Publications by authors named "Nai-Tzu Chen"

34 Publications

Influence of Indoor Temperature Exposure on Emergency Department Visits Due to Infectious and Non-Infectious Respiratory Diseases for Older People.

Int J Environ Res Public Health 2021 05 15;18(10). Epub 2021 May 15.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan City 70403, Taiwan.

Previous studies have demonstrated that outdoor temperature exposure was an important risk factor for respiratory diseases. However, no study investigates the effect of indoor temperature exposure on respiratory diseases and further assesses cumulative effect. The objective of this study is to study the cumulative effect of indoor temperature exposure on emergency department visits due to infectious (IRD) and non-infectious (NIRD) respiratory diseases among older adults. Subjects were collected from the Longitudinal Health Insurance Database in Taiwan. The cumulative degree hours (CDHs) was used to assess the cumulative effect of indoor temperature exposure. A distributed lag nonlinear model with quasi-Poisson function was used to analyze the association between CDHs and emergency department visits due to IRD and NIRD. For IRD, there was a significant risk at 27, 28, 29, 30, and 31 °C when the CDHs exceeded 69, 40, 14, 5, and 1 during the cooling season (May to October), respectively, and at 19, 20, 21, 22, and 23 °C when the CDHs exceeded 8, 1, 1, 35, and 62 during the heating season (November to April), respectively. For NIRD, there was a significant risk at 19, 20, 21, 22, and 23 °C when the CDHs exceeded 1, 1, 16, 36, and 52 during the heating season, respectively; the CDHs at 1 was only associated with the NIRD at 31 °C during the cooling season. Our data also indicated that the CDHs was lower among men than women. We conclude that the cumulative effects of indoor temperature exposure should be considered to reduce IRD risk in both cooling and heating seasons and NIRD risk in heating season and the cumulative effect on different gender.
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http://dx.doi.org/10.3390/ijerph18105273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156969PMC
May 2021

Emergency room visits for childhood atopic dermatitis are associated with floods?

Sci Total Environ 2021 Jun 28;773:145435. Epub 2021 Jan 28.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli 35053, Taiwan; Department of Environmental and Occupational Medicine, College of Medicine, National Taiwan University (NTU) and NTU Hospital, Taipei, Taiwan; Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 10055, Taiwan. Electronic address:

Floods are known to increase the level of allergens such as molds in the environments. Under climate change, the frequency of floods could be increased, which highlights the importance of understanding the impacts of floods on atopic diseases. However, there was a lack of studies. This study examines whether floods induce attacks of childhood atopic dermatitis (AD). A retrospective population-based study was conducted in Taiwan Island using Taiwan's National Health Insurance Research Database. Emergency room (ER) visits for AD were identified among children aged 0-12 years. Weekly data of flood occurrence, number of flood sites, temperature, and air pollution were obtained for each township of the identified cases. A time-stratified case-crossover design was used. The relationship between ER visits for AD and floods was assessed by conditional logistic regression, adjusting for weekly mean temperature, PM and NO. There were a total of 55,488 ER visits due to AD during the study period. Such visits increased when flood occurred, and then declined. The effects of floods at the week of flood remained robust, with OR of 1.14 (95% CI = 1.01-1.28) for flood occurrence and 1.31 (95% CI = 1.10-1.55) for the number of flood sites, after adjusting for covariates. Such effects were slightly higher in boys and children aged 1-12 years. This study demonstrated the impact of floods on flare-up of childhood AD, and the effect was most prominently at the week of flood. Healthcare workers should be alarmed for potential increase of AD flare ups after flood events.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145435DOI Listing
June 2021

Associations among phthalate exposure, DNA methylation of TSLP, and childhood allergy.

Clin Epigenetics 2021 Apr 9;13(1):76. Epub 2021 Apr 9.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Cheng-Hsing Campus, No. 1, University Road, Tainan City, Taiwan.

Background: Dysregulation of thymic stromal lymphopoietin (TSLP) expressions is linked to asthma and allergic disease. Exposure to phthalate esters, a widely used plasticizer, is associated with respiratory and allergic morbidity. Dibutyl phthalate (DBP) causes TSLP upregulation in the skin. In addition, phthalate exposure is associated with changes in environmentally induced DNA methylation, which might cause phenotypic heterogeneity. This study examined the DNA methylation of the TSLP gene to determine the potential mechanism between phthalate exposure and allergic diseases.

Results: Among all evaluated, only benzyl butyl phthalate (BBzP) in the settled dusts were negatively correlated with the methylation levels of TSLP and positively associated with children's respiratory symptoms. The results revealed that every unit increase in BBzP concentration in the settled dust was associated with a 1.75% decrease in the methylation level on upstream 775 bp from the transcription start site (TSS) of TSLP (β =  - 1.75, p = 0.015) after adjustment for child's sex, age, BMI, parents' smoking status, allergic history, and education levels, PM, formaldehyde, temperature; and relative humidity. Moreover, every percentage increase in the methylation level was associated with a 20% decrease in the risk of morning respiratory symptoms in the children (OR 0.80, 95% CI 0.65-0.99).

Conclusions: Exposure to BBzP in settled dust might increase children's respiratory symptoms in the morning through decreasing TSLP methylation. Therefore, the exposure to BBzP should be reduced especially for the children already having allergic diseases.
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http://dx.doi.org/10.1186/s13148-021-01061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035749PMC
April 2021

Using a land use regression model with machine learning to estimate ground level PM.

Environ Pollut 2021 May 1;277:116846. Epub 2021 Mar 1.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Department of Geomatics, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Ambient fine particulate matter (PM) has been ranked as the sixth leading risk factor globally for death and disability. Modelling methods based on having access to a limited number of monitor stations are required for capturing PM spatial and temporal continuous variations with a sufficient resolution. This study utilized a land use regression (LUR) model with machine learning to assess the spatial-temporal variability of PM. Daily average PM data was collected from 73 fixed air quality monitoring stations that belonged to the Taiwan EPA on the main island of Taiwan. Nearly 280,000 observations from 2006 to 2016 were used for the analysis. Several datasets were collected to determine spatial predictor variables, including the EPA environmental resources dataset, a meteorological dataset, a land-use inventory, a landmark dataset, a digital road network map, a digital terrain model, MODIS Normalized Difference Vegetation Index (NDVI) database, and a power plant distribution dataset. First, conventional LUR and Hybrid Kriging-LUR were utilized to identify the important predictor variables. Then, deep neural network, random forest, and XGBoost algorithms were used to fit the prediction model based on the variables selected by the LUR models. Data splitting, 10-fold cross validation, external data verification, and seasonal-based and county-based validation methods were used to verify the robustness of the developed models. The results demonstrated that the proposed conventional LUR and Hybrid Kriging-LUR models captured 58% and 89% of PM variations, respectively. When XGBoost algorithm was incorporated, the explanatory power of the models increased to 73% and 94%, respectively. The Hybrid Kriging-LUR with XGBoost algorithm outperformed the other integrated methods. This study demonstrates the value of combining Hybrid Kriging-LUR model and an XGBoost algorithm for estimating the spatial-temporal variability of PM exposures.
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http://dx.doi.org/10.1016/j.envpol.2021.116846DOI Listing
May 2021

Ambient viral and bacterial distribution during long-range transport in Northern Taiwan.

Environ Pollut 2021 Feb 11;270:116231. Epub 2020 Dec 11.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Long-range transport (LRT) reportedly carries air pollutants and microorganisms to downwind areas. LRT can be of various types, such as dust storm (DS) and frontal pollution (FP); however, studies comparing their effects on bioaerosols are lacking. This study evaluated the effect of LRT on viral and bacterial concentrations in Northern Taiwan. When LRT occurred and possibly affected Taiwan from August 2013 to April 2014, air samples (before, during, and after LRT) were collected in Cape Fugui (CF, Taiwan's northernmost point) and National Taiwan University (NTU). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was applied to quantify influenza A virus. qPCR and qPCR coupled with propidium monoazide were, respectively, used to quantify total and viable bacteria. Types and occurrence of LRT were confirmed according to the changing patterns of meteorological factors and air pollution, air mass sources (HYSPLIT model), and satellite images. Two Asian DS and three FP cases were included in this study. Influenza A virus was detected only on days before and during FP occurred on January 3-5, 2014, with concentrations of 0.87 and 10.19 copies/m, respectively. For bacteria, the increase in concentrations of total and viable cells during Asian DSs (17-19 and 25-29 November 2013) was found at CF only (from 3.13 to 3.40 and from 2.62 to 2.85 log copies/m, respectively). However, bacterial levels at NTU and CF both increased during FP and lasted for 2 days after FP. In conclusion, LRT increased the levels of influenza A virus and bacteria in the ambient air of Northern Taiwan, particularly at CF. During and 2 days (at least) after LRT, people should avoid outdoor activities, especially in case of FP.
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http://dx.doi.org/10.1016/j.envpol.2020.116231DOI Listing
February 2021

Annealing-modulated nanoscintillators for nonconventional X-ray activation of comprehensive photodynamic effects in deep cancer theranostics.

Theranostics 2020 20;10(15):6758-6773. Epub 2020 May 20.

Institute of Biomedical Engineering and Nanomedicine Research, National Health Research Institutes, 35 Keyan Road, Zhunan 350, Taiwan.

Photodynamic therapy (PDT), which involves the generation of reactive oxygen species (ROS) through interactions of a photosensitizer (PS) with light and oxygen, has been applied in oncology. Over the years, PDT techniques have been developed for the treatment of deep-seated cancers. However, (1) the tissue penetration limitation of excitation photon, (2) suppressed efficiency of PS due to multiple energy transfers, and (3) insufficient oxygen source in hypoxic tumor microenvironment still constitute major challenges facing the clinical application of PDT for achieving effective treatment. We present herein a PS-independent, ionizing radiation-induced PDT agent composed of yttrium oxide nanoscintillators core and silica shell (YO:[email protected]) with an annealing process. Our results revealed that annealed YO:[email protected] could directly induce comprehensive photodynamic effects under X-ray irradiation without the presence of PS molecules. The crystallinity of YO:[email protected] was demonstrated to enable the generation of electron-hole (e-h) pairs in YO under ionizing irradiation, giving rise to the formation of ROS including superoxide, hydroxyl radical and singlet oxygen. In particular, combining YO:[email protected] with fractionated radiation therapy increased radio-resistant tumor cell damage. Furthermore, photoacoustic imaging of tumors showed re-distribution of oxygen saturation (O) and reoxygenation of the hypoxia region. The results of this study support applicability of the integration of fractionated radiation therapy with YO:[email protected], achieving synchronously in-depth and oxygen-insensitive X-ray PDT. Furthermore, we demonstrate YO:[email protected] exhibited radioluminescence (RL) under X-ray irradiation and observed the virtually linear correlation between X-ray-induced radioluminescence (X-RL) and the YO:[email protected] concentration . With the pronounced X-RL for imaging and dosimetry, it possesses significant potential for utilization as a precision theranostics producing highly efficient X-ray PDT for deep-seated tumors.
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http://dx.doi.org/10.7150/thno.41752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295068PMC
May 2021

Biodegradable Polymers for Gene-Delivery Applications.

Int J Nanomedicine 2020 30;15:2131-2150. Epub 2020 Mar 30.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan.

Gene-based therapies have emerged as a new modality for combating a myriad of currently incurable diseases. However, the fragile nature of gene therapeutics has significantly hampered their biomedical applications. Correspondingly, the development of gene-delivery vectors is of critical importance for gene-based therapies. To date, a variety of gene-delivery vectors have been created and utilized for gene delivery. In general, they can be categorized into viral- and non-viral vectors. Due to safety issues associated with viral vectors, non-viral vectors have recently attracted much more research focus. Of these non-viral vectors, polymeric vectors, which have been preferred due to their low immunogenicity, ease of production, controlled chemical composition and high chemical versatility, have constituted an ideal alternative to viral vectors. In particular, biodegradable polymers, which possess advantageous biocompatibility and biosafety, have been considered to have great potential in clinical applications. In this context, the aim of this review is to introduce the recent development and progress of biodegradable polymers for gene delivery applications, especially for their chemical structure design, gene delivery capacity and additional biological functions. Accordingly, we first define and categorize biodegradable polymers, followed by describing their corresponding degradation mechanisms. Various types of biodegradable polymers resulting from natural and synthetic polymers will be introduced and their applications in gene delivery will be examined. Finally, a future perspective regarding the development of biodegradable polymer vectors will be given.
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http://dx.doi.org/10.2147/IJN.S222419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125329PMC
June 2020

Seeing Better and Going Deeper in Cancer Nanotheranostics.

Int J Mol Sci 2019 Jul 16;20(14). Epub 2019 Jul 16.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 350, Taiwan.

Biomedical imaging modalities in clinical practice have revolutionized oncology for several decades. State-of-the-art biomedical techniques allow visualizing both normal physiological and pathological architectures of the human body. The use of nanoparticles (NP) as contrast agents enabled visualization of refined contrast images with superior resolution, which assists clinicians in more accurate diagnoses and in planning appropriate therapy. These desirable features are due to the ability of NPs to carry high payloads (contrast agents or drugs), increased in vivo half-life, and disease-specific accumulation. We review the various NP-based interventions for treatments of deep-seated tumors, involving "seeing better" to precisely visualize early diagnosis and "going deeper" to activate selective therapeutics in situ.
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http://dx.doi.org/10.3390/ijms20143490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678689PMC
July 2019

Highly sensitive electron paramagnetic resonance nanoradicals for quantitative intracellular tumor oxymetric images.

Int J Nanomedicine 2019 29;14:2963-2971. Epub 2019 Apr 29.

Department of Radiology, University of Chicago, Chicago, IL 60637 USA.

Tumor oxygenation is a critical parameter influencing the efficacy of cancer therapy. Low levels of oxygen in solid tumor have been recognized as an indicator of malignant progression and metastasis, as well as poor response to chemo- and radiation therapy. Being able to measure oxygenation for an individual's tumor would provide doctors with a valuable way of identifying optimal treatments for patients. Electron paramagnetic resonance imaging (EPRI) in combination with an oxygen-measuring paramagnetic probe was performed to measure tumor oxygenation in vivo. Triarylmethyl (trityl) radical exhibits high specificity, sensitivity, and resolution for quantitative measurement of O concentration. However, its in vivo applications in previous studies have been limited by the required high dosage, its short half-life, and poor intracellular permeability. To address these limitations, we developed high-capacity nanoformulated radicals that employed fluorescein isothiocyanate-labeled mesoporous silica nanoparticles (FMSNs) as trityl radical carriers. The high surface area nanostructure and easy surface modification of physiochemical properties of FMSNs enable efficient targeted delivery of highly concentrated, nonself-quenched trityl radicals, protected from environmental degradation and dilution. We successfully designed and synthesized a tumor-targeted nanoplatform as a carrier for trityl. In addition, the nanoformulated trityl does not affect oxygen-sensing capacity by a self-relaxation or broadening effect. The FMSN-trityl exhibited high sensitivity/response to oxygen in the partial oxygen pressure range from 0 to 155 mmHg. Furthermore, MSN-trityl displayed outstanding intracellular oxygen mapping in both in vitro and in vivo animal studies. The highly sensitive nanoformulated trityl spin probe can profile intracellular oxygen distributions of tumor in a real-time and quantitative manner using in vivo EPRI.
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http://dx.doi.org/10.2147/IJN.S194779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503311PMC
July 2019

Long-term exposure to high temperature associated with the incidence of major depressive disorder.

Sci Total Environ 2019 Apr 29;659:1016-1020. Epub 2018 Dec 29.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, Taiwan; Department of Environmental and Occupational Medicine, College of Medicine, National Taiwan University (NTU) and NTU Hospital, Taipei, Taiwan; Graduate Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan. Electronic address:

Temperature was reported to have acute effects on mental disorders. However, the effect of long-term temperature exposure is unclear, especially in warmer regions. This research aimed to evaluate the association between long-term exposure to temperature and the incidence of major depressive disorder (MDD). A retrospective population-based study was conducted using Taiwan nationwide Longitudinal Health Insurance Database 2005. Subjects without MDD diagnosis were followed from 2003 to 2013 for MDD occurrence. Weather factors including temperature (°C), sunshine duration (hrs/day), and precipitation (mm/day) were 11-year average of daily data collected from weather monitoring stations of Taiwan Central Weather Bureau. Cox proportional hazard model was performed to examine the association between MDD incidence and weather factors. Covariates including age, gender, and insurance amount were adjusted. A total of 9,539,752 person-years were followed. People residing in regions with long-term temperature of 20-23 °C had the lowest risk of developing MDD. Risk for MDD incidence was higher among residents in regions with average temperature > 23 °C, at 7% increase per 1 °C increment (95% CI = 2-12%). The elderly was more vulnerable to such impact of heat exposure. For the elderly, males were more susceptible to heat-related MDD than females (HR = 1.18 vs. 1.14). However, the younger group showed a reverse finding (i.e. females 1.07 > males 1.04). Long-term residence in regions with extreme cold or heat may increase the risk of MDD incidence, especially higher temperature. Under global warming, these findings have great health implications and warrant further confirmation.
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http://dx.doi.org/10.1016/j.scitotenv.2018.12.434DOI Listing
April 2019

Asian Culturally Specific Predictors in a Large-Scale Land Use Regression Model to Predict Spatial-Temporal Variability of Ozone Concentration.

Int J Environ Res Public Health 2019 04 11;16(7). Epub 2019 Apr 11.

Department of Geomatics, National Cheng Kung University, Tainan 70101, Taiwan.

This paper developed a land use regression (LUR) model to study the spatial-temporal variability of O₃ concentrations in Taiwan, which has typical Asian cultural characteristics with diverse local emission sources. The Environmental Protection Agency's (EPA) data of O₃ concentrations from 2000 and 2013 were used to develop this model, while observations from 2014 were used as the external data verification to assess model reliability. The distribution of temples, cemeteries, and crematoriums was included for a potential predictor as an Asian culturally specific source for incense and joss money burning. We used stepwise regression for the LUR model development, and applied 10-fold cross-validation and external data for the verification of model reliability. With the overall model R² of 0.74 and a 10-fold cross-validated R² of 0.70, this model presented a mid-high prediction performance level. Moreover, during the stepwise selection procedures, the number of temples, cemeteries, and crematoriums was selected as an important predictor. By using the long-term monitoring data to establish an LUR model with culture specific predictors, this model can better depict O₃ concentration variation in Asian areas.
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http://dx.doi.org/10.3390/ijerph16071300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480950PMC
April 2019

Microwave-Synthesized Platinum-Embedded Mesoporous Silica Nanoparticles as Dual-Modality Contrast Agents: Computed Tomography and Optical Imaging.

Int J Mol Sci 2019 Mar 28;20(7). Epub 2019 Mar 28.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.

Nanoparticle-based imaging contrast agents have drawn tremendous attention especially in multi-modality imaging. In this study, we developed mesoporous silica nanoparticles (MSNs) for use as dual-modality contrast agents for computed tomography (CT) and near-infrared (NIR) optical imaging (OI). A microwave synthesis for preparing naked platinum nanoparticles (nPtNPs) on MSNs (MSNs-Pt) was developed and characterized with physicochemical analysis and imaging systems. The high density of nPtNPs on the surface of the MSNs could greatly enhance the CT contrast. Inductively coupled plasma mass spectrometry (ICP-MS) revealed the MSNs-Pt compositions to be ~14% Pt by weight and TEM revealed an average particle diameter of ~50 nm and covered with ~3 nm diameter nPtNPs. To enhance the OI contrast, the NIR fluorescent dye Dy800 was conjugated to the MSNs-Pt nanochannels. The fluorescence spectra of MSNs-Pt-Dy800 were very similar to unconjugated Dy800. The CT imaging demonstrated that even modest degrees of Pt labeling could result in substantial X-ray attenuation. In vivo imaging of breast tumor-bearing mice treated with PEGylated MSNs-Pt-Dy800 (PEG-MSNs-Pt-Dy800) showed significantly improved contrasts in both fluorescence and CT imaging and the signal intensity within the tumor retained for 24 h post-injection.
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http://dx.doi.org/10.3390/ijms20071560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480439PMC
March 2019

Enantiomeric Recognition and Separation by Chiral Nanoparticles.

Molecules 2019 Mar 13;24(6). Epub 2019 Mar 13.

Institute of New Drug Development, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.

Chiral molecules are stereoselective with regard to specific biological functions. Enantiomers differ considerably in their physiological reactions with the human body. Safeguarding the quality and safety of drugs requires an efficient analytical platform by which to selectively probe chiral compounds to ensure the extraction of single enantiomers. Asymmetric synthesis is a mature approach to the production of single enantiomers; however, it is poorly suited to mass production and allows for only specific enantioselective reactions. Furthermore, it is too expensive and time-consuming for the evaluation of therapeutic drugs in the early stages of development. These limitations have prompted the development of surface-modified nanoparticles using amino acids, chiral organic ligands, or functional groups as chiral selectors applicable to a racemic mixture of chiral molecules. The fact that these combinations can be optimized in terms of sensitivity, specificity, and enantioselectivity makes them ideal for enantiomeric recognition and separation. In chiral resolution, molecules bond selectively to particle surfaces according to homochiral interactions, whereupon an enantiopure compound is extracted from the solution through a simple filtration process. In this review article, we discuss the fabrication of chiral nanoparticles and look at the ways their distinctive surface properties have been adopted in enantiomeric recognition and separation.
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http://dx.doi.org/10.3390/molecules24061007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470864PMC
March 2019

A novel mouse model of sporadic colon cancer induced by combination of conditional Apc genes and chemical carcinogen in the absence of Cre recombinase.

Carcinogenesis 2019 11;40(11):1376-1386

Department of Medicine, The University of Chicago, Chicago, IL, USA.

Although valuable insights into colon cancer biology have been garnered from human colon cancer cell lines and primary colonic tissues, and animal studies using human colon cancer xenografts, immunocompetent mouse models of spontaneous or chemically induced colon cancer better phenocopy human disease. As most sporadic human colon tumors present adenomatous polyposis coli (APC) gene mutations, considerable effort has gone into developing mice that express mutant Apc alleles that mimic human colon cancer pathogenesis. A serious limitation of many of these Apc-mutant murine models, however, is that these mice develop numerous tumors in the small intestine but few, if any, in the colon. In this work, we examined three spontaneous mouse models of colon tumorigenesis based upon the widely used multiple intestinal neoplasia (Min) mouse: mice with either constitutive or conditional Apc mutations alone or in combination with caudal-related homeobox transcription factor CDX2P-Cre transgene - either with or without exposure to the potent colon carcinogen azoxymethane. Using the CDX2 promoter to drive Cre recombinase transgene expression effectively inactivated Apc in colonocytes, creating a model with earlier tumor onset and increased tumor incidence/burden, but without the Min mouse model's small intestine tumorigenesis and susceptibility to intestinal perforation/ulceration/hemorrhage. Most significantly, azoxymethane-treated mice with conditional Apc expression, but absent the Cre recombinase gene, demonstrated nearly 50% tumor incidence with two or more large colon tumors per mouse of human-like histology, but no small intestine tumors - unlike the azoxymethane-resistant C57BL/6J-background Min mouse model. As such this model provides a robust platform for chemoprevention studies.
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http://dx.doi.org/10.1093/carcin/bgz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875902PMC
November 2019

Intensifying the Antimicrobial Activity of Poly[2-( tert-butylamino)ethyl Methacrylate]/Polylactide Composites by Tailoring Their Chemical and Physical Structures.

Mol Pharm 2019 02 11;16(2):709-723. Epub 2019 Jan 11.

Department of Fiber and Composite Materials , Feng Chia University , Taichung 40724 , Taiwan.

Poly[2-( tert-butylaminoethyl) methacrylate] (PTA), an important class of antimicrobial polymers, has demonstrated its great biocidal efficiency, favorable nontoxicity, and versatile applicability. To further enhance its antimicrobial efficiency, an optimization of the chemical structure of PTA polymers is performed via atom transfer radical polymerization (ATRP) in terms of the antimicrobial ability against Escherichia coli ( E. coli) and Staphylococcus aureus ( S. aureus). After the optimization, the resulting PTA is blended into a polylactide (PLA) matrix to form PTA/PLA composite thin films. It is first found, that the antimicrobial efficiency of PTA/PLA composites was significantly enhanced by controlling the PLA crystallinity and the PLA spherulite size. A possible mechanistic route regarding this new finding has been rationally discussed. Lastly, the cytotoxicity and mechanical properties of a PTA/PLA composite thin film exhibiting the best biocidal effect are evaluated for assessing its potential as a new material for creating antimicrobial biomedical devices.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b01011DOI Listing
February 2019

Spatial Clustering of Dengue Fever Incidence and Its Association with Surrounding Greenness.

Int J Environ Res Public Health 2018 08 29;15(9). Epub 2018 Aug 29.

Department of Geomatics, National Cheng Kung University, Tainan 70101, Taiwan.

With more than 58,000 cases reported by the country's Centers for Disease Control, the dengue outbreaks from 2014 to 2015 seriously impacted the southern part of Taiwan. This study aims to assess the spatial autocorrelation of the dengue fever (DF) outbreak in southern Taiwan in 2014 and 2015, and to further understand the effects of green space (such as forests, farms, grass, and parks) allocation on DF. In this study, two different greenness indexes were used. The first green metric, the normalized difference vegetation index (NDVI), was provided by the long-term NASA MODIS satellite NDVI database, which quantifies and represents the overall vegetation greenness. The latest 2013 land use survey GIS database completed by the National Land Surveying and Mapping Center was obtained to access another green metric, green land use in Taiwan. We first used Spearman's rho to find out the relationship between DF and green space, and then three spatial autocorrelation methods, including Global Moran's I, high/low clustering, and Hot Spot were employed to assess the spatial autocorrelation of DF outbreak. In considering the impact of social and environmental factors in DF, we used generalized linear mixed models (GLMM) to further clarify the relationship between different types of green land use and dengue cases. Results of spatial autocorrelation analysis showed a high aggregation of dengue epidemic in southern Taiwan, and the metropolitan areas were the main hotspots. Results of correlation analysis and GLMM showed a positive correlation between parks and dengue fever, and the other five green space metrics and land types revealed a negative association with DF. Our findings may be an important asset for improving surveillance and control interventions for dengue.
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http://dx.doi.org/10.3390/ijerph15091869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163306PMC
August 2018

Pollen-Structured Gold Nanoclusters for X-ray Induced Photodynamic Therapy.

Materials (Basel) 2018 Jul 9;11(7). Epub 2018 Jul 9.

Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan.

Photodynamic therapy (PDT) is a cancer treatment that employs the production of cytotoxic reactive oxygen species (ROS), subsequently triggering tumor apoptosis and tumor size reduction. However, this approach suffers from insufficient light penetration depth. In order to mitigate this issue, pollen-structured gold clusters (PSGCs) were designed for mediating X-ray-induced PDT for radiotherapy enhancement. The structure of PSGCs provides a large surface area that is able to generate ROS upon X-ray irradiation. The synthesized PSGCs were exposed to different X-ray doses and the generated ROS was then quantified by dihydroethidium (DHE) assay. Furthermore, at the cellular level, the PDT efficacy of PSGCs was evaluated via immunofluorescence staining with γ-H2AX and comet assay. The results demonstrated that PSGCs possess a significantly high ROS-generating capacity and a remarkable PDT efficacy in the treatment of breast cancer cells, thus showing potential clinical uses in deep-tissue cancer treatment.
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http://dx.doi.org/10.3390/ma11071170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073926PMC
July 2018

Ambient VOCs in residential areas near a large-scale petrochemical complex: Spatiotemporal variation, source apportionment and health risk.

Environ Pollut 2018 Sep 3;240:95-104. Epub 2018 May 3.

National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli, 35053, Taiwan; Department of Occupational Safety and Health, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan. Electronic address:

This study investigated ambient volatile organic compounds (VOCs) and assessed excess health risks for child, adult and elderly populations in a residential area near a large-scale petrochemical complex in central Taiwan. A total of 155 daily VOC samples were collected in canisters from nine sites in spring, summer and winter during 2013-2014. We used a positive matrix factorization (PMF) model incorporating a conditional probability function (CPF) to quantify the potential sources of VOCs with the influences of local source directions. We then evaluated the non-cancer and cancer risks of specific VOCs with probabilistic distributions by performing a Monte-Carlo simulation for the child, adult, and elderly populations. Most of the VOCs were higher in summer than in winter or spring for the sampling sites. The presence of vinyl acetate, chloroethene, and 1,2-dichloroethane were significantly high within a 5-km radius of the petrochemical complex. Four potential sources of ambient VOCs, industrial emission (49.2%-63.6%), traffic-related emission (13.9%-19.1%), fuel evaporation (12.3%-16.9%), and aged emission (10.2%-14.8%), were identified. The cancer risk of ambient VOC exposure was mainly attributed to the industrial source in the study area, while the non-cancer risk was of less concern. Benzene associated with fuel evaporation resulted in the highest cancer risk (4.1 × 10-5.5 × 10) as compared to that of the other toxic VOCs.
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http://dx.doi.org/10.1016/j.envpol.2018.04.076DOI Listing
September 2018

Development of an efficient viral aerosol collector for higher sampling flow rate.

Environ Sci Pollut Res Int 2018 Feb 25;25(4):3884-3893. Epub 2017 Nov 25.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, No. 1 University Road, Tainan, Taiwan.

Viral aerosol infection through cough generates large amounts of viral aerosol and can result in many adverse health effects such as influenza flu and severe acute respiratory syndrome (SARS). To characterize the coughed viral aerosol, the sampler needs to sample at higher flow rate and possess high physical collection efficiency as well as high viral preservation. However, most current inertia-based high flow bioaerosol samplers are not suited for viral aerosol sampling since the viability will be lost doing the sampling process. Current condensation growth methods only have good physical collection efficiency and viral preservation at low flow rate (< 10 LPM). In this study, we developed a viral aerosol sampling system using a cooler and steam-jet aerosol collector (SJAC) for bioaerosol collection for the first time. The system is based on mixing condensation growth method and has high viral preservation at a higher flow rate (12.5 LPM). We control the inlet aerosol flow temperature and the SJAC mixing reservoir temperature to improve the physical collection efficiency and viability preservation of the viral aerosol. Results indicate that the physical collection efficiency is 70-99% for aerosol 30-100 nm when the aerosol flow and mixing reservoir temperature was 19 and 50 °C, respectively. In addition, the system was 7 and 22 times more efficient for viability preservation of MS2 bacteriophage than the commonly used All Glass Impinger 30 (AGI-30) and BioSampler®, respectively. Finally, the system can be applied to sample at a lower concentration (10 PFU/m), and results shows the system was 4.7 times more efficient for viability preservation than using AGI-30 alone. The developed viral collection system will improve our understanding of the characteristics of coughed aerosol and can be used for future evaluation of respiratory protective equipment and environmental sampling.
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http://dx.doi.org/10.1007/s11356-017-0754-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089394PMC
February 2018

Lectin-functionalized mesoporous silica nanoparticles for endoscopic detection of premalignant colonic lesions.

Nanomedicine 2017 Aug 29;13(6):1941-1952. Epub 2017 Mar 29.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes Zhunan, Miaoli, Taiwan. Electronic address:

Colorectal cancer (CRC) is one of the leading causes of cancer-deaths worldwide. Methods for the early in situ detection of colorectal adenomatous polyps and their precursors - prior to their malignancy transformation into CRC - are urgently needed. Unfortunately at present, the primary diagnostic method, colonoscopy, can only detect polyps and carcinomas by shape/morphology; with sessile polyps more likely to go unnoticed than polypoid lesions. Here we describe our development of polyp-targeting, fluorescently-labeled mesoporous silica nanoparticles (MSNs) that serve as targeted endoscopic contrast agents for the early detection of colorectal polyps and cancer. In vitro cell studies, ex vivo histopathological analysis, and in vivo colonoscopy and endoscopy of murine colorectal cancer models, demonstrate significant binding specificity of our nanoconstructs to pathological lesions via targeting aberrant α-L-fucose expression. Our findings strongly suggest that lectin-functionalized fluorescent MSNs could serve as a promising endoscopic contrast agent for in situ diagnostic imaging of premalignant colonic lesions.
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http://dx.doi.org/10.1016/j.nano.2017.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673680PMC
August 2017

Ambient PM in the residential area near industrial complexes: Spatiotemporal variation, source apportionment, and health impact.

Sci Total Environ 2017 Jul 6;590-591:204-214. Epub 2017 Mar 6.

National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli 35053, Taiwan; Department of Occupational Safety and Health, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan. Electronic address:

This study systemically investigated the ambient PM (n=108) with comprehensive analyses of the chemical composition, identification of the potential contributors, and estimation of the resultant respiratory physician visits in the residential regions near energy-consuming and high-polluting industries in central Taiwan. The positive matrix fraction (PMF) model with chemical profiles of trace metals, water-soluble ions, and organic/elemental carbons (OC/EC) was applied to quantify the potential sources of PM. The influences of local sources were also explored using the conditional probability function (CPF). Associations between the daily PM concentration and the risk of respiratory physician visits for the elderly (≥65years of age) were estimated using time-series analysis. A seasonal variation, with higher concentrations of PM, metals (As, Cd, Sb, and Pb), OC/EC and ions (i.e., NO, SO and NH) in the winter than in the spring and summer, was observed. Overall, an increase of 10μgm in the same-day PM was associated with an ~2% (95% CI: 1.5%-2.5%) increase in respiratory physician visits. Considering the health benefits of an effective reduction, we suggest that the emission from coal combustion (23.5%), iron ore and steel industry (17.1%), and non-ferrous metallurgy (14.4%), accounting for ~70% of the primary PM in the winter are prioritized to control.
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http://dx.doi.org/10.1016/j.scitotenv.2017.02.212DOI Listing
July 2017

Ambient PM-bound polycyclic aromatic hydrocarbons (PAHs) in Changhua County, central Taiwan: Seasonal variation, source apportionment and cancer risk assessment.

Environ Pollut 2016 Nov 14;218:372-382. Epub 2016 Jul 14.

Department of Safety, Health and Environmental Engineering, Hungkuang University, Sha-Lu, Taichung 433, Taiwan.

This study investigates PM-bound PAHs for rural sites (Dacheng and Fangyuan) positioned close to heavy air-polluting industries in Changhua County, central Taiwan. A total of 113 PM samples with 22 PAHs collected from 2014 to 2015 were analyzed, and Positive Matrix Factorization (PMF) and diagnostic ratios of PAHs were applied to quantify potential PAH sources. The influences of local and regional sources were also explored using the conditional probability function (CPF) and potential source contribution function (PSCF) with PMF-modeled results, respectively. Annual mean concentrations of total PAHs were 2.91 ± 1.34 and 3.04 ± 1.40 ng/m for Dacheng and Fangyuan, respectively, and their corresponding BaP were measured at 0.534 ± 0.255 and 0.563 ± 0.273 ng/m in concentration. Seasonal variations with higher PAHs found for the winter than for the spring and summer were observed for both sites. The lifetime excess cancer risk (ECR) from inhalation exposure to PAHs was recorded as 4.7 × 10 overall. Potential sources of PM-bound PAHs include unburned petroleum and traffic emissions (42%), steel industry and coal combustion (31%), and petroleum and oil burning (27%), and unburned petroleum and traffic emission could contribute the highest ECR (2.4 × 10). The CPF results show that directional apportionment patterns were consistent with the actual locations of local PAH sources. The PSCF results indicate that mainly northeastern regions of China have contributed elevated PM-bound PAHs from long-range transports.
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http://dx.doi.org/10.1016/j.envpol.2016.07.016DOI Listing
November 2016

Precipitation increases the occurrence of sporadic legionnaires' disease in Taiwan.

PLoS One 2014 4;9(12):e114337. Epub 2014 Dec 4.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Legionnaires' disease (LD) is an acute form of pneumonia, and changing weather is considered a plausible risk factor. Yet, the relationship between weather and LD has rarely been investigated, especially using long-term daily data. In this study, daily data was used to evaluate the impacts of precipitation, temperature, and relative humidity on LD occurrence in Taiwan from 1995-2011. A time-stratified 2:1 matched-period case-crossover design was used to compare each case with self-controlled data using a conditional logistic regression analysis, and odds ratios (ORs) for LD occurrence was estimated. The city, gender and age were defined as a stratum for each matched set to modify the effects. For lag day- 0 to 15, the precipitation at lag day-11 significantly affected LD occurrence (p<0.05), and a 2.5% (95% CIs = 0.3-4.7%) increased risk of LD occurrence was associated with every 5-mm increase in precipitation. In addition, stratified analyses further showed that positive associations of precipitation with LD incidence were only significant in male and elderly groups and during the warm season ORs = 1.023-1.029). However, such an effect was not completely linear. Only precipitations at 21-40 (OR = 1.643 (95% CIs = 1.074-2.513)) and 61-80 mm (OR = 2.572 (1.106-5.978)) significantly increased the risk of LD occurrence. Moreover, a negative correlation between mean temperature at an 11-day lag and LD occurrence was also found (OR = 0.975 (0.953-0.996)). No significant association between relative humidity and LD occurrence was identified (p>0.05). In conclusion, in warm, humid regions, an increase of daily precipitation is likely to be a critical weather factor triggering LD occurrence where the risk is found particularly significant at an 11-day lag. Additionally, precipitation at 21-40 and 61-80 mm might make LD occurrence more likely.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114337PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256405PMC
December 2015

When are we most vulnerable to temperature variations in a day?

PLoS One 2014 2;9(12):e113195. Epub 2014 Dec 2.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Daily temperature measures are commonly used when examining the association between temperature and mortality. In fact, temperature measures are available 24 hours a day and more detailed records may provide a better prediction of mortality compared to daily statistics. In this article, monthly stratified analysis modeling for mortality is conducted for the total population as well as the stratified elderly and younger subgroups. We identified the most significant time during the day that is associated with daily mortality. Surprisingly, the estimates of relative risk and magnitude of associations derived from the hourly temperature measures are similar or even stronger compared to those modeled by the daily statistics. This phenomenon remains true for lagged hourly temperature measures and the changing patterns of associations from January through December are revealed. In summary, people are the most vulnerable to temperature variations in the early morning around 5 am and the night time around 8 pm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113195PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251982PMC
July 2015

Radioluminescence characterization of x-ray nanodosimeters: Potential real-time monitors and modulators of external beam radiation therapy.

Appl Phys Lett 2014 Nov 20;105(20):203110. Epub 2014 Nov 20.

Department of Radiology, The University of Chicago , Chicago, Illinois 60637, USA.

Europium-doped yttrium oxide (YO:Eu) has garnered considerable interest recently for its use as a highly efficient, red phosphor in a variety of lighting applications that include fluorescent lamps, plasma, and field emission display panels, light emitting diodes (LEDs), and lasers. In the present work, we describe the development of YO:Eu nanoparticles for a very different application: , x-ray dosimetry. Spectroscopic analyses of these nanoparticles during x-ray irradiation reveal surprisingly bright and stable radioluminescence at near-infrared wavelengths, with markedly linear response to changes in x-ray flux and energy. Monte Carlo modeling of incident flux and broadband, wide-field imaging of mouse phantoms bearing both YO:Eu nanoparticles and calibrated LEDs of similar spectral emission demonstrated significant transmission of radioluminescence, in agreement with spectroscopic studies; with approximately 15 visible photons being generated for every x-ray photon incident. Unlike the dosimeters currently employed in clinical practice, these nanodosimeters can sample both dose and dose rate rapidly enough as to provide real-time feedback for x-ray based external beam radiotherapy (EBRT). The technique's use of remote sensing and absence of supporting structures enable perturbation-free dosing of the targeted region and complete sampling from any direction. With the conjugation of pathology-targeting ligands onto their surfaces, these nanodosimeters offer a potential paradigm shift in the real-time monitoring and modulation of delivered dose in the EBRT of cancer .
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http://dx.doi.org/10.1063/1.4900962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240777PMC
November 2014

Enhanced plasmonic resonance energy transfer in mesoporous silica-encased gold nanorod for two-photon-activated photodynamic therapy.

Theranostics 2014 30;4(8):798-807. Epub 2014 May 30.

1. Institute of Biomedical Engineering and Nanomedicine (I-BEN), National Health Research Institutes, Zhunan, Miaoli 350, Taiwan.

The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging. Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue. Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity. In this work we report the design, synthesis, and evaluation of mesoporous silica-encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two-photon-activated photodynamic therapy (TPA-PDT). The PSs, doped into the nano-channels of the mesoporous silica shell, can be efficiently excited via intra-particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication. In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods. These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer.
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http://dx.doi.org/10.7150/thno.8934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063978PMC
February 2015

The transcriptional repression activity of STAF65γ is facilitated by promoter tethering and nuclear import of class IIa histone deacetylases.

Biochim Biophys Acta 2014 Jul 19;1839(7):579-91. Epub 2014 May 19.

Institute of Molecular Biology, National Chung Hsing University, Taichung 40227, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan. Electronic address:

Aberrant expression levels of transcriptional regulators result in alterations in transcriptional control. STAF65γ is a structural subunit of the GCN5 transcriptional co-activator complex. Reports showed that STAF65γ is highly expressed in several human cancer cells, but the consequences of this aberrant expression pattern remain elusive. Here, we show that the STAF65γ protein is highly expressed in lung adenocarcinoma patients and high levels of STAF65γ correlate with poor prognosis. High levels of STAF65γ cause repression of the c-Myc oncogene through physical association with transcription factor YY1 and co-repressors HDACs. Physical interactions between STAF65γ and class IIa HDACs facilitate nuclear enrichment and regulate the assembly of HDAC complexes. Moreover, SUMOylation of STAF65γ is necessary for maintaining the co-repressor complex containing YY1 and class IIa HDACs at the promoter. Our findings reveal a distinct role of STAF65γ in nuclear import, transcriptional repression, and cell cycle regulation at high levels of expression, which is associated with poor clinical outcomes of lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.bbagrm.2014.05.007DOI Listing
July 2014

Theranostic applications of mesoporous silica nanoparticles and their organic/inorganic hybrids.

J Mater Chem B 2013 Jul 16;1(25):3128-3135. Epub 2013 May 16.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan, Taiwan, R. O. C..

Mesoporous silica nanoparticles (MSNs), with their intrinsically large and easily functionalized surface areas and pore volumes, are particularly well-suited to efficient conveyance of a wide variety of therapeutic agents. When combined with other organic/inorganic nanomaterials, the resultant organic/inorganic-MSN hybrids demonstrate unique synergies and even greater versatility. In this paper, we describe the current status and future prospects of MSNs and organic/inorganic-MSN hybrids for combined therapeutic and diagnostic - theranostic - biomedical applications.
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http://dx.doi.org/10.1039/c3tb20249fDOI Listing
July 2013

Recent advances in nanoparticle-based Förster resonance energy transfer for biosensing, molecular imaging and drug release profiling.

Int J Mol Sci 2012 Dec 5;13(12):16598-623. Epub 2012 Dec 5.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan 35053, Miaoli County, Taiwan.

Förster resonance energy transfer (FRET) may be regarded as a "smart" technology in the design of fluorescence probes for biological sensing and imaging. Recently, a variety of nanoparticles that include quantum dots, gold nanoparticles, polymer, mesoporous silica nanoparticles and upconversion nanoparticles have been employed to modulate FRET. Researchers have developed a number of "visible" and "activatable" FRET probes sensitive to specific changes in the biological environment that are especially attractive from the biomedical point of view. This article reviews recent progress in bringing these nanoparticle-modulated energy transfer schemes to fruition for applications in biosensing, molecular imaging and drug delivery.
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http://dx.doi.org/10.3390/ijms131216598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546710PMC
December 2012

Probing the dynamics of doxorubicin-DNA intercalation during the initial activation of apoptosis by fluorescence lifetime imaging microscopy (FLIM).

PLoS One 2012 18;7(9):e44947. Epub 2012 Sep 18.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan, Taiwan.

Doxorubicin is a potent anthracycline antibiotic, commonly used to treat a wide range of cancers. Although postulated to intercalate between DNA bases, many of the details of doxorubicin's mechanism of action remain unclear. In this work, we demonstrate the ability of fluorescence lifetime imaging microscopy (FLIM) to dynamically monitor doxorubicin-DNA intercalation during the earliest stages of apoptosis. The fluorescence lifetime of doxorubicin in nuclei is found to decrease rapidly during the first 2 hours following drug administration, suggesting significant changes in the doxorubicin-DNA binding site's microenvironment upon apoptosis initiation. Decreases in doxorubicin fluorescence lifetimes were found to be concurrent with increases in phosphorylation of H2AX (an immediate signal of DNA double-strand breakage), but preceded activation of caspase-3 (a late signature of apoptosis) by more than 150 minutes. Time-dependent doxorubicin FLIM analyses of the effects of pretreating cells with either Cyclopentylidene-[4-(4-chlorophenyl)thiazol-2-yl)-hydrazine (a histone acetyltransferase inhibitor) or Trichostatin A (a histone deacetylase inhibitor) revealed significant correlation of fluorescence lifetime with the stage of chromatin decondensation. Taken together, our findings suggest that monitoring the dynamics of doxorubicin fluorescence lifetimes can provide valuable information during the earliest phases of doxorubicin-induced apoptosis; and implicate that FLIM can serve as a sensitive, high-resolution tool for the elucidation of intercellular mechanisms and kinetics of anti-cancer drugs that bear fluorescent moieties.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044947PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445590PMC
March 2013
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