Publications by authors named "Hsin-Yang Li"

51 Publications

Validating the Use of Corifollitropin Alfa in Progestin-Primed Ovarian Stimulation Protocol on Normal and High Responders by Comparing with Conventional Antagonist Protocol: A Retrospective Study.

Life (Basel) 2020 Jun 21;10(6). Epub 2020 Jun 21.

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 201, Shih-Pai Road Section 2, Taipei 112, Taiwan.

Our previous study showed a satisfactory reproductive outcome resulting from the patient-friendly ovarian stimulation protocol using long-acting follicle stimulation hormone (FSH) plus oral medroxyprogesterone acetate (MPA). The present retrospective study aims to compare the efficacy of the patient-friendly ovarian stimulation protocol with that of the antagonist protocol on normal and high responders aged between 24 and 39 years in a tertiary fertility center in Taiwan. To prevent premature luteinizing hormone (LH) surge, oral MPA was given to patients in group 1 ( = 57), whereas antagonist protocol was applied to group 2 ( = 53). Duration and dosage of stimulation, number of injections and visits before trigger, incidence of premature LH surge, number of oocytes retrieved, fertilization rate, cleavage rate, rate of good embryos available, incidence of ovarian hyperstimulation syndrome, cumulative clinical pregnancy rate and live birth rate per retrieval were compared between groups. We conclude that our patient-friendly ovarian stimulation protocol with MPA demonstrates satisfactory stimulation and reproductive outcomes that are comparable to those of an antagonist protocol.
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http://dx.doi.org/10.3390/life10060090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344689PMC
June 2020

Dysregulated immunological and metabolic functions discovered by a polygenic integrative analysis for PCOS.

Reprod Biomed Online 2020 Jan 28;40(1):160-167. Epub 2019 Sep 28.

Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei Taiwan, Republic of China; Medical Center of Ageing Research, China Medical University Hospital, Taichung Taiwan, Republic of China; Department of Biotechnology, College of Health Science, Asia University, Taichung Taiwan, Republic of China; Department of Medical Research, Taipei Veterans General Hospital, Taipei Taiwan, Republic of China. Electronic address:

Research Question: Polycystic ovary syndrome (PCOS) is a complex disease and its pathophysiology is still unclear. This polygenic study may provide some clues.

Design: A polygenic, functionome-based study with the ovarian gene expression profiles downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, including 48 PCOS and 181 normal control samples. These profiles were converted to the gene set regularity (GSR) indices, which were computed by the modified differential rank conversion algorithm and were defined by the gene ontology terms.

Results: Machine learning could accurately recognize the patterns of functional regularities between PCOS and normal controls. The significantly aberrant functions in PCOS included transporter activity, catalytic activity, the receptor signalling pathway via signal transducer and activator of transcription (STAT), the cellular metabolic process, and immune response.

Conclusion: This study provided a comprehensive view of the dysregulated functions and information for further studies on the management of PCOS.
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http://dx.doi.org/10.1016/j.rbmo.2019.09.011DOI Listing
January 2020

Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network.

Nucleic Acids Res 2019 11;47(19):10115-10133

Department of Medical Research, Taipei VeteransGeneral Hospital, Taipei 11217, Taiwan.

Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l-Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.
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http://dx.doi.org/10.1093/nar/gkz801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821267PMC
November 2019

Key Immunological Functions Involved in the Progression of Epithelial Ovarian Serous Carcinoma Discovered by the Gene Ontology-Based Immunofunctionome Analysis.

Int J Mol Sci 2018 Oct 24;19(11). Epub 2018 Oct 24.

School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.

Serous carcinoma (SC) is the most common and lethal subtype of epithelial ovarian carcinoma; immunotherapy is a potential treatment for SC, however, the global immunological functions of SC as well as their change during the progression of SC have not been investigated in detail till now. We conducted a genome-wide integrative analysis to investigate the immunofunctionomes of SC at four tumor stages by quantifying the immunological functions defined by the Gene Ontology gene sets. DNA microarray gene expression profiles of 1100 SCs and 136 normal ovarian tissue controls were downloaded from the Gene Expression Omnibus database and converted to the functionome. Then the immunofunctionomes were reconstructed by extracting the offspring from the functionome for the four SC staging groups. The key immunological functions extracted from immunofunctionomes with a series of filters revealed that the immunopathy of SC consisted of a group of deregulated functions with the core members including B cell activation and differentiation, regulation of leukocyte chemotaxis/cellular extravasation, antigen receptor mediated signaling pathway, T helper mediated immunity and macrophage activation; and the auxiliary elements included leukocyte mediated immunity, regulation of inflammatory response, T cell differentiation, mononuclear cell migration, megakaryocyte differentiation, complement activation and cytokine production. These deregulated immunological functions reveal the candidates to target in the immunotherapy.
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http://dx.doi.org/10.3390/ijms19113311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274992PMC
October 2018

Successful prevention of follicular rupture at 45 h after hCG and GnRHa triggering by emergent administration of indomethacin: A case report.

Taiwan J Obstet Gynecol 2018 Oct;57(5):760-762

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan. Electronic address:

Objective: To report the management and prevention of pre-operative ovulation before oocyte retrieval with emergent administration of indomethacin.

Case Report: During in vitro fertilization (IVF) treatment, the patient described here mistakenly administered 6500 IU of hCG and 0.2 mg of triptorelin (GnRHa) 9 h earlier than scheduled triggering. To avoid emergent oocyte retrieval in the midnight, indomethacin was given (150 mg/day, there times a day) from 2 h after incorrect hCG and GnRHa injection to the night before ovum pickup. The oocyte retrieval was performed at originally scheduled time. The result showed that pre-operative ovulation was effectively prevented and we successfully collected the expected number Andersen et al., 1995 of oocytes at 45 h after triggering.

Conclusion: The presented case demonstrates that indomethacin can be used safely and effectively as an emergent prescription to prevent and postpone ovulation till up to 45 h after hCG and GnRHa triggering.
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http://dx.doi.org/10.1016/j.tjog.2018.08.029DOI Listing
October 2018

An extremely patient-friendly and efficient stimulation protocol for assisted reproductive technology in normal and high responders.

Reprod Biol Endocrinol 2018 Mar 5;16(1):18. Epub 2018 Mar 5.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 201, Shih-Pai Road Section 2, Taipei, 112, Taiwan, Republic of China.

Background: The use of oral progestin has been shown to effectively prevent luteining hormone (LH) surge during ovarian stimulation with daily human menopausal gonadotropin injections. This study was aimed to investigate the efficacy of long-acting follicle stimulating hormone (long-acting FSH; corifollitropin alfa, Elonva®) use in progestin-primed ovarian stimulation for normal and high responders undergoing IVF/ICSI.

Methods: This is a retrospective and proof-of-concept study. We developed an extremely patient-friendly protocol to be applied to forty-five normal or high responders, in which a single injection of corifollitropin alfa (Elonva®) was administered and medroxyprogesterone acetate (MPA) was taken orally every day from the day after Elonva injection to the day of trigger. Seven days after Elonva injection, folliculometry and hormone tests were performed, followed by short-acting daily FSH/LH injections, if needed, until the day before trigger. Duration of stimulation, number of injections and visits before trigger, incidence of premature LH surge, the number of oocytes retrieved, fertilization rate, cleavage rate, the rate of day 2 good embryos available, and cumulative ongoing pregnancy rate per retrieval were assessed.

Results: The average age of the population was 34.7 years. Duration of stimulation was 9.4 days in average. Before trigger, only 3.6 injection shots and 1.4 visits were needed on average. There was no case of premature LH surge. Number of oocytes retrieved was 13.7, fertilization rate was 79.04%, cleavage rate was 91.11%, and day 2 good embryo rate was 64.34%, in average respectively. There was no case of ovarian hyperstimulation syndrome. The cumulative ongoing pregnancy rate per oocyte retrieval achieved a satisfactory level as 53.1%.

Conclusions: Our protocol consisting of long-acting FSH injection and oral MPA preventing LH surge reduces the number of injections and visits to an extreme and achieves a satisfactory reproductive outcome, and, therefore, is a really patient-friendly and effective approach to ovarian stimulation.
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http://dx.doi.org/10.1186/s12958-018-0335-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836459PMC
March 2018

Promoting Induced Pluripotent Stem Cell-driven Biomineralization and Periodontal Regeneration in Rats with Maxillary-Molar Defects using Injectable BMP-6 Hydrogel.

Sci Rep 2018 01 8;8(1):114. Epub 2018 Jan 8.

Institute of Oral Biology, National Yang-Ming University, Taipei, 112, Taiwan.

Periodontal disease may cause considerable destruction of alveolar bone, periodontal ligaments (PDLs) and cementum and even lead to progressive oral dysfunction. Periodontal tissue regeneration is the ultimate goal of periodontal disease treatment to reconstruct both structures and functions. However, the regenerative efficiency is low, possibly due to the lack of a proper periodontal microenvironment. In this study, we applied an injectable and thermosensitive chitosan/gelatin/glycerol phosphate hydrogel to provide a 3D environment for transplanted stem cells and to enhance stem cell delivery and engraftment. The iPSCs-BMP-6-hydrogel complex promoted osteogenesis and the differentiation of new connective tissue and PDL formation. In animal models of maxillary-molar defects, the iPSCs-BMP-6-hydrogel-treated group showed significant mineralization with increased bone volume, trabecular number and trabecular thickness. Synergistic effects of iPSCs and BMP-6 increased both bone and cementum formation. IPSCs-BMP-6-hydrogel-treated animals showed new bone synthesis (increased ALP- and TRAP-positive cells), new PDL regeneration (shown through Masson's trichrome staining and a qualification assay), and reduced levels of inflammatory cytokines. These findings suggest that hydrogel-encapsulated iPSCs combined with BMP-6 provide a new strategy to enhance periodontal regeneration. This combination not only promoted stem cell-derived graft engraftment but also minimized the progress of inflammation, which resulted in highly possible periodontal regeneration.
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http://dx.doi.org/10.1038/s41598-017-18415-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758833PMC
January 2018

Mesenchymal stem cells and their conditioned medium can enhance the repair of uterine defects in a rat model.

J Chin Med Assoc 2018 03 4;81(3):268-276. Epub 2017 Sep 4.

Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. Electronic address:

Background: Our aim was to examine the roles of mesenchymal stem cell (MSC) transplantation in the repair of large uterine defects.

Methods: Uterine defects were created in both uterine horns of female rats by a punch instrument, and bone marrow-derived MSCs, MSC-conditioned medium (MSC-CM) or vehicle were injected into the myometrium around the defect. The rate of uterine defect repair was monitored on day 2 and 4 after operation. Cytokine array of MSC-CM was performed, followed by neutralizing antibody experiments to clarify the exact cytokine participating in the MSC-CM-enhanced wound repair.

Results: Transplantation of MSCs, but not myometrial cells, significantly enhanced uterine defect repair. The transplanted MSCs were detected in the uterine horn with no signs of rejection on day 4 after transplantation, when the MSC-transplanted uterine wound was nearly healed. Moreover, uterine defect repair was also accelerated by injection of MSC-CM, indicating the paracrine effects of MSCs on uterine wound healing. Cytokine array analysis further revealed that MSC-CM contained abundant cytokines and chemokines, among which high levels of interleukin-6 (IL-6) were found. Additionally, antibodies against IL-6 were shown to block MSC-CM-enhanced uterine defect repair.

Conclusion: This study demonstrated that transplantation of MSCs could enhance uterine defect repair by paracrine effects involving IL-6, which are findings that may be applied to facilitate uterine wound healing in the removal of huge intramural masses.
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http://dx.doi.org/10.1016/j.jcma.2017.03.013DOI Listing
March 2018

Impact of hysterosalpingography after operative treatment for ectopic pregnancy in Taiwan: A 16-year Nationwide Population-Based Analysis.

Medicine (Baltimore) 2017 Jun;96(25):e7263

Department of Radiology Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Beitou District, Taipei City, Taiwan, R.O.C; and School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C School of Medicine, National Yang-Ming University; School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan, R.O.C; and Department of Orthopaedics, Cheng Hsin General Hospital, Taipei City, Taiwan R.O.C Department of Family Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan, R.O.C; and Institute of Hospital and Health Care Administration, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C.

By retrieving records from Taiwan's National Health Insurance (NHI) system's database, the current study aimed to investigate the impacts of hysterosalpingography (HSG) to patients after ectopic pregnancy (EP) operations in Taiwan.In this retrospective cohort study, insurance claims data from 1997 to 2013, derived from a cohort of 1 million people randomly sampled to represent all NHI beneficiaries, were analyzed. Patients after ectopic pregnancy (EP) operations were identified via the inclusion of the corresponding NHI procedure codes. We further divided the patients into 2 groups by whether received subsequent HSG, EP-HSG, and EP-no-HSG. Patients with history of previous pregnancies (PP) and subsequent HSG were grouped as PP-HSG. We sought to evaluate the following pregnancies (FP) rate, interval to FP in EP-HSG compared with that in EP-no-HSG, and PP-HSG.EP-HSG had significantly higher FP rate odds ratio than EP-no-HSG (OR, 1.64; 95% CI, 1.24-2.16, P < .001). EP-HSG had lower FP rate odds ratio than that in PP-HSG, but no significant difference (33.1% vs 34.6%, P  =  .654). The INTERVAL(HSG-FP) in EP-HSG was no significantly different from that in PP-HSG (843.34 ± 82 days vs 644.72 ± 24.30 days, P  =  .077). There was significant positive correlation between FP after EP and number of HSG (r  =  0.070, P < .001). There were significant negative correlation between FP and EP age (r  =  -0.270, P < .001), FP and INTERVAL(EP-HSG) (r  =  -0.212, P  =  .001). The multivariate analysis showed that INTERVAL(EP-HSG) less than 1 year is the predictor factor of INTERVAL(EP-FP) (hazard ratio: 1.422; 95% CI: 1.130-1.788; P = .003). It was evident that the longer the INTERVAL(EP-HSG), the lower the FP rate odds ratio; and the older the EP age, the lower the FP rate odds ratio. (OR, 95% CI; >1 year: 0.59, 0.41-0.86; >2 year: 0.42, 0.32-0.55; >25 years old: 0.47, 0.38-0.57; >30 years old: 0.29, 0.24-0.35; >35 years old: 0.12, 0.08-0.18, all P < .001).Receiving HSG after EP, short INTERVAL(EP-HSG), EP age less than 30 years old, had significant positive impacts on the FP. We encourage shortening the INTERVAL(EP-HSG), and the counseling of women on the most appropriate way to conceive thereafter.
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http://dx.doi.org/10.1097/MD.0000000000007263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484238PMC
June 2017

Acute kidney injury and risk of deep vein thrombosis and pulmonary embolism in Taiwan: A nationwide retrospective cohort study.

Thromb Res 2017 Mar 6;151:29-35. Epub 2017 Jan 6.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Biostatistics Consulting Center, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Public Health, College of Medicine, National Cheng-Kung University, Tainan, Taiwan. Electronic address:

Introduction: Chronic kidney disease (CKD) increases risk for deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have investigated the relationship between acute kidney injury (AKI) and risk of DVT and PE. Therefore, we conducted a nationwide longitudinal cohort study to determine whether patients with AKI are associated with increased risk of developing DVT and PE.

Methods: We included >30years-old inpatients (n=4734) receiving the diagnosis of AKI from 2000 to 2006 and their age-and sex-matched non-AKI inpatients using medical service in the same year (n=47.340). Diagnosis of DVT and PE was recorded within 5-year after the AKI event or index use of medical service. The hazard ratios were analyzed using Cox regression model and adjustments were made for demographic factors, selected comorbidities and treatments. A time-dependent covariate survival analysis was performed for variations of some comorbidities, treatments and hospitalization. Competing risk regression (CRR) model was also used to adjust the risk for death. Propensity score matching was used to minimize potential selection bias. We also performed sensitivity analysis to examine the effect of other possible residual confounding factors.

Results: After adjusting for demographic characteristics, selected comorbidities and treatment, AKI remained a predisposing factor with a 1.44-fold (95% CI, 1.04-2.01) and 1.49-fold (95% CI, 1.12-1.97) increase in patients who were at a risk for developing DVT within 3 and 5years. AKI also remained a significant predisposing factor with a 2.66-fold (95% CI, 1.49-3.20) increase in patients who were at a risk for developing PE within 3years. However, there were no significant results for PE within 5years. The hazard ratios of time-dependent covariate survival analysis and CRR model showed the similar results.

Conclusions: Risk of DVT and PE is higher in patients with AKI than in the general population.
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http://dx.doi.org/10.1016/j.thromres.2017.01.004DOI Listing
March 2017

Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation.

Oncotarget 2016 Dec;7(52):87161-87179

Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Rationale: A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown.

Objective: Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC.

Results And Methods: The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients' sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs.

Conclusion: Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation.
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http://dx.doi.org/10.18632/oncotarget.13552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349979PMC
December 2016

Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation.

Reprod Biol Endocrinol 2016 Oct 6;14(1):64. Epub 2016 Oct 6.

Department of Obstetrics and Gynaecology, Taipei Veterans General Hospital, No.201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan.

Background: Iatrogenic parasitic myomas (PMs), caused by intra-corporeal power morcellation during laparoscopy is gradually increasing. However, the pathogenesis and medical treatment of PMs remain largely unelucidated.

Methods: Laparoscopically-induced PM xenografted mouse model was conducted by xenografting human uterine myoma fragments into the abdominal cavity of SCID mice and hormonal manipulation was performed using this mouse model to demonstrate the role of oestrogen in the development of implanted PMs. Immunohistochemistry of oestrogen receptor α (ERα), progesterone receptor (PR), vimentin, vascular endothelial growth factor (VEGF), microvessel density (MVD) and Ki-67 index was performed and compared.

Results: In the patient with PMs, ERα, PR, angiogenesis and proliferative property expression were upregulated in PM lesions compared to uterine myomas. In the laparoscopically-induced PM mouse model, implanted myomas had more steroid receptor expressions, angiogenesis and proliferative property compared with pre-xenografted or non-implanted myoma. Depletion of oestrogen in the ovariectomized (OVX) mice decreased laparoscopically-induced PM implantations. In comparison, the implantations of PMs were increased with additional E2 supplement. Hormonal manipulation in the PM mouse model, including AI, GnRHa and SERM groups, were compared and AI significantly decreased the implantations, steroid receptor, angiogenesis, cell density, and proliferative index of PMs compared with control group. Furthermore, GnRHa significantly decreased VEGF and MVD expressions compared with control group.

Conclusions: These data highlight the crucial role of oestrogen in the development of laparoscopically-induced PMs and suggest that hormone manipulation may be a potential therapeutic agent.

Trial Registration: This protocol was approved by the Human and Animal Institutional Review Board of Taipei Veterans General Hospital ( VGHIRB No 2014-10-002C on Nov. 17, 2014; IACUC 2014-119 on Aug. 22, 2014).
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http://dx.doi.org/10.1186/s12958-016-0200-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053344PMC
October 2016

The benefit of individualized low-dose hCG support for high responders in GnRHa-triggered IVF/ICSI cycles.

J Chin Med Assoc 2016 Jul 1;79(7):387-93. Epub 2016 May 1.

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. Electronic address:

Background: To assess the pregnancy outcome and ovarian hyperstimulation syndrome (OHSS) incidence in high responders receiving gonadotropin-releasing hormone agonist (GnRHa) trigger plus individualized support of low-dose human chorionic gonadotropin (hCG). Such support includes 500-1000 IU hCG given at trigger and, if serum estradiol (E2) dropped to below 800 pg/mL before the 6(th) day after oocyte retrieval, an additional rescue dose of 300 IU hCG.

Methods: This was a retrospective study of potential high responders aged from 28 years to 40 years at a tertiary fertility center in Taiwan. By means of chart review, we assessed the pregnancy outcome and OHSS incidence in high responders receiving GnRHa trigger plus individualized low-dose hCG support. The main outcomes were measured by ongoing pregnancy rate and OHSS incidence (SPSS), in which statistical significance was determined by Chi-square test.

Results: Moderate to severe OHSS did not develop in any patient receiving GnRHa trigger plus individualized low-dose hCG support. In fact, a satisfactory ongoing pregnancy rate (46.9%) was noted in patients receiving GnRHa trigger plus individualized low-dose hCG support.

Conclusion: Our study suggested that GnRHa trigger combined with individualized low-dose hCG support appears to be a safe approach with a satisfactory pregnancy outcome.
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http://dx.doi.org/10.1016/j.jcma.2016.02.006DOI Listing
July 2016

Delivery of double singleton pregnancies in a woman with a double uterus, double cervix, and complete septate vagina.

J Chin Med Assoc 2015 Dec 14;78(12):746-8. Epub 2015 Oct 14.

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

Uterine anomalies involving a double uterus, double cervix, also known as didelphys uterus, and complete septate vagina are rarely seen and have an associated fertility problem. However, artificial reproductive technology with embryo transfers can help solve this fertility challenge. Conception in the uterus in just one side is commonly seen for embryos, which are always transferred through the usually used (dilated) vagina. We here present a patient with the above uterine anomaly who conceived with the aid of in vitro fertilization and embryo transfer to both uterine cavities under general anesthesia, which resulted in successful double singleton pregnancies with one fetus in each uterus. With intensive prenatal care, the pregnancy course for each fetus was rather uneventful. Although both fetuses were in cephalic presentation, cesarean section was performed at the 39(th) week of gestation with good outcomes in order to preclude anticipated difficulties if the baby had been delivered through the rarely dilated vagina. However, order of birth between the two fetuses was a crucial decision during the operation.
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http://dx.doi.org/10.1016/j.jcma.2015.06.020DOI Listing
December 2015

Dysregulation of Mitochondrial Functions and Osteogenic Differentiation in Cisd2-Deficient Murine Induced Pluripotent Stem Cells.

Stem Cells Dev 2015 Nov 10;24(21):2561-76. Epub 2015 Aug 10.

1 Institute of Pharmacology, National Yang-Ming University , Taipei, Taiwan .

Wolfram syndrome 2 (WFS2) is a premature aging syndrome caused by an irreversible mitochondria-mediated disorder. Cisd2, which regulates mitochondrial electron transport, has been recently identified as the causative gene of WFS2. The mouse Cisd2 knockout (KO) (Cisd2(-/-)) recapitulates most of the clinical manifestations of WFS2, including growth retardation, osteopenia, and lordokyphosis. However, the precise mechanisms underlying osteopenia in WFS2 and Cisd2 KO mice remain unknown. In this study, we collected embryonic fibroblasts from Cisd2-deficient embryos and reprogrammed them into induced pluripotent stem cells (iPSCs) via retroviral transduction with Oct4/Sox2/Klf4/c-Myc. Cisd2-deficient mouse iPSCs (miPSCs) exhibited structural abnormalities in their mitochondria and an impaired proliferative capability. The global gene expression profiles of Cisd2(+/+), Cisd2(+/-), and Cisd2(-/-) miPSCs revealed that Cisd2 functions as a regulator of both mitochondrial electron transport and Wnt/β-catenin signaling, which is critical for cell proliferation and osteogenic differentiation. Notably, Cisd2(-/-) miPSCs exhibited impaired Wnt/β-catenin signaling, with the downregulation of downstream genes, such as Tcf1, Fosl1, and Jun and the osteogenic regulator Runx2. Several differentiation markers for tridermal lineages were globally impaired in Cisd2(-/-) miPSCs. Alizarin red S staining and flow cytometry analysis further revealed that Cisd2(-/-) miPSCs failed to undergo osteogenic differentiation. Taken together, our results, as determined using an miPSC-based platform, have demonstrated that Cisd2 regulates mitochondrial function, proliferation, intracellular Ca(2+) homeostasis, and Wnt pathway signaling. Cisd2 deficiency impairs the activation of Wnt/β-catenin signaling and thereby contributes to the pathogeneses of osteopenia and lordokyphosis in WFS2 patients.
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http://dx.doi.org/10.1089/scd.2015.0066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620525PMC
November 2015

CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling During the Early-Stage Cell Reprogramming.

Stem Cells 2015 Oct;33(10):2961-72

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

PARP1 and poly(ADP-ribosyl)ation (PARylation) have been shown to be essential for the initial steps of cellular reprogramming. However, the mechanism underlying PARP1/PARylation-regulated activation of pluripotency loci remains undetermined. Here, we demonstrate that CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during reprogramming. We found that this interaction is mediated through the interplay of the CHD1L macro-domain and the PAR moiety of PARylated-PARP1. Chromatin immunoprecipitation assays demonstrated the co-occupancy of CHD1L and PARP1 at Pou5f1, Nanog, and Esrrb pluripotency loci. Knockdown of CHD1L significantly blocked the binding activity of PARP1 at pluripotency loci and inhibited the efficiency of PARP1-driven reprogramming. Notably, we found that CHD1L-promoted reprogramming requires both a PARP1-interacting domain and DNA helicase activity, partly contributing to the chromatin-remodeling states of pluripotency loci. Taken together, these results identify CHD1L as a key chromatin remodeler involved in PARP1/PARylation-regulated early-stage reprogramming and pluripotency in stem cells.
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http://dx.doi.org/10.1002/stem.2116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832376PMC
October 2015

Poly(ADP-Ribose) Polymerase 1: Cellular Pluripotency, Reprogramming, and Tumorogenesis.

Int J Mol Sci 2015 Jul 9;16(7):15531-45. Epub 2015 Jul 9.

School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.

Poly(ADP-ribos)ylation (PARylation) is the catalytic function of the Poly(ADP-ribose) polymerases (Parps) family for post-translational modification in cellular process. Being a major member of Parps, Parp1 is a crucial nuclear factor with biological significance in modulating DNA repair, DNA replication, transcription, DNA methylation and chromatin remodeling through PARylation of downstream proteins. In addition, high expression level and activity of Parp1 are correlated with pluripotent status, reprogramming, and cancer. Furthermore, epigenetic modulation of Parp1 is explored for regulating wide variety of gene expression. Genetic and pharmaceutical disruption of Parp1 further confirmed the importance of Parp1 in cell growth, DNA repair, and reprogramming efficiency. Taken together, the proximity toward the understanding of the modulation of Parp1 including interaction and modification in different fields will provide new insight for future studies. In this review, the biological significance of Parp1 in transcription and the epigenetic modulation of Parp1 in pluripotent status, reprogramming process and cancer will be summarized.
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http://dx.doi.org/10.3390/ijms160715531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519911PMC
July 2015

The role of nitric oxide in the outgrowth of trophoblast cells on human umbilical vein endothelial cells.

Taiwan J Obstet Gynecol 2015 Jun;54(3):227-31

Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan; Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. Electronic address:

Objective: Embryo implantation is a complex process that requires coordinated trophoblast-endometrial interactions. Previous studies demonstrated that the identification of nitric oxide synthase (NOS) in trophoblast cells and the remodeling of the implantation process by nitric oxide (NO) support the important role of NO during implantation. However, the role of NO in trophoblast-endometrial interactions is unclear and is therefore examined in this study.

Materials And Methods: We cocultured BeWo trophoblast spheroids with human umbilical vein endothelial cell (HUVEC) monolayers to mimic the trophoblast-endometrial interaction. N(ω)-Nitro-l-arginine methyl ester hydrochloride (l-NAME), a competitive inhibitor of NOS, and sodium nitroprusside (SNP), an NO donor, were used to test the role of NO in the trophoblast-endometrial interaction.

Results: l-NAME diminished spheroid expansion on HUVEC monolayers in a concentration-dependent manner (p < 0.05). However, trophoblast spreading on HUVEC-free culture surfaces was unaffected by l-NAME treatment (p > 0.05). Significant suppression of spheroid expansion was found at the higher dose (1mM) of SNP (p < 0.05).

Conclusion: NO may be needed in the process of implantation, and an adequate but not overly NO-containing environment might be an important factor for successful implantation. This finding is worthy of further investigation.
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http://dx.doi.org/10.1016/j.tjog.2013.11.010DOI Listing
June 2015

Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure.

Cell Transplant 2015 9;24(3):541-59. Epub 2015 Feb 9.

Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.
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http://dx.doi.org/10.3727/096368915X686986DOI Listing
December 2015

Synergistic effects of carboxymethyl-hexanoyl chitosan, cationic polyurethane-short branch PEI in miR122 gene delivery: accelerated differentiation of iPSCs into mature hepatocyte-like cells and improved stem cell therapy in a hepatic failure model.

Acta Biomater 2015 Feb 21;13:228-44. Epub 2014 Nov 21.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

MicroRNA122 (miR122), a liver-specific microRNA, plays critical roles in homeostatic regulation and hepatic-specific differentiation. Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but it remains unknown whether non-viral vector-mediated miR122 delivery can enhance the differentiation of iPSCs into hepatocyte-like cells (iPSC-Heps) and rescue thioacetamide-induced acute hepatic failure (AHF) in vivo. In this study, we demonstrated that embedment of miR122 complexed with polyurethane-graft-short-branch polyethylenimine copolymer (PU-PEI) in nanostructured amphiphatic carboxymethyl-hexanoyl chitosan (CHC) led to dramatically enhanced miR122 delivery into human dental pulp-derived iPSCs (DP-iPSCs) and facilitated these DP-iPSCs to differentiate into iPSC-Heps (miR122-iPSC-Heps) with mature hepatocyte functions. Microarray and bioinformatics analysis further indicated that CHC/PU-PEI-miR122 promoted the gene-signature pattern of DP-iPSCs to shift into a liver-specific pattern. Furthermore, intrahepatic delivery of miR122-iPSC-Heps, but not miR-Scr-iPSC-Heps, improved liver functions and rescued recipient survival, and CHC-mediated delivery showed a better efficacy than that using phosphate buffered saline as a delivery vehicle. In addition, these transplanted miR122-iPSC-Heps remained viable and could produce circulatory albumin for 4 months. Taken together, our findings demonstrate that non-viral delivery of miR122 shortens the time of iPSC differentiation into hepatocytes and the delivery of miR122-iPSC-Heps using CHC as a vehicle exhibited promising hepatoprotective efficacy in vivo. miR122-iPSC-Heps may represent a feasible cell source and provide an efficient and alternative strategy for hepatic regeneration in AHF.
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http://dx.doi.org/10.1016/j.actbio.2014.11.018DOI Listing
February 2015

Induction of dental pulp-derived induced pluripotent stem cells in the absence of c-Myc for differentiation into neuron-like cells.

J Chin Med Assoc 2014 Dec;77(12):618-25

Background: A recent research breakthrough has demonstrated that the ectopic expression of four genes is sufficient to reprogram human fibroblasts into inducible pluripotent stem cells (iPSCs). However, whether human dental pulp cells (DPCs) could be reprogrammed into iPSCs remains an open question. In this study, we demonstrated that DPCs from deciduous and permanent teeth can be reprogrammed into iPSCs without c-Myc and had the capacity to differentiate into neuron-like cells.

Methods: DPCs were obtained from donors and reprogrammed into iPSCs using retroviral transduction with SOX2, OCT4, and KLF4. Then, these iPSCs were differentiated into neuron-like cells. Microarray and bioinformatics were used to compare the gene expression profile among these iPSCs and iPSC-derived neuron-like cells.

Results: The DPCs displayed a high vitality and capability to quickly restart proliferation and expressed elevated pluripotency similar to mesenchymal stem cells. According to our results, DPC-derived iPSC colonies that could be subcultured and propagated were established as early as 10 days after transduction, in comparison with the skin fibroblast (DPC-derived iPSCs) without c-Myc presented embryonic stem cell-like properties and the pluripotent potential to differentiate into neuron-like cells, which resemble neurons both morphologically and functionally.

Conclusion: The human DPCs from deciduous and permanent teeth can undergo reprogramming to establish pluripotent stem cell lines without c-Myc. These surgical residues, usually regarded as medical waste, can be used as an alternative source of pluripotent stem cells for personalized medicine.
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http://dx.doi.org/10.1016/j.jcma.2014.08.009DOI Listing
December 2014

Human induced pluripotent stem cell and nanotechnology-based therapeutics.

Cell Transplant 2015 8;24(11):2185-95. Epub 2014 Oct 8.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.

Human induced pluripotent stem cells (hiPSCs) can be genetically reprogrammed to an embryonic stem cell-like state and can provide promising medical applications, such as diagnosis, prognosis, drug screening for therapeutical development, and monitoring disease progression. Despite myriad advances, traditional viral-based reprogramming for generating hiPSCs has safety risks that hinder further practical applications of hiPSCs. In the past decade, nonviral-based reprogramming has been used as an alternative to produce hiPSCs and enhance their differentiation. In addition, the efficiency of nonviral-based reprogramming is generally poor, compared to that of viral-based reprogramming. Recent studies in nanoscale-structured particles have made progress in addressing many applications of hiPSCs for clinical practice. The combination of hiPSCs and nanotechnology will actually act as the therapeutic platform for personalized medicine and can be the remedies against various diseases in the future. In this article, we review recent advances in cellular reprogramming and hiPSC-related research, such as cell source, delivery system, and direct reprogramming, as well as some of its potential clinical applications, including mitochondrial and retinal disease. We also briefly summarize the current incorporation of nanotechnology in patient-specific hiPSCs for future treatments.
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http://dx.doi.org/10.3727/096368914X685113DOI Listing
October 2016

Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells.

J Cell Mol Med 2014 Jul 24;18(7):1358-71. Epub 2014 Apr 24.

National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.

Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen-associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial-mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug-VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2-Slug-VEGF pathway.
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http://dx.doi.org/10.1111/jcmm.12300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124020PMC
July 2014

SMN is required for the maintenance of embryonic stem cells and neuronal differentiation in mice.

Brain Struct Funct 2015 17;220(3):1539-53. Epub 2014 Mar 17.

Institute of Biotechnology, National Taiwan University, No. 81, Chang-Xiang St., Da-an District, Taipei, 106, Taiwan, ROC.

Survival motor neuron (SMN) is the determining factor in spinal muscular atrophy, the most common genetic cause of childhood mortality. We have previously found that SMN regulates stem cell division, proliferation and differentiation in Drosophila. However, it is unknown whether a similar effect exists in vertebrates. Here, we show that SMN is enriched in highly proliferative embryonic stem cells (ESCs) in mice and reduction of SMN impairs the pluripotency of ESCs. Moreover, we find that SMN reduction activates ERK signaling and affects neuronal differentiation in vitro. Teratomas with reduced SMN grow more slowly and show weaker signals of neuronal differentiation than those with a normal level of SMN. Finally, we show that over-expression of SMN is protective for ESCs from retinoic acid-induced differentiation. Taken together, our results suggest that SMN plays a role in the maintenance of pluripotent ESCs and neuronal differentiation in mice.
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http://dx.doi.org/10.1007/s00429-014-0743-7DOI Listing
January 2016

A tumor necrosis factor-α inhibitor reduces the embryotoxic effects of endometriotic peritoneal fluid.

Fertil Steril 2013 Nov 4;100(5):1476-85. Epub 2013 Sep 4.

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Objective: To determine whether a tumor necrosis factor-α (TNF-α) inhibitor can reduce the embryotoxicity of the peritoneal fluid (PF) of women with endometriosis.

Design: Experimental clinical study.

Setting: University hospital.

Patient(s): Twelve women with chocolate cysts and 12 control women without endometriosis.

Intervention(s): None.

Main Outcome Measure(s): We collected the PF from patients with chocolate cysts (CH-PF) and patients without endometriosis (N-PF) during laparoscopic surgery. For the in vitro studies, development and apoptosis were evaluated in two-cell stage mouse embryos after incubation with CH-PF and N-PF, with or without a TNF-α inhibitor.

Result(s): We found that CH-PF significantly decreased the rate of blastocyst development and increased the percentage of apoptotic cells in the embryos. Cytokine assays showed that the concentrations of several cytokines, including TNF-α, were higher in embryos incubated with CH-PF than in those incubated with N-PF. Furthermore, the treatment of embryos with TNF-α retarded development and induced apoptosis. Important, adalimumab, a TNF-α inhibitor, effectively abrogated the embryotoxicity that was induced by CH-PF.

Conclusion(s): These data collectively highlight the crucial role of TNF-α in CH-PF-induced embryotoxicity and suggest that TNF-α inhibitors may be potential therapeutic agents for treating endometriosis-induced infertility.
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http://dx.doi.org/10.1016/j.fertnstert.2013.07.1985DOI Listing
November 2013

An overview of a 30-year experience with amniocentesis in a single tertiary medical center in Taiwan.

Taiwan J Obstet Gynecol 2012 Jun;51(2):206-11

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.

Objective: Amniocentesis is a popular and effective prenatal diagnostic tool for chromosomal disorders. It is well-established that the risk of chromosomal abnormalities increases with maternal age; however, other related indications are seldom reported. Herein, we report our 30-year experience with amniocentesis from a single medical center, focusing on the indications and rates of abnormality.

Material And Methods: A retrospective review of 16,749 pregnant women in the mid-trimester between January 1981 and December 2010 was conducted. The medical records were analyzed.

Results: The indications for amniocentesis were advanced maternal age (≥ 34 years old) (n=10,970, 65.5%), increasing-risk maternal triple-marker Down's screening test (≥ 1/270) (n=2090, 12.5%), history of abnormal offspring birth (n=792, 4.7%), abnormal ultrasound findings (n=484, 2.9%), parent with abnormal karyotype (n=252, 1.5%), family history of chromosomal abnormality (n=183, 1.1%), drug and radiation exposure (n=165), abnormal chorionic villus sampling (CVS) results (n=25), intrauterine fetal death (n=50), and other non-specific causes (n=1662, 9.9%). The rate of abnormality for each indication was 16% in the abnormal CVS group, 12% in the intrauterine fetal death group, 11.5% for parental chromosomal abnormality, 8.7% in the abnormal ultrasound finding group, 3.0% in the increasing-risk maternal triple-marker Down's screening test group, 2.5% in the advanced maternal age group, 1.5% for other non-specific causes, 1.4% for history of abnormal offspring birth, and 1.1% for family history of chromosomal abnormality.

Conclusions: Both parents with abnormal karyotype and abnormal ultrasound findings are indications for which consideration of further amniocentesis is highly recommended.
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http://dx.doi.org/10.1016/j.tjog.2012.04.007DOI Listing
June 2012

Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c-Myc.

Int J Mol Sci 2012 16;13(3):3598-617. Epub 2012 Mar 16.

Department of Optics and Photonics, National Central University, Chung-Li, Taiwan; E-Mails: (H.-M.C.); (S.-Y.C.).

The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl(4))-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl(4)-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl(4)-treated mice. CCl(4)-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases.
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http://dx.doi.org/10.3390/ijms13033598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317730PMC
August 2015

Reprogramming human endometrial fibroblast into induced pluripotent stem cells.

Taiwan J Obstet Gynecol 2012 Mar;51(1):35-42

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.

Objective: A recent breakthrough demonstrated that ectopic expression of four genes is sufficient to reprogram human fibroblasts into inducible pluripotent stem cells (iPSCs). However, it remains unknown whether human endometrial fibroblasts (EMFs) are capable of being reprogrammed into EMF-derived iPSCs (EMF-iPSCs).

Methods: EMFs were obtained from donors in their third and fourth decade of life and were reprogrammed into iPSCs using retroviral transduction with Oct-4, Sox2, Klf4, and c-Myc.

Results: The EMF-iPSCs displayed the accelerated expression of endogenous Nanog and OCT-4 during reprogramming compared with EMFs. As a result, EMF-iPSC colonies that could be subcultured and propagated were established as early as 12 days after transduction. After 2 weeks of reprogramming, the human endometrial cells yielded significantly higher numbers of iPSC colonies and formed more 3D spheroid bodies than the EMFs. We have shown that human EMF-iPSCs are able to differentiate into neuronal-like cells, adipocytes, and osteocyte-like cells that express specific osteogenic genes.

Conclusion: Human EMFs can undergo reprogramming to establish pluripotent stem cell lines in female donors by the retroviral transduction of Oct-4, Sox2, Klf4, and c-Myc.
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http://dx.doi.org/10.1016/j.tjog.2012.01.008DOI Listing
March 2012

Anti-Mullerian hormone serum level as a predictive marker of ovarian function in Taiwanese women.

J Chin Med Assoc 2012 Feb 23;75(2):70-4. Epub 2012 Jan 23.

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: Anti-Mullerian hormone (AMH), which is secreted by preantral and small antral follicles, has been found to be a valuable marker of ovarian reserve. The purpose of this study was to determine age-related changes in AMH levels that occur in Taiwanese women and to determine whether measuring AMH is a highly sensitive and specific tool for diagnosing polycystic ovarian syndrome (PCOS) in Taiwanese women.

Methods: A group of 59 healthy, fertile, regularly cycling women, a second group of seven patients with premature ovarian failure or menopause, and a third group of 45 PCOS patients were enrolled. Serum AMH concentrations were measured using an enzyme-linked immunosorbent assay.

Results: AMH levels in healthy fertile women with regular menstrual cycles demonstrated an age-related decline, with a rapid drop between 30-40 years of age that was followed by a slow decrease after 40 years old. All patients with premature ovarian failure and menopause had undetectable AMH levels. AMH levels in PCOS patients were found to be significantly higher than those measured in healthy fertile controls. The sensitivity and specificity of AMH for detecting PCOS in patients aged 29-38 years were calculated to be 74% and 79%, respectively, using an AMH cut-off value of 3.5 ng/mL.

Conclusion: Here, we provide data on Taiwanese women that demonstrate age-related decline in AMH levels and establish an AMH-based method for detecting PCOS, which may be used as reference data for future AMH studies on Taiwanese women.
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http://dx.doi.org/10.1016/j.jcma.2011.12.007DOI Listing
February 2012
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