Publications by authors named "Kuan-Yu Chen"

189 Publications

Using High-Frequency Information and RH to Estimate AQI Based on SVR.

Sensors (Basel) 2021 May 23;21(11). Epub 2021 May 23.

Department of Information and Communication Engineering, Chaoyang University of Technology, 168, Jifeng E. Rd., Wufeng District, Taichung 413310, Taiwan.

The Environmental Protection Administration of Taiwan's Executive Yuan has set up many air quality monitoring stations to monitor air pollution in the environment. The current weather forecast also includes information used to predict air pollution. Since air quality indicators have a considerable impact on people, the development of a simple, fast, and low-cost method to measure the AQI value is a worthy topic of research. In this study, a method was proposed to estimate AQI. Visibility had a clear positive relationship with AQI. When images and AQI were compared, it was easy to see that visibility decreased with the AQI value increase. Distance is the main factor affecting visibility, so measuring visibility with images has also become a research topic. Images with high and low PM concentrations were used to obtain regions of interest (RoI). The pixels in the RoI were calculated to obtain high-frequency information. The high-frequency information of RoI, RH, and true AQI was used for training via SVR, which was used to generate the model for AQI estimation. One year of experimental samples was collected for the experiment. Two indices were used to evaluate the performance of the proposed method. The results showed that the proposed method could be used to estimate AQI with acceptable performance in a simple, fast, and low-cost way.
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http://dx.doi.org/10.3390/s21113630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197084PMC
May 2021

Mixed-stock analysis using Rapture genotyping to evaluate stock-specific exploitation of a walleye population despite weak genetic structure.

Evol Appl 2021 May 30;14(5):1403-1420. Epub 2021 Mar 30.

Aquatic Ecology Laboratory, Department of Evolution, Ecology, and Organismal Biology The Ohio State University Columbus OH USA.

Mixed-stock analyses using genetic markers have informed fisheries management in cases where strong genetic differentiation occurs among local spawning populations, yet many fisheries are supported by multiple, weakly differentiated stocks. Freshwater fisheries exemplify this problem, with many populations supported by multiple stocks of young evolutionary age and isolated across small spatial scales. Consequently, attempts to conduct genetic mixed-stock analyses of inland fisheries have often been unsuccessful. Advances in genomic sequencing offer the ability to discriminate among populations with weak population structure, providing the necessary resolution to conduct mixed-stock assignment among previously indistinguishable stocks. We used genomic data to conduct a mixed-stock analysis of eastern Lake Erie's commercial and recreational walleye () fisheries and estimate the relative harvest of weakly differentiated stocks (pairwise  < 0.01). Using RAD-capture (Rapture), we sequenced and genotyped individuals from western and eastern basin local spawning stocks at 12,081 loci with 95% reassignment accuracy, which was not possible in the past using microsatellite markers. A baseline assessment of 395 walleye from 11 spawning stocks identified three reporting groups and refined previous assessments of gene flow among walleye stocks. Genetic assignment of 1,075 walleye harvested in eastern Lake Erie's recreational and commercial fisheries indicated that western basin stocks constituted the majority of harvest during the peak walleye fishing season (July-September), whereas eastern basin individuals comprised much of the early season harvest (May-June). Clear spatial structure in harvest composition existed; catches in more easterly sites contained more individuals of eastern basin origin than did more westerly sites. Our study provides important stock contribution estimates for Lake Erie fishery management and demonstrates the utility of genomic data to facilitate mixed-stock analysis in exploited fish populations having weak population structure or limited existing genetic resources.
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http://dx.doi.org/10.1111/eva.13209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127713PMC
May 2021

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1 and Excess Foetal Growth.

J Clin Endocrinol Metab 2021 May 22. Epub 2021 May 22.

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

Background: Maternal lipids during pregnancy and placental growth factors are associated with excess foetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglyceride (TG) and free fatty acids (FAs) during pregnancy, cord blood insulin-like growth factors (IGF) and LGA. In a cell model, we studied the effect of different FAs on placental IGF-1 secretion.

Methods: This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TG and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2 and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FAs on placental IGF-1 secretion.

Results: We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 (152.5-185.5) vs. 166 (133-206) mg/dL, p=0.04) and cord blood IGF-1 concentrations (72.7 ± 23.0 vs. 54.1 ± 22.8 ng/mL, p=0.0001) were higher in the LGA group and were significantly associated with birth weight z-score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion.

Conclusions: Certain FAs can induce placental IGF-1 secretion, which suggest a potential pathophysiology linking maternal plasma lipids and LGA.
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http://dx.doi.org/10.1210/clinem/dgab364DOI Listing
May 2021

Monitoring levels of vimentin-positive circulating cancer stem cells and tumor cells in patients with advanced EGFR-mutated non-small cell lung cancer.

Lung Cancer 2021 06 18;156:50-58. Epub 2021 Apr 18.

Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taiwan.

Objectives: Circulating tumor cells (CTCs) are associated with tumor spread, whereas cancer stem cells may be related to drug resistance. However, few studies have analyzed the levels of circulating cancer stem cells (CCSCs) and CTCs in patients with advanced non-small cell lung cancer (NSCLC).

Materials And Methods: Treatment-naïve patients with EGFR-mutated NSCLC who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy were recruited prospectively. The cell surface vimentin antibody was used for CTC detection and CD133 antibody for CCSC detection. CCSC and CTC levels were measured as cell count per 4 mL of blood, before treatment, after 2 and 12 weeks of treatment, and at disease progression. Data on clinical characteristics and outcomes were also collected.

Results: At diagnosis (n = 29), the median CCSC and CTC levels were 0 (interquartile range, 0-2) and 3 (2-9), respectively. After 12 weeks, the CCSC and CTC levels were lower than those at diagnosis (CCSC: 0 (0-0), p = 0.14; CTC: 1 (0-4), p = 0.048). At disease progression, the median CCSC and CTC levels were 0 (0-1) and 1 (0-2), respectively. Patients with higher CCSC and CTC levels at diagnosis had a numerically shorter progression-free survival.

Conclusion: In patients with EGFR-mutated NSCLC, CCSC and CTC levels became lower after 12 weeks of EGFR-TKI therapy and remained low at disease progression. High pre-treatment CCSC and CTC levels may be associated with a trend towards poor treatment outcomes.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.014DOI Listing
June 2021

Changing epidemiology and viral interplay of hepatitis B, C and D among injecting drug user-dominant prisoners in Taiwan.

Sci Rep 2021 Apr 20;11(1):8554. Epub 2021 Apr 20.

Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.

The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10-0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13-0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04-40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.
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http://dx.doi.org/10.1038/s41598-021-87975-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058093PMC
April 2021

Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues.

Sci Rep 2021 Apr 14;11(1):8184. Epub 2021 Apr 14.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan.

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11-19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35-24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03-6.54, P < 0.001), male gender (HR/CI 2.69/1.29-5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03-1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04-19.09, P = 0.04) and BMI (HR/CI 1.11/1.03-1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.
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http://dx.doi.org/10.1038/s41598-021-87679-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047028PMC
April 2021

Ultrarapid Endoscopic-Aided Hematoma Evacuation in Patients with Thalamic Hemorrhage.

Behav Neurol 2021 19;2021:8886004. Epub 2021 Jan 19.

Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Thalamic hemorrhage bears the worst outcome among supratentorial intracerebral hemorrhage (ICH). Minimally invasive endoscopic-aided surgery (MIS) has been proved to be safe and effective in evacuating ICH. However, the ideal timing of MIS is still a controversy. In this study, we present our experience in the treatment of patients with thalamic hemorrhage by ultrarapid MIS evacuation. This retrospective analysis enrolled seven patients treated with ultrarapid MIS evacuation of thalamic hemorrhage. Seven patients treated with EVD with similar ICH score were included as match control. Primary endpoints included rebleeding, morbidity, and mortality. Hematoma evacuation rate was evaluated by comparing the pre- and postoperative computed tomography (CT) scans. Glasgow Outcome Scale Extended (GOSE) and modified Rankin Score (mRS) were noted at the 6-month and 1-year postoperative follow-up. Among the seven patients, six were accompanied with intraventricular hemorrhage. All patients received surgery within 6 hours after the onset of stroke. The mean hematoma volume was 35 mL, and the mean operative time was 116.4 minutes. The median hematoma evacuation rate was 74.9%. There was no rebleeding or death reported after the surgery. The median GOSE and mRS were 3 and 5, respectively, at 6 months postoperatively. Further, 1-year postoperative median GOSE and mRS were 3 and 5, respectively. The data suggest that the ultrarapid MIS technique is a safe and effective way in the management of selected cases with thalamic hemorrhage, with favorable long-term functional outcomes. However, a large, prospective, randomized-controlled trial is needed to confirm these findings.
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http://dx.doi.org/10.1155/2021/8886004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843189PMC
January 2021

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

Environ Int 2021 02 29;147:105975. Epub 2020 Dec 29.

Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
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http://dx.doi.org/10.1016/j.envint.2020.105975DOI Listing
February 2021

Enhanced Piezoelectric Properties of Poly(Vinylidenefluoride-Co-Trifluoroethylene)/Carbon-Based Nanomaterial Composite Films for Pressure Sensing Applications.

Polymers (Basel) 2020 Dec 16;12(12). Epub 2020 Dec 16.

Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei 10607, Taiwan.

In this study, heat and polarization treatments were applied to poly(vinylidenefluoride-co-trifluoroethylene (PVDF-TrFE) films to improve their crystallinity and piezoelectric effect. Carbon-based nanomaterials (CBNs) of multiple dimensions (i.e., modified zero-dimensional (0D) carbon black (OCB), one-dimensional (1D) modified carbon nanotubes (CNT-COOH) and two-dimensional (2D) graphene oxide (GO)) were added to the copolymer to study the effects of different CBN dimensions on the crystallinity and piezoelectric effect of PVDF-TrFE films. Additionally, amphiphilic polymeric dispersants were added to improve the dispersibility of CBNs; the dispersant was synthesized by the amidation, and imidization reactions of styrene-maleic anhydride copolymer (SMAz) and polyoxyalkylene amine (M1000). Polymer solutions with different ratios of CBN to dispersant (z = 10:1, 5:1, 1:1, 1:5, 1:10) were prepared. The enhanced dispersibility enabled the fluorine atoms in the PVDF-TrFE molecular chain to more efficiently form hydrogen bonds with the -COOH group in the CBN, thereby increasing the content of the β crystal phase (the origin of the piezoelectric effect) of the film. Therefore, the resulting film exhibited a higher output voltage on the application side and better sensitivity on the sensing element. The addition of CNT-COOH and polymeric dispersants increased the β-phase content in PVDF-TrFE from 73.6% to 86.4%, which in turn raised the piezoelectric coefficient from 19.8 ± 1.0 to 26.4 ± 1.3 pC/N. The composite film-based pressure sensor also exhibited a high degree of sensitivity, which is expected to have commercial potential in the future.
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http://dx.doi.org/10.3390/polym12122999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765614PMC
December 2020

Directed self-propulsion of droplets on surfaces absent of gradients for cargo transport.

J Colloid Interface Sci 2021 Mar 4;586:469-478. Epub 2020 Nov 4.

Department of Chemical and Materials Engineering, National Central University, Jhongli 320, Taiwan, ROC; Department of Physics, National Central University, Jhongli 320, Taiwan, ROC. Electronic address:

Hypothesis: Manipulating droplet transportation without inputting work is desired and important in microfluidic systems. Although the creation of wettability gradient on surfaces has been employed to achieve this goal, the transport distance is very limited, hindering its applications in long-term operations.

Experiments: Here, we show that programming long-ranged transport of droplets on surfaces can be achieved by the addition of trisiloxane surfactants and the creation of deep grooves. The former provides Marangoni stress to actuate the droplet motion and also reduces the inherent contact line pinning. The latter acts as a railing to guide the motion of surfactant-laden droplets to follow various layouts with geometric features of roads.

Findings: It is found that the droplets with microliters can move over 20 cm. This work-free method is applicable to a variety of substrate materials and liquids. By using self-running shuttles, a convenient platform for liquid cargos transport is developed and demonstrated. Moreover, the coalescence of cargos carried by different shuttles is accomplished in a three-branch layout, revealing new droplet microreactors.
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http://dx.doi.org/10.1016/j.jcis.2020.10.110DOI Listing
March 2021

Role of hepatitis D virus in persistent alanine aminotransferase abnormality among chronic hepatitis B patients treated with nucleotide/nucleoside analogues.

J Formos Med Assoc 2021 Jan 24;120(1 Pt 2):303-310. Epub 2020 Oct 24.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Center for Intelligent Drug Systems and Smart Bio-devices (IDS(2)B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan; Center for Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: The biochemical response is a crucial indicator of prognosis in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs). The impact of hepatitis D virus (HDV) infection on alanine aminotransferase normalization is elusive.

Methods: The longitudinal study recruited 1185 CHB patients who received NAs. These patients were tested for anti-HDV antibody and HDV RNA at the initiation of anti-hepatitis B virus (HBV) therapy and annually for patients who were HDV-seropositive. ALT levels were examined at the first and second year of anti-HBV therapy. ALT abnormality was defined as ALT levels above 40 IU/mL in both male and female, and the risk factors associated with ALT abnormality were analysed.

Results: Rates of seropositivity for anti-HDV and HDV RNA were 2.0% and 0.8% among 1185 NA-treated CHB patients, respectively. The strongest factor associated with ALT abnormality (>40 IU/mL) after first year treatment with NAs was HDV RNA seropositivity at year 1 (odds ratio [OR]/95% confidence interval [CI]: 31.44/3.49-283.56, P = 0.002), followed by liver cirrhosis (2.18/1.51-3.15, P < 0.001), detectable HBV DNA at year 1 (OR/CI: 1.99/1.36-2.92, P < 0.001), diabetes (OR/CI: 1.75/1.10-2.78, P = 0.02), body mass index (BMI) (OR/CI: 1.13/1.09-1.18, P < 0.001) and age (OR/CI: 0.97/0.96-0.98, P < 0.001). Among patients who were seronegative for HBV DNA at year 1, the strongest factor associated with ALT abnormality was HDV RNA seropositivity at year 1 (OR/CI: 30.00/3.28-274.05, P = 0.003), followed by liver cirrhosis (OR/CI: 1.83/1.21-2.75, P = 0.004), BMI (OR/CI: 1.16/1.11-1.21, P < 0.001) and age (OR/CI: 0.97/0.96-0.99, P < 0.001). Similarly, the impact of HDV RNA seropositivity on ALT abnormality was noted in patients without detectable HBV DNA but not in those with hepatitis B viremia at treatment year 2 (OR/CI: 10.16/1.33-77.74, P = 0.03).

Conclusion: HDV infection played an important role in ALT abnormality in CHB patients receiving 1-year and 2-year NAs. The impact was particularly noted in patients who had successfully suppressed HBV DNA.
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http://dx.doi.org/10.1016/j.jfma.2020.10.002DOI Listing
January 2021

Hemostatic Enhancement via Chitosan Is Independent of Classical Clotting Pathways-A Quantitative Study.

Polymers (Basel) 2020 Oct 17;12(10). Epub 2020 Oct 17.

Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan.

Hemostasis is a process causing bleeding to stop, and it is known from the literature that hemostasis can be enhanced using chitosan on wound gauzes. We proposed here a continuous flow-through device, with the test blood flowing through the gauze sample at a constant flow rate and the pressure drop across the gauze measured, for assessing the hemostatic performance of the gauze. Experiments were performed using the device with both whole blood and washed blood (with clotting factors and platelets removed from the whole blood), and their results agree with each other within 10% discrepancy, indicating quantitatively that hemostatic enhancement via chitosan is essentially independent of classical clotting pathways, which was demonstrated qualitatively through animal tests in the literature. The proposed device and method can be applied for evaluating quantitatively the hemostatic performance of various gauzes in a flowing blood environment (in comparison with static tests) with less test blood (20-60% less, in comparison with that of a flow-through device driven by a constant pressure gradient), and are thus, helpful for designing better wound gauzes. In particular, it is effective to enhance the hemostatic performance further (additional 30%) through acidification (changing the amino group to the ammonium group) of the gauze for chitosan-based wound gauzes.
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http://dx.doi.org/10.3390/polym12102391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603022PMC
October 2020

Viral Interference Between Dengue Virus and Hepatitis C Virus Infections.

Open Forum Infect Dis 2020 Aug 3;7(8):ofaa272. Epub 2020 Jul 3.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Both dengue virus (DENV) and hepatitis C virus (HCV) belong to the family and could induce hepatitis. We aimed to investigate the interference between them. In total, 515 patients confirmed with dengue fever (DF) were enrolled. Thirty-two patients (6.21%) were seropositive for anti-HCV; 12 of 32 anti-HCV-positive patients had detectable HCV-RNA at presentation of DF. The proportion of dengue hemorrhagic fever was comparable between patients with or without anti-HCV and between those with or without HCV-RNA. Eleven of 32 patients received HCV-RNA testing during a median interval of 23 months after DF, which revealed significantly increased HCV-RNA levels (5.43 ± 0.77 vs 3.09 ± 1.24 log IU/mL, follow-up vs acute-DF phase;  = .003). Four of 11 patients with baseline HCV-RNA values before DF demonstrated a nadir viremia during acute DF. We also included age-, sex-, and follow-up duration-matched HCV-monoinfected patients as controls; higher delta HCV-RNA changes were demonstrated in patients with DF than in controls during the follow-up period (2.34 ± 1.15 vs -0.27 ± 0.76 log IU/mL;  < .001). Further in vitro experiments showed that HCV nonstructural protein 5A was downregulated in Con1 HCV replicon cells infected by DENV1. These clinical and experimental findings suggested possible viral interference in DENV/HCV. However, HCV viremia did not affect the disease outcomes of DF.
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http://dx.doi.org/10.1093/ofid/ofaa272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452371PMC
August 2020

Simplifying the screening of gestational diabetes by maternal age plus fasting plasma glucose at first prenatal visit: A prospective cohort study.

PLoS One 2020 20;15(8):e0237224. Epub 2020 Aug 20.

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

Aim: The addition of maternal age to fasting plasma glucose (FPG) at 24-28 gestational weeks improves the performance of GDM screening as maternal age increases. However, this method delays the diagnosis of GDM. Since FPG at the first prenatal visit (FPV) is a screening option for pre-existing diabetes, we evaluated the performance of age plus FPG at the FPV to reduce the need for the OGTT.

Methods: Pregnant women were recruited consecutively in 2013-2018 (the training cohort) and 2019 (the validation cohort). We excluded women with twin pregnancies, unavailable FPG at the FPV or OGTT data, pre-pregnancy diabetes, or a history of GDM. All participants underwent FPG and haemoglobin A1c (HbA1c) at the FPV and received 75-g OGTT at 24-28 gestational weeks if FPG at the FPV was <92 mg/dL. GDM was diagnosed by the IADPSG criteria. Two algorithms were developed with the cutoffs determined when the percentage requiring OGTT (OGTT%) was the lowest and the sensitivity was ≥90%.

Results: The incidence of GDM increased with age. The "FPG at the FPV" algorithm reduced OGTT% to 68.8% with the FPG cutoff at 79 mg/dl. The "age plus FPG at the FPV" algorithm, with the cutoff of 114, further reduced OGTT% to 58.3%, with the sensitivity of 90.7% (9.3% GDM missed) and the specificity of 100%. These findings were replicated in the validation cohort.

Conclusions: Screening GDM by maternal age plus FPG at the FPV can reduce OGTT%, especially in populations with a significant proportion of pregnant women with advanced ages.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444589PMC
October 2020

Anti-inflammatory effects of powdered product of Bu Yang Huan Wu decoction: Possible role in protecting against Transient Focal Cerebral Ischemia.

Int J Med Sci 2020 11;17(12):1854-1863. Epub 2020 Jul 11.

Institute of Medical Sciences, Tzu Chi University, Hualien city, Taiwan.

Bu Yang Huan Wu decoction (BYHW) is a traditional Chinese medicine (TCM) that consists of several herbs and has been used in patients with ischemic stroke for centuries. Although powdered formula of BYHW has widely been prescribed in clinic nowadays, evidence-based effectiveness and mechanism of action of BYHW powdered product in stroke remain to be characterized. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion for 24 h (ischemia/reperfusion; I/R) or sham surgery. After I/R, the rats were then given low dose (0.5 g/kg) and high dose (2.5 g/kg) of BYHW or vehicle by oral gavage twice a day for seven consecutive days. The results showed that I/R induced obvious cerebral infarction and neurobehavioral defects, in parallel with histological aberrations and extensive signaling of proinflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), in the stroke model. Post-I/R treatment with BYHW powdered product significantly reduced the infarct area and ameliorated neurofunctional defects in a dose-dependent manner. The dose dependence was associated with TNF-α downregulation and interleukin-10 (IL-10) induction. In summary, the present findings demonstrated that BYHW powdered product exhibited therapeutic efficacy for experimental stroke and a higher dose treatment may strengthen the effectiveness via inflammatory modulation.
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http://dx.doi.org/10.7150/ijms.46581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378667PMC
June 2021

Hydrolyzed Chicken Extract (ProBeptigen) on Cognitive Function in Healthy Middle-Aged People: A Randomized Double-Blind Trial.

Nutrients 2020 May 10;12(5). Epub 2020 May 10.

Department of Neurology, Shuang-Ho Hospital, Taipei Medical University, New Taipei 235, Taiwan.

Cognitive decline is an important issue of global public health. Cognitive aging might begin at middle adulthood, the period particularly vulnerable to stress in lifespan. Essence of chicken (EOC) has consistently demonstrated its beneficial effects on various cognitive domains as nutritional supplementation. This study primarily aimed to examine the cognitive enhancement effects of ProBeptigen® (previously named CMI-168), hydrolyzed peptides extracted from EOC, in healthy middle-aged people under mild stress. Ninety healthy subjects were randomly assigned into the ProBeptigen® or placebo group for eight weeks. Neurocognitive assessment, event-related potentials (ERPs), and blood tests were conducted before, during, and after the treatment. The ProBeptigen® group outperformed placebo group on Logical Memory subtests of Wechsler Memory Scale-third edition (WMS-III) and Spatial Working Memory task in the Cambridge Neuropsychological Test Automated Battery (CANTAB). The anti-inflammatory effects of ProBeptigen® in humans were also confirmed, with progressively declining high-sensitivity C-reactive protein (hs-CRP) levels. Regular dietary supplementation of ProBeptigen® is suggested to improve verbal short- and long-term memory as well as spatial working memory, and reduce inflammation in middle-aged healthy individuals with stress. The effects of ProBeptigen® on cognition warrant further investigation. (NCT03612752).
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http://dx.doi.org/10.3390/nu12051362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284526PMC
May 2020

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

Oncologist 2020 08 13;25(8):702-711. Epub 2020 May 13.

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

Background: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib.

Materials And Methods: PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.

Results: A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression.

Conclusion: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib.

Implications For Practice: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.
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http://dx.doi.org/10.1634/theoncologist.2020-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418350PMC
August 2020

Inhibition of Long-Term Variability in Decoding Forelimb Trajectory Using Evolutionary Neural Networks With Error-Correction Learning.

Front Comput Neurosci 2020 31;14:22. Epub 2020 Mar 31.

Department of Biomedical Engineering, National Yang Ming University, Taipei, Taiwan.

In brain machine interfaces (BMIs), the functional mapping between neural activities and kinematic parameters varied over time owing to changes in neural recording conditions. The variability in neural recording conditions might result in unstable long-term decoding performance. Relevant studies trained decoders with several days of training data to make them inherently robust to changes in neural recording conditions. However, these decoders might not be robust to changes in neural recording conditions when only a few days of training data are available. In time-series prediction and feedback control system, an error feedback was commonly adopted to reduce the effects of model uncertainty. This motivated us to introduce an error feedback to a neural decoder for dealing with the variability in neural recording conditions. We proposed an evolutionary constructive and pruning neural network with error feedback (ECPNN-EF) as a neural decoder. The ECPNN-EF with partially connected topology decoded the instantaneous firing rates of each sorted unit into forelimb movement of a rat. Furthermore, an error feedback was adopted as an additional input to provide kinematic information and thus compensate for changes in functional mapping. The proposed neural decoder was trained on data collected from a water reward-related lever-pressing task for a rat. The first 2 days of data were used to train the decoder, and the subsequent 10 days of data were used to test the decoder. The ECPNN-EF under different settings was evaluated to better understand the impact of the error feedback and partially connected topology. The experimental results demonstrated that the ECPNN-EF achieved significantly higher daily decoding performance with smaller daily variability when using the error feedback and partially connected topology. These results suggested that the ECPNN-EF with partially connected topology could cope with both within- and across-day changes in neural recording conditions. The error feedback in the ECPNN-EF compensated for decreases in decoding performance when neural recording conditions changed. This mechanism made the ECPNN-EF robust against changes in functional mappings and thus improved the long-term decoding stability when only a few days of training data were available.
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http://dx.doi.org/10.3389/fncom.2020.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136463PMC
March 2020

Serial serologic changes of hepatitis D virus in chronic hepatitis B patients receiving nucleos(t)ides analogues therapy.

J Gastroenterol Hepatol 2020 Nov 16;35(11):1886-1892. Epub 2020 Apr 16.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background And Aim: The serial serologic changes of hepatitis D virus (HDV) infection among chronic hepatitis B virus (HBV) infected patients who received oral nucleotide/nucleoside analogues are elusive.

Methods: Serum anti-HDV and HDV RNA among chronic hepatitis B (CHB) patients were tested at the time of initiating anti-HBV therapy and subsequently during the follow-up period.

Results: The seropositive rate of anti-HDV and HDV RNA among 2850 CHB patients, was 2.7% and 0.9%, respectively. Factors associated with anti-HDV seropositivity were platelet counts (odds ratio [OR]/95% confidence intervals [CI]: 0.995/0.992-0.999; P = 0.006), HBV DNA levels (OR/CI: 0.81/0.70-0.94; P = 0.005), and hepatitis B e-antigen (HBeAg) seropositivity (OR/CI: 0.22/0.05-0.95; P = 0.04). The only factor associated with HDV RNA positivity among anti-HDV seropositive patients was age (OR/CI: 0.95/0.90-1.00; P = 0.03). The spontaneous clearance rate of serum anti-HDV antibody was 3.0 per 100 person-years with a median follow-up period of 3.5 years (range 2-12 years), whereas the seroclearance rate of HDV RNA was 4.3 per 100 person-years among anti-HDV seropositive patients after a median follow-up period of 6.0 years (range 2-11 years). A baseline anti-HDV titer < 0.5 cut-off index was the only factor predictive of anti-HDV seroclearance (hazard ratio [HR]/CI: 30.11/3.73-242.85; P = 0.001).

Conclusions: HDV infection was not common among patients treated for HBV in Taiwan. Seroclearance of anti-HDV and HDV RNA did occur over time, albeit the chance is rare.
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http://dx.doi.org/10.1111/jgh.15061DOI Listing
November 2020

Clinical factors associated with treatment toxicity of pemetrexed plus platinum in elderly patients with non-small cell lung cancer.

J Formos Med Assoc 2020 Oct 6;119(10):1506-1513. Epub 2020 Jan 6.

Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: This study was to explore the clinical factors associated with treatment toxicities of pemetrexed plus platinum in elderly patients with non-small cell lung cancer (NSCLC).

Methods: Chemo-naive patients aged ≥ 70 with advanced NSCLC treated with pemetrexed plus platinum were included. Medical records were reviewed and clinical data, including age, gender, smoking status, comorbidities, EGFR mutation status, chemotherapy regimens, previous use of epidermal growth factor receptor-tyrosine kinase inhibitors, treatment-related hematologic, renal, and hepatic toxicities, and treatment responses, were analyzed. Comorbidity conditions were evaluated by using the Simplified Comorbidity Score (SCS) and Charlson Comorbidity Index Score (CCIS).

Results: A total of 144 patients were included. In the univariate analysis, patients with SCS >9 (p = 0.006) and cigarette smoking (p = 0.028) were associated with a significantly higher rate of grade 3/4 neutropenia than their counterpart. Carboplatin use was associated with a higher rate of grade 3/4 thrombocytopenia than cisplatin use (p = 0.028). In the multivariate analysis, SCS >9 was associated with a significantly higher risk of anemia of any grade (odds ratio [OR]: 2.72, 95% confidence interval [CI]: 1.09-6.77). Carboplatin use was associated a higher risk of any grade (OR: 4.61, 95% CI: 1.07-19.90) and grade 3/4 thrombocytopenia (OR: 7.37, 95% CI: 1.36-39.92). No clinical factors were found to be associated with hepatic and renal toxicities.

Conclusion: High SCS and carboplatin use were associated with hematological toxicities with pemetrexed plus platinum use in elderly patients with NSCLC.
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http://dx.doi.org/10.1016/j.jfma.2019.12.007DOI Listing
October 2020

Predicting Lung Cancer Occurrence in Never-Smoking Females in Asia: TNSF-SQ, a Prediction Model.

Cancer Epidemiol Biomarkers Prev 2020 02 17;29(2):452-459. Epub 2019 Dec 17.

Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria.

Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case-control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2).

Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660-0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95-5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04-36.28) had risk higher than 0.0151.

Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention.

Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1221DOI Listing
February 2020

Overweight and obesity are associated with clustering of metabolic risk factors in early pregnancy and the risk of GDM.

PLoS One 2019 3;14(12):e0225978. Epub 2019 Dec 3.

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

Aim: Overweight and obesity are important risk factors of gestational diabetes mellitus (GDM). Clustering of metabolic risk factors in early pregnancy may be a potential pathogenesis between the link of overweight/obesity and GDM. Since it remains unexplored, we investigated if overweight and obesity are associated with clustering of metabolic risk factors in early pregnancy and the risk of GDM in this cohort study.

Methods: Total 527 women who visited National Taiwan University Hospital for prenatal care in between November 2013 to April 2018 were enrolled. Risk factors of GDM in the first prenatal visit (FPV) were recorded. Overweight/obesity was defined if body mass index ≥24 kg/m2. GDM was diagnosed from the result of a 75g oral glucose tolerance test in 24-28 gestational weeks.

Results: Overweight/obesity was associated with clustering of metabolic risk factors of GDM, including high fasting plasma glucose, high HbA1c, insulin resistance, high plasma triglyceride and elevated blood pressure in FPV (p<0.05). There was a positive relationship between the number of metabolic risk factors and the incidence of GDM (p <0.05). The odds ratios of HbA1c and diastolic blood pressure were higher in overweight/obese women, compared with those in normal-weight women.

Conclusions: Overweight/obesity is associated with clustering of metabolic risk factors in early pregnancy, which is correlated with higher risk of GDM. Our findings suggest that metabolic risk factors during early pregnancy should be evaluated in overweight/obese women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890240PMC
March 2020

Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors.

Eur J Cancer 2020 01 21;124:110-122. Epub 2019 Nov 21.

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

Introduction: Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression.

Methods And Materials: Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments.

Results: A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses.

Conclusions: Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.
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http://dx.doi.org/10.1016/j.ejca.2019.10.019DOI Listing
January 2020

The Transcriptional Regulator Lrp Contributes to Toxin Expression, Sporulation, and Swimming Motility in .

Front Cell Infect Microbiol 2019 17;9:356. Epub 2019 Oct 17.

Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

is a Gram-positive, spore-forming bacterium, and major cause of nosocomial diarrhea. Related studies have identified numerous factors that influence virulence traits such as the production of the two primary toxins, toxin A (TcdA) and toxin B (TcdB), as well as sporulation, motility, and biofilm formation. However, multiple putative transcriptional regulators are reportedly encoded in the genome, and additional factors are likely involved in virulence regulation. Although the leucine-responsive regulatory protein (Lrp) has been studied extensively in Gram-negative bacteria, little is known about its function in Gram-positive bacteria, although homologs have been identified in the genome. This study revealed that disruption of the lone homolog in decelerated growth under nutrient-limiting conditions, increased TcdA and TcdB production. Lrp was also found to negatively regulate sporulation while positively regulate swimming motility in strain R20291, but not in strain 630. The Lrp appeared to function through transcriptional repression or activation. In addition, the mutant was relatively virulent in a mouse model of infection. The results of this study collectively demonstrated that Lrp has broad regulatory function in toxin expression, sporulation, motility, and pathogenesis.
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http://dx.doi.org/10.3389/fcimb.2019.00356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811523PMC
June 2020

Intranasal lidocaine for acute migraine: A meta-analysis of randomized controlled trials.

PLoS One 2019 23;14(10):e0224285. Epub 2019 Oct 23.

Emergency Department, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

Background: Intranasal lidocaine has been shown to be effective in treating patients with acute migraines; however, its efficacy is still controversial. In this study, we intend to assess the efficacy and safety of intranasal lidocaine compared with a placebo or an active comparator for the treatment of migraines.

Method: PubMed, EMBASE, Cochrane library, and Scopus databases were searched from their inceptions to November 2018. Randomized controlled studies investigating the efficacy of intranasal lidocaine compared with a placebo or an active comparator were selected. Two reviewers independently extracted and synthesized data using a random-effects model. The primary outcome was pain intensity. The secondary outcomes were success rate, the need for rescue medicine, and relapse occurrences. We registered the study at PROSPERO with an ID of CRD42018116226.

Results: Six studies (n = 613) were eligible for the meta-analysis. Overall, the results revealed that the study population who was administered intranasal lidocaine had a lower pain intensity at 5 min (standardized mean difference (SMD) = -0.61; 95% CI = -1.04 to -0.19) and 15 min (SMD = -0.72; 95% CI = -1.14 to -0.19), had a higher success rate (RR = 3.55; 95% CI: 1.89 to 6.64) and a less frequent need for rescue medicine (RR = 0.51; 95% CI = 0.36 to 0.72) than the control group. These beneficial effects were not observed when an antiemetic was administered. Furthermore, intranasal lidocaine use had no significant influence on the relapse rate (RR = 0.89; 95% CI = 0.51-1.56), regardless of the use of antiemetics. Using lidocaine caused local irritation in up to 49.4% of the patients in one report but did not cause major adverse events.

Conclusion: Intranasal lidocaine can be considered a useful option for patients with an acute migraine. It yields a high success rate, a low pain intensity, an infrequent need for rescue medicine, and tolerable adverse events. The administration of antiemetics is an important confounding factor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224285PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808552PMC
March 2020

In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer.

J Cell Mol Med 2019 12 22;23(12):8184-8195. Epub 2019 Oct 22.

Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.

Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti-CSC agent may lead to improved disease control. We used CSC-associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top-ranked candidate. In non-small-cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR-98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.
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http://dx.doi.org/10.1111/jcmm.14689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850923PMC
December 2019

Scleromyxedema and lichen myxedematosus: Is it associated with viral hepatitis?

J Dermatol 2019 Oct 28;46(10):879-885. Epub 2019 Aug 28.

Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan.

Scleromyxedema (SM) was previously known to be associated with monoclonal gammopathy. The association of SM and its counterpart lichen myxedematosus (LM) with chronic hepatitis has rarely been reported. We retrospectively reviewed medical records and histopathological reports of consecutive patients who presented at our department with the diagnosis of SM or LM from January 2001 to September 2017. The patients' demographic details, cutaneous presentation, associated underlying diseases and hepatitic profile were studied and compared with previous published cases. In all, 28 patients were enrolled, including one SM, 19 LM and eight atypical LM. Of the patients, 50% (n = 14/28) had hepatitis. Of these, 21.4% (n = 6/28) had hepatitis C, 10.7% (n = 3/28) hepatitis B, 7.1% (n = 2/28) concurrent hepatitis B and C, whereas 10.7% (n = 3/28) had alcoholic liver disease. The prevalence of hepatitis C in our patients was 6.5-times higher than that of the general population (28.6% vs 4.4%) and the prevalence of hepatitis B was similar (17.9% vs 17.3%). Polyclonal gammopathy was found in 28.6% (n = 8/28) of the patients and monoclonal gammopathy was found in 7.1% (n = 2/28). The extent of clonality did not correlate with disease severity. Our study did not notice a significant association with monoclonal gammopathy but the prevalence of hepatitis C was found to increase 6.5-times in these patients compared with the general population. We recommend dermatologists to be aware of hepatitis investigations in such patients and future studies are warranted to understand the mechanism behind such association.
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http://dx.doi.org/10.1111/1346-8138.15039DOI Listing
October 2019

Non-small cell lung cancer harbouring non-resistant uncommon EGFR mutations: Mutation patterns, effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors and prognostic factors.

Eur J Cancer 2019 09 16;119:77-86. Epub 2019 Aug 16.

Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan.

Introduction: Non-small cell lung cancer (NSCLC) harbouring EGFR exon 19 deletions or L858R mutation usually respond to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), whereas T790M mutation and exon 20 insertion are frequently resistant to EGFR-TKIs. EGFR mutations other than those above are seldom investigated.

Methods: In this multicentre, retrospective study, we enrolled NSCLC patients with non-resistant uncommon EGFR mutations, which were defined as mutations other than L858R, exon 19 deletions, exon 20 insertions and T790M. The mutation patterns, clinical data and treatment outcomes were analysed. Patients were classified as gefitinib/erlotinib and afatinib groups according to the EGFR-TKIs received as the first-line therapy.

Results: A total of 177 patients were identified (177/1983, 8.9%). Sixty-six patients had more than one EGFR mutation, including those coexisting with exon 19 deletion or L858R mutation. In treatment-naïve patients with advanced stages (n = 72), the objective response rate was 35.8% for gefitinib/erlotinib group and 60.6% for afatinib group (p = 0.036). In multivariate analysis, no significant differences were found between gefitinib/erlotinib and afatinib groups in median progression-free survival (PFS) and overall survival (OS). Brain metastasis at diagnosis was associated with a shorter PFS (hazard ratio [HR] = 2.49, 95% confidence interval [CI] = 1.29-4.83) and OS (HR = 3.22, 95% CI = 1.41-7.35).

Conclusions: For patients with NSCLC harbouring non-resistant uncommon EGFR mutations, afatinib use as the first-line therapy may provide a better treatment response but no survival benefit, as compared with gefitinib or erlotinib. Brain metastasis at diagnosis is associated with a poor prognosis.
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http://dx.doi.org/10.1016/j.ejca.2019.06.025DOI Listing
September 2019

Ribavirin facilitates early viral kinetics in chronic hepatitis C patients receiving daclatasvir/asunaprevir.

J Gastroenterol Hepatol 2020 Jan 15;35(1):151-156. Epub 2019 Aug 15.

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background And Aim: Ribavirin (RBV) remains crucial in difficult-to-cure chronic hepatitis C patients receiving directly acting antivirals (DAAs). The current study aimed to address whether RBV enhanced early viral kinetics in patients with DAAs.

Methods: Hepatitis C virus (HCV) genotype-1b patients were allocated to daclatasvir/asunaprevir +weight-based RBV (1000-1200 mg/day) for 12-24 weeks. HCV RNA levels were compared at day 1, week 1, week 2, and week 4 of treatment.

Results: The sustained virological response rate was 100% (67/67) and 96.7% (59/61) in the RBV and non-RBV group, respectively. The HCV RNA levels at treatment week 2 (W2) were significantly lower in the RBV group than in the non-RBV group (0.42 ± 0.81 log IU/mL vs 0.79 ± 1.03 log IU/mL, P = 0.04). Among the intermediate responders who remained to have detectable RNA after W1 of treatment, patients with RBV had a significantly higher rate of undetectable HCV RNA (71.4% vs 36.0%, P = 0.003) and lower HCV RNA level at W2 (0.55 ± 0.89 log IU/mL vs 1.32 ± 1.04 log IU/mL, P = 0.001). A more significant magnitude of HCV RNA reduction was also noted from baseline to day 1 (3.15 ± 0.38 log IU/mL vs 2.80 ± 0.70 log IU/mL, P = 0.009) and W1 to W2 (1.40 ± 0.65 log IU/mL vs 0.88 ± 0.78 log IU/mL, P = 0.007) in the RBV group compared to the non-RBV group among the intermediate responders. Logistic regression analysis revealed that adding RBV independently predicted undetectable HCV RNA at W2 (odds ratio/confidence interval: 4.74/1.54-14.57, P = 0.007) in the intermediate responders.

Conclusions: Adding RBV to DAAs improved early viral kinetic, in particular, for intermediate responders.
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http://dx.doi.org/10.1111/jgh.14815DOI Listing
January 2020

Resveratrol induced premature senescence and inhibited epithelial-mesenchymal transition of cancer cells via induction of tumor suppressor Rad9.

PLoS One 2019 16;14(7):e0219317. Epub 2019 Jul 16.

Department of Nutrition, College of Medical and Health Care, Hung Kuang University, Taichung, Taiwan.

Resveratrol (RSV) has been reported to influence many biological processes, including the stimulation of cellular senescence and inhibition of epithelial-mesenchymal transition (EMT). In this research, we explored the mechanisms of RSV on EMT and cellular senescence through the expression of a DNA damage response (DDR) protein, Rad9, in breast and lung cancer cell lines. Upon treating breast and lung cancer cell lines with RSV at the concentrations of 10-50 μM, Rad9 expression was increased at both transcriptional and translational levels. The results indicated that RSV-induced Rad9 expression, mediated by DNA damage and ROS, can significantly suppress proliferation by activating cellular senescence, and diminishing the expression of EMT markers with concomitant downregulation of Slug in breast and lung cancer cell lines. By using a siRNA approach, RSV was shown to mediate cellular senescence and EMT through a Rad9-dependent mechanism. The treatment with RSV can inhibit the proliferation, EMT, and increase cellular senescence of breast and lung cancer cell lines by activating Rad9. Our results suggest that the breast and lung tumor suppressive activities of RSV are, at least in part, mediated by the upregulation of Rad9.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219317PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634400PMC
March 2020