Effects of Nurse-Led Interventions on Comprehensive Rehabilitation of Atrial Fibrillation: A Systematic Review And Meta-Analysis.

Objective: This meta-analysis aimed to assess and evaluate the effect of nurse-led health management on the quality of life of patients with atrial fibrillation. Methods: We compared the outcomes of patients who received nurse-led intervention during hospitalization with those who did not, using a systematic retrospective and randomized controlled trial (RCT) analysis. We searched the studies in Cochrane Central Register, including PubMed, EmBase, Web of Science, Cochrane Library, WAN Data, CBM, CNKI, etc. Bias risks included in the study were evaluated by Cochrane Bias risk tool , and combined risk estimates were calculated. The main endpoints are the SF-36 and HADS scores and endpoints after surgery. We used a random effects model to combine the data. For continuous variables (such as SF-36 and HADS scores), we used standard mean difference for analysis, and for binary variables (such as the presence or absence of mental health problems), we used hazard ratio for analysis. The data are based on fixed or stochastic effects models, with standard mean differences and risk ratios for continuous and heterotaxic variables. Results: 3064 patients from 7 clinical studies were included in this meta-analysis. Postoperative SF-36 scores at 6 months in the nurse-led group were significantly higher than those in the routine nursing group in Role-Physical and Mental health. Postoperative SF-36 scores at 12 months in the nurse-led group were not significantly higher than those in the routine nursing group. The nurse-led group had a significantly lower HADS depression score than the conventional care group, but there was no significant difference in HADS anxiety score between the two groups. Conclusion: The main findings of this meta-analysis are that the nurse-led comprehensive management of atrial fibrillation can significantly improve the role-physical and mental health status of SF-36, reduce the HADS depression score, the incidence of cardiovascular hospitalization and atrial fibrillation at 6 months atrial fibrillation surgery. Additional high-quality RCTs should be conducted in the future. nurse-led interventions have the potential to significantly impact the care of patients with atrial fibrillation. By providing comprehensive management, education, and support, nurses can improve patient outcomes, enhance quality of life, and reduce healthcare burdens for both patients and providers. While this meta-analysis provides valuable insights, there are limitations that should be considered. Standardizing interventions and outcome measures, conducting larger studies with longer follow-up periods, including diverse populations and settings, and assessing the economic impact of nurse-led interventions are potential directions for future research in this field. Addressing these limitations would provide a more comprehensive understanding of the role of nurse-led interventions in the care of patients with atrial fibrillation.

A disulfiram/copper gluconate co-loaded bi-layered long-term drug delivery system for intraperitoneal treatment of peritoneal carcinomatosis.

To develop a long-term drug delivery system for the treatment of primary and metastatic peritoneal carcinoma (PC) by intraperitoneal (IP) injection, a disulfiram (DSF)/copper gluconate (Cu-Glu)-co-loaded bi-layered poly (lactic acid-coglycolic acid) (PLGA) microspheres (Ms) - thermosensitive hydrogel system (DSF-Ms-Cu-Glu-Gel) was established. Rate and mechanisms of drug release from DSF-Ms-Cu-Glu-Gel were explored. The anti-tumor effects of DSF-Ms-Cu-Glu-Gel by IP injection were evaluated using H22 xenograft tumor model mice. The accumulative release of DSF from Ms on the 10th day was 83.79% without burst release. When Ms were dispersed into B-Gel, burst release at 24 h decreased to 14.63%. The results showed that bis (diethyldithiocarbamate)-copper (Cu(DDC)2) was formed in DSF-Ms-Cu-Glu-Gel and slowly released from B-Gel. In a pharmacodynamic study, the mount of tumor nodes and ascitic fluid decreased in the DSF-Ms-Cu-Glu-Gel group. This was because: (1) DSF-Ms-Cu-Glu-Gel system co-loaded DSF and Cu-Glu, and physically isolated DSF and Cu-Glu before injection to protect DSF; (2) space and water were provided for the formation of Cu(DDC)2; (3) could provide an effective drug concentration in the abdominal cavity for a long time; (4) both DSF and Cu(DDC)2 were effective anti-tumor drugs, and the formation of Cu(DDC)2 occurred in the abdominal cavity, which further enhanced the anti-tumor activity. Thus, the DSF-Ms-Cu-Glu-Gel system can be potentially used for the IP treatment of PC in the future.

Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming.

Aldehyde dehydrogenase 3A1 (ALDH3A1) is an NAD+-dependent enzyme that is closely related to tumor development. However, its role in non-small-cell lung cancer (NSCLC) has not been elucidated. This study aimed to clarify the mechanism of ALDH3A1 and identify potential therapeutic targets for NSCLC. Here, for the first time, we found that ALDH3A1 expression could be induced by a hypoxic environment in NSCLC. ALDH3A1 was highly expressed in NSCLC tissue, especially in some late-stage patients, and was associated with a poor prognosis. In mechanistic terms, ALDH3A1 enhances glycolysis and suppresses oxidative phosphorylation (OXPHOS) to promote cell proliferation by activating the HIF-1α/LDHA pathway in NSCLC. In addition, the results showed that ALDH3A1 was a target of ß-elemene. ALDH3A1 can be downregulated by ß-elemene to inhibit glycolysis and enhance OXPHOS, thus suppressing NSCLC proliferation in vitro and in vivo. In conclusion, hypoxia-induced ALDH3A1 is related to the energy metabolic status of tumors and the efficacy of ß-elemene, providing a new theoretical basis for better clinical applications in NSCLC.

Retracted: Upregulation of Serine Proteinase Inhibitor Clade B Member 3 (SERPINB3) Expression by Stromal Cell-Derived Factor (SDF-1)/CXCR4/Nuclear Factor kappa B (NF-κB) Promotes Migration and Invasion of Gastric Cancer Cells.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Jing Gong, Yongxi Song, Ling Xu, Xiaofang Che, Kezuo Hou, Tianshu Guo, Yu Cheng, Yunpeng Liu, Xiujuan Qu. Upregulation of Serine Proteinase Inhibitor Clade B Member 3 (SERPINB3) Expression by Stromal Cell-Derived Factor (SDF-1)/CXCR4/Nuclear Factor kappa B (NF-kB) Promotes Migration and Invasion of Gastric Cancer Cells. Med Sci Monit, 2020; 26: e927411. DOI: 10.12659/MSM.927411.

Propineb induced notochord deformity, craniofacial malformation, and osteoporosis in zebrafish through dysregulated reactive oxygen species generation.

Dithiocarbamate (DTC) fungicides are contaminants that are ubiquitous in the environment. Exposure to DTC fungicides has been associated with a variety of teratogenic developmental effects. Propineb, a member of DTCs, was evaluated for the toxicological effects on notochord and craniofacial development, osteogenesis in zebrafish model. Embryos at 6 hours post-fertilization (hpf) were exposed to propineb at dosages of 1 and 4 µM. Morphological parameters were evaluated at exposure times of 24, 48, 72, and 120 hpf after propineb exposure. The survival and hatching rates as well as body length decreased at 1 and 4 µmol/L groups. Besides, transgenic zebrafish exposed to propineb showed abnormal vacuole biogenesis in notochord cells at the early stage of development. The expression of collagen type 2 alpha 1a (col2a1a), sonic hedgehog (shh), and heat shock protein family B member 11 (hspb11) measured by quantitative PCR and in situ hybridization experiment of col8a1a gene have consolidated the proposal process. Besides, Alcian blue, calcein, and alizarin red staining profiles displayed craniofacial malformations and osteoporosis were induced following propineb exposure. PPB exposure induced the changes in oxidative stress and reactive oxygen species inhibitor alleviated the deformities of PPB. Collectively, our data suggested that propineb exposure triggered bone abnormalities in different phenotypes of zebrafish. Therefore, propineb is a potential toxicant of high priority concern for aquatic organisms.

TRIM27 is an adverse prognostic biomarker and associated with immune and molecular profiles in right-sided colon cancer.

Right-sided colon cancer (RCC), as an independent tumor entity, shows a poor prognosis. It is imperative to detect immune microenvironment-related genes for predicting RCC patient prognosis and study their function in RCC. Tripartite motif-containing 27 (TRIM27) was identified as a risk signature from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets by using weighted gene co-expression network analysis, differentially expressed analysis, and univariate Cox analysis. It predicted a poorer overall survival and increased lymph node metastasis, which were then validated in our 48 clinical samples. Using immunohistochemistry, TRIM27 was found to be highly expressed in both cancer cells and surrounding immunocytes, and its expression in tumor or immune cells both predicted a poorer prognosis. Thereafter, the functional mechanism, immune and molecular characteristics of TRIM27 were investigated using gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and gene set variation analysis (GSVA) at the single-cell, somatic mutation, and RNA-seq level. Patients with highly expressed TRIM27 presented lower CD4+ T cell infiltration and activation of the mTORC1/glycolysis pathway. In addition, patients with highly expressed TRIM27 were characterized by hypermetabolism, higher tumor purity, more BRAF mutation, and more chromosomal instability. Collectively, TRIM27 is an important immune-related prognostic biomarker in patients with RCC. It may function via activating the mTORC1/glycolysis pathway and suppressing CD4+ T cells. These results indicated that TRIM27 could be a promising therapeutic target in RCC.

microRNA-569 inhibits tumor metastasis in pancreatic cancer by directly targeting NUSAP1.

MicroRNAs (miRNAs) are known to be involved in the development and progression of pancreatic cancer (PC). In this study, the prognostic significance and mechanistic role of microRNA-569 in PC were explored. Quantitative real-time PCR was used to detect the expression of microRNA-569 in PC tissues and cell lines. Scratch test and Transwell assay were conducted to detect migration and invasion ability. The xenograft nude mice model was used to determine tumor metastasis in vivo. The direct targets of microRNA-569 were determined by using bioinformatics analysis and a dual-luciferase reporter assay. The expression level of microRNA-569 was down-regulated in PC patients with a poor prognosis. In vitro and in vivo experiments indicated that over-expression of microRNA-569 inhibited the migration and invasion of PC cells. MicroRNA-569 negatively regulated NUSAP1 by directly binding its 3'-untranslated region. Further mechanism research implied that the ZEB1 pathway was involved in microRNA-569/NUSAP1 mediation of the biological behaviors in PC. These data demonstrated that microRNA-569 may exert a tumor-suppressing effect in PC and maybe a potential therapeutic target for PC patients.

Corrigendum: DYNC1I1 Promotes the Proliferation and Migration of Gastric Cancer by Up-Regulating IL-6 Expression.

[This corrects the article DOI: 10.3389/fonc.2019.00491.].

Kang-Ai Injection Inhibits Gastric Cancer Cells Proliferation through IL-6/STAT3 Pathway.

OBJECTIVE: To explore the mechanisms underlying the proliferative inhibition of Chinese herbal medicine Kang-Ai injection (KAI) in gastric cancer cells. METHODS: Gastric cancer cell lines MGC803 and BGC823 were treated by 0, 0.3%, 1%, 3% and 10% KAI for 24, 48 and 72 h, respectively. The cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The apoptosis and cell cycle were evaluated by flow cytometry. Interleukin (IL)-6 mRNA and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immune sorbent assay (ELISA), respectively. The protein expression levels of cyclin A, cyclin E, cyclin B1, cyclin D1, p21, retinoblastoma (RB), protein kinase B (AKT), extracellular regulated protein kinases (ERK), signal transducer and activator of transcription (STAT) 1 and STAT3 were detected by Western blot. RESULTS: KAI inhibited the proliferation of MGC803 and BGC823 gastric cancer cells in dose- and time-dependent manner. After treated with KAI for 48 h, the proportion of G1 phase was increased, expression level of cyclin D1 and phosphorylation-RB were down-regulated, whereas the expression of p21 was up-regulated (all P<0.01). Furthermore, 48-h treatment with KAI decreased the phosphorylation level of STAT3, inhibited the mRNA and protein expressions of IL-6 (all P<0.01). IL-6 at dose of 10 ng/mL significantly attenuated the proliferative effect of both 3% and 10% KAI, and recovered KAI-inhibited STAT3 phosphorylation and cyclin D1 expression level (all P<0.01). CONCLUSION: KAI exerted an anti-proliferative function by inhibiting IL-6/STAT3 signaling pathway followed by the induction of G1 phase arrest in gastric cancer cells.

Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3.

Colorectal cancers (CRCs) with the BRAF V600E mutation exhibit upregulation of programmed death ligand 1 (PD-L1) but fail to respond to immunotherapy targeting programmed cell death protein 1 (PD-1)/PD-L1. Recent studies have explored the intracellular functions of PD-L1. Here, we demonstrate that PD-L1 was highly expressed in both the cytoplasm and nucleus of BRAF-mutated CRC tumor cells and tissues. Nuclear PD-L1 (nPD-L1) promoted the growth of tumor cells both in vitro and in vivo. Mechanistic investigations revealed that PD-L1 translocation into the nucleus was facilitated by the binding of p-ERK. Further, nPD-L1 upregulated the expression of cell cycle regulator BUB1 via interactions with thyroid hormone receptor-associated protein 3 (THRAP3), thereby accelerating cell cycle progression and promoting cell proliferation. Moreover, BRAF V600E-mutated CRC cells exhibited upregulation of PD-L1 expression via the transcription factor LEF-1. These findings reveal a novel role of nPD-L1, which promotes cell cycle progression in an immune-independent manner in BRAF V600E-mutated CRC. Our study provides novel insight into the mechanisms underlying BRAF V600E-mutated CRC progression.

Corrigendum: CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment.

[This corrects the article DOI: 10.3389/fonc.2020.01612.].

N6-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1.

Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin ß1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.

Identification of Prognostic Signature and Gliclazide as Candidate Drugs in Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, with high incidence and mortality. To improve the curative effect and prolong the survival of patients, it is necessary to find new biomarkers to accurately predict the prognosis of patients and explore new strategy to treat high-risk LUAD. METHODS: A comprehensive genome-wide profiling analysis was conducted using a retrospective pool of LUAD patient data from the previous datasets of Gene Expression Omnibus (GEO) including GSE18842, GSE19188, GSE40791 and GSE50081 and The Cancer Genome Atlas (TCGA). Differential gene analysis and Cox proportional hazard model were used to identify differentially expressed genes with survival significance as candidate prognostic genes. The Kaplan-Meier with log-rank test was used to assess survival difference. A risk score model was developed and validated using TCGA-LUAD and GSE50081. Additionally, The Connectivity Map (CMAP) was used to predict drugs for the treatment of LUAD. The anti-cancer effect and mechanism of its candidate drugs were studied in LUAD cell lines. RESULTS: We identified a 5-gene signature (KIF20A, KLF4, KRT6A, LIFR and RGS13). Risk Score (RS) based on 5-gene signature was significantly associated with overall survival (OS). Nomogram combining RS with clinical pathology parameters could potently predict the prognosis of patients with LUAD. Moreover, gliclazide was identified as a candidate drug for the treatment of high-RS LUAD. Finally, gliclazide was shown to induce cell cycle arrest and apoptosis in LUAD cells possibly by targeting CCNB1, CCNB2, CDK1 and AURKA. CONCLUSION: This study identified a 5-gene signature that can predict the prognosis of patients with LUAD, and Gliclazide as a potential therapeutic drug for LUAD. It provides a new direction for the prognosis and treatment of patients with LUAD.

Integrin α5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells.

Patients with non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs) ultimately develop drug resistance and metastasis. Therefore, there is a need to identify the underlying mechanisms of resistance to EGFR-TKIs. In the present study, colony formation and MTT assays were performed to investigate cell viability following treatment with icotinib. Gene Expression Omnibus datasets were used to identify genes associated with resistance. Wound healing and Transwell assays were used to detect cell migration and invasion with icotinib treatment and integrin α5-knockdown. The expression levels of integrin α5 and downstream genes were detected using western blotting. Stable icotinib-resistant (IcoR) cell lines (827/IcoR and PC9/IcoR) were established that showed enhanced malignant properties compared with parental cells (HCC827 and PC9). Furthermore, the resistant cell lines were resistant to icotinib in terms of proliferation, migration and invasion. The enrichment of function and signaling pathways analysis showed that integrin α5-upregulation was associated with the development of icotinib resistance. The knockdown of integrin α5 attenuated the migration and invasion capability of the resistant cells. Moreover, a combination of icotinib and integrin α5 siRNA significantly inhibited migration and partly restored icotinib sensitivity in IcoR cells. The expression levels of phosphorylated (p)-focal adhesion kinase (FAK), p-STAT3 and p-AKT decreased after knockdown of integrin α5, suggesting that FAK/STAT3/AKT signaling had a notable effect on the resistant cells. The present study revealed that the integrin α5/FAK/STAT3/AKT signaling pathway promoted icotinib resistance and malignancy in IcoR NSCLC cells. This signaling pathway may provide promising targets against acquired resistance to EGFR-TKI in patients with NSCLC.

Atezolizumab Monotherapy or Plus Chemotherapy in First-Line Treatment for Advanced Non-Small Cell Lung Cancer Patients: A Meta-Analysis.

Background: Atezolizumab plus chemotherapy has been recommended as a first-line treatment option for patients with advanced non-small cell lung carcinoma (NSCLC) irrespective of programmed cell death-ligand 1 (PD-L1) expression. Currently, little is known about the efficacy and treatment-related adverse effects (TRAEs) of subtracting chemotherapy from the combination for patients with high PD-L1 expression. Thus, we performed an indirect comparison between atezolizumab plus chemotherapy and atezolizumab alone. Methods: A total of five eligible randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central controlled trial registries, using keywords including atezolizumab, PD-1, PD-L1, NSCLC, and RCT. The clinical outcomes of objective response rate (ORR), progression-free survival (PFS), OS, and TRAEs were extracted and evaluated. Using indirect analysis, the efficacy and TRAEs were compared between arm A (atezolizumab plus chemotherapy) and arm C (atezolizumab), linked by arm B (chemotherapy). Results: Direct comparison revealed that both atezolizumab plus chemotherapy (HR 0.65, P = 0.003) and atezolizumab alone (HR 0.59, P = 0.010) significantly improved OS compared with chemotherapy. More importantly, the indirect comparison showed that atezolizumab plus chemotherapy was not superior to atezolizumab regarding OS (RR 1.10, P =0.695) and ORR (RR 1.11, P = 0.645). However, patients who received atezolizumab combined with chemotherapy experienced more ≥ grade 3 TRAEs (RR 4.23, P<0.001) and TRAEs leading to drug discontinuation (RR 3.60, P<0.001) than those treated with atezolizumab monotherapy. Conclusions: Atezolizumab monotherapy might be a better treatment option for patients with advanced NSCLC and high PD-L1 expression than atezolizumab plus chemotherapy.

Comparative Analysis and in vitro Experiments of Signatures and Prognostic Value of Immune Checkpoint Genes in Colorectal Cancer.

PURPOSE: Immune checkpoints, as pivotal regulators of immune escape in cancer, can motivate the emergence of immune checkpoint inhibitors (ICIs). The aim of this study is to identify the expression of the immune checkpoint genes (ICGs) in colorectal cancer (CRC) and to relate their individual as well as combined expression to prognosis and therapeutic effectiveness in CRC. METHODS: RNA expression of 47 ICGs and clinical information of CRC patients were collected from two public databases to elucidate the expression levels and prognostic values of these ICGs in CRC. Then, the Shapiro-Wilk normality test was used to determine the normality of variables. Overall survival (OS) rates of each subset were found by Kaplan-Meier method, and the statistical significance was determined by the Log rank test (p < 0.05). RESULTS: The expression of 13 and 9 ICGs was significantly associated with CRC prognosis in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. A series of ICGs was found to be significantly associated with TMB, neoantigens and MMR in CRC indicating that the combination of immunotherapy treatment biomarkers and ICGs may achieve accurate prognostic stratification of CRC, and potentially identify CRC cases that might respond to checkpoint inhibitors (CPIs). The subsets of high or low PD1/PD-L1/IDO1 expression stratified by CD48 were accurately associated with prognosis in CRC. In addition, in vitro experiments confirmed that VTCN1(B7-H4)-KD increases anti-PD-L1-mediated NK cell cytotoxicity on CRC tumor cells. CONCLUSION: Although the expression of a single immune-checkpoint molecule does not predict the efficacy of immunotherapy in CRC, our findings infer that subsets defined by ICGs are associated with prognosis and imply the possibility that VTCN1 and CD48 serve as new immunotherapeutic targets.