Publications by authors named "Yu-An Chen"

76 Publications

Association Between Caregivers' Burden and Neuropsychiatric Symptoms in Female Patients with Alzheimer's Disease with Varying Dementia Severity.

J Multidiscip Healthc 2021 28;14:929-940. Epub 2021 Apr 28.

Department of Business Administration, National Changhua University of Education, Changhua, Taiwan.

Purpose: This study examined the attributes causing higher burdens for caregivers caring for female patients with Alzheimer's disease by analyzing a combination of various variables, including demographic data, dementia severity, and neuropsychiatric symptoms.

Patients And Methods: This study included 99 female patients with Alzheimer's disease who were cared for by the dementia collaborative care team at Changhua Christian Hospital, Taiwan. Neuropsychiatric symptoms used in this study included affections (9 types), behavior symptoms (9 symptoms), and psychological symptoms (3 symptoms). The Apriori algorithm was employed to identify association rules that reveal the relationships among demographic data, dementia severity, neuropsychiatric symptoms, and caregivers' burden.

Results: A total of 185 rules were determined, including 51 rules with little or no burden, 108 rules with mild to moderate burden, and 26 rules with moderate to severe burden. The major findings are as follows. Neuropsychiatric symptoms were associated with varying degrees of caregivers' burden among female patients aged 75 to 84 years with mild dementia. Crying spells and aggression were specifically associated with a moderate to severe burden. Delusion was associated with a mild to moderate and moderate to severe burden. Dysthymia and depression were associated with little or no burden to moderate to severe burden.

Conclusion: Clinicians can provide early interventions to reduce the burden of caregivers caring for female patients with Alzheimer's disease and can refer caregivers for timely assistance to reduce their burden.
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http://dx.doi.org/10.2147/JMDH.S298196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090980PMC
April 2021

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Nat Med 2021 May 3. Epub 2021 May 3.

Department of Pathology, Harvard Medical School, Brigham and Woman's Hospital, Boston, MA, USA.

Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
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http://dx.doi.org/10.1038/s41591-021-01331-8DOI Listing
May 2021

The Optimal Application of Medium Potency Topical Corticosteroids in Preventing Laser-Induced Inflammatory Responses-An Animal Study.

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Department and Graduate Institute of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan.

Background: During ablative fractional resurfacing (AFR) laser therapy, thermal damage to the skin is inevitable, resulting in inflammatory responses and small wounds. Corticosteroids are known for their anti-inflammatory effect. However, inappropriate application of corticosteroids carries the risk of delayed wound healing. Therefore, we aimed to find the optimal administration route, timing, and duration of medium potency corticosteroid treatment to prevent AFR laser-induced inflammatory responses and to minimize the risk of delayed wound healing.

Methods: We determined the anti-inflammatory efficacy of corticosteroids by skin erythema and tissue biopsies on C57BL/6 mice. Wound healing was evaluated by crust area and epithelial gap. Finally, Masson's trichrome stain and α-SMA immunohistochemistry stain were used to analyze scar contracture.

Results: Our results demonstrated that one dose of medium-potency topical corticosteroid applied immediately after AFR laser treatment could prevent erythema effectively with minimal disruption to wound healing. Notably, when more than one dose was administered, wound healing was delayed and scar contracture was aggravated by the application of medium-potency topical corticosteroids in a dosage-dependent manner.

Conclusion: Our findings suggested that single-dose medium-potency topical corticosteroids could potentially improve AFR laser-induced acute inflammatory responses in clinical applications.
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http://dx.doi.org/10.3390/life11040350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073345PMC
April 2021

Base-width modulation effects on the optoelectronic characteristics of n-ITO/p-NiO/n-ZnO heterojunction bipolar phototransistors.

Nanotechnology 2021 Apr 22. Epub 2021 Apr 22.

Department of Electrophysics, National Chiayi University, Chiayi, TAIWAN.

ITO/NiO/ZnO npn heterojunction bipolar phototransistors (HBPTs) with various base widths are fabricated using a radio-frequency sputtering system. The effects of base-width modulation on the optoelectronic characteristics of the prepared HBPTs are studied. The dark current of HBPTs decreases with increasing base width because the injected electrons from the emitter are recombined in the wide base region. The photocurrent increases with decreasing base width, which is attributed to higher emitter-base injection efficiency. The responsivity increases with the collector-emitter voltage (VCE) in the HBPTs with a 100 nm base width, whereas the responsivity sharply decreases at VCE > 4 V for the HBPTs with a thinner base width (80 nm) due to the punch-through effect. In contrast, the responsivity approaches saturation at large VCE for HBPTs with a thicker base width (120 nm). The responsivity and detectivity decrease with increasing incident light intensity, which is caused by an increase in the base recombination loss. The HBPTs with a base width of 100 nm exhibits the largest responsivity and detectivity; their detectivity is higher than that of HBPTs with base widths of 80 and 120 nm by approximately two and three orders, respectively.
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http://dx.doi.org/10.1088/1361-6528/abfabdDOI Listing
April 2021

Bacterial Genotoxin-Coated Nanoparticles for Radiotherapy Sensitization in Prostate Cancer.

Biomedicines 2021 Feb 4;9(2). Epub 2021 Feb 4.

Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan.

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and usually becomes refractory because of recurrence and metastasis. CD44, a transmembrane glycoprotein, serves as a receptor for hyaluronic acid (HA). It has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin (CDT), produced by , is a tripartite genotoxin composed of CdtA, CdtB, and CdtC subunits. Among the three, CdtB acts as a type I deoxyribonuclease (DNase I), which creates DNA double-strand breaks (DSBs). Nanoparticles loaded with antitumor drugs and specific ligands that recognize cancerous cell receptors are promising methods to overcome the therapeutic challenges. In this study, HA-decorated nanoparticle-encapsulated CdtB (HA-CdtB-NPs) were prepared and their targeted therapeutic activity in radioresistant PCa cells was evaluated. Our results showed that HA-CdtB-NPs sensitized radioresistant PCa cells by enhancing DSB and causing G2/M cell-cycle arrest, without affecting the normal prostate epithelial cells. HA-CdtB-NPs possess maximum target specificity and delivery efficiency of CdtB into the nucleus and enhance the effect of radiation in radioresistant PCa cells. These findings demonstrate that HA-CdtB-NPs exert target specificity accompanied with radiomimetic activity and can be developed as an effective strategy against radioresistant PCa.
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http://dx.doi.org/10.3390/biomedicines9020151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913852PMC
February 2021

Multi-scalar and Multi-dimensional Conceptions of Social Capital and Mental Health Impacts After Disaster: The case of Hurricane Harvey.

Disasters 2021 Jan 11. Epub 2021 Jan 11.

University at Buffalo.

While much research investigates how social capital relates to mental health after disasters, less work employs a multi-scalar, multi-dimensional framework on social capital. We apply such a framework of social capital to an analysis of novel survey data of approximately 1,000 urban and rural Texans after Hurricane Harvey. On the individual level, we find that greater social support is linked to less mental health impacts, but that greater civic and organizational engagement is linked to greater mental health impacts. At the community level, we find that neither a density of bridging social capital organizations nor of bonding social capital organizations is associated with poorer mental health, although we find that greater bonding organizations are linked to negative mental health impacts for rural residents. We conclude by focusing on how individual and community social capital relationships with mental health are contingent on measurement, scale, and rural or urban location. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/disa.12474DOI Listing
January 2021

Epigallocatechin Gallate Reduces Homocysteine-Caused Oxidative Damages through Modulation SIRT1/AMPK Pathway in Endothelial Cells.

Am J Chin Med 2021 26;49(1):113-129. Epub 2020 Dec 26.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.

Elevated plasma concentration of total homocysteine is a pathological condition that causes vascular endothelial injury and subsequently leads to the progression of endothelial apoptosis in atherosclerosis. Epigallocatechin gallate (EGCG), a well-known anti-oxidant in green tea, has been reported with benefits on metabolic and cardiovascular diseases. This study aimed to explore that EGCG ameliorates homocysteine-induced endothelial cell apoptosis through enhancing the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) survival signaling pathway. Human umbilical endothelial cells were treated with homocysteine in the presence or absence of EGCG. We found that EGCG significantly increased the activities of SIRT1 and AMPK. EGCG diminished homocysteine-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation by inhibiting protein kinase C activation as well as reactive oxygen species (ROS) generation and recovered the activity of the endogenous antioxidant enzyme, superoxidase dismutase (SOD). Besides, EGCG also restores homocysteine-mediated dephosphorylation of Akt and decreases endothelial NO synthase (eNOS) expression. Furthermore, EGCG ameliorates homocysteine-activated pro-apoptotic events. The present study shows that EGCG prevents homocysteine-induced endothelial cell apoptosis via enhancing SIRT1/AMPK as well as Akt/eNOS signaling pathways. Results from this study indicated that EGCG might have some benefits for hyperhomocysteinemia.
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http://dx.doi.org/10.1142/S0192415X21500063DOI Listing
December 2020

Quantitative measurements of IR780 in formulations and tissues.

J Pharm Biomed Anal 2021 Feb 20;194:113780. Epub 2020 Nov 20.

Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address:

Purpose: IR780 iodide, a promising near-infrared dye, is widely used to prepare nanoparticles as a theranostic agent for tumor imaging and therapy. However, there are no validated (bio)analytical methods to measure IR780 in nanoparticles and tissues in literature. The aim of this study is to develop and validate a new HPLC method to measure IR780 concentration in IR780 formulations as well as a new LC-MS/MS method to measure IR780 concentration in tissue samples, particularly in liver and lung.

Materials And Methods: IR780 granules that produced IR780 in situ self-assembled nanoparticles upon contact with water were prepared at two drug loadings (0.2 % and 0.37 %). An HPLC method was developed and validated to measure IR780 concentrations in IR780 granules and nanoparticles. Furthermore, a validated LC-MS/MS method was developed to measure IR780 in mouse liver and lung. Both HPLC method and LC-MS/MS method were validated in terms of specificity, stability, linearity, limit of detection, limit of quantification, accuracy and precision.

Results: Both HPLC method and LC-MS/MS method achieved the criteria for method validation. The HPLC method was accurate in the concentration range of 0.5-25 μg/mL. The measured drug loadings were 95 % of the theoretical drug loadings. The validated LC-MS/MS method can quantitatively measure the concentrations of IR780 in liver and lung. The linear range of the LC-MS/MS method was 1-1000 ng/mL for both liver and lung samples. IR780 granules showed the lung selectivity compared to IR780 solution at 2 h after oral administration.

Conclusion: A validated HPLC method was developed to measure IR780 concentration in pharmaceutical formulations and a validated LC-MS/MS method was developed to measure IR780 concentration in tissues. These quantitative methods provide reliable measurements of IR780 in pharmaceutic formulations and biological samples, which will significantly facilitate the research of IR780 as a theranostic agent for cancer therapy and imaging.
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http://dx.doi.org/10.1016/j.jpba.2020.113780DOI Listing
February 2021

Ambient sulfur dioxide could have an impact on testicular volume from a observational study on a population of infertile male.

BMC Urol 2020 Oct 2;20(1):149. Epub 2020 Oct 2.

Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, No.1, Changde St., Zhongzheng Dist, Taipei City, 10048, Taiwan.

Background: The effect of ambient pollutants on the male reproductive system is controversial. This retrospective study investigated the effect of environmental pollutants on male reproductive health.

Methods: Male patients with primary infertility (n = 282) were identified from a single center between January 2016 and December 2017. Patients were physically examined for the presence of varicocele and for the volume of both testicles. Semen quality was measured in terms of the total sperm count, sperm concentration, and the percentage of sperm cells with motility and normal morphology. Data were acquired on the concentration of ambient pollutants, namely particulate matters of diameter < 2.5 μm, sulfur dioxide (SO), nitrogen oxides (NO), and ozone (O), measured on daily and hourly basis, from the Environmental Protection Administration Executive Yuan, Taiwan. Individual exposure to pollutants was estimated based on the reported residential address of each participant. Statistical analysis indicated the effect of each pollutant on the testicular volume, sex hormone profile, and semen parameters.

Results: The mean ± standard deviation of age was 36.7 ± 7.3 years. The average sperm count and concentration were 41.9 million/mL and 34.1 million/mL, respectively. The mean levels of serum testosterone, follicle-stimulating hormone, and luteinizing hormone were 3.57 ± 1.68 ng/mL, 7.59 ± 6.3 IU/L, and 4.68 ± 3.49 IU/L, respectively. According to the multivariate linear regression model, NO exposure was a risk factor for decreased sperm concentration and motility (p = 0.043 and 0.032). Furthermore, SO exposure was negatively associated and testicular volume (p < 0.01).

Conclusions: NO and SO exposure were negatively associated with the seminal parameter and decreased testicular volume, respectively, in a population of men with infertility. However, additional prospective studies are needed to ascertain the cause-effect relation of current results.
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http://dx.doi.org/10.1186/s12894-020-00710-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530959PMC
October 2020

Anticancer Efficacy of Oral Docetaxel Nanoformulation for Metronomic Chemotherapy in Metastatic Lung Cancer.

J Biomed Nanotechnol 2020 May;16(5):583-593

Metronomic chemotherapy, giving low doses of chemotherapeutics (e.g., docetaxel) on a frequent schedule over a long time, may improve outcomes and reduce side effects for cancer patients. Oral medications are vital for applying metronomic chemotherapy. However, low solubility, low absorption, low drug availability in the targeted tissue, and side effects limit the development of oral chemotherapeutics. Many chemotherapeutics are intravenously delivered. In this work, we developed a new docetaxel granule that produces docetaxel-loaded self-assembled nanoparticle (180 nm) upon contact with water. The process of manufacturing docetaxel granules is scalable in industrial settings. The lung selectivity of docetaxel granule was observed in animals. The mechanistic studies demonstrated the nanoparticle bound with red blood cells, which selectively delivers docetaxel to the lungs. Finally, docetaxel granule (5 mg/kg twice per week) can profoundly inhibit the tumor growth of lung-metastatic cancer xenograft model over 24 days. The material-based lungselective oral nanoformulation provides an opportunity for conventionally intravenous chemotherapy drugs to be easily applied in oral administration for metronomic chemotherapy for cancer patients with lung cancers.
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http://dx.doi.org/10.1166/jbn.2020.2925DOI Listing
May 2020

Hyperfluorescence Imaging of Kidney Cancer Enabled by Renal Secretion Pathway Dependent Efflux Transport.

Angew Chem Int Ed Engl 2021 01 26;60(1):351-359. Epub 2020 Oct 26.

Department of Chemistry and Biochemistry, The University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX, 75080, USA.

Renal tubular secretion is an active efflux pathway for the kidneys to remove molecules but has yet to be used to enhance kidney cancer targeting. We report indocyanine green (ICG) conjugated with a 2100 Da PEG molecule (ICG-PEG45) as a renal-tubule-secreted near-infrared-emitting fluorophore for hyperfluorescence imaging of kidney cancers, which cannot be achieved with hepatobiliary- and glomerular-clearable ICG. This pathway-dependent targeting of kidney cancer arises from the fact that the secretion pathway enables ICG-PEG45 to be effectively effluxed out of normal proximal tubules through P-glycoprotein transporter while being retained in cancerous kidney tissues with low P-glycoprotein expression. Tuning elimination pathways and utilizing different efflux kinetics of medical agents in normal and diseased tissues could be a new strategy for tackling challenges in disease diagnosis and treatments that cannot be addressed with passive and ligand-receptor-mediated active targeting.
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http://dx.doi.org/10.1002/anie.202010187DOI Listing
January 2021

Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.

Nat Cell Biol 2020 09 24;22(9):1130-1142. Epub 2020 Aug 24.

Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.

Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
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http://dx.doi.org/10.1038/s41556-020-0560-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484425PMC
September 2020

Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo.

Cancers (Basel) 2020 Aug 5;12(8). Epub 2020 Aug 5.

Laboratory of Molecular Immunology, Institute of Molecular Medicine, National Cheng Kung University, College of Medicine, Tainan 70101 Taiwan.

Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.
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http://dx.doi.org/10.3390/cancers12082189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464583PMC
August 2020

Colonization With Multidrug-Resistant Organisms Among Healthy Adults in the Community Setting: Prevalence, Risk Factors, and Composition of Gut Microbiome.

Front Microbiol 2020 24;11:1402. Epub 2020 Jun 24.

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

Background: The prevalence of colonization with multidrug-resistant organisms (MDROs) among healthy adults in the community is largely unknown. This study investigated the colonization rate of multidrug-resistant , methicillin-resistant (MRSA), and vancomycin-resistant enterococci (VRE) in the community in Taiwan, and compared the gut microbiota between MDRO carriers and non-carriers.

Methods: This prospective cohort study was conducted from March 2017 to February 2018 at the Hsin-Chu and Jin-Shan branches of National Taiwan University Hospital. Nasal swabs and stool samples were obtained from healthy adults attending a health examination to screen for MDROs. Bacteria isolates of MDROs were tested for antibiotic susceptibility and resistant genes. Relevant data were collected using a standardized questionnaire to evaluate the risk factors for MDROs carriage, and 16S rRNA metagenomics sequencing was performed to analyze gut microbiota.

Results: Among 187 participants, 4.6% (8/174) carried MRSA and 41.4% (77/186) carried third-generation cephalosporin-resistant (3GC-R) or . The carriage rate of AmpC beta-lactamases and ESBL-producing strains were 16.1 and 27.4%, respectively. No carbapenem-resistant (CRE) or VRE were detected. The dominant resistant gene of isolates was CTX-M-type (73%), while that of was AmpC beta-lactamases (80%). In the multivariate analysis, the significant risk factors for carrying 3GC-R or were being an employee of technology company A [adjusted odds ratio (aOR) 4.127; 95% confidence interval (CI) 1.824-9.336; = 0.001], and traveling to Southeast Asia in the past year (aOR 6.545; 95% CI 1.071-40.001; = 0.042). The gut microbiota analysis showed that the phylum and the family were significantly more abundant in 3GC-R and carriers.

Conclusion: A high rate of Taiwanese adults in the community carried 3GC-R , while no CRE or VRE colonization was noted. Compared with non-carriers, an expansion of in gut microbiota was found among 3GC-R carriers.
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http://dx.doi.org/10.3389/fmicb.2020.01402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328365PMC
June 2020

Three-Dimensional Two-Color Dual-Particle Tracking Microscope for Monitoring DNA Conformational Changes and Nanoparticle Landings on Live Cells.

ACS Nano 2020 07 15;14(7):7927-7939. Epub 2020 Jul 15.

Department of Biomedical Engineering, The University of Texas at Austin, 107 West Dean Keeton Street, BME Building, Austin, Texas 78712, United States.

Here, we present a three-dimensional two-color dual-particle tracking (3D-2C-DPT) technique that can simultaneously localize two spectrally distinct targets in three dimensions with a time resolution down to 5 ms. The dual-targets can be tracked with separation distances from 33 to 250 nm with tracking precisions of ∼15 nm (for static targets) and ∼35 nm (for freely diffusing targets). Since each target is individually localized, a wealth of data can be extracted, such as the relative 3D position, the 2D rotation, and the separation distance between the two targets. Using this technique, we turn a double-stranded DNA (dsDNA)-linked dumbbell-like dimer into a nanoscopic optical ruler to quantify the bending dynamics of nicked or gapped dsDNA molecules in free solution by manipulating the design of dsDNA linkers (1-nick, 3-nt, 6-nt, or 9-nt single-strand gap), and the results show the increase of (linear to bent) from 3.2 to 10.7 s. The 3D-2C-DPT is then applied to observe translational and rotational motions of the landing of an antibody-conjugated nanoparticle on the plasma membrane of living cells, revealing the reduction of rotations possibly due to interactions with membrane receptors. This study demonstrates that this 3D-2C-DPT technique is a new tool to shed light on the conformational changes of biomolecules and the intermolecular interactions on plasma membrane.
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http://dx.doi.org/10.1021/acsnano.9b08045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456512PMC
July 2020

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.

Nat Commun 2020 03 19;11(1):1459. Epub 2020 Mar 19.

Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
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http://dx.doi.org/10.1038/s41467-020-15315-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081234PMC
March 2020

Long-Term Surveillance of Antibiotic Prescriptions and the Prevalence of Antimicrobial Resistance in Non-Fermenting Gram-Negative Bacilli.

Microorganisms 2020 Mar 12;8(3). Epub 2020 Mar 12.

School of Medicine, Department of Medical Laboratory Science and Biotechnology, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.

The increasing emergence of multidrug-resistant (MDR) bacteria has been recognized as a public health threat worldwide. Hospitalized patients and outpatients are commonly infected by non-fermenting Gram-negative bacilli (NFGNB), particularly the - complex (ACB) and . Antimicrobial agents are critical for treating the nosocomial infections caused by NFGNB. The aim of this study was to assess antimicrobial resistance and the use of antimicrobial agents. The bacterial isolates of 638,152 specimens from both inpatients and outpatients, retrieved from 2001 to 2008 at a medical center in central Taiwan, were examined for their susceptibility to various antimicrobial agents, including cefepime, imipenem, ciprofloxacin, gentamicin, amikacin, meropenem, and levofloxacin. Administrated prescriptions of the monitored antibiotics were analyzed using the Taiwan National Health Insurance Research Database (NHIRD). Our results show that the defined daily doses (DDDs) for cefepime, imipenem, and ciprofloxacin increased with time, and a trend toward reduced antimicrobial sensitivities of both ACB and was noticeable. In conclusion, the antimicrobial sensitivities of ACB and were reduced with the increased use of antibiotics. Continuous surveillance of antibiotic prescriptions and the prevalence of emerging resistance in nosocomial infections is warranted.
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http://dx.doi.org/10.3390/microorganisms8030397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142802PMC
March 2020

Comparative Performance of Comorbidity Measures in Predicting Health Outcomes in Patients with Chronic Obstructive Pulmonary Disease.

Int J Chron Obstruct Pulmon Dis 2020 12;15:335-344. Epub 2020 Feb 12.

Faculty of Pharmacy, School of Pharmaceutical Science, National Yang-Ming University, Taipei 112, Taiwan.

Purpose: Multiple studies have suggested that comorbidities pose negative impacts on the survival of patients with chronic obstructive pulmonary disease (COPD); few have applied comorbidity measures driven from health insurance claims databases to predict various health outcomes. We aimed to examine the performance of commonly used comorbidity measures based on diagnosis and pharmacy dispensing claims information in predicting future death and hospitalization in COPD patients.

Methods: We identified COPD patients in a population-based Taiwanese database. We built logistic regression models with age, sex, and baseline comorbidities measured by either diagnosis or pharmacy claims information as predictors of subsequent-year death or hospitalization in a random 50% sample and validated the discrimination in the other 50%. The diagnosis-based comorbidity measures included the Charlson Index and the Elixhauser comorbidity measure; the pharmacy-based comorbidity measures included the updated Chronic Disease Score (CDS) and the Pharmacy-Based Comorbidity Index (PBDI).

Results: We identified 428,251 eligible patients. For overall death, the Elixhauser comorbidity measure showed the best predictive performance (c-statistic=0.832), followed by the PBDI (c-statistic=0.822), the Charlson Index (c-statistic=0.815), and the updated CDS (c-statistic=0.808). For overall hospitalization, the PBDI (c-statistics=0.730) and the Elixhauser comorbidity measure (c-statistics=0.724) outperformed the updated CDS (c-statistics=0.714) and the Charlson Index (c-statistics=0.710). For hospitalization due to cardiovascular, cerebrovascular, or respiratory diseases, the comorbidity models showed similar predictive ranks and demonstrated c-statistics higher than 0.75. However, none of the models could adequately predict hospitalization due to other reasons (c-statistics < 0.60).

Conclusion: Our study comprehensively compared the predictive performance of comorbidity measures. The Elixhauser comorbidity measure and the PBDI are useful tools for describing comorbid conditions and predicting health outcomes in COPD patients.
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http://dx.doi.org/10.2147/COPD.S229646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024789PMC
February 2021

Cellular evasion strategies of Helicobacter pylori in regulating its intracellular fate.

Semin Cell Dev Biol 2020 05 4;101:59-67. Epub 2020 Feb 4.

Biomedical Science and Engineering Center, National Tsing Hua University, Hsinchu, Taiwan; Institute of Molecular and Cellular Biology & Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Helicobacter pylori colonizes human stomach mucosa and its infection causes gastrointestinal diseases with variable severity. Bacterial infection stimulates autophagy, which is a part of innate immunity used to eliminate intracellular pathogens. Several intracellular bacteria have evolved multipronged strategies to circumvent this conserved system and thereby enhance their chance of intracellular survival. Nonetheless, studies on H. pylori have produced inconsistent results, showing either elevated or reduced clearance efficiency of intracellular bacteria through autophagy. In this review, we summarize recent studies on the mechanisms involved in autophagy induced by H. pylori and the fate of intracellular bacteria.
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http://dx.doi.org/10.1016/j.semcdb.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102552PMC
May 2020

Minerva: a light-weight, narrative image browser for multiplexed tissue images.

J Open Source Softw 2020 15;5(54). Epub 2020 Oct 15.

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA.

Advances in highly multiplexed tissue imaging are transforming our understanding of human biology by enabling detection and localization of 10-100 proteins at subcellular resolution (Bodenmiller, 2016). Efforts are now underway to create public atlases of multiplexed images of normal and diseased tissues (Rozenblatt-Rosen et al., 2020). Both research and clinical applications of tissue imaging benefit from recording data from complete specimens so that data on cell state and composition can be studied in the context of overall tissue architecture. As a practical matter, specimen size is limited by the dimensions of microscopy slides (2.5 × 7.5 cm or ~2-8 cm of tissue depending on shape). With current microscopy technology, specimens of this size can be imaged at sub-micron resolution across ~60 spectral channels and ~10 cells, resulting in image files of terabyte size. However, the rich detail and multiscale properties of these images pose a substantial computational challenge (Rashid et al., 2020). See Rashid et al. (2020) for an comparison of existing visualization tools targeting these multiplexed tissue images.
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http://dx.doi.org/10.21105/joss.02579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989801PMC
October 2020

Highly multiplexed immunofluorescence images and single-cell data of immune markers in tonsil and lung cancer.

Sci Data 2019 12 17;6(1):323. Epub 2019 Dec 17.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

In this data descriptor, we document a dataset of multiplexed immunofluorescence images and derived single-cell measurements of immune lineage and other markers in formaldehyde-fixed and paraffin-embedded (FFPE) human tonsil and lung cancer tissue. We used tissue cyclic immunofluorescence (t-CyCIF) to generate fluorescence images which we artifact corrected using the BaSiC tool, stitched and registered using the ASHLAR algorithm, and segmented using ilastik software and MATLAB. We extracted single-cell features from these images using HistoCAT software. The resulting dataset can be visualized using image browsers and analyzed using high-dimensional, single-cell methods. This dataset is a valuable resource for biological discovery of the immune system in normal and diseased states as well as for the development of multiplexed image analysis and viewing tools.
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http://dx.doi.org/10.1038/s41597-019-0332-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917801PMC
December 2019

Semaphorin 5A suppresses the proliferation and migration of lung adenocarcinoma cells.

Int J Oncol 2020 Jan 2;56(1):165-177. Epub 2019 Dec 2.

Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan, R.O.C.

Semaphorin 5A (SEMA5A), a member of the semaphorin family, plays an important role in axonal guidance. Previously, the authors identified another possible role of SEMA5A as a prognostic biomarker for non‑smoking women with lung adenocarcinoma in Taiwan, and this phenomenon has been validated in other ethnic groups. However, the functional significance of SEMA5A in lung adenocarcinoma remains unclear. Therefore, we assessed the function of SEMA5A in three lung adenocarcinoma cell lines in this study. Kaplan‑Meier Plotter for lung cancer was conducted for survival analyses. Reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis were performed to investigate the expression and post‑translational regulation of SEMA5A in lung adenocarcinoma cell lines. A pre‑designed PyroMark CpG assay and 5‑aza‑2'‑deoxycytidine treatment were used to measure the methylation levels of SEMA5A. The biological functions of lung adenocarcinoma cells overexpressing SEMA5A were investigated by microarrays, and validated both in vitro (proliferation, colony formation and migration assays) and in vivo (tumor xenografts) experiments. The results revealed that the hypermethylation of SEMA5A and the cleavage of the extracellular domain of SEMA5A were responsible for the downregulation of the SEMA5A levels in lung adenocarcinoma cells (A549 and H1299) as compared to the normal controls. Functional analysis of SEMA5A‑regulated genes revealed that they were involved in cellular growth and proliferation. The overexpression of SEMA5A in A549 and H1299 cells significantly decreased the proliferation (P<0.01), colony formation (P<0.001) and migratory ability (P<0.01) of the cells. The suppressive effects of SEMA5A on the proliferative and migratory ability of the cells were also observed in both in vitro and in vivo experiments using brain metastatic Bm7 lung adenocarcinoma cells. On the whole, the findings of this study suggest a suppressive role for SEMA5A in lung adenocarcinoma involving the inhibition of the proliferation and migration of lung transformed cells.
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http://dx.doi.org/10.3892/ijo.2019.4932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910195PMC
January 2020

WWOX Possesses -Terminal Cell Surface-Exposed Epitopes WWOX and WWOX for Signaling Cancer Growth Suppression and Prevention In Vivo.

Cancers (Basel) 2019 Nov 19;11(11). Epub 2019 Nov 19.

Laboratory of Molecular Immunology, Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal-2. Alternatively, WWOX undergoes self-polymerization and localizes in the cell membrane. Proapoptotic pY33-WWOX binds Hyal-2, and TGF-β induces internalization of the pY33-WWOX/Hyal-2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14-WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface-exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3-dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7-21 peptide, or truncation to 5-amino acid WWOX7-11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33-WWOX, downregulation of prosurvival pERK, prompt increases in Ca influx, and disruption of the IkBα/WWOX/ERK prosurvival signaling. In contrast, pS14-WWOX7-21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib-mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14-WWOX significantly enhanced the ceritinib-induced apoptosis. Together, the -terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.
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http://dx.doi.org/10.3390/cancers11111818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895976PMC
November 2019

The paracrine induction of prostate cancer progression by caveolin-1.

Cell Death Dis 2019 11 4;10(11):834. Epub 2019 Nov 4.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer (CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial-mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.
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http://dx.doi.org/10.1038/s41419-019-2066-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828728PMC
November 2019

Induces IL-33 Production and Recruits ST-2 to Lipid Rafts to Exacerbate Inflammation.

Cells 2019 10 21;8(10). Epub 2019 Oct 21.

Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

colonizes human gastric epithelial cells and contributes to the development of several gastrointestinal disorders. Interleukin (IL)-33 is involved in various immune responses, with reported proinflammatory and anti-inflammatory effects, which may be associated with colitis and colitis-associated cancer. IL-33 induces the inflammatory cascade through its receptor, suppression of tumorigenicity-2 (ST-2). Binding of IL-33 to membrane-bound ST-2 (mST-2) recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates intracellular signaling pathways. However, whether IL-33/ST-2 is triggered by infection and whether this interaction occurs in lipid rafts remain unclear. Our study showed that both IL-33 and ST-2 expression levels were significantly elevated in -infected cells. Confocal microscopy showed that ST-2 mobilized into the membrane lipid rafts during infection. Depletion of membrane cholesterol dampened -induced IL-33 and IL-8 production. Furthermore, in vivo studies revealed IL-33/ST-2 upregulation, and severe leukocyte infiltration was observed in gastric tissues infected with . Together, these results demonstrate that ST-2 recruitment into the lipid rafts serves as a platform for IL-33-dependent infection, which aggravates inflammation in the stomach.
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http://dx.doi.org/10.3390/cells8101290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830106PMC
October 2019

The dysfunctional lipids in prostate cancer.

Am J Clin Exp Urol 2019 15;7(4):273-280. Epub 2019 Aug 15.

Department of Urology, University of Texas Southwestern Medical Center Dallas, TX 75390, USA.

Prostate cancer (PCa) is well-recognized as a lipid-enriched tumor. Lipids represent a diverse array of molecules essential to the cellular structure, defense, energy, and communication. Lipid metabolism can often become dysregulated during tumor development. The increasing body of knowledge on the biological actions of steroid hormone-androgens in PCa has led to the development of several targeted therapies that still represent the standard of care for cancer patients to this day. Sequencing technologies for functional analyses of androgen receptors (ARs) have revealed that AR is also a master regulator of cellular energy metabolism such as fatty acid ß-oxidation, and de novo lipid synthesis. In addition, bioactive lipids are also used as physiological signaling molecules, which have been shown to be involved in PCa progression. This review discusses the potent player(s) in altered lipid metabolism of PCa and describes how lipids and their interactions with proteins can be used for therapeutic advantage. We also discuss the possibility that the altered bioactive lipid mediators affect intracellular signaling pathway and the related transcriptional regulation be of therapeutic interest.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734041PMC
August 2019

Using proteomic profiling to characterize protein signatures of different thymoma subtypes.

BMC Cancer 2019 Aug 13;19(1):796. Epub 2019 Aug 13.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.

Background: Histology is a traditional way to classify subtypes of thymoma, because of low cost and convenience. Yet, due to the diverse morphology of thymoma, this method increases the complexity of histopathologic classification, and requires experienced experts to perform correct diagnosis. Therefore, in this study, we developed an alternative method by identifying protein biomarkers in order to assist clinical practitioners to make right classification of thymoma subtypes.

Methods: In total, 204 differentially expressed proteins in three subtypes of thymoma, AB, B2, and B3, were identified using mass spectrometry. Pathway analysis showed that the differentially expressed proteins in the three subtypes were involved in activation-related, signaling transduction-related and complement system-related pathways. To predict the subtypes of thymoma using the identified protein signatures, a support vector machine algorithm was used. Leave-one-out cross validation methods and receiver operating characteristic analysis were used to evaluate the predictive performance.

Results: The mean accuracy rates were > 80% and areas under the curve were ≧0.93 across these three subtypes. Especially, subtype B3 had the highest accuracy rate (96%) and subtype AB had the greatest area under the curve (0.99). One of the differentially expressed proteins COL17A2 was further validated using immunohistochemistry.

Conclusions: In summary, we identified specific protein signatures for accurately classifying subtypes of thymoma, which could facilitate accurate diagnosis of thymoma patients.
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http://dx.doi.org/10.1186/s12885-019-6023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693091PMC
August 2019

Strategies by which WWOX-deficient metastatic cancer cells utilize to survive via dodging, compromising, and causing damage to WWOX-positive normal microenvironment.

Cell Death Discov 2019 21;5:97. Epub 2019 May 21.

1Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.

Proapoptotic tumor suppressor WWOX is upregulated in the early stage of cancer initiation, which probably provides limitation to cancer growth and progression. Later, WWOX protein is reduced to enhance cancer cell growth, migration, invasiveness and metastasis. To understand how WWOX works in controlling cancer progression, here we demonstrate that apoptotic stress mediated by ectopic WWOX stimulated cancer cells to secrete basic fibroblast growth factor (bFGF) in order to support capillary microtubule formation. This event may occur in the cancer initiation stage. Later, when WWOX loss occurs in cancer cells, hyaluronidase production is then increased in the cancer cells to facilitate metastasis. We determined that inhibition of membrane hyaluronidase Tyr216-phosphorylated Hyal-2 by antibody suppresses cancer growth in vivo. WWOX-negative (WWOX-) cells dodged WWOX+cells in the microenvironment by migrating individually backward to avoid physical contacts and yet significantly upregulating the redox activity of WWOX+parental cells or other WWOX+cell types for causing apoptosis. Upon detecting the presence of WWOX+cells from a distance, WWOX- cells exhibit activation of MIF, Hyal-2, Eph, and Wnt pathways, which converges to MEK/ERK signaling and enables WWOX- cells to evade WWOX+cells. Inhibition of each pathway by antibody or specific chemicals enables WWOX- cells to merge with WWOX+cells. In addition, exogenous TGF-β assists WWOX- cells to migrate collectively forward and merge with WWOX+cells. Metastatic WWOX- cancer cells frequently secrete high levels of TGF-β, which conceivably assists them to merge with WWOX+cells in target organs and secure a new home base in the WWOX+microenvironment. Together, loss of WWOX allows cancer cells to develop strategies to dodge, compromise and even kill WWOX-positive cells in microenvironment.
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http://dx.doi.org/10.1038/s41420-019-0176-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529460PMC
May 2019

Generation of induced pluripotent stem cell line-NTUHi001-A from a premature ovarian failure patient with Turner's syndrome mosaicism.

Stem Cell Res 2019 05 2;37:101422. Epub 2019 Apr 2.

Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan. Electronic address:

Turner's syndrome (TS) is one of the main causes of premature ovarian failure (POF). However, the mechanisms underlying POF are difficult to study due to the lack of suitable disease models. Herein, we have generated a human induced pluripotent stem cell (hiPSC) line derived from the peripheral blood mononuclear cells of a female patient with Turner's syndrome mosaicism via integration-free Sendai-virus system. The hiPSCs were confirmed with a 45, X karyotype and the acquisition of pluripotency. It's likely that hiPSCs can serve as a feasible cellular model for further pathophysiological studies of POF cases, especially for those originating in TS.
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http://dx.doi.org/10.1016/j.scr.2019.101422DOI Listing
May 2019