Publications by authors named "Ching-Ying Huang"

48 Publications

Generation of IBMS-iPSC-015, -016, -017 human induced pluripotent stem cells (IBMSi013-A, IBMSi014-A, and IBMSi015-A) derived from patients with atrial fibrillation.

Stem Cell Res 2021 Jul 10;54:102419. Epub 2021 Jun 10.

Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Atrial fibrillation is the most common heart disease in the world, with around 35 million patients in 2020. Here we reported the generation of IBMS-iPSC-015-06, IBMS-iPSC-016-06, and IBMS-iPSC-017-02 as human induced pluripotent stem cell (iPSC) lines from patients' peripheral blood mononuclear cells (PBMCs) with atrial fibrillation. The cell lines expressed properties of pluripotent stem cells, including pluripotent markers and the ability to differentiate into three germ layers. These cell lines served as suitable models for studying alternative therapies of atrial fibrillation.
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http://dx.doi.org/10.1016/j.scr.2021.102419DOI Listing
July 2021

Generation of IBMS-iPSC-021, -022, -023 human induced pluripotent stem cells (IBMSi016-A, IBMSi017-A, and IBMSi018-A) derived from patients with the ALDH2 rs671 polymorphism.

Stem Cell Res 2021 Jul 10;54:102416. Epub 2021 Jun 10.

Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

ALDH2 gene is coded for the aldehyde dehydrogenase (ALDH), which is an enzyme involved in alcohol metabolism. Compared to normal aldehyde dehydrogenases, a homozygous point mutation on exon 12 from G to A significantly reduces its efficiency. In this study, we have reported the generation of IBMS-iPSC-021-04, IBMS-iPSC-022-01, and IBMS-iPSC-023-03 as induced pluripotent stem cell (iPSC) lines carrying the homozygous form of ALDH2 with the rs671 genetic polymorphism (E487K mutation). These cell lines were characterized in terms of pluripotency and differentiation potential. They serve as useful platforms to study alcohol metabolism and other chronic diseases associated with alcohol consumption.
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http://dx.doi.org/10.1016/j.scr.2021.102416DOI Listing
July 2021

Effects of positive end-expiratory pressure on the predictability of fluid responsiveness in acute respiratory distress syndrome patients.

Sci Rep 2021 May 13;11(1):10186. Epub 2021 May 13.

Department of Respiratory Therapy, College of Medicine, Chang Gung University, Taoyuan, 33353, Taiwan.

The prediction accuracy of pulse pressure variation (PPV) for fluid responsiveness was suggested to be unreliable in low tidal volume (VT) ventilation. However, high PEEP can cause ARDS patients relatively hypovolemic and more fluid responsive. We hypothesized that high PEEP 15 cmHO can offset the disadvantage of low VT and improve the predictive performance of PPV. We prospectively enrolled 27 hypovolemic ARDS patients ventilated with low VT 6 ml/kg and three levels of PEEP (5, 10, 15 cmHO) randomly. Each stage lasted for at least 5 min to allow for equilibration of hemodynamics and pulmonary mechanics. Then, fluid expansion was given with 500 ml hydroxyethyl starch (Voluven 130/70). The hemodynamics and PPV were automatically measured with a PiCCO2 monitor. The PPV values were significantly higher during PEEP15 than those during PEEP5 and PEEP10. PPV during PEEP15 precisely predicts fluid responsiveness with a cutoff value 8.8% and AUC (area under the ROC curve) of ROC (receiver operating characteristic curve) 0.847, higher than the AUC during PEEP5 (0.81) and PEEP10 (0.668). Normalizing PPV with driving pressure (PPV/Driving-P) increased the AUC of PPV to 0.875 during PEEP15. In conclusions, high PEEP 15 cmHO can counteract the drawback of low VT and preserve the predicting accuracy of PPV in ARDS patients.
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http://dx.doi.org/10.1038/s41598-021-89463-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119684PMC
May 2021

Efficacy of clarithromycin-naproxen-oseltamivir combination therapy versus oseltamivir alone in hospitalized pediatric influenza patients.

J Microbiol Immunol Infect 2020 Sep 12. Epub 2020 Sep 12.

Department of Pediatric Infectious Diseases, MacKay Children's Hospital, Taipei, Taiwan; Department of Medicine, MacKay Medicine College, New Taipei, Taiwan; Taiwan Digital Healthcare Association. Electronic address:

Purpose: This study aimed to compare the safety and efficacy of clarithromycin-naproxen-oseltamivir combination therapy to that of oseltamivir therapy alone in hospitalized pediatric influenza patients.

Methods: This prospective, single-blind study included children aged 1-18 years hospitalized with influenza, in MacKay Children's Hospital, Taiwan, between December 2017 and December 2019. The primary outcomes were the time to defervescence and decrease of the Pediatric Respiratory Severity Score (PRESS) during hospitalization. The secondary outcomes were serial changes in virus titers, measured using real-time polymerase chain reaction.

Results: Fifty-four patients were enrolled (28 in the control group and 26 in the combination group) in total. There were no differences in the patients' baseline characteristics between the groups. The time to defervescence was significantly shorter in the combination group than the oseltamivir group (13.2 h vs. 32.1 h, p = 0.002). The decrease in the virus titer from days 1-3 (log Δ13) was more pronounced in the combination group than the oseltamivir group. (39% vs. 19%, p = 0.001). There were no differences in adverse effects such as vomiting, diarrhea, and abdominal pain during the study or within 30 days after antiviral therapy.

Conclusion: The clarithromycin-naproxen-oseltamivir combination group experienced a more rapid defervescence and a more rapid decline of influenza virus titer than the group treated with oseltamivir alone. Further consideration should be given to whether the overall benefits of combination therapy in hospitalized pediatric influenza patients outweigh the risks.
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http://dx.doi.org/10.1016/j.jmii.2020.08.017DOI Listing
September 2020

Copy number variant hotspots in Han Taiwanese population induced pluripotent stem cell lines - lessons from establishing the Taiwan human disease iPSC Consortium Bank.

J Biomed Sci 2020 Sep 4;27(1):92. Epub 2020 Sep 4.

Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.

Background: The Taiwan Human Disease iPSC Service Consortium was established to accelerate Taiwan's growing stem cell research initiatives and provide a platform for researchers interested in utilizing induced pluripotent stem cell (iPSC) technology. The consortium has generated and characterized 83 iPSC lines: 11 normal and 72 disease iPSC lines covering 21 different diseases, several of which are of high incidence in Taiwan. Whether there are any reprogramming-induced recurrent copy number variant (CNV) hotspots in iPSCs is still largely unknown.

Methods: We performed genome-wide copy number variant screening of 83 Han Taiwanese iPSC lines and compared them with 1093 control subjects using an Affymetrix genome-wide human SNP array.

Results: In the iPSCs, we identified ten specific CNV loci and seven "polymorphic" CNV regions that are associated with the reprogramming process. Additionally, we established several differentiation protocols for our iPSC lines. We demonstrated that our iPSC-derived cardiomyocytes respond to pharmacological agents and were successfully engrafted into the mouse myocardium demonstrating their potential application in cell therapy.

Conclusions: The CNV hotspots induced by cell reprogramming have successfully been identified in the current study. This finding may be used as a reference index for evaluating iPSC quality for future clinical applications. Our aim was to establish a national iPSC resource center generating iPSCs, made available to researchers, to benefit the stem cell community in Taiwan and throughout the world.
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http://dx.doi.org/10.1186/s12929-020-00682-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487458PMC
September 2020

Inoculation age of Bacillus Calmette-Guérin Tokyo-172 strain and vaccine-related adverse reactions in Taiwan birth cohort of 2012-2017.

Clin Infect Dis 2020 Aug 22. Epub 2020 Aug 22.

Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan.

Background: In Taiwan, the inoculation of Bacillus Calmette-Guérin (BCG) Tokyo-172 strain vaccine was postponed from 24 hours after birth to 5-8 months of age from 2016. We reviewed BCG-induced adverse reactions reported to Vaccine Injury Compensation Program (VICP) to identify differences between early and delayed BCG inoculation.

Methods: Clinical presentations of BCG-related adverse reactions reported to VICP for the 2012-2017 birth cohort were reviewed until end of 2019. The correlation between inoculation age and complications were evaluated.

Results: We analyzed 233 BCG adverse reactions, namely regional lymphadenitis (33.9%), injection site reactions (35.2%), osteitis/osteomyelitis (27.9%), and distant soft tissue infections (3.0%). Incidence of osteitis/osteomyelitis was less when vaccination was done after 5 months of age (RR, 0.32; 95% CI, 0.16-0.64). Injection site reactions (RR, 8.82; 95% CI, 5.04-15.44) and lymphadenitis (RR, 2.24; 95% CI, 1.44-3.45) were significantly more common in vaccinees older than 5 months. Shorter onset durations of mild adverse reactions (lymphadenitis and injection site reactions) were reported in vaccinees older than 5 months, while no statistical significance was found regarding osteitis/osteomyelitis.

Conclusions: Osteomyelitis and distant soft tissue infection may occur less frequently when BCG is inoculated after 5 months of age, although mild adverse reactions can be more frequent, along with shortened symptoms onset time. As few severe reactions might occur more than two years after BCG inoculation and the policy of delayed BCG inoculation was implemented since 2016, longer observational period is needed to clarify the exact severe complications decrement.
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http://dx.doi.org/10.1093/cid/ciaa1235DOI Listing
August 2020

Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy.

Nutrients 2020 Jun 10;12(6). Epub 2020 Jun 10.

Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan.

The anti-inflammatory effect of hispolon has identified it as one of the most important compounds from . The research objectives were to study this compound using an animal model by lipopolysaccharide (LPS)-induced acute lung injury. Hispolon treatment reduced the production of the pro-inflammatory mediator NO, TNF-α, IL-1β, and IL-6 induced by LPS challenge in the lung tissues, as well as decreasing their histological alterations and protein content. Total cell number was also reduced in the bronchoalveolar lavage fluid (BALF). Moreover, hispolon inhibited iNOS, COX-2 and IκB-α and phosphorylated IKK and MAPK, while increasing catalase, SOD, GPx, TLR4, AKT, HO-1, Nrf-2, Keap1 and PPARγ expression, after LPS challenge. It also regulated apoptosis, ER stress and the autophagy signal transduction pathway. The results of this study show that hispolon regulates LPS-induced ER stress (increasing CHOP, PERK, IRE1, ATF6 and GRP78 protein expression), apoptosis (decreasing caspase-3 and Bax and increasing Bcl-2 expression) and autophagy (reducing LC3 I/II and Beclin-1 expression). This in vivo experimental study suggests that hispolon suppresses the LPS-induced activation of inflammatory pathways, oxidative injury, ER stress, apoptosis and autophagy and has the potential to be used therapeutically in major anterior segment lung diseases.
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http://dx.doi.org/10.3390/nu12061742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352175PMC
June 2020

Generation of a gene corrected human isogenic IBMS-iPSC-014-C from polycystic-kidney-disease induced pluripotent stem cell line using CRISPR/Cas9.

Stem Cell Res 2020 05 20;45:101784. Epub 2020 Apr 20.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

We report the engendering an isogenic iPSC line from the IBMS-iPSC-014-05 with homozygous correction of the R803X, Chr4: 88989098C > T in PKD2, using CRISPR/Cas9 technology. The results from the isogenic control, IBMS-iPSC-014-05C, showed that mutation had been corrected, while maintaining normal morphology, pluripotency, and differentiation capacity into three germ layers.
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http://dx.doi.org/10.1016/j.scr.2020.101784DOI Listing
May 2020

Generation of a human induced pluripotent stem cell (iPSC) line (IBMS-iPSC-048-05) from a patient with ALS and parkinsonism having a hexanucleotide repeat expansion mutation in C9orf72 gene.

Stem Cell Res 2020 04 27;44:101734. Epub 2020 Feb 27.

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) gene causes a heterogeneous neurodegenerative disorder that includes amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and parkinsonism. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a male patient with an increased hexanucleotide repeat expansion in C9orf72. The resulting iPSCs exhibited pluripotency, confirmed by immunofluorescent staining for pluripotency markers, and differentiated into three germ layers in vivo. This cellular model will provide a useful platform for further pathophysiological studies of C9orf72-related neurodegeneration.
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http://dx.doi.org/10.1016/j.scr.2020.101734DOI Listing
April 2020

Systemic Infection Caused by Malassezia pachydermatis in Infants: Case Series and Review of the Literature.

Pediatr Infect Dis J 2020 05;39(5):444-448

From the Department of Pediatrics, MacKay Children's Hospital and MacKay Memorial Hospital, Taipei, Taiwan.

Background: Malassezia pachydermatis is a rare cause of systemic infection in infants.

Methods: A total of 4 cases of M. pachydermatis fungemia that occurred in our neonatal intensive care unit over a 21-month period were reviewed, as well as 27 cases reported in the literature since 1988.

Results: The patients were preterm with multiple complications and had birth weights ranging from 490 to 810 g and gestational age between 23 and 26 weeks. All patients had received prophylactic fluconazole, broad-spectrum antibiotics and parenteral lipid supplements before fungemia onset, which occurred between the age of 7 and 28 days. Symptoms were nonspecific and thrombocytopenia was the primary laboratory finding. All patients received intravenous antifungal treatment and recovered from their infection. The 27 cases from review of the literature also indicated that the infected infants were extremely low birth weight (77.8%), with multiple underlying diseases (94.7%), receiving lipid-supplementation (100%) from a central vascular catheter. Most infants received antifungal treatment (73.1%) and catheter removal (73.1%) as the management.

Conclusions: M. pachydermatis is a pathogenic agent that causes late onset sepsis in critically ill low birth weight infants with generally good outcomes. Targeted antifungal treatment as well as catheter removal appear to be key factors for infection management.
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http://dx.doi.org/10.1097/INF.0000000000002591DOI Listing
May 2020

Distinct patterns of interleukin-12/23 and tumor necrosis factor α synthesis by activated macrophages are modulated by glucose and colon cancer metabolites.

Chin J Physiol 2020 Jan-Feb;63(1):7-14

Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.

Chronic inflammation is a major risk factor for colitis-associated colorectal carcinoma (CRC). Macrophages play a key role in altering the tumor microenvironment by producing pro-inflammatory and anti-inflammatory cytokines. Our previous studies showed that glucose metabolism conferred death resistance for tumor progression and exerted anti-inflammatory effects in ischemic gut mucosa. However, the effect of glucose and cancer metabolites in modulating macrophage cytokine profiles remains poorly defined. We used an in vitro system to mimic intestinal microenvironment and to investigate the roles of glucose and cancer metabolites in the cross-talk between carcinoma cells and macrophages. Human monocyte-derived THP-1 macrophages were stimulated with bacterial lipopolysaccharide (LPS) in the presence of conditioned media (CM) collected from human CRC Caco-2 cells incubated in either glucose-free or glucose-containing media. Our results demonstrated that glucose modulated the macrophage cytokine production, including decreased LPS-induced pro-inflammatory cytokines (i.e., tumor necrosis factor [TNF]α and interleukin [IL]-6) and increased anti-inflammatory cytokine (i.e., IL-10), at resting state. Moreover, glucose-containing CM reduced the macrophage secretion of TNFα and IL-8 but elevated the IL-12 and IL-23 levels, showing an opposite pattern of distinct pro-inflammatory cytokines modulated by cancer glucose metabolites. In contrast, LPS-induced production of macrophage inflammatory protein-1 (a macrophage-derived chemoattractant for granulocytes) was not altered by glucose or CM, indicating that resident macrophages may play a more dominant role than infiltrating granulocytes for responding to cancer metabolites. In conclusion, glucose metabolites from CRC triggered distinct changes in the cytokine profiles in macrophages. The downregulation of death-inducing TNFα and upregulation of Th1/17-polarizing IL-12/IL-23 axis in macrophages caused by exposure to cancer-derived glucose metabolites may contribute to tumor progression.
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http://dx.doi.org/10.4103/CJP.CJP_75_19DOI Listing
February 2020

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance.

Front Oncol 2019 21;9:1282. Epub 2019 Nov 21.

Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.

Reprogrammed glucose metabolism and increased glycolysis have been implicated in tumor chemoresistance. The aim was to investigate the distinct roles of the glucose metabolites pyruvate and ATP in chemoresistance mechanisms, including cell death and proliferation. Our data showed higher glucose transporters in colorectal cancer (CRC) from non-responsive patients than those responsive to chemotherapy. Human CRC cell lines exposed to 5-fluorouracil (5-FU) displayed elevated cell viability and larger tumors in xenograft mouse models if cultured in high-glucose medium. Glucose conferred resistance to 5-FU-induced necroptosis via pyruvate scavenging of mitochondrial free radicals, whereas ATP replenishment had no effect on cell death. Glucose attenuated the 5-FU-induced G0/G1 shift but not the S phase arrest. Opposing effects were observed by glucose metabolites; ATP increased while pyruvate decreased the G0/G1 shift. Lastly, 5-FU-induced tumor spheroid destruction was prevented by glucose and pyruvate, but not by ATP. Our finding argues against ATP as the main effector for glucose-mediated chemoresistance and supports a key role of glycolytic pyruvate as an antioxidant for dual modes of action: necroptosis reduction and a cell cycle shift to a quiescent state.
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http://dx.doi.org/10.3389/fonc.2019.01282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881467PMC
November 2019

Tumor sidedness and efficacy of first-line therapy in patients with RAS/BRAF wild-type metastatic colorectal cancer: A network meta-analysis.

Crit Rev Oncol Hematol 2020 Jan 15;145:102823. Epub 2019 Nov 15.

Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng-Kung University, Tainan, Taiwan. Electronic address:

We conducted a systemic search of several databases for randomized controlled trials (RCTs) that reported efficacy and safety outcomes of drugs for left-sided and right-sided metastatic colorectal cancer (mCRC), to identify the best available treatment. A network meta-analysis with mixed comparisons was created to interpret the best treatment option using the surface under the cumulative ranking curve. In the left-sided rat sarcoma (RAS) wild-type (WT) mCRC patients, bevacizumab, panitumumab, or cetuximab with chemotherapy groups showed a significantly better objective response rate than the chemotherapy alone group. The progression-free survival (PFS) and overall survival were better with panitumumab or cetuximab with chemotherapy than with chemotherapy alone. In the right-sided RAS WT mCRC patients, PFS for bevacizumab with chemotherapy was significantly better than that for cetuximab with chemotherapy. Cetuximab, closely followed by panitumumab, is the most effective treatment in left-sided RAS WT mCRC. Bevacizumab is more effective in right-sided mCRC.
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http://dx.doi.org/10.1016/j.critrevonc.2019.102823DOI Listing
January 2020

Human iPSC banking: barriers and opportunities.

J Biomed Sci 2019 Oct 28;26(1):87. Epub 2019 Oct 28.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

The introduction of induced pluripotent stem cells (iPSCs) has opened up the potential for personalized cell therapies and ushered in new opportunities for regenerative medicine, disease modeling, iPSC-based drug discovery and toxicity assessment. Over the past 10 years, several initiatives have been established that aim to collect and generate a large amount of human iPSCs for scientific research purposes. In this review, we compare the construction and operation strategy of some iPSC banks as well as their ongoing development. We also introduce the technical challenges and offer future perspectives pertaining to the establishment and management of iPSC banks.
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http://dx.doi.org/10.1186/s12929-019-0578-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819403PMC
October 2019

Clinical features of neonatal listeriosis in Taiwan: A hospital-based study.

J Microbiol Immunol Infect 2020 Dec 21;53(6):866-874. Epub 2019 Aug 21.

Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan.

Background: Neonatal listeriosis is a major cause of mortality in newborn; however, there is limited information about this disease in Taiwan. The aim of our study was to identify the outcome determinants, clinical features, and incidence of pregnancy-associated listeriosis, which includes both neonatal and maternal listeriosis.

Methods: We retrospectively analyzed the medical records of neonatal and maternal patients with pregnancy-associated listeriosis at two hospitals in Taiwan from January 2000 to December 2018. Listeriosis was indicated by positive Listeria monocytogenes culture.

Results: Our study examined 18 neonates and 19 mothers. The neonatal and fetal death rate was 24%. All five cases of fetal losses or neonatal deaths occurred before 29 weeks of gestational age. The annual incidence of confirmed neonatal listeriosis increased significantly from 0.94/10,000 neonatal inpatients in 2000-2011 to 5.45/10,000 neonatal inpatients in 2012-2018 (p = 0.026). Clinical presentations of neonatal listeriosis included respiratory distress (85%), leukocytosis or leukopenia (77%), bandemia (69%), thrombocytopenia (77%), hypocalcemia (100%) and elevated C-reactive protein (CRP) levels (92%). Lower gestation correlated with a higher fatality rate (p = 0.002). Among the maternal cases investigated, 67% had a diagnosis of listeriosis, and 72% presented with fever. However, only 21% of the 19 mothers received complete antepartum ampicillin treatment.

Conclusions: The incidence of neonatal listeriosis is increasing, especially in preterm neonates. Maternal listeriosis should be adequately treated with appropriate empirical antibiotics.
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http://dx.doi.org/10.1016/j.jmii.2019.08.001DOI Listing
December 2020

Generation of induced pluripotent stem cells (IBMSi011-A) from a patient with Parkinson's disease carrying LRRK2 p.I1371V mutation.

Stem Cell Res 2019 05 22;37:101447. Epub 2019 Apr 22.

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Leucine rich repeat kinase 2 (LRRK2) is the causative gene for autosomal-dominant familial forms of Parkinson's disease (PD). Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a female patient with LRRK2 c.4111A > G (p.I1371V) mutation by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype. The iPSCs also showed pluripotency confirmed by immunofluorescent staining and differentiated into the three germ layers in vivo. This cellular model will provide a platform for studying the role of LRRK2 in the disease process.
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http://dx.doi.org/10.1016/j.scr.2019.101447DOI Listing
May 2019

Reprogramming of a human induced pluripotent stem cell (iPSC) line (IBMSi012-A) from an early-onset Parkinson's disease patient harboring a homozygous p.D331Y mutation in the PLA2G6 gene.

Stem Cell Res 2019 05 5;37:101432. Epub 2019 Apr 5.

Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

A recessive mutation in PLA2G6, which is known to cause a heterogeneous neurodegenerative clinical spectrum, has recently been shown to be responsible for autosomal-recessive familial forms of Parkinson's disease (PD). Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a female patient with a homozygous PLA2G6 c.991G > T (p.D331Y) mutation by using the Sendai-virus delivery system. The resulting iPSCs showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. This cellular model will provide a good resource for further pathophysiological studies of PD.
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http://dx.doi.org/10.1016/j.scr.2019.101432DOI Listing
May 2019

Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytes.

EBioMedicine 2019 Feb 11;40:675-684. Epub 2019 Jan 11.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States. Electronic address:

Background: Mutations in PKD1 or PKD2 gene lead to autosomal dominant polycystic kidney disease (ADPKD). The mechanism of ADPKD progression and its link to increased cardiovascular mortality is still elusive.

Methods: We differentiated ADPKD patient induced pluripotent stem cells (iPSCs) to cardiomyocytes (CMs). The electrophysiological properties at the cellular level were analyzed by calcium imaging and whole cell patch clamping.

Findings: The ADPKD patient iPSC-CMs had decreased sarcoplasmic reticulum calcium content compared with Control-CMs. Spontaneous action potential of the PKD2 mutation line-derived CMs demonstrated slower beating rate and longer action potential duration. The PKD1 mutation line-derived CMs showed a comparable dose-dependent shortening of phase II repolarization with the Control-CMs, but a significant increase in beating frequency in response to L-type calcium channel blocker. The PKD1-mutant iPSC-CMs also showed a relatively unstable baseline as a greater percentage of cells exhibited delayed afterdepolarizations (DADs). Both the ADPKD patient iPSC-CMs showed more β-adrenergic agonist-elicited DADs compared with Control-CMs.

Interpretation: Characterization of ADPKD patient iPSC-CMs provides new insights into the increased clinical risk of arrhythmias, and the results enable disease modeling and drug screening for cardiac manifestations of ADPKD. FUND: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Technology Supporting Platform Axis Scheme, Thematic Research Program and Summit Research Program, and Kaohsiung Medical University Hospital, Taiwan.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413318PMC
February 2019

Recommendations and guidelines for the treatment of pneumonia in Taiwan.

J Microbiol Immunol Infect 2019 Feb 6;52(1):172-199. Epub 2018 Dec 6.

Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung, Taiwan.

Pneumonia is a leading cause of death worldwide, ranking third both globally and in Taiwan. This guideline was prepared by the 2017 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group, formed under the auspices of the Infectious Diseases Society of Taiwan (IDST). A consensus meeting was held jointly by the IDST, Taiwan Society of Pulmonary and Critical Care Medicine (TSPCCM), the Medical Foundation in Memory of Dr. Deh-Lin Cheng, the Foundation of Professor Wei-Chuan Hsieh for Infectious Diseases Research and Education and CY Lee's Research Foundation for Pediatric Infectious Diseases and Vaccines. The final guideline was endorsed by the IDST and TSPCCM. The major differences between this guideline and the 2007 version include the following: the use of GRADE methodology for the evaluation of available evidence whenever applicable, the specific inclusion of healthcare-associated pneumonia as a category due to the unique medical system in Taiwan and inclusion of recommendations for treatment of pediatric pneumonia. This guideline includes the epidemiology and recommendations of antimicrobial treatment of community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, healthcare-associated pneumonia in adults and pediatric pneumonia.
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http://dx.doi.org/10.1016/j.jmii.2018.11.004DOI Listing
February 2019

Clinical Manifestations, Management, and Outcomes of Osteitis/Osteomyelitis Caused by Mycobacterium bovis Bacillus Calmette-Guérin in Children: Comparison by Site(s) of Affected Bones.

J Pediatr 2019 04 18;207:97-102. Epub 2018 Dec 18.

Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan.

Objective: To evaluate the clinical manifestations, management, and outcomes of Mycobacterium bovis Bacillus Calmette-Guérin (BCG) osteitis/osteomyelitis.

Study Design: We reviewed 71 cases of BCG osteitis/osteomyelitis registered in Taiwan's vaccine injury compensation program (VICP) in 1998-2014. Demographic, clinical, laboratory, treatment, and outcome data were compared according to site(s) of infection.

Results: Involvement of a long bone of the lower extremity was present in 36.6% of the children, followed by foot bone (23.9%), rib or sternum (15.5%), upper extremity long bone (9.9%), hand bone (7%), multiple bones (4.2%), and vertebrae (2.8%). Children with lower extremity long bone involvement had a longer interval from receipt of BCG vaccine to presentation (median, 16.0 months; P = .02), and those with foot bone infection had higher rates of swelling (94.1%; P = .02) and local tenderness (76.5%; P = .004). Surgical intervention was performed in 70 children, with no significant difference in the number of procedures by site (median, 1.0 procedure per patient). Among the 70 children who received antimicrobial therapy, those with vertebral and multifocal infections had a longer duration of treatment (P < .001) and/or second-line antituberculosis medications (P = .002). Three children with vertebral and multifocal infections had major sequelae with kyphosis or leg length discrepancy. Outcomes were good for children with involvement of the ribs, sternum, and peripheral bones without multifocal involvement. The average time for functional recovery was 6.2 ± 3.9 months.

Conclusion: Children with BCG osteitis/osteomyelitis in different bones had distinct presentations and outcomes. Pediatricians should consider BCG bone infection in young vaccinated children with insidious onset of signs and symptoms, and consider affected site(s) in the management plan.
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http://dx.doi.org/10.1016/j.jpeds.2018.11.042DOI Listing
April 2019

The diagnostic value of serological studies in pediatric patients with acute Mycoplasma pneumoniae infection.

J Microbiol Immunol Infect 2020 Apr 12;53(2):351-356. Epub 2018 Sep 12.

Department of Pediatrics, MacKay Children's Hospital and MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, MacKay Medicine College, New Taipei, Taiwan; MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Background: Mycoplasma pneumoniae is a common pathogen of respiratory tract infections in pediatric patients. Serological studies are traditional methods for the diagnosis. However, early diagnosis of M. pneumoniae infections remains problematic. We investigate the value of early serum immunoglobulin A (IgA), in addition to immunoglobulin G (IgG), and immunoglobulin M (IgM) levels, in children infected with M. pneumoniae.

Methods: From August 2016 to February 2017, we enrolled pediatric patients based on both clinical symptoms and chest x-ray, and confirmed by positive throat culture for M. pneumoniae. Serum titers of M. pneumoniae IgM, IgG, and IgA during the acute phase were checked. All respiratory samples were further analyzed by polymerase chain reaction (PCR). Diagnostic values of different tests were evaluated.

Results: Fifty-six patients fulfilled the diagnostic criteria, with a median age of 4.84 years. Most of them (89.3%) were enrolled within 7 days of disease onset. PCR was positive in 71.4% of the study population. Early IgG samples were of limited value in diagnosing M. pneumoniae infection, of which 89.3% showed a negative result. Positive rates of early serum IgA and IgM were 48.2% and 46.4%, respectively. In combination with IgA and/or IgM, the sensitivity increased to 71.4% during their early clinical course.

Conclusions: In the pediatric population, combined serological tests of M. pneumoniae IgA and IgM, offer an accurate method of early diagnosis comparable to that of PCR, and can be an alternative choice for prompt detection of mycoplasma infections when PCR and culture are not available.
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http://dx.doi.org/10.1016/j.jmii.2018.09.001DOI Listing
April 2020

Respiratory tract infections in children with tracheostomy.

J Microbiol Immunol Infect 2020 Apr 9;53(2):315-320. Epub 2018 Aug 9.

Department of Pediatrics, MacKay Children's Hospital, Taipei, Taiwan.

Background: Children with tracheostomy are at increased risk for respiratory tract infections, yet the risk involved in tracheostomy related infections is unclear.

Methods: We conducted a retrospective review of the medical records of children who underwent tracheostomy between January 2002 and December 2016 at a teaching hospital in Taipei. Demographics, underlying disease, indication for tracheostomy, laboratory data and management, and long-term outcome data were collected. Infection episodes were grouped into definite, possible, non-bacterial pneumonia, and local infection groups.

Results: Ninety patients were enrolled. Forty-two (46.7%) patients had infections that required hospitalization. Definite bacterial pneumonia accounted for 12 (8.5%) episodes, 113 episodes (80.1%) were possible bacterial pneumonia, 12 (8.5%) were non-bacterial pneumonia, and 4 (2.8%) were local infections. Patients with definite and possible bacterial pneumonia were found to have a longer hospital duration than patients with non-bacterial pneumonia (p=0.024), with mean hospitalization stays of 8.83±5.59 days and 5.67±2.55 days, respectively. The median duration from tracheostomy to bacterial pneumonia was 1.78 years (range, 0.04- 11.38) whereas for the non-bacterial pneumonia group it was 0.57 years (range, 0.04-6.61). Cerebral palsy (CP) (adjusted odds ratio [AOR] 3.65; 95% confidence interval [CI]: 1.11-11.99; p=0.033) and gastroesophageal reflux disease (GERD) (AOR 2.84; 95% CI: 1.09-7.38; p=0.033) were independently associated with respiratory tract infections in these children.

Conclusion: In this study, CP and GERD were associated with infections in children with tracheostomy. Bacterial and non-bacterial pneumonia are difficult to differentiate clinically which may lead to unnecessary antibiotics use.
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http://dx.doi.org/10.1016/j.jmii.2018.07.002DOI Listing
April 2020

The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling.

Theranostics 2018 9;8(12):3176-3188. Epub 2018 May 9.

Institute of Biomedical Sciences, Academia Sinica, Taiwan.

Lapatinib (LAP) is a crucial alternative to trastuzumab upon the onset of drug resistance during treatment of metastatic human epidermal growth factor receptor 2-positive breast cancer. Like trastuzumab, LAP is commonly used alongside anthracyclines as a combination therapy, due to enhanced anti-cancer efficacy. However, this is notably associated with cardiotoxicity so it is imperative to understand the mechanisms driving this cardiotoxicity and develop cardioprotective strategies. To this end, here we utilize human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), which exhibit several characteristics representative of cardiomyocytes that make them breakthrough models to study drug toxicity. We investigated LAP- and doxorubicin (DOX)-induced toxicity in hPSC-CMs and evaluated the involvement of inducible nitric oxide (NO) synthase (iNOS). The significance of iNOS-mediated cardiotoxicity was furthermore evaluated in animal studies. LAP synergistically increased DOX toxicity in hPSC-CMs in a dose- and time-dependent manner. At concentrations that were otherwise non-apoptotic when administered separately, LAP significantly potentiated DOX-induced hPSC-CM apoptosis. This was accompanied by increased iNOS expression and pronounced production of NO. iNOS inhibition significantly reduced hPSC-CM sensitivity to LAP and DOX co-treatment (LAP-plus-DOX), leading to reduced apoptosis. Consistent with our observations , delivery of an iNOS inhibitor in mice treated with LAP-plus-DOX attenuated myocardial apoptosis and systolic dysfunction. Moreover, inhibition of iNOS did not compromise the anti-cancer potency of LAP-plus-DOX in a murine breast cancer xenograft model. Our findings suggest that iNOS inhibition is a promising cardioprotective strategy to accompany HER2-inhibitor/anthracycline combination therapies. Furthermore, these results support the promise of hPSC-CMs as a platform for investigating cardiotoxicity and developing cardioprotectants as a whole.
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http://dx.doi.org/10.7150/thno.23207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010982PMC
August 2019

Generation of novel induced pluripotent stem cell (iPSC) line from a 16-year-old sialidosis patient with NEU-1 gene mutation.

Stem Cell Res 2018 04 31;28:39-43. Epub 2018 Jan 31.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:

Sialidosis is a rare autosomal recessive disorder that affects the intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in NEU1, which encodes the sialidase enzyme, result in sialidosis. Sialidosis is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. In this study, we used Sendai virus reprogramming to generate an induced pluripotent stem cell (iPSC) line carrying the A544G mutation combined with the 667-679 deletion of the NEU1 gene from a sialidosis patient. The patient-specific iPSCs expressed pluripotent markers, possessed a normal karyotype, and displayed the capability to differentiate into three germ layers.
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http://dx.doi.org/10.1016/j.scr.2018.01.024DOI Listing
April 2018

Generation of 2 induced pluripotent stem cell lines derived from patients with Parkinson's disease carrying LRRK2 G2385R variant.

Stem Cell Res 2018 04 28;28:1-5. Epub 2018 Feb 28.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:

Leucine rich repeat kinase (LRRK2) is the most prevalent genetic cause for Parkinson's disease. LRRK2 p.G2385R is an Asian specific genetic risk factor for sporadic Parkinson's disease. We generated two induced pluripotent stem cells (iPSCs), IBMS-iPSC-018-09 and IBMS-iPSC-020-01, from the peripheral blood mononuclear cells of two patients carrying LRRK2 p.G2385R variant by using the Sendai-virus delivery system. These iPSCs had a normal karyotype and exhibited pluripotency, such as an embryonic stem cell-like morphology, expression of pluripotent markers, and capacity to differentiate into three germ layers. This cellular model will provide a platform for pathophysiological studies of neurodegeneration in Parkinson's disease.
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http://dx.doi.org/10.1016/j.scr.2018.01.034DOI Listing
April 2018

Generation of an induced pluripotent stem cell (iPSC) line from a 40-year-old patient with the A8344G mutation of mitochondrial DNA and MERRF (myoclonic epilepsy with ragged red fibers) syndrome.

Stem Cell Res 2018 03 19;27:10-14. Epub 2017 Dec 19.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:

Mitochondrial defects are associated with clinical manifestations from common diseases to rare genetic disorders. Myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome results from an A to G transition at nucleotide position 8344 in the tRNA gene of mitochondrial DNA (mtDNA) and is characterized by myoclonus, myopathy and severe neurological symptoms. In this study, Sendai reprogramming method was used to generate an iPS cell line carrying the A8344G mutation of mtDNA from a MERRF patient. This patient-specific iPSC line expressed pluripotent stem cell markers, possessed normal karyotype, and displayed the capability to differentiate into mature cells in three germ layers.
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http://dx.doi.org/10.1016/j.scr.2017.12.013DOI Listing
March 2018

Generation of an induced pluripotent stem cell line from a 39-year-old female patient with severe-to-profound non-syndromic sensorineural hearing loss and a A1555G mutation in the mitochondrial MTRNR1 gene.

Stem Cell Res 2017 12 8;25:245-249. Epub 2017 Nov 8.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:

Sensorineural hearing loss (SNHL) is a prevalent form of deafness commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. In this study, Sendai virus was used to generate an induced pluripotent stem cell (iPSC) line from a 39-year-old female patient diagnosed with severe-to-profound, non-syndromic SNHL. The patient also carries a A1555G mutation in the mitochondrial 12S ribosome RNA gene (MTRNR1). This iPSC line was verified to express pluripotent markers, possess normal karyotype, harbor the specific mutation and demonstrated the capacity to differentiate into three germ layers.
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http://dx.doi.org/10.1016/j.scr.2017.10.024DOI Listing
December 2017

Generation of induced pluripotent stem cells from a patient with Parkinson's disease carrying LRRK2 p.I2012T mutation.

Stem Cell Res 2017 12 31;25:123-127. Epub 2017 Oct 31.

Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan. Electronic address:

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by interactions between genetic and environmental factors. Leucine rich repeat kinase (LRRK2) is the most prevalent mutation in autosomal-dominant inheritance of PD. Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a female patient with p.I2012T mutation in LRRK2 gene by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype. The iPSCs also showed pluripotency confirmed by immunofluorescent staining and differentiated into the 3 germ layers in vivo. This cellular model will provide a useful platform for further pathophysiological studies of PD.
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http://dx.doi.org/10.1016/j.scr.2017.10.020DOI Listing
December 2017

Induced pluripotent stem cells derived from an autosomal dominant polycystic kidney disease patient carrying a PKD1 Q533X mutation.

Stem Cell Res 2017 12 28;25:83-87. Epub 2017 Oct 28.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent monogenic kidney disorder leading to kidney failure. We generated induced pluripotent stem cells (iPSCs) from a 37-year-old man carrying a PKD1 Q533X mutation who suffered from kidney failure and a myocardial infarction. The iPSCs were reprogrammed from the patient's peripheral blood mononuclear cells using the Sendai virus system, and were confirmed to possess the specific PKD1 Q533X mutation and normal karyotype. Pluripotency was confirmed using in vitro and in vivo assays. This iPSC line will be useful for studying the mechanisms driving the complicated pathophysiology of ADPKD.
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http://dx.doi.org/10.1016/j.scr.2017.10.026DOI Listing
December 2017

Generation of an induced pluripotent stem cell line, IBMS-iPSC-014-05, from a female autosomal dominant polycystic kidney disease patient carrying a common mutation of R803X in PKD2.

Stem Cell Res 2017 12 10;25:38-41. Epub 2017 Oct 10.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address:

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited forms of polycystic kidney disease, and is characterized by the growth of numerous cysts in both kidneys. Here we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a 63-year-old female ADPKD patient carrying an R803X mutation in the PKD2 gene using the Sendai-virus delivery system. Downstream characterization of these iPSCs showed that they possessed normal karyotyping, were free of genomic integration, retained the disease-causing PKD2 mutation, expressed pluripotency markers and could differentiate into three germ layers.
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http://dx.doi.org/10.1016/j.scr.2017.10.005DOI Listing
December 2017
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