PEI, a new transfection method, augments the inhibitory effect of RBM5 on prostate cancer.

PEI is a cationic polymer, serving as a non-viral transfection carrier grounded in nanotechnology that enhances transfection efficiency via the proton sponge effect. RBM5 is an RNA-binding protein that can inhibit tumor development. This study involved the transfection of RBM5 in prostate cancer cells with PEI, Lipo2000, and their combination. Transwell and wound healing assays were used to observe invasion and migration of prostate cancer cells and flow cytometry was used to observe the apoptosis. Detect the expression of invasion and migration-related protein MMP9 through western blotting experiment. An activity detection kit was used to detect the activity of apoptotic protein caspase-3. We found that there was no significant difference in transfection efficiency when PEI and Lipo2000 were used alone but it significantly improved when they are combined. RBM5 reduced invasion, migration, and proliferation of prostate cancer and enhanced apoptosis. MMP9 expression was reduced, and the activity of caspase-3 was increased. PEI transfection could improve the inhibition of RBM5 on tumors more than Lipo2000. The inhibitory effect is more obvious when the two are used together. RBM5 transfected with PEI can amplify its inhibitory effect on prostate cancer, and this effect is more evident when combined with Lipo2000.

Systematic and Comprehensive Analysis of tRNA-Derived Small RNAs Reveals Their Potential Regulatory Roles and Clinical Relevance in Sarcoidosis.

Introduction: The pathogenesis of sarcoidosis, which involves several systems, is unclear, and its pathological type is non-caseating epithelioid granulomas. tRNA-derived small RNA (tsRNA) is a novel class of short non-coding RNAs with potential regulatory functions. However, whether tsRNA contributes to sarcoidosis pathogenesis remains unclear. Methods: Deep sequencing technology was used to identify alterations in tsRNA relative abundance profiles between patients with sarcoidosis and healthy controls and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate. The clinical parameters were analysis to evaluate the clinical feature correlations initially. Target prediction and bioinformatics analysis of validated tsRNA were conducted to explore the mechanisms of tsRNAs in sarcoidosis pathogenesis. Results: A total of 360 tsRNAs were identified for exact matches. Among them, the relative abundance of three tRNAs (tiRNA-Glu-TTC-001, tiRNA-Lys-CTT-003, and tRF-Ser-TGA-007) was markedly regulated in sarcoidosis. The levels of various tsRNAs were significantly correlated with age, the number of affected systems, and calcium levels in the blood. Additionally, target prediction and bioinformatics analyses revealed that these tsRNAs may play roles in chemokine, cAMP, cGMP-PKG, retrograde endorphin, and FoxO signalling pathways. The related genes, APP, PRKACB, ARRB2, and NR5A1 finding may participate in the occurrence and development of sarcoidosis through immune inflammation. Conclusion: This study provides novel insights to explore tsRNA as a novel and efficacious pathogenic target of sarcoidosis.

RBM10 recruits METTL3 to induce N6-methyladenosine-MALAT1-dependent modification, inhibiting the invasion and migration of NSCLC.

AIMS: Previous studies have shown that RNA binding motif 10 (RBM10) is a potential tumor suppressor protein that can inhibit proliferation and promote apoptosis of non-small cell lung cancer (NSCLC). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in promoting the development of lung cancer. Inhibiting its m6A methylation can effectively inhibit the invasion and metastasis of lung cancer. There is concern that RBM10 could affect MALAT1 m6A methylation for the invasion and migration of NSCLC. MAIN METHODS AND FINDINGS: Transwell and wound healing assays showed that RBM10 significantly inhibited the invasion and migration of NSCLC. CLIP-Seq showed that among all RBM10 binding RNAs, MALAT1 had the highest binding peak among all non-coding RNAs. RNA immunoprecipitation verified the direct combination of RBM10 and MALAT1. The rescue experiment confirmed that RBM10 affected the phosphorylation of the PI3K/AKT/mTOR pathway protein as well as the invasion and migration ability by regulating MALAT1. MeRIP-qPCR confirmed that RBM10 could inhibit the MALAT1 m6A methylation level by recruiting Methyltransferase Like 3 (METTL3). SIGNIFICANCE: The study suggests that RBM10, as an RNA-binding protein, may inhibit the m6A methylation of MALAT1 by recruiting METTL3 and affecting phosphorylation of the downstream PI3K/AKT/mTOR pathway by binding and regulating MALAT1, ultimately affecting the invasion and migration of NSCLC.

RBM10 regulates alternative splicing of lncRNA Neat1 to inhibit the invasion and metastasis of NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 85% of the total cases with lung cancer. NSCLC is characterized by easy metastasis, which often spreads to bones, brains and livers. RNA-binding motif protein 10 (RBM10) is an alternative splicing (AS) regulator frequently mutated in NSCLC. We found that there were multiple peak binding sites between RBM10 and long non-coding RNA nuclear enriched abundant transcript 1 (LncRNA Neat1) by crosslinking-immunprecipitation and high-throughput sequencing (Clip-Seq). LncRNA Neat1 plays an indispensable role in promoting cancer in a variety of tumors and produces two splicing variants: Neat1_1 and Neat1_2. This study aims to explore the mechanism of RBM10 and LncRNA Neat1 in invasion and metastasis of NSCLC. METHODS: Through histological and cytological experiments, we assessed the expression level of RBM10 protein expression. The interaction between RBM10 and Neat1 was evaluated via Clip-Seq and RNA immunoprecipitation assay. The effect of RBM10 on Neat1 and its splicing variants was identified by RT-qPCR. The effect of RBM10 and Neat1 on invasive and metastasis phenotypes of NSCLC was analyzed using transwell invasion assay and scratch test. Additionally, downstream signaling pathway of RBM10 were identified by immunofluorescence and western blot. RESULTS: RBM10 exhibited low levels of expression in NSCLC tissues and cells. RBM10 inhibited the invasion and metastasis of NSCLC and recruited Neat1 and Neat1_2. Overexpression of RBM10 simultaneously inhibited Neat1 and Neat1_2, and promoted the expression of Neat1_1. On the other hand, silencing RBM10 promoted Neat1 and Neat1_2, and inhibited the expression of Neat1_1. From this, we concluded that RBM10 regulated AS of Neat1, and the tumor-promoting effect of Neat1 was mainly attributed to Neat1_2. RBM10 had a negative correlation with Neat1_2. In addition, RBM10 upregulated the expression of PTEN and downregulated the phosphorylation of PI3K/AKT/mTOR through Neat1_2, which ultimately inhibited the invasion and metastasis of NSCLC. CONCLUSION: The RBM10 regulated AS of Neat1 to cause the imbalance of Neat1_1 and Neat1_2, and RBM10 suppressed the activation of the PTEN/PI3K/AKT/mTOR signal by downregulating Neat1_2, finally affected the invasion and metastasis of NSCLC.

The role of serine metabolism in lung cancer: From oncogenesis to tumor treatment.

Metabolic reprogramming is an important hallmark of malignant tumors. Serine is a non-essential amino acid involved in cell proliferation. Serine metabolism, especially the de novo serine synthesis pathway, forms a metabolic network with glycolysis, folate cycle, and one-carbon metabolism, which is essential for rapidly proliferating cells. Owing to the rapid development in metabolomics, abnormal serine metabolism may serve as a biomarker for the early diagnosis and pathological typing of tumors. Targeting serine metabolism also plays an essential role in precision and personalized cancer therapy. This article is a systematic review of de novo serine biosynthesis and the link between serine and folate metabolism in tumorigenesis, particularly in lung cancer. In addition, we discuss the potential of serine metabolism to improve tumor treatment.

RBM10 Regulates Tumor Apoptosis, Proliferation, and Metastasis.

The RNA-binding motif protein 10 (RBM10) is involved in alternative splicing and modifies mRNA post-transcriptionally. RBM10 is abnormally expressed in the lung, breast, and colorectal cancer, female genital tumors, osteosarcoma, and other malignant tumors. It can inhibit proliferation, promote apoptosis, and inhibit invasion and metastasis. RBM10 has long been considered a tumor suppressor because it promotes apoptosis through the regulation of the MDM2-p53 negative feedback loop, Bcl-2, Bax, and other apoptotic proteins and inhibits proliferation through the Notch signaling and rap1a/Akt/CREB pathways. However, it has been recently demonstrated that RBM10 can also promote cancer. Given these different views, it is necessary to summarize the research progress of RBM10 in various fields to reasonably analyze the underlying molecular mechanisms, and provide new ideas and directions for the clinical research of RBM10 in various cancer types. In this review, we provide a new perspective on the reasons for these opposing effects on cancer biology, molecular mechanisms, research progress, and clinical value of RBM10.

A novel nonparametric confidence interval for differences of proportions for correlated binary data.

Various confidence interval estimators have been developed for differences in proportions resulted from correlated binary data. However, the width of the mostly recommended Tango's score confidence interval tends to be wide, and the computing burden of exact methods recommended for small-sample data is intensive. The recently proposed rank-based nonparametric method by treating proportion as special areas under receiver operating characteristic provided a new way to construct the confidence interval for proportion difference on paired data, while the complex computation limits its application in practice. In this article, we develop a new nonparametric method utilizing the U-statistics approach for comparing two or more correlated areas under receiver operating characteristics. The new confidence interval has a simple analytic form with a new estimate of the degrees of freedom of n - 1. It demonstrates good coverage properties and has shorter confidence interval widths than that of Tango. This new confidence interval with the new estimate of degrees of freedom also leads to coverage probabilities that are an improvement on the rank-based nonparametric confidence interval. Comparing with the approximate exact unconditional method, the nonparametric confidence interval demonstrates good coverage properties even in small samples, and yet they are very easy to implement computationally. This nonparametric procedure is evaluated using simulation studies and illustrated with three real examples. The simplified nonparametric confidence interval is an appealing choice in practice for its ease of use and good performance.

The Changing Therapeutic Role of Chemo-radiotherapy for Loco-regionally Advanced Nasopharyngeal Carcinoma from Two/Three-Dimensional Radiotherapy to Intensity-Modulated Radiotherapy: A Network Meta-Analysis.

Purpose: We used randomized trials of radiotherapy (RT) with or without chemotherapy in non-metastatic nasopharyngeal carcinoma to investigate the survival benefit of chemoradiotherapy regimens between two/three-dimensional radiotherapy (2D/3D RT) and intensity-modulated radiotherapy (IMRT). Methods: Overall, 27 trials and 7,940 patients were included. Treatments were grouped into seven categories including RT alone, induction chemotherapy (IC) followed by RT (IC-RT), RT followed by adjuvant chemotherapy (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concurrent chemo-radiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). To distinguish between 2D/3D RT and IMRT, three categories in IMRT were newly added, including CRT in IMRT, IC-CRT in IMRT, and CRT-AC in IMRT. The P score was used to rank the treatments. Results: Both fixed- and random-effects frequentist and Bayesian network meta-analysis models were applied, which provided similar results and the same ranking. IC-CRT was the most effective regimen compared with CRT-AC and CRT in the IMRT era for overall survival (OS) (HR, 95% CI, IC-CRT vs. CRT-AC, 0.61 (0.45, 0.82); IC-CRT vs. CRT 0.65 (0.47, 0.91)), progression-free survival (PFS) (0.69 (0.54, 0.88); 0.63 (0.49, 0.80)), and distant metastasis-free survival (DMFS) (0.58 (0.28, 1.21); 0.60 (0.42, 0.85)). CRT-AC achieved the highest survival benefit compared with CRT, and IC-CRT for loco-regional relapse-free survival (LRRFS) (0.44 (0.15, 1.28); 0.72 (0.22, 2.33)). Among these 10 categories, after distinguishing between 2D/3D RT and IMRT, IC-CRT in IMRT ranked first for OS, PFS, and DMFS, and CRT-AC in IMRT ranked first for LRRFS. Conclusion: IC-CRT should be the most suitable regimen for loco-regionally advanced NPC in the IMRT era.

Identification of Driver Genes and Key Pathways of Pediatric Brain Tumors and Comparison of Molecular Pathogenesis Based on Pathologic Types.

OBJECTIVE: This study is to identify pediatric brain tumors (PBT) driver genes and key pathways to detect the expression of the driver genes and also to clarify the relationship between patients' prognosis and expression of driver genes. METHODS: The gene expression profile of GSE50161 was analyzed to identify the differentially expressed genes (DEGs) between tumor tissue and the normal tissue. Gene ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interaction network analysis were conducted to identify the enrichment functions, pathways, and hub genes. After hub genes were identified, quantitative reverse transcription polymerase chain reaction was used to confirm the differential expression of these hub genes. Survival data of 325 patients' were analyzed to clarify the relationship between prognosis and expression levels of the mutual hub genes. RESULTS: Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that there were 13 common functions and 3 common pathways which were upregulated or downregulated among the 4 groups. Mutual hub genes were somatostatin (SST), glutamate decarboxylase 2 (GAD2), and single copy human parvalbumin gene (PVALB). The expression of SST, GAD2, and PVALB in glioma cells significantly decreased compared with normal glial cells (P < 0.05). In addition, survival analysis showed a favorable progression-free and overall survival in patients with glioma with SST, GAD2, and PVALB high expression (P < 0.05). CONCLUSIONS: SST, GAD2, and PVALB significantly decrease in glioma cells compared with normal glial cells. Survival analysis suggests that patients with high-expressed SST, GAD2, and PVALB have a longer overall and progression-free survival. The differential expressed genes identified in this study provide novel targets for diagnosis and treatment.

The Prevalence of Sleep Apnea in Type B Aortic Dissection: Implications for False Lumen Thrombosis.

Introduction: Obstructive sleep apnea (OSA) has been implicated in aortic dissection. Thrombosis of the false lumen is associated with a prognosis of type B aortic dissection (AoD), and partial thrombosis has been reported to be an independent predictor of mortality. This study sought to explore whether the severity of OSA is associated with false lumen thrombosis. Aims and Methods: In this observational study, 151 type B AoD patients were recruited consecutively from 2013 to 2015. The status of the false lumen was classified as patent, partially thrombosed, or completely thrombosed based on a computer tomography angiography image. Patients were divided into non-OSA group (apnea-hypopnea index [AHI] < 5), and mild (5 ≤ AHI ≤ 15), moderate (15 < AHI ≤ 30), and severe OSA groups (AHI > 30) using the AHI. Results: The prevalence of OSA in type B dissection was 66.2%. Among 151 cases, 51 patients (33.8%) were in the non-OSA group, 56 (37.1%) were in the mild group, 21 (13.9%) were in the moderate group, and 23 (15.2%) were in the severe group. Additionally, a partially thrombosed false lumen was observed in 88 patients (58.3%). Multivariable analysis revealed that OSA severity was positively associated with partial thrombosis (odds ratio, 1.784, 95% confidence interval: 1.182-2.691, P = .006) after adjusting for other confounding factors. Conclusions: OSA was present in two-thirds of patients with type B AoD. The severity of OSA was significantly associated with an increased risk of partial false lumen thrombosis. OSA may therefore be implicated in both the etiology and prognosis of AoD.

A New Preprocedure Risk Score for Predicting Contrast-Induced Acute Kidney Injury.

BACKGROUND: Most of the risk models for predicting contrast-induced acute kidney injury (CI-AKI) are available for only postcontrast exposure prediction; however, prediction before the procedure is more valuable in practice. This study aimed to develop a risk scoring system based on preprocedural characteristics for early prediction of CI-AKI in patients after coronary angiography or percutaneous coronary intervention (PCI). METHODS: We prospectively recruited 1777 consecutive patients who were randomized in an approximate 3:2 ratio to create a development data set (n = 1076) and a validation data set (n = 701). A risk score model based on preprocedural risk factors was developed using stepwise logistic regression. Validation was performed by bootstrap and split-sample methods. RESULTS: The occurrence of CI-AKI was 5.97% (106 of 1777), 5.95% (64 of 1076), and 5.99% (42 of 701) in the overall, developmental, and validation data sets, respectively. The risk score was developed with 5 prognostic factors (age, serum creatinine levels, N-terminal pro b-type natriuretic peptide levels, high-sensitivity C-reactive protein, and primary PCI), ranged from 0-36, and was well calibrated (Hosmer-Lemeshow χ2 = 4.162; P = 0.842). Good discrimination was obtained both in the developmental and validation data sets (C-statistic, 0.809 and 0.798, respectively). The risk score was highly and positively associated with CI-AKI (P for trend < 0.001) in-hospital and long-term outcomes. CONCLUSIONS: The novel risk score model we developed is a simple and accurate tool for early/preprocedural prediction of CI-AKI in patients undergoing coronary angiography or PCI. This tool allows assessment of the risk of CI-AKI before contrast exposure, allowing for timely initiation of appropriate preventive measures.