Publications by authors named "Yen-Lin Chen"

238 Publications

A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability.

Sci Signal 2021 Mar 2;14(672). Epub 2021 Mar 2.

Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The endothelial cell barrier regulates the passage of fluid between the bloodstream and underlying tissues, and barrier function impairment exacerbates the severity of inflammatory insults. To understand how inflammation alters vessel permeability, we studied the effects of the proinflammatory cytokine TNFα on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries. We found that TNFα specifically decreased the barrier function of venous endothelium without affecting that of arterial endothelium. On the basis of RNA expression profiling and protein analysis, we found that claudin-11 (CLDN11) was the predominant claudin in venous endothelial cells and that there was little, if any, CLDN11 in arterial endothelial cells. Consistent with a difference in claudin composition, TNFα increased the permselectivity of Cl over Na in venous but not arterial endothelium. The vein-specific effects of TNFα also required the activation of Pannexin 1 (Panx1) channels and the CD39-mediated hydrolysis of ATP to adenosine, which subsequently stimulated A adenosine receptors. Moreover, the increase in vein permeability required the activation of the Ca channel TRPV4 downstream of Panx1 activation. Panx1-deficient mice resisted the pathologic effects of sepsis induced by cecal ligation and puncture on life span and lung vascular permeability. These data provide a targetable pathway with the potential to promote vein barrier function and prevent the deleterious effects of vascular leak in response to inflammation.
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http://dx.doi.org/10.1126/scisignal.aba2940DOI Listing
March 2021

First-phase insulin secretion is positively correlated with alanine aminotransferase in young adults.

Adv Clin Exp Med 2021 Jan;30(1):35-40

Department of Pathology, Cardinal Tien Hospital, Fu Jen Catholic University, School of Medicine, New Taipei City, Taiwan.

Background: Type 2 diabetes (T2D) is known to be one of the most prevalent diseases, and its prevalence is significantly associated with age and metabolic syndrome (MetS). Few studies have been conducted on liver function, MetS and insulin secretion among young adults.

Objectives: In the present study, we explored the relationship between the liver function enzyme - alanine aminotransferase (ALT) - and first-phase insulin secretion (FPIS) among young adults.

Material And Methods: There were 22,971 men and 28,740 women, aged 18-27 years, assigned to subgroups according to the presence of MetS and quartiles of ALT values. Simple correlation was applied to evaluate their relationship. The difference between the slopes of these relationships and FPIS were statistically analyzed with Chris's calculator.

Results: Most values for metabolic parameters, including ALT and FPIS, were determined to be relatively high in individuals with MetS. By contrast, individuals with MetS had lower high-density-lipoprotein cholesterol (HDL-C) counts and FPIS. Similar results were observed in the quartiles of ALT. Significant positive results were also found in the linear model. Depending on the ALT level, the slope change of FPIS still demonstrated a positive correlation between ALT and FPIS. This correlation was stronger for men than for women.

Conclusions: A positive correlation between ALT and FPIS exists among young adults. Moreover, this correlation was stronger for men than for women. Both the cause and the effect require further investigation.
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http://dx.doi.org/10.17219/acem/128229DOI Listing
January 2021

CCAAT/Enhancer-binding protein delta mediates glioma stem-like cell enrichment and ATP-binding cassette transporter ABCA1 activation for temozolomide resistance in glioblastoma.

Cell Death Discov 2021 Jan 12;7(1). Epub 2021 Jan 12.

Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.

Glioblastoma (GBM) is the most aggressive brain tumor and relapses after chemo- or radiotherapy in a short time. The anticancer drug temozolamide (TMZ) is commonly used for GBM treatment, but glioma stem-like cells (GSCs) often lead to drug resistance and therapeutic failure. To date, the mechanism of GSC formation in TMZ-treated GBM remains largely unknown. CCAAT/Enhancer-binding protein delta (CEBPD) is an inflammation-responsive transcription factor and is proposed to be oncogenic in the context of drug resistance, prompting us to clarify its role in TMZ-resistant GBM. In this study, we first found that the CEBPD protein levels in GBM patients were significantly increased and further contributed to TMZ resistance by promoting GSC formation. Accordingly, the protein levels of stemness transcription factors, namely, SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG, and ATP-binding cassette subfamily A member 1 (ABCA1), were increased in GSCs and TMZ-treated GBM cells. Increased binding of CEBPD to promoter regions was observed in GSCs, indicating the direct regulation of these GSC-related genes by CEBPD. In addition, an ABCA1 inhibitor increased the caspase 3/7 activity of TMZ-treated GSCs, suggesting that TMZ efflux is controlled by ABCA1 activity and that the expression levels of the ABCA1 gene are an indicator of the efficiency of TMZ treatment. Together, we revealed the mechanism of CEBPD-mediated GSC drug resistance and proposed ABCA1 inhibition as a potential strategy for the treatment of TMZ-resistant GBM.
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http://dx.doi.org/10.1038/s41420-020-00399-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804954PMC
January 2021

TD-92, a novel erlotinib derivative, depletes tumor-associated macrophages in non-small cell lung cancer via down-regulation of CSF-1R and enhances the anti-tumor effects of anti-PD-1.

Cancer Lett 2021 Feb 21;498:142-151. Epub 2020 Nov 21.

SupremeCure Pharma Inc., Taipei, Taiwan.

Recent advances in immune checkpoint inhibition, which augment T-cell immune responses, have highlighted the potential of exploiting one's immune system to combat cancer. However, only a relatively small number of non-small cell lung cancer (NSCLC) patients benefit from immune checkpoint blockade due to the immunosuppressive tumor microenvironment. Therefore, combination immunotherapies are now being developed to achieve maximal therapeutic benefits. In this study, we assessed whether a novel erlotinib derivative, TD-92, which possesses anti-tumor effects across several cancer cell lines, could enhance anti-PD-1 treatment. Our results demonstrated that the combined treatment of anti-PD-1 and TD-92 resulted in a potent anti-tumor response in a Lewis lung carcinoma cancer model, as evidenced by the reduced tumor growth and increased survival. Analysis of immune cell population counts revealed that TD-92 reduced the number of pro-tumorigenic CD11b F4/80 tumor-associated macrophages, without significantly affecting the total numbers of other major immunocytes. Further experiments showed that TD-92 induced a marked decline in colony stimulating factor 1 receptor (CSF-1R) expression in macrophage cell lines. The results also suggested that c-Cbl-mediated proteasome degradation was involved in TD-92-mediated CSF-1R downregulation. Our data paves the way for the development of additional combination immunotherapies for NSCLC patients.
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http://dx.doi.org/10.1016/j.canlet.2020.10.043DOI Listing
February 2021

Elucidating the Role of Microprocessor Protein DGCR8 in Bending RNA Structures.

Biophys J 2020 Dec 13;119(12):2524-2536. Epub 2020 Nov 13.

Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania. Electronic address:

Although conformational dynamics of RNA molecules are potentially important in microRNA (miRNA) processing, the role of the protein binding partners in facilitating the requisite structural changes is not well understood. In previous work, we and others have demonstrated that nonduplex structural elements and the conformational flexibility they support are necessary for efficient RNA binding and cleavage by the proteins associated with the two major stages of miRNA processing. However, recent studies showed that the protein DGCR8 binds primary miRNA and duplex RNA with similar affinities. Here, we study RNA binding by a small recombinant construct of the DGCR8 protein and the RNA conformation changes that result. This construct, the DGCR8 core, contains two double-stranded RNA-binding domains (dsRBDs) and a C-terminal tail. To assess conformational changes resulting from binding, we applied small-angle x-ray scattering with contrast variation to detect conformational changes of primary-miR-16-1 in complex with the DGCR8 core. This method reports only on the RNA conformation within the complex and suggests that the protein bends the RNA upon binding. Supporting work using smFRET to study the conformation of RNA duplexes bound to the core also shows bending. Together, these studies elucidate the role of DGCR8 in interacting with RNA during the early stages of miRNA processing.
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http://dx.doi.org/10.1016/j.bpj.2020.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822732PMC
December 2020

Relationships between white blood cell count and insulin resistance, glucose effectiveness, and first- and second-phase insulin secretion in young adults.

Medicine (Baltimore) 2020 Oct;99(43):e22215

Department of Pathology, Cardinal Tien Hospital, Fu Jen Catholic University, School of Medicine, New Taipei City, Taiwan, ROC.

The Increasing prevalence of type 2 diabetes mellitus (T2DM) has been observed in younger adults. Insulin resistance [IR], decreased first-, second-phase insulin secretion, and glucose effectiveness (GE) (IR, first phase insulin secretion [FPIS], second phase insulin secretion [SPIS], and GE), denoted as diabetes factors (DF), are core for developing T2DM. A body of evidence has shown that inflammation contributes to the development of diabetes. In the present study, our goals were first, evaluate the relationships between white blood cell (WBC) count and, second, examine the relative tightness between the 4 DFs to WBC count. Thus, the pathophysiology of T2DM in Chinese young men could be more understood.21112 non-obese males between 18 to 27 years old were recruited (mean age: 24.3 ± 0.017), including 1745 subjects with metabolic syndrome. DFs were calculated by the published equations by our groups as follows:The association between DFs and WBC count was analyzed using a simple correlation. The r-values of the simple correlation are regarded as the tightness of the relationships.Higher WBC, FPIS, SPIS, IR, age, BMI, blood pressure, FPG, TG, Cholesterol, low-density lipoprotein cholesterol and lower HDL-C and GE were observed in subjects with metabolic syndrome. A similar trend was seen across the quartiles of WBC levels. Among the 4 DFs, GE has the highest r-value (r = -0.093, P < .001), followed by IR (r = 0.067, P < .001), SPIS (r = 0.029, P < .001) and FPIS (r = 0.027, P < .001).Elevated WBC count is significantly associated with all the 4 DFs and the relative order of the tightness, from the highest to the lowest, are GE, IR, SPIS, and FPIS in Chinese young men.
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http://dx.doi.org/10.1097/MD.0000000000022215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581030PMC
October 2020

Comprehensive analysis in mucin-producing urothelial-type adenocarcinoma of the prostate: case study with literature review.

Pol J Pathol 2020 ;71(3):244-253

Department of Pathology, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.

It is critical to distinguish the rare neoplasm of mucin-producing urothelial-type adenocarcinoma of the prostate (MPUAP) from either prostate origin or metastatic adenocarcinoma. This is mainly because they have different tumor staging, clinical behavior and treatment plans. In the current study, we try to fulfill the lack of knowledge in this field. There were totally 24 MPUAP cases including previous reported 23 cases and adding one new MPUAP case in the current study. We performed IHC and 78 genes panel analysis in two cases of ours. Most of the cases had urinary obstruction symptoms and normal PSA level. Pathological features showed dissection of the stroma by mucin pools and glands lined by pseudostratified columnar mucinous epithelium with varying degrees of cytological atypia. The IHC results showed positive for CK20, CEA, CDX-2, β-catenin, p53, MUC2 and MUC5AC, negative for PSA, AMACR, GATA3, MUC6, AR and NKX3.1 and variable expression for HMWCK and CK7. Genetic analysis revealed concurrent mutations of FAT1 (c.10001 T>C) and HNF1A in both cases. The similar morphology features of MPUAP and colorectal adenocarcinoma were seen. Membranous staining pattern of β-catenin and genetic mutation of FAT1 and HNF1A are two distinct features in MPUAP.
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http://dx.doi.org/10.5114/pjp.2020.99791DOI Listing
January 2021

A Real-Time Vehicle Detection System under Various Bad Weather Conditions Based on a Deep Learning Model without Retraining.

Sensors (Basel) 2020 Oct 9;20(20). Epub 2020 Oct 9.

Department of Computer Science and Information Engineering, National Taipei University of Technology, 1, Sec. 3, Chung-hsiao E. Rd., Taipei 10608, Taiwan.

Numerous vehicle detection methods have been proposed to obtain trustworthy traffic data for the development of intelligent traffic systems. Most of these methods perform sufficiently well under common scenarios, such as sunny or cloudy days; however, the detection accuracy drastically decreases under various bad weather conditions, such as rainy days or days with glare, which normally happens during sunset. This study proposes a vehicle detection system with a visibility complementation module that improves detection accuracy under various bad weather conditions. Furthermore, the proposed system can be implemented without retraining the deep learning models for object detection under different weather conditions. The complementation of the visibility was obtained through the use of a dark channel prior and a convolutional encoder-decoder deep learning network with dual residual blocks to resolve different effects from different bad weather conditions. We validated our system on multiple surveillance videos by detecting vehicles with the You Only Look Once (YOLOv3) deep learning model and demonstrated that the computational time of our system could reach 30 fps on average; moreover, the accuracy increased not only by nearly 5% under low-contrast scene conditions but also 50% under rainy scene conditions. The results of our demonstrations indicate that our approach is able to detect vehicles under various bad weather conditions without the need to retrain a new model.
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http://dx.doi.org/10.3390/s20205731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600474PMC
October 2020

Application of Transthoracic Shear-Wave Ultrasound Elastography in Lung Lesions.

Eur Respir J 2020 Oct 8. Epub 2020 Oct 8.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Introduction: The tissue stiffness information may help in the diagnosis of lung lesions. This study aimed to investigate and validate the application of transthoracic two-dimensional shear-wave ultrasound elastography in differentiating malignant from benign subpleural lung lesions.

Methods: This study involved one retrospective observational derivation cohort from January 2016 to December 2017 and one prospective observational validation cohort from December 2017 to December 2019. The inclusion criterion was radiographic evidence of pulmonary lesions. The patients were categorised into the air-bronchogram and hypoechoic groups based on the B-mode grayscale images. The elasticity of subpleural lung lesions with acceptable shear-wave propagation was measured. Diagnoses were made on the basis of pathology, microbiological studies, or following up the clinical course for at least 6 months.

Results: A total of 354 patients were included. Among the 121 patients in the derivation cohort, a receiver operating characteristic curve was constructed and the cut-off point to differentiate benign from malignant lesions was 65 kPa with Youden index 0.60 and accuracy 84.3%. Among the 233 patients in the validation cohort, the diagnostic performance was maintained with Youden index 0.65 and accuracy 86.7%. Upon applying the cut-off point to the air-bronchogram group, Youden index was 0.70 and accuracy 85.0%.

Conclusions: This study validated the application of transthoracic shear-wave ultrasound elastography for assessing lung malignancy. A cut-off point of 65 kPa is suggested for predicting lung malignancy. Furthermore, for pulmonary air-bronchogram lesions with high elasticity, tissue proofing should be considered because of the high possibility of malignancy.
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http://dx.doi.org/10.1183/13993003.02347-2020DOI Listing
October 2020

Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice.

PLoS Genet 2020 09 25;16(9):e1009020. Epub 2020 Sep 25.

Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.

Approximately 2-15% of couples experience infertility, and around half of these cases are attributed to male infertility. We previously identified TBC1D21 as a sterility-related RabGAP gene derived from infertile men. However, the in vivo function of TBC1D21 in male fertility remains unclear. Here, we show that loss of Tbc1d21 in mice resulted in male infertility, characterized by defects in sperm tail structure and diminished sperm motility. The mitochondria of the sperm-tail had an abnormal irregular arrangement, abnormal diameter, and structural defects. Moreover, the axoneme structure of sperm tails was severely disturbed. Several TBC1D21 interactors were selected via proteomic analysis and functional grouping. Two of the candidate interactors, a subunit protein of translocase in the outer membrane of mitochondria (TOMM20) and an inner arm component of the sperm tail axoneme (Dynein Heavy chain 7, DNAH7), confirmed in vivo physical co-localization with TBC1D21. In addition, TOMM20 and DNAH7 detached and dispersed outside the axoneme in Tbc1d21-deficient sperm, instead of aligning with the axoneme. From a clinical perspective, the transcript levels of TBC1D21 in sperm from teratozoospermia cases were significantly reduced when compared with those in normozoospermia. We concluded that TBC1D21 is critical for mitochondrial and axoneme development of mammalian sperm.
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http://dx.doi.org/10.1371/journal.pgen.1009020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549768PMC
September 2020

Machine learning deciphers structural features of RNA duplexes measured with solution X-ray scattering.

IUCrJ 2020 Sep 12;7(Pt 5):870-880. Epub 2020 Aug 12.

School of Applied and Engineering Physics, Cornell University, Ithaca, New York 14853, United States.

Macromolecular structures can be determined from solution X-ray scattering. Small-angle X-ray scattering (SAXS) provides global structural information on length scales of 10s to 100s of Ångstroms, and many algorithms are available to convert SAXS data into low-resolution structural envelopes. Extension of measurements to wider scattering angles (WAXS or wide-angle X-ray scattering) can sharpen the resolution to below 10 Å, filling in structural details that can be critical for biological function. These WAXS profiles are especially challenging to interpret because of the significant contribution of solvent in addition to solute on these smaller length scales. Based on training with molecular dynamics generated models, the application of extreme gradient boosting (XGBoost) is discussed, which is a supervised machine learning (ML) approach to interpret features in solution scattering profiles. These ML methods are applied to predict key structural parameters of double-stranded ribonucleic acid (dsRNA) duplexes. Duplex conformations vary with salt and sequence and directly impact the foldability of functional RNA molecules. The strong structural periodicities in these duplexes yield scattering profiles with rich sets of features at intermediate-to-wide scattering angles. In the ML models, these profiles are treated as 1D images or features. These ML models identify specific scattering angles, or regions of scattering angles, which correspond with and successfully predict distinct structural parameters. Thus, this work demonstrates that ML strategies can integrate theoretical molecular models with experimental solution scattering data, providing a new framework for extracting highly relevant structural information from solution experiments on biological macromolecules.
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http://dx.doi.org/10.1107/S2052252520008830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467162PMC
September 2020

Hyperglycemia Augments Endothelin-1-Induced Constriction of Human Retinal Venules.

Transl Vis Sci Technol 2020 08 3;9(9). Epub 2020 Aug 3.

Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA.

Purpose: Endothelin-1 (ET-1) is a potent vasoactive factor implicated in development of diabetic retinopathy, which is commonly associated with retinal edema and hyperglycemia. Although the vasomotor activity of venules contributes to the regulation of tissue fluid homeostasis, responses of human retinal venules to ET-1 under euglycemia and hyperglycemia remain unknown and the ET-1 receptor subtype corresponding to vasomotor function has not been determined. Herein, we addressed these issues by examining the reactivity of isolated human retinal venules to ET-1, and results from porcine retinal venules were compared.

Methods: Retinal tissues were obtained from patients undergoing enucleation. Human and porcine retinal venules were isolated and pressurized to assess diameter changes in response to ET-1 after exposure to 5 mM control glucose or 25 mM high glucose for 2 hours.

Results: Both human and porcine retinal venules exposed to control glucose developed similar basal tone and constricted comparably to ET-1 in a concentration-dependent manner. ET-1-induced constrictions of human and porcine retinal venules were abolished by ET receptor antagonist BQ123. During high glucose exposure, basal tone of human and porcine retinal venules was unaltered but ET-1-induced vasoconstrictions were enhanced.

Conclusions: ET-1 elicits comparable constriction of human and porcine retinal venules by activation of ET receptors. In vitro hyperglycemia augments human and porcine retinal venular responses to ET-1.

Translational Relevance: Similarities in vasoconstriction to ET-1 between human and porcine retinal venules support the latter as an effective model of the human retinal microcirculation to help identify vascular targets for the treatment of retinal complications in patients with diabetes.
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http://dx.doi.org/10.1167/tvst.9.9.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442874PMC
August 2020

DNA polymerase theta repression enhances the docetaxel responsiveness in metastatic castration-resistant prostate cancer.

Biochim Biophys Acta Mol Basis Dis 2020 12 30;1866(12):165954. Epub 2020 Aug 30.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. Electronic address:

Objective: Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients.

Methods: We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays.

Results: We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells.

Conclusion: Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.
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http://dx.doi.org/10.1016/j.bbadis.2020.165954DOI Listing
December 2020

Predictors of abnormality in thallium myocardial perfusion scans for type 2 diabetes.

Heart Vessels 2021 Feb 20;36(2):180-188. Epub 2020 Aug 20.

Division of Endocrinology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, ROC.

Type 2 diabetes mellitus (T2DM) increases coronary artery disease (CAD) risk. In this study, we used T2DM clinical variables to predict abnormality in thallium-201 myocardial perfusion scans (Th-201 scans). These clinical variables were summed stress score (SSS), summed rest score, and summed difference score (SDS), with data obtained from 368 male and 428 female participants with T2DM. Multiple linear regression results were as follows. In male participants, body mass index (BMI) and creatinine (Cr) were associated with SSS (β = 0.224, p < 0.001; β = 0.140, p = 0.022, respectively), and only BMI was associated with SDS (β = 0.174, p = 0.004). In female participants, BMI and high-density lipoprotein cholesterol level were associated with SSS (β = 0.240, p < 0.001; β =  - 0.120, p = 0.048, respectively), and only BMI was correlated with SDS (β = 0.123, p = 0.031). Our multivariate logistic regression indicated that in male and female participants, BMI was the only independent indicator of high SSS (SSS ≥ 9). In this study, we demonstrated that male patients have a higher SSS and SDS than female patients do in Th-201 scans for T2DM in a Chinese population. For male and female patients, BMI was the strongest predictor of abnormality in Th-201 scans. Our results can help clinicians identify patients with T2DM at high risk of CAD.
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http://dx.doi.org/10.1007/s00380-020-01681-2DOI Listing
February 2021

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

Lancet Oncol 2020 08 20;21(8):1110-1122. Epub 2020 Jul 20.

Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA.

Background: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.

Methods: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867.

Findings: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related.

Interpretation: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up.

Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.
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http://dx.doi.org/10.1016/S1470-2045(20)30325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745646PMC
August 2020

TNFSF13 upregulation confers chemotherapeutic resistance via triggering autophagy initiation in triple-negative breast cancer.

J Mol Med (Berl) 2020 09 15;98(9):1255-1267. Epub 2020 Jul 15.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 110, Taipei, Taiwan.

Since chemotherapy is a main strategy to treat triple-negative breast cancer (TNBC) patients currently, identifying a biomarker to predict chemotherapeutic responses is urgently needed for patients to avoid suffering through unnecessary chemotherapeutic treatments. Here, we found that the endogenous expression of TNFSF13 in a panel of TNBC cell lines highly correlates with paclitaxel (PTX) and doxorubicin IC concentrations. Whereas knocking down TNFSF13 enhances PTX effectiveness in PTX-insensitive MDA-MB231 cells, recombinant TNFSF13 (recTNFSF13) desensitizes PTX-sensitive HCC1806 cells to PTX treatment. Moreover, Kaplan-Meier analysis revealed that higher TNFSF13 mRNA expression significantly predicts an increased risk for cancer recurrence in estrogen receptor (ER)-negative breast cancer patients receiving an anthracycline-based treatment. Accordingly, immunohistochemistry experiments indicated that higher levels of TNFSF13 protein are detected in TNBC patients who do not respond to an anthracycline-based treatment. The in silico analysis and Western blotting demonstrated that TNFSF13 expression inversely associates with the activity of the Akt-mTOR pathway, which acts as a negative regulator of autophagy activity. Significantly, the pharmaceutical inhibition of autophagy activity restores the therapeutic effectiveness of PTX in TNFSF13-treated HCC1806 cells. These findings suggest that TNFSF13 can serve as a predictive biomarker for TNBC patients, who can use it to decide whether to receive chemotherapy. KEY MESSAGES: TNFSF13 upregulation correlates with a poor response to chemotherapy in TNBCs. TNFSF13 promotes autophagy initiation in chemotherapeutic resistant TNBCs. Therapeutic targeting of autophagy initiation overcomes the TNFSF13-related chemoresistance. TNFSF13 could be a predictive biomarker for TNBC patients receiving chemotherapy.
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http://dx.doi.org/10.1007/s00109-020-01952-5DOI Listing
September 2020

4-Acetylantrocamol LT3, a New Ubiquinone from , Inhibits Hepatocellular Carcinoma HepG2 Cell Growth by Targeting YAP/TAZ, mTOR, and WNT/β-Catenin Signaling.

Am J Chin Med 2020 ;48(5):1243-1261

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.

4-acetylantrocamol LT3 (4AALT3), a new ubiquinone from the mycelium of (Polyporaceae), has been recently shown to possess anticancer activity. However, the detailed mechanisms of such action remain unclear. In this study, the molecular mechanisms of 4AALT3 on hepatocellular carcinoma cells (HCC) were investigated. Human hepatocellular carcinoma cell line HepG2 cells were treated with concentrations of 4AALT3. Cell viability, colony formation, and the underlying mechanisms were then analyzed by CCK-8, colony formation, qPCR, and Western blotting assays. We found that 4AALT3 significantly decreased cell viability and colony formation in a dose-dependent manner. Accordingly, 4AALT3 significantly decreased protein levels of cyclin B, E1, D1, and D3, thereby facilitating cell cycle arrest. In addition, 4AALT3 significantly suppressed the nuclear localization of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), mammalian target of rapamycin (mTOR), and WNT/[Formula: see text]-catenin signaling pathways, all of which are well-known signaling pathways that contribute to the malignant properties of HCC. These effects are associated with activation of 5' AMP-activated protein kinase (AMPK) and autophagy. Our findings indicate that 4AALT3 exerts inhibitory effects on HepG2 cell growth via multiple signaling pathways and may be a potential agent for HCC therapy.
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http://dx.doi.org/10.1142/S0192415X20500615DOI Listing
October 2020

Multi-institutional analysis of stereotactic body radiotherapy for sarcoma pulmonary metastases: High rates of local control with favorable toxicity.

J Surg Oncol 2020 Oct 25;122(5):877-883. Epub 2020 Jun 25.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Background/objectives: Oligometastatic sarcoma pulmonary metastases (PM's) are traditionally treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) is an effective, safe alternative to surgery that can achieve excellent local control (LC) with a favorable toxicity profile.

Methods: Patients treated with SBRT for sarcoma PM's from 2011 to 2016 at Massachusetts General Hospital and the University of Pennsylvania were included. Median dose was 50 Gy. Patients underwent computed tomography (CT) or positron emission tomography/CT Q3 months post-SBRT.

Results: 44 patients with 56 separate PM's were treated with SBRT. Median age was 59 (range 19-82). 82% received prior chemotherapy, 66% had prior pulmonary resections (range, 1-5 resections), and 32% received prior thoracic radiotherapy. Median lesion size was 2.0 cm (range, 0.5-8.1 cm). Median follow-up was 16 months and 25 months for patients alive at last follow-up. Overall survival at 12 and 24 months was 74% (95% confidence interval [CI], 67%-81%) and 46% (95% CI, 38%-55%). LC at 12 and 24 months was 96% (95% CI, 93%-98%) and 90% (95% CI, 84%-96%). LC and overall survival did not differ based on age, gender, histology, fractionation, lesion location, or size (P > .05). Three developed Common Terminology Criteria for Adverse Events version 4 grade-2 chest-wall toxicities; one had grade-2 pneumonitis.

Conclusions: In the first multi-institutional series on SBRT for sarcoma PM's, SBRT has excellent LC and is well-tolerated. SBRT should be considered as an alternative/complement to resection.
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http://dx.doi.org/10.1002/jso.26078DOI Listing
October 2020

Hemogram-based decision tree for predicting the metabolic syndrome and cardiovascular diseases in the elderly.

QJM 2020 Jun 23. Epub 2020 Jun 23.

School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.

Background: This study aimed to build a hemogram-based decision tree to evaluate the association between current probability of metabolic syndrome (MetS) and prediction of future hypertension, type 2 diabetes, and cardiovascular diseases (CVD) risk.

Methods: A total of 40,395 elder participants (≥60 years) were enrolled in a standard health examination program in Taiwan from January 1999 to December 2014. A decision tree classification of the presence or absence of MetS at baseline, using age, sex, and hemogram (white blood cell, hemoglobin, and platelet) as independent variables, was conducted for the randomly assigned training (70%) and validation (30%) groups. Participants without MetS at baseline (n = 25,643) were followed up to observe whether they developed MetS, hypertension, type 2 diabetes, or CVD in the future.

Results: Modest accuracy of the decision tree in the training and validation groups with area under the curves of 0.653 and 0.652, respectively, indicated an acceptable generalizability of results. The predicted probability of baseline MetS was obtained from decision tree analysis. Participants without MetS at baseline were categorized into three equally-sized groups according to the predicted probability. Participants in the third tertile had significantly higher risks of future MetS (hazard ratio 1.40, 95% confidence interval 1.25-1.58); type 2 diabetes (1.46, 1.17-1.83); hypertension (1.14, 1.01-1.28); and CVD (1.21, 1.01-1.44), compared with those in the first tertile.

Conclusions: Execution of hemogram-based decision tree analysis can assist in early identification and prompt management of elderly patients at a high risk of future hypertension, type 2 diabetes, and CVD.
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http://dx.doi.org/10.1093/qjmed/hcaa205DOI Listing
June 2020

Supraventricular bigeminy in the elderly may mimic panic disorder deterioration.

Psychogeriatrics 2020 Sep 8;20(5):787-789. Epub 2020 Jun 8.

Department of Family Medicine, Cardinal Tien Hospital, New Taipei, Taiwan.

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http://dx.doi.org/10.1111/psyg.12564DOI Listing
September 2020

Mechanisms underlying selective coupling of endothelial Ca signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries.

J Physiol 2020 09 11;598(17):3577-3596. Epub 2020 Jun 11.

Robert M. Berne Cardiovascular Research Center, University of Virginia-School of Medicine, Charlottesville, VA, USA.

Key Points: Endothelial cell TRPV4 (TRPV4 ) channels exert a dilatory effect on the resting diameter of resistance mesenteric and pulmonary arteries. Functional intermediate- and small-conductance K (IK and SK) channels and endothelial nitric oxide synthase (eNOS) are present in the endothelium of mesenteric and pulmonary arteries. TRPV4 sparklets preferentially couple with IK/SK channels in mesenteric arteries and with eNOS in pulmonary arteries. TRPV4 channels co-localize with IK/SK channels in mesenteric arteries but not in pulmonary arteries, which may explain TRPV4 -IK/SK channel coupling in mesenteric arteries and its absence in pulmonary arteries. The presence of the nitric oxide-scavenging protein, haemoglobin α, limits TRPV4 -eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4 channels with eNOS and the absence of haemoglobin α favour TRPV4 -eNOS signalling in pulmonary arteries.

Abstract: Spatially localized Ca signals activate Ca -sensitive intermediate- and small-conductance K (IK and SK) channels in some vascular beds and endothelial nitric oxide synthase (eNOS) in others. The present study aimed to uncover the signalling organization that determines selective Ca signal to vasodilatory target coupling in the endothelium. Resistance-sized mesenteric arteries (MAs) and pulmonary arteries (PAs) were used as prototypes for arteries with predominantly IK/SK channel- and eNOS-dependent vasodilatation, respectively. Ca influx signals through endothelial transient receptor potential vanilloid 4 (TRPV4 ) channels played an important role in controlling the baseline diameter of both MAs and PAs. TRPV4 channel activity was similar in MAs and PAs. However, the TRPV4 channel agonist GSK1016790A (10 nm) selectively activated IK/SK channels in MAs and eNOS in PAs, revealing preferential TRPV4 -IK/SK channel coupling in MAs and TRPV4 -eNOS coupling in PAs. IK/SK channels co-localized with TRPV4 channels at myoendothelial projections (MEPs) in MAs, although they lacked the spatial proximity necessary for their activation by TRPV4 channels in PAs. Additionally, the presence of the NO scavenging protein haemoglobin α (Hbα) within nanometer proximity to eNOS limits TRPV4 -eNOS signalling in MAs. By contrast, co-localization of TRPV4 channels and eNOS at MEPs, and the absence of Hbα, favour TRPV4 -eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4 -IK/SK vs. TRPV4 -eNOS coupling in resistance arteries.
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http://dx.doi.org/10.1113/JP279570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484264PMC
September 2020

Endothelial TRPV4 channels and vasodilator reactivity.

Curr Top Membr 2020 12;85:89-117. Epub 2020 Feb 12.

Robert M. Berne Cardiovascular Research Center, University of Virginia-School of Medicine, Charlottesville, VA, United States; Department of Molecular Physiology and Biological Physics, University of Virginia-School of Medicine, Charlottesville, VA, United States. Electronic address:

Transient receptor potential vanilloid 4 (TRPV4) ion channels on the endothelial cell membrane are widely regarded as a crucial Ca influx pathway that promotes endothelium-dependent vasodilation. The downstream vasodilatory targets of endothelial TRPV4 channels vary among different vascular beds, potentially contributing to endothelial cell heterogeneity. Although numerous studies have examined the role of endothelial TRPV4 channels using specific pharmacological tools over the past decade, their physiological significance remains unclear, mainly due to a lack of endothelium-specific knockouts. Moreover, the loss of endothelium-dependent vasodilation is a significant contributor to vascular dysfunction in cardiovascular disease. The activity of endothelial TRPV4 channels is impaired in cardiovascular disease; therefore, strategies targeting the mechanisms that reduce endothelial TRPV4 channel activity may restore vascular function and provide therapeutic benefit. In this chapter, we discuss endothelial TRPV4 channel-dependent signaling mechanisms, the heterogeneity in endogenous activators and targets of endothelial TRPV4 channels, and the role of endothelial TRPV4 channels in the pathogenesis of cardiovascular diseases. We also discuss potentially interesting future research directions that may provide novel insights into the physiological and pathological roles of endothelial TRPV4 channels.
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http://dx.doi.org/10.1016/bs.ctm.2020.01.007DOI Listing
February 2020

Creating Personalized Recommendations in a Smart Community by Performing User Trajectory Analysis through Social Internet of Things Deployment.

Sensors (Basel) 2020 Apr 8;20(7). Epub 2020 Apr 8.

Department of Computer Science and Information Engineering, National Taipei University of Technology, 1, Sec. 3, Chung-hsiao E. Rd., Taipei 10608, Taiwan.

Despite advancements in the Internet of Things (IoT) and social networks, developing an intelligent service discovery and composition framework in the Social IoT (SIoT) domain remains a challenge. In the IoT, a large number of things are connected together according to the different objectives of their owners. Due to this extensive connection of heterogeneous objects, generating a suitable recommendation for users becomes very difficult. The complexity of this problem exponentially increases when additional issues, such as user preferences, autonomous settings, and a chaotic IoT environment, must be considered. For the aforementioned reasons, this paper presents an SIoT architecture with a personalized recommendation framework to enhance service discovery and composition. The novel contribution of this study is the development of a unique personalized recommender engine that is based on the knowledge-desire-intention model and is suitable for service discovery in a smart community. Our algorithm provides service recommendations with high satisfaction by analyzing data concerning users' beliefs and surroundings. Moreover, the algorithm eliminates the prevalent cold start problem in the early stage of recommendation generation. Several experiments and benchmarking on different datasets are conducted to investigate the performance of the proposed personalized recommender engine. The experimental precision and recall results indicate that the proposed approach can achieve up to an approximately 28% higher F-score than conventional approaches. In general, the proposed hybrid approach outperforms other methods.
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http://dx.doi.org/10.3390/s20072098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181154PMC
April 2020

Gaze Tracking and Point Estimation Using Low-Cost Head-Mounted Devices.

Sensors (Basel) 2020 Mar 30;20(7). Epub 2020 Mar 30.

Department of Computer Science and Information Engineering, National Taipei University of Technology, Taipei 10608, Taiwan.

In this study, a head-mounted device was developed to track the gaze of the eyes and estimate the gaze point on the user's visual plane. To provide a cost-effective vision tracking solution, this head-mounted device is combined with a sized endoscope camera, infrared light, and mobile phone; the devices are also implemented via 3D printing to reduce costs. Based on the proposed image pre-processing techniques, the system can efficiently extract and estimate the pupil ellipse from the camera module. A 3D eye model was also developed to effectively locate eye gaze points from extracted eye images. In the experimental results, average accuracy, precision, and recall rates of the proposed system can achieve an average of over 97%, which can demonstrate the efficiency of the proposed system. This study can be widely used in the Internet of Things, virtual reality, assistive devices, and human-computer interaction applications.
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http://dx.doi.org/10.3390/s20071917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181118PMC
March 2020

The roles of first phase, second phase insulin secretion, insulin resistance, and glucose effectiveness of having prediabetes in nonobese old Chinese women.

Medicine (Baltimore) 2020 Mar;99(12):e19562

Division of Endocrinology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University; Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University.

It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes.Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models.The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (-0.003 × GE - 212.6 × SPIS - 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635).Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.
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http://dx.doi.org/10.1097/MD.0000000000019562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220224PMC
March 2020

MicroRNA-mRNA networks define translatable molecular outcome phenotypes in osteosarcoma.

Sci Rep 2020 03 10;10(1):4409. Epub 2020 Mar 10.

Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

There is a lack of well validated prognostic biomarkers in osteosarcoma, a rare, recalcitrant disease for which treatment standards have not changed in over 20 years. We performed microRNA sequencing in 74 frozen osteosarcoma biopsy samples, constituting the largest single center translationally analyzed osteosarcoma cohort to date, and we separately analyzed a multi-omic dataset from a large NCI supported national cooperative group cohort. We validated the prognostic value of candidate microRNA signatures and contextualized them in relevant transcriptomic and epigenomic networks. Our results reveal the existence of molecularly defined phenotypes associated with outcome independent of clinicopathologic features. Through machine learning based integrative pharmacogenomic analysis, the microRNA biomarkers identify novel therapeutics for stratified application in osteosarcoma. The previously unrecognized osteosarcoma subtypes with distinct clinical courses and response to therapy could be translatable for discerning patients appropriate for more intensified, less intensified, or alternate therapeutic regimens.
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http://dx.doi.org/10.1038/s41598-020-61236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064533PMC
March 2020

Study of Postural Stability Features by Using Kinect Depth Sensors to Assess Body Joint Coordination Patterns.

Sensors (Basel) 2020 Feb 27;20(5). Epub 2020 Feb 27.

Department of Computer Science and Information Engineering, National Taipei University of Technology, Taipei 10608, Taiwan.

A stable posture requires the coordination of multiple joints of the body. This coordination of the multiple joints of the human body to maintain a stable posture is a subject of research. The number of degrees of freedom (DOFs) of the human motor system is considerably larger than the DOFs required for posture balance. The manner of managing this redundancy by the central nervous system remains unclear. To understand this phenomenon, in this study, three local inter-joint coordination pattern (IJCP) features were introduced to characterize the strength, changing velocity, and complexity of the inter-joint couplings by computing the correlation coefficients between joint velocity signal pairs. In addition, for quantifying the complexity of IJCPs from a global perspective, another set of IJCP features was introduced by performing principal component analysis on all joint velocity signals. A Microsoft Kinect depth sensor was used to acquire the motion of 15 joints of the body. The efficacy of the proposed features was tested using the captured motions of two age groups (18-24 and 65-73 years) when standing still. With regard to the redundant DOFs of the joints of the body, the experimental results suggested that an inter-joint coordination strategy intermediate to that of the two extreme coordination modes of total joint dependence and independence is used by the body. In addition, comparative statistical results of the proposed features proved that aging increases the coupling strength, decreases the changing velocity, and reduces the complexity of the IJCPs. These results also suggested that with aging, the balance strategy tends to be more joint dependent. Because of the simplicity of the proposed features and the affordability of the easy-to-use Kinect depth sensor, such an assembly can be used to collect large amounts of data to explore the potential of the proposed features in assessing the performance of the human balance control system.
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http://dx.doi.org/10.3390/s20051291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085587PMC
February 2020

The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research.

Nat Med 2020 02 10;26(2):181-187. Epub 2020 Feb 10.

Count Me In, Cambridge, MA, USA.

Despite rare cancers accounting for 25% of adult tumors, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.
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http://dx.doi.org/10.1038/s41591-019-0749-zDOI Listing
February 2020

Correction: Patterned liquid metal contacts for high density, stick-and-peel 2D material device arrays.

Nanoscale 2020 Feb;12(7):4751

Department of Physics, National Taiwan University, Taipei 10617, Taiwan.

Correction for 'Patterned liquid metal contacts for high density, stick-and-peel 2D material device arrays' by Yen-Lin Chen et al., Nanoscale, 2018, 10, 14510-14515.
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http://dx.doi.org/10.1039/d0nr90021dDOI Listing
February 2020