Publications by authors named "Chao Cheng"

458 Publications

Bioinformatics Analysis of Expression Profiles and Prognostic Values of the Signal Transducer and Activator of Transcription Family Genes in Glioma.

Front Genet 2021 2;12:625234. Epub 2021 Jul 2.

Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.

Signal transducer and activator of transcription () family genes-of which there are seven members: , and -have been associated with the progression of multiple cancers. However, their prognostic values in glioma remain unclear. In this study, we systematically investigated the expression, the prognostic value, and the potential mechanism of the family genes in glioma. The expression of 1/2/3/5A/6 members were significantly higher and positively correlated with mutations, while the expression of was lower and negatively correlated with mutations in glioma. Survival analysis indicated that the upregulation of and downregulation of expression was associated with poorer overall survival in glioma. Joint effects analysis of expression suggested that the prognostic value of the group was more significant than that of each individual gene. Thus, we constructed a risk score model to predict the prognosis of glioma. The receiver operating characteristic curve and calibration curves showed good performance as prognostic indicators in both TCGA (The Cancer Genome Atlas) and the CGGA (Chinese Glioma Genome Atlas) databases. Furthermore, we analyzed the correlation between expression with immune infiltration in glioma. The Protein-protein interaction network and enrichment analysis showed that members and co-expressed genes mainly participated in signal transduction activity, Hepatitis B, the Jak-STAT signaling pathway, transcription factor activity, sequence-specific DNA binding, and the cytokine-mediated signaling pathway in glioma. In summary, our study analyzed the expression, prognostic values, and biological roles of the gene family members in glioma, based on which we developed a new risk score model to predict the prognosis of glioma more precisely.
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http://dx.doi.org/10.3389/fgene.2021.625234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283826PMC
July 2021

Impact of Oncotype DX testing on ER+ breast cancer treatment and survival in the first decade of use.

Breast Cancer Res 2021 Jul 17;23(1):74. Epub 2021 Jul 17.

Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.

Background: The Oncotype DX breast recurrence score has been introduced more than a decade ago to aid physicians in determining the need for systemic adjuvant chemotherapy in patients with early-stage, estrogen receptor (ER)+, lymph node-negative breast cancer.

Methods: In this study, we utilized data from The Surveillance, Epidemiology, and End Results (SEER) Program to investigate temporal trends in Oncotype DX usage among US breast cancer patients in the first decade after the introduction of the Oncotype DX assay.

Results: We found that the use of Oncotype DX has steadily increased in the first decade of use and that this increase is associated with a decreased usage of chemotherapy. Patients who utilized the Oncotype DX test tended to have improved survival compared to patients who did not use the assay even after adjusting for clinical variables associated with prognosis. In addition, chemotherapy usage in patients with high-risk scores is associated with significantly longer overall and breast cancer-specific survival compared to high-risk patients who did not receive chemotherapy. On the contrary, patients with low-risk scores who were treated with chemotherapy tended to have shorter overall survival compared to low-risk patients who forwent chemotherapy.

Conclusion: We have provided a comprehensive temporal overview of the use of Oncotype DX in breast cancer patients in the first decade after Oncotype DX was introduced. Our results suggest that the use of Oncotype DX is increasing in ER+ breast cancer and that the Oncotype DX test results provide valuable information for patient treatment and prognosis.
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http://dx.doi.org/10.1186/s13058-021-01453-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285794PMC
July 2021

A positive feedback loop of LINC00662 and STAT3 promotes malignant phenotype of glioma.

Pathol Res Pract 2021 Jul 5;224:153539. Epub 2021 Jul 5.

Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, PR China. Electronic address:

Background: Long noncoding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and development of glioma. LINC00662 has been involved in the pathogenesis of various human cancers. However, the mechanism underlying which LINC00662 exerts its role in glioma needs further exploration. In addition, regulation mechanism of LINC00662 expression in glioma remains unknown.

Methods And Materials: RT-qPCR was performed to evaluate the expression levels of LINC00662, miR-340-5p in glioma tissues and cell lines. The effect of LINC00662 and miR-340-5p in cell proliferation and invasion was assessed by Cell Counting Kit-8(CCK-8), clone colony formation and Transwell assay. Luciferase reporter assays and RNA immunoprecipitation assay validated the miR-340-5p-target relationships with LINC00662 or STAT3. CHIP-qPCR and Luciferase reporter assays were used to demonstrate the interaction between STAT3 and the promoter region of LINC00662. A tumor xenografts model was implemented to verify the effect of LINC00662 on glioma development in vivo.

Results: We found that LINC00662 was frequently highly expressed and related to the malignant phenotype of glioma. LINC00662 knockdown inhibited the proliferation, invasion and glioma genesis of glioma. LINC00662 acted as a ceRNA sponging miR-340-5p to protect the expression of STAT3. In addition, STAT3 was forced to the promoter region of LINC00662 and promoted its transcription. In vivo experiments demonstrated that targeting LINC00662 may be a potential strategy in glioma therapy.

Conclusion: There was a positive regulation loop between LINC00662 and STAT3 in glioma. LINC00662 might be an oncogene in glioma. Targeting LINC00662 was a potential strategy in glioma therapy.
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http://dx.doi.org/10.1016/j.prp.2021.153539DOI Listing
July 2021

MiR-17-5p and MKL-1 modulate stem cell characteristics of gastric cancer cells.

Int J Biol Sci 2021 4;17(9):2278-2293. Epub 2021 Jun 4.

Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China.

Effectively targeting cancer stem cells to treat cancer has great therapeutic prospects. However, the effect of microRNA miR-17/MKL-1 on gastric cancer stem cells has not been studied yet. This study preliminarily explored the mechanism of miR-17/MKL-1 in gastric cancer stem cells. Many previous reports have indicated that microRNA and EMT regulated cancer stem cell characteristics, and miR-17 and MKL-1 were involved as a critical gene in migration and invasion in the EMT pathway. Through RT-PCR, Western Blot, flow cytometry, immunofluorescence, sphere formation xenograft tumor assays and drug resistance, the role of miR-17-5p and MKL-1 on promoting stem cell-like properties of gastric cancer were verified . Next, MKL-1 targets CD44, EpCAM, and miR -17-5p promoter verified by luciferase assay and . Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. It is found that MKL-1 promotes expression by targeting miR-17, CD44 and EpCAM promoters. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. These findings reveal new regulatory signaling pathways for gastric cancer stem cells, thus it give new insights on potential early diagnosis and/or molecular therapy for gastric cancer.
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http://dx.doi.org/10.7150/ijbs.57338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241736PMC
June 2021

Statistical methods for analysis of combined biomarker data from multiple nested case-control studies.

Stat Methods Med Res 2021 Jul 7:9622802211025992. Epub 2021 Jul 7.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

By combining data across multiple studies, researchers increase sample size, statistical power, and precision for pooled analyses of biomarker-disease associations. However, researchers must adjust for between-study variability in biomarker measurements. Previous research often treats the biomarker measurements from a reference laboratory as a gold standard, even though those measurements are certainly not equal to their true values. This paper addresses measurement error and bias arising from both the reference and study-specific laboratories. We develop two calibration methods, the exact calibration method and approximate calibration method, for pooling biomarker data drawn from nested or matched case-control studies, where the calibration subset is obtained by randomly selecting controls from each contributing study. Simulation studies are conducted to evaluate the empirical performance of the proposed methods. We apply the proposed methods to a pooling project of nested case-control studies to evaluate the association between circulating 25-hydroxyvitamin D (25(OH)D) and colorectal cancer risk.
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http://dx.doi.org/10.1177/09622802211025992DOI Listing
July 2021

The clinical and prognostic values of optic nerve sheath diameter and optic nerve sheath diameter/eyeball transverse diameter ratio in comatose patients with supratentorial lesions.

BMC Neurol 2021 Jul 2;21(1):259. Epub 2021 Jul 2.

Department of Neurology, Peking University People's Hospital, No. 11 South Avenue, Xi Zhi Men Xicheng District, Beijing, 100044, China.

Background: The optic nerve sheath diameter (ONSD) and ONSD/eyeball transverse diameter (ETD) ratio have been proven to be correlated with intracranial pressure. This study aimed to evaluate the prognostic roles of ONSD and the ONSD/ETD ratio in comatose patients with supratentorial lesions and to determine the relationship of these two indices with the prognosis of such patients.

Methods: A total of 54 comatose patients with supratentorial lesions and 50 healthy controls were retrospectively included in this study. ONSD and ETD were measured by unenhanced computed tomography (CT). The differences in ONSD and the ONSD/ETD ratio between the two groups were compared. The prognosis of comatose patients was scored using the Glasgow Outcome Scale (GOS) at the 3-month follow-up, and these patients were classified into good (GOS score ≥ 3) and poor (GOS score < 3) prognosis groups. The differences in ONSD and the ONSD/ETD ratio were compared between comatose patients with good prognoses and those with poor prognoses.

Results: The ONSD and ONSD/ETD ratios in the comatose patients were 6.30 ± 0.60 mm and 0.27 ± 0.03, respectively, and both were significantly greater than those in the healthy controls (5.10 ± 0.47 mm, t = 11.426, P < 0.0001; 0.22 ± 0.02, t = 11.468, P < 0.0001; respectively). ONSD in patients with poor prognosis was significantly greater than that in patients with good prognosis (6.40 ± 0.56 vs. 6.03 ± 0.61 mm, t = 2.197, P = 0.032). The ONSD/ETD ratio in patients with poor prognosis was significantly greater than that in patients with good prognosis (0.28 ± 0.02 vs. 0.26 ± 0.03, t = 2.622, P = 0.011). The area under the receiver operating characteristic (ROC) curve, used to predict the prognosis of comatose patients, was 0.650 (95% confidence interval (CI): 0.486-0.815, P = 0.078) for ONSD and 0.711 (95% CI: 0.548-0.874, P = 0.014) for the ONSD/ETD ratio.

Conclusions: The ONSD and ONSD/ETD ratios were elevated in comatose patients. The ONSD/ETD ratio might be more valuable than ONSD in predicting the prognoses of comatose patients with supratentorial lesions.
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http://dx.doi.org/10.1186/s12883-021-02285-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252315PMC
July 2021

Slow feature analysis-aided detection and diagnosis of incipient faults for running gear systems of high-speed trains.

ISA Trans 2021 Jun 23. Epub 2021 Jun 23.

Institute of Energy Systems, Energy Efficiency and Energy Economics, TU Dortmund University, Dortmund 44227, Germany. Electronic address:

Incipient faults in running gear systems corrupt the overall performance of high-speed trains, increasing the necessity of fault detection and diagnosis whose purpose is to maintain the safe and stable operation of high-speed trains. For this purpose, a novel data-driven method, that utilizes Hellinger distance and slow feature analysis, is proposed in this study. By integrating Hellinger distance into slow feature analysis, a new test statistic is defined for detecting incipient faults in running gear systems. Furthermore, the hidden Markov method is developed for performing reliable fault diagnosis tasks. The salient strengths of the proposed method lie in its satisfactory fault detectability on the one hand and the considerable robustness against high-level noises on the other hand. Finally, the effectiveness of the proposed method is verified through a numerical example and a running gear system of high-speed trains under actual working conditions.
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http://dx.doi.org/10.1016/j.isatra.2021.06.023DOI Listing
June 2021

Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy.

Nat Cancer 2021 Mar 24;2(3):300-311. Epub 2021 Mar 24.

Department of Norris Cotton Cancer Center, The Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756.

While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8 T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (T) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell receptor sequencing further identified clonotypes in tumors that co-existed as T in skin and as effector memory T (T) cells in blood. Clonotypes that dispersed throughout tumor, skin, and blood preferentially expressed a / -high signature, which had a strong prognostic value for melanoma patients. Remarkably, clonotypes from tumors were found in patient skin and blood up to nine years later, with skin maintaining the most focused tumor-associated clonal repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, broadly-distributed T and T compartments.
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http://dx.doi.org/10.1038/s43018-021-00180-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223731PMC
March 2021

Upregulation of Long Noncoding RNA FGD5-AS1 Ameliorates Myocardial Ischemia/Reperfusion Injury via MicroRNA-106a-5p and MicroRNA-106b-5p.

J Cardiovasc Pharmacol 2021 07;78(1):e45-e54

Department of Cardiology, The Second Hospital of Shandong University, Jinan, China.

Abstract: Long noncoding RNAs have been known to play key roles in myocardial ischemia/reperfusion injury. This study was conducted to investigate whether upregulation of FGD5-AS1 can improve hypoxia/reoxygenation (H/R) injury of cardiomyocytes and its underlying mechanisms. Pc-FGD5-AS1 was used to overexpress FGD5-AS1 in cardiomyocytes. Cholecystokinin octapeptide and flow cytometry assays were performed to detect the effect of FGD5-AS1 on myocardial cell H/R injury. Quantitative real-time polymerase chain reaction and luciferase reporter assay were performed to assess the relationship between FGD5-AS1 and microRNA-106a-5p (miR-106a-5p) or miR-106b-5p. In patients with acute myocardial infarction and in H/R cardiomyocytes and ischemia/reperfusion myocardium, the expression levels of FGD5-AS1 were reduced, whereas the expression levels of miR-106a-5p and miR-106b-5p were increased. Overexpression of FGD5-AS1 increased the viability of H/R-treated cardiomyocytes and reduced the levels of apoptosis and creatine kinase-MB. In addition, FGD5-AS1 could bind to miR-106a-5p or miR-106b-5p and showed a mutual inhibitory effect between them. Furthermore, overexpression of miR-106a-5p or miR-106b-5p inhibited the expression of SMAD5. FGD5-AS1 upregulated the expression of SMAD5. In conclusion, FGD5-AS1 may be a potential therapeutic target for myocardial H/R injury, and its cardioprotective effect may be realized by reducing inflammatory response and cell apoptosis.
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http://dx.doi.org/10.1097/FJC.0000000000001036DOI Listing
July 2021

SUVA: splicing site usage variation analysis from RNA-seq data reveals highly conserved complex splicing biomarkers in liver cancer.

RNA Biol 2021 Jun 21:1-15. Epub 2021 Jun 21.

ABLife BioBigData Institute, Wuhan, Hubei China.

Most of the current alternative splicing (AS) analysis tools are powerless to analyse complex splicing. To address this, we developed SUVA (Splice sites Usage Variation Analysis) that decomposes complex splicing events into five types of splice junction pairs. By analysing real and simulated data, SUVA showed higher sensitivity and accuracy in detecting AS events than the compared methods. Notably, SUVA detected extensive complex AS events and screened out 69 highly conserved and dominant AS events associated with cancer. The cancer-associated complex AS events in FN1 and the co-regulated RNA-binding proteins were significantly correlated with patient survival.
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http://dx.doi.org/10.1080/15476286.2021.1940037DOI Listing
June 2021

AutoEncoder-Based Computational Framework for Tumor Microenvironment Decomposition and Biomarker Identification in Metastatic Melanoma.

Front Genet 2021 27;12:665065. Epub 2021 May 27.

Department of Medicine, Baylor College of Medicine, Houston, TX, United States.

Melanoma is one of the most aggressive cancer types whose prognosis is determined by both the tumor cell-intrinsic and -extrinsic features as well as their interactions. In this study, we performed systematic and unbiased analysis using The Cancer Genome Atlas (TCGA) melanoma RNA-seq data and identified two gene signatures that captured the intrinsic and extrinsic features, respectively. Specifically, we selected genes that best reflected the expression signals from tumor cells and immune infiltrate cells. Then, we applied an AutoEncoder-based method to decompose the expression of these genes into a small number of representative nodes. Many of these nodes were found to be significantly associated with patient prognosis. From them, we selected two most prognostic nodes and defined a tumor-intrinsic (TI) signature and a tumor-extrinsic (TE) signature. Pathway analysis confirmed that the TE signature recapitulated cytotoxic immune cell related pathways while the TI signature reflected MYC pathway activity. We leveraged these two signatures to investigate six independent melanoma microarray datasets and found that they were able to predict the prognosis of patients under standard care. Furthermore, we showed that the TE signature was also positively associated with patients' response to immunotherapies, including tumor vaccine therapy and checkpoint blockade immunotherapy. This study developed a novel computational framework to capture the tumor-intrinsic and -extrinsic features and identified robust prognostic and predictive biomarkers in melanoma.
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http://dx.doi.org/10.3389/fgene.2021.665065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191580PMC
May 2021

Silica-confined Ru highly dispersed on ZrO with enhanced activity and thermal stability in dichloroethane combustion.

Nanoscale 2021 Jun;13(24):10765-10770

State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, No. 30 Puzhu South Road, Nanjing 211816, China.

An efficient strategy (spontaneous deposition to enhance noble metal dispersity and core-shell confinement to inhibit noble metal sintering) is presented to synthesize highly active and thermally stable Ru/[email protected] catalysts for dichloroethane combustion.
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http://dx.doi.org/10.1039/d1nr01538aDOI Listing
June 2021

MicroRNA-145-5p inhibits hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes by targeting ROCK1.

Exp Ther Med 2021 Aug 25;22(2):796. Epub 2021 May 25.

Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China.

There is increasing evidence that microRNAs (miRs) play critical roles in the pathological and physiological processes associated with myocardial ischemia reperfusion (I/R). miR-145 has been extensively studied in the cardiovascular system; however, the role of miR-145 in myocardial I/R remains unclear. Therefore, the present study aimed to investigate the role and mechanism of miR-145-5p in myocardial I/R by establishing a hypoxia/reoxygenation (H/R) model using H9c2 cardiomyocytes. The expression of miR-145-5p was regulated by transfection and the potential target of miR-145-5p was identified. In addition, apoptosis of the cardiomyocytes was evaluated using flow cytometry and the detection of cleaved caspase-3 by western blotting. The results revealed that miR-145-5p expression was decreased while cell apoptosis and Rho-associated coiled-coil-containing kinase 1 (ROCK1) expression were increased in H/R-stimulated H9c2 cardiomyocytes. The upregulation of miR-145-5p reduced apoptosis and the expression of ROCK1 in H/R-stimulated H9c2 cardiomyocytes. Furthermore, the overexpression of ROCK1 significantly attenuated the miR-145-5p-induced reduction of apoptosis following H/R. In conclusion, the present study indicates that the overexpression of miR-145-5p inhibits H/R-induced cardiomyocyte apoptosis by targeting ROCK1.
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http://dx.doi.org/10.3892/etm.2021.10228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170661PMC
August 2021

The effect of controlling the heart rate on the heart failure index and on heart function in heart failure patients with atrial fibrillation.

Am J Transl Res 2021 15;13(4):3487-3493. Epub 2021 Apr 15.

Department of Cardiology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine Xiangyang, Hubei Province, China.

Objective: To explore the effect of controlling the heart rate on the heart failure index and on heart function in patients with heart failure and atrial fibrillation.

Methods: 82 patients with heart failure and atrial fibrillation were divided into a control group (n=41) and a study group (n=41). The patients in the control group underwent conventional treatment. In addition to the conventional treatment, the patients in the study group were administered metoprolol to actively control their heart rates and to decrease their resting heart rates down to 55-60 beats/min as the target heart rate. After three months of treatment, the heart function, the levels of N terminal pro B type natriuretic peptide (NT-proBNP), and the inflammatory factors were compared between the two groups. At the same time, the readmission rates and prognoses were calculated.

Results: After the treatment, the left ventricular ejection fraction (LVEF) and the cardiac output (CO) levels in the two groups were increased, and the levels in the study group were higher than the levels in the control group; there were opposite trends in the left ventricular end-systolic diameter (LVESD) levels, the left ventricular end-diastolic dimension (LVEDD) levels, and the NT-proBNP, serum CRP, TNF-α and IL-6 levels (all P<0.05). After a six month follow up, the readmission and heart failure rates, and the incidence of adverse events in the study group were lower than they were in the control group (all P<0.05).

Conclusion: The effective control of the ventricular rate can more significantly benefit the heart failure symptoms and atrial fibrillation, alleviate the inflammatory response, and thus improve the heart function and prognoses of heart failure patients with atrial fibrillation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129306PMC
April 2021

Effects of His bundle pacing and right ventricular apex pacing on cardiac electrical and mechanical synchrony and cardiac function in patients with heart failure and atrial fibrillation.

Am J Transl Res 2021 15;13(4):3294-3301. Epub 2021 Apr 15.

Department of Cardiology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine Xiangyang, Hubei Province, China.

Objective: To investigate the effects of right ventricular apex pacing and His bundle pacing on cardiac mechanical and electrical synchrony and cardiac function in patients with heart failure and atrial fibrillation.

Methods: A total of 72 patients with heart failure and atrial fibrillation who received permanent pacemaker implantation in our hospital were randomly divided into two groups, with 36 patients in each group. The control group received the right ventricular apex pacing, and the study group received His bundle pacing. In the two groups, the pacing parameters, cardiac function, cardiac electricity, mechanical synchrony, complications and living quality were compared.

Results: During operation and 12 months after the operation, the study group's pacing threshold was higher than the pacing threshold of the control group (all P<0.001). Compared with that before the procedure, NYHA grade and LVEDD of the two groups 12 months after operation were decreased (all P<0.001), while LVEF and various quality of life scores were increased (all P<0.001). The study group's NYHA grade and LVEDD were lower than those of the control group 12 months after operation (all P<0.001), while the study group's quality of life scores and LVEF were higher than those of the control group (all P<0.001). Twelve months after operation, the study group's QRS width and IVMD were lower than QRS width and IVMD of the control group (all P<0.001). The study group's complication rate was 5.56% (2/36), which was lower than the control group's complication rate (22.22% (8/36), P<0.05).

Conclusion: Compared with right ventricular apical pacing, His bundle pacing in the treatment of heart failure with atrial fibrillation can better maintain the cardiac electrical and mechanical synchronization, promote the recovery of cardiac function, improve living quality, and has fewer complications and significant advantages.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129246PMC
April 2021

A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks.

Genome Biol 2021 May 17;22(1):156. Epub 2021 May 17.

Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Background: Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression.

Results: A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD.

Conclusions: Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.
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http://dx.doi.org/10.1186/s13059-021-02376-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127276PMC
May 2021

Correspondence on 'Warfarin use and risk of knee and hip replacements'.

Ann Rheum Dis 2021 May 13. Epub 2021 May 13.

Department of Emergency Medicine, Xiangya Hospital Central South University, Changsha, Hunan, China

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http://dx.doi.org/10.1136/annrheumdis-2021-220580DOI Listing
May 2021

Pan-cancer association of HLA gene expression with cancer prognosis and immunotherapy efficacy.

Br J Cancer 2021 May 12. Epub 2021 May 12.

Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.

Background: The function of major histocompatibility complex (MHC) molecules is to bind peptide fragments derived from genomic mutations or pathogens and display them on the cell surface for recognition by cognate T cells to initiate an immune response.

Methods: In this study, we provide a comprehensive investigation of HLA gene expression in a pan-cancer manner involving 33 cancer types. We utilised gene expression data from several databases and immune checkpoint blockade-treated patient cohorts.

Results: We show that MHC expression varies strongly among cancer types and is associated with several genomic and immunological features. While immune cell infiltration was generally higher in tumours with higher HLA gene expression, CD4+ T cells showed significantly different correlations among cancer types, separating them into two clusters. Furthermore, we show that increased HLA gene expression is associated with prolonged survival in the majority of cancer types. Lastly, HLA gene expression is associated with patient response to immune checkpoint blockade, which is especially prominent for HLA class II expression in tumour biopsies taken during treatment.

Conclusion: We show that HLA gene expression is an important feature of tumour biology that has significant impact on patient prognosis.
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http://dx.doi.org/10.1038/s41416-021-01400-2DOI Listing
May 2021

CircRNA_2646 functions as a ceRNA to promote progression of esophageal squamous cell carcinoma via inhibiting miR-124/PLP2 signaling pathway.

Cell Death Discov 2021 May 11;7(1):99. Epub 2021 May 11.

Department of Thoracic Surgery, the First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, China.

MicroRNA-124 (miR-124) has been predicted as a tumor suppressor in esophageal squamous cell carcinoma (ESCC). However, factors contributing to miR-124 reduction remain unclear. Circular RNAs (circRNAs) are a new family of non-coding RNAs with gene regulatory potential via interacting with miRNAs. We predicted three circRNAs, including CircRNA_14359, CircRNA_2646, and CircRNA_129, that could interact with miR-124 by bioinformatics analysis and determined their expressions in ESCC tissues and adjacent normal tissues. We found that CircRNA_2646 was up-regulated in ESCC, negatively correlated with the expression of miR-124 and positively associated with TNM stage and lymph node metastasis of ESCC. Luciferase reporter assay showed that CircRNA_2646 interacted with miR-124 in ESCC Eca109 and TE-1 cells. Moreover, ectopical overexpression of CircRNA_2646 accelerated cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), but restoration of miR-124 abrogated these functions and promoted Bcl-2-dependent cell apoptosis. Furthermore, it was found that the oncogene Proteolipid Protein 2 (PLP2) was the target gene of miR-124. In Eca109 and TE-1 cells, restoration of miR-124 decreased the level of PLP2 and inhibited PLP2-induced cell proliferation, migration, invasion, and EMT, but enhanced cell apoptosis. The in vivo study confirmed that CircRNA_2646 promoted ESCC development by repressing miR-124 and activating PLP2. Taken together, we identified that CircRNA_2646 functioned as an inhibitor in miR-124 signaling pathway in ESCC for carcinogenesis and could be a promising target for ESCC therapy.
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http://dx.doi.org/10.1038/s41420-021-00461-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113544PMC
May 2021

A Resonant Pressure Microsensor with a Wide Pressure Measurement Range.

Micromachines (Basel) 2021 Apr 1;12(4). Epub 2021 Apr 1.

Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, China.

This paper presents a resonant pressure microsensor with a wide range of pressure measurements. The developed microsensor is mainly composed of a silicon-on-insulator (SOI) wafer to form pressure-sensing elements, and a silicon-on-glass (SOG) cap to form vacuum encapsulation. To realize a wide range of pressure measurements, silicon islands were deployed on the device layer of the SOI wafer to enhance equivalent stiffness and structural stability of the pressure-sensitive diaphragm. Moreover, a cylindrical vacuum cavity was deployed on the SOG cap with the purpose to decrease the stresses generated during the silicon-to-glass contact during pressure measurements. The fabrication processes mainly contained photolithography, deep reactive ion etching (DRIE), chemical mechanical planarization (CMP) and anodic bonding. According to the characterization experiments, the quality factors of the resonators were higher than 15,000 with pressure sensitivities of 0.51 Hz/kPa (resonator I), -1.75 Hz/kPa (resonator II) and temperature coefficients of frequency of 1.92 Hz/°C (resonator I), 1.98 Hz/°C (resonator II). Following temperature compensation, the fitting error of the microsensor was within the range of 0.006% FS and the measurement accuracy was as high as 0.017% FS in the pressure range of 200 ~ 7000 kPa and the temperature range of -40 °C to 80 °C.
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http://dx.doi.org/10.3390/mi12040382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066463PMC
April 2021

Nephroprotective effect of gastrodin against lead-induced oxidative stress and inflammation in mice by the GSH, Trx, Nrf2 antioxidant system, and the HMGB1 pathway.

Toxicol Res (Camb) 2021 Mar 23;10(2):249-263. Epub 2021 Mar 23.

School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Tongshan New Area, Xuzhou, Jiangsu 221116, P. R. China.

Gastrodin (GAS), the main phenolic glycoside derivative from Blume, has several bio-activities. However, the molecular mechanisms of these protective actions currently remain unclear. This study aimed to investigate the mechanisms of GAS on lead (Pb)-induced oxidative stress and inflammation in the kidneys and primary kidney mesangial cells. Results indicated that GAS improved Pb-induced renal dysfunction and morphological changes in mice. GAS ameliorated Pb-induced inflammation in kidneys by reducing the TNF-α and IL-6 levels. GAS inhibited Pb-induced oxidative stress by regulating the glutathione, thioredoxin (Trx), and Nrf2 antioxidant systems. Furthermore, GAS supplementation increased the activation of SOD, GPx, HO-1, and NQO1 in the kidneys. GAS decreased the expression levels of HMGB1, TLR4, RAGE, MyD88, and NF-κB. These results were further confirmed in primary kidney mesangial cells. Collectively, this study demonstrated that GAS alleviated Pb-induced kidney oxidative stress and inflammation by regulating the antioxidant systems and the Nrf2 signaling pathway. Gastrodin ameliorated Pb-induced kidney injury in mice.Gastrodin inhibited oxidative stress and inflammation in kidneys.Gastrodin activated the GSH, Trx and Nrf2 antioxidant system in kidneys.Gastrodin inhibited the activities of HMGB1. RAGE, TLR4, and MyD88.
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http://dx.doi.org/10.1093/toxres/tfab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045586PMC
March 2021

Microbiological Concordance in the Management of Diabetic Foot Ulcer Infections with Osteomyelitis, on the Basis of Cultures of Different Specimens at a Diabetic Foot Center in China.

Diabetes Metab Syndr Obes 2021 6;14:1493-1503. Epub 2021 Apr 6.

Department of Critical Care Medicine, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei, People's Republic of China.

Objective: This study aimed to assess the microbiological concordance between swab and soft tissue cultures, and corresponding bone specimen cultures from patients with diabetic foot osteomyelitis (DFO). We aimed to analyze the bone specimens' antimicrobial susceptibilities, and to improve clinical management of diabetic foot ulcer infections by using proper antibiotics.

Methods: The microbial culture results of ulcer swabs, and soft tissue and bone tissue specimens, and the antimicrobial susceptibility tests of bone specimens from patients with DFO were analyzed in a single diabetic foot center.

Results: A total of 60 patients with results from three specimens were included. was the most common bacterium isolated from the three specimens. The microbiological results for the three specimens were identical in 12 cases, the culture results from swabs and bone tissue specimens were identical in 14 cases, and the results from soft tissue and bone tissue were identical in 46 cases. The concordance of the results of pathogens isolated between soft tissue and bone specimen cultures was higher than that between the swab and bone cultures. Gram-positive bacteria were more sensitive to moxifloxacin, linezolid, and vancomycin, while Gram-negative bacteria were more sensitive to piperacillin/tazobactam, cefoperazone/sulbactam, and carbapenems.

Conclusion: Soft tissue culture results have more reliable microbiological concordance to identify DFO bacteria than swab culture results and targeted antibiotic therapy for DFO should be based on antimicrobial susceptibility testing in bone tissue specimen cultures.
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http://dx.doi.org/10.2147/DMSO.S296484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040074PMC
April 2021

Surrogate Residuals for Discrete Choice Models.

J Comput Graph Stat 2021 9;30(1):67-77. Epub 2020 Jul 9.

Department of Biostatistics, School of Public Health, Yale University, New Haven, CT.

Discrete choice models (DCMs) are a class of models for modeling response variables that take values from a set of alternatives. Examples include logistic regression, probit regression, and multinomial logistic regression. These models are also referred together as generalized linear models. Although there exist methods for the goodness of fit of DCMs, defining intuitive residuals for such models has been difficult due to the fact that the responses are categorical values instead of continuous numbers. In this article, we propose the surrogate residual for DCMs based on the surrogate approach (Liu and Zhang 2018), which deals with an ordinal response. We consider categorical responses that may or may not be ordered. We shall show that our residual can be used to diagnose misspecification in the aspects of mean structure, individual-specific coefficients, and interaction effects. Supplementary materials for this article are available online.
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http://dx.doi.org/10.1080/10618600.2020.1775618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018589PMC
July 2020

Accurate diagnosis of pulmonary nodules using a noninvasive DNA methylation test.

J Clin Invest 2021 May;131(10)

AnchorDx Medical Co., Guangzhou, China.

BACKGROUNDCurrent clinical management of patients with pulmonary nodules involves either repeated low-dose CT (LDCT)/CT scans or invasive procedures, yet causes significant patient misclassification. An accurate noninvasive test is needed to identify malignant nodules and reduce unnecessary invasive tests.METHODWe developed a diagnostic model based on targeted DNA methylation sequencing of 389 pulmonary nodule patients' plasma samples and then validation in 140 plasma samples independently. We tested the model in different stages and subtypes of pulmonary nodules.RESULTSA 100-feature model was developed and validated for pulmonary nodule diagnosis; the model achieved a receiver operating characteristic curve-AUC (ROC-AUC) of 0.843 on 140 independent validation samples, with an accuracy of 0.800. The performance was well maintained in (a) a 6 to 20 mm size subgroup (n = 100), with a sensitivity of 1.000 and adjusted negative predictive value (NPV) of 1.000 at 10% prevalence; (b) stage I malignancy (n = 90), with a sensitivity of 0.971; (c) different nodule types: solid nodules (n = 78) with a sensitivity of 1.000 and adjusted NPV of 1.000, part-solid nodules (n = 75) with a sensitivity of 0.947 and adjusted NPV of 0.983, and ground-glass nodules (n = 67) with a sensitivity of 0.964 and adjusted NPV of 0.989 at 10% prevalence. This methylation test, called PulmoSeek, outperformed PET-CT and 2 clinical prediction models (Mayo Clinic and Veterans Affairs) in discriminating malignant pulmonary nodules from benign ones.CONCLUSIONThis study suggests that the blood-based DNA methylation model may provide a better test for classifying pulmonary nodules, which could help facilitate the accurate diagnosis of early stage lung cancer from pulmonary nodule patients and guide clinical decisions.FUNDINGThe National Key Research and Development Program of China; Science and Technology Planning Project of Guangdong Province; The National Natural Science Foundation of China National.
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http://dx.doi.org/10.1172/JCI145973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121527PMC
May 2021

The Appearance of Sjögren Syndrome on 68Ga-PSMA-11 PET/CT.

Clin Nucl Med 2021 06;46(6):517-519

From the Department of Nuclear Medicine, Shanghai Changhai Hospital, Shanghai, China.

Abstract: Significant 68Ga-PSMA-11 activity is commonly observed in the lacrimal and salivary glands on PSMA PET/CT. An 80-year-old man after radical prostatectomy was evaluated with 68Ga-PSMA-11 PET/CT. There was no obvious PSMA uptake in the bilateral lacrimal, parotid, and submandibular glands. Subsequently, based on laboratory examination results and 99mTcO4 salivary gland scintigraphy, this patient was diagnosed with Sjögren syndrome, which accounted for the absence of uptake by the glands. This case showed the potential of 68Ga-PSMA-11 PET/CT in the evaluation of the lacrimal glands and major salivary glands.
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http://dx.doi.org/10.1097/RLU.0000000000003584DOI Listing
June 2021

Tumor immune infiltration estimated from gene expression profiles predicts colorectal cancer relapse.

Oncoimmunology 2021 03 9;10(1):1862529. Epub 2021 Mar 9.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AIC:238.1-238.9; CMS-AIC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance.
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http://dx.doi.org/10.1080/2162402X.2020.1862529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951964PMC
March 2021

LINC01116 promotes the proliferation and invasion of glioma by regulating the microRNA‑744‑5p‑MDM2‑p53 axis.

Mol Med Rep 2021 05 24;23(5). Epub 2021 Mar 24.

Department of Neurosurgery, Hangzhou First People's Hospital of Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.

Long non‑coding RNAs (lncRNAs) have been implicated in the development and progression of tumors. However, the roles and underlying mechanisms of long intergenic non‑protein coding RNA 1116 (LINC01116), a member of the lncRNA family, in glioma progression are largely unclear. The expression of LINC01116 and microRNA (miR)‑744‑5p in glioma tissues and cells was detected by reverse transcription‑quantitative PCR. The influences of LINC01116 or miR‑744‑5p on cell proliferation and invasion were evaluated by Cell Counting Kit‑8, colony formation and Transwell assays, and western blotting was used to detect the expression of p53 pathway proteins. A dual‑luciferase reporter system was used to locate common binding sites between miR‑744‑5p and LINC01116 or the 3' untranslated region of E3 ubiquitin‑protein ligase Mdm2 (MDM2). RNA immunoprecipitation was used to determine the interactions between RNAs and proteins. Moreover, a xenograft mouse model was constructed to investigate the effects of LINC01116 , followed by a TdT‑mediated dUTP nick end labeling assay to determine the degree of apoptosis in nude mouse tumors. LINC01116 was found to be highly expressed in glioma tissues, which was associated with a malignant phenotype. LINC01116 promoted the proliferation and invasiveness of glioma cells, and inhibited the p53 pathway by preserving the expression of MDM2 mRNA via miR‑744‑5p sponging. Furthermore, a low degree of miR‑744‑5p expression was observed in glioma tissues, which was negatively associated with the expression of LINC01116. Overexpression of miR‑744‑5p inhibited the proliferation and invasiveness of glioma cells, which was rescued by LINC01116. Finally, LINC01116 knockdown inhibited tumor growth in nude mice. In conclusion, LINC01116 is aberrantly expressed and promotes the progression of glioma by regulating the miR‑744‑5p‑MDM2‑p53 pathway. In future, targeting LINC01116 may therefore be a potential therapeutic approach for patients with glioma.
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http://dx.doi.org/10.3892/mmr.2021.12005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986001PMC
May 2021

miR-1254 induced by NESG1 inactivates HDGF/DDX5-stimulated nuclear translocation of β-catenin and suppresses NPC metastasis.

Mol Ther Methods Clin Dev 2021 Mar 4;20:615-624. Epub 2021 Feb 4.

Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Chinese and other Southeast Asians. We aimed to explore the precise mechanism for NESG1 in NPC for understanding the pathogenesis of NPC. Transwell, Boyden assays, and wounding healing were respectively performed for cell metastasis. The microRNA (miRNA) microarray and luciferase reporter assays were designed to clarify NESG1-modulated miRNAs and miR-1254-targeted protein. Western blotting assays examined the pathways regulated by miR-1254, the (Hepatoma-Derived Growth Factor) HDGF/DDX5 complex, and NESG1. The chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and co-immunoprecipitation (coIP) assays were used to explore the DNA-protein complex and protein-protein complex. NESG1 suppressed NPC migration and invasion via Wnt/β-catenin signaling. Further, miR-1254 was confirmed as a positive downstream modulator of NESG1 reducing metastatic abilities of NPC cells and . Transduction of HDGF significantly restored cell migration and invasion ability in miR-1254-overexpressing NPC cells. In clinical samples, miR-1254 expression was negatively correlated with HDGF and positively correlated with NESG1 expression. miR-1254 acts as an independent prognostic factor for NPC, which was induced by NESG1 to suppress NPC metastasis via inactivating Wnt/β-catenin pathway and its downstream EMT signals.
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http://dx.doi.org/10.1016/j.omtm.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907678PMC
March 2021