ABSTRACT
BACKGROUND: Pexidartinib (Turalio) is the only systemic therapy approved by the FDA for the treatment of adult patients with symptomatic tenosynovial giant-cell tumor (TGCT) associated with severe morbidity or functional limitations, and not amenable to improvement with surgery. This study assessed patient-reported treatment experiences and symptom improvement among patients receiving pexidartinib. METHODS: A cross-sectional, web-based survey collected data on demographics, disease history, pexidartinib dosing, and symptoms before and after pexidartinib use. RESULTS: Of 288 patients enrolled in the Turalio REMS program in May 2021, 83 completed the survey: mean age was 44.2 years, 62.7% were female, and most common tumor sites were in knee (61%) and ankle (12%). Mean initial dose was 622 mg/day: 29 patients reported reduction from initial dose and 8 had dose reduction after titrating up to a higher dose. At the time of survey completion, median time on pexidartinib was 6.0 months; 22 (26.5%) patients discontinued pexidartinib due to physician suggestion, abnormal laboratory results, side effect, or symptom improvement. Compared with before pexidartinib initiation, most patients reported improvement in overall TGCT symptom (78.3%) and physical function (77.2%) during pexidartinib treatment. Significant improvement was reported during pexidartinib treatment in worst stiffness numeric rating scale (NRS) (3.0 vs. 6.2, Pâ <â .05) and worst pain NRS (2.7 vs. 5.7, Pâ <â .05). CONCLUSION: Findings from this cross-sectional survey confirmed the benefit of pexidartinib in improving symptoms and functional outcomes among patients with symptomatic TGCTs from the patients' perspective. Future research is warranted to examine the long-term benefit and risk of pexidartinib.
Subject(s)
Giant Cell Tumor of Tendon Sheath , Pyrroles , Adult , Humans , Female , Male , Cross-Sectional Studies , Giant Cell Tumor of Tendon Sheath/drug therapy , Giant Cell Tumor of Tendon Sheath/pathology , Giant Cell Tumor of Tendon Sheath/surgery , Aminopyridines/therapeutic use , Patient Outcome AssessmentABSTRACT
BACKGROUND: [18 F]-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has the ability to detect local and/or regional recurrence as well as distant metastasis. We aimed to evaluate the prognosis value of PET/CT in locoregional recurrent nasopharyngeal (lrNPC). METHODS: A total of 451 eligible patients diagnosed with recurrent I-IVA (rI-IVA) NPC between April 2009 and December 2015 were retrospectively included in this study. The differences in overall survival (OS) of lrNPC patients with and without PET/CT were compared in the I-II, III-IVA, r0-II, and rIII-IVA cohorts, which were grouped by initial staging and recurrent staging (according to MRI). RESULTS: In the III-IVA and rIII-IVA NPC patients, with PET/CT exhibited significantly higher OS rates in the univariate analysis (P = 0.045; P = 0.009; respectively). Multivariate analysis revealed that with PET/CT was an independent predictor of OS in the rIII-IVA cohort (hazard ratio [HR] = 0.476; 95% confidence interval [CI]: 0.267 to 0.847; P = 0.012). In the rIII-IVA NPC, patients receiving PET/CT sacns before salvage surgery had a better prognosis compared with MRI alone (P = 0.036). The recurrent stage (based on PET/CT) was an independent predictor of OS. (r0-II versus [vs]. rIII-IVA; HR = 0.376; 95% CI: 0.150 to 0.938; P = 0.036). CONCLUSION: The present study showed that with PET/CT could improve overall survival for rIII-IVA NPC patients. PET/CT appears to be an effective method for assessing rTNM staging.
Subject(s)
Nasopharyngeal Neoplasms , Positron Emission Tomography Computed Tomography , Humans , Positron Emission Tomography Computed Tomography/methods , Fluorodeoxyglucose F18 , Nasopharyngeal Carcinoma/diagnostic imaging , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/pathology , Prognosis , Retrospective Studies , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/pathology , Nasopharyngeal Neoplasms/diagnostic imaging , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/pathology , Positron-Emission Tomography/methods , Radiopharmaceuticals , Neoplasm StagingABSTRACT
PURPOSE: Prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) is a superior method to predict patients' risk of cancer progression and response to specific therapies. However, its performance is limited for neuroendocrine prostate cancer (NEPC) and PSMA-low prostate cancer cells, resulting in diagnostic blind spots. Hence, identifying novel specific targets is our aim for diagnosing those prostate cancers with low PSMA expression. METHODS: The Cancer Genome Atlas (TCGA) database and our cohorts from men with biopsy-proven high-risk metastatic prostate cancer were used to identify CDK19 and PSMA expression. PDX lines neP-09 and P-16 primary cells were used for cellular uptake and imaging mass cytometry in vitro. To evaluate in vivo CDK19-specific uptake of gallium(Ga)-68-IRM-015-DOTA, xenograft mice models and blocking assays were used. PET/CT imaging data were obtained to estimate the absorbed dose in organs. RESULTS: Our study group had reported the overexpression of a novel tissue-specific gene CDK19 in high-risk metastatic prostate cancer and CDK19 expression correlated with metastatic status and tumor staging, independently with PSMA and PSA levels. Following up on this new candidate for use in diagnostics, small molecules targeting CDK19 labeled with Ga-68 (68Ga-IRM-015-DOTA) were used for PET in this study. We found that the 68Ga-IRM-015-DOTA was specificity for prostate cancer cells, but the other cancer cells also took up little 68Ga-IRM-015-DOTA. Importantly, mouse imaging data showed that the NEPC and CRPC xenografts exhibited similar signal strength with 68Ga-IRM-015-DOTA, but 68Ga-PSMA-11 only stained the CRPC xenografts. Furthermore, target specificity was elucidated by a blocking experiment on a CDK19-bearing tumor xenograft. These data concluded that 68Ga-CDK19 PET/CT was an effective technology to detect lesions with or without PSMA in vitro, in vivo, and in the PDX model. CONCLUSION: Thus, we have generated a novel PET small molecule with predictive value for prostate cancer. The findings indicate that 68Ga-CDK19 may merit further evaluation as a predictive biomarker for PET scans in prospective cohorts and may facilitate the identification of molecular types of prostate cancer independent of PSMA.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Prostatic Neoplasms , Humans , Male , Animals , Mice , Gallium Radioisotopes , Positron Emission Tomography Computed Tomography/methods , Prospective Studies , Prostatic Neoplasms/pathology , Positron-Emission Tomography , Cyclin-Dependent KinasesABSTRACT
Oral squamous cell carcinoma is the sixth most common malignant tumor in the world, and the clinical treatment effect is not satisfactory. Because of the special nature of its location, oral cancer is inextricably linked with a wide variety of microorganisms, and its pathogenesis and development are also extremely susceptible to microbial regulation. In addition, the mediating role of the immune system is also indispensable to the course of tumor pathogenesis and development, especially tumor-associated macrophages, which amplify the regulatory role of microorganisms, and in turn regulate the microbial population components--two complementary effects that jointly exacerbate oral cancer. Herein, we summarized the existing research on the relationship between microorganisms and macrophages, as well as the regulatory role of microorganisms and macrophages in the pathogenesis and development of oral cancer. We also discussed the current status of and gaps in research on the relationship between microorganisms and macrophages and oral cancer. Both microorganisms and macrophages are considered promising indicators for prognosis, showing potentials to be used as new therapeutic targets. Despite some research interest in the role of microorganisms and macrophages in oral cancer, very few studies have linked them to oral precancerous lesions, and the mutual regulatory relationship between microorganisms and macrophages remains unclear. Therefore, in-depth exploration of the relationship network of microorganisms, macrophages and oral cancer is expected to provide more possibilities for the early diagnosis and treatment of tumors.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mouth Neoplasms , Humans , Carcinoma, Squamous Cell/pathology , Macrophages , Squamous Cell Carcinoma of Head and Neck , Head and Neck Neoplasms/pathologyABSTRACT
Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms.
Subject(s)
Mycorrhizae , Soil , Animals , Biodiversity , Ecosystem , Forests , Fungi , Humans , Plants , Soil MicrobiologyABSTRACT
LncRNAs play a vital role in the tumorigenesis of gastric cancer (GC). This study determined that LINC01235 expression has greater fold changes by analyzing TCGA RNA-Seq data. The qRT-PCR assay confirmed that LINC01235 is significantly over-expressed in GC cells and tissues. Additionally, the overall survival analysis showed that patients with a higher LINC01235 expression had a poorer prognosis than those with a lower LINC01235 expression. Univariate Cox regression analysis indicated that high LINC01235 expression is positively correlated with poor prognosis. Moreover, LINC01235 was an independent poor prognostic marker for GC in multivariate Cox analysis. Invitro assays suggested that LINC01235 knockdown suppresses GC cell migration and invasion. GSEA revealed that high LINC01235 expression is strongly enriched in the EMT pathway. Western blotting results revealed that LINC01235 silencing decreases the expression of EMT-induced proteins. In conclusion, LINC01235 can promote GC cell metastasis via EMT and function as a prognostic biomarker.
Subject(s)
Epithelial-Mesenchymal Transition , RNA, Long Noncoding , Stomach Neoplasms , Cell Line, Tumor , Cell Movement , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Prognosis , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/pathologyABSTRACT
Accurate segmentation of drivable areas and road obstacles is critical for autonomous mobile robots to navigate safely in indoor and outdoor environments. With the fast advancement of deep learning, mobile robots may now perform autonomous navigation based on what they learned in the learning phase. On the other hand, existing techniques often have low performance when confronted with complex situations since unfamiliar objects are not included in the training dataset. Additionally, the use of a large amount of labeled data is generally essential for training deep neural networks to achieve good performance, which is time-consuming and labor-intensive. Thus, this paper presents a solution to these issues by proposing a self-supervised learning method for the drivable areas and road anomaly segmentation. First, we propose the Automatic Generating Segmentation Label (AGSL) framework, which is an efficient system automatically generating segmentation labels for drivable areas and road anomalies by finding dissimilarities between the input and resynthesized image and localizing obstacles in the disparity map. Then, we train RGB-D datasets with a semantic segmentation network using self-generated ground truth labels derived from our method (AGSL labels) to get the pre-trained model. The results showed that our AGSL achieved high performance in labeling evaluation, and the pre-trained model also obtains certain confidence in real-time segmentation application on mobile robots.
Subject(s)
Image Processing, Computer-Assisted , Robotics , Image Processing, Computer-Assisted/methods , Neural Networks, Computer , UncertaintyABSTRACT
OBJECTIVE: The purpose of this study was to develop a classification method based on support vector machine (SVM) to improve the diagnostic performance of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to detect the lymph node (LN) metastasis in non-small cell lung cancer (NSCLC). METHOD: Two hundred nineteen lymph nodes (37 metastatic) from 71 patients were evaluated in this study. SVM models were developed with 7 LN features. The area under the curve (AUC) and accuracy of 9 models were compared to select the best model. The best SVM model was simplified on the basis of the feature weights and value distribution to further suit the clinical application. RESULTS: The maximum, minimum, and mean accuracy of the best model was 91.89% (68/74, 95% CI 83.11~96.54%), 66.22% (49/74, 95% CI 54.85~75.98%), and 80.09% (59,266/74,000, 95% CI 70.27~89.19%), respectively, with an AUC of 0.94, 0.66, and 0.81, respectively. The best SVM model was finally simplified into a score rule: LNs with scores more than 3.0 were considered as malignant ones, whereas LNs with scores less than 1.5 tended to be benign ones. For the LNs with scores within a range of 1.5-3.0, metastasis was suspected. CONCLUSION: An SVM model based on 18F-FDG PET/CT images was able to predict the metastatic LNs for patients with NSCLC. The ratio of the maximum of standard uptake value of LNs to aortic arch played a major role in the model. After simplification, the model could be transferred into a scoring method which may partly help clinicians determine the clinical staging of patients with NSCLC relatively easier. KEY POINTS: ⢠The SVM model based on 18F-FDG PET/CT features may help clinicians to make a decision for metastatic mediastinal lymph nodes in patients with NSCLC. ⢠The SURblood plays a major role in the SVM model. ⢠The score rule based on the SVM model simplified the complexity of the model and may partly help clinicians determine the clinical staging of patients with NSCLC relatively easier.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/pathology , Fluorodeoxyglucose F18 , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Lymphatic Metastasis , Neoplasm Staging , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Retrospective Studies , Support Vector MachineABSTRACT
BACKGROUND: Sleep deprivation (SD) has become a serious concern worldwide. This study aimed to identify key modules and candidate hub genes correlated with diseases caused by SD, using co-expression analysis. METHODS: The weighted gene co-expression network analysis was performed to construct a co-expression network of hub genes correlated with SD. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to search for signaling pathways. The protein-protein interaction network analysis of central genes was performed to recognize the interactions among central genes. Molecular Complex Detection, a plugin in Cytoscape, was used to discover the hub gene clusters involved in SD. RESULTS: A total of 564 genes in the yellow module were identified based on the results of topological overlap measure-based clustering. The yellow module showed a pivotal correlation with SD. Six hub gene clusters prominently associated with SD were identified. Heat shock protein family and circadian clock genes among them may be the hub genes involved in SD. CONCLUSIONS: These genes and pathways might become therapeutic targets with clinical usefulness in the future.
Subject(s)
Gene Expression Profiling , Gene Regulatory Networks/genetics , Signal Transduction/genetics , Sleep Deprivation/genetics , HumansABSTRACT
BACKGROUND: Hypertension remains the major modifiable risk factor of stroke recurrence. The study aimed to determine the up-to-date epidemiological features of hypertension among the survivors of ischemic stroke. METHODS: Our cross-sectional study included 18,796 adults aged ≥40 years and residing in northeast China. Ischemic stroke was diagnosed according to the World Health Organization's criteria, which requires the clinical record, computed tomography (CT) and/or magnetic resonance imaging (MRI) during the hospital stay. Hypertension was defined according to the Chinese hypertension guidelines (mean SBP ≥140 mmHg and/or mean DBP ≥90 mmHg, and/or self-reported use of anti-hypertensive medication in the past 2 weeks). RESULTS: Of the 986 survivors of ischemic stroke, 819 (83.1%) were identified with hypertension (535 were pre-stroke hypertension and 284 were post-stroke hypertension). Among hypertensive patients, the awareness and treatment rates were 76.8 and 66.7% respectively. Only 11.0% achieved an appropriate blood pressure (< 140 mmHg and < 90 mmHg) among those who took hypertensive medications. 16.8% of treated hypertensive patients received combination therapy, and calcium channel blockers were the most frequently used anti-hypertensive medication as monotherapy. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the stroke population was 155.3 ± 22.9 mmHg and 89.2 ± 12.3 mmHg. Both SBP and DBP were higher in rural patients than in urban patients (158.5 ± 23.8 mmHg vs. 146.4 ± 17.5 mmHg and 90.3 ± 12.9 mmHg vs. 85.9 ± 10.1 mmHg, respectively; p < 0.001). The rates of stage 2 and above hypertension in the ischemic stroke population were 32.5 and 18.7%, and was significantly higher in rural areas than in urban areas. CONCLUSIONS: The prevalence of poorly-controlled hypertension and the high rates of blood pressures at stages 2 and above in patients with prior ischemic stroke demonstrated an alarming situation in northeast China.
Subject(s)
Hypertension , Antihypertensive Agents/therapeutic use , Blood Pressure , China/epidemiology , Cross-Sectional Studies , Humans , Hypertension/drug therapy , Hypertension/epidemiology , SurvivorsABSTRACT
Device-free passive intrusion detection is a promising technology to determine whether moving subjects are present without deploying any specific sensors or devices in the area of interest. With the rapid development of wireless technology, multi-input multi-output (MIMO) and orthogonal frequency-division multiplexing (OFDM) which were originally exploited to improve the stability and bandwidth of Wi-Fi communication, can now support extensive applications such as indoor intrusion detection, patient monitoring, and healthcare monitoring for the elderly. At present, most research works use channel state information (CSI) in the IEEE 802.11n standard to analyze signals and select features. However, there are very limited studies on intrusion detection in real home environments that consider scenarios that include different motion speeds, different numbers of intruders, varying locations of devices, and whether people are present sleeping at home. In this paper, we propose an adaptive real-time indoor intrusion detection system using subcarrier correlation-based features based on the characteristics of narrow frequency spacing of adjacent subcarriers. We propose a link-pair selection algorithm for choosing an optimal link pair as a baseline for subsequent CSI processing. We prototype our system on commercial Wi-Fi devices and compare the overall performance with those of state-of-the-art approaches. The experimental results demonstrate that our system achieves impressive performance regardless of intruder's motion speeds, number of intruders, non-line-of-sight conditions, and sleeping occupant conditions.
ABSTRACT
Farnesyltransferase (FTase) is an important enzyme that catalyses the modification of protein isoprene downstream of the mevalonate pathway. Previous studies have shown that the tissue of the heart in the suprarenal abdominal aortic coarctation (AAC) group showed overexpression of FTaseß (FNTB) and the activation of the downstream protein Ras was enhanced. FTase inhibitor (FTI) can alleviate myocardial fibrosis and partly improve cardiac remodelling in spontaneously hypertensive rats. However, the exact role and mechanism of FTase in myocardial hypertrophy and remodelling are not fully understood. Here, we used recombinant adenovirus to transfect neonatal rat ventricular cardiomyocytes to study the effect of FNTB overexpression on myocardial remodelling and explore potential mechanisms. The results showed that overexpression of FNTB induces neonatal rat ventricular myocyte hypertrophy and reduces the survival rate of cardiomyocytes. FNTB overexpression induced a decrease in mitochondrial membrane potential and increased apoptosis in cardiomyocytes. FNTB overexpression also promotes autophagosome formation and the accumulation of autophagy substrate protein, LC3II. Transmission electron microscopy (TEM) and mCherry-GFP tandem fluorescent-tagged LC3 (tfLC3) showed that FNTB overexpression can activate autophagy flux by enhancing autophagosome conversion to autophagolysosome. Overactivated autophagy flux can be blocked by bafilomycin A1. In addition, salirasib (a Ras farnesylcysteine mimetic) can alleviate the hypertrophic phenotype of cardiomyocytes and inhibit the up-regulation of apoptosis and autophagy flux induced by FNTB overexpression. These results suggest that FTase may have a potential role in future treatment strategies to limit the adverse consequences of cardiac hypertrophy, cardiac dysfunction and heart failure.
Subject(s)
Apoptosis/physiology , Autophagic Cell Death/physiology , Cardiomegaly/metabolism , Farnesyltranstransferase/metabolism , Myocytes, Cardiac/metabolism , ras Proteins/metabolism , Animals , Autophagosomes/metabolism , Autophagosomes/pathology , Autophagy/physiology , Cardiomegaly/pathology , Heart Failure/metabolism , Heart Failure/pathology , Heart Ventricles/metabolism , Heart Ventricles/pathology , Membrane Potential, Mitochondrial/physiology , Microtubule-Associated Proteins/metabolism , Myocardium , Myocytes, Cardiac/pathology , Rats , Rats, Inbred SHR/metabolism , Rats, Sprague-Dawley , Ventricular Remodeling/physiologyABSTRACT
Transcription initiation factor 90 (TIF-90), an alternatively spliced variant of TIF-IA, differs by a 90 base pair deletion of exon 6. TIF-90 has been shown to regulate ribosomal RNA (rRNA) synthesis by interacting with polymerase I (Pol I) during the initiation of ribosomal DNA (rDNA) transcription in the nucleolus. Recently, we showed that TIF-90-mediated rRNA synthesis can play an important role in driving tumorigenesis in human colon cancer cells. Here we show that TIF-90 binds GTP at threonine 310, and that GTP binding is required for TIF-90-enhanced rRNA synthesis. Overexpression of activated AKT induces TIF-90 T310, but not a GTP-binding site (TIF-90 T310N) mutant, to translocate into the nucleolus and increase rRNA synthesis. Complementing this result, treatment with mycophenolic acid (MPA), an inhibitor of GTP production, dissociates TIF-90 from Pol I and hence abolishes AKT-increased rRNA synthesis by way of TIF-90 activation. Thus, TIF-90 requires bound GTP to fulfill its function as an enhancer of rRNA synthesis. Both TIF variants are highly expressed in colon cancer cells, and depletion of TIF-IA expression in these cells results in significant sensitivity to MPA-inhibited rRNA synthesis and reduced cell proliferation. Finally, a combination of MPA and AZD8055 (an inhibitor of both AKT and mTOR) synergistically inhibits rRNA synthesis, in vivo tumor growth, and other oncogenic activities of primary human colon cancer cells, suggesting a potential avenue for the development of therapeutic treatments by targeting the regulation of rRNA synthesis by TIF proteins.
Subject(s)
Carcinogenesis/genetics , Colonic Neoplasms/genetics , Guanosine Triphosphate/genetics , RNA, Ribosomal/genetics , Ribosomes/genetics , Transcription Factors/genetics , Transcription, Genetic/genetics , Cell Line, Tumor , Cell Proliferation/genetics , DNA, Ribosomal/genetics , HCT116 Cells , Humans , RNA Polymerase I/genetics , Signal Transduction/geneticsABSTRACT
From a metabolic perspective, cancer may be considered as a metabolic disease characterized by reprogrammed glycolytic metabolism. The aim of the present study was to investigate CD147-mediated glucose metabolic regulation in hepatocellular carcinoma (HCC) and its contribution to altered immune responses in the tumor microenvironment. Several HCC cell lines and corresponding nude mice xenografts models differing in CD147 expressions were established to directly investigate the role of CD147 in the reprogramming of glucose metabolism, and to determine the underlying molecular mechanisms. Immunohistochemistry (IHC) analyses and flow cytometry were used to identify the relationship between reprogrammed glycolysis and immunosuppression in HCC. Upregulated CD147 expressions were found to be associated with enhanced expressions of GLUT1, MCT1 in HCC tumorous tissues. CD147 promoted the glycolytic metabolism in HCC cell lines in vitro via the PI3K/Akt/mTOR signaling pathway. A positive correlation existed between a profile of immunosuppressive lymphocytes infiltration and CD147 expression in HCC tissues. Accumulation of FOXP3-expressing regulatory T cells was induced under a stimulation with lactate in vitro. In conclusion, CD147 promoted glycolytic metabolism in HCC via the PI3K/Akt/mTOR signaling pathway, and was related to immunosuppression in HCC.
Subject(s)
Basigin/metabolism , Carcinoma, Hepatocellular/metabolism , Glucose/metabolism , Glycolysis , Liver Neoplasms/metabolism , Adult , Animals , Basigin/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Female , Gene Expression Regulation, Neoplastic , HEK293 Cells , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice, Nude , Middle Aged , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transplantation, Heterologous , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologyABSTRACT
BACKGROUND: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) participate in progression of gastric cancer (GC). Nevertheless, the function and expression level of DLX6-AS1 in GC remain unknown. METHODS: We explored the sequencing data of DLX6-AS1 downloaded from The Cancer Genome Atlas. The expression of DLX6-AS1, miR-204-5p and OCT1 in 56 GC patients and GC cell lines was quantified by qRT-PCR and western blotting. Furthermore, we performed in vitro functional assays to assess proliferation, invasion and migration of GC cells by knockdown of DLX6-AS1. The expression level of epithelial-mesenchymal transition (EMT)-related genes was also determined by qRT-PCR and western blotting. Actin remodeling was detected by F-actin phalloidin staining. The luciferase reporter assay and chromatin immunoprecipitation assay was utilized to confirm the bioinformatic prediction. The function of the DLX6-AS1/miR-204-5p/OCT1 axis in GC proliferation was clarified by rescue assays. RESULTS: We first demonstrated that DLX6-AS1 was upregulated in GC tissues and cell lines and was associated with T3/T4 invasion, distant metastasis and poor clinical prognosis. Further functional analysis showed that downregulation of DLX6-AS1 inhibited GC cell proliferation, migration, invasion and EMT in vitro. Mechanistic investigation indicated that DLX6-AS1 acted as a cancer-promoting competing endogenous RNA (ceRNA) by binding miR-204-5p and upregulating OCT1. Moreover, the transcription factor OCT1 was confirmed to enhance DLX6-AS1 expression by targeting the promoter region. CONCLUSIONS: This study revealed that OCT1-induced DLX6-AS1 promoted GC progression and the EMT via the miR-204-5p/OCT1 axis, suggesting that this lncRNA might be a promising prognostic biomarker and therapeutic target for GC.
Subject(s)
Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , MicroRNAs/genetics , Octamer Transcription Factor-1/metabolism , RNA, Long Noncoding/genetics , Stomach Neoplasms/pathology , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Movement , Cell Proliferation , Disease Progression , Feedback, Physiological , Homeodomain Proteins/antagonists & inhibitors , Humans , Neoplasm Invasiveness , Octamer Transcription Factor-1/genetics , Prognosis , RNA, Antisense/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Survival Rate , Tumor Cells, CulturedABSTRACT
BACKGROUND AND AIMS: Recent studies have recognized triglyceride-glucose index (TyG) as a practical surrogate of insulin resistance. Previous studies have demonstrated that insulin resistance contributes to ischemic stroke via multiple mechanisms. Our study aimed to investigate the association between TyG and prevalent ischemic stroke, exploring the value of TyG to optimize the risk stratification of ischemic stroke. METHODS AND RESULTS: This cross-sectional study included 10,900 subjects (mean age: 59.95 years, 59.8% females) from rural areas of northeast China between September 2017 to May 2018. TyG was calculated as ln[fasting triglyceride (mg/dl) × fasting plasma glucose (mg/dl)/2]. The prevalence of ischemic stroke was 5.49%. After adjusting for all covariates, each SD increment of TyG caused 22.8% additional risk for ischemic stroke. When dividing TyG into quartiles, the top quartile had a 1.776 times risk for ischemic stroke against the bottom category. Furthermore, smoothing curve fitting demonstrated this association was linear in the whole range of TyG. Finally, AUC revealed an improvement when introducing TyG into clinical risk factors (0.746 vs 0.751, p = 0.029). Consistently, category-free net reclassification index (0.195, 95% CI: 0.112-0.277, P < 0.001) and integrated discrimination index (0.003, 95% CI: 0.001-0.004, P < 0.001) confirmed the improvement by TyG to stratify ischemic stroke risk. CONCLUSION: The prevent ischemic stroke correlated proportionally with the increment of TyG, implicating the linearity of TyG as an indicator of ischemic stroke. Our findings suggest the potential value of TyG to optimize the risk stratification of ischemic stroke in a general population.
Subject(s)
Blood Glucose/analysis , Brain Ischemia/blood , Dyslipidemias/blood , Hyperglycemia/blood , Stroke/blood , Triglycerides/blood , Aged , Biomarkers/blood , Brain Ischemia/diagnosis , Brain Ischemia/epidemiology , China/epidemiology , Cross-Sectional Studies , Dyslipidemias/diagnosis , Dyslipidemias/epidemiology , Female , Humans , Hyperglycemia/diagnosis , Hyperglycemia/epidemiology , Insulin Resistance , Male , Middle Aged , Prevalence , Prognosis , Risk Assessment , Risk Factors , Rural Health , Stroke/diagnosis , Stroke/epidemiologyABSTRACT
BACKGROUND AND AIMS: Management of dyslipidemia remains the cornerstone for prevention of cardiovascular diseases. We aimed to evaluate the epidemiology of dyslipidemia in northeast China. METHODS AND RESULTS: This cross-sectional survey was administered on 18,796 participants aged ≥40 years from September 2017 to March 2019 through a multistage, stratified, and cluster random sampling method. Lipid profiles were proposed by National Cholesterol Education Program Adult Treatment Panel III. The crude prevalence of dyslipidemia was 35.8%, higher in urban and women than their counterparts (49.5% vs 30.2%, 37.6% vs 33.0%, p < 0.001). The age-standardized prevalence of dyslipidemia was 34.0% (urban 47.9%, and rural 28.9%; men 36.2%, and women 33.4%). The prevalence of high total cholesterol (TC), high triglyceride (TG), high low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) were 14.2%, 17.7%, 5.7% and 11.4% respectively. Noticeably, the prevalence of high LDL-C and low HDL-C in urban areas showed a 2.2-fold and 6.3-fold increase over the rural areas (9.3% vs 4.2% and 28.4% vs 4.5%, respectively). Among participants with dyslipidemia, 14.7% were aware of their condition; 5.9% were taking lipid-regulating medications; and only 2.9% had their dyslipidemia controlled. Comorbidities including hypertension (63.6%), and diabetes (25.2%) were highly prevalent in patients with dyslipidemia, however, the control rates of those comorbidities were only 40.0% and 6.6%. CONCLUSIONS: Patients with dyslipidemia showed high cardiovascular burden with low control rates of dyslipidemia, high prevalence of coexisting risk factors. Therefore, region- and sex-specific strategies to manage dyslipidemia and related risk factors should be highlighted.
Subject(s)
Cardiovascular Diseases/epidemiology , Dyslipidemias/epidemiology , Adult , Age Distribution , Age Factors , Aged , Aged, 80 and over , Biomarkers/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/prevention & control , China/epidemiology , Comorbidity , Cross-Sectional Studies , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/drug therapy , Female , Health Surveys , Heart Disease Risk Factors , Humans , Hypolipidemic Agents/therapeutic use , Lipids/blood , Male , Middle Aged , Prevalence , Risk Assessment , Rural Health , Sex Distribution , Sex Factors , Urban HealthABSTRACT
The ErbB3-binding protein 1 (Ebp1) has been reported as either an oncogenic regulator or a tumor suppressor in a variety of cancers. Here, we show that Ebp1 p48, a predominant expression isoform, is highly expressed in the majority of human colon tumor cells compared with normal adjacent tissues and its expression is required for the oncogenic activities of these cells. Depletion of Ebp1 expression in primary colon cancer cells inhibits cell proliferation, colony forming, and invasion in vitro as well as tumor formation in vivo and enhances cell sensitivity to irradiation. We further demonstrated that Ebp1 interacts with TIF-90, a splice variant of transcription initiation factor IA (TIF-IA) of the RNA polymerase I complex, allowing for regulation of ribosomal RNA (rRNA) synthesis and oncogenesis in human colon cancer cells. Moreover, Ebp1 expression is essential for Akt protected TIF-90 stability by preventing TIF-90's ubiquitination by Mdm2 and hence, its proteasomal degradation. The results of the present study support a mechanism of underlying oncogenic activities by means of Ebp1 through regulation of TIF-90-mediated rRNA synthesis and suggest the potential therapeutic treatment of colon cancer by targeting Ebp1 and its signaling.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Colonic Neoplasms/metabolism , Pol1 Transcription Initiation Complex Proteins/metabolism , RNA, Ribosomal/biosynthesis , RNA-Binding Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Carcinogenesis/genetics , Carcinogenesis/metabolism , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Models, Biological , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Stability , Proto-Oncogene Proteins c-mdm2/metabolism , RNA, Ribosomal/genetics , RNA-Binding Proteins/genetics , Signal Transduction , Tumor Cells, Cultured , UbiquitinationABSTRACT
BACKGROUND: Currently, cancer-related competing endogenous RNA (ceRNA) networks are attracting significant interest. As long noncoding RNA ZEB1-AS1 has been reported to function as an oncogene due to sponging microRNAs (miRNAs) in several cancers, we hypothesized that it could interact with specific miRNAs to form regulatory networks and facilitate the growth of gastric cancer (GC). METHODS: MiRNAs interacting with ZEB1-AS1 were screened for and selected by bioinformatics analysis. Overexpression or repression of ZEB1-AS1 was performed to determine whether it could regulate selected miRNAs. Quantitative real-time polymerase chain reactions (qPCR) validated the expression profiles of ZEB1-AS1 and miR-149-3p in GC cell lines and tissue. Statistical analysis determined the clinical significance of ZEB1-AS1 in relation to miR-149-3p. Cell counting, wound healing and transwell assays were performed to assess cell proliferation, migration and invasion. A luciferase reporter assay was utilized to confirm the putative miR-149-3p-binding sites in ZEB1-AS1. RESULTS: Briefly, bioinformatics analysis inferred that ZEB1-AS1 interacts with miR-204, miR-610, and miR-149. Gain- or loss-of function assays suggested that ZEB1-AS1 negatively regulates miR-149-3p, miR-204-5p and miR-610 in GC cells. Validated by qPCR, ZEB1-AS1 was up-regulated and miR-149-3p down-regulated in GC cells and tissue. Data analyses indicated that ZEB1-AS1 and miR-149-3p are associated with the independent diagnosis and prognosis of GC. Functional assays support the theory that miR-149-3p hinders GC proliferation, migration and invasion, whereas its overexpression abrogates the corresponding effects induced by ZEB1-AS1. Lastly, dissection of the molecular mechanisms involved indicated that ZEB1-AS1 can regulate GC partly via a ZEB1-AS1/miR-149-3p axis. CONCLUSIONS: ZEB1-AS1 can interact with specific miRNAs, forming a miRNA-mediated ceRNA network and promoting GC progress, partly through a ZEB1-AS1/miR-149-3p axis.
ABSTRACT
[This corrects the article DOI: 10.1186/s12935-019-0742-0.].