Publications by authors named "Hung-Wei Cheng"

50 Publications

Commercially available garden products as important sources of antibiotic resistance genes-a survey.

Environ Sci Pollut Res Int 2021 Apr 9. Epub 2021 Apr 9.

Civil and Environmental Engineering Department, University of California Los Angeles, 420 Westwood Plaza, Los Angeles, CA, 90095, USA.

The dissemination of antibiotic resistance genes (ARGs) in the environment contributes to the global rise in antibiotic resistant infections. Therefore, it is of importance to further research the exposure pathways of these emerging contaminants to humans. This study explores commercially available garden products containing animal manure as a source of ARGs in a survey of 34 garden products, 3 recently landscaped soils, and 5 native soils. DNA was extracted from these soils and quantified for 5 ARGs, intI1, and 16S rRNA. This study found that both absolute and relative gene abundances in garden products ranged from approximately two to greater than four orders of magnitude higher than those observed in native soils. Garden products with Organic Materials Review Institute (OMRI) certification did not have significantly different ARG abundances. Results here indicate that garden products are important sources of ARGs to gardens, lawns, and parks.
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http://dx.doi.org/10.1007/s11356-021-13333-7DOI Listing
April 2021

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

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

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

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

FRET processes of bi-fluorophoric sensor material containing tetraphenylethylene donor and optical-switchable merocyanine acceptor for lead ion (Pb) detection in semi-aqueous media.

Dyes Pigm 2021 May 21;189. Epub 2021 Feb 21.

Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu 300, Taiwan.

A novel aggregation-induced emission (AIE) structure containing a tetraphenylethene (TPE) unit covalently linked with a merocyanine (MC) unit was synthesized and investigated in semi-aqueous solutions with 90% water fraction. The open-form structure of red-emissive MC unit combined with TPE unit was utilized as a bi-fluorophoric sensor to detect lead(II) ion, which could be transformed from the close-form structure of non-emissive SP unit upon UV exposure. Moreover, the TPE unit as an energy donor with the blue-green photoluminescence (PL) emission at 480 nm was combined with the MC unit as an energy acceptor with the red PL emission at 635 nm. Due to the Förster resonance energy transfer (FRET) processes, the bi-fluorophoric sensor produced more efficient ratiometric PL behavior to induce a stronger red PL emission than that of the mono-fluorophoric MC unit. Hence, the PL sensor responses of the AIE bi-fluorophoric structure toward lead(II) ion could be further amplified via the FRET-OFF processes to turn off red PL emission of the coordinated MC acceptor and to recover blue-green PL emission of the TPE donor. Accordingly, the best LOD value for the AIE sensor detection toward Pb was 0.27 μM. The highest red MC emission with the optimum FRET process of AIE sensor could be utilized in cell viability tests to prove the non-toxic and remarkable bio-marker of AIE sensor to detect lead(II) ion in live cells. The developed FRET-OFF processes with ratiometric PL behavior of the bi-fluorophoric AIE sensor can be utilized for future chemo- and bio-sensor applications.
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http://dx.doi.org/10.1016/j.dyepig.2021.109238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968855PMC
May 2021

Mobile resistomes of human pathogens in swine wastewater treatment plants.

J Microbiol Immunol Infect 2021 Feb 27. Epub 2021 Feb 27.

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

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http://dx.doi.org/10.1016/j.jmii.2021.02.007DOI Listing
February 2021

Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity.

Nat Immunol 2021 Apr 11;22(4):510-519. Epub 2021 Mar 11.

Institute for Bioinnovation, BSRC "Alexander Fleming", Vari, Greece.

Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.
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http://dx.doi.org/10.1038/s41590-021-00894-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610542PMC
April 2021

PspC domain-containing protein (PCP) determines Streptococcus mutans biofilm formation through bacterial extracellular DNA release and platelet adhesion in experimental endocarditis.

PLoS Pathog 2021 Feb 12;17(2):e1009289. Epub 2021 Feb 12.

Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.

Bacterial extracellular DNA (eDNA) and activated platelets have been found to contribute to biofilm formation by Streptococcus mutans on injured heart valves to induce infective endocarditis (IE), yet the bacterial component directly responsible for biofilm formation or platelet adhesion remains unclear. Using in vivo survival assays coupled with microarray analysis, the present study identified a LiaR-regulated PspC domain-containing protein (PCP) in S. mutans that mediates bacterial biofilm formation in vivo. Reverse transcriptase- and chromatin immunoprecipitation-polymerase chain reaction assays confirmed the regulation of pcp by LiaR, while PCP is well-preserved among streptococcal pathogens. Deficiency of pcp reduced in vitro and in vivo biofilm formation and released the eDNA inside bacteria floe along with reduced bacterial platelet adhesion capacity in a fibrinogen-dependent manner. Therefore, LiaR-regulated PCP alone could determine release of bacterial eDNA and binding to platelets, thus contributing to biofilm formation in S. mutans-induced IE.
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http://dx.doi.org/10.1371/journal.ppat.1009289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906467PMC
February 2021

Development and Immunological Function of Lymph Node Stromal Cells.

J Immunol 2021 01;206(2):257-263

Institute of Immunobiology, Medical Research Center, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland; and

Stromal cells have for a long time been viewed as structural cells that support distinct compartments within lymphoid tissues and little more. Instead, an active cross-talk between endothelial and fibroblastic stromal cells drives the maturation of lymphoid niches, a relationship that is recapitulated during lymph node organogenesis, steady-state conditions, and following inflammation. In this review, we go over recent advances in genetic models and high-resolution transcriptomic analyses that have propelled the finer resolution of the stromal cell infrastructure of lymph nodes, revealing that the distinct subsets are strategically positioned to deliver a catered mixture of niche factors to interacting immune cell populations. Moreover, we discuss how changes in the activation state of poised stromal cell-underpinned niches rather than on-demand differentiation of new stromal cell subsets govern the efficient interaction of Ag, APC, and cognate B and T lymphocytes during adaptive immune responses.
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http://dx.doi.org/10.4049/jimmunol.2000914DOI Listing
January 2021

Dextran-modified Quercetin-Cu(II)/hyaluronic acid nanomedicine with natural poly(ADP-ribose) polymerase inhibitor and dual targeting for programmed synthetic lethal therapy in triple-negative breast cancer.

J Control Release 2021 Jan 2;329:136-147. Epub 2020 Dec 2.

Materials Science and Engineering, National Chiao Tung University, 300 Hsinchu, Taiwan; Graduate Institute of Biomedical Science, China Medical University, 404 Taichung, Taiwan; Frontier Research Centre on Fundamental and Applied Sciences of Matters National Tsing Hua University, 300 Hsinchu, Taiwan; School of Dentistry, College of Dental Medicine Kaohsiung Medical University Kaohsiung, Taiwan. Electronic address:

Serious side effects from chemotherapies are the main problem with cancer treatments. To solve these issues, precision cancer nanomedicine based on natural therapeutic materials is developed, which enables specifically apoptosis by interacting with genetic mutation in cancer cells, while leaving normal cells unaffected. Here, we report a novel nanomedicine (CuQDA/IO@HA) composed of hyaluronic acid (HA) / copper ion (Cu(II))-chelated dextran-aldehyde (DA)-quercetin (Q) with dual targeting for synthetic lethal therapy. The CuQDA/IO@HA prepared using a ratio of metal/Q at 0.5:1 resulted in a stable particle structure with uniform particle distribution. The CuQDA/IO@HA can specifically target and induce specific cytotoxicity in BRCA-mutant cancer cells in vitro. Combination treatment with CuQDA/IO@HA and magnetic navigation can induce poly (ADP-ribose) polymerase (PARP) inhibition and DNA damage in BRCA-mutant triple-negative breast cancer (TNBC) via CD44 targeting. The dual-targeting CuQDA/IO@HA can extend the median survival of the BRCA-mutant xenograft mice from 34 to 61 days in comparison to Q treatment alone in vivo, which is attributed to the significant increase in γH2AX, leading to significant apoptosis. More importantly, the CuQDA/IO@HA displayed biocompatibility and no obvious side-effect in normal organs. These results demonstrate the promising potential of integrating natural and metal ions into a nanomedicine that can provide precision medicine through synthetic lethality.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.061DOI Listing
January 2021

Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.

Immunity 2020 11;53(5):1015-1032.e8

Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10117 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an institute of the Leibniz Association, 10117 Berlin, Germany. Electronic address:

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6 ILC3 via lymphotoxin-β receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.
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http://dx.doi.org/10.1016/j.immuni.2020.10.012DOI Listing
November 2020

Advances in Magnetic Nanoparticle-Mediated Cancer Immune-Theranostics.

Adv Healthc Mater 2021 01 1;10(1):e2001451. Epub 2020 Nov 1.

Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu, 30010, Taiwan.

Cancer immunotherapy is a cutting-edge strategy that eliminates cancer cells by amplifying the host's immune system. However, the low response rate and risks of inducing systemic toxicity have raised uncertainty in the treatment. Magnetic nanoparticles (MNPs) as a versatile theranostic tool can be used to target delivery of multiple immunotherapeutics and monitor cell/tissue responses. These capabilities enable the real-time characterization of the factors that contribute to immunoactivity so that future treatments can be optimized. The magnetic properties of MNPs further allow the implementation of magnetic navigation and magnetic hyperthermia for boosting the efficacy of immunotherapy. The multimodal approach opens an avenue to induce robust immune responses, minimize safety issues, and monitor immune activities simultaneously. Thus, the object of this review is to provide an overview of the burgeoning fields and to highlight novel technologies for next-generation immunotherapy. The review further correlates the properties of MNPs with the latest treatment strategies to explore the crosstalk between magnetic nanomaterials and the immune system. This comprehensive review of MNP-derived immunotherapy covers the obstacles and opportunities for future development and clinical translation.
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http://dx.doi.org/10.1002/adhm.202001451DOI Listing
January 2021

Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8 T cells.

Sci Immunol 2020 09;5(51)

Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Fibroblastic reticular cells (FRCs) are stromal cells that actively promote the induction of immune responses by coordinating the interaction of innate and adaptive immune cells. However, whether and to which extent immune cell activation is determined by lymph node FRC reprogramming during acute viral infection has remained unexplored. Here, we genetically ablated expression of the type I interferon-α receptor () in Ccl19-Cre cells and found that sensing of type I interferon imprints an antiviral state in FRCs and thereby preserves myeloid cell composition in lymph nodes of naive mice. During localized lymphocytic choriomeningitis virus infection, IFNAR signaling precipitated profound phenotypic adaptation of all FRC subsets enhancing antigen presentation, chemokine-driven immune cell recruitment, and immune regulation. The IFNAR-dependent shift of all FRC subsets toward an immunostimulatory state reduced exhaustive CD8 T cell activation. In sum, these results unveil intricate circuits underlying type I IFN sensing in lymph node FRCs that enable protective antiviral immunity.
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http://dx.doi.org/10.1126/sciimmunol.abb7066DOI Listing
September 2020

Development and Characterization of a Fucoidan-Based Drug Delivery System by Using Hydrophilic Anticancer Polysaccharides to Simultaneously Deliver Hydrophobic Anticancer Drugs.

Biomolecules 2020 06 28;10(7). Epub 2020 Jun 28.

Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu 30010, Taiwan.

Fucoidan, a natural sulfated polysaccharide, which can activate the immune response and lessen adverse effects, is expected to be an adjuvant agent in combination with chemotherapy. Using natural hydrophilic anticancer polysaccharides to simultaneously encapsulate hydrophobic anticancer drugs is feasible, and a reduced side effect can be achieved to amplify the therapeutic efficacy. In this study, a novel type of fucoidan-PLGA nanocarrier (FPN-DTX) was developed for the encapsulation of the hydrophobic anticancer drug, docetaxel (DTX), as a drug delivery system. From the comparison between FPN-DTX and the PLGA particles without fucoidan (PLGA-DTX), FPNs-DTX with fucoidan were highly stable with smaller sizes and dispersed well without aggregations in an aqueous environment. The drug loading and release can be further modified by modulating relative ratios of Fucoidan (Fu) to PLGA. The (FPN 3-DTX) nanoparticles with a 10:3 ratio of Fu:PLGA displayed uniform particle size with higher encapsulation efficiency than PLGA NPs and sustained drug release ability. The biocompatible fucoidan-PLGA nanoparticles displayed low cytotoxicity without drug loading after incubation with MDA-MB-231 triple-negative breast cancer cells. Despite lower cellular uptake than that of PLGA-DTX due to a higher degree of negative zeta potential and hydrophilicity, FPN 3-DTX effectively exerted better anticancer ability, so FPN 3-DTX can serve as a competent drug delivery system.
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http://dx.doi.org/10.3390/biom10070970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408464PMC
June 2020

Circulating tumor-cell-targeting Au-nanocage-mediated bimodal phototherapeutic properties enriched by magnetic nanocores.

J Mater Chem B 2020 07;8(25):5460-5471

Graduate Institute of Biomedical Science, China Medical University, Taichung 40440, Taiwan. and Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu, Taiwan. and Frontier Research Centre on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan and School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Metastasis resulting from circulating tumor cells (CTCs) is associated with 90% of all cancer mortality. To disrupt cancer dissemination, therapeutic targeting of CTCs by extracorporeal photodynamic therapy (PDT) has emerged; however, it still remains impractical due to its limited therapeutic window. Herein, we developed a photosensitive and magnetic targeted core-satellite nanomedicine (TCSN) to augment the light-induced damage to the targeted cells. The magnetic nanocore (MNC) with multiple iron oxide nanoparticles stabilized using thiolated polyvinyl alcohol can magnetize the CTCs to achieve magnetic enrichment under a magnetic field. Multiple gold nanocage (AuNC) satellites were conjugated on the MNC to facilitate bimodal photothermal therapy and PDT. Adjusting the thiol content in the MNC allows manipulating the AuNC density on TCSNs, which has been found to demonstrate a density-dependent bimodal phototherapeutic effect under laser irradiation at 808 and 940 nm. Moreover, with the immobilization of anti-epithelial cell adhesion molecule (anti-EpCAM), TCSN exhibited an enhanced affinity toward EpCAM-expressing 4T1 cells. We demonstrate that TCSN-labeled 4T1 cells can be isolated and photo-eradicated in a microfluidic channel with a dynamic flow. Our studies showed that TCSN with the complementary properties of MNC and AuNCs can largely augment the therapeutic window by magnetic enrichment and bimodal phototherapy, serving as an advanced extracorporeal strategy to remove CTCs.
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http://dx.doi.org/10.1039/d0tb00501kDOI Listing
July 2020

Remodeling of light and dark zone follicular dendritic cells governs germinal center responses.

Nat Immunol 2020 06 18;21(6):649-659. Epub 2020 May 18.

Institute of Immunobiology, Medical Research Center, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Efficient generation of germinal center (GC) responses requires directed movement of B cells between distinct microenvironments underpinned by specialized B cell-interacting reticular cells (BRCs). How BRCs are reprogrammed to cater to the developing GC remains unclear, and studying this process is largely hindered by incomplete resolution of the cellular composition of the B cell follicle. Here we used genetic targeting of Cxcl13-expressing cells to define the molecular identity of the BRC landscape. Single-cell transcriptomic analysis revealed that BRC subset specification was predetermined in the primary B cell follicle. Further topological remodeling of light and dark zone follicular dendritic cells required CXCL12-dependent crosstalk with B cells and dictated GC output by retaining B cells in the follicle and steering their interaction with follicular helper T cells. Together, our results reveal that poised BRC-defined microenvironments establish a feed-forward system that determines the efficacy of the GC reaction.
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http://dx.doi.org/10.1038/s41590-020-0672-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610477PMC
June 2020

Visualization of T Cell Migration in the Spleen Reveals a Network of Perivascular Pathways that Guide Entry into T Zones.

Immunity 2020 05 15;52(5):794-807.e7. Epub 2020 Apr 15.

University of Oxford, Kennedy Institute of Rheumatology, OX3 7FY Oxford, UK. Electronic address:

Lymphocyte homeostasis and immune surveillance require that T and B cells continuously recirculate between secondary lymphoid organs. Here, we used intravital microscopy to define lymphocyte trafficking routes within the spleen, an environment of open blood circulation and shear forces unlike other lymphoid organs. Upon release from arterioles into the red pulp sinuses, T cells latched onto perivascular stromal cells in a manner that was independent of the chemokine receptor CCR7 but sensitive to Gi protein-coupled receptor inhibitors. This latching sheltered T cells from blood flow and enabled unidirectional migration to the bridging channels and then to T zones, entry into which required CCR7. Inflammatory responses modified the chemotactic cues along the perivascular homing paths, leading to rapid block of entry. Our findings reveal a role for vascular structures in lymphocyte recirculation through the spleen, indicating the existence of separate entry and exit routes and that of a checkpoint located at the gate to the T zone.
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http://dx.doi.org/10.1016/j.immuni.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237890PMC
May 2020

Patient-centered modeling of dynamic postoperative pain trajectories.

J Chin Med Assoc 2020 05;83(5):423-424

Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

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http://dx.doi.org/10.1097/JCMA.0000000000000294DOI Listing
May 2020

Completing Circular Bacterial Genomes With Assembly Complexity by Using a Sampling Strategy From a Single MinION Run With Barcoding.

Front Microbiol 2019 4;10:2068. Epub 2019 Sep 4.

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

The Oxford Nanopore MinION is an affordable and portable DNA sequencer that can produce very long reads (tens of kilobase pairs), which enable bacterial genome assembly. Although many algorithms and tools have been developed for base calling, read mapping, assembly, and polishing, an automated pipeline is not available for one-stop analysis for circular bacterial genome reconstruction. In this paper, we present the pipeline CCBGpipe for completing circular bacterial genomes. Raw current signals are demultiplexed and base called to generate sequencing data. Sequencing reads are assembled several times by using a sampling strategy to produce circular contigs that have a sequence in common between their start and end. The circular contigs are polished by using raw signals and sequencing reads; then, duplicated sequences are removed to form a linear representation of circular sequences. The circularized contigs are finally rearranged to start at the start position of / or a replication origin based on the GC skew. CCBGpipe implemented in Python is available at https://github.com/jade-nhri/CCBGpipe. Using sequencing data produced from a single MinION run, we obtained 48 circular sequences, comprising 12 chromosomes and 36 plasmids of 12 bacteria, including , , and . With adequate quantities of sequencing reads (80×), CCBGpipe can provide a complete and automated assembly of circular bacterial genomes.
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http://dx.doi.org/10.3389/fmicb.2019.02068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737777PMC
September 2019

Corrigendum to "The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells" [Chem. Biol. Interact. 302 (2019) 28-35].

Chem Biol Interact 2019 10 5;312:108812. Epub 2019 Sep 5.

Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.cbi.2019.108812DOI Listing
October 2019

Innovation in sedation and analgesia training.

Curr Opin Anaesthesiol 2019 Aug;32(4):472-479

Department of Anesthesiology, Taipei Veterans General Hospital.

Purpose Of Review: We reviewed evidence of recent innovations in sedation education and discuss experiences with sedation training in Taiwan.

Recent Findings: Current Status of Sedation Training: Didactic training and supervised clinical mentoring are common methods of sedation training. Although training course designed by professional societies to meet individual hospital credentialing requirements, the course content and training expectations vary and are likely inadequate to non-anesthesiologist sedation practitioners. Less Common Forms of Sedation Training: These include screen-based simulation, high-fidelity manikin-based simulation. Screen-based simulation sedation training is popular, convenient, and relatively inexpensive. Although there are numerous courses available, course content has not been standardized. High-fidelity simulation has been accepted to improve knowledge, self-confidence, awareness of emergency, crisis resource management, and teamwork, but it is costly, time intensive, and requires expertise in using simulation equipment. Although screen-based training is attractive and convenient, there is no evidence to suggest that it can replace high-fidelity simulation. Another recently developed education modality is virtual reality simulation. It has gained recent popularity as an immersive approach to medical training, but minimal content has been developed for sedation training. Beyond training, several other potential innovations may improve sedation effectiveness and patient safety. These include adherence to practice guidelines established by professional organizations, utilization of a pre-procedure sedation checklist, interpreting capnography, and implementation of real-time bedside drug displays that provide predictions of concentrations and their associated effects.

Summary: Effective sedation education and training, especially for nonanesthesiologists, is essential to improve patient safety for procedural sedation. Several innovative approaches have been proposed and are relatively early in their development and implementation. Further studies designed to assess the impact of these new training modalities on patient safety and outcomes are warranted.
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http://dx.doi.org/10.1097/ACO.0000000000000757DOI Listing
August 2019

A copper(ii)-dipicolylamine-coumarin sensor for maltosyltransferase assay.

Dalton Trans 2019 Jun 9;48(23):8026-8029. Epub 2019 May 9.

Department of Chemistry, National Taiwan University, Taipei 106, Taiwan. and The Genomics Research Centre, Academia Sinica, Taipei 115, Taiwan.

A Cu(ii)-[di(2-methylpyridyl)methylamino]coumarin fluorescence turn-on sensor (Cu-1b) is designed to detect phosphate ions with K = 1.4 × 10 M in HEPES buffer. Cu-1b is applied to probe the GlgE-catalyzed maltose-transfer reaction of α-maltose-1-phosphate to α-1,4-glucan with concomitant release of phosphate ions in Mycobacterium tuberculosis.
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http://dx.doi.org/10.1039/c9dt01339cDOI Listing
June 2019

Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer.

JAMA Oncol 2019 Jul;5(7):1043-1047

Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland.

Importance: Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy.

Objective: To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer.

Design, Setting, And Participants: This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year.

Main Outcomes And Measures: Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations).

Results: Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy.

Conclusions And Relevance: These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.
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http://dx.doi.org/10.1001/jamaoncol.2019.0402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487908PMC
July 2019

Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp.

Nat Commun 2019 04 15;10(1):1739. Epub 2019 Apr 15.

Institute of Immunobiology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.

The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here we establish fibroblastic reticular cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all reticular cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular reticular cells function both as adult lymphoid organizer cells and mural cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a multipotent periarterial progenitor cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of reticular cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.
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http://dx.doi.org/10.1038/s41467-019-09728-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465367PMC
April 2019

Centrosome guides spatial activation of Rac to control cell polarization and directed cell migration.

Life Sci Alliance 2019 02 8;2(1). Epub 2019 Feb 8.

Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

Directed cell migration requires centrosome-mediated cell polarization and dynamical control of focal adhesions (FAs). To examine how FAs cooperate with centrosomes for directed cell migration, we used centrosome-deficient cells and found that loss of centrosomes enhanced the formation of acentrosomal microtubules, which failed to form polarized structures in wound-edge cells. In acentrosomal cells, we detected higher levels of Rac1-guanine nucleotide exchange factor TRIO (Triple Functional Domain Protein) on microtubules and FAs. Acentrosomal microtubules deliver TRIO to FAs for Rac1 regulation. Indeed, centrosome disruption induced excessive Rac1 activation around the cell periphery via TRIO, causing rapid FA turnover, a disorganized actin meshwork, randomly protruding lamellipodia, and loss of cell polarity. This study reveals the importance of centrosomes to balance the assembly of centrosomal and acentrosomal microtubules and to deliver microtubule-associated TRIO proteins to FAs at the cell front for proper spatial activation of Rac1, FA turnover, lamillipodial protrusion, and cell polarization, thereby allowing directed cell migration.
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http://dx.doi.org/10.26508/lsa.201800135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369537PMC
February 2019

The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells.

Chem Biol Interact 2019 Apr 28;302:28-35. Epub 2019 Jan 28.

Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address:

The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.
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http://dx.doi.org/10.1016/j.cbi.2019.01.033DOI Listing
April 2019

Integrative Computational Modeling of the Lymph Node Stromal Cell Landscape.

Front Immunol 2018 23;9:2428. Epub 2018 Oct 23.

Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Adaptive immune responses develop in secondary lymphoid organs such as lymph nodes (LNs) in a well-coordinated series of interactions between migrating immune cells and resident stromal cells. Although many processes that occur in LNs are well understood from an immunological point of view, our understanding of the fundamental organization and mechanisms that drive these processes is still incomplete. The aim of systems biology approaches is to unravel the complexity of biological systems and describe emergent properties that arise from interactions between individual constituents of the system. The immune system is greater than the sum of its parts, as is the case with any sufficiently complex system. Here, we review recent work and developments of computational LN models with focus on the structure and organization of the stromal cells. We explore various mathematical studies of intranodal T cell motility and migration, their interactions with the LN-resident stromal cells, and computational models of functional chemokine gradient fields and lymph flow dynamics. Lastly, we discuss briefly the importance of hybrid and multi-scale modeling approaches in immunology and the technical challenges involved.
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http://dx.doi.org/10.3389/fimmu.2018.02428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206207PMC
September 2019

Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity.

Sci Immunol 2018 08;3(26)

Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in nonclassical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). Compared with classical secondary lymphoid organs such as lymph nodes and Peyer's patches, FALCs develop along distinct differentiation trajectories and display a reduced structural complexity. Although it is well established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of classical secondary lymphoid organs, the role of FRCs in FALC-dependent peritoneal immunity remains unclear. Using FRC-specific gene targeting, we found that FRCs play an essential role in FALC-driven immune responses. Specifically, we report that initiation of peritoneal immunity was governed through FRC activation in a myeloid differentiation primary response 88 (MYD88)-dependent manner. FRC-specific ablation of MYD88 blocked recruitment of inflammatory monocytes into FALCs and subsequent CD4 T cell-dependent B-cell activation and IgG class switching. Moreover, containment of infection was compromised in mice lacking MYD88 expression in FRCs, indicating that FRCs in FALCs function as an initial checkpoint in the orchestration of protective immune responses in the peritoneal cavity.
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http://dx.doi.org/10.1126/sciimmunol.aar4539DOI Listing
August 2018

Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy.

Nat Nanotechnol 2018 08 14;13(8):746-754. Epub 2018 May 14.

Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu, Taiwan, Republic of China.

Checkpoint immunotherapy that inhibits tumour immune evasion has demonstrated significant clinical success. However, the therapeutic response is limited to certain patient populations, and immunotoxicity as well as autoimmunity have compromised the therapeutic benefits. Here, we report on an inherently therapeutic fucoidan-dextran-based magnetic nanomedicine (IO@FuDex) conjugated with a checkpoint inhibitor (anti-PD-L1) and T-cell activators (anti-CD3 and anti-CD28). IO@FuDex can repair the immunosuppressive tumour microenvironment by reinvigorating tumour-infiltrating lymphocytes, while targeting the nanomedicine via magnetic navigation to the tumour to minimize off-target effects. Treatment that combines IO@FuDex and magnetic navigation reduces the occurrence of adverse events and extends the median survival from 32 to 63 days with less than 1 per cent dose compared with soluble anti-PD-L1. Thus, we demonstrate the potential of integrating anti-PD-L1 and T-cell activators as a form of inherently therapeutic nanomedicine to augment the therapeutic index of combination checkpoint immunotherapy.
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http://dx.doi.org/10.1038/s41565-018-0146-7DOI Listing
August 2018

Interleukin 7-expressing fibroblasts promote breast cancer growth through sustenance of tumor cell stemness.

Oncoimmunology 2018;7(4):e1414129. Epub 2018 Jan 3.

Institute of Immunobiology, Kantonsspital St. Gallen, Rorschacherstrasse 95, St. Gallen, Switzerland.

The tumor microenvironment harbors cancer-associated fibroblasts that function as major modulators of cancer progression. Here, we assessed to which extent distinct cancer-associated fibroblast subsets impact mammary carcinoma growth and cancer cell stemness in an orthotopic murine model. We found that fibroblasts expressing the Cre recombinase under the control of the interleukin 7 promoter occupied mainly the tumor margin where they physically interacted with tumor cells. Intratumoral ablation of interleukin 7-expressing fibroblasts impaired breast tumor growth and reduced the clonogenic potential of cancer cells. Moreover, cDNA expression profiling revealed a distinct oncogenic signature of interleukin 7-producing fibroblasts. In particular, expression was strongly enhanced in interleukin 7-producing fibroblasts and cell type-specific genetic ablation and systemic pharmacological inhibition revealed that the CXCL12/CXCR4 axis impacts breast tumor cell stemness. Elevated expression of and other stem cell factors in primary human breast cancer-associated fibroblasts indicates that certain fibroblast populations support tumor cell stemness and thereby promote breast cancer growth.
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http://dx.doi.org/10.1080/2162402X.2017.1414129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889213PMC
January 2018

A novel implant removal technique by endoscopy.

J Orthop Surg Res 2018 Apr 6;13(1):74. Epub 2018 Apr 6.

Department of Orthopaedic surgery, Chang Gung Memorial Hospital, Linkou Medical Center, #5, Fusing Street, Gueishan Township, Taoyuan County, 33305, Taiwan, Republic of China.

Background: Routine implant removal after fracture healing remains controversial. However, it has been suggested that implant removal should be performed in cases of joint impingement, painful scar adhesion, and implant malposition. Entrance selection is relatively critical in patients with poor soft tissue conditions or sloughing coverage. We propose an innovative technique using endoscopy.

Methods: Consecutive surgeries of endoscopic implant removal performed between 2005 and 2016 by a single experienced arthroscopic surgeon were included. Overall, 73 patients were enrolled; 44 were not eligible for inclusion and were excluded from the study.

Results: Twenty-nine patients, including 32 surgical sites, were included. Twenty-four plates and 166 screws were removed using this technique. There were five complications during the follow-up period (range, 0.5 to 104 months; mean, 8.8), including one broken screw, one persistent knee joint contracture, and three wound dehiscence. There were no infections or neurovascular injuries.

Conclusion: Implant removal using endoscopy is a minimally invasive surgery that ensures that the screw axis does not strip, and treats the intra-articular pathology concomitantly. This innovative technique may be considered as an alternative to the traditional open method in cases with good surgical indications.
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http://dx.doi.org/10.1186/s13018-018-0783-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889551PMC
April 2018

CCL19-producing fibroblastic stromal cells restrain lung carcinoma growth by promoting local antitumor T-cell responses.

J Allergy Clin Immunol 2018 10 31;142(4):1257-1271.e4. Epub 2018 Jan 31.

Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland. Electronic address:

Background: A particular characteristic of non-small cell lung cancer is the composition of the tumor microenvironment with a very high proportion of fibroblastic stromal cells (FSCs).

Objective: Lapses in our basic knowledge of fibroblast phenotype and function in the tumor microenvironment make it difficult to define whether FSC subsets exist that exhibit either tumor-promoting or tumor-suppressive properties.

Methods: We used gene expression profiling of lung versus tumor FSCs from patients with non-small cell lung cancer. Moreover, CCL19-expressing FSCs were studied in transgenic mouse models by using a lung cancer metastasis model.

Results: CCL19 mRNA expression in human tumor FSCs correlates with immune cell infiltration and intratumoral accumulation of CD8 T cells. Mechanistic dissection in murine lung carcinoma models revealed that CCL19-expressing FSCs form perivascular niches to promote accumulation of CD8 T cells in the tumor. Targeted ablation of CCL19-expressing tumor FSCs reduced immune cell recruitment and resulted in unleashed tumor growth.

Conclusion: These data suggest that a distinct population of CCL19-producing FSCs fosters the development of an immune-stimulating intratumoral niche for immune cells to control cancer growth.
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http://dx.doi.org/10.1016/j.jaci.2017.12.998DOI Listing
October 2018