Publications by authors named "Y M Dennis Lo"

2,506 Publications

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USP24 promotes drug resistance during cancer therapy.

Cell Death Differ 2021 Apr 12. Epub 2021 Apr 12.

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

Drug resistance has remained an important issue in the treatment and prevention of various diseases, including cancer. Herein, we found that USP24 not only repressed DNA-damage repair (DDR) activity by decreasing Rad51 expression to cause the tumor genomic instability and cancer stemness, but also increased the levels of the ATP-binding cassette (ABC) transporters P-gp, ABCG2, and ezrin to enhance the pumping out of Taxol from cancer cells, thus resulted in drug resistance during cancer therapy. A novel USP24 inhibitor, NCI677397, was screened for specific inhibiting the catalytic activity of USP24. This inhibitor was identified to suppress drug resistance via decreasing genomic instability, cancer stemness, and the pumping out of drugs from cancer cells. Understanding the role and molecular mechanisms of USP24 in drug resistance will be beneficial for the future development of a novel USP24 inhibitor. Our studies provide a new insight of USP24 inhibitor for clinically implication of blocking drug resistance during chemotherapy.
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http://dx.doi.org/10.1038/s41418-021-00778-zDOI Listing
April 2021

The ratio and difference of urine protein-to-creatinine ratio and albumin-to-creatinine ratio facilitate risk prediction of all-cause mortality.

Sci Rep 2021 Apr 12;11(1):7851. Epub 2021 Apr 12.

Division of Nephrology, Department of Internal Medicine, China Medical University Hospital and College of Medicine, China Medical University, Taichung, Taiwan.

The role of the difference and ratio of albuminuria (urine albumin-to-creatinine ratio, uACR) and proteinuria (urine protein-to-creatinine ratio, uPCR) has not been systematically evaluated with all-cause mortality. We retrospectively analyzed 2904 patients with concurrently measured uACR and uPCR from the same urine specimen in a tertiary hospital in Taiwan. The urinary albumin-to-protein ratio (uAPR) was derived by dividing uACR by uPCR, whereas urinary non-albumin protein (uNAP) was calculated by subtracting uACR from uPCR. Conventional severity categories of uACR and uPCR were also used to establish a concordance matrix and develop a corresponding risk matrix. The median age at enrollment was 58.6 years (interquartile range 45.4-70.8). During the 12,391 person-years of follow-up, 657 deaths occurred. For each doubling increase in uPCR, uACR, and uNAP, the adjusted hazard ratios (aHRs) of all-cause mortality were 1.29 (95% confidence interval [CI] 1.24-1.35), 1.12 (1.09-1.16), and 1.41 (1.34-1.49), respectively. For each 10% increase in uAPR, it was 1.02 (95% CI 0.98-1.06). The linear dose-response association with all-cause mortality was only observed with uPCR and uNAP. The 3 × 3 risk matrices revealed that patients with severe proteinuria and normal albuminuria had the highest risk of all-cause mortality (aHR 5.25, 95% CI 1.88, 14.63). uNAP significantly improved the discriminative performance compared to that of uPCR (c statistics: 0.834 vs. 0.828, p-value = 0.032). Our study findings advocate for simultaneous measurements of uPCR and uACR in daily practice to derive uAPR and uNAP, which can provide a better mortality prognostic assessment.
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http://dx.doi.org/10.1038/s41598-021-86541-3DOI Listing
April 2021

Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies.

Science 2021 04;372(6538)

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

Liquid biopsies that analyze cell-free DNA in blood plasma are used for noninvasive prenatal testing, oncology, and monitoring of organ transplant recipients. DNA molecules are released into the plasma from various bodily tissues. Physical and molecular features of cell-free DNA fragments and their distribution over the genome bear information about their tissues of origin. Moreover, patterns of DNA methylation of these molecules reflect those of their tissue sources. The nucleosomal organization and nuclease content of the tissue of origin affect the fragmentation profile of plasma DNA molecules, such as fragment size and end motifs. Besides double-stranded linear fragments, other topological forms of cell-free DNA also exist-namely circular and single-stranded molecules. Enhanced by these features, liquid biopsies hold promise for the noninvasive detection of tissue-specific pathologies with a range of clinical applications.
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http://dx.doi.org/10.1126/science.aaw3616DOI Listing
April 2021

Association of Bcr-Abl Tyrosine Kinase Inhibitors With Hepatitis B Virus Reactivation Requiring Antiviral Treatment in Taiwan.

JAMA Netw Open 2021 Apr 1;4(4):e214132. Epub 2021 Apr 1.

Health Data Research Center, National Taiwan University.

Importance: The US Food and Drug Administration (FDA) highlighted the potential risk of hepatitis B reactivation that was associated with Bcr-Abl tyrosine kinase inhibitor (TKI) treatment and has required updated product labels.

Objective: To examine the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs.

Design, Setting, And Participants: This nested case-control study included patients who entered a hepatitis B carrier cohort in Taiwan after January 1, 2005. Patients who received their first antiviral agents for hepatitis B flare for more than 28 days after the cohort entry date were included as case patients. For each case, a corresponding risk set was formed that included all eligible patients in the study cohort who had the same age (within 1 year), same sex, and were at risk of developing hepatitis B flare at the case date. As many as 10 control patients were randomly selected from the risk set for each case patient. TKIs were evaluated before the hepatitis B flare for case patients and before the corresponding index date for control patients. Data were collected from the Taiwan National Health Insurance research database from January 2000 to 2015. Data analysis was conducted from January to June 2019.

Exposure: Use of Bcr-AbL TKIs.

Main Outcomes And Measures: Conditional logistic regression was used to estimate the rate ratio for the association between hepatitis B flare and exposure to Bcr-Abl TKIs compared with non-Bcr-Abl TKIs.

Results: Among 698 342 patients who carried incident hepatitis B virus, 66 702 patients with hepatitis B flare that required antiviral treatment (47 492 [71.2%] men; mean [SD] age at index date, 50.2 [13.8] years) were included as case patients, and 666 989 age and sex-matched patients (474 903 [71.2%] men; mean [SD] age, 50.2 [13.8] years) were included as control patients. Analysis revealed that Bcr-Abl TKI use during the previous 90 days was independently associated with a 56% higher risk of hepatitis B flare (adjusted rate ratio [aRR], 1.56; 95% CI, 1.11-2.20), and the aRR increased to 1.66 (95% CI, 1.20-2.28) for Bcr-Abl TKI use during the previous 365 days. Use of Bcr-AbL TKIs during the previous 60 days was associated with a significantly increased risk of flare among women (aRR, 3.20; 95% CI, 1.70-6.03) but not among men (aRR, 1.14; 95% CI, 0.72-1.81).

Conclusions And Relevance: These findings suggest that sex-specific strategies may be needed to monitor for hepatitis B reactivation among patients receiving Bcr-Abl TKIs.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.4132DOI Listing
April 2021

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Qualitative IgG Assays: The Value of Numeric Reporting.

Arch Pathol Lab Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Pathology (Forest, Orner, Goldstein, Campbell, Cadoff, Weiss, Fox, Prystowsky, Wolgast), Department of Microbiology and Immunology (Wirchnianski, Bortz III, Laudermilch, Florez, Chandran), Department of Biochemistry (Malonis, Georgiev, Vergnolle, Lai), and the Department of Epidemiology and Population Medicine (Lo), at Albert Einstein College of Medicine, Bronx, NY; Department of Chemistry and Life Sciences, United States Military Academy, West Point, NY (Florez, Barnhill); Department of Radiology, Uniformed Services University of Health Science, Bethesda, MD (Barnhill).

Context: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG testing is used for serosurveillance and will be important to evaluate vaccination status. Given the urgency to release coronavirus disease 2019 (COVID-19) serology tests, most manufacturers have developed qualitative tests.

Objective: To evaluate clinical performance of six different SARS-CoV-2 IgG assays and their quantitative results to better elucidate the clinical role of serology testing in COVID-19.

Design: Six SARS-CoV-2 IgG assays were tested using remnant specimens from 190 patients. Sensitivity and specificity were evaluated for each assay with the current manufacturer's cutoff and a lower cutoff. A numeric result analysis and discrepancy analysis were performed Results: The specificity was >93% for all assays, and sensitivity was >80% for all assays (≥ 7 days post-polymerase chain reaction [PCR] testing). Inpatients with more severe disease had higher numeric values compared to health care workers with mild or moderate disease. Several discrepant serology results were those just below the manufacturers cutoff.

Conclusions: SARS-CoV-2 IgG antibody testing can aid in the diagnosis of COVID-19 especially with negative PCR. Quantitative COVID-19 IgG results are important to better understand the immunological response and disease course of this novel virus and to assess immunity as part of future vaccination programs.
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http://dx.doi.org/10.5858/arpa.2020-0851-SADOI Listing
April 2021

Cytokine Signature of Dengue Patients at Different Severity of the Disease.

Int J Mol Sci 2021 Mar 12;22(6). Epub 2021 Mar 12.

Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan.

Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.
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http://dx.doi.org/10.3390/ijms22062879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999441PMC
March 2021

Triptolide prevents lipopolysaccharide-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway.

Br J Pharmacol 2021 Mar 31. Epub 2021 Mar 31.

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

Background And Purpose: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy.

Experimental Approach: The effects of triptolide on skeletal muscle atrophy were investigated in lipopolysaccharide (LPS)-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analyzed by western blot and qPCR respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength respectively. Locomotor activity was measured by the open field testing.

Key Results: Triptolide (10-100 fM) upregulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and downregulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml )-treated C2C12 myotubes, triptolide upregulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3), and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β, and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mg·kg , i.p.)-challenged mice, triptolide (5 and 20 μg·kg ·day , i.p.) decreased plasma TNF-α levels, and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion.

Conclusions And Implications: These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.
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http://dx.doi.org/10.1111/bph.15472DOI Listing
March 2021

Amyloid related cerebral microbleed and plasma Aβ40 are associated with cognitive decline in Parkinson's disease.

Sci Rep 2021 Mar 29;11(1):7115. Epub 2021 Mar 29.

Department of Neurology, National Taiwan University Hospital, Taipei, 100, Taiwan.

Cerebral microbleeds (MBs) have been found in patients with cognitive decline. We aimed to examine whether MBs are associated with motor or cognitive decline in patients with Parkinson's disease (PD). We enrolled 135 PD patients and 34 healthy controls. All participants underwent brain MRI and plasma biomarker assays, including tau, Aβ42, Aβ40, and α-synuclein. PD with dementia (PDD) was operationally defined as Mini-Mental State Examination (MMSE) score < 26 and advanced motor stage was defined as Hoehn-Yahr stage ≥ 3 during "on" status. The association between MBs and disease severity was examined using multivariate logistic regression models. More lobar MBs were observed in PD patients than controls (20.7% vs. 3.3%, p = 0.031). PDD patients had more lobar MBs (33.3% vs. 15.6%, p = 0.034), more white matter hyperintensity (p = 0.021) and reduced hippocampal volume (p = 0.001) than PD with normal cognition. The presence of lobar MB (odds ratio = 2.83 [95% confidence interval 1.04-7.70], p = 0.042) and severe white matter hyperintensity (3.29 [1.21-8.96], p = 0.020) was independently associated with PDD after adjusting for vascular risk factors and other confounders. Furthermore, plasma Aβ40 levels were associated the MMSE score (p = 0.004) after adjusting for age and sex. Our findings demonstrated that lobar MBs, reduced hippocampal volume, and elevated plasma Aβ40 levels are associated with PDD.
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http://dx.doi.org/10.1038/s41598-021-86617-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007804PMC
March 2021

Recurrent ipsilateral hemiparesis in a patient with both uncrossed corticospinal tracts and reorganization of cortical motor areas - An opportune visitation of the motor tracts.

J Clin Neurosci 2021 Apr 4;86:139-144. Epub 2021 Feb 4.

Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore.

We report the case of a patient who experienced recurrent ipsilateral hemiparesis in the setting of predominantly-uncrossed corticospinal tracts, with concomitant neuronal reorganization of the cortical motor maps, and the presence of aberrant interhemispheric connections. Their presence was supported by our results from diffusion tensor imaging tractography, functional magnetic resonance imaging, and transcranial magnetic stimulation. To our knowledge, this has never been reported before, and provides valuable insights into the mechanisms behind post-stroke motor recovery.
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http://dx.doi.org/10.1016/j.jocn.2021.01.022DOI Listing
April 2021

4D spatiotemporal modulation of biomolecules distribution in anisotropic corrugated microwrinkles via electrically manipulated microcapsules within hierarchical hydrogel for spinal cord regeneration.

Biomaterials 2021 Apr 20;271:120762. Epub 2021 Mar 20.

Department of Materials Science and Engineering, National Chiao Tung University, No. 1001 Ta-Hsueh Rd., Hsinchu, 300, Taiwan, ROC; Department of Materials Science and Engineering, National Yang Ming Chiao Tung University, No. 1001 Ta-Hsueh Rd., Hsinchu, 300, Taiwan, ROC; Frontier Research Centre on Fundamental and Applied Sciences of Matters, National Tsing Hua University, No. 101-1, Sec. 2, Guangfu Rd., Hsinchu, 300, Taiwan, ROC; School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Rd., Kaohsiung, 807, Taiwan, ROC; Graduate Institute of Biomedical Science, China Medical University, No. 100, Sec. 1, Jingmao Rd., Taichung, 406, Taiwan, ROC. Electronic address:

Although traditional 3D scaffolds or biomimetic hydrogels have been used for tissue engineering and regenerative medicine, soft tissue microenvironment usually has a highly anisotropic structure and a dynamically controllable deformation with various biomolecule distribution. In this study, we developed a hierarchical hybrid gelatin methacrylate-microcapsule hydrogel (HGMH) with Neurotrophin-3(NT-3)-loaded PLGA microcapsules to fabricate anisotropic structure with patterned NT-3 distribution (demonstrated as striped and triangular patterns) by dielectrophoresis (DEP). The HGMH provides a dynamic biomimetic sinuate-microwrinkles change with NT-3 spatial gradient and 2-stage time-dependent distribution, which was further simulated using a 3D finite element model. As demonstrated, in comparison with striped-patterned hydrogel, the triangular-patterned HGMH with highly anisotropic array of microcapsules exhibits remarkably spatial NT-3 gradient distributions that can not only guide neural stem cells (NSCs) migration but also facilitate spinal cord injury regeneration. This approach to construct hierarchical 4D hydrogel system via an electromicrofluidic platform demonstrates the potential for building various biomimetic soft scaffolds in vitro tailed to real soft tissues.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120762DOI Listing
April 2021

Factors affecting locoregional recurrence in breast cancer patients undergoing surgery following neoadjuvant treatment.

BMC Surg 2021 Mar 23;21(1):160. Epub 2021 Mar 23.

Department of General Surgery, Chang Gung Memorial Hospital, Linkou, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 333, Taiwan.

Background: Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). Locoregional recurrence (LRR) rate is still high after NAC. The aim of this study was to determine predictive factors for LRR in breast cancer patients in association with the operation types after NAC.

Methods: Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence.

Results: The median follow-up time was 59.2 months (range 3.13-186.75 months). The mean initial tumor size was 4.89 cm (SD ± 2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41.3% and 58.7%, respectively. One hundred four patients developed LRR (9.9%). Comparing between patients who underwent BCS and those who underwent mastectomy revealed no significant difference in the overall LRR rate of the two groups, 8.8% in BCS group vs 10.7% in mastectomy group (p = 0.303). Multivariate analysis indicated that independent factors for the prediction of LRR included clinical N2 status, negative estrogen receptor (ER), and failure to achieve pCR. In subgroups of multivariate analysis, only negative ER was the independent factor to predict LRR in mastectomy group (p = 0.025) and hormone receptor negative/human epidermal growth factor receptor 2 positive (HR-/HER2 +) subtype (p = 0.006) was an independent factor to predict LRR in BCS patients. Further investigation according to the molecular subtype showed that following BCS, non-pCR group had significantly increased LRR compared with the pCR group, in HR-/HER2 + subtype (25.0% vs 8.3%, p = 0.037), and HR-/HER2- subtype (20.4% vs 0%, p = 0.002).

Conclusion: Clinical N2 status, negative ER, and failure to achieve pCR after NAC were independently related to the risk of developing LRR. Operation type did not impact on the LRR. In addition, the LRR rate was higher in non-pCR hormone receptor-negative patients undergoing BCS comparing with pCR patients.
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http://dx.doi.org/10.1186/s12893-021-01158-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988904PMC
March 2021

Species delimitation and taxonomic revision of Oxyopes (Araneae: Oxyopidae) of Taiwan, with description of two new species.

Zootaxa 2021 Feb 11;4927(1):zootaxa.4927.1.4. Epub 2021 Feb 11.

Department of Life Science, National Taiwan Normal University, No. 88, Sec. 4, Tingzhou Rd., Taipei 11677, Taiwan Zoology Division, Taiwan Endemic Species Research Institute, No. 1, Minsheng E. Rd., Jiji Township, Nantou 55244, Taiwan..

This study revised the spider genus Oxyopes Latreille, 1804 in Taiwan and delineated the species boundaries based on morphological and molecular characters. A total of seven Oxyopes spiders were recognized, including two newly described species, O. hasta sp. nov. and O. taiwanensis sp. nov. Oxyopes fujianicus Song Zhu 1993 from Yilan County, Nantou County, and Kaohsuing City, and O. striagatus Song 1999 from New Taipei City, Taichung City, Nantou County, and Kaohsiung City were recorded for the first time in Taiwan. An identification key and a distributional map of Taiwanese Oxyopes species were provided. Partial COI sequences were obtained for molecular phylogenetic and species delimitation analyses. Maximum likelihood and Bayesian phylogenies, and DNA barcoding gap analysis supported morphologically defined species. However, molecular species delimitation based on Automatic Barcode Gap Discovery (ABGD), PID (Liberal), and generalized mixed Yule coalescent (GMYC) were incongruent in species assignment. The results showed that the interspecific genetic divergence between O. sertatus and O. taiwanensis was relatively low (1.28 ± 0.43%), and the intraspecific genetic divergence of O. striagatus was relatively high (1.69 ± 0.35%). Ecological data, additional samples and genetic loci are required to further examine the level of reproductive isolation and patterns of population genetic structure in Taiwanese Oxyopes.
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http://dx.doi.org/10.11646/zootaxa.4927.1.4DOI Listing
February 2021

On a New Insular Subspecies of Chrysozephyrus mushaellus (Matsumura) (Lepidoptera: Lycaenidae) Discovered from Hainan.

Zootaxa 2021 Jan 13;4908(1):zootaxa.4908.1.7. Epub 2021 Jan 13.

Department of Life Science, National Taiwan Normal University, Taipei, Taiwan 116, R. O. C..

Chrysozephyrus mushaellus paolongkoui, ssp. nov. is described and illustrated from Hainan island of southern China. This new subspecies possesses diagnosable characters different from previously recognized subspecies of C. mushaellus in wing marking and genitalia of both sexes. It utilizes Lithocarpus litseifolius (Fagaceae) as the larval hostplant.
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http://dx.doi.org/10.11646/zootaxa.4908.1.7DOI Listing
January 2021

Type I Interferon Signaling Accelerates Liver Regeneration by Metabolic Modulation in Noninfectious Conditions.

Am J Pathol 2021 Mar 19. Epub 2021 Mar 19.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan. Electronic address:

Type I interferon (IFN-I) has a well-known function in controlling viral infections, but its contribution in hepatocyte proliferation and hepatocellular carcinoma (HCC) formation remains unclear. Mice deficient in IFN-α receptor expression in whole mice or only in hepatocytes (Ifnar and Ifnar) were used to investigate the role of IFN-I signaling in cell proliferation and cancer formation in the liver. We found that Ifnar mice were resistant to chemical-induced HCC formation in the absence of infection. Our results showed that low grade of IFN-I and interferon-stimulated gene were expressed substantially in naïve mouse liver. The low level of IFN-I activation is constantly present in mouse liver after weaning and negatively modulates forkhead box O hepatic expression. The IFN-I signaling can be partially blocked by the clearance of lipopolysaccharide. Mice lacking IFN-I signaling have lower basal proliferation activity and delayed liver regeneration processes after two-thirds partial hepatectomy. The activation of IFN-I signaling on hepatocyte controls glucose homeostasis and lipid metabolism to support proliferation potency and long-term tumorigenesis. Our results reveal a positive role of low-grade IFN-I singling to hepatocyte proliferation and HCC formation by modulating glucose homeostasis and lipid metabolism.
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http://dx.doi.org/10.1016/j.ajpath.2021.03.006DOI Listing
March 2021

Applications of genetic-epigenetic tissue mapping for plasma DNA in prenatal testing, transplantation and oncology.

Elife 2021 Mar 23;10. Epub 2021 Mar 23.

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

We developed genetic-epigenetic tissue mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung transplant recipients, we showed that, at 72 hr after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles, and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring, and cancer screening.
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http://dx.doi.org/10.7554/eLife.64356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997656PMC
March 2021

Magnolol may contribute to barrier function improvement on imiquimod-induced psoriasis-like dermatitis animal model via the downregulation of interleukin-23.

Exp Ther Med 2021 May 1;21(5):448. Epub 2021 Mar 1.

Department of Dermatology, Cathay General Hospital, Taipei 10630, Taiwan, R.O.C.

Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess T helper type-1 (Th-1) and Th-17 cell infiltration are the main histopathological features of psoriasis. Magnolol is a polyphenolic compound that exerts its biological properties through a variety of mechanisms such as the NF-κB/MAPK, Nrf2/HO-1 and PI3K/Akt pathways. Magnolol has been demonstrated to exert a number of therapeutic effects on dermatological processes, including acting as an anti-inflammation, antiproliferation and antioxidation agent. However, few studies have been published on the effect of magnolol on psoriasis. Therefore, the present study aimed to elucidate the mechanism of action of magnolol on psoriasis. BALB/c mice were treated topically with imiquimod (IMQ) to induce psoriasis-like dermatitis, and were randomly assigned to the control, vehicle control, low- and high-dose magnolol, and 0.25% desoximetasone ointment treatment groups in order to investigate skin barrier function, any changes in the levels of cytokines and for the histological assessment. High doses of magnolol were indicated to be able to improve the barrier function following IMQ-induced barrier disruption. Magnolol activated peroxisome proliferator-activated receptor-γ, and also significantly inhibited the protein expression of interleukin (IL)-23, IL-1β, IL-6, tumor necrosis factor-α and interferon-γ. However, administering a high dose of magnolol did not lead to any improvement in the clinical and pathological features of the psoriasis severity Taken together, these results demonstrated that downregulation of IL-23 may contribute to barrier function improvement in a psoriatic skin model.
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http://dx.doi.org/10.3892/etm.2021.9876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967813PMC
May 2021

Mediation effects of thyroid function in the associations between phthalate exposure and glucose metabolism in adults.

Environ Pollut 2021 Mar 8;278:116799. Epub 2021 Mar 8.

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Safety, Health and Environmental Engineering, National United University, Miaoli, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

The mediating influence of thyroid function on the association of phthalate exposure with glucose metabolism, including insulin resistance, remains unclear. We explored the mediating influence of thyroid hormone levels on the phthalate exposure-insulin resistance association. This cross-sectional study of 217 Taiwanese adults assessed insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR scores) and the levels of 11 urinary phthalate metabolites and 5 thyroid hormones. Multiple regression models were used to analyze the associations among serum thyroid hormone levels, urinary phthalate metabolite levels, and HOMA-IR scores. The mediation analysis assessed the influence of thyroid function on the phthalate exposure-HOMA-IR association. Our data indicated urinary mono-ethylhexyl phthalate (MEHP) levels was negatively associated with free thyroxine (T) (β = -0.018; 95% confidence interval [CI]: -0.031, -0.005) and positively associated with HOMA-IR scores (β = 0.051, 95% CI: 0.012, 0.090). The study also revealed urinary mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels was negatively associated with free T (β = -0.036, 95% CI: -0.056, -0.017) and HOMA-IR (β = 0.070, 95% CI: 0.013, 0.126). Free T and HOMA-IR had a negative association (β = -0.757, 95% CI: -1.122, -0.392). In the mediation analysis, free T mediated 24% and 35% of the associations of urinary MEHP and MEOHP with HOMA-IR, respectively. Our findings revealed the mediating role of thyroid function in the phthalate exposure-glucose metabolism association in adults.
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http://dx.doi.org/10.1016/j.envpol.2021.116799DOI Listing
March 2021

A Persistent Homology Approach to Heart Rate Variability Analysis With an Application to Sleep-Wake Classification.

Front Physiol 2021 1;12:637684. Epub 2021 Mar 1.

Department of Mathematics and Department of Statistical Science, Duke University, Durham, NC, United States.

Persistent homology is a recently developed theory in the field of algebraic topology to study shapes of datasets. It is an effective data analysis tool that is robust to noise and has been widely applied. We demonstrate a general pipeline to apply persistent homology to study time series, particularly the instantaneous heart rate time series for the heart rate variability (HRV) analysis. The first step is capturing the shapes of time series from two different aspects-the persistent homologies and hence persistence diagrams of its sub-level set and Taken's lag map. Second, we propose a systematic and computationally efficient approach to summarize persistence diagrams, which we coined . To demonstrate our proposed method, we apply these tools to the HRV analysis and the sleep-wake, REM-NREM (rapid eyeball movement and non rapid eyeball movement) and sleep-REM-NREM classification problems. The proposed algorithm is evaluated on three different datasets via the cross-database validation scheme. The performance of our approach is better than the state-of-the-art algorithms, and the result is consistent throughout different datasets.
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http://dx.doi.org/10.3389/fphys.2021.637684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959762PMC
March 2021

Generation of avian-derived anti-B7-H4 antibodies exerts a blockade effect on the immunosuppressive response.

Exp Anim 2021 Mar 15. Epub 2021 Mar 15.

TMU Research Center of Cancer Translational Medicine, Taipei Medical University.

For highly conserved mammalian protein, chicken is a suitable immune host to generate antibodies. Monoclonal antibodies have been successfully targeted with immunity checkpoint proteins as a means of cancer treatment; this treatment enhances tumor-specific immunity responses through immunoregulation. Studies have identified the importance of B7-H4 in immunoregulation and its use as a potential target for cancer treatment. High levels of B7-H4 expression are found in tumor tissues and are associated with adverse clinical and pathological characteristics. Using the phage display technique, this study isolated specific single-chain antibody fragments (scFvs) against B7-H4 from chickens. Our experiment proved that B7-H4 clearly induced the inhibition of T-cell activation. Therefore, use of anti-B7-H4 scFvs can effectively block the exhaustion of immunity cells and also stimulate and activate T-cells in peripheral blood mononuclear cells. Sequence analysis revealed that two isolated scFv S2 and S4 have the same VH complementarity-determining regions (CDRs) sequence. Molecule docking was employed to simulate the complex structures of scFv with B7-H4 to analyze the interaction. Our findings revealed that both scFvs employed CDR-H1 and CDR-H3 as main driving forces and had strong binding effects with the B7-H4. The affinity of scFv S2 was better because the CDR-L2 loop of the scFv S2 had three more hydrogen bond interactions with B7-H4. The results of this experiment suggest the usefulness of B7-H4 as a target for immunity checkpoints; the isolated B7-H4-specific chicken antibodies have the potential for use in future cancer immunotherapy applications.
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http://dx.doi.org/10.1538/expanim.20-0178DOI Listing
March 2021

Correlation of Coagulation Parameters With Clinical Outcomes During the Coronavirus-19 Surge in New York: Observational Cohort.

Front Physiol 2021 23;12:618929. Epub 2021 Feb 23.

Division of Hematology, Departments of Oncology and Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, New York City, NY, United States.

Importance: COVID-19 has caused a worldwide illness and New York became the epicenter of COVID-19 in the United States from Mid-March to May 2020.

Objective: To investigate the coagulopathic presentation of COVID and its natural course during the early stages of the COVID-19 surge in New York. To investigate whether hematologic and coagulation parameters can be used to assess illness severity and death.

Design: Retrospective case study of positive COVID inpatients between March 20, 2020-March 31, 2020.

Setting: Montefiore Health System main hospital, Moses, a large tertiary care center in the Bronx.

Participants: Adult inpatients with positive COVID tests hospitalized at MHS.

Exposure For Observational Studies: Datasets of participants were queried for demographic (age, sex, socioeconomic status, and self-reported race and/or ethnicity), clinical and laboratory data.

Main Outcome And Measures: Relationship and predictive value of measured parameters to mortality and illness severity.

Results: Of the 225 in this case review, 75 died during hospitalization while 150 were discharged home. Only the admission PT, absolute neutrophil count (ANC) and first D-Dimer could significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 2.1 μg/mL. 15% of discharged patients required readmission and more than a third of readmitted patients died (5% of all initially discharged).

Conclusion: We describe here a comprehensive assessment of hematologic and coagulation parameters in COVID-19 and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments. Furthermore, D-Dimer may be useful to follow up discharged patients.
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http://dx.doi.org/10.3389/fphys.2021.618929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940374PMC
February 2021

Dexmedetomidine sedation for endobronchial ultrasound-guided transbronchial needle aspiration, a randomised controlled trial.

ERJ Open Res 2020 Oct 10;6(4). Epub 2020 Nov 10.

Dept of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan.

Background And Aim: Appropriate sedation is important to the success of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Dexmedetomidine is a sedative agent that operates the α2 adrenergic agonist, which provides sleep-like sedation with little respiratory suppression. This study compared the efficacy and safety of dexmedetomidine sedation with propofol in cases of EBUS-TBNA.

Methods: Patients requiring EBUS-TBNA were randomly assigned dexmedetomidine sedation (D, n=25) or propofol sedation (P, n=25). Vital signs, diagnostic yield and the bispectral index (BIS) were recorded throughout the bronchoscopic procedure and recovery period. The tolerance and cooperation of the patients were evaluated using questionnaires.

Measurements And Results: The lowest mean arterial blood pressure in group D (79.2±9.9 72.5±12.9 mmHg, p=0.049) exceeded that in group P, the lowest heart rate was lower (60.9±10.2 71.4±11.8 beats·min, p=0.006) and the mean BIS during sedation was significantly higher (84.1±8.3 73.6±5.7, p<0.001). Patients in group D were more likely to report perceiving procedure-related symptoms and express an unwillingness to undergo the bronchoscopy again, if indicated (41.1 83.3%, p=0.007). One subject in group D aborted EBUS-TBNA due to intolerance. Many of the variables in the two groups were similar, including the proportion of hypoxaemic events, recovery times, patient cooperation and diagnostic yield.

Conclusions: The effects of dexmedetomidine on haemodynamics were in line with its pharmacodynamic features. Patients who received dexmedetomidine were more likely than those who received propofol to perceive the procedures. Overall, dexmedetomidine did not prove inferior to propofol sedation in terms of patient cooperation or diagnostic yield.
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http://dx.doi.org/10.1183/23120541.00064-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927785PMC
October 2020

Dynamic Changes of Post-Radiotherapy Plasma Epstein-Barr Virus DNA in a Randomized Trial of Adjuvant Chemotherapy Versus Observation in Nasopharyngeal Cancer.

Clin Cancer Res 2021 Mar 10. Epub 2021 Mar 10.

Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.

Purpose: To study the dynamic changes in plasma Epstein-Barr virus (pEBV) DNA after radiotherapy in nasopharyngeal cancer (NPC).

Experimental Design: We conducted a randomized controlled trial of adjuvant chemotherapy versus observation in patients with NPC who had detectable pEBV DNA at 6 weeks post-radiotherapy. Randomized patients had a second pEBV DNA checked at 6 months post-randomization. The primary endpoint was progression-free survival (PFS).

Results: We prospectively enrolled 789 patients. Baseline post-radiotherapy pEBV DNA was undetectable in 573 (72.6%) patients, and detectable in 216 (27.4%) patients, of whom 104 (13.2%) patients were eligible for randomization to adjuvant chemotherapy ( = 52) versus observation ( = 52). The first post-radiotherapy pEBV DNA had a sensitivity of 0.48, specificity of 0.81, area under receiver-operator characteristics curve (AUC) of 0.65, false positive (FP) rate of 13.8%, and false negative (FN) rate of 14.4% for disease progression. The second post-radiotherapy pEBV DNA had improved sensitivity of 0.81, specificity of 0.75, AUC of 0.78, FP rate of 14.3%, and FN rate of 8.1%. Patients with complete clearance of post-radiotherapy pEBV DNA (51%) had survival superior to that of patients without post-radiotherapy pEBV DNA clearance (5-year PFS, 85.5% vs. 23.3%; HR, 9.6; < 0.0001), comparable with patients with initially undetectable post-radiotherapy pEBV DNA (5-year PFS, 77.1%), irrespective of adjuvant chemotherapy or observation.

Conclusions: Patients with NPC with detectable post-radiotherapy pEBV DNA who experienced subsequent pEBV DNA clearance had superior survival comparable with patients with initially undetectable post-radiotherapy pEBV DNA. Post-radiotherapy pEBV DNA clearance may serve as an early surrogate endpoint for long-term survival in NPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3519DOI Listing
March 2021

Genetic Differentiation and Demographic Trajectory of the Insular Formosan and Orii's Flying Foxes.

J Hered 2021 Mar;112(2):192-203

Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Insular flying foxes are keystone species in island ecosystems due to their critical roles in plant pollination and seed dispersal. These species are vulnerable to population decline because of their small populations and low reproductive rates. The Formosan flying fox (Pteropus dasymallus formosus) is one of the 5 subspecies of the Ryukyu flying fox. Pteropus dasymallus formosus has suffered from a severe decline and is currently recognized as a critically endangered population in Taiwan. On the contrary, the Orii's flying fox (Pteropus dasymallus inopinatus) is a relatively stable population inhabiting Okinawa Island. Here, we applied a genomic approach called double digest restriction-site associated DNA sequencing to study these 2 subspecies for a total of 7 individuals. We detected significant genetic structure between the 2 populations. Despite their contrasting contemporary population sizes, both populations harbor very low degrees of genetic diversity. We further inferred their demographic history based on the joint folded site frequency spectrum and revealed that both P. d. formosus and P. d. inopinatus had maintained small population sizes for a long period of time after their divergence. Recently, these populations experienced distinct trajectories of demographic changes. While P. d. formosus suffered from a drastic ~10-fold population decline not long ago, P. d. inopinatus underwent a ~4.5-fold population expansion. Our results suggest separate conservation management for the 2 populations-population recovery is urgently needed for P. d. formosus while long-term monitoring for adverse genetic effects should be considered for P. d. inopinatus.
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http://dx.doi.org/10.1093/jhered/esab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006818PMC
March 2021

Prognostic Significance of Cytoplasmic SPNS2 Expression in Patients with Oral Squamous Cell Carcinoma.

Medicina (Kaunas) 2021 Feb 12;57(2). Epub 2021 Feb 12.

Department of Surgical Pathology, Changhua Christian Hospital, Changhua 500, Taiwan.

Oral squamous cell carcinoma (OSCC) is a malignant disease with a particularly high incidence in Taiwan. Our objective in this study was to elucidate the involvement of sphingolipid transporter 2 (SPNS2) expression and SPNS2 protein expression in the clinicopathological indexes and the clinical outcomes of OSCC patients. Immunohistochemistry analysis was performed for SPNS2 protein expression in samples from 264 cases of OSCC. Correlations of SPNS2 expression with clinicopathological variables and patient survival were analyzed. Our results revealed that the cytoplasmic protein expression of SPNS2 in OSCC tissue specimens was lower than in normal tissue specimens. Negative cytoplasmic protein expression of SPNS2 was significantly correlated with T status and stage. Kaplan-Meier survival curve analysis revealed that negative cytoplasmic SPNS2 expression was predictive of poorer overall survival of OSCC patients in stage III/IV. We also determined that low SPNS2 expression was an independent prognostic factor related to overall survival among OSCC patients in stage III/IV from univariate Cox proportional hazard models. Multivariate Cox proportional hazard models revealed that cytoplasmic SPNS2 expression, T status, lymph node metastasis, and histological grade were independent prognostic factors for survival. Overall, this study determined that SPNS2 protein may be a useful prognostic marker for OSCC patients and potential therapeutic target for OSCC treatment.
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http://dx.doi.org/10.3390/medicina57020164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917906PMC
February 2021

Long-term exposure to fine particulate matter and osteoporotic fracture: A case-control study in Taiwan.

Environ Res 2021 Mar 1;196:110888. Epub 2021 Mar 1.

Department of Occupational Safety and Health, College of Public Health, China Medical University, Taichung, Taiwan; Department of Occupational Therapy, College of Medical and Health Science, Asia University, Taichung, Taiwan. Electronic address:

Few studies have explored the relationship between long-term exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM) and osteoporotic fracture, particularly in high PM level areas. The aim of this study was to assess the association between long-term exposure to PM and osteoporotic fracture. We performed a matched case-control study of 16,175 participants obtained from a hospital registry during 2005-2014 in Taiwan. A major osteoporotic fracture was defined as a fracture of the spine, hip, proximal humerus, and forearm. We applied satellite-based spatiotemporal models with 1-km resolution to individually calculate the 1-year average PM concentration before the index date which was defined as the first visit date for the osteoporotic fracture. Logistic regression models with and without potential confounding factors were used to estimate odds ratios (OR) and 95% confidence intervals (CI) between PM and osteoporotic fracture, whereas a restricted cubic spline model was used to estimate the dose-response relationship. The sample's median age was 44.7 years (interquartile range: 30.7, 63.1 years). We observed that long-term PM exposure was associated with osteoporotic fracture, the OR was 1.12 (95% CI: 1.03, 1.22) per 10-μg/m increase in PM in women. In the dose-response association, the OR of osteoporotic fracture was significantly increased for PM exposures more than 41 μg/m. We did not find a significant association between PM (per 10-μg/m increase) and osteoporotic fracture among overall population (adjusted OR, 1.02 [95% CI, 0.97 to 1.08]) and men (adjusted OR, 0.94 [95% CI, 0.86 to 1.02]). The results of the stratified analysis showed that women were more sensitive to the adverse impact of PM2.5 that were men, and evidence was obtained of sex-based effect modification (P for interaction = 0.002). Our findings suggest that long-term exposure to PM is associated with osteoporotic fracture, particularly among women.
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http://dx.doi.org/10.1016/j.envres.2021.110888DOI Listing
March 2021

A territory-wide study on the factors associated with recurrent asthma exacerbations requiring hospitalization in Hong Kong.

Immun Inflamm Dis 2021 Mar 3. Epub 2021 Mar 3.

Department of Medicine & Therapeutics, Chinese University of Hong Kong, Hong Kong, China.

Background: The real-world relationships between the demographic and clinical characteristics of asthma patients, their prehospitalization management and the frequency of hospitalization due to asthma exacerbation is poorly established.

Objective: To determine the risk factors of recurrent asthma exacerbations requiring hospitalizations and evaluate the standard of baseline asthma care.

Methods: A territory-wide, multicentre retrospective study in Hong Kong was performed. Medical records of patients aged ≥18 years admitted to 11 acute general hospitals from January 1 to December 31, 2016 for asthma exacerbations were reviewed.

Results: There were 2280 patients with 3154 admissions (36.7% male, median age 66.0 [interquartile range: 48.0-81.0] years, 519 had ≥2 admissions). Among them, 1830 (80.3%) had at least one asthma-associated comorbidity, 1060 (46.5%) and 885 (38.9%) of patients had Accident and Emergency Department (AED) attendance and hospitalization in the preceding year, respectively. Patients with advancing age (incidence rate ratio [IRR]: 1.003 for every year increment), a history of AED visits or hospitalization (IRR: 1.018 and 1.070 for every additional episode, respectively) for asthma exacerbation in the preceding year, the presence of neuropsychiatric (IRR: 1.142) and gastrointestinal (IRR: 1.154) comorbidities were risk factors for an increasing number of admissions for asthma exacerbation. For patients with ≥2 admissions, 17.1% were not prescribed inhaled corticosteroid and only 44.6% had spirometry checked before the index admission. Asthma phenotyping was often incomplete, as assessment of atopy (total serum immunoglobulin E level and senitization to aeroallergens) was only performed in 30 (5.8%) patients with ≥2 admissions.

Conclusions And Clinical Relevance: Improving asthma care, especially in elderly patients with a prior history of urgent healthcare utilization and comorbidities, may help reduce healthcare burden. Suboptimal management before the index admission was common in patients hospitalized for asthma exacerbations. Early identification of patients at risk and enhancement of baseline asthma management may help to prevent recurrent asthma exacerbation and subsequent hospitalization.
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http://dx.doi.org/10.1002/iid3.419DOI Listing
March 2021

β-glucan therapy converts the inhibition of myeloid-derived suppressor cells in oral cancer patients.

Oral Dis 2021 Mar 3. Epub 2021 Mar 3.

School of Dentistry, National Taiwan University, Taipei, Taiwan.

Objectives: The myeloid-derived suppressor cells (MDSCs) frequently have a high expansion in cancer patients. This research explored whether administration of β-glucan could increase anti-tumor immunity in oral squamous cell carcinoma (OSCC) patients.

Materials And Methods: This study evaluated the MDSC level of circulating blood as CD33 /CD11b /HLA-DR by flow cytometry in 30 healthy donors (HDs, group I), in 48 oral squamous cell carcinoma (OSCC) patients before and after 14-day preoperative administration of β-glucan (group II), and in 52 OSCC patients without taking β-glucan (group III).

Results: A significantly higher mean MDSC level was observed in 100 OSCC patients than in 30 HDs (p < .001). There was a significant reduction of the mean MDSC level in group II patients after taking β-glucan (p < .001). Moreover, we discovered a significantly higher recurrence-free survival (RFS) in group II than in group III patients (p = .026). Finally, the multivariate Cox regression further identified the MDSC level ≤1% and administration of β-glucan as more favorable prognostic factors for OSCC patients.

Conclusion: Preoperative administration of β-glucan can augment anti-tumor immunity and increase RFS rate via subversion of suppressive function of MDSC in OSCC patients.
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http://dx.doi.org/10.1111/odi.13827DOI Listing
March 2021

Characteristics of Fetal Extrachromosomal Circular DNA in Maternal Plasma: Methylation Status and Clearance.

Clin Chem 2021 Feb 22. Epub 2021 Feb 22.

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

Background: Although the characterization of cell-free extrachromosomal circular DNA (eccDNA) has gained much research interest, the methylation status of these molecules is yet to be elucidated. We set out to compare the methylation densities of plasma eccDNA of maternal and fetal origins, and between small and large molecules. The clearance of fetal eccDNA from maternal circulation was also investigated.

Methods: We developed a sequencing protocol for eccDNA methylation analysis using tagmentation and enzymatic conversion approaches. A restriction enzyme-based approach was applied to verify the tagmentation results. The efficiency of cell-free fetal eccDNA clearance was investigated by fetal eccDNA fraction evaluations at various postpartum time points.

Results: The methylation densities of fetal eccDNA (median: 56.3%; range: 40.5-67.6%) were lower than the maternal eccDNA (median: 66.7%; range: 56.5-75.7%) (P = 0.02, paired t-test). In addition, eccDNA molecules from the smaller peak cluster (180-230 bp) were of lower methylation levels than those from the larger peak cluster (300-450 bp). Both of these findings were confirmed using the restriction enzyme approach. We also observed comparable methylation densities between linear and eccDNA of both maternal and fetal origins. The average half-lives of fetal linear and eccDNA in the maternal blood were 30.2 and 29.7 min, respectively.

Conclusions: We found that fetal eccDNA in plasma was relatively hypomethylated compared to the maternal eccDNA. The methylation densities of eccDNA were positively correlated with their sizes. In addition, fetal eccDNA was found to be rapidly cleared from the maternal blood after delivery, similar to fetal linear DNA.
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http://dx.doi.org/10.1093/clinchem/hvaa326DOI Listing
February 2021

Use of calcium channel blockers in dermatology: a narrative review.

Expert Rev Clin Pharmacol 2021 Feb 26:1-9. Epub 2021 Feb 26.

Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

: Calcium channel blockers (CCB) are commonly used for cardiovascular diseases. The evidence supporting the use of CCB in dermatology is mostly anecdotal and limited to case reports or small case series.: This review article is divided into two parts. The first part discusses the therapeutic use of CCB in dermatology. The second part focuses on mucocutaneous adverse reactions due to the administration of CCB.: The use of CCB in dermatology is mainly based on its properties as a vasodilator and the inhibition of muscle contractions, such as pernio, anal fissures, facial wrinkles, and painful leiomyoma. However, there remain other modes of action to explain its clinical use in calcinosis, keloid, pressure ulcer, and fibromatosis. Compared to oral CCB, the lack of systemic side effects would make topical use of CCB an attractive alternative in the treatment of skin diseases, but the evidence for topical CCB is still limited, and there is a lack of standardized topical formulation. The main mucocutaneous adverse effects of CCB include gingival hyperplasia, phototoxicity, eczema, psoriasis and risk of skin cancers. Plausible factors for these adverse events include CCB's photoinstability, aldosterone synthesis inhibition, disturbed calcium homeostasis and immunosuppressive properties.
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http://dx.doi.org/10.1080/17512433.2021.1894128DOI Listing
February 2021

Disentangling the complex bidirectional associations between COVID-19 and psychiatric disorder.

Lancet Psychiatry 2021 03;8(3):179

Department of Psychiatry, Beitou Branch, National Defense Medical Center, Taipei 112, Taiwan; Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(20)30565-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906693PMC
March 2021