Publications by authors named "Tzu-Hao Chang"

76 Publications

Correction: A COVID-19 Pandemic Artificial Intelligence-Based System With Deep Learning Forecasting and Automatic Statistical Data Acquisition: Development and Implementation Study.

J Med Internet Res 2021 Jul 9;23(7):e31085. Epub 2021 Jul 9.

Professional Master Program in Artificial Intelligence in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

[This corrects the article DOI: 10.2196/27806.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/31085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304106PMC
July 2021

COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells.

Oncogene 2021 Jul 11;40(26):4503-4519. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-β3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-β3 antibody. Human tumors with high TGF-β3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-β3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-021-01865-8DOI Listing
July 2021

Biomarker Identification through Multiomics Data Analysis of Prostate Cancer Prognostication Using a Deep Learning Model and Similarity Network Fusion.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.

This study is to identify potential multiomics biomarkers for the early detection of the prognostic recurrence of PC patients. A total of 494 prostate adenocarcinoma (PRAD) patients (60-recurrent included) from the Cancer Genome Atlas (TCGA) portal were analyzed using the autoencoder model and similarity network fusion. Then, multiomics panels were constructed according to the intersected omics biomarkers identified from the two models. Six intersected omics biomarkers, , cg00687383 (), and cg02318866 (; ), were collected for multiomics panel construction. The difference between the Kaplan-Meier curves of high and low recurrence-risk groups generated from the multiomics panel achieved -value = 5.33 × 10, which is better than the former study (-value = 5 × 10). Additionally, when evaluating the selected multiomics biomarkers with clinical information (Gleason score, age, and cancer stage), a high-performance prediction model was generated with C-index = 0.713, -value = 2.97 × 10, and AUC = 0.789. The risk score generated from the selected multiomics biomarkers worked as an effective indicator for the prediction of PRAD recurrence. This study helps us to understand the etiology and pathways of PRAD and further benefits both patients and physicians with potential prognostic biomarkers when making clinical decisions after surgical treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196729PMC
May 2021

Maternal Vegetable and Fruit Consumption during Pregnancy and Its Effects on Infant Gut Microbiome.

Nutrients 2021 May 5;13(5). Epub 2021 May 5.

Department of Family Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan.

Maternal nutrition intake during pregnancy may affect the mother-to-child transmission of bacteria, resulting in gut microflora changes in the offspring, with long-term health consequences in later life. Longitudinal human studies are lacking, as only a small amount of studies showing the effect of nutrition intake during pregnancy on the gut microbiome of infants have been performed, and these studies have been mainly conducted on animals. This pilot study explores the effects of high or low fruit and vegetable gestational intake on the infant microbiome. We enrolled pregnant women with a complete 3-day dietary record and received postpartum follow-up. The 16S rRNA gene sequence was used to characterize the infant gut microbiome at 2 months ( = 39). Principal coordinate analysis ordination revealed that the infant gut microbiome clustered differently for high and low maternal fruit and vegetable consumption ( < 0.001). The linear discriminant analysis effect size and feature selection identified 6 and 17 taxa from both the high and low fruit and vegetable consumption groups. Among the 23 abundant taxa, we observed that six maternal intake nutrients were associated with nine taxa (e.g., , , Lachnospiraceae, Betaproteobacteria, Burkholderiaceae, , Clostridia, Clostridiales, and ). The amount of gestational fruit and vegetable consumption is associated with distinct changes in the infant gut microbiome at 2 months of age. Therefore, strategies involving increased fruit and vegetable consumption during pregnancy should be employed for modifying the gut microbiome early in life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu13051559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148194PMC
May 2021

Tissue microbiota in nasopharyngeal adenoid and its association with pneumococcal carriage.

Microb Pathog 2021 Aug 24;157:104999. Epub 2021 May 24.

Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan. Electronic address:

The microbial colonization in the nasopharynx is a prerequisite for the onset of infectious diseases. For successful infection, pathogens should overcome host defenses as well as compete effectively with the resident microbiota. Hence, elucidating the richness and diversity of the microbiome at the site of pathogen colonization is pivotal. Here, we investigated the adenoidal tissue microbiota collected through adenoidectomy to evaluate the impact of Streptococcus pneumoniae. Prospectively, children with sleep-disordered breathing (SDB) and otitis media with effusion (OME) were enrolled. During adenoidectomy, the nasopharyngeal swab and adenoid tissues were collected to determine the pneumococcal carriage and tissue microbiota, using multiplex PCR and 16S ribosomal RNA (16S rRNA) pyrosequencing. A total of 66 pediatric patients comprising 38 children with SDB and 28 children with OME were enrolled. There was no difference between the bacterial cultures from the surface of the nasopharyngeal adenoid in the SDB and OME groups. Thirty-four samples (17 SDB and 17 OME) underwent 16S rRNA pyrosequencing and fulfilled the criteria for further analysis. The Shannon diversity index for the samples from the SDB patients was found to be higher than that observed for the samples from OME patients, although the difference was not significant (p = 0.095). The Shannon diversity index for the samples negative for the pneumococcal carriage was significantly higher than that for the samples positive for pneumococcal carriage (p = 0.038). Alloprevotella, Staphylococcus, Moraxella, and Neisseriaceae were significantly dominant in the samples positive for the pneumococcal carriage. Dialister was significantly less present in the adenoid tissue positive for the pneumococcal carriage. Streptococcus pneumoniae, one of the most common pathogens of the airway, significantly influences the composition and diversity of the microbiota in the nasopharyngeal adenoid. Thus, bacterial community analysis based on 16S rRNA pyrosequencing allows for better understanding of the relationship between the adenoidal microbial communities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.micpath.2021.104999DOI Listing
August 2021

CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation.

Mol Psychiatry 2021 Apr 30. Epub 2021 Apr 30.

Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.

Glucoregulatory efficiency and ATP production are key regulators for neuronal plasticity and memory formation. Besides its chemotactic and neuroinflammatory functions, the CC chemokine--CCL5 displays neurotrophic activity. We found impaired learning-memory and cognition in CCL5-knockout mice at 4 months of age correlated with reduced hippocampal long-term potentiation and impaired synapse structure. Re-expressing CCL5 in knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity and cognitive function. Using metabolomics coupled with FDG-PET imaging and seahorse analysis, we found that CCL5 participates in hippocampal fructose and mannose degradation, glycolysis, gluconeogenesis as well as glutamate and purine metabolism. CCL5 additionally supports mitochondrial structural integrity, purine synthesis, ATP generation, and subsequent aerobic glucose metabolism. Overexpressing CCL5 in WT mice also enhanced memory-cognition performance as well as hippocampal neuronal activity and connectivity through promotion of de novo purine and glutamate metabolism. Thus, CCL5 actions on glucose aerobic metabolism are critical for mitochondrial function which contribute to hippocampal spine and synapse formation, improving learning and memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-021-01103-3DOI Listing
April 2021

A COVID-19 Pandemic Artificial Intelligence-Based System With Deep Learning Forecasting and Automatic Statistical Data Acquisition: Development and Implementation Study.

J Med Internet Res 2021 05 20;23(5):e27806. Epub 2021 May 20.

Professional Master Program in Artificial Intelligence in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Background: More than 79.2 million confirmed COVID-19 cases and 1.7 million deaths were caused by SARS-CoV-2; the disease was named COVID-19 by the World Health Organization. Control of the COVID-19 epidemic has become a crucial issue around the globe, but there are limited studies that investigate the global trend of the COVID-19 pandemic together with each country's policy measures.

Objective: We aimed to develop an online artificial intelligence (AI) system to analyze the dynamic trend of the COVID-19 pandemic, facilitate forecasting and predictive modeling, and produce a heat map visualization of policy measures in 171 countries.

Methods: The COVID-19 Pandemic AI System (CPAIS) integrated two data sets: the data set from the Oxford COVID-19 Government Response Tracker from the Blavatnik School of Government, which is maintained by the University of Oxford, and the data set from the COVID-19 Data Repository, which was established by the Johns Hopkins University Center for Systems Science and Engineering. This study utilized four statistical and deep learning techniques for forecasting: autoregressive integrated moving average (ARIMA), feedforward neural network (FNN), multilayer perceptron (MLP) neural network, and long short-term memory (LSTM). With regard to 1-year records (ie, whole time series data), records from the last 14 days served as the validation set to evaluate the performance of the forecast, whereas earlier records served as the training set.

Results: A total of 171 countries that featured in both databases were included in the online system. The CPAIS was developed to explore variations, trends, and forecasts related to the COVID-19 pandemic across several counties. For instance, the number of confirmed monthly cases in the United States reached a local peak in July 2020 and another peak of 6,368,591 in December 2020. A dynamic heat map with policy measures depicts changes in COVID-19 measures for each country. A total of 19 measures were embedded within the three sections presented on the website, and only 4 of the 19 measures were continuous measures related to financial support or investment. Deep learning models were used to enable COVID-19 forecasting; the performances of ARIMA, FNN, and the MLP neural network were not stable because their forecast accuracy was only better than LSTM for a few countries. LSTM demonstrated the best forecast accuracy for Canada, as the root mean square error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) were 2272.551, 1501.248, and 0.2723075, respectively. ARIMA (RMSE=317.53169; MAPE=0.4641688) and FNN (RMSE=181.29894; MAPE=0.2708482) demonstrated better performance for South Korea.

Conclusions: The CPAIS collects and summarizes information about the COVID-19 pandemic and offers data visualization and deep learning-based prediction. It might be a useful reference for predicting a serious outbreak or epidemic. Moreover, the system undergoes daily updates and includes the latest information on vaccination, which may change the dynamics of the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/27806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139395PMC
May 2021

Collagen type VI regulates the CDK4/6-p-Rb signaling pathway and promotes ovarian cancer invasiveness, stemness, and metastasis.

Am J Cancer Res 2021 1;11(3):668-690. Epub 2021 Mar 1.

Department of Pathology, Cathay General Hospital Taipei, Taiwan.

The expression of collagen VI in primary ovarian tumors may correlate with tumor grade and response to chemotherapy. We have sought to elucidate the role of collagen VI in promoting ovarian cancer tumor growth and metastasis. Here we examined the effects of collagen VI on ovarian carcinoma stromal progenitor cells (OCSPCs). Epithelial-like OCSPCs (epi-OCSPCs) and mesenchymal-like OCSPCs (msc-OCSPCs) were analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Differentially expressed genes were integrated with survival-related genes using The Cancer Genome Atlas (TCGA) data and confirmed in our samples. The roles of candidate genes and signaling pathways were further explored. We found that SKOV3/msc-OCSPCs possessed greater migration, invasion, and spheroid formation than SKOV3/epi-OCSPCs ( < 0.001). Expression of collagen alpha-3 (VI; COL6A3), which encodes collagen VI, was 90-fold higher in msc-OCSPCs than in epi-OCSPCs. Analysis of TCGA data and our samples indicated that high expression of COL6A3 was correlated with advanced-stage carcinoma ( < 0.01) and shorter overall survival ( < 0.01). In vitro, adding collagen VI, msc-OCSPCs, or knockdown collagen VI in msc-OCSPCs to epithelial ovarian carcinoma (EOC) cells augmented or decreased invasion and spheroid formation. Tumor dissemination to the peritoneal cavity and lung in mice following intraperitoneal coinjection with msc-OCSPCs and SKOV3-Luc cells and intravenous injection with COL6A3 and ES2 cells derived spheroids was significantly greater compare to coinjection with SKOV3-Luc cells alone or in combination with msc-OCSPCs/shCOL6A3 cells and msc-OCSPCs and ES2 derived spheroids. Knockdown of COL6A3 abolished the expression of DNMT1, CDK4, CDK6, and p-Rb in msc-OCSPCs and EOC spheroids. In contrast, overexpression of COL6A3 enhanced the expression of CDK4, CDK6, and p-Rb in SKOV3 cells. EOC spheroid formation, invasion, tumor growth, and metastasis were inhibited when COL6A3 downstream signaling pathway was blocked using CDK4/6 inhibitor LEE011. Our results suggested that collagen VI regulates the CDK4/6-p-Rb signaling pathway and promotes EOC invasiveness, stemness, and metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994167PMC
March 2021

Platelet autophagic machinery involved in thrombosis through a novel linkage of AMPK-MTOR to sphingolipid metabolism.

Autophagy 2021 Apr 5:1-18. Epub 2021 Apr 5.

Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Basal macroautophagy/autophagy has recently been found in anucleate platelets. Platelet autophagy is involved in platelet activation and thrombus formation. However, the mechanism underlying autophagy in anucleate platelets require further clarification. Our data revealed that LC3-II formation and SQSTM1/p62 degradation were noted in HO-activated human platelets, which could be blocked by 3-methyladenine and bafilomycin A, indicating that platelet activation may cause platelet autophagy. AMPK phosphorylation and MTOR dephosphorylation were also detected, and block of AMPK activity by the AMPK inhibitor dorsomorphin reversed SQSTM1 degradation and LC3-II formation. Moreover, autophagosome formation was observed through transmission electron microscopy and deconvolution microscopy. These findings suggest that platelet autophagy was induced partly through the AMPK-MTOR pathway. In addition, increased LC3-II expression occurred only in HO-treated platelets, but not in HO-treated platelets, suggesting that platelet autophagy occurs during platelet activation. platelets also exhibited a lower aggregation in response to agonists, and platelet-specific mice exhibited delayed thrombus formation in mesenteric microvessles and decreased mortality rate due to pulmonary thrombosis. Notably, metabolic analysis revealed that sphingolipid metabolism is involved in platelet activation, as evidenced by observed several altered metabolites, which could be reversed by dorsomorphin. Therefore, platelet autophagy and platelet activation are positively correlated, partly through the interconnected network of sphingolipid metabolism. In conclusion, this study for the first time demonstrated that AMPK-MTOR signaling could regulate platelet autophagy. A novel linkage between AMPK-MTOR and sphingolipid metabolism in anucleate platelet autophagy was also identified: platelet autophagy and platelet activation are positively correlated.: 3-MA: 3-methyladenine; A.C.D.: citric acid/sod. citrate/glucose; ADP: adenosine diphosphate; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ANOVA: analysis of variance; ATG: autophagy-related; B4GALT/LacCS: beta-1,4-galactosyltransferase; Baf-A1: bafilomycin A; BECN1: beclin 1; BHT: butylate hydrooxytoluene; BSA: bovine serum albumin; DAG: diacylglycerol; ECL: enhanced chemiluminescence; EDTA: ethylenediamine tetraacetic acid; ELISA: enzyme-linked immunosorbent assay; GALC/GCDase: galactosylceramidase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA/GluSDase: glucosylceramidase beta; GPI: glycosylphosphatidylinositol; HO: hydrogen peroxide; HMDB: human metabolome database; HRP: horseradish peroxidase; IF: immunofluorescence; IgG: immunoglobulin G; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPV: mean platelet volume; MTOR: mechanistic target of rapamycin kinase; ox-LDL: oxidized low-density lipoprotein; pAb: polyclonal antibody; PC: phosphatidylcholine; PCR: polymerase chain reaction; PI3K: phosphoinositide 3-kinase; PLS-DA: partial least-squares discriminant analysis; PRP: platelet-rich plasma; Q-TOF: quadrupole-time of flight; RBC: red blood cell; ROS: reactive oxygen species; RPS6KB/p70S6K: ribosomal protein S6 kinase B; SDS: sodium dodecyl sulfate; S.E.M.: standard error of the mean; SEM: scanning electron microscopy; SGMS: sphingomyelin synthase; SM: sphingomyelin; SMPD/SMase: sphingomyelin phosphodiesterase; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; UGT8/CGT: UDP glycosyltransferase 8; UGCG/GCS: UDP-glucose ceramide glucosyltransferase; ULK1: unc-51 like autophagy activating kinase 1; UPLC: ultra-performance liquid chromatography; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; WBC: white blood cell; WT: wild type.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2021.1904495DOI Listing
April 2021

Early Chronic Kidney Disease Care Programme delays kidney function deterioration in patients with stage I-IIIa chronic kidney disease: an observational cohort study in Taiwan.

BMJ Open 2021 01 19;11(1):e041210. Epub 2021 Jan 19.

Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei, Taiwan

Objectives: To investigate the effect of the Early Chronic Kidney Disease (CKD) Care Programme on CKD progression in patients with CKD stage I-IIIa.

Design: Observational cohort study.

Setting: Taipei Medical University Research Database from three affiliated hospitals.

Participants: Adult non-pregnant patients with CKD stage I-IIIa from Taipei Medical University Research Database between 1 January 2012 and 31 August 2017 were recruited. These patients were divided into Early CKD Care Programme participants (case) and non-participants (control). The models were matched by age, sex, estimated glomerular filtration rate and CKD stage with 1:2 propensity score to reduce bias between two groups.

Outcome Measures: The risks of CKD stage I-IIIa progression to IIIb between Early CKD Care Programme participants and non-participants.

Results: Compared with the control group, the case group demonstrated more comorbidities and higher proportions of hypertension, diabetes mellitus, gout, dyslipidaemia, heart disease and cerebrovascular disease, but had lower risk of progression to CKD stage IIIb before and (HR 0.72; 95% CI 0.61 to 0.85) and after (adjusted HR (aHR) 0.67; 95% CI 0.55 to 0.81) adjustments. Moreover, Kaplan-Meier analysis revealed the cumulative incidence of CKD stage IIIb was significantly lower in the case group than in the control group. Finally, the programme was an independent protective factor against progression to stage IIIb, especially in patients with CKD stage IIIa before (HR 0.72; 95% CI 0.61 to 0.85) and after (aHR 0.67; 95% CI 0.55 to 0.81) adjustments.

Conclusions: The Early CKD Care Programme is an independent protective factor against progression of early CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-041210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817788PMC
January 2021

Classification of Changes in the Fecal Microbiota Associated with Colonic Adenomatous Polyps Using a Long-Read Sequencing Platform.

Genes (Basel) 2020 11 20;11(11). Epub 2020 Nov 20.

College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.

The microbiota is the community of microorganisms that colonizes the oral cavity, respiratory tract, and gut of multicellular organisms. The microbiota exerts manifold physiological and pathological impacts on the organism it inhabits. A growing body of attention is being paid to host-microbiota interplay, which is highly relevant to the development of carcinogenesis. Adenomatous polyps are considered a common hallmark of colorectal cancer, the second leading cause of carcinogenesis-mediated death worldwide. In this study, we examined the relevance between targeted operational taxonomic units and colonic polyps using short- and long-read sequencing platforms. The gut microbiota was assessed in 132 clinical subjects, including 53 healthy participants, 36 patients with occult blood in the gut, and 43 cases with adenomatous polyps. An elevation in the relative abundance of , , and was identified in patients with adenomatous polyps compared with the other groups using long-read sequencing workflow. In contrast, the relatively high abundances of , , and were characterized in the healthy groups. The diversities in gut microbiota communities were similar in all recruited samples. These results indicated that alterations in gut microbiota were characteristic of participants with adenomatous polyps, which might be relevant to the further development of CRC. These findings provide a potential contribution to the early prediction and interception of CRC occurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11111374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699842PMC
November 2020

Radiomic Immunophenotyping of GSEA-Assessed Immunophenotypes of Glioblastoma and Its Implications for Prognosis: A Feasibility Study.

Cancers (Basel) 2020 Oct 19;12(10). Epub 2020 Oct 19.

Translational Imaging Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan.

Characterization of immunophenotypes in glioblastoma (GBM) is important for therapeutic stratification and helps predict treatment response and prognosis. Radiomics can be used to predict molecular subtypes and gene expression levels. However, whether radiomics aids immunophenotyping prediction is still unknown. In this study, to classify immunophenotypes in patients with GBM, we developed machine learning-based magnetic resonance (MR) radiomic models to evaluate the enrichment levels of four immune subsets: Cytotoxic T lymphocytes (CTLs), activated dendritic cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). Independent testing data and the leave-one-out cross-validation method were used to evaluate model effectiveness and model performance, respectively. We identified five immunophenotypes (G1 to G5) based on the enrichment level for the four immune subsets. G2 had the worst prognosis and comprised highly enriched MDSCs and lowly enriched CTLs. G3 had the best prognosis and comprised lowly enriched MDSCs and Tregs and highly enriched CTLs. The average accuracy of T1-weighted contrasted MR radiomics models of the enrichment level for the four immune subsets reached 79% and predicted G2, G3, and the "immune-cold" phenotype (G1) according to our radiomics models. Our radiomic immunophenotyping models feasibly characterize the immunophenotypes of GBM and can predict patient prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12103039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603270PMC
October 2020

Characterization of Fecal Microbiota with Clinical Specimen Using Long-Read and Short-Read Sequencing Platform.

Int J Mol Sci 2020 Sep 26;21(19). Epub 2020 Sep 26.

PhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.

Accurate and rapid identification of microbiotic communities using 16S ribosomal (r)RNA sequencing is a critical task for expanding medical and clinical applications. Next-generation sequencing (NGS) is widely considered a practical approach for direct application to communities without the need for in vitro culturing. In this report, a comparative evaluation of short-read (Illumina) and long-read (Oxford Nanopore Technologies (ONT)) platforms toward 16S rRNA sequencing with the same batch of total genomic DNA extracted from fecal samples is presented. Different 16S gene regions were amplified, bar-coded, and sequenced using the Illumina MiSeq and ONT MinION sequencers and corresponding kits. Mapping of the sequenced amplicon using MinION to the entire 16S rRNA gene was analyzed with the cloud-based EPI2ME algorithm. V3-V4 reads generated using MiSeq were aligned by applying the CLC genomics workbench. More than 90% of sequenced reads generated using distinct sequencers were accurately classified at the genus or species level. The misclassification of sequenced reads at the species level between the two approaches was less substantial as expected. Taken together, the comparative results demonstrate that MinION sequencing platform coupled with the corresponding algorithm could function as a practicable strategy in classifying bacterial community to the species level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582668PMC
September 2020

Preclinical Evaluation of the Novel Small-Molecule MSI-N1014 for Treating Drug-Resistant Colon Cancer via the LGR5/β-catenin/miR-142-3p Network and Reducing Cancer-Associated Fibroblast Transformation.

Cancers (Basel) 2020 Jun 16;12(6). Epub 2020 Jun 16.

Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

Colorectal cancer represents one of the most prevalent malignancies globally, with an estimated 140,000 new cases in the United States alone in 2019. Despite advancements in interventions, drug resistance occurs in virtually all patients diagnosed with late stages of colon cancer. Amplified epidermal growth factor receptor (EGFR) signaling is one of the most prevalent oncogenic drivers in patients and induces increased Janus kinase (JAK)/signal transduction and activator of transcription (STAT) and β-catenin functions, all of which facilitate disease progression. Equally important, cancer-associated fibroblasts (CAFs) transformed by cancer cells within the tumor microenvironment (TME) further facilitate malignancy by secreting interleukin (IL)-6 and augmenting STAT3 signaling in colon cancer cells and promoting the generation of cancer stem-like cells (CSCs). Based on these premises, single-targeted therapeutics have proven ineffective for treating malignant colon cancer, and alternative multiple-targeting agents should be explored. Herein, we synthesized a tetracyclic heterocyclic azathioxanthone, MSI-N1014, and demonstrated its therapeutic potential both in vitro and in vivo. First, we used a co-culture system to demonstrate that colon cancer cells co-cultured with CAFs resulted in heightened 5-fluorouracil (5-FU) resistance and tumor sphere-forming ability and increased side populations, accompanied by elevated expression of cluster of differentiation 44 (CD44), β-catenin, leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), and ATP-binding cassette super-family G member 2 (ABCG2). MSI-N1014 suppressed cell viability, colony formation, and migration in both DLD1 and HCT116 cells. MSI-N1014 treatment led to decreased expressions of oncogenic markers, including mammalian target of rapamycin (mTOR), EGFR, and IL-6 and stemness markers such as CD44, β-catenin, and LGR5. More importantly, MSI-N1014 treatment suppressed the transformation of CAFs, and was associated with decreased secretion of IL-6 and vascular endothelial growth factor (VEGF) by CAFs. Furthermore, MSI-N1014 treatment resulted in significantly reduced oncogenic properties, namely the migratory ability, tumor-sphere generation, and resistance against 5-FU. Notably, an increased level of the tumor suppressor, miR-142-3p, whose targets include LGR5, IL-6, and ABCG2, was detected in association with MSI-N1014 treatment. Finally, we demonstrated the therapeutic potential of MSI-N1014 in vivo where combined treatment with MSI-N1014 and 5-FU led to the lowest tumor growth, followed by MSI-N1014 only, 5-FU, and the vehicle control. Tumor samples from the MSI-N1014 group showed markedly reduced expressions of LGR5, β-catenin, IL-6, and mTOR, but increased expression of the tumor suppressor, miR-142-3p, according to qRT-PCR analysis. Collectively, we present preclinical support for the application of MSI-N1014 in treating 5-FU-resistant colon cancer cells. Further investigation is warranted to translate these findings into clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12061590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352915PMC
June 2020

Incorporating deep learning and multi-omics autoencoding for analysis of lung adenocarcinoma prognostication.

Comput Biol Chem 2020 May 12;87:107277. Epub 2020 May 12.

Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei City, Taiwan; Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei City, Taiwan. Electronic address:

Lung cancer is the most occurring cancer type, and its mortality rate is also the highest, among them lung adenocarcinoma (LUAD) accounts for about 40 % of lung cancer. There is an urgent need to develop a prognosis prediction model for lung adenocarcinoma. Previous LUAD prognosis studies only took single-omics data, such as mRNA or miRNA, into consideration. To this end, we proposed a deep learning-based autoencoding approach for combination of four-omics data, mRNA, miRNA, DNA methylation and copy number variations, to construct an autoencoder model, which learned representative features to differentiate the two optimal patient subgroups with a significant difference in survival (P = 4.08e-09) and good consistency index (C-index = 0.65). The multi-omics model was validated though four independent datasets, i.e. GSE81089 for mRNA (n = 198, P = 0.0083), GSE63805 for miRNA (n = 32, P = 0.018), GSE63384 for DNA methylation (n = 35, P = 0.009), and TCGA independent samples for copy number variations (n = 94, P = 0.0052). Finally, a functional analysis was performed on two survival subgroups to discover genes involved in biological processes and pathways. This is the first study incorporating deep autoencoding and four-omics data to construct a robust survival prediction model, and results show the approach is useful at predicting LUAD prognostication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiolchem.2020.107277DOI Listing
May 2020

Untargeted metabolomics predicts the functional outcome of ischemic stroke.

J Formos Med Assoc 2021 Jan 13;120(1 Pt 1):234-241. Epub 2020 May 13.

Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan. Electronic address:

Background/purpose: Metabolites in blood have been found associated with the occurrence of vascular diseases, but its role in the functional recovery of stroke is unclear. The aim of this study is to investigate whether the untargeted metabolomics at the acute stage of ischemic stroke is able to predict functional recovery.

Methods: One hundred and fifty patients with acute ischemic stroke were recruited and followed up for 3 months. Fasting blood samples within 7 days of stroke were obtained, liquid chromatography and mass spectrometry were applied to identify outcome-associated metabolites. The patients' clinical characteristics and identified metabolites were included for constructing the outcome prediction model using machine learning approaches.

Results: By using multivariate analysis, 220 differentially expressed metabolites (DEMs) were discovered between patients with favorable outcomes (modified Rankin Scale, mRS ≤ 2 at 3 months, n = 77) and unfavorable outcomes (mRS ≥ 3 at 3 months, n = 73). After feature selection, 63 DEMs were chosen for constructing the outcome prediction model. The predictive accuracy was below 0.65 when including patients' clinical characteristics, and could reach 0.80 when including patients' clinical characteristics and 63 selected DEMs. The functional enrichment analysis identified platelet activating factor (PAF) as the strongest outcome-associated metabolite, which involved in proinflammatory mediators release, arachidonic acid metabolism, eosinophil degranulation, and production of reactive oxygen species.

Conclusion: Metabolomics is a potential method to explore the blood biomarkers of acute ischemic stroke. The patients with unfavorable outcomes had a lower PAF level compared to those with favorable outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2020.04.026DOI Listing
January 2021

Computational analysis for identification of the extracellular matrix molecules involved in endometrial cancer progression.

PLoS One 2020 21;15(4):e0231594. Epub 2020 Apr 21.

Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Recurrence and poorly differentiated (grade 3 and above) and atypical cell type endometrial cancer (EC) have poor prognosis outcome. The mechanisms and characteristics of recurrence and distal metastasis of EC remain unclear. The extracellular matrix (ECM) of the reproductive tract in women undergoes extensive structural remodelling changes every month. Altered ECMs surrounding cells were believed to play crucial roles in a cancer progression. To decipher the associations between ECM and EC development, we generated a PAN-ECM Data list of 1516 genes including ECM molecules (ECMs), synthetic and degradation enzymes for ECMs, ECM receptors, and soluble molecules that regulate ECM and used RNA-Seq data from The Cancer Genome Atlas (TCGA) for the studies. The alterations of PAN-ECM genes by comparing the RNA-Seq expressions profiles of EC samples which have been grouped as tumorigenesis and metastasis group based on their pathological grading were identified. Differential analyses including functional enrichment, co-expression network, and molecular network analysis were carried out to identify the specific PAN-ECM genes that may involve in the progression of EC. Eight hundred and thirty-one and 241 PAN-ECM genes were significantly involved in tumorigenesis (p-value <1.571e-15) and metastasis (p-value <2.2e-16), respectively, whereas 140 genes were in the intersection of tumorigenesis and metastasis. Interestingly, 92 of the 140 intersecting PAN-ECM genes showed contrasting fold changes between the tumorigenesis and metastasis datasets. Enrichment analysis for the contrast PAN-ECM genes indicated pathways such as GP6 signaling, ILK signaling, and interleukin (IL)-8 signaling pathways were activated in metastasis but inhibited in tumorigenesis. The significantly activated ECM and ECM associated genes in GP6 signaling, ILK signaling, and interleukin (IL)-8 signaling pathways may play crucial roles in metastasis of EC. Our study provides a better understanding of the etiology and the progression of EC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173926PMC
July 2020

Pilot Study to Establish a Novel Five-Gene Biomarker Panel for Predicting Lymph Node Metastasis in Patients With Early Stage Endometrial Cancer.

Front Oncol 2019 21;9:1508. Epub 2020 Jan 21.

School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, China.

In the United States and Europe, endometrial endometrioid carcinoma (EEC) is the most prevalent gynecologic malignancy. Lymph node metastasis (LNM) is the key determinant of the prognosis and treatment of EEC. A biomarker that predicts LNM in patients with EEC would be beneficial, enabling individualized treatment. Current preoperative assessment of LNM in EEC is not sufficiently accurate to predict LNM and prevent overtreatment. This pilot study established a biomarker signature for the prediction of LNM in early stage EEC. We performed RNA sequencing in 24 clinically early stage (T1) EEC tumors (lymph nodes positive and negative in 6 and 18, respectively) from Cathay General Hospital and analyzed the RNA sequencing data of 289 patients with EEC from The Cancer Genome Atlas (lymph node positive and negative in 33 and 256, respectively). We analyzed clinical data including tumor grade, depth of tumor invasion, and age to construct a sequencing-based prediction model using machine learning. For validation, we used another independent cohort of early stage EEC samples ( = 72) and performed quantitative real-time polymerase chain reaction (qRT-PCR). Finally, a PCR-based prediction model and risk score formula were established. Eight genes (, and ) plus one clinical parameter (depth of myometrial invasion) were identified for use in a sequencing-based prediction model. After qRT-PCR validation, five genes (, and ) were identified as predictive biomarkers. Receiver operating characteristic curve analysis revealed that these five genes can predict LNM. Combined use of these five genes resulted in higher diagnostic accuracy than use of any single gene, with an area under the curve of 0.898, sensitivity of 88.9%, and specificity of 84.1%. The accuracy, negative, and positive predictive values were 84.7, 98.1, and 44.4%, respectively. We developed a five-gene biomarker panel associated with LNM in early stage EEC. These five genes may represent novel targets for further mechanistic study. Our results, after corroboration by a prospective study, may have useful clinical implications and prevent unnecessary elective lymph node dissection while not adversely affecting the outcome of treatment for early stage EEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985442PMC
January 2020

Microbiota Dysbiosis in Fungal Rhinosinusitis.

J Clin Med 2019 Nov 14;8(11). Epub 2019 Nov 14.

Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei City 110, Taiwan.

Fungal rhinosinusitis is a unique phenotype of chronic rhinosinusitis with unique clinical and histological characteristics. The role of bacterial microbiota in various phenotypes chronic rhinosinusitis is not thoroughly understood. Therefore, we conducted 16s rRNA amplification sequencing to determine differences in bacterial communities between phenotypes (fungal vs. non- fungal) and anatomical sites (middle meatus vs. nasopharynx). Endoscope-guided swabs were used to collect samples from the middle meatus and nasopharynx of seven consecutive patients with fungal and 18 consecutive patients with non-fungal rhinosinusitis. DNA was extracted and investigated through 16S rRNA amplification. Among samples from the middle meatus, Shannon diversity was significantly lower in those from the fungal rhinosinusitis group ( = 0.029). However, no significant differences in diversity were noted between nasopharynx samples ( = 0.85). Fungal rhinosinusitis samples exhibited a distinct distribution of taxon relative abundance, which involved not only the absence of rhinosinusitis-associated commensal and in the middle meatus but also a significant increase in prevalence and abundance. This is the first study to compare bacterial communities in fungal and non-fungal rhinosinusitis samples. Our findings demonstrated that bacterial community dysbiosis was more apparent in fungal rhinosinusitis samples and was limited to the middle meatus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8111973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912393PMC
November 2019

Diversity of nasal microbiota and its interaction with surface microbiota among residents in healthcare institutes.

Sci Rep 2019 04 16;9(1):6175. Epub 2019 Apr 16.

Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei City, Taiwan.

Nasal microbial communities may have crucial implications for human health, including for residents of healthcare institutes (HCIs). Factors that determine the diversity of nasal microbiota in HCIs remain unclear. Herein, we used 16S rRNA amplicon sequencing to investigate the relationship between nasal and surface microbiota in three HCIs. Participants were classified into a hospitalised or nonhospitalised group based on their most recent date of hospitalisation. A total of 88 nasal samples and 83 surface samples were analysed. Dysgonomonas and Corynebacterium were the most abundant taxa in the surface and nasal samples, respectively. Significant differences were discovered in microbiota diversity among HCIs when comparing the surface and nasal samples. Fifteen taxa were identified as present in all the surface and nasal samples. SourceTracker analysis revealed that the ventilation conditions of environment might be associated with the proportion of shared microbial communities between nasal and surface. Additionally, as compared with the nonhospitalised group, the hospitalised group had a higher proportion of surface microbiota in their nasal samples, which might lead to a higher risk of human-related microorganisms or pathogens colonising the nasal cavity. The data suggest that nasal bacterial diversity could be influenced by both health status and living environment. Our results therefore highlight the importance of the indoor environment for HCI residents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-42548-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467918PMC
April 2019

Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR-TMU study.

J Cachexia Sarcopenia Muscle 2019 08 2;10(4):756-766. Epub 2019 Apr 2.

Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Background: Weight-reduction therapies, including bariatric surgery (BS), are standard treatments for severely obese patients with type 2 diabetes; however, the outcomes of these therapies are inconclusive for obese patients with chronic kidney disease (CKD). This study aimed to investigate the effects of BS or non-surgical interventions on the estimated glomerular filtration rate (eGFR) and to determine whether BS can be recommended for renal function preservation based on body mass index (BMI) and eGFR changes in obese patients with CKD.

Methods: This study used data from the weight Reduction Intervention on GFR in Obese Patients with Renal Impairment-Taipei Medical University (TMU) study, which was a large, long-term, propensity score-matched cohort study based on clinical data from patients who registered at weight-reduction centres at TMU and its affiliated hospitals from 2008 to 2016. The patients were stratified according to whether they had undergone BS and into the mild, moderate, and high CKD risk groups using the Kidney Disease: Improving Global Outcomes guidelines. The primary outcome was the eGFR calculated using the Taiwan Chronic Kidney Disease-Epidemiology Collaboration equation. Cox regression models were used to determine hazard ratios (HRs) for eGFR decreases ≥25%.

Results: A total of 4332 obese patients were enrolled in this study. After propensity score matching, 1620 patients, including 60.2% women, with a mean age of 36.5 (9.9) years were divided into BS or non-surgery groups (n = 810 per group). The overall mean eGFRs increased by 4.4 (14) mL/min·1.73 m and decreased by 6.4 (16.0) mL/min·1.73 m in the BS and non-surgery groups, respectively. The decrease in BMI in the BS and non-surgery groups were 2.5 and 1.3 kg/m , respectively. In the moderate/high CKD risk BS group, a significant correlation was evident between an increased eGFR and a reduced BMI (Spearman's correlation -0.229, P < 0.001). The Cox regression analysis showed that the BS group had a significantly lower risk of an eGFR decline ≥25% at 12 months [adjusted HR (aHR) 0.47, P = 0.03). After BS, obese patients with hypertension or albuminuria had significantly lower risks of eGFR declines ≥25% (aHR 0.37, P = 0.02 and aHR 0.13, P = 0.0018, respectively).

Conclusions: Bariatric surgery was associated with eGFR preservation in all obese patients and, particularly, in those with moderate-to-high CKD risks. A longer term outcome study is warranted to determine the benefits of BS for CKD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcsm.12423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711419PMC
August 2019

Identification of potential biomarkers related to glioma survival by gene expression profile analysis.

BMC Med Genomics 2019 Mar 20;11(Suppl 7):34. Epub 2019 Mar 20.

Research Center of Translational Imaging, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.

Background: Recent studies have proposed several gene signatures as biomarkers for different grades of gliomas from various perspectives. However, most of these genes can only be used appropriately for patients with specific grades of gliomas.

Methods: In this study, we aimed to identify survival-relevant genes shared between glioblastoma multiforme (GBM) and lower-grade glioma (LGG), which could be used as potential biomarkers to classify patients into different risk groups. Cox proportional hazard regression model (Cox model) was used to extract relative genes, and effectiveness of genes was estimated against random forest regression. Finally, risk models were constructed with logistic regression.

Results: We identified 104 key genes that were shared between GBM and LGG, which could be significantly correlated with patients' survival based on next-generation sequencing data obtained from The Cancer Genome Atlas for gene expression analysis. The effectiveness of these genes in the survival prediction of GBM and LGG was evaluated, and the average receiver operating characteristic curve (ROC) area under the curve values ranged from 0.7 to 0.8. Gene set enrichment analysis revealed that these genes were involved in eight significant pathways and 23 molecular functions. Moreover, the expressions of ten (CTSZ, EFEMP2, ITGA5, KDELR2, MDK, MICALL2, MAP 2 K3, PLAUR, SERPINE1, and SOCS3) of these genes were significantly higher in GBM than in LGG, and comparing their expression levels to those of the proposed control genes (TBP, IPO8, and SDHA) could have the potential capability to classify patients into high- and low- risk groups, which differ significantly in the overall survival. Signatures of candidate genes were validated, by multiple microarray datasets from Gene Expression Omnibus, to increase the robustness of using these potential prognostic factors. In both the GBM and LGG cohort study, most of the patients in the high-risk group had the IDH1 wild-type gene, and those in the low-risk group had IDH1 mutations. Moreover, most of the high-risk patients with LGG possessed a 1p/19q-noncodeletion.

Conclusion: In this study, we identified survival relevant genes which were shared between GBM and LGG, and those enabled to classify patients into high- and low-risk groups based on expression level analysis. Both the risk groups could be correlated with the well-known genetic variants, thus suggesting their potential prognostic value in clinical application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-019-0479-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402580PMC
March 2019

Adverse Outcomes after Major Surgeries in Patients with Diabetes: A Multicenter Matched Study.

J Clin Med 2019 Jan 16;8(1). Epub 2019 Jan 16.

Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.

The impact of diabetes on perioperative outcomes remains incompletely understood. Our purpose is to evaluate post-operative complications and mortality in patients with diabetes. Using the institutional and clinical databases of three university hospitals from 2009⁻2015, we conducted a matched study of 16,539 diabetes patients, aged >20 years, who underwent major surgery. Using a propensity score matching procedure, 16,539 surgical patients without diabetes who underwent surgery were also selected. Logistic regressions were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs) for post-operative complications and in-hospital mortality associated with diabetes. Patients with diabetes had a higher risk of postoperative septicemia (OR 1.33, 95% CI 1.01⁻1.74), necrotizing fasciitis (OR 3.98, 95% CI 1.12⁻14.2), cellulitis (OR 2.10, 95% CI 1.46⁻3.03), acute pyelonephritis (OR 1.86, 95% CI 1.01⁻3.41), infectious arthritis (OR 3.89, 95% CI 1.19⁻12.7), and in-hospital mortality (OR 1.51, 95% CI 1.07⁻2.13) compared to people without diabetes. Previous admission for diabetes (OR 2.33, 95% CI 1.85⁻2.93), HbA1c >8% (OR 1.96, 95% CI 1.64⁻2.33) and fasting glucose >180 mg/dL (OR 1.90, 95% CI 1.68⁻2.16) were predictors for post-operative adverse events. Diabetes patients who underwent surgery had higher risks of infectious complications and in-hospital mortality compared with patients without diabetes who underwent similar major surgeries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8010100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352271PMC
January 2019

Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing-Induced Cardiomyopathy.

J Am Heart Assoc 2019 01;8(1):e009146

4 Division of Cardiology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Chang Gung University College of Medicine Kaohsiung Taiwan.

Background The molecular mechanisms through which high-demand pacing induce myocardial dysfunction remain unclear. Methods and Results We created atrioventricular block in pigs using dependent right ventricular septal pacing for 6 months. Echocardiography was performed to evaluate dyssynchrony between pacing (n=6) and sham control (n=6) groups. Microarray and enrichment analyses were used to identify differentially expressed genes ( DEG s) in the left ventricular ( LV ) myocardium between pacing and sham control groups. Histopathological and protein changes were also analyzed and an A cell pacing model was also performed. Pacing significantly increased mechanical dyssynchrony. Enrichment analysis using Ingenuity Pathway Analysis and the activation z-score analysis method demonstrated that there were 5 DEG s ( ABCA 1, APOD , CLU , LY 96, and SERPINF 1) in the LV septum (z-score=-0.447) and 5 DEG s ( APOD , CLU , LY 96, MSR 1, and SERPINF 1) in the LV free wall (z-score=-1.000) inhibited the liver X receptor/retinoid X receptor ( LXR / RXR ) pathway, and 4 DEG s ( ACTA 2, MYL 1, PPP 2R3A, and SNAI 2) activated the integrin-linked kinase ( ILK ) pathway in the LV septum (z-score=1.000). The pacing group had a larger cell size, higher degree of myolysis and fibrosis, and increased expression of intracellular lipid, inflammatory cytokines, and apoptotic markers than the sham control group. The causal relationships between pacing and DEG s related to LXR / RXR and ILK pathways, apoptosis, fibrosis, and lipid expression after pacing were confirmed in the cell pacing model. Luciferase reporter assay in the cell pacing model also supported inhibition of the LXR pathway by pacing. Conclusions Right ventricular septal-dependent pacing was associated with persistent LV dyssynchrony-induced cardiomyopathy through inhibition of the LXR / RXR pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.118.009146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405706PMC
January 2019

Vaginal microbiome variances in sample groups categorized by clinical criteria of bacterial vaginosis.

BMC Genomics 2018 Dec 31;19(Suppl 10):876. Epub 2018 Dec 31.

Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.

Background: One of the most common and recurrent vaginal infections is bacterial vaginosis (BV). The diagnosis is based on changes to the "normal" vaginal microbiome; however, the normal microbiome appears to differ according to reproductive status and ethnicity, and even among individuals within these groups. The Amsel criteria and Nugent score test are widely used for diagnosing BV; however, these tests are based on different criteria, and so may indicate distinct changes in the vaginal microbial community. Nevertheless, few studies have compared the results of these test against metagenomics analysis.

Methods: Vaginal flora samples from 77 participants were classified according to the Amsel criteria and Nugent score test. The microbiota composition was analyzed using 16S ribosome RNA gene amplicon sequencing. Bioinformatics analysis and multivariate statistical analysis were used to evaluate the microbial diversity and function.

Results: Only 3 % of the participants diagnosed BV negative using the Amsel criteria (A-) were BV-positive according to the Nugent score test (N+), while over half of the BV-positive patients using the Amsel criteria (A+) were BV-negative according to the Nugent score test (N-). Thirteen genera showed significant differences in distribution among BV status defined by BV tests (e.g., A - N-, A + N- and A + N+). Variations in the four most abundant taxa, Lactobacillus, Gardnerella, Prevotella, and Escherichia, were responsible for most of this dissimilarity. Furthermore, vaginal microbial diversity differed significantly among the three groups classified by the Nugent score test (N-, N+, and intermediate flora), but not between the Amsel criteria groups. Numerous predictive microbial functions, such as bacterial chemotaxis and bacterial invasion of epithelial cells, differed significantly among multiple BV test, but not between the A- and A+ groups.

Conclusions: Metagenomics analysis can greatly expand our current understanding of vaginal microbial diversity in health and disease. Metagenomics profiling may also provide more reliable diagnostic criteria for BV testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-018-5284-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311936PMC
December 2018

Differential Gene Expression Profile of Renin-Angiotensin System in the Left Atrium in Mitral Regurgitation Patients.

Dis Markers 2018 18;2018:6924608. Epub 2018 Nov 18.

Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Background: Left atrial enlargement is a mortality and heart failure risk factor in primary mitral regurgitation (MR) patients. Pig models of MR have shown differential expression of genes linked to the renin-angiotensin system. Therefore, the aim of this study was to investigate the key genes of the renin-angiotensin that are expressed differentially in the left atrial myocardium in MR patients.

Methods: Quantitative RT-PCR was used to compare gene expression in the renin-angiotensin system in the left atrium in MR patients, aortic valve disease patients, and normal subjects.

Results: Plasma angiotensin II concentrations did not significantly differ between MR patients and aortic valve disease patients ( = 0.582). Compared to normal controls, however, MR patients had significantly downregulated expressions of angiotensin-converting enzyme, angiotensin I converting enzyme 2, type 1 angiotensin II receptor, glutamyl aminopeptidase, angiotensinogen, cathepsin A (), thimet oligopeptidase 1, neurolysin, alanyl aminopeptidase, cathepsin G, leucyl/cystinyl aminopeptidase (), neprilysin, and carboxypeptidase A3 in the left atrium. The MR patients also had significantly upregulated expressions of oncogene () and mineralocorticoid receptor compared to normal controls. Additionally, in comparison with aortic valve disease patients, MR patients had significantly downregulated and expression and significantly upregulated expression in the left atrium.

Conclusions: Expressions of genes in the renin-angiotensin system, especially , , and , in the left atrium in MR patients significantly differed from expressions of these genes in aortic valve disease patients and normal controls. Notably, differences in expression were independent of circulating angiotensin II levels. The results of this study provide a rationale for pharmacological therapies or posttranslational regulation therapies targeting genes expressed differentially in the renin-angiotensin system to remedy structural remodeling associated with atrial enlargement and heart failure progression in patients with MR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/6924608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276386PMC
April 2019

and Are Affected by Stretch in HL-1 Atrial Myocytes.

Int J Mol Sci 2018 Dec 18;19(12). Epub 2018 Dec 18.

Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

Background: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR.

Methods: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes).

Results: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (, , , , , , ) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (, , , , , , , , ) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the "superpathway of cholesterol biosynthesis" were (upregulated) and (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of ( < 0.05) and was significantly decreased by plasmid transfection of ( = 0.004).

Conclusions: The and genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19124094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321625PMC
December 2018

Alteration of mesenchymal stem cells polarity by laminar shear stimulation promoting β-catenin nuclear localization.

Biomaterials 2019 01 23;190-191:1-10. Epub 2018 Oct 23.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Mesenchymal stem cell (MSC) is mechanosensitive and the respond to mechanical force is pattern specific. We previously reported that oscillatory shear stress at 0.5 ± 4 dyne/cm guided MSCs polarity vertical to net flow direction before apolaric stage at 30 min resulting in phosphorylation of β-catenin and inhibition of Wnt signaling. This time, we explored laminar shear stress (LS) at 0.5 dyne/cm polarized MSCs by guiding F-actin orientation parallel to the flow direction before apolarity at 30 min accompanied with activation of Wnt signaling. Time-dependent microarray analysis supported cell-cell junctional complex of MSCs was the major mechanosensor on MSCs to respond 0.5 dyne/cm LS. Three-dimensional immunofluorescence image confirmed LS promoting β-catenin nuclear localization during 15 min to 1 h with a peak at 30 min. Functional analysis of proteomic study on MSC with 30 min LS stimulation indicated that upregulation of β-catenin downstream proteins related to cardiovascular development, endothelial cell protection and angiogenesis. Conditioned medium from MSCs with 30 min LS stimulation improved the viability of human endothelial cells from oxidative damage. In conclusion, 0.5 dyne/cm LS on MSCs for 30 min guides MSCs lack of polarity and promotes β-catenin nuclear translocation favoring Wnt activation and paracrine cardiovascular support.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2018.10.026DOI Listing
January 2019

State-of-the-Art on Viral microRNAs in HPV Infection and Cancer Development.

Microrna 2018 ;7(2):85-91

Department of Computer Science & Engineering, Graduate Program in Biomedical Informatics, Yuan Ze University, Chung-Li, Taiwan.

Background: High-risk HPV subtypes are driving forces for human cancer development: HPV-16 and HPV-18 are responsible for most HPV-caused cancers.

Objective: This review describes the present knowledge on HR-HPV genomes coding potential for viral miRNAs.

Methods: HPV subtypes miRNA database, VIRmiRtar, has been constructed applying bioinformatics and a computational method, ViralMir, exploiting structural features, the presence of hairpins, and validation by comparison with RNA sequencing datasets.

Results: Several miRNA candidates have been localised in the genomes of high-risk HPV subtypes. Among these, HPV-16 miR-1, miR-2 and miR-3. The database contains a list of host candidate gene targets that may be responsible for the oncogenesis in the various cellular environments.

Conclusion: miRNA silencing therapies, based on specific cellular uptake of miRNA mimics and antagomiRs, directed towards HPV encoded miRNAs and/or microRNAs deregulated in the host cells, could be a valuable approach to support pharmaceutical interventions in the treatment of HPV dependent cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/2211536607666180328115155DOI Listing
November 2018

A Three-MicroRNA Signature as a Potential Biomarker for the Early Detection of Oral Cancer.

Int J Mol Sci 2018 Mar 7;19(3). Epub 2018 Mar 7.

Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 300, Taiwan.

Oral squamous cell carcinoma (OSCC) is often diagnosed at a late stage and may be malignantly transformed from oral leukoplakia (OL). This study aimed to identify potential plasma microRNAs (miRNAs) for the early detection of oral cancer. Plasma from normal, OL, and OSCC patients were evaluated. Small RNA sequencing was used to screen the differently expressed miRNAs among the groups. Next, these miRNAs were validated with individual samples by quantitative real-time polymerase chain reaction (qRT-PCR) assays in the training phase ( = 72) and validation phase ( = 178). The possible physiological roles of the identified miRNAs were further investigated using bioinformatics analysis. Three miRNAs (miR-222-3p, miR-150-5p, and miR-423-5p) were identified as differentially expressed among groups; miR-222-3p and miR-423-5p negatively correlated with T stage, lymph node metastasis status, and clinical stage. A high diagnostic accuracy (Area under curve = 0.88) was demonstrated for discriminating OL from OSCC. Bioinformatics analysis reveals that miR-423-5p and miR-222-3p are significantly over-expressed in oral cancer tissues and involved in various cancer pathways. The three-plasma miRNA panel may be useful to monitor malignant progression from OL to OSCC and as potential biomarkers for early detection of oral cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19030758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877619PMC
March 2018
-->