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Objectives The aim of this study is to examine the prognostic value of T1 mapping and the extracellular volume (ECV) fraction in patients with dilated cardiomyopathy (DCM). Background Patients with DCM with functional left ventricular remodeling have poorer prognoses. Noninvasive assessment of myocardial fibrosis using T1 mapping and the ECV fraction may improve risk stratification of patients with DCM; however, this has not yet been systematically evaluated. Methods A total of 659 consecutive patients with DCM (498 men; 45 ± 15 years) who underwent cardiac magnetic resonance with T1 mapping and late gadolinium enhancement (LGE) imaging with a 1.5-T magnetic resonance scanner were enrolled in this study. Primary endpoints were cardiac-related death and heart transplantation. Secondary endpoints were hospitalization for heart failure, ventricular arrhythmias, and implantable cardioverter-defibrillator or cardiac resynchronization therapy implantation. Survival estimates were calculated by Kaplan-Meier curves with the log-rank test. Results During a mean follow-up of 66.3 ± 20.9 months, 122 and 205 patients with DCM reached the primary and secondary endpoints, respectively. The presence of LGE had an association with both of the primary and secondary endpoints observed in the patients with DCM (both P Conclusions T1 mapping and the ECV fraction had prognostic value in patients with DCM and were particularly important in patients with DCM without LGE. Using a combination of T1 mapping, ECV fraction, and LGE provided optimal risk stratification for patients with DCM.

Treating traumatic osteomyelitis of extremities (TOE) clinically is difficult because of the increase of multi-drug resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Finding new materials that are degradable, antibacterial, and biocompatible has become an effective treatment of TOE. In this study, the silver ions were directly reduced at the reduction site to generate the silver nanoparticles (AgNPs) using the double reduction characteristics of silk fibroin (SF) and formic acid, and different concentrations (0, 0.05%, 0.3%, and 1%) of AgNPs-SF stent was generated. The physical characterization of the AgNPs-SF stent was performed. The osteoblasts (mouse bone cells, MC-3T3 cells, and MC-3T3) were selected to detect cell growth on AgNPs-SF stent at different concentrations. The Kirby-Bauer inhibition zone method was adopted to detect the antibacterial properties of AgNPs-SF stent at different concentrations against MRSA. The AgNPs-SF stent loaded with gentamicin (effective microorganism (EM) were applied in the treatment of patients with TOE. It was found that the SF stent containing different concentrations of AgNPs had a uniform structure with multiple-space interconnection. Infrared spectroscopy analysis showed that AgNPs had no effect on the amide bond of the SF stent, and the antibacterial effect of the AgNPs-SF stent on MRSA was positively correlated to the concentration and dosage of AgNPs. The combination of EM helped patients to resolve inflammation and abscess, and contributed to the generation of fibrosis and neovascularization. In short, the AgNPs-SF stent could be used as a potential filling material and drug-loading platform for the treatment of TOE.

This study attempted to evaluate the characteristics and prognostic value of myocardial fibrosis (MF) in aortic insufficiency (AI) patients with bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV) by cardiac magnetic resonance (CMR). A total of 314 adults with CMR-diagnosed AI were retrospectively retrieved. Of them, 166 patients with moderate or severe AI were included and divided into two groups: BAV group (N = 46) and a TAV group (N = 120). The presence and characteristics of MF were assessed with CMR. The patients were followed for adverse clinical events. The prognostic capability of the parameters was assessed using Cox regression model. LV fibrosis was more common in the BAV group than in the TAV group (65.2% vs. 45.0%; p = 0.020). There was a strong association between BAV and MF even after adjusting for clinical and imaging variables (odds ratio: 3.57; p = 0.031). Kaplan-Meier analysis showed a higher rate of clinical adverse events in AI+BAV patients with MF during a median follow-up of 4.7 years. Multivariate Cox regression analysis showed that late gadolinium enhancement (LGE) was an independent predictor of clinical adverse outcome. MF is more common in AI with BAV than with TAV and is a predictor of clinical adverse events. • The presence and extent of late gadolinium enhancement of left ventricular were more common and severer in the bicuspid aortic valve group than in the tricuspid aortic valve group in aortic insufficiency patients. • Bicuspid aortic valve was an independent factor for myocardial fibrosis in aortic insufficiency patients. • Late gadolinium enhancement could be used as an independent predictor of adverse clinical events in this population.

Background Long non-coding RNA (lncRNA) XIST has been implicated in the progression of a variety of tumor diseases. The purpose of this study was to explore the molecular role of lncRNA XIST in human hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods The expression levels of lncRNA XIST, miR-192 and TRIM25 in HBV-related HCC tissues and HepG2.2.15 cells were detected by qRT-PCR. Biological information and luciferin gene reporter assay were performed to detect the interaction among lncRNA XIST, miR-192 and TRIM25. CCk-8 assay, wound healing assay and colony formation assay were conducted to detect the proliferation and migration ability of HepG2.2.15 cells. Results qRT-PCR results showed that the expression levels of lncRNA XIST were remarkably increased in HBV-related HCC tissues and HepG2.2.15 cells. In addition, miR-192 was a direct target gene of lncRNA XIST, and the expression of miR-192 and lncRNA XIST were negatively correlated. Moreover, overexpression of miR-192 observably inhibited the proliferation and migration of HCC cells, while overexpression of lncRNA XIST showed an opposite effect. Furthermore, TRIM25 was a direct target of miR-192, and lncRNA XIST could up-regulate the expression of TRIM25 by targeting miR-192. Conclusion LncRNA XIST could up-regulate the expression of TRIM25 by targeting and binding to miR-192, thus accelerating the occurrence and development of HCC.

Purpose and objective Auto planning might reduce the manual time required for the optimization and could also potentially improve the overall plan quality. The aim of this study is to demonstrate the statistical comparison of automatic (AU) and manually (MA) generated nasopharyngeal carcinoma (NPC) intensity-modulated radiation therapy (IMRT) plans. Materials and methods The study included 105 nasopharyngeal carcinoma patients, admitted to our hospital. The patients underwent IMRT treatments. The clinically delivered plans were performed with Eclipse (Version 11.0) using manual optimization. The same plans were optimized successively in PinnacleTM3 (version 9.10) treatment planning system using the auto plan software package module. D95 (dose of 95% volume) and D98 (dose of 98% volume) were calculated for the targets and maximum dose (Dmax) and mean dose (Dmean) for the organ at risks (OARs); moreover, the average doses of each target and OARs for 105 patients were evaluated. Results There is no significant difference in the homogeneity of the target between AU and MA treatment plans, while a significant difference is observed for what is concerning the OARs or most of OARs in 105 patients, OAR doses were significantly reduced in AU plan. For OARs which have no significant difference between AU and MA plans are highlighted, the mean dose of OARs in AU plans was at least not higher than MA plans. Conclusion Nasopharyngeal carcinoma IMRT plans made by an automatic planning tool met the clinical requirements for target prescription dose; moreover, the dose of normal tissues was lower than in MA plans. Clinical physicists' time can be saved and the influence of factors such as the lack of experience in treatment planning can be avoided.

N6-methyladenosine (m6A) RNA methylation, involved in cancer initiation and progression, is dynamically regulated by the m6A RNA methylation regulators. However, the expression of m6A RNA methylation regulators in ovarian cancer and their correlation with prognosis remain elusive. Here, we demonstrated that the 18 central m6A RNA methylation regulators were expressed differently between ovarian cancer (OC) and normal tissues. By applying consensus clustering, all ovarian cancer patient cases can be divided into three subgroups (cluster1/2/3) based on overall expression levels of all 18 m6A RNA methylation regulators. We systematically analyzed the prognostic value of transcription levels of 18 m6A RNA methylation regulators in ovarian cancer and found that insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), vir like m6A methyltransferase associated (VIRMA), and zinc finger CCCH-type containing 13 (ZC3H13) yield the highest scores for predicting the prognosis of ovarian cancer. Accordingly, we derived a risk signature consisting of transcription levels of these three selected m6A RNA methylation regulators as an independent prognostic marker for OC and validated our findings with data derived from a different ovarian cancer cohort. Moreover, by the Gene Set Enrichment Analysis (GSEA), we demonstrated that the three selected regulators were all correlated with pathways in cancer and WNT signaling pathways. In conclusion, m6A RNA methylation regulators are vital participants in ovarian cancer pathology; and IGF2BP1, VIRMA, and ZC3H13 mRNA levels are valuable factors for prognosis prediction and treatment strategy development.

Purpose: The dilation of proximal arch (PArc) was suspected to develop as a result of valve-related hemodynamics or in consequence to the upward extension of the ascending aorta (AAo) dilation. We aimed to investigate the one that could be the possible contributing factor in patients with bicuspid aortic valve (BAV). Methods: All enrolled BAV patients underwent four-dimensional flow magnetic resonance imaging. Contour-averaged circumferential wall shear stress (WSScirc,avg) and the diameter of the middle of AAo (mid-AAo) were compared between the patients with and without PArc dilation. Additionally, we analyzed the correlation between WSScirc,avg and aortic diameter at PArc section, as well as the correlation between the diameter of mid-AAo and that of PArc. Results: No significant difference was observed in WSScirc,avg at PArc section between the patients with and without PArc dilation (P = .621). However, the diameter of mid-AAo in the patients who suffered PArc dilation was higher than those without it (P = .007). In addition, the aortic diameter did not correlate with the WSScirc,avg at PArc level (R = -0.068, P = .701). The correlation was observed between PArc diameter and mid-AAo diameter (R = 0.521, P = .002). Conclusion: Hemodynamics may not contribute to the development of PArc dilation. PArc diameter correlated with mid-AAo diameter, indicating PArc dilation may be secondary to the upward extension of AAo dilation. The influence of AAo dilation extending upward could be treated by AAo replacement; hence, a selective approach to transverse PArc replacement might be appropriate.

Introduction Increasing studies have demonstrated that noncoding RNAs, including miRNAs and lncRNAs, have vital roles in mediating cancer progression. However, the expression features and biological functions of LINC00689 in gastric cancer (GC) remain largely unknown. This study was designed to investigate the functions of LINC00689, miR-526b-3p and ADAM9 as well as their interactions in GC. Methods Real time PCR(RT-PCR) was used to detect the expression of LINC0068, miR-526b-3p and ADAM9 in both GC tissues or cell lines. Gain- and loss- of functions of assays were conducted to verify the role of LINC0068, miR-526b-3p and ADAM9 in GC development. Cell proliferation were determined by CCK8 assay and transwell assay and scratch wound-healing assay were used to test cell invasion and migration. Further, the relationships between LINC00689 and miR-526b-3p, miR-526b-3p and ADAM9 were predicted by bioinformatics analysis and then proved by Luciferase reporter assay and RNA Immunoprecipitation(RIP) assay. Results We found that LINC00689 was upregulated in GC tissues and positively correlated with advanced tumor stage and tumor size, while miR-526b-3p was downregulated. Furthermore, gain- and loss-of-function experiments revealed that LINC00689 promoted the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GC cells, while miR-526b-3p had the opposite effects. The underlying mechanisms indicated that LINC00689 functioned as a competing endogenous RNA (ceRNA) by sponging miR-526b-3p in GC cells. Further investigations confirmed that ADAM9 was a direct target of miR-526b-3p and positively modulated the progression of GC. Conclusion Our study suggests that LINC00689 functions as a novel oncogenic lncRNA in the development of GC by promoting ADAM9 expression through suppression of miR-526b-3p.

Cancer stem cells have been identified as the major cause of cancer initiation and progression. To investigate the effects of puerarin 6″-O-xyloside (PXY), derived from Pueraria lobata (Willd.) Ohwi, on lung cancer stem cells, we enriched and identified a subpopulation of lung cancer stem-like cells (LCSLCs) derived from lung adenocarcinoma A549 cells with traits including high self-renewal and invasive capability in vitro, elevated tumourigenicity in vivo, and high expression of stem cell markers CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1). We found that PXY could impair cell viability, suppress self-renewal and invasive capability, and decrease CD133, CD44 and ALDH1 mRNA expression in LCSLCs in a dose-dependent manner. Furthermore, we showed that PXY suppressed the self-renewal and invasive capability of LCSLCs at least in part through suppressing the activation of Akt/c-Myc signalling. In conclusion, PXY can block the traits of LCSLCs, indicating that PXY may be a candidate compound for lung adenocarcinoma therapy via eliminating LCSLCs.

Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully re-acquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally non-functional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a sub-classification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.

BACKGROUND: The value of native myocardial T1 mapping and extracellular volume (ECV) fraction in patients who have hypertrophic cardiomyopathy (HCM) but no late gadolinium enhancement (LGE) and no hemodynamic obstruction are currently unknown. PURPOSE: To evaluate myocardial fibrosis in patients with nonobstructive HCM and no LGE by using native myocardial T1 mapping and ECV fraction and to study their relationships to left ventricular (LV) function and LV hypertrophy. MATERIALS AND METHODS: Patients with HCM who underwent cardiac MRI between 2012 and 2015 were retrospectively evaluated. Patients were included if they had no LGE at MRI, LV ejection fraction greater than or equal to 45%, and no LV outflow tract obstruction. Healthy participants had similar age and sex distribution. Native myocardial T1 and ECV were measured with MRI. RESULTS: A total of 258 patients with HCM (mean age ± standard deviation, 49 years ± 15; 74% men) and 122 healthy participants (mean age, 50 years ± 14; 76% men) were evaluated. Native myocardial T1 was longer and ECV fraction was higher in the patients with HCM relative to the healthy participants (mean native T1, 950 msec ± 48 vs 913 msec ± 46; mean ECV, 24.5% ± 2.8 vs 23.0% ± 2.7; both P < .001). Maximum T1 and ECV values correlated strongly with LV mass index for the entire patient cohort with HCM (both r = 0.86; P < .001) and for the subgroups (r = 0.86 and 0.85 for interventricular septal group and r = 0.88 and 0.86 for apical group; all P < .001). CONCLUSION: Prolonged myocardial T1 and elevated extracellular volume in hypertrophic cardiomyopathy suggests diffuse myocardial fibrosis, even in the absence of regionally apparent late gadolinium enhancement and hemodynamic obstruction, and is associated with left ventricular hypertrophy. © RSNA, 2019 See also the editorial by Bluemke and Lima in this issue.

Danzhi Jiangtang capsule (DJC), a traditional medicinal formula composed of cortex moutan, heterophylly falsestarwort root, unprocessed rehmannia root, oriental waterplantain rhizome, dodder seed and leech, has been used to treat type 2 diabetes in clinic for almost 10 years. In addition, DJC was also confirmed that it could relieved oxidative stress of vascular endothelium in diabetic macroangiopathy. Based on the fact that the DJC could regulated the level of free fatty acids in diabetes patients and the constituents of DJC also possess potential anti-hyperlipidemic effect, thus, the present work aimed to evaluate the anti-hyperlipidemic effect of DJC and further investigated potential molecular mechanism of this action. As in vivo results revealed, DJC could reduced the levels of TC, TG, LDL, increased HDL level as well as decreased the level of ALT and AST of model rats. In addition, DJC also showed significant antioxidant effect by decreasing the level of MDA and increasing the level of SOD and GSH-Px. Furthermore, western blot analysis showed that DJC could up-regulated the expression of phosphorylated JAK2 and STAT3, and down-regulated the expression of SCOC3 protein, which indicated that DJC could regulate the metabolism of lipid via JAK2/STAT3 pathway.

IntroductionBladder cancer (BC) is one of the most prevalent urinary cancers, and its management is still a problem causing recurrence and progression, elevating mortality.Materials and MethodsWe aimed at the nuclear mitochondria-related genes (MTRGs), collected from the MITOMAP: A Human Mitochondrial Genome Database. Meanwhile, the expression profiles and clinical information of BC were downloaded from the Cancer Genome Atlas (TCGA) as a training group. The univariate, multivariate, and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a nuclear mitochondrial-related multi-genes signature and the prognostic nomogram.ResultsA total of 17 nuclear MTRGs were identified to be correlated with the overall survival (OS) of BC patients, and a nuclear MTRGs signature based on 16 genes expression was further determined by the LASSO Cox regression analysis. Based on a nuclear MTRGs scoring system, BC patients from the TCGA cohort were divided into high- and low- nuclear MTRGs score groups. Patients with a high nuclear MTRGs score exhibited a significantly poorer outcome (median OS: 92.90 vs 20.20 months, pvs 98.00 months, pvs unreached, pvs unreached, pConclusionsNot only could the signature and prognostic nomogram predict the prognosis of BC, but it also had potential therapeutic guidance.

Background: Cardiac magnetic resonance (CMR) has been shown to improve the diagnosis of myocarditis, but no systematic comparison of this technique is currently available. The purpose of this study was to compare the 2009 and 2018 Lake Louise Criteria (LLC) for the diagnosis of acute myocarditis using 3.0 T MRI with endomyocardial biopsy (EMB) as a reference and to provide the cutoff values for multiparametric CMR techniques.Methods: A total of 73 patients (32 ± 14 years, 71.2% men) with clinically suspected myocarditis undergoing EMB and CMR with 3.0 T were enrolled in the study. Patients were divided into two groups according to EMB results (EMB-positive and -negative groups). The CMR protocol consisted of cine-SSFP, T2 STIR, T2 mapping, early and late gadolinium enhancement (EGE, LGE), and pre- and post-contrast T1 mapping. Their potential diagnostic ability was assessed with receiver operating characteristic curves.Results: The myocardial T1 and T2 relaxation times were significantly higher in the EMB-positive group than in the EMB-negative group. Optimal cutoff values were 1,228 ms for T1 relaxation times and 58.5 ms for T2 relaxation times with sensitivities of 86.0 and 83.7% and specificities of 93.3 and 93.3%, respectively. The 2018 LLC had a better diagnostic performance than the 2009 LLC in terms of sensitivity, specificity, positive predictive value, and negative predictive value. T1 mapping + T2 mapping had the largest area under the curve (0.95) compared to other single or combined parameters (2018 LLC: 0.91; 2009 LLC: 0.76; T2 ratio: 0.71; EGEr: 0.67; LGE: 0.73; ). The diagnostic accuracy for the 2018 LLC was the highest (91.8%), followed by T1 mapping (89.0%) and T2 mapping (87.7%).Conclusion: Emerging technologies such as T1/ T2 mapping have significantly improved the diagnostic performance of CMR for the diagnosis of acute myocarditis. The 2018 LLC provided the overall best diagnostic performance in acute myocarditis compared to other single standard CMR parameters or combined parameters. There was no significant gain when 2018LLC is combined with the EGE sequence.

Background and importance Primary tumors of the brachial plexus are rare. Most are benign and characterized as Schwannoma and neurofibroma, whereas malignant peripheral nerve sheath tumors are less common. Here, we report a rare case of primary embryonal carcinoma in the brachial plexus. Clinical presentation A 17-yr-old male presented with a 3-mo history of a mass growing in the left supraclavicular region over the middle part of the clavicle. Magnetic resonance imaging revealed a well-defined mass (diameter 2.5 cm) straddling the brachial plexus. After surgical resection, and the mass was histologically confirmed to be an embryonal carcinoma. Conclusion Primary embryonal carcinoma in the brachial plexus has not been reported previously. This case highlights the importance of considering the possibility that some primary brachial plexus tumors may be malignant and should be treated promptly.

To evaluate whether early left atrial (LA) dysfunction in hypertension (HTN), with or without left ventricular hypertrophy (LVH), can be detected by cardiovascular magnetic resonance feature tracking (CMR-FT). Seventy-three HTN patients and 29 healthy controls were retrospectively recruited. HTN patients were divided into the LVH (n = 29) and non-LVH group (n = 44). LA performance was analysed using CMR-FT in 2- and 4-chamber cine images, including LA reservoir function (total ejection fraction [EF], total strain [es], peak positive strain rate [SRs]), conduit function (passive EF, passive strain [ee], peak early negative strain rate [SRe]) and booster pump function (booster EF, active strain [ea], late peak negative strain rate [SRa]). One-way analysis of variance with post hoc LSD tests, Spearman analysis, receiver operating characteristic curve and intra-class correlation coefficient analysis were applied for statistical analyses. Compared with healthy controls, LA reservoir (LA total EF, es, SRs) and conduit function (LA passive EF, ee, SRe) were significantly impaired in HTN patients with or without LVH, and these parameters significantly correlated with mitral E/A

Background/aim The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs). Materials and methods TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a. Results The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control. Conclusion AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

The dysregulation of transcriptional factors (TFs) leads to malignant growth and the development of colorectal cancer (CRC). Herein, we sought to identify the transcription factors relevant to the prognosis of colorectal cancer patients. We found 526 differentially expressed TFs using the TCGA database of colorectal cancer patients (n = 544) for the differential analysis of TFs (n = 1,665) with 210 upregulated genes as well as 316 downregulated genes. Subsequently, GO analysis and KEGG pathway analysis were performed for these differential genes for investigating their pathways and function. At the same time, we established a genetic risk scoring model for predicting the overall survival (OS) by using the mRNA expression levels of these differentially regulated TFs, and defined the CRC into low and high-risk categories which showed significant survival differences. The genetic risk scoring model included four high-risk genes (HSF4, HEYL, SIX2, and ZNF26) and two low-risk genes (ETS2 and SALL1), and validated the OS in two GEO databases (p = 0.0023 for the GSE17536, p = 0.0193 for the GSE29623). To analyze the genetic and epigenetic changes of these six risk-related TFs, a unified bioinformatics analysis was conducted. Among them, ZNF26 is progressive in CRC and its high expression is linked with a poor diagnosis as well. Knockdown of ZNF26 inhibits the proliferative capacity of CRC cells. Moreover, the positive association between ZNF26 and cyclins (CDK2, CCNE2, CDK6, CHEK1) was also identified. Therefore, as a novel biomarker, ZNF26 may be a promising candidate in the diagnosis and prognostic evaluation of colorectal cancer.

Peripheral nerve injury (PNI) is a common clinical problem, which can cause severe disability and dramatically affect a patient’s quality of life. Neural regeneration after PNI is a complex biological process that involves a variety of signaling pathways and genes. Emerging studies demonstrated that long non-coding RNAs (lncRNAs) were abnormally expressed after PNI and played pivotal roles in peripheral nerve regeneration. Based on the rat sciatic nerve injury model, we found that the expression levels of several lncRNAs were increased significantly in the sciatic nerve after injury. Software prediction prompted us to focus on one up-regulated lncRNA, MSTRG.24008.1. Dual-luciferase reporter assay, RNA pull-down assay and RNA interference approach verified that MSTRG.24008.1 regulated neuroregeneration via the miR-331-3p/nucleotide-binding oligomerization domain-like pyrin domain containing 3 (NLRP3)/myelin and lymphocyte protein (MAL) axis in vitro. Subsequently, we performed gastrocnemius muscle gravity and sciatic functional index experiments to evaluate the recovery of injured sciatic nerves after MSTRG.24008.1 siRNA interference in vivo. In conclusion, knockdown of MSTRG.24008.1 promotes the regeneration of the sciatic nerve via the miR-331-3p/NLRP3/MAL axis, which may provide a new strategy to evaluate and repair injured peripheral nerves clinically.

Background Patients who have unexplained giant T-wave inversions but do not meet criteria for hypertrophic cardiomyopathy (HCM) (left ventricular (LV) wall thickness Methods Seventy-one patients with unexplained giant T-wave inversion who did not fulfill HCM criteria were studied. The mean interval time of the follow-up CMR was 24.4 ± 8.3 months. The LV wall thickness was measured in each LV segment according to the American Heart Association 17-segmented model. The apical angle (ApA) was also measured. A receiver operating curve (ROC) was used to identify the predictive values of the CMR variables. Results Of 71 patients, 16 (22.5%) progressed to typical apical HCM, while 55 (77.5%) did not progress to HCM criteria. The mean apical wall thickness was significantly different between the two groups at both baseline and follow-up, with the apical HCM group having greater wall thickness at both time points (all p p Conclusions CMR metrics identify predictors for progression to HCM in patients with unexplained giant T-wave inversion.

Although astragaloside IV protects from acute myocardial infarction (AMI)-induced chronic heart failure (CHF), the underlying mechanism of action is unclear. We determined the potential therapeutic effect of astragaloside IV using molecular docking approaches and validated the findings by the ligation of the left anterior descending (LAD) coronary artery-induced AMI rat model. The interaction between astragaloside IV and myeloid differentiation factor 88 (MyD88) was evaluated by SwissDock. To explore the mechanisms underlying the beneficial effects of astragaloside IV in the LAD coronary artery ligation-induced AMI model, we administered the rats with astragaloside IV for 4 weeks. Hemodynamic indexes were used to evaluate the degree of myocardial injury in model rats. The histopathological changes in myocardium were detected by hematoxylin & eosin (H&E) staining and Masson's staining. Myocardium homogenate contents of collagen I and collagen III were evaluated by ELISA. The level of myocardial hydroxyproline (HYP) was determined by alkaline hydrolysis. Immunohistochemistry was used to examine collagen I. Western blotting was used to examine relevant proteins. As per the molecular docking study results, astragaloside IV may act on MyD88. Furthermore, astragaloside IV improved hemodynamic disorders, alleviated pathological changes, and reduced abnormal collagen deposition and myocardial HYP in vivo. Astragaloside IV significantly reduced the overexpression of TLR4, MyD88, NF-Κb, and TGF-β, which further validated the molecular docking findings. Hence, astragaloside IV ameliorates AMI by reducing inflammation and blocking TLR4/MyD88/NF-κB signaling. These results indicate that astragaloside IV may alleviate AMI. PRACTICAL APPLICATIONS: Astragaloside IV, a small active substance extracted from Astragalus membranaceus, has demonstrated potent protective effects against cardiovascular ischemia/reperfusion, diabetic nephropathy, and other diseases. Molecular docking experiments showed that astragaloside IV might act on the myeloid differentiation factor 88 (MyD88). Astragaloside IV can effectively reduce the overexpression of TLR4, MyD88, and NF-κB p65, indicating that astragaloside IV inhibits inflammation via TLR4/MyD88/NF-κB signaling pathway. These results indicate that astragaloside IV may alleviate acute myocardial infarction.

To promote the rehabilitation of motor function in children with cerebral palsy (CP), we developed motor imagery (MI) based training system to assist their motor rehabilitation. Eighteen CP children, ten in short- and eight in long-term rehabilitation, participated in our study. In short-term rehabilitation, every 2 days, the MI datasets were collected; whereas the duration of two adjacency MI experiments was ten days in the long-term protocol. Meanwhile, within two adjacency experiments, CP children were requested to daily rehabilitate the motor function based on our system for 30 min. In both strategies, the promoted motor information processing was observed. In terms of the relative signal power spectra, a main effect of time was revealed, as the promoted power spectra were found for the last time of MI recording, compared to that of the first one, which first validated the effectiveness of our intervention. Moreover, as for network efficiency related to the motor information processing, compared to the first MI, the increased network properties were found for the last MI, especially in long-term rehabilitation in which CP children experienced a more obvious efficiency promotion. These findings did validate that our MI-based rehabilitation system has the potential for CP children to assist their motor rehabilitation.

Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury, whereby it can inhibit microglial neurotoxicity. Therefore, luteolin holds the potential to be useful for treatment of retinal diseases. The purpose of this study was to investigate whether luteolin exhibits neuroprotective effects on rod cells in rd10 mice, a slow photoreceptor-degenerative model of retinitis pigmentosa. Luteolin (100 mg/kg) intraperitoneally injected daily from postnatal day 14 (P14) to P25 significantly enhanced the visual performance and retinal light responses of rd10 mice at P25. Moreover, it increased the survival of photoreceptors and improved retinal structure. Mechanistically, luteolin treatment attenuated increases in reactive oxygen species, photoreceptor apoptosis, and reactive gliosis; increased mRNA levels of anti-inflammatory cytokines while lowering that of pro-inflammatory and chemoattractant cytokines; and lowered the ratio of phospho-JNK/JNK. Application of the JNK inhibitor SP600125 exerted a similar protective effect to luteolin, suggesting that luteolin delays photoreceptor degeneration and functional deterioration in rd10 mice through regulation of retinal oxidation and inflammation by inhibiting the JNK pathway. Therefore, luteolin may be useful as a supplementary treatment for retinitis pigmentosa. This study was approved by the Qualified Ethics Committee of Jinan University, China (approval No. IACUC-20181217-02) on December 17, 2018.

B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.

Background Central nervous system injury (CNSI) comprises a series of common diseases that severely affect patients' motor function and quality of life and is associated with high disability and mortality rates. Previous studies have shown that contralateral lumbosacral nerve root transfer significantly improved the function of the paralyzed limb in rat models of CNSI. These studies showed that severing the sacral 1 nerve root (S1) did not damage the function of the ipsilateral lower extremity. Thus, we speculate that contralateral S1 nerve root transfer can improve the recovery of a paralyzed limb. Because no associated rigorously designed randomized controlled trial has evaluated the effectiveness of contralateral S1 nerve transfer thus far, we designed this clinical trial to compare the effects of this new treatment approach with those of traditional treatments in paralyzed patients after chronic CNSI. Methods This is a single-center, prospective, randomized controlled trial. Forty patients, who meet the inclusion criteria and have hemiplegia caused by chronic CNSI, will be randomly divided into the surgical or non-surgical group. The treatment effect in the 2 groups will be assessed before and 3, 6, 9, 12, 18, and 24 months after intervention by using numerous scales and resting-state functional magnetic resonance imaging. The primary outcome will be the Fugl-Meyer score for the lower limbs 24 months after treatment. The secondary outcomes include the modified Ashworth spasm scale, the modified Barthel scale, 10-m walking speed measurement results, three-dimensional gait analysis, muscle strength testing, electromyography, and resting-state functional magnetic resonance imaging findings. Safety outcomes and adverse events will be observed simultaneously. Discussion We expect that the surgery will improve the sensorimotor functions of the paralyzed limb, and the results of this trial will provide high-quality clinical evidence for a new efficient treatment strategy for disability after CNSI. Trial registration Chinese Clinical Trial Registry: ChiCTR1800014414, registration date: 12 January 2018.

We performed a meta-analysis to fully investigate the hypertension of anti-VEGF mAbs in cancer patients. Databases were searched for randomized controlled trials (RCTs) treated with anti-VEGF mAbs till January 2021. The relevant RCTs in cancer patients treated with anti-VEGF mAbs were retrieved and the systematic evaluation was conducted. One hundred and five RCTs and 65358 patients were included. Our study suggests that anti-VEGF mAbs significantly increased the risks of all-grade (RR, 3.22; 95%CI, 2.83-3.65; p < 0.00001; I2=71%) and high-grade (RR, 6.15; 95%CI, 5.58-6.78; p < 0.00001; I2=48%) hypertension in cancer patients. Those risks may be dependent on drug type. Icrucumab did not association with an increased risk of hypertension. The RR of hypertension did not vary significantly according to the type of cancer, line of therapy, and treatment duration. The available data suggested that the use of anti-VEGF mAbs were associated with a significantly increased risk of hypertension.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental brain disorders in childhood. Despite extensive researches, the neurobiological mechanism underlying ADHD is still left unveiled. Since the deficit functions, such as attention, have been demonstrated in ADHD, in our present study, based on the oddball P3 task, the corresponding electroencephalogram (EEG) of both healthy controls (HCs) and ADHD children was first collected. And we then not only focused on the event-related potential (ERP) evoked during tasks but also investigated related brain networks. Although an insignificant difference in behavior was found between the HCs and ADHD children, significant electrophysiological differences were found in both ERPs and brain networks. In detail, the dysfunctional attention occurred during the early stage of the designed task; as compared to HCs, the reduced P2 and N2 amplitudes in ADHD children were found, and the atypical information interaction might further underpin such a deficit. On the one hand, when investigating the cortical activity, HCs recruited much stronger brain activity mainly in the temporal and frontal regions, compared to ADHD children; on the other hand, the brain network showed atypical enhanced long-range connectivity between the frontal and occipital lobes but attenuated connectivity among frontal, parietal, and temporal lobes in ADHD children. We hope that the findings in this study may be instructive for the understanding of cognitive processing in children with ADHD.

PURPOSE: To investigate the MRI characteristics, prevalence, and outcomes of hypertrophic cardiomyopathy (HCM) with restrictive phenotype. MATERIALS AND METHODS: A total of 2592 consecutive patients with HCM were evaluated to identify individuals who fulfilled the diagnostic criteria of restrictive phenotype. Thirty-four patients with HCM (mean age, 41 years ± 16 [standard deviation]; range, 21–62 years, 16 men) with restrictive phenotype were retrospectively identified. Thirty-four patients with HCM with the same age and sex distributions were randomly selected as a control group. Kaplan-Meier survival curves were compared using log-rank statistics for survival analysis. RESULTS: The anteroposterior diameters of the left and right atria were 55 mm ± 5 and 61 mm ± 9, respectively, which were larger than those of the control group (P < .001). The maximum wall thickness in the restrictive group was lower than that in the control group (16 mm ± 2 vs 19 mm ± 3, P < .001). No significant difference was found in late gadolinium enhancement fraction between the restricted phenotype and the control group (15% ± 8 vs 13% ± 7, P = .376). The 5-year event-free survival from any cause of death and cardiac transplantation was 81% in the restrictive group, compared with 94% in the control group (log-rank P = .018). CONCLUSION: Restrictive phenotype is a rare subtype of HCM and is associated with severe clinical symptoms and poor prognosis. The MRI features of this phenotype include mild to moderate left ventricular hypertrophy, markedly enlarged atria, moderate myocardial fibrosis, and pericardial effusion. © RSNA, 2020

The high variability of hypertrophic cardiomyopathy (HCM) genetic phenotypes has prompted the establishment of risk-stratification systems that predict the risk of a positive genetic mutation based on clinical and echocardiographic profiles. This study aims to improve mutation-risk prediction by extracting cardiovascular magnetic resonance (CMR) morphological features using a deep learning algorithm. We recruited 198 HCM patients (48% men, aged 47 ± 13 years) and divided them into training (147 cases) and test (51 cases) sets based on different genetic testing institutions and CMR scan dates (2012, 2013, respectively). All patients underwent CMR examinations, HCM genetic testing, and an assessment of established genotype scores (Mayo Clinic score I, Mayo Clinic score II, and Toronto score). A deep learning (DL) model was developed to classify the HCM genotypes, based on a nonenhanced four-chamber view of cine images. The areas under the curve (AUCs) for the test set were Mayo Clinic score I (AUC: 0.64, sensitivity: 64.29%, specificity: 47.83%), Mayo Clinic score II (AUC: 0.70, sensitivity: 64.29%, specificity: 65.22%), Toronto score (AUC: 0.74, sensitivity: 75.00%, specificity: 56.52%), and DL model (AUC: 0.80, sensitivity: 85.71%, specificity: 69.57%). The combination of the DL and the Toronto score resulted in a significantly higher predictive performance (AUC = 0.84, sensitivity: 83.33%, specificity: 78.26%), compared with Mayo I (p = 006), Mayo II (p = 022), and Toronto score (p = 0.029). The combination of the DL model, based on nonenhanced cine CMR images and the Toronto score yielded significantly higher diagnostic performance in detecting HCM mutations. • Deep learning method could enable the extraction of image features from cine images. • Deep learning method based on cine images performed better than established scores in identifying HCM patients with positive genotypes. • The combination of the deep learning method based on cine images and the Toronto score could further improve the performance of the identification of HCM patients with positive genotypes.

Engrailed-2 (EN2), a member of the engrailed homeobox family, has been shown to be abnormally expressed in a variety of cancers. However, the expression and the clinical significance of EN2 in colorectal cancer (CRC) are largely unknown. Firstly, we found that EN2 acted as an oncogene in CRC. EN2 was upregulated in colorectal cancer tissues compared with adjacent normal tissues. Higher EN2 expression was significantly associated with poorer survival rate. Knockdown of EN2 markedly inhibited proliferation and migration capacities of SW480 cells in vitro, and suppressed tumorigenicity in vivo. Mechanistically, Chemokine ligand 20 (CCL20), a member of the C-C motif chemokine subfamily, was identified as a direct target gene of EN2 in CRC. CCL20 expression was positively correlated with EN2 expression in CRC tissues. Moreover, EN2 promoted the proliferation and migration of CRC cells by regulating the expression of CCL20 in vitro. These results suggest that EN2 plays a critical role in the CRC tumor progression and may serve as a potential target for CRC prevention and therapy.

Human integrin receptors are important for cell-cell and cell-matrix adhesion in normal epithelial cells. Emerging evidences have indicated integrin members are involved in cancer development and progression as well. However, the expression patterns and clinical significance of the whole integrin family in ovarian cancer (OC) have not yet been well understood. In the present study, we utilized the public datasets including GEPIA, GEO, ONCOMINE, cBioPortal, Kaplan-Meier Plotter, TIMER databases, to analyze the expression and prognostic value of integrin members in OC. We found ITGA3/B4/B6/B7/B8 were abnormally overexpressed in OC; ITGA6 was good prognosis predictor in OC; ITGA3/ B4/B8 were poor prognosis predictor specially in advanced OC patients; elevated ITGA3/B4 might promote metastasis and elevated ITGA3/B8 might promote platinum resistance of OC; ITGA3 and ITGB4 might synergistically or independently regulate cell adhesion and proliferation; ITGA4/AL/AM/AX/B2/B7 showed strong correlations with various tumor immune infiltrates (TILs), especially with pro-tumor immunes cell types like monocyte, M2 macrophage and exhaustion T cells infiltration; ITGAL/AM/B2/B7 and residing memory CD8+ T cells marker ITGAE were specially associated with early OC patients outcome. Our results implied that ITGA3/B4 were important prognostic markers of advanced OC, ITGAL/AM/ B2/B7 were immune associated prognosis markers of early OC, together they might render important therapeutic targets for OC.

Aim: To deliver syringic acid (SA) with a nanocarrier and enhance its function. Materials & methods: mPEG-PLGA-PLL (PEAL) nanoparticles were used to deliver SA. The characterization, storage stability, drug release, blood-compatibility and biocompatibility of SA-PEAL were detected by in vitro and in vivo assays. Cellular phenotypic experiments and rat sciatic nerve injury models were used to evaluate the function of SA-PEALs. Results: SA-PEAL had good storage stability, blood-compatibility and biocompatibility and could slowly release SA. SA-PEAL significantly enhanced the proliferation and migration ability of Schwann cells and function recovery of injured sciatic nerves. Conclusion: Our study provides an effective nano-delivery system for enhancing the neural repair function of SA and promoting further applications of SA.

Background Intracranial infections with Corynebacterium striatum (C. striatum) have been described sporadically in the literature over the last two decades. However, C. striatum meningitis combined with multiple abscesses has not been published before. Case presentation In this report, we describe the clinical and imaging findings in a 54-year-old woman with meningitis caused by C. striatum and combined with suspected brain and lung abscesses. This patient who underwent multiple fractures and a recent cut presented with headache and paraphasia. C. striatum was isolated in cerebrospinal fluid and supposedly transmitted from the skin purulent wound through blood. The patient was treated with intravenous vancomycin and had a transient improvement, but died finally. Multiple abscesses, especially in the brain, could be a reason to explain her conditions were deteriorating rapidly. Conclusions Note that C. striatum can cause life-threatening infections. Early identification and diagnosis, early administration of antibiotics to which the bacterium is susceptible, and treatment of complications will be beneficial in patients with C. striatum-related infection.

The mortality rate of ovarian cancer is the highest among gynaecological cancers, primarily due to metastatic symptoms. Recent studies have shown that HOX genes are crucial in tumour progression, but the underlying mechanisms remain unclear. Here, HOXC10 expression was examined in ovarian cancer tissues. The function of HOXC10 in ovarian cancer metastasis was investigated in vitroand via intraperitoneal injection in vivo. A total of 158 ovarian cancer patients with adequate records were enrolled for analysis. HOXC10 was associated with metastasis and poor prognosis in ovarian cancer. In vitro, HOXC10 overexpression promoted ovarian cancer cell migration. Moreover, HOXC10 positively regulated Slug expression, altering the migration ability of cancer cells. Furthermore, our study showed that miR-222-3p was a suppressor of HOXC10. In vivo, a decrease in hepatic metastasis was seen in xenograft mice harbouring tumours with stable HOXC10 overexpression after miR-222-3p agomir (an overexpression reagent) injection. This study provides the first evidence that HOXC10 promotes ovarian cancer metastasis by regulating the transcription of the EMT-related gene Slug. Moreover, we found that HOXC10 is regulated by miR-222-3p. These data highlight the crucial role of HOXC10 in enhancing ovarian cancer metastasis and may provide a therapeutic target for ovarian cancer.

The clinical features, CMR characteristics and outcomes of arrhythmogenic left ventricular cardiomyopathy (ALVC), which is a very rare nonischemic cardiomyopathy, are currently not well studied. The purpose of the study is to investigate the clinical and cardiovascular magnetic resonance (CMR) imaging characteristics of arrhythmogenic left ventricular cardiomyopathy (ALVC). Fifty-three consecutive patients with ALVC were divided into two groups: ALVC patients without right ventricular (RV) involvement (n = 36, group 1) and those with RV involvement (n = 17, group 2). Clinical symptoms, cardiac electrophysiological findings, and CMR parameters (morphology, ventricular function, and myocardial fibrosis and fatty infiltration) were evaluated in both groups. The two groups showed no significant difference in age, gender, or presenting symptoms (P > 0.05). Right bundle branch block ventricular arrhythmia was less common in patients without RV involvement (50.0% vs.64.7%, P = 0.031). There were no significant differences in left ventricular function between the two groups, however right ventricular ejection fraction was significantly lower in group 2 (40.1 ± 4.0% vs. 48.7 ± 3.9%, P

Background: The six most common malignancies in the world include ovarian cancer (OC), which is a severe tumor that seriously threatens women's lives. And it’s also one of the leading causes of death of patients with various gynecological tumors. Although many papers have reported that high TMB can generate many neoantigens to incited anti-tumor immune response and the immune infiltration degree of the tumor has an essential influence on prognosis, the interrelationship between TMB and immune scores in OC and its effect on prognosis were not examined systematically. Under this circumstance, our current study aims to discover the novel biomarkers in OC, and seek to investigate the role of hub genes in OC. Results: We divided OC cases into two groups: the low tumor mutational burden (TMB) group and the high TMB group hinged on the somatic mutation data from the Cancer Genome Atlas (TCGA). Our researches found that the higher TMB, the better the survival prognosis of ovarian cancer. And we also categorized OC cases into low immune scores group and high immune scores group based on ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm from TCGA. It’s shown that the B cells naive, macrophages M0, and dendritic cells activated tended to be down-regulated in the low immune scores group, and the T cells CD8, T cells CD4 memory activated, and macrophages M2 tended to be up-regulated in the high immune scores group. To better explain the effects of TMB and the genes involved in immune cells on prognosis, we filtrated differential expression genes (DEGs) whose expression considerably linked to prognosis in OC patients. In addition, we analyzed Up-DGEs (Up-regulated DEGs) and Down-DEGs (Down-regulated DEGs) and then screened the top ten small-molecule drugs in CMap (ConnectivityMap), six candidate small molecule drugs were identified that are closely related to the clinical treatment of OC. Meanwhile, our researches further demonstrated that Up-DEGs were mainly involved in immune response and T cell proliferation by functional enrichment analysis and protein‐protein interaction (PPI) network. Finally, we validated these genes from the Group on Earth Observations (GEO) which included CXCL13, FCRLA, PLA2G2D and MS4A1. Funding Statement: Contributions received from the TCGA network, the GTEx network and the CCLE Network. This study was supported by grants from the National Natural Science Foundation of China (No. 81572900). The Fundamental Research Funds for the Central Universities of Central South University (No. 502221804). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Not required.

Objective. The rate of neuronal apoptosis increases after spinal cord injury (SCI). Anastomosing the normal nerve roots above the SCI level to the injured sacral nerve roots can enhance the functional recovery of neurons. Therefore, we evaluated the effect of sacral nerve root transfer after SCI on pontine neuronal survival. Methods. Sprague–Dawley rats were randomly divided into three groups: Group A, reconstruction of afferent and efferent nerve pathways of the bladder after SCI; Group B, SCI only; and Group C, control group. We examined pontine neuronal morphology using hematoxylin and eosin (H&E) staining after SCI and nerve transfer. Bcl-2 and Bax protein expression changes in the pontine micturition center were quantified by immunohistochemistry. The number of apoptotic neurons was determined by TUNEL staining. We examined pontine neuronal apoptosis by transmission electron microscopy (TEM) at different time points. Results. H&E staining demonstrated that the number of neurons had increased in Group A, but more cells in Group B displayed nuclear pyknosis, with the disappearance of the nucleus. Compared with Group B, Group A had significantly higher Bcl-2 expression, significantly lower Bax expression, and a significantly higher Bcl-2/Bax ratio. The number of apoptotic neurons and neuron bodies in Group A was significantly lower than that in Group B, as indicated by TUNEL staining and TEM. Conclusions. These findings demonstrate that lumbosacral nerve transfer can reduce neuronal apoptosis in the pontine micturition center and enhance functional recovery of neurons. This result further suggests that lumbosacral nerve transfer can be used as a new approach for reconstructing bladder function after spinal cord injury.

N6-methyladenosine (m6A) RNA methylation, involved in cancer initiation and progression, is dynamically regulated by the m6A RNA methylation regulators, including ‘writers’, ‘erasers’ and ‘readers’. However, the expression of m6A RNA methylation regulators in ovarian cancer and their correlation with prognosis remain elusive. Here, we demonstrated that the 18 central m6A RNA methylation regulators were expressed differently between ovarian cancer (OC) and normal tissues, and can be divided into two categories according to their enrichment in tumor vs normal tissues. Additionally, by applying consensus clustering, all OC patients cases can be divided into three subgroups (cluster1/2/3) based on expression levels of all 18 m6A RNA methylation regulators. Moreover, we systematically analyzed the prognostic value of 18 m6A RNA methylation regulators in OC and found that IGF2BP1, VIRMA, and ZC3H13 yield the highest scores for predicting the prognosis of OC. Therefore, we derived a risk signature consisting of these three selected m6A RNA methylation regulators as an independent prognostic marker for OC and validated our findings with data derived from a different OC cohort. Moreover, by the Gene Set Enrichment Analysis (GSEA), we demonstrated that the three selected regulators were all correlated with pathways in cancer and WNT signaling pathways. In conclusion, m6A methylation regulators are vital participants in OC, and IGF2BP1, VIRMA, and ZC3H13 are valuable for prognosis prediction and treatment strategy development. Funding Statement: Contributions were made by the TCGA network, the GTEx network and the CCLE Network. This study was supported by grants from the National Natural Science Foundation of China (No. 81572900). The National Key R&D Program of China, Stem Cell and Translation Research (No. 2016YFA0102000). The Fundamental Research Funds for the Central Universities of Central South University (No. 502221804). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Not required.

Background Atrial fibrillation (AF) is the most common arrhythmia in hypertrophic cardiomyopathy (HCM) and is associated with adverse outcomes in HCM patients. Although the left atrial (LA) diameter has consistently been identified as a strong predictor of AF in HCM patients, the relationship between LA dysfunction and AF still remains unclear. The aim of this study is to evaluate the LA function in patients with non-obstructive HCM (NOHCM) utilizing cardiovascular magnetic resonance feature tracking (CMR-FT). Methods Thirty-three patients with NOHCM and 28 healthy controls were studied. The global and regional LA function and left ventricular (LV) function were compared between the two groups. The following LA global functional parameters were quantitively analyzed: reservoir function (total ejection fraction [LA total EF], total strain [εs], peak positive strain rate [SRs]), conduit function (passive ejection fraction [LA passive EF], passive strain [εe], peak early-negative SR [SRe]), and booster pump function (active ejection fraction [LA active EF], active strain [εa], peak late-negative SR [SRa]). The LA wall was automatically divided into 6 segments: anterior, antero-roof, inferior, septal, septal-roof and lateral. Three LA strain parameters (εs, εe, εa) and their corresponding strain rate parameters (SRs, SRe, SRa) during the reservoir, conduit and booster pump LA phases were segmentally measured and analyzed. Results The LA reservoir (LA total EF: 57.6 ± 8.2% vs. 63.9 ± 6.4%, p s: 35.0 ± 12.0% vs. 41.5 ± 11.2%, p = 0.03; SRs: 1.3 ± 0.4 s− 1 vs. 1.5 ± 0.4 s− 1, p = 0.02) and conduit function (LA passive EF: 28.7 ± 9.1% vs. 37.1 ± 10.0%, p e: 18.7 ± 7.9% vs. 25.9 ± 10.0%, p − 1 vs. -1.1 ± 0.4 s− 1, p s, εe, SRe of inferior, SRs, SRe of septal-roof, and SRa of antero-roof walls (all p s and LA total EF(r = 0.84, p a and LA active EF (r = 0.83, p Conclusions Compared with healthy controls, patients with NOHCM have LA reservoir and conduit dysfunction, and regional LA deformation before LA enlargement. CMR-FT identifies LA dysfunction and deformation at an early stage.

In order to explore the mechanism of dexmedetomidine on brain damage in sepsis, mice were used to detect the staining of cells with hematoxylin-eosin and terminal-deoxynucleotidyl transferase mediated nick end labeling, the content of Evans blue in the brain, and the expression of TNF-α, IL-1β, malonaldehyde, reactive oxygen species, Bcl-2, Bax, cleaved caspase-3 were explored to understand possible mechanism of dexmedetomidine brain protection. The results showed that firstly, dexmedetomidine could attenuate the abnormal morphological changes of neurons in the brain and neuronal apoptosis, secondly, dexmedetomidine could attenuate the expression of TNF-α, IL-1β, MDA, ROS, Bcl-2, Bax, cleaved caspase-3 and iNOS. In summary, the cerebral protection mechanism of dexmedetomidine in septic mice might be connected with reducing the blood brain barrier destruction, reducing brain inflammation and oxidative stress levels, as well as inhibition of apoptosis by altering the expression of Bax, Bcl-2, and cleaved caspase-3. Despite some shortcomings in this investigation, these results still provide clear guidance for future research.

Yaqi Gan,1,2,* Yimin Li,1,2,* Tong Li,1,2 Guang Shu,2 Gang Yin1,2 1Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China; 2Department of Pathology, School ofBasic Medical Sciences, Central South University, Changsha, Hunan Province, China *These authors contributed equally to this work Objective: Colorectal cancer (CRC) is considered to be the most prevalent malignant tumors that contribute to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We seek to discover a novel biomarker in CRC. Materials and methods: All clinical CRC samples (n=33) were from Xiangya Hospital. We first selected CCNA2 by integrated bioinformatics analysis of four GSE databases. Next, the expression of CCNA2 in tissues and cell lines was verified by quantitative real-time PCR. The effects of CCNA2 on cell growth, proliferation, cell cycle, and apoptosis were examined by in vitro assays. Results: We identified 498 shared DEGs (294 upregulated and 204 downregulated), and the top ten hub genes were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of CCNA2 in CRC tissues is higher than that in normal tissues. The CCNA2 knockdown could significantly suppress CRC cell growth by impairing cell cycle progression and inducing cell apoptosis. Conclusion: CCNA2, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis. It could be used as a new biomarker for diagnosis and therapy in CRC. Keywords: CCNA2, colorectal cancer, bioinformatics analysis, proliferation, cell cycle, apoptosis

Objectives To investigate the expression of amyloid precursor protein in bladder cancer, and to study its role in malignant bladder cancer cell behaviors. Methods Immunohistochemistry and western blotting analysis were used to detect the amyloid precursor protein level in bladder cancer tissues and cell lines. The effect of amyloid precursor protein on bladder cancer cell proliferation, migration, invasion and cell cycle was evaluated by using small interfering ribonucleic acid. The levels of RAS, RAF, MEK, phosphorylated MEK, extracellular regulated protein kinases, phosphorylated extracellular regulated protein kinases, protein kinase B and phosphorylated protein kinase B were determined by western blot after amyloid precursor protein knockdown. The effect of amyloid precursor protein on the extracellular regulated protein kinases pathway was further evaluated using extracellular regulated protein kinases pathway agonist, ceramide C6. Results The expression of amyloid precursor protein was significantly increased in the human bladder cancer tissues compared with matched normal bladder tissues. The overexpression of amyloid precursor protein was significantly associated with tumor stage, tumor size, histological grade and lymph node metastasis. The proliferation, migration and invasion of human bladder cancer cells were significantly inhibited by the silencing of amyloid precursor protein. In addition, knockdown of amyloid precursor protein arrested the cell cycle progression of bladder cancer cells in the G2/M phase. Mechanistic analysis showed that knockdown of amyloid precursor protein significantly decreased the phosphorylation of extracellular regulated protein kinases. Ceramide C6 could rescue the malignant bladder cancer cell behaviors inhibited by the silencing of amyloid precursor protein. Conclusions Amyloid precursor protein is upregulated in bladder cancer, and might be closely associated with bladder cancer cell growth and survival. Amyloid precursor protein could potentially be used as a therapeutic target for bladder cancer treatment.

To evaluate the prognostic value of texture features based on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) images in hypertrophic cardiomyopathy (HCM) patients with systolic dysfunction. 67 HCM patients with systolic dysfunction (41 male and 26 female, mean age ± standard deviation, 46.20 years ± 13.38) were enrolled. All patients underwent 1.5 T CMR cine and LGE imaging. Texture features were extracted from LGE images. Cox proportional hazard analysis and Kaplan-Meier analysis were used to determine the association of texture features and traditional parameters with event free survival. Family history (hazard ratio [HR]=2.558, 95 % confidence interval [CI]=1.060–6.180), NYHA III-IV (HR=5.627, CI=1.652–19.173), left ventricular ejection fraction (HR=0.945, CI=0.902–0.991), left ventricular end-diastolic volume index (HR=1.006, CI=1.000–1.012), LGE extent (HR=1.911, CI=1.348–2.709) and three texture parameters [X0_H_skewness (HR=0.783, CI=0.691–0.889), X0_GLCM_cluster_tendency (HR=0.735, CI=0.616–0.877) and X0_GLRLM_energy (HR=1.344, CI=1.173–1.540)] were significantly associated with event free survival in univariate analysis (p

Chemotherapy plays an important role in the treatment of breast cancer. However, chemoresistance remains the main obstacle for effective treatment, leading to poor prognosis. This study aims to investigate the value of detection of S100A8 and ASAH1 in predicting the chemotherapy response. Miller and Payne grades were used to assess the chemotherapy response in breast cancers. The expression of S100A8 and ASAH1, as well as ER, PR, HER2 and Ki-67 were assessed by immunohistochemical staining in 120 cases of non-special type invasive ductal carcinoma (IDC-NOS). S100A8 expression was higher in chemosensitive breast cancers than chemoresistant ones. Moreover, S100A8 expression was significantly correlated with the molecular subtypes and histological grade, but not with patients' age, tumor size and lymph nodes status. However, there was no significant difference in ASAH1 expression between chemoresistant and chemosensitive group. We also found that higher ASAH1 expression was correlated with positive lymph nodes status, but not with age, tumor size, molecular subtypes and histological grade. S100A8 was valuable in predicting chemotherapy response in breast cancers. The expression of ASAH1 was associated significantly with lymph nodes metastasis, indicating that ASAH1 may serve as a biomarker to predict patients' lymph nodes status in breast cancers.

Malaria, one of the most common vector borne human diseases, is a major world health issue. In 2015 alone, more than 200 million people were infected with malaria, out of which, 429 000 died. Even though artemisinin-based combination therapies (ACT) are highly effective at treating malaria infections, novel efforts toward development of vaccines to prevent transmission are still needed. Pfs25, a postfertilization stage parasite surface antigen, is a leading transmission-blocking vaccine (TBV) candidate. It is postulated that Pfs25 anchors to the cell membrane using a glycosylphosphatidylinositol (GPI) linker, which itself possesses pro-inflammatory properties. In this study, Escherichia coli derived extract (XtractCF+TM) was used in cell free protein synthesis [CFPS] to successfully express >200 mg/L of recombinant Pfs25 with a C-terminal non-natural amino acid (nnAA), namely, p-azidomethyl phenylalanine (pAMF), which possesses a reactive azide group. Thereafter, a unique conjugate vaccine (CV), namely, Pfs25-GPI was generated with dibenzocyclooctyne (DBCO) derivatized glycan core of malaria GPI using a simple but highly efficient copper free click chemistry reaction. In mice immunized with Pfs25 or Pfs25-GPI, the Pfs25-GPI group showed significantly higher titers compared to the Pfs25 group. Moreover, only purified IgGs from Pfs25-GPI group were able to significantly block transmission of parasites to mosquitoes, as judged by a standard membrane feeding assay [SMFA]. To our knowledge, this is the first report of the generation of a CV using Pfs25 and malaria specific GPI where the GPI is shown to enhance the ability of Pfs25 to elicit transmission blocking antibodies.

Traditional Chinese medicine has been widely used in cancer treatment in China. Yangyin Fuzheng Decoction is a traditional Chinese compound medicine, composed of 12 traditional Chinese herbs. This study aimed to investigate anti-tumor activity and the underlying mechanisms of Yangyin Fuzheng Decoction combined with cisplatin in the treatment of lung cancer. We established lung cancer model in C57BL/6 mice injected with mouse Lewis lung cancer cells. Our results demonstrated that Yangyin Fuzheng Decoction treatment increased necrotic area in tumor tissue, and significantly enhanced the recruitment of inflammatory cells into the tumor. In addition, Yangyin Fuzheng Decoction treatment enhanced the anti-tumor efficacy of cisplatin and partially recovered mouse body weight loss caused by cisplatin treatment. Mechanistically, we found that Yangyin Fuzheng Decoction upregulated the expression of pro-apoptotic proteins p53 and Bax and suppressed the expression of anti-apoptotic protein Bcl-2. Combined treatment of Yangyin Fuzheng Decoction and cisplatin further increased p53 and Bax levels and suppressed Bcl-2 level. Taken together, these data suggest that Yangyin Fuzheng Decoction could synergistically enhance the apoptotic signaling in cancer cells during chemotherapy. In addition, it has health improving and immune response enhancing effects. Yangyin Fuzheng Decoction could be a promising adjunct agent for lung cancer chemotherapy.

This study aimed to assess the relationship between local mechanical stimuli and regional aortic tissue degeneration using fluid–structure interaction (FSI) analysis in patients with bicuspid aortic valve (BAV) disease. Nine patients underwent ascending aortic replacement were recruited. Tissues were collected to evaluate the pathology features in four regions, greater curvature (GC-region), posterior (P-region), anterior (A-region), and lesser curvature (LC-region). FSI analysis was performed to quantify vessel structural stress (VSS) and flow-induced parameters, including wall shear stress (WSS), oscillatory shear index (OSI), and particle relative residence time (RRT). The correlation between these biomechanical metrics and tissue degeneration was analyzed. Elastin in the medial layer and media thickness were thinnest and the gap between fibers was biggest in the GC-region, followed by the P-region and A-region, while the elastin and media thickness were thickest and the gap smallest in the LC-region. The collagen deposition followed a pattern with the biggest in the GC-region and least in the LC-region. There is a strong negative correlation between mean or peak VSS and elastin thickness in the arterial wall in the GC-region (r = -0.917; p = 0.001 and r = -0.899; p = 0.001), A-region (r = -0.748; p = 0.020 and r = -0.700; p = 0.036) and P-region (r = -0.773; p = 0.014 and r = -0.769; p = 0.015), and between mean VSS and fiber distance in the A-region (r = -0.702, p = 0.035). Moreover, strong negative correlation between mean or peak VSS and media thickness was also observed. No correlation was found between WSS, OSI, and RRT and aortic tissue degeneration in these four regions. These findings indicate that increased VSS correlated with local elastin degradation and aortic media degeneration, implying that it could be a potential biomechanical parameter for a refined risk stratification for patients with BAV.

// Gang Yin 1 , 2, * , Jin Fan 1, * , Wei Zhou 1 , Qingfeng Ding 1 , Jun Zhang 1 , Xuan Wu 1 , Pengyu Tang 1 , Hao Zhou 1 , Bowen Wan 1 and Guoyong Yin 1 1 Department of Spine Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China 2 Department of Orthopaedics, Changzhou Wujin Hospital Affiliated to Jiangsu University, Changzhou, Jiangsu 213017, China * These authors have contributed equally to this work Correspondence to: Guoyong Yin, email: guoyong_yin@sina.com, drguoyongyin@163.com Keywords: osteosarcoma, mTOR, CZ415, ERK, molecular-targeted therapy Received: April 11, 2017 Accepted: April 18, 2017 Published: May 30, 2017 ABSTRACT mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415. ERK inhibition (by MEK162/U0126) or knockdown (by targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced osteosarcoma cell apoptosis. In vivo , CZ415 oral administration efficiently inhibited U2OS tumor growth in mice. Its activity was further potentiated with co-administration of MEK162. Collectively, we demonstrate that ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo . CZ415 could be further tested as a promising anti-osteosarcoma agent, alone or in combination of ERK inhibition.

// Chunyan Gu 1, 2, 3, * , Hailin Peng 4, * , Yue Lu 5 , Hongbao Yang 6 , Zhidan Tian 7 , Gang Yin 2 , Wen Zhang 8 , Sicheng Lu 2 , Yi Zhang 9 and Ye Yang 1, 2, 10 1 The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China 2 School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing 210023, China 3 Department of Pathology, School of Medicine, University of Iowa, Iowa City, Iowa 52242, USA 4 Department of Laboratory Medicine, Taizhou People’s Hospital, Taizhou 225300, China 5 Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing 210009, China 6 Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China 7 Department of Pathology, Nanjing First Hospital, Nanjing 210006, China 8 Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, China 9 Department of Burns and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China 10 Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, China * These authors have contributed equally to this work Correspondence to: Yi Zhang, email: 198zy@163.com Ye Yang, email: yangye876@sina.com Keywords: multiple myeloma, BTK, senescence, AKT, CGI-1746 Received: February 25, 2017 Accepted: April 04, 2017 Published: May 23, 2017 ABSTRACT We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro . Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo . Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM.

In this study the relationship between brain structure and brain metastases (BM) occurrence was analyzed. A model for predicting the time of BM onset in patients with non-small cell lung cancer (NSCLC) was proposed. Twenty patients were used to develop the model, whereas the remaining 69 were used for independent validation and verification of the model. Magnetic resonance images were segmented into cerebrospinal fluid, gray matter (GM), and white matter using voxel-based morphometry. Automatic anatomic labeling template was used to extract 116 brain regions from the GM volume. The elapsed time between the MRI acquisitions and BM diagnosed was analyzed using the least absolute shrinkage and selection operator method. The model was validated using the leave-one-out cross validation (LOOCV) and permutation test. The GM volume of the extracted 11 regions of interest increased with the progression of BM from NSCLC. LOOCV test on the model indicated that the measured and predicted BM onset were highly correlated (r = 0.834, P = 0.0000). For the 69 independent validating patients, accuracy, sensitivity, and specificity of the model for predicting BM occurrence were 70, 75, and 66%, respectively, in 6 months and 74, 82, and 60%, respectively, in 1 year. The extracted brain GM volumes and interval times for BM occurrence were correlated. The established model based on MRI data may reliably predict BM in 6 months or 1 year. Further studies with larger sample size are needed to validate the findings in a clinical setting.