte cell death in vivo and H2O2-induced cell death in vitro by maintaining cardiac architecture and restoring cardiac function. FTZ decreased the NLRP3 expression and inhibited pyroptosis-correlated genes, including NLRP3, ASC, GSDMD, C-Caspase-1, and GSDMD-N. NLRP3 overexpression impaired the efficacy of FTZ by inducing pyroptosis. Conclusion: FTZ could preserve cardiac function resulting from ischemic insult by inhibiting pyroptosis, which was partially reversed by NLRP3 overexpression, indicating that NLRP3 could be a potential target of FTZ in treating myocardial infarction.

Is it justified to assess the resectability of pancreatic cancer combined with biological and conditional factors?

Background: This study aimed to investigate the biological and conditional resectability criteria for pancreatic ductal adenocarcinoma (PDAC), as proposed by the International Association of Pancreatology (IAP), as well as to identify the role of biological and conditional factors in assessing the resectability of PDAC. Methods: The clinical data of PDAC patients who underwent upfront open/laparoscopic pancreaticoduodenectomy (PD/LPD) or distal pancreatectomy (DP/LDP) at our hospital between January 2013 to June 2019 were retrospectively analyzed. Patients who were diagnosed with anatomically resectable PDAC, as defined by National Comprehensive Cancer Network (NCCN) guideline of PDAC guideline Version 1.2020, were enrolled. Based on IAP-criteria, these patients were divided into two groups, including IAP-resectable (IAP-R) and IAP Borderline Resectable (IAP-BR). Clinical characteristics and outcomes were compared between the two groups. In order to identify independent biological and conditional predictors of recurrence-free survival (RFS) and overall survival (OS) of enrolled patients, an analysis was performed through the use of a Cox proportional-hazard model. Results: Overall, 97 patients were included in this study. Among them, 38 patients were IAP-R and 59 patients were IAP-BR. Compared to the IAP-R group, the IAP-BR group had a higher early recurrence rate (62.7% vs. 42.1%; P=0.047), and the median RFS (9.2 vs. 18.3 months, P<0.01) and OS (19.1 vs. 30.6 months, P<0.05) were also significantly worse. Preoperative CA19-9 serum levels that exceeded 500 U/mL and/or an imaging diagnosis of regional lymph nodes metastasis were independently associated with OS and RFS of anatomically resectable PDAC. Conclusions: The prognosis of patients with PDAC that undergo resection can be predicted more accurately by assessing the resectability of pancreatic cancer combined with anatomical and biological factors according to IAP criteria. Whether conditional factors should be included in the resectability criteria needs to be validated by prospective and large cohorts.

BAG3 Alleviates Atherosclerosis by Inhibiting Endothelial-to-Mesenchymal Transition via Autophagy Activation.

Atherosclerosis is a chronic systemic inflammatory disease that causes severe cardiovascular events. B cell lymphoma 2-associated athanogene (BAG3) was proven to participate in the regulation of tumor angiogenesis, neurodegenerative diseases, and cardiac diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the role of BAG3 in atherosclerosis and elucidate the potential molecular mechanism. In this study, ApoE-/- mice were given a tail-vein injection of BAG3-overexpressing lentivirus and fed a 12-week high-fat diet (HFD) to investigate the role of BAG3 in atherosclerosis. The overexpression of BAG3 reduced plaque areas and improved atherosclerosis in ApoE-/- mice. Our research proves that BAG3 promotes autophagy in vitro, contributing to the suppression of EndMT in human umbilical vein endothelial cells (HUVECs). Mechanically, autophagy activation is mediated by BAG3 via the interaction between BAG3 and its chaperones HSP70 and HSPB8. In conclusion, BAG3 facilitates autophagy activation via the formation of the chaperone-assisted selective autophagy (CASA) complex interacting with HSP70 and HSPB8, leading to the inhibition of EndMT during the progression of atherosclerosis and indicating that BAG3 is a potential therapeutic target for atherosclerosis.

The Chinese medicine Fufang Zhenzhu Tiaozhi capsule protects against atherosclerosis by suppressing EndMT via modulating Akt1/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu Tiaozhi (FTZ) is a traditional Chinese herbal prescription that has been used to treat dyslipidemia, nonalcoholic fatty liver disease, atherosclerosis, diabetes and its complications in the clinic for almost ten years. Endothelial-mesenchymal transition (EndMT) is the key driver of atherosclerosis. However, the effects of FTZ on endothelial dysfunction and EndMT remain unknown. AIM OF THE STUDY: To evaluate the therapeutic effects of FTZ against EndMT and the underlying mechanisms. MATERIALS AND METHODS: An in vivo model of atherosclerosis was established by feeding ApoE-/- mice with a high-fat diet (HFD). The body weight, lipid levels, plaque area, lipid deposition and EndMT were evaluated using standard assays 12 weeks after intragastric administration of FTZ and simvastatin. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to simulate EndMT in vitro. The degree of EndMT was assessed after treating the cells with FTZ or transfection with si-Akt1. The expression levels of genes involved in EndMT were quantified by real-time PCR or western blotting. RESULTS: FTZ ameliorated dyslipidemia and endothelial dysfunction in the atherosclerotic mice. In addition, FTZ reduced body weight and the total cholesterol, triglycerides and low-density lipoprotein levels, and increased that of high-density lipoproteins. FTZ also upregulated the expression of endothelial markers (CD31 and VE-cadherin) and decreased that of mesenchymal markers (ɑ-SMA and FSP1), indicating that it inhibits EndMT. Knocking down Akt1 exacerbated EndMT and reversed the therapeutic effect of FTZ. CONCLUSION: FTZ delayed atherosclerosis by inhibiting EndMT via the Akt1/ß-catenin pathway.

Prognostic alternative splicing signature in cervical squamous cell carcinoma.

Basing on alternative splicing events (ASEs) databases, the authors herein aim to explore potential prognostic biomarkers for cervical squamous cell carcinoma (CESC). mRNA expression profiles and relevant clinical data of 223 patients with CESC were obtained from The Cancer Genome Atlas (TCGA). Correlated genes, ASEs and percent-splice-in (PSI) were downloaded from SpliceSeq, respectively. The PSI values of survival-associated alternative splicing events (SASEs) were used to construct the basis of a prognostic index (PI). A protein-protein interaction (PPI) network of genes related to SASEs was generated by STRING and analysed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Consequently, 41,776 ASEs were discovered in 19,724 genes, 2596 of which linked with 3669 SASEs. The PPI network of SASEs related genes revealed that TP53 and UBA52 were core genes. The low-risk group had a longer survival period than high-risk counterparts, both groups being defined according to PI constructed upon the top 20 splicing events or PI on the overall splicing events. The AUC value of ROC reached up to 0.88, demonstrating the prognostic potential of PI in CESC. These findings suggested that ASEs involve in the pathogenesis of CESC and may serve as promising prognostic biomarkers for this female malignancy.