Risk factors, prognostic factors, and nomograms for distant metastases in patients with gastroenteropancreatic neuroendocrine tumors: a population-based study.

Background: Patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor prognosis for distant metastasis. Currently, there are no studies on predictive models for the risk of distant metastasis in GEP-NETs. Methods: In this study, risk factors associated with metastasis in patients with GEP-NETs in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed by univariate and multivariate logistic regression, and a nomogram model for metastasis risk prediction was constructed. Prognostic factors associated with distant metastasis in patients with GEP-NETs were analyzed by univariate and multivariate Cox, and a nomogram model for prognostic prediction was constructed. Finally, the performance of the nomogram model predictions is validated by internal validation set and external validation set. Results: A total of 9145 patients with GEP-NETs were enrolled in this study. Univariate and multivariate logistic analysis demonstrated that T stage, N stage, tumor size, primary site, and histologic types independent risk factors associated with distant metastasis in GEP-NETs patients (p value < 0.05). Univariate and multivariate Cox analyses demonstrated that age, histologic type, tumor size, N stage, and primary site surgery were independent factors associated with the prognosis of patients with GEP-NETs (p value < 0.05). The nomogram model constructed based on metastasis risk factors and prognostic factors can predict the occurrence of metastasis and patient prognosis of GEP-NETs very effectively in the internal training and validation sets as well as in the external validation set. Conclusion: In conclusion, we constructed a new distant metastasis risk nomogram model and a new prognostic nomogram model for GEP-NETs patients, which provides a decision-making reference for individualized treatment of clinical patients.

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction.

Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

Phthalate drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis.

As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment.

A meta-analysis of the prognostic impact of tissue golgi protein 73 (tGP73) in hepatocellular carcinoma.

INTRODUCTION: To date, an increasing number of studies have revealed that GP73 may have prognostic value in liver cancer. However, most of the studies evaluated serum GP73, and the results regarding the prognostic value of tGP73 in liver cancer are still controversial. Therefore, in this meta-analysis, we aimed to determine whether tGP73 has any prognostic value in patients with HCC. MATERIALS AND METHODS: Relevant publications were searched for in PubMed, EMBASE, OVID, the Cochrane Library, and the Web of Science databases up to March 2023. The hazard ratio (HR) or odds ratio (OR) with corresponding 95% confidence intervals (95% CIs) of eligible studies were assessed by fixed-effects or random-effects models. In addition, subgroup analyses were conducted to investigate the possible causes of heterogeneity, and publication bias analysis was also performed to assess the reliability of the meta-analysis results. RESULTS: A total of 10 studies were included. These studies included 1569 HCC patients, and a meta-analysis was performed. The results of our meta-analysis showed that higher GP73 expression levels were significantly associated with poorer OS (HR = 1.87, 95% CI: 1.41-2.48, P < 0.0001, I2 = 58%). However, there was no significant correlation between high GP73 expression and disease-free survival (DFS) (HR: 1.43, 95% CI: 0.93-2.33, P = 0.100). In addition, abnormal GP73 expression was also related to higher tumour tissue differentiation grade (OR = 3.03, 95% CI = 2.01-4.57, P < 0.0001, I2 = 89%), later tumour stage (OR = 5.89, 95% CI = 2.31-14.99, P < 0.0001, I2 = 0%), vascular invasion (OR = 1.72, 95% CI = 1.12-2.64, P = 0.010, I2 = 0%), multiple tumours (OR = 2.44, 95% CI = 1.37-3.68, P = 0.001, I2 = 44%) and early postoperative tumour recurrence (OR = 1.92, 95% CI = 1.10-3.28, P = 0.020, I2 = 62%). CONCLUSIONS: The meta-analysis showed that the overexpression of GP73 may be related to a poor prognosis of HCC, and it may also have a predictive effect on the invasion and metastasis of HCC.

Predictive value for mortality of left ventricular wall thickness in dilated cardiomyopathy.

AIMS: The purpose of this study was to explore the predictive value of wall thickness measured by cardiac magnetic resonance (CMR) for all-cause mortality in dilated cardiomyopathy (DCM) patients. METHODS AND RESULTS: DCM patients who underwent CMR and completed the regular follow-up were included in this study. The left ventricular end-diastolic diameter (LVDd), left ventricular end-diastolic volume (LVEDV), left ventricular posterior wall thickness (PWT), interventricular septum thickness (IVST), left ventricular ejection fraction, and left ventricular mass (LVM) were measured by CMR. The presence and extent of late gadolinium enhancement (LGE) were also assessed. The relative posterior wall thickness (RWTPW ) and relative interventricular septum wall thickness (RWTIVS ) were defined by the following equations: RWTPW  = (2 × PWT)/LVDd, and RWTIVS  = (2 × IVST)/LVDd. All patients received regular telephone and outpatient follow-up. The primary endpoint was all-cause mortality. A total of 161 patients were enrolled in this study, including 126 (78.3%) males. The mean age was 52.3 ± 13.6 years. During the median follow-up of 47 months (interquartile range 32-57 months), 41 (24.8%) patients died. Compared with the non-death group, LVDd (75.2 ± 11.9 vs. 70.5 ± 8.8 mm; P = 0.025) was greater in the death group, while PWT [5.2 mm (3.7-6.8) vs. 6.9 mm (5.3-8.6); P < 0.001], IVST [8.2 mm (6.5-9.5) vs. 9.3 mm (7.4-10.5); P = 0.005], RWTPW [0.15 (0.11-0.19) vs. 0.20 (0.15-0.25); P < 0.001], RWTIVS [0.22 (0.17-0.26) vs. 0.26 (0.22-0.31); P < 0.001], and LVM/LVEDV ratio (0.5 ± 0.2 vs. 0.7 ± 0.2 g/mL; P < 0.001) were lower. The presence of LGE [LGE(+)] was more frequent in the death group (75.6% vs. 58.3%; P = 0.048). However, the LGE extent was not significantly different between the two groups [4 (1-7) vs. 2 (0-6); P = 0.096]. Multivariate Cox regression analysis showed that PWT [hazard ratio (HR) 0.086, 95% confidence interval (CI) 0.665-0.976; P < 0.05] and RWTPW (HR 0.001, 95% CI 0.000-0.502; P < 0.05) were independent predictors of all-cause death. In contrast, IVST, RWTIVS , and the presence of LGE were not clearly associated with death. CONCLUSIONS: PWT measured by CMR is an independent predictor of all-cause mortality in DCM patients. However, there was no significant correlation between septum wall thickness and mortality.

Characterization of the genomic and transcriptional structure of chicken NRG4 gene.

Neuregulin 4 (NRG4) is an important adipocytokine, which plays crucial roles in maintaining energy balance, regulating glucose and lipid metabolism, and preventing non-alcoholic fatty liver disease in mammals. At present, the genomic organization, transcript and protein isoforms of human NRG4 gene have been fully explored. Previous studies in our laboratory have shown that the NRG4 gene is expressed in chicken adipose tissue, but the chicken NRG4 (cNRG4) genomic structure, transcript and protein isoforms are still unknown. To this end, in this study, the genomic and transcriptional structure of the cNRG4 gene were systematically investigated using rapid amplification of cDNA ends (RACE) and reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the coding region (CDS) of the cNRG4 gene was small, but it had a very complex transcriptional structure characterized by multiple transcription start sites, alternative splicing, intron retention, cryptic exons, and alternative polyadenylation, thus leading to production of four 5?UTR isoforms (cNRG4 A, cNRG4 B, cNRG4 C, and cNRG4 D) and six 3?UTR isoforms (cNRG4 a, cNRG4 b, cNRG4 c, cNRG4 d, cNRG4 e, and cNRG4 f) of the cNRG4 gene. The cNRG4 gene spanned 21,969 bp of genomic DNA (Chr.10:3,490,314~3,512,282) and consisted of 11 exons and 10 introns. Compared with the cNRG4 gene mRNA sequence (NM_001030544.4), two novel exons and one cryptic exon of the cNRG4 gene were identified in this study. Bioinformatics analysis, RT-PCR, cloning and sequencing analysis showed that the cNRG4 gene could encode three protein isoforms (cNRG4-1, cNRG4-2 and cNRG4-3). This study lays a foundation for further research on the function and regulation of the cNRG4 gene.

Circ_0060967 facilitates proliferation, migration, and invasion of non-small-cell lung cancer cells by sponging miR-660-3p/UBN2.

Growing evidence has implied that circular RNAs (circRNAs) are involved in multiple tumors progression. This study firstly uncovered the function of circ_0060967 in non-small-cell lung cancer (NSCLC) progression. Quantitative real-time polymerase chain reaction was employed to monitor circ_0060967, miR-660-3p, and ubinuclein-2 (UBN2) mRNA expression in clinical tissues and cell lines. Cell counting kit-8 assay, 5-ethynyl-20-deoxyuridine assay, and Transwell assay were recruited to research cells viability, proliferation, migration, and invasion. BALB/c nude mice were applied to perform in vivo study. Fluorescence in situ hybridization was adopted to explore the subcellular location of circ_0060967 in NSCLC cells. Dual luciferase reporter gene assay and RNA pull-down assay were utilized to identify the interaction among circ_0060967, miR-660-3p, and UBN2. Western blot was employed for UBN2 protein expression investigation in NSCLC cells. Immunohistochemistry was utilized to research UBN2 protein expression in clinical tissues and xenograft tumor tissues. Circ_0060967 was aberrantly over-modulated in NSCLC tissues and cells. High circ_0060967 expression implied grim prognosis. Loss of circ_0060967 weakened NSCLC cells viability, proliferation, migration, invasion, and in vivo growth. Circ_0060967 was mainly distributed in the cytoplasm of NSCLC cells. Down-modulated miR-660-3p and up-regulated UBN2 were found in NSCLC patients. miR-660-3p was sponged by circ_0060967 and it directly targeted UBN2. miR-660-3p down-modulation rescued the suppression of circ_0060967 loss on NSCLC cells viability, proliferation, migration, and invasion. Circ_0060967 facilitated NSCLC progression by enhancing UBN2 expression via sponging miR-660-3p. It might be a promising target for NSCLC treatment.

Knockout and Restoration Reveal Differential Functional Roles of PPARγ1 and PPARγ2 in Chicken Adipogenesis.

Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipogenesis and is expressed as two isoforms, PPARγ1 and PPARγ2. Our previous lentiviral overexpression study showed that PPARγ1 and PPARγ2 differentially regulated proliferation, differentiation, and apoptosis of the immortalized chicken preadipocyte cell line (ICP2). However, we cannot rule out the possibility that the endogenous expression of PPARγ isoforms may compromise our findings. In this study, using the dual sgRNA-directed CRISPR/Cas9 system, we generated PPARγ (PPARγ-/-) and PPARγ2-specific knockout (PPARγ2-/-) ICP2 cell lines and investigated the differences in proliferation and differentiation among PPARγ-/-, PPARγ2-/-, and wild-type ICP2 cells. EdU proliferation assay showed that both PPARγ2-specific and PPARγ knockouts significantly increased the proliferation rates. Consistently, real-time RT-PCR analysis showed that both PPARγ2-specific and PPARγ knockouts significantly upregulated the expression of proliferation marker genes PCNA and cyclinD1. FACS analysis revealed that PPARγ knockout significantly increased the number of cells accumulating in the S phase and decreased the number of cells accumulating in the G1/G0 phase. Oil Red O staining and gene expression analysis showed both PPARγ2-specific and PPARγ knockouts dramatically reduced capacity for adipogenic differentiation. To corroborate our previous findings, PPARγ1 and PPARγ2 expression were restored in PPARγ-/- cells by using the lentiviruses expressing chicken PPARγ1 (LV-PPARγ1) and PPARγ2 (LV-PPARγ2), respectively. Subsequent assays showed that restoration of expression of either PPARγ1 or PPARγ2 suppressed proliferation and stimulated differentiation of the PPARγ-/- cells. By comparison, PPARγ2 had stronger anti-proliferative and pro-adipogenic effects than PPARγ1. To understand the molecular mechanism underlying their differential effects on differentiation of the PPARγ-/- cells, we performed RNA-seq in the PPARγ-/- cells in which individual PPARγ isoform expression was restored at 72 h of differentiation. Transcriptomic analysis revealed that restoring PPARγ1 expression caused far more differentially expressed genes (DEGs) than restoring PPARγ2 expression. GO and KEGG pathway enrichment analyses indicated that PPARγ1 and PPARγ2 had distinct and overlapping functions in adipogenesis. Taken together, our results clearly indicate that PPARγ1 and PPARγ2 differentially impact chicken adipogenesis.

Lncrna FGD5-AS1 Aggravates Myocardial Ischemia-Reperfusion Injury by Sponging Mir-129-5p.

Background: LncRNA FGD5-AS1 regulates the pathogenesis of many human diseases. We aimed to elucidate the function of lncRNA FGD5-AS1 and the regulatory mechanism of lncRNA FGD5-AS1/miR-129-5p in myocardial ischemia-reperfusion (I/R) injury. Methods: Myocardial I/R injury mice model and H/R treated H9c2 cells were established. RT-qPCR and Western blot analysis were used to detect the mRNA and protein expression. Cell viability was detected by MTT assay. Dual luciferase reporter assay was applied to confirm the relationship between lncRNA FGD5-AS1 and miR-129-5p. Results: LncRNA FGD5-AS1 was upregulated in myocardial I/R injury mice models and H/R treated H9c2 cells. Functionally, knockdown of lncRNA FGD5-AS1 promoted cell viability and inhibited apoptosis in H/R treated H9c2 cells. In addition, lncRNA FGD5-AS1 directly targets miR-129-5p. Upregulation of lncRNA FGD5-AS1 weakened the protective effect of miR-129-5p on myocardial I/R injury. Conclusion: LncRNA FGD5-AS1 aggravates myocardial I/R injury by downregulating miR-129-5p.

Does authoritarianism necessarily stifle creativity? The role of discipline-focused authoritarian leadership.

A burgeoning body of research has shown that authoritarian leadership (AL) embodies the characteristics of "light" and "dark," meaning that it does not always have a negative impact on employees' creative activities. However, studies explaining this potential positive effect are insufficient. To extend the AL and creativity literature, we draw on self-determination theory and event system theory, and elicit discipline-focused AL and appointment event criticality to examine whether, when, and how authoritarian leaders affect employee creativity positively. With time-lagged data collected from 435 employees and their direct leaders in China, we found that discipline-focused AL has an indirect positive effect on employee creativity through creative self-efficacy. Additionally, appointment event criticality strengthens the positive relationship between discipline-focused AL and creative self-efficiency, and the indirect impact of discipline-focused AL on employee creativity through creative self-efficiency. The theoretical and practical implications are discussed.

An effective method to reduce lymphatic drainage post-lateral cervical lymph node dissection of differentiated thyroid cancer: a retrospective analysis.

BACKGROUND: Lymph or chyle leak (LL/CL) is severe complications after lateral cervical lymph node dissection (LLND), mainly due to iatrogenic injury of the lymphatic duct. Efficient and well-operated methods to reduce postoperative drainage are still lacking. This was a feasibility study to evaluate a new method of preventing LL/CL compared to conventional treatment. METHOD: We retrospectively analyzed 20 consecutive patients who used the "pedicled omohyoid flap covering (POFC)" method during LLND from January 2019 to December 2021 in our center as an observation group. Another 20 consecutive patients used the conventional method during LLND in this period as a control group. The clinical and pathological features of the two groups were compared, and the related factors that affected postoperative lymphatic drainage were analyzed with Cox proportional hazards models. RESULTS: The drainage volume per 24 h and the incidence of LL/CL in the control group were both higher than that in the observation group (all P < 0.05), and the number of lymph nodes dissected in the IV region > 10 and the use of the POFC method were the independent risk factors that significantly affected the incidence of LL/CL post LLND (all P < 0.05). CONCLUSIONS: POFC is a safe and useful method for reducing drainage and preventing LL/CL post-LLND, especially for patients with heavy metastasis of the lymph nodes in the IV region.

Effect of PFKFB4 on the Prognosis and Immune Regulation of NSCLC and Its Mechanism.

Background: NSCLC (non-small cell lung cancer) has become the malignancy with the highest incidence and mortality rate worldwide. Fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a key regulator of glycolysis with both kinase and phosphatase activities. The Warburg effect, or increased glycolysis in tumors, provides the metabolic basis for cancer cell proliferation and metastasis, and the Warburg pathway enzyme PFKFB4 is a newly identified important kinase. This study aimed to elucidate the poor prognostic relevance of PFKFB4 in non-small cell lung cancer tissues and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints. Methods: In this study, immunohistochemical methods were used to assess PFKFB4 expression levels in 140 surgical specimens from patients with histologically confirmed non-small cell lung cancer and to investigate the relationship between PFKFB4 expression levels and the patients' clinicopathological characteristics. The impact of PFKFB4 expression on prognosis was evaluated using Kaplan-Meier survival analysis and Cox regression analysis. Results: When compared to normal paracrine tissues, PFKFB4 expression was enhanced in lung cancer tissues, and Kaplan-Meier survival analysis revealed that patients with high PFKFB4 expression had a worse prognosis. In NSCLC, PFKFB4 was found to be associated with immune cell infiltration and immunological checkpoints. Conclusion: PFKFB4 expression may be upregulated as a sign of poor prognosis in NSCLC, and PFKFB4 may be implicated not only in the genesis and progression of NSCLC but also in its immunological control.

SLC6A8 is a Potential Biomarker for Poor Prognosis in Lung Adenocarcinoma.

Background: Recent studies have demonstrated that creatine can promote tumor metastasis and has implications for immune cell function. SLC6A8 encodes a membrane protein that can transport creatine inside and outside the cell. However, there are currently no studies of SLC6A8 in lung adenocarcinoma (LUAD). Methods: In this study, the expression of SLC6A8 in LUAD was analyzed using the Oncomine database, the Cancer Genome Atlas (TCGA) database, and immunohistochemical staining analysis. Survival analysis of patients with LUAD was performed using the cBioPortal and the Kaplan-Meier Plotter websites and clinical follow-up data. An analysis of the association between SLC6A8 and the tumor immune microenvironment (TIME) of LUAD was performed through the TISIDB database and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm. Then, based on the curated list of SLC6A8-related immunomodulators, three genes (NT5E, CD40LG, CD80) were selected to construct SLC6A8-related immune signatures to further evaluate the immune aspect of LUAD prognosis. Results: Our studies indicated that SLC6A8 was overexpressed in LUAD, and the high expression of SLC6A8 was associated with poor survival. Genetic alteration of SLC6A8 was also associated with a poorer prognosis. Furthermore, multivariate Cox analysis indicated that SLC6A8 could be used as an independent risk prognostic factor. Then, immune infiltration analysis indicated that SLC6A8 was also strongly associated with poor prognosis in the TIME of LUAD. A multivariate Cox proportional hazard model was then constructed, and was shown effective at identifying high-risk patients. Univariate and multivariate Cox analysis showed that the risk scoring of the model was an independent prognostic risk factor in LUAD. Conclusion: SLC6A8 may serve as a biomarker for poor prognosis in LUAD.

Corrigendum: Long Non-Coding RNA AL513318.2 as ceRNA Binding to hsa-miR-26a-5p Upregulates SLC6A8 Expression and Predicts Poor Prognosis in Non-Small Lung Cancer.

[This corrects the article DOI: 10.3389/fonc.2022.781903.].

Long Non-Coding RNA AL513318.2 as ceRNA Binding to hsa-miR-26a-5p Upregulates SLC6A8 Expression and Predicts Poor Prognosis in Non-Small Lung Cancer.

BACKGROUND: Studies have demonstrated that the regulatory role of competitive endogenous RNA (ceRNA) networks is closely related to tumorigenesis, which provides new targets for tumor therapy. In this study, the focus was to explore the ceRNA networks that regulate SLC6A8 expression and their prognosis in non-small cell lung cancer (NSCLC). METHODS: Firstly, the Cancer Genome Atlas (TCGA) data combined with immunohistochemical staining was used to compare SLC6A8 expression in NSCLC tissues and normal tissues. Thereafter, samples from the immunohistochemical staining of NSCLC were integrated with clinical follow-up data for prognostic analysis. The Starbase database was employed to search for SLC6A8-targeted miRNAs and lncRNAs, and survival analysis was performed using clinical data from TCGA to obtain SLC6A8 expression and prognosis-related ceRNA networks. Finally, the prognostic and therapeutic prospects of SLC6A8 in NSCLC were further analyzed from methylation sites and the immune microenvironment. RESULTS: The study results revealed that SLC6A8 was significantly overexpressed in NSCLC tissues compared to normal tissues, and clinical follow-up data showed that the overexpression group was associated with poor prognosis. In addition, the Starbase data combined with TCGA clinical data analysis demonstrated that the AL513318.2/hsa-miR-26a-5p/SLC6A8 network regulates SLC6A8 overexpression in NSCLC and is associated with poor prognosis. Methylation analysis revealed that 11 methylation sites were closely associated with the prognosis of NSCLC. In addition, the immune prognostic risk model showed that the high-risk group was associated with a poorer prognosis than the low-risk group, despite showing a better immunotherapy outcome. CONCLUSION: In summary, the AL513318.2/hsa-miR-26a-5p/SLC6A8 network upregulates SLC6A8 expression in NSCLC and is associated with poor prognosis. Therefore it may be a prognostic biomarker of NSCLC and a potential therapeutic target.

m6A Regulator-Mediated Methylation Modification Patterns and Characterisation of Tumour Microenvironment Infiltration in Non-Small Cell Lung Cancer.

Purpose: The role of RNA N6-methyladenosine (m6A) modification in the progression of multiple tumours and the tumour microenvironment (TME) has been progressively demonstrated and promises a new direction for tumour therapy. However, there have been no reports on systematic analyses of RNA m6A modification in TME in non-small cell lung cancer (NSCLC). Patients and Methods: In this study, we used unsupervised cluster analysis to identify three m6A modification patterns of 28 m6A regulators and three m6A gene signature subgroups of commonly differentially expressed genes (co-DEGs) in the three m6A modification patterns. Quantifying these subtypes using the ssGSEA and ESTIMATE algorithms to characterise the tumour immune microenvironment (TIME) in NSCLC. Based on the principal component analysis (PCA), we used co-DEGs to construct m6A scores to analyse the characteristics of m6A modifications in individual patients and assessed the practical clinical utility of m6A scores using a nomogram for survival prediction. Results: A total of 28 m6A regulators in 1210 NSCLC samples were mainly enriched in RNA modification and metabolic biological processes. The three following m6A modification patterns were identified based on the role of the 28 m6A regulators in TME: immune inflammation, immune evasion and immune desert. The m6A scores calculated based on co-DEGs in these modification patterns were significantly positively correlated with immune infiltration and significantly negatively correlated with tumour mutational burden (TMB). Survival was significantly better in the high-m6A-score group than in the low-m6A-score group, and the m6A score could be used as an independent favourable prognostic factor. In addition, assessment of both immune checkpoint inhibitors (ICIs) and immunophenoscore (IPS) revealed a better immunotherapeutic effect in the high-m6A-score group. Conclusion: The modification characteristics of 28 m6A regulators in the TIME of NSCLC were analysed from a comprehensive to an individual basis, which may facilitate the development of more effective clinical immunotherapeutic strategies.

The Effect of the Appropriate Timing of Radiotherapy on Survival Benefit in Patients with Metastatic Esophageal Cancer Who Have Undergone Resection of Primary Site: A SEER Database Analysis.

Background: Metastatic esophageal cancer (MEC) is an advanced stage of esophageal cancer. However, still, resection of primary site and radiotherapy are considered treatment modalities to treat patients with MEC. Hence, this study is aimed at exploring the effect of the appropriate timing of radiotherapy on the survival benefit of these patients by comparing cancer-specific survival (CSS). Method: The patient information was obtained from the National Surveillance Epidemiology and End Results (SEER) database between the years 2004 and 2017. We used the SEER∗ STAT (V8.3.9.2) software to search and download data. Patients treated with pre- and postoperative radiotherapy were divided into two groups. The propensity score matching (PSM) analysis was performed to increase the comparability of data within two groups. We used the Kaplan-Meier method to analyze and compare the CSS between the two groups. The Cox risk model was used to analyze variables affecting patient survival. Results: A total of 599 patients with MEC who experienced resection of the primary site and radiotherapy were recruited. 144 pairings formed through PSM. The 5-year CSS was 23.0% and 11.7% for patients who have undergone pre- and postoperative radiotherapy, respectively. Patients who have undergone preoperative radiotherapy showed better CSS than those who received postoperative radiotherapy (P < 0.001). The multivariate Cox analysis of the entire cohort showed that age > 60 years at the time of diagnosis (HR = 1.481, 95% CI: 1.1341-1.934, and P = 0.04) and other histological types of esophageal cancer (HR = 1.581, 95% CI: 1.067-2.341, and P = 0.022) increased the risk of cancer-related death. Inversely, marriage (HR = 0.696, 95% CI: 0.514-0.942, and P = 0.019) and preoperative radiotherapy (HR = 0.664, 95% CI: 0.517-0.853, and P < 0.001) reduced the risk of death from cancer. Conclusions: For patients with MEC, preoperative radiotherapy might have a significant effect on the survival benefit over those who receive postoperative radiotherapy.

Circular RNA-UBE2D2 accelerates the proliferation and metastasis of non-small cell lung cancer cells via modulating microRNA-376a-3p/Eukaryotic Translation Initiation Factor 4γ2 axis.

Non-small cell lung cancer (NSCLC) ranks first in the morbidity and mortality of malignant tumors in China. As reported, circular RNAs (circRNAs) are emerged in the progress of NSCLC. The study was to figure out the potential mechanism of circ-UBE2D2 in the progression of NSCLC. First, plasmid vectors intervening circ-UBE2D2, microRNA (miR)-376a-3p or Eukaryotic Translation Initiation Factor 4γ2 (EIF4G2) expression were transfected into NSCLC cells, and the expression of circ-UBE2D2, miR-376a-3p and EIF4G2 was detected by reverse transcription quantitative polymerase chain reaction or Western blot. Then, cell proliferation was detected by Cell counting kit-8 assay and plate cloning. Cell apoptosis was tested by flow cytometry. Plate scratches and Transwell were used to detect cell migration and invasion. Finally, the binding sites of circRNA UBE2D2, EIF4G2 and miR-376a-3p were verified by bioinformatics website starBase analysis and dual luciferase reporter gene assay. The results manifested the up-regulation of circ-UBE2D2 expression in NSCLC tissues and cells. Circ-UBE2D2 promoted the proliferation, migration and invasion, but repressed apoptosis of NSCLC cells. Interestingly, circ-UBE2D2 directly targeted miR-376a-3p and up-regulated miR-376a-3p restrained proliferation, migration and invasion, but accelerated apoptosis of NSCLC cells. More importantly, EIF4G2 was the target of miR-376a-3p, and overexpression of EIF4G2 reversed the effects of circ-UBE2D2 downregulation on proliferation, migration, invasion and apoptosis of NSCLC cells. These results suggest that circ-UBE2D2 promotes the proliferation, migration and invasion but restrains apoptosis of lung cancer cells by regulating miR-376a-3p/EIF4G2 axis.

NCAPG is a prognostic biomarker of immune infiltration in non-small-cell lung cancer.

Purpose: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. The protein NCAPG plays a significant role in tumor development. Patients & methods: We set up a tissue microarray (containing 140 NSCLC and ten normal lung tissues) and performed immunohistochemistry to assess NCAPG expression in the tissues of 140 patients. The prognostic value of NCAPG in NSCLC was assessed using the univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots. We analyzed the association between NCAPG and immune infiltration in NSCLC. Results: Multifactorial analysis and Kaplan-Meier plots revealed that upregulation of NCAPG expression was an independent factor in the prognosis of NSCLC. Data from CIBERSORT showed a negative correlation between NCAPG and the expression of memory CD4+ T cells, CD8+ T cells, dendritic cells, macrophages, mast cells and natural killer cells (p < 0.001). Gene set enrichment analysis revealed that cell cycle, adhesion and proliferation were significantly enriched in samples with a high NCAPG expression. Conclusion:NCAPG is a novel biomarker of prognosis and is associated with immune cell infiltration in the tumor microenvironment. Thus it may be a potential target in NSCLC treatment.

High platelet count predicts poor prognosis in HCC patients undergoing TACE: a propensity score-matched analysis.

BACKGROUND: The aim of this study was to retrospectively evaluate the prognostic value of the pretreatment platelet (PLT) count in patients with hepatitis B virus (HBV)-related intermediate-advanced hepatocellular carcinoma (HCC) complicated with cirrhosis undergoing transcatheter arterial chemoembolization (TACE). RESEARCH DESIGN AND METHODS: We assessed 362 patients with HBV-related intermediate-advanced HCC complicated with cirrhosis undergoing TACE. Patients were divided into low (≤96 × 109/L) and high (>96 × 109/L) PLT groups. Propensity score matching (PSM) was performed to eliminate the imbalance in potential confounding factors. The endpoint was time to progression (TTP). RESULTS: After PSM, the high and low PLT groups had 97 patients each. The TTP was significantly longer in the low PLT group than in the high PLT group (log-rank test, p < 0.001). A high pretreatment PLT count was an independent predictor of poor tumor response (OR 4.724; 95% CI 1.889-11.815; P = 0.001) and short TTP (HR = 3.598; 95% CI: 2.570-5.036; P < 0.001). Subgroup analysis showed that a high PLT count increased the risk of progression across almost all subgroups. CONCLUSIONS: The pretreatment PLT count has potential value in predicting the prognosis of patients with intermediate-advanced HCC undergoing TACE.