BACKGROUND: Lung cancer is one of the leading causes of cancer-related mortality worldwide, with above 80% of cases be non-small cell lung cancer (NSCLC), among which lung squamous cell carcinoma (LUSC) occupies a significant proportion. Although comprehensive cancer therapies have considerably improved the overall survival of patients, patients with advanced LUSC have a poorer prognosis. Therefore, there is a need for a biomarker to predict the progress of advanced LUSC in order to improve prognosis through early diagnosis. Previous studies have shown that miRNAs are differentially expressed in lung cancer tissues and play roles as potential oncogenes or tumor suppressors. The aim of this study is to identify differentially expressed miRNAs between early-stage and advanced-stage LUSC, and to establish a set of miRNAs that can predict the progress of advanced LUSC. METHODS: Clinical data and miRNA-related data of LUSC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Bioinformatic methods were applied to analyze the data. Receiver operating characteristic (ROC) curves were plotted, and various online tools were used to predict target genes, with subsequent analysis of the potential biological mechanisms of these genes. RESULTS: A total of 58 differentially expressed miRNAs were identified between the experiment group and the control group. Seven miRNAs were selected for potential construction of a miRNA biomarker through LASSO regression, and based on the area under the curve (AUC) values of each miRNA, four of these miRNAs (miR-377-3p, miR-4779, miR-6803-5p, miR-3960) were ultimately chosen as biomarkers for predicting advanced LUSC. The AUC under the ROC curve for the combined four miRNAs was 0.865. Enrichment analysis showed that these target genes were involved in several pathways, including cancer-related pathways, mitogen-activated protein kinase (MAPK) signaling pathway, serine/threonine kinase, and tyrosine kinase signaling pathways. CONCLUSIONS The combined use of miR-377-3p, miR-4779, miR-6803-5p and miR-3960 provides a good predictive ability for the progress of advanced LUSC patients, with an AUC of 0.865.
Humans ; MicroRNAs/metabolism* ; Lung Neoplasms/metabolism* ; Biomarkers, Tumor/metabolism* ; Carcinoma, Squamous Cell/pathology* ; Gene Expression Regulation, Neoplastic ; Male ; Female ; Prognosis ; ROC Curve ; Middle Aged

Background and purpose:Abnormal DNA methylation is closely associated with the onset and progression of tumors.This study aimed to investigate the expression of intermediate filament family orphan 1(IFFO1),a methylation-driven gene(MDG)in pancreatic adenocarcinoma(PAAD),along with its effects on the invasion and metastasis of PAAD cells,as well as its potential as a diagnostic and prognostic biomarker.Methods:mRNA expression data(TCGA-PAAD-mRNA),DNA methylation data(TCGA-PAAD-meth,GSE53051,PACA-AU)of PAAD and adjacent normal tissues,as well as DNA methylation data of healthy individuals'blood(GSE69270),were obtained from the The Cancer Genome Atlas(TCGA),International Cancer Genome Consortium(ICGC)and Gene Expression Omnibus(GEO)databases.By performing differential expression analysis combined with differential methylation analysis,we screened for MDG in PAAD.In the TCGA database,Pearson correlation tests were employed to verify the relationship between IFFO1 promoter methylation level and its expression level.Additionally,Kaplan-Meier survival analysis was conducted to evaluate the relationship among IFFO1 promoter methylation level,expression level,and the prognosis of PAAD.Pathological sections of cancer tissues and corresponding adjacent tissues from 27 PAAD patients were obtained from Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine.All samples involved in this study were approved by the human ethics committee of Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine(ethics number:hospital ethics review[2017]No.53).Immunohistochemistry staining(IHC)was utilized to detect the expression of IFFO1 in cancer tissues and corresponding adjacent tissues from 27 PAAD patients.Based on the median expression level of IFFO1,patients in the TCGA database were classified into high-expression and low-expression groups.Subsequently,differential analysis,gene ontology(GO)enrichment analysis and gene set enrichment analysis(GSEA)were performed.Western blot and real-time fluorescence quantitative polymerase chain reaction(RTFQ-PCR)were employed to assess the expression variations of IFFO1 between the normal pancreatic ductal epithelial cell line H6C7 and the PAAD cell lines MIA PaCa2,BxPC-3,AsPC-1 and Capan-2.The impact of IFFO1 overexpression on the migration and invasion capacities of PAAD cell lines AsPC-1 and Capan-2 was evaluated using scratch and invasion assays.Additionally,receiver operating characteristic(ROC)curves and Kaplan-Meier survival analysis were utilized to assess the diagnostic and prognostic significance of IFFO1 methylation levels in the TCGA pan-cancer cohort.Results:Through the cross-screening of five datasets,41 MDG in PAAD were identified.Among these,IFFO1 was found to be the gene most closely associated with the prognosis of PAAD[hazard ratio(HR)=0.28,P＜0.001].IFFO1 exhibited high methylation and low expression levels in PAAD.Moreover,a significant negative correlation was observed between the methylation level of its promoter and its expression level(r=-0.55,P＜0.001).IHC results indicated that IFFO1 expression was significantly lower in PAAD tissues than in adjacent non-tumor tissues(P＜0.05).TCGA survival analysis demonstrated that patients with high methylation or low expression of IFFO1 had poorer overall survival(P＜0.05).Both GO and GSEA analyses indicated that the pathway"Negative regulation of cell migration"was enriched in patients with high IFFO1 expression.Western blot and RTFQ-PCR results demonstrated that IFFO1 expression in normal pancreatic ductal epithelial cells H6C7 was significantly higher compared with PAAD cell lines MIA PaCa2,BxPC-3,AsPC-1,and Capan-2.Overexpression of IFFO1 significantly inhibited the migration and invasion of the PAAD cell lines AsPC-1 and Capan-2.Additionally,pan-cancer analysis revealed that IFFO1 exhibited abnormal promoter methylation and low expression across various cancer types,with its methylation levels demonstrating significant diagnostic and prognostic prediction value among different tumors.Conclusion:Promoter hypermethylation results in decreased expression of IFFO1 in PAAD.IFFO1 may suppress the invasion and migration abilities of PAAD cells.Furthermore,IFFO1 methylation holds great promise as a novel biomarker for the diagnosis and prognosis of PAAD.

BACKGROUND: Lung cancer represents the main cause of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) is the most main subtype. More than half of NSCLC patients have already developed distant metastasis (DM) at the time of diagnosis and have a poor prognosis. Therefore, it is necessary to find new biomarkers for predicting NSCLC DM in order to guide subsequent treatment and thus improve the prognosis of NSCLC patients. Numerous studies have shown that microRNAs (miRNAs) are abnormally expressed in lung cancer tissues and play an important role in tumorigenesis and progression. The aim of this study is to identify differentially expressed miRNAs in lung adenocarcinoma tissues with DM group compared to those with non-distant metastasis (NDM) group, and to construct a miRNA signature for predicting DM of lung adenocarcinoma. METHODS: We first obtained miRNA and clinical data for patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database. Subsequently, bioinformatics analysis, which included different R packages, Kaplan-Meier analysis, receiver operating characteristic (ROC) curve, and a range of online analysis tools, was performed to analyze the data. RESULTS A total of 12 differentially expressed miRNAs were identified between the DM and NDM groups, and 8 miRNAs (miR-377-5p, miR-381-5p, miR-490-5p, miR-519d-5p, miR-3136-5p, miR-320e, miR-2355-5p, miR-6784-5p) were screened for constructing a miRNA signature. The efficacy of this miRNA signature in predicting DM was good with an area under the curve (AUC) of 0.831. Logistic regression analysis showed that this miRNA signature was an independent risk factor for DM of lung adenocarcinoma. Next, target genes of the eight miRNAs were predicted, and enrichment analysis showed that these target genes were enriched in a variety of pathways, including pathways in cancer, herpes simplex virus I infection, PI3K-Akt pathway, MAPK pathway, Ras pathway, etc. CONCLUSIONS: This miRNA signature has good efficacy in predicting DM of lung adenocarcinoma and has the potential to be a predictor of DM of lung adenocarcinoma.
Humans ; MicroRNAs/metabolism* ; Lung Neoplasms/diagnosis* ; Male ; Neoplasm Metastasis ; Female ; Gene Expression Regulation, Neoplastic ; Middle Aged ; Prognosis ; Gene Expression Profiling ; Aged ; Biomarkers, Tumor/genetics*

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

Objective:To compare the laparoscopic and open surgery in the treatment of Mirizzi syndrome (MS).Methods:The clinical data of 125 patients with MS undergoing surgery in Tianjin Nankai Hospital from May 2013 to April 2020 were retrospectively analyzed, including 59 males and 66 females, aged (57.7±13.6) years old. Patients were divided into the laparoscopic group ( n=84) and open group ( n=41). General data, operation time, intraoperative blood loss, postoperative complications, postoperative and total hospital were compared between the groups. Patients were followed up and screened for biliary stone recurrence or biliary stenosis by phone or Wechat. Results:The postoperative hospital stay [8.00(5.25, 12.00) d vs. 13.00(10.00, 17.50) d, P<0.001] and total hospital stay [15.00 (10.25, 22.75) d vs. 22.00 (16.00, 27.50) d, P<0.001] were shorter in laparoscopic group. The conversion rate of laparoscopic group was 15.5% (13/84). No perioperative death occurred in either group. The incidence of postoperative complications were comparable between the groups [9.5%(8/84) vs. 7.3%(3/41), P>0.05]. In laparoscopic group, 64 patients were followed up [76.2% (64/84)]. During follow-up, there were two deaths, five cases of bile duct stones recurrence and one case of bile duct stenosis. In open group, 37 patients were followed up [90.2% (37/41)]. During follow-up, there were four deaths, four cases of bile duct stones recurrence. All deaths during follow-ups were non-MS-related. Conclusion:Compared to open surgery, laparoscopic surgery could shorten the total/postoperative hospital stay while does not increase the morbidity and mortality, which could be safe and feasible in the treatment of MS.

Objective:To explore the value of radiomics model based on intratumoral and peritumoral early dynamic contrast-enhanced (DCE) MRI for identifying benign and malignant in breast imaging reporting and data system (BI-RADS) 4 tumors.Methods:A total of 191 patients diagnosed with BI-RADS 4 breast tumors by breast MRI examination with clear pathological diagnosis from January 2016 to December 2020 in the First Affiliated Hospital of Bengbu Medical College were analyzed retrospectively, including 77 benign and 114 malignant cases, aged 23-68 (46±10) years. The one-slice image with the largest area of the lesion of the second stage DCE-MRI images was selected to outline the region of interest, and automatically conformal extrapolated by 5 mm to extract the intra-tumoral and peritumoral radiomics features. The included cases were randomly divided into training and testing cohorts in the ratio of 8∶2. The statistical and machine learning methods were used for feature dimensionality reduction and selection of optimal radiomics features, and logistic regression was used as the classifier to establish the intratumoral, peritumoral, and intratumoral combined with peritumoral radiomics models. The independent risk factors that could predict the benignity and malignancy of breast tumors were retained as clinical-radiological characteristics by univariate and multivariate logistic regression to establish a clinical-radiological model. Finally, the intratumoral and peritumoral radiomics features were combined with clinical-radiological features to develop a combined model of the three. The receiver operating curve was used to analyze the predictive performance of each model and calculate the area under the curve (AUC),the AUC was compared by DeLong test. The stability of the three-component combined diagnostic model was tested by 10-fold cross-validation, and the model was visualized by plotting nomogram and calibration curves.Results:In the training cohort, the AUC of the three-component combined model for identifying benign and malignant BI-RADS 4 breast tumors was significantly higher than that of the intratumoral radiomics model ( Z=3.38, P<0.001), the peritumoral radiomics model ( Z=4.01, P<0.001), the intratumoral combined with peritumoral radiomics model ( Z=3.11, P=0.002), and the clinical-radiological model ( Z=3.24, P=0.001). And the AUC, sensitivity, specificity, accuracy, and F1-score of the three-component combined model were 0.932, 91.2%, 86.9%, 87.0% and 0.89, respectively. In the testing cohort, the three-component combined model also had the highest AUC value (0.875), and diagnostic sensitivity, specificity, accuracy and malignancy F1-score were 95.7%, 62.5%, 76.9%, and 0.89, respectively. The AUC calculated by 10-fold cross-validation was 0.90 (0.85-0.92), and the predicted curve of the three-component combined model in the calibration curve was in good agreement with the ideal curve. Conclusion:The three-component combined diagnostic model based on the intratumoral and peritumoral radiomics features and clinical-radiological features of early DCE-MRI has good performance and stability for identifying the benign and malignant in BI-RADS 4 breast tumors, and it can provide guidance for clinical decision non-invasively.

We report the clinical characteristics of congenital malignant rhabdoid tumor (MRT) of the neck in a fetus. Prenatal ultrasound and MRI at 33 +4 and 34 weeks gestation revealed a round solid mass on the right side of the fetus' neck. An initial differential diagnosis was between neuroblastoma and vascular malformation. Re-examination with ultrasound at 36 gestational weeks revealed an enlarged fetal neck mass, with concomitant multiple subcutaneous solid masses all over his body, right-side hydrothorax, and abnormal liver echo, which were highly suspicious of metastasis of a malignant tumor. The baby boy was delivered by cesarean section at 37 weeks of gestation with a normal Apgar score and slight shortness of breath. Physical examination showed scattered lesions in the neck, armpits, and limbs, etc. The condition of the infant deteriorated rapidly with the increasing number and volume of the masses after admission. The boy was confirmed as MRT (stage Ⅳ) by pathological biopsy on the left upper arm and died on postnatal day 10 after treatment was withdrawn.

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor ROR