BACKGROUND:Conventional obesity definitions overlook heterogeneity related to metabolic health and muscle strength. This study examined the associations between dynapenic-metabolic obesity (DMO) and incident stroke among middle-aged and older Chinese adults. METHODS:Our study included 11,770 participants aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018) with 2011 as baseline. Dynapenia was defined by handgrip strength (<28 kg for men, <18 kg for women); metabolic dysfunction by ≥2 of 4 criteria (hypertension, dyslipidemia, impaired glycemia, or low HDL-C); and obesity by BMI ≥25 kg/m2 (general obesity) or waist circumference ≥ 90 cm for men and ≥ 85 cm for women (abdominal obesity). Cox models estimated hazard ratios (HRs) for stroke, adjusting for covariates. Mediation analysis evaluated the roles of C-reactive protein (CRP) and intrinsic capacity (IC). RESULTS:During follow-up, 787 participants (6.7%) experienced stroke. Obesity alone, without dynapenia or metabolic dysfunction, was associated with elevated stroke risk (general obesity: HR 1.50, 95% CI 1.15-1.95; abdominal obesity: HR 1.55, 95% CI 1.21-1.98). The highest risk was observed in participants with combined dynapenia and metabolic dysfunction (DMGO: HR 2.97, 95% CI 2.01-4.37; DMAO: HR 2.96, 95% CI 2.08-4.21). Mediation analyses indicated that systemic inflammation and reduced intrinsic capacity partially explained these associations. Findings were consistent across subgroups and sensitivity analyses. CONCLUSIONS:Dynapenic-metabolic obesity is strongly associated with incident stroke, but even obesity alone increases risk. Systemic inflammation and impaired intrinsic capacity partially mediate these effects, highlighting the importance of integrated strategies targeting adiposity, metabolic health, and muscle function to prevent stroke in aging populations.

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function, high morbidity and mortality, and a lack of effective early diagnostic markers or targeted therapies. To address this critical unmet need, we employed an integrated multi-omics and network pharmacology approach to systematically investigate the molecular mechanisms and potential therapeutic targets of AKI. Core targets were identified through differential gene expression (DEG) analysis combined with weighted gene co-expression network analysis (WGCNA), followed by exploration using protein-protein interaction (PPI) networks and pathway enrichment analyses. Inflammation, oxidative stress, and energy metabolism emerged as key pathways involved in AKI pathogenesis. Using ten CytoHubba algorithms and the MCODE module for comprehensive screening, we identified three hub genes-ACO2, FBP1, and PFKL. Their expression patterns and cellular specificity were further characterized using single-cell RNA sequencing data from AKI renal tissues. Additionally, we constructed a miRNA-hub gene regulatory network, providing insights into miRNA-based therapeutic strategies. Molecular docking analysis identified three approved drugs-Ajmaline, Cimetidine, and Tretinoin-with strong binding affinities to the hub proteins, suggesting their potential for repurposing in AKI treatment. Finally, by reviewing knockout mouse models from the Mouse Genome Informatics (MGI) database and conducting in vitro cell experiments, we explored the in vivo and in vitro roles of these core targets, providing experimental evidence of their physiological relevance. Overall, this study integrates cross-cohort transcriptomic profiling, network-based hub prioritization, single-nucleus cell-type localization, translational drug repurposing analyses, and in vitro experimental validation thereby providing a multi-layered framework to prioritize candidate biomarkers for AKI.

BACKGROUND:Previous studies on the risk factors and prognosis of acute stroke in pregnancy and puerperium (ASPP) mainly used European and American national healthcare databases, lacking detailed patient-level data and precise event timing. AIM:(1) To identify the risk factors and prognostic factors for ASPP, (2) to assess the risk of recurrent stroke, particularly during subsequent pregnancies, and (3) to evaluate offspring prognosis. DESIGN:This study is a retrospective, observational, nationwide, multicenter research project planned to include 400 ASPP patients from 36 centers across 22 provinces in China, from 2015 to 2024. ASPP is defined as acute ischemic or hemorrhagic stroke during pregnancy or within 6 weeks postpartum, confirmed by neuroimaging. Two matched groups will be included for comparison: 400 pregnant/puerperal participants without a stroke history and 400 nonpregnant/puerperal participants with a recent stroke, matched by age and/or stroke etiology. METHODS:All participants will be followed up through telephone interviews. The initial follow-up is scheduled to take place between December 2024 and February 2025. The follow-up phase will consist of three rounds, each lasting 3 months and conducted every 3 years. Primary outcomes include unfavorable functional outcomes (mRS > 2 or EQ-5D index score < 0.7) at follow-up for Aim 1, recurrent strokes (neuroimaging-confirmed) for Aim 2, and neonatal asphyxia (Apgar scoring) and future development (ASQ-3) of offspring for Aim 3. DISCUSSION:The ASPP study is the first nationwide multicenter study to systematically evaluate the risk factors, prognosis, and risk of recurrent stroke in ASPP patients, particularly during subsequent pregnancies. This research may offer new insights into the long-term impacts of pregnancy-related stroke. TRIAL REGISTRATION:ClinicalTrials.gov (NCT06527807).

Objective: This study aims to identify the clinical characteristics of Moyamoya disease (MMD) combined with psychiatric disorders and explore the potential pathogenesis. Material and methods: Psychiatric disorders between 88 MMD patients and 72 health controls were investigated using psychological testing scales. We subsequently analyzed the clinical features of 72 MMD patients with psychiatric comorbidities retrospectively. Finally, neurotransmitters analysis was conducted to further explore the pathogenesis. Results: Results of self-testing scales revealed a significantly higher susceptibility of psychiatric disorders in MMD patients. Compared with MMD group, clinical features of combined group demonstrated significant differences in age (51.3 +/- 9.6 vs. 40.9 +/- 10.4, p = 0.000), gender of female (68.1 % vs. 51.3 %, p = 0.018), duration time (33.3 +/- 44.6mon vs. 8.1 +/- 15.3mon, p = 0.000), cerebral infarction (55.2 % vs. 70.8 %, p = 0.025), initial type, Suzuki stage and mRS scores (p < 0.05). The perfusion results revealed significantly decreased time to peak in frontal parietal lobe (1854.14 +/- 238.62 vs. 1242.79 +/- 115.99, p = 0.025), temporal occipital lobe (1721.55 +/- 245.15 vs. 1165.71 +/- 111.55, p = 0.040), lateral ventricle (1840.03 +/- 256.88 vs. 1221.95 +/- 115.53, p = 0.028), and the cerebral blood volume of temporal occipital lobe was found significantly decreased (300.36 +/- 34.93 vs. 403.23 +/- 19.70, p = 0.026), and remarkable lower incidence of hyperperfusion syndrome and subdural effusion were demonstrated. Differential neurotransmitters of decreased 3-htdroxybutyric acid expression and increased sarcosine, tyrosine, betaine aldehyde chloride, kynurenic acid, glycine, succinic acid and lysine were identified in combined group. Conclusions: Patients of MMD combined with psychiatric disorders presented unique clinical characteristics. Neurotransmitters disorder may be involved in the pathogenesis. These results provided novel clinical management evidence and new insights in pathologic mechanism of MMD combined with psychiatric disorders.

This study aims to develop and validate nomograms for predicting the risk of aneurysm rupture and adverse prognosis in patients with Moyamoya disease (MMD) and associated intracranial aneurysms (IAs). We analyzed 286 saccular and 22 non-saccular IAs from 231 MMD patients. We used logistic regression to identify risk factors for IA rupture and Cox regression to find factors associated with prognosis. Nomograms were constructed using R 4.3.3 software based on these risk factors and validated via receiver operating characteristic (ROC) curves, calibration curves, and clinical decision curves. Among 3293 MMD patients, 231 (7.01%) harbored IAs. Saccular IAs had a higher rupture rate (24.2%) compared to non-saccular IAs (13.64%). Independent risk factors for rupture in non-saccular IAs included the presence of a daughter sac, whereas the location, flow angle, and aspect ratiowere risk factors for saccular IA rupture. Prognostic factors included rerupture and modified Fisher scale. The constructed nomograms demonstrated robust predictive performance in the validation cohort. Our nomograms effectively predict the risk of rupture in saccular IAsand poor prognosis in MMD patients with IAs, offering valuable tools for clinical decision-making.

Cerebral ischemiareperfusion injury (CIRI) is a type of secondary brain damage caused by reperfusion after ischemic stroke due to vascular obstruction. In this study, a CIRI diagnostic model was established by identifying hypoxia-related differentially expressed genes (HRDEGs) in patients with CIRI. The ischemiareperfusion injury (IRI)-related datasets were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo), and hypoxia-related genes in the Gene Cards database were identified. After the datasets were combined, hypoxia-related differentially expressed genes (HRDEGs) expressed in CIRI patients were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the HRDEGs were performed using online tools. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed with the combined gene dataset. CIRI diagnostic models based on HRDEGs were constructed via least absolute shrinkage and selection operator (LASSO) regression analysis and a support vector machine (SVM) algorithm. The efficacy of the 9 identified hub genes for CIRI diagnosis was evaluated via mRNAmicroRNA (miRNA) interaction, mRNA-RNA-binding protein (RBP) network interaction, immune cell infiltration, and receiver operating characteristic (ROC) curve analyses. We then performed logistic regression analysis and constructed logistic regression models based on the expression of the 9 HRDEGs. We next established a nomogram and calibrated the prediction data. Finally, the clinical utility of the constructed logistic regression model was evaluated via decision curve analysis (DCA). This study revealed 9 critical genes with high diagnostic value, offering new insights into the diagnosis and selection of therapeutic targets for patients with CIRI. : Not applicable.

Rationale and Objectives: To evaluate the potential of Synthetic Magnetic Resonance Imaging (SynMRI) in identifying muscular invasion in bladder cancer (BCa), and explore whether there is additional value in combination with the Vesical Imaging-Reporting and Data System (VI-RADS). Methods: In this prospective single-center study, pathologically-confirmed BCa were enrolled between May 2023 and November 2023. All participants underwent preoperative multiparametric MRI, including T1/T2 weighted, SynMRI and diffusion-weighted imaging. T1/T2/PD values and apparent diffusion coefficient (ADC) values were compared between muscle invasive (MIBC) and non-invasive (NMIBC) groups. Receiver operating characteristic (ROC) analysis with the variables and their combination was performed to explore the performance of distinguishing the MIBC from NMIBC, and the ROC curves were compared using DeLong's test. Results: A total of 54 BCa patients were enrolled (38 males; NMIBC/MIBC = 37/19) and all assessed with VI-RADS without dynamic enhanced imaging (DCE). Compared to NMIBC group, MIBC group had significantly larger diameter, higher VI-RADS score, lower T2 and ADC values (P < 0.05). VI-RADS score and T2 showed independent predictive value in differentiating NMIBC and MIBC. The combined model (T2 + VI-RADS + Diameter) resulted in significantly improved specificity (0.842), sensitivity (0.914), and AUC (0.943), in comparison to VI-RADS or ADC alone (P < 0.05). Conclusion: T2 relaxation time can be easily obtained from SynMRI in routine clinical protocol and assist VI-RADS score system without DCE to improve differentiation performance in identifying NMIBC and MIBC.

Moyamoya disease (MMD) suffers from impaired cerebrovascular hemodynamics and high perioperative complications occurrence. This study aims to propose and evaluate the relationship between intraoperative hemodynamics and perioperative complications, and propose a potential compensatory self-recirculation network in MMD. We prospectively enrolled 63 MMD patients undergone combined revascularization, and patients were divided into decreased and increased group according to decreased and increased microvascular transit time (MVTT), respectively. Mean age of all patients was 45.9 +/- 9.4 years. The post-bypass hyperperfusion syndrome occurrence was significantly higher in the decreased MVTT group, and the cerebral infarction occurrence was significantly higher in the increased MVTT group. For the hemodynamics of the recipient artery around anastomosis, the parameters of distal site demonstrated a significant higher intensity and shorter time in the decreased MVTT group, while the parameters of the proximal site demonstrated a significant higher intensity and shorter time in the increased MVTT group. Pre-bypass and post-bypass collision of blood flow in artery and vein were firstly observed and illustrated. Intraoperative hemodynamics showed close relationship with perioperative complications. The blood flow of MMD seems to develop a unique compensatory self-recirculation system and contribute to the clinical complications, providing a new insight to the clinical management the pathology of the disease.

Glioma is the most common brain malignancy, characterized by high morbidity, high mortality, and treatment-resistance. Inverted CCAAT box Binding Protein of 90 kDa (ICBP90) has been reported to be involved in tumor progression and the maintenance of DNA methylation. Herein, we constructed ICBP90 over-expression and knockdown glioma cell lines, and found that ICBP90 knockdown inhibited glioma cell proliferation, migration, and invasion. ICBP90 silencing potentially enhanced cellular sensitivity to cis-platinum (DDP) and exacerbated DDP-induced pyroptosis, manifested by the elevated levels of gasdermin D-N-terminal and cleaved caspase 1; whereas, ICBP90 over-expression exhibited the opposite effects. Consistently, ICBP90 knockdown inhibited tumor growth in an in vivo mouse xenograft study using U251 cells stably expressing sh-ICBP90 and oe-ICBP90. Further experiments found that ICBP90 reduced the expression of Dickkopf 3 homolog (DKK3), a negative regulator of β-catenin, by binding its promoter and inducing DNA methylation. ICBP90 knockdown prevented the nuclear translocation of β-catenin and suppressed the expression of c-Myc and cyclin D1. Besides, DKK3 over-expression restored the effects of ICBP90 over-expression on cell proliferation, migration, invasion, and DDP sensitivity. Our findings suggest that ICBP90 inhibits the expression of DKK3 in glioma by maintaining DKK3 promoter methylation, thereby conducing to ICBP90-mediated carcinogenesis and drug insensitivity.

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease that can be treated with revascularization. Surgery increases the risk of poor wound healing (PWH) due to the impact on the blood supply to the flap. We aimed to analyze risk factors for PWH in MMD with a complete Y-shaped incision. A total of 125 patients with MMD were enrolled in this prospective observational study. The wounds were assessed and measured on the third and seventh days after surgery. The mean age of these patients was 43.3 ± 10.0 years. The ratio of male to female was 1:1.3. 15 (12.0%) patients had incision complications. 5 patients (4.0%) had redness; 2 patients (1.6%) had swelling; 2 patients (1.6%) had fat necrosis; 3 patients (2.4%) had incision infection; and 3 patients (2.4%) had flap necrosis. Student's t test showed significant differences in BMI (P = 0.040) and fever time (P = 0.050). The standard chi-squared test showed significant differences in incision infection (P = 0.010), suture mode (P = 0.047), and cutting off large branch vessels in the flap (P < 0.001). Multivariate logistic regression analysis suggested that incision infection (P = 0.026, OR 12.958), using a skin stapler (P = 0.030, OR 4.335), cutting off large branch vessels in the flap (P = 0.009, OR 5.227), and BMI (P = 0.027, OR 1.204) were risk factors. The area under the curve for risk factors for PWH on a receiver operating characteristic curve was 0.853. Incision infection, using a skin stapler, higher BMI, and cutting off large branch vessels in the flap are risk factors for PWH.

Objective:This study aimed to explore the hemodynamic changes before and after anastomosis in patients with Moyamoya disease (MMD) using multiple models.Methods:We prospectively enrolled 42 MMD patients who underwent combined revascularization. Intraoperative FLOW800 was performed before and after anastomosis, and parameters was collected, including maximum intensity, delay time, rise time, slope, blood flow index, and microvascular transit time (MVTT). Additionally, preoperative and postoperative hemodynamic parameters were measured using color Doppler ultrasonography (CDUS), including peak systolic velocity, end-diastolic velocity, resistance index (RI), pulsatility index (PI), and flow volume. Subsequently, the correlation between FLOW800 and CDUS parameters was explored.Results:A total of 42 participants took part with an average age of 46.5 years, consisting of 19 men and 23 women. The analysis of FLOW800 indicated that both the delay time and rise time experienced a substantial decrease in both the recipient artery and vein. Additionally, the MVTT was found to be significantly reduced after the surgery (5.7 ± 2.2 s vs. 4.9 ± 1.6, p = 0.021). However, no statistically significant differences were observed among the other parameters. Similarly, all postoperative parameters in CDUS hemodynamics exhibited significant alterations in comparison to the preoperative values. The correlation analysis between FLOW800 and CDUS parameters indicated a significant association between MVTT and RI and PI, no significant relationships were found among the other parameters in the two groups.Conclusion:The hemodynamic outcomes of the donor and recipient arteries demonstrated significant changes following bypass surgery. The parameter of time appears to be more precise and sensitive in assessing hemodynamics using FLOW800. Multiple evaluations of hemodynamics could offer substantial evidence for perioperative management.

Ischemic stroke (IS), resulting from the occlusion of the cerebral artery and subsequent interruption of blood flow, represents a major and critical threat to public health. Oxidative stress (OS) has been confirmed to play a role in the IS pathological process and neural death. Understanding the essential role of OS-related genes in ischemic stroke is critical to understanding the current perception of the pathophysiological process in IS. Herein, by integrating three IS datasets (GSE16561, GSE22255, and GSE58294), we divided IS samples into the low- and high-OS groups by calculating the OS score identified by the oxidative stress gene set. The functional enrichment analysis of differentially expressed genes (DEGs) between the low- and high-OS groups indicated that DEGs were associated with hypoxia, the inflammatory response, and oxidative phosphorylation pathways. Furthermore, nine hub genes (namely TLR1, CXCL1, MMP9, TLR4, IL1R2, EGR1, FOS, CXCL10, and DUSP1) were identified through the Girvan-Newman algorithm and cytoHubba algorithms. Nine hub genes were highly expressed in IS samples and positively related to neutrophils and macrophages. Drug-sensitive analysis targeting hub genes defined allopurinol and nickel sulfate as potential candidates for impairing the neural death caused by oxidative stress in IS. Finally, we employed five machine learning methods to check the efficacy of the predictive model identified by nine hub genes. The results showed that our model had superior power for predicting the OS activity of IS patients. TLR4 was found to have excellent diagnostic value and a wide-spectrum interaction with other hub genes. Our research emphasized the impact of oxidative stress on ischemic stroke, which supports the idea that antioxidants hold great promise in ischemic stroke therapy.

Objective:To compare the short-term efficacy and complications of superficial temporal artery to middle cerebral artery bypass combined encephalo-myo-synangiosis (STA-MCA+ EMS) and encephalo-duro-arterio-synangiosis (STA-MCA+ EDAS) in the treatment of Moyamoya disease.Methods:A retrospective analysis was conducted on the clinical data of adult patients with Moyamoya disease who underwent STA-MCA+ EMS ( n=75, EMS group) or STA-MCA+ EDAS ( n=176, EDAS group) in the Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University from January 2016 to June 2021. The modified Rankin scale score (mRS) was evaluated at discharge. At 3 and 6 months after surgery, follow-up by telephone or outpatient service was conducted to assess mRS and the presence or absence of recent complications, and re-examination of imaging examinations was performed to assess the bypass vessel patency rate and Matsushima grade. We compared the baseline data, clinical efficacy and complications of the two groups of patients. Results:Intraoperative indocyanine green angiography of 251 patients revealed the patency of bypass vessels. There was 1 death in the EMS group and 2 deaths in the EDAS group. The median follow-up time (quartiles) of 248 patients was 5 (4, 8) months. The first postoperative angiography showed that the bypass vessels of 1 patient in each group were not developed, and the bypass vessel patency rate was 99.2% (246/248). At the last follow-up, among the 248 patients, the mRS score of 0 was reported in 210 cases, 1 in 25 cases, 2 in 7 cases, 3 in 3 cases, 4 in 2 cases, and 5 in 1 case. Matsushima grade A was reported in 96 cases, grade B in 115 cases, and grade C in 37 cases. There were no statistically significant differences in age, gender, underlying disease, clinical type, Suzuki stage, mRS score at admission, or the surgical side between the two groups of patients (all P>0.05). There were no significant differences in the mRS at discharge, follow-up time, bypass patency rate, Matsushima grade, or the mRS at the last follow-up between the two groups of patients (all P>0.05). Compared with the EDAS group, the EMS group had higher incidences of perioperative cerebral infarction [10.8% (8/74) vs. 4.0% (7/174)], cerebral hemorrhage [8.1% (6/74) vs. 1.1% (2/174)], epilepsy [5.4% (4/74) vs. 0.6% (1/174)], and subdural effusion [14.9% (11/74) vs. 5.7% (10/174)] (all P<0.05). In terms of postoperative recent complications, the incidence of cerebral infarction in the EMS group was higher than that in the EDAS group [5.4% (4/74) vs. 0.6% (1/174), P=0.029]. Conclusions:Both types of bypass surgery have relatively high patency rates and favorable short-term therapeutic outcomes. The risk of cerebral infarction, cerebral hemorrhage, epilepsy, subdural effusion during perioperative period and postoperative recent cerebral infarction of STA-MCA+ EDAS seems lower.

To explore the hemodynamic changes of the superficial temporal artery in adult Moyamoya Disease (MMD) who underwent combined revascularization surgery. A number of 40 patients with MMD were enrolled, and all of them underwent a direct superficial temporal artery (STA)-middle cerebral artery (STA-MCA) bypass combined with an encephalo-duro-arterio-synangiosis (EDAS). Hemodynamic parameters were detected by Color Doppler Ultrasonography (CDUS) at the preoperative, perioperative and follow-up time, including peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistance index (RI). The control group were selected randomly during the same period. Researchers applied the SPSS 21 to conduct the two-sample analysis, Chi-Squared test and one-way repeated measures ANOVA between groups. P < 0.05 was considered statistically significant. In this study, 21 males and 19 females with an average age of 44.9 years (Range 28 y–56 y) were enrolled in the MMD group. Among them, 21 patients (52.5%) had perioperative complications, and all symptoms were transient neurological dysfunctions. Intermittent speech disorder was the most common complication during the period of operation. The preoperative hemodynamic of STA showed no significant difference between MMD and the control group. The perioperative hemodynamics had significant carnages compared with preoperative, and there was a trend of fluctuation. The perioperative PSV in the group with complications was significantly higher than the group without complications, except for EDV and RI. In the follow-up (X¯ = 5 months), PSV (60.21 ± 22.24 cm/s, P = 0.712) showed no difference compared with baseline data, while EDV (25.12 ± 9.94 cm/s, P = 0.000) and RI (0.575 ± 0.092, P = 0.000) showed significant difference between MMD and control group. The blood flow spectrogram showed high resistance in preoperative, but most patients showed a low resistance pattern during the follow-up time. It was the first time to demonstrate that the hemodynamic changes of STA fluctuated significantly within one week and eventually remained stable after combined revascularization. The PSV may play a more important role in postoperative complications. In the follow-up, PSV had no significant difference, EDV increased significantly, and RI decreased significantly. The blood flow spectrogram mainly shows a low resistance pattern when the hemodynamic is stable.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. The etiology and pathogenesis of MMD are still obscure. The biggest obstacles in the basic research of MMD are difficulty in obtaining specimens and the lack of an animal model. It is necessary to use appropriate and rationally designed animal models for the correct evaluation. Several animal models and methods have been developed to produce an effective MMD model, such as zebrafish, mice and rats, rabbits, primates, felines, canines, and peripheral blood cells, each with advantages and disadvantages. There are three mechanisms for developing animal models, including genetic, immunological/inflammatory, and ischemic animal models. This review aims to analyze the characteristics of currently available models, providing an overview of the animal models framework and the convenience of selecting model types for MMD research. It will be a great benefit to identify strategies for future model generations.

AIMS:The effects of PFKFB4 on glycolysis during the cancer progression has been investigated, while its role in glioma remains unclear. The present study evaluated the molecular mechanism of PFKFB4 in glycolysis of glioma progression.MATERIALS AND METHODS:The pan-cancer platform SangerBox was inquired to investigate the E2F2 expression in tumors. The E2F2 expression was studied by qRT-PCR and immunohistochemistry in collected glioma and normal brain tissues and by qRT-PCR and western blot in glioma cells. The relationship between the E2F2 expression in glioma tissues and patients' prognosis was analyzed. The cell malignant phenotype, glycolysis, growth and metastasis were examined by CCK-8, EdU, colony formation, flow cytometry, wound healing, Transwell assays, ELISA kits, and tumorigenesis and metastasis assays. Downstream targets of E2F2 were searched in hTFtarget, followed by pathway enrichment analysis. The expression of these targets and their correlation with E2F2 expression in gliomas were investigated through the GEPIA website. After ChIP and luciferase assays, the effect of the target on glioma was investigated.KEY FINDINGS:E2F2 was overexpressed in glioma patients and predicted poor prognoses. E2F2 promoted cell proliferation, colony formation, DNA synthesis, migration, invasion and glycolysis, and inhibited apoptosis. Meanwhile, inhibition of E2F2 suppressed the growth and metastasis of gliomas. E2F2 elevated the PFKFB4 expression transcriptionally by binding to its promoter and activated PI3K/AKT pathway. The promotion of glioma metastasis and glycolysis by E2F2 was mitigated by PFKFB4 knockdown.SIGNIFICANCE:E2F2-mediated transcriptional enhancement of PFKFB4 expression regulated the phosphorylation of PI3K/AKT to promote glioma malignancy progression.

The epigenetic abnormality is believed as a major driver for cancer initiation. Histone modification plays a vital role in tumor formation and progression. Particularly, alteration in histone acetylation has been highly associated with gene expression, cell cycle, as well as carcinogenesis. By analyzing glioblastoma (GBM)-related microarray from the GEO database and conducting chromatin immunoprecipitation-sequencing (ChIP-seq), we discovered that solute carrier family 30 member 3 (SLC30A3), a super enhancer (SE)-regulated factor, was significantly reduced in GBM tissues. Furthermore, histone deacetylase 1 (HDAC1), overexpressed in GBM tissues, could inhibit SLC30A3 expression by promoting histone H3K27ac deacetylation modification of the SE region of SLC30A3. Our functional validation revealed that SLC30A3 can inhibit the growth and metastatic spread of GBM cells in vitro and in vivo, and can activate the MAPK signaling pathway to promote apoptosis of GBM cells. Moreover, overexpression of HDAC1 resulted in a significant increase in DNA replication activity, a significant decline in apoptosis and cell cycle arrest in GBM cells. In a word, these findings indicate that combined epigenetic targeting of SLC30A3 by HDAC1 and SE is potentially therapeutically feasible in GBM.

BACKGROUND/AIM:Multidrug resistance (MDR) is largely responsible for the failure of chemotherapy. The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript (MALAT1) has been reported to be closely related to tumor biology. In the present study, whether MALAT1 contributes to the resistance of glioblastoma cell lines to temozolomide (TMZ) was investigated.METHODS:The glioblastoma cell lines U251 and U87 were exposed to increasing concentrations of TMZ to generate TMZ-resistant colonies (the U251/TMZ and U87/TMZ cell lines). The expression levels of MALAT1 and proteins related to epithelial-mesenchymal transition (EMT) were detected by real-time PCR and western blot, respectively. After the transfection of si-MALAT1 or pcDNA-MALAT1, cell viability, mRNA expression of MDR-associated proteins (MDR1, MRP5 and LRP1), and protein expression of EMT related proteins (ZEB1, Snail and SLUG) were evaluated.RESULTS:The expression of MALAT1 was upregulated in the U251/TMZ and U87/TMZ cell lines compared to that in U251 and U87 cell lines, respectively. The treatment of si-MALAT1 decreased MDR1, MRP5, and LRP1 expression, enhanced cell sensitivity to TMZ, and downregulated ZEB1 protein expression, whereas pcDNA-MALAT1 had the opposite effects. However, the effects of si-MALAT1 on MDR -associated protein expression, cell viability, and EMT status were reversed by the transfection of pcDNA-ZEB1, and the effects of pcDNA-MALAT1 were reversed by the transfection of si-ZEB1. In vivo, MALAT1 overexpression enhanced tumors' TMZ resistance and upregulated ZEB1 expression.CONCLUSION:MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by regulating ZEB1.

We combine the telomerase extension reaction and microRNA (miRNA)-induced rolling circle amplification, followed by graphene oxide (GO) and nicking enzyme-assisted signal amplification as a method to analyze telomerase and miRNA-21 in urine samples with the following merits. First, it is a binary assay and can simultaneously output double signals that correspond to the quantities of telomerase and miRNA, respectively. Second, telomerase activity is enhanced by using a DNA molecular beacon probe to inhibit the formation of G-quadruplex. Third, background noise is decreased significantly via introduction of GO. Fourth, performance tests on about 258 urine samples demonstrate that this binary assay can distinguish between urine from bladder cancer patients, those with cystitis, and normal individuals. Finally, this strategy also shows great potential in distinguishing between muscle-invasive bladder cancers and non-muscle-invasive bladder cancers. The proposed strategy will greatly contribute to clinical decision-making and individualized treatments.

AIMS:Atypical chemokine receptors (ACRs) have been reported to scavenge or alter the localization of their chemokine ligands. However, CRAM, a newly identified ACR member, is lack of ligand scavenging properties. The present study was to investigate the clinical significance of CRAM in cervical carcinoma.METHODS:The expression of CRAM in primary cervical cancer and paired normal tissues from adjacent regions was examined using Real time PCR. Moreover, CRAM protein expression was analyzed in 272 cervical specimens including 50 normal cervical tissues, 40 cases of carcinoma in situ of cervix (CIS), and 182 cases of cervical cancer by immunohistochemistry.RESULTS:Real time PCR showed that the expression level of CRAM was markedly higher in cervical cancer than that in normal cervical tissues. The expression rate of CRAM in normal cervical tissues, CIS, and cervical cancer increased gradually (p < 0.01). In addition, the expression level of CCL19 was positively associated with that of CRAM (p < 0.05). Moreover, high expression level of CRAM was correlated with lymph node metastasis and histological subtype. In multivariate Cox regression analysis, high expression level of CRAM was a negative indicator for both overall (p = 0.028) and recurrence-free survival (p = 0.010).CONCLUSION:The present study suggested that CRAM could be a clinical prognostic marker for patients with cervical cancer and might be a potential therapeutic target for cervical cancer. Our data extended previous research on the predictive value of ACRs.