Publications by authors named "Chung-Yi Hu"

22 Publications

  • Page 1 of 1

Cardiac-specific microRNA-125b deficiency induces perinatal death and cardiac hypertrophy.

Sci Rep 2021 01 27;11(1):2377. Epub 2021 Jan 27.

Cardiovascular Division, Institute of Biomedical Science, Academia Sinica, National Taiwan University College of Medicine, 128 Academia Road, Sec. 2, Nankang, Taipei, 115, Taiwan.

MicroRNA-125b, the first microRNA to be identified, is known to promote cardiomyocyte maturation from embryonic stem cells; however, its physiological role remains unclear. To investigate the role of miR-125b in cardiovascular biology, cardiac-specific miR-125b-1 knockout mice were generated. We found that cardiac-specific miR-125b-1 knockout mice displayed half the miR-125b expression of control mice resulting in a 60% perinatal death rate. However, the surviving mice developed hearts with cardiac hypertrophy. The cardiomyocytes in both neonatal and adult mice displayed abnormal mitochondrial morphology. In the deficient neonatal hearts, there was an increase in mitochondrial DNA, but total ATP production was reduced. In addition, both the respiratory complex proteins in mitochondria and mitochondrial transcription machinery were impaired. Mechanistically, using transcriptome and proteome analysis, we found that many proteins involved in fatty acid metabolism were significantly downregulated in miR-125b knockout mice which resulted in reduced fatty acid metabolism. Importantly, many of these proteins are expressed in the mitochondria. We conclude that miR-125b deficiency causes a high mortality rate in neonates and cardiac hypertrophy in adult mice. The dysregulation of fatty acid metabolism may be responsible for the cardiac defect in the miR-125b deficient mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-81700-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840921PMC
January 2021

Thromboelastography characterized CD36 null subjects as slow clot formation and indicative of hypocoagulability.

Thromb Res 2019 Jun 6;178:79-84. Epub 2019 Apr 6.

Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Background: Platelet CD36 is the receptor for oxidized low-density lipoprotein and collagen. The conventional platelet test cannot distinguish CD36-null subjects from normal expression subjects. Thromboelastography (TEG) testing can analyze global hemostasis. TEG testing data on CD36-null subjects are not available.

Methods: Our subjects were 40 apheresis platelet donors, including 8 CD36-null individuals. We grouped the donors according to the platelet CD36 expression levels to assess the effects of platelet CD36 expression levels on TEG measurement variables.

Results: The whole blood TEG test revealed that CD36-null subjects had prolonged reaction time of fibrin formation (TEG R time) and a slower rate to build up cross-linked fibrin (TEG α angle). The final maximal amplitudes of clot formation showed little difference between CD36-null individuals and normal expression individuals. Correlation analysis showed that CD36 expression levels were negatively correlated with TEG R time (r = -0.342, p = 0.031) and positively correlated with the TEG α angle (0.379, p = 0.016). TEG testing on apheresis platelet samples with diminished heterocellular interaction did not reveal differences between CD36-null and normal expression individuals. A subanalysis of the data of a group of healthy subjects showed that platelet CD36 levels correlated positively with platelet-monocyte aggregates (PMAs). Low PMA can diminish heterocellular interaction and likely explain the abnormal TEG results observed in CD36-null individuals.

Conclusion: TEG distinguishes CD36-null subjects from normal CD36 expression subjects as having a slower rate of fibrin formation and reassessment of TEG-based diagnostic monitoring is necessary for CD36 null subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2019.04.006DOI Listing
June 2019

Cytarabine-Resistant -ITD Leukemia Cells are Associated with Mutation and Multiple Pathway Alterations-Possible Therapeutic Efficacy of Cabozantinib.

Int J Mol Sci 2019 Mar 11;20(5). Epub 2019 Mar 11.

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from -ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The -ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20051230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429333PMC
March 2019

Cabozantinib is selectively cytotoxic in acute myeloid leukemia cells with FLT3-internal tandem duplication (FLT3-ITD).

Cancer Lett 2016 07 6;376(2):218-25. Epub 2016 Apr 6.

Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan; Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Cabozantinib is an oral multikinase inhibitor that exhibits anti-tumor activity in several cancers. We found that cabozantinib was significantly cytotoxic to MV4-11 and Molm-13 cells that harbored FLT3-ITD, resulting in IC50 values of 2.4 nM and 2.0 nM, respectively. However, K562, OCI-AML3 and THP-1 (leukemia cell lines lacking FLT3-ITD) were resistant to cabozantinib, showing IC50 values in the micromolar range. Cabozantinib arrested MV4-11 cell growth at the G0/G1 phase within 24 h, which was associated with decreased phosphorylation of FLT3, STAT5, AKT and ERK. Additionally, cabozantinib induced MV4-11 cell apoptosis in a dose-dependent manner (as indicated by annexin V staining and high levels of cleaved caspase 3 and PARP-1), down-regulated the anti-apoptotic protein survivin and up-regulated the pro-apoptotic protein Bak. Thus, cabozantinib is selectively cytotoxic to leukemia cells with FLT3-ITD, causing cell-cycle arrest and apoptosis. In mouse xenograft model, cabozantinib significantly inhibited MV4-11 and Molm-13 tumor growth at a dosage of 10 mg/kg and showed longer survival rate. Clinical trials evaluating the efficacy of cabozantinib in acute myeloid leukemia (AML) with FLT3-ITD are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2016.04.004DOI Listing
July 2016

A Double Negative Loop Comprising ETV6/RUNX1 and MIR181A1 Contributes to Differentiation Block in t(12;21)-Positive Acute Lymphoblastic Leukemia.

PLoS One 2015 18;10(11):e0142863. Epub 2015 Nov 18.

Departments of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Childhood acute lymphoblastic leukemia (ALL) with t(12;21), which results in expression of the ETV6/RUNX1 fusion gene, is the most common chromosomal lesion in precursor-B (pre-B) ALL. We identified 17 microRNAs that were downregulated in ETV6/RUNX1+ compared with ETV6/RUNX1- clinical samples. Among these microRNAs, miR-181a-1 was the most significantly reduced (by ~75%; P < 0.001). Using chromatin immunoprecipitation, we demonstrated that ETV6/RUNX1 directly binds the regulatory region of MIR181A1, and knockdown of ETV6/RUNX1 increased miR-181a-1 level. We further showed that miR-181a (functional counterpart of miR-181a-1) could target ETV6/RUNX1 and cause a reduction in the level of the oncoprotein ETV6/RUNX1, cell growth arrest, an increase in apoptosis, and induction of cell differentiation in ETV6/RUNX1+ cell line. Moreover, ectopic expression of miR-181a also resulted in decreased CD10 hyperexpression in ETV6/RUNX1+ primary patient samples. Taken together, our results demonstrate that MIR181A1 and ETV6/RUNX1 regulate each other, and we propose that a double negative loop involving MIR181A1 and ETV6/RUNX1 may contribute to ETV6/RUNX1-driven arrest of differentiation in pre-B ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142863PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651427PMC
June 2016

An Exploratory Analysis of the Relationship between Cardiometabolic Risk Factors and Cognitive/Academic Performance among Adolescents.

Biomed Res Int 2015 7;2015:520619. Epub 2015 Jun 7.

Science Education Center and Graduate Institute of Science Education, National Taiwan Normal University, 88 Section 4, Ting-Chou Road, Taipei 116, Taiwan ; Department of Earth Sciences, National Taiwan Normal University, 88 Section 4, Ting-Chou Road, Taipei 116, Taiwan.

This exploratory study examines the relationship between cardiometabolic risk factors (blood pressure, waist circumference, BMI, and total cholesterol) and cognitive/academic performance. In this study, 1297 Taiwanese tenth-grade volunteers are recruited. Scores from the Basic Competency Test, an annual national competitive entrance examination, are used to evaluate academic performance. Cognitive abilities are accessed via the Multiple Aptitude Test Battery. The results indicate that systolic blood pressure is significantly, negatively associated with academic performance, both in male and female subjects. BMI and waist circumference are associated with verbal reasoning performance with an inverse U-shaped pattern, suggesting that both low and high BMI/waist circumference may be associated with lower verbal reasoning performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/520619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475517PMC
March 2016

MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine.

Med Oncol 2015 Jul 19;32(7):206. Epub 2015 Jun 19.

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan,

Genetic alterations in the PI3K/AKT cascade have been linked to various human cancers including acute myeloid leukemia (AML) and have emerged to be promising targets for treatment. In this study, we explored the molecular mechanism and clinical implication of a specific allosteric AKT inhibitor, MK-2206, in the treatment of AML. Four leukemia cell lines, MV-4-11, MOLM-13, OCI/AML3, and U937, were used. Apoptosis and cell cycle distribution were determined by flow cytometry analysis. Expression of anti-apoptotic protein family and glycogen synthase kinase 3β (GSK3β) signaling was determined by western blotting. Drug combination effects of MK-2206 with cytarabine were evaluated by cell proliferation assay, and the combination index values were calculated by CompuSyn software. MK-2206 had no effect on normal peripheral blood mononuclear cells, but induced G1-phase arrest and apoptosis in leukemia cells. Among anti-apoptotic Bcl-2 family members, only myeloid cell leukemia-1 (Mcl-1) was significantly suppressed. Mcl-1 suppression by MK-2206 was closely associated with decreased GSK3β phosphorylation at Ser9, an event leads to GSK3β activation. Furthermore, the effect of MK-2206 on Mcl-1 downregulation was abolished by GSK3β inhibitor, lithium chloride and proteasome inhibitor, MG-132, suggesting that MK-2206 acted through a GSK3β-mediated, proteasome-dependent protein degradation. In addition, co-administration of MK-2206 with cytarabine could enhance the cytotoxic efficacy of cytarabine in leukemia cell lines. In conclusion, we have demonstrated that MK-2206 is an active agent in AML and its efficacy as in combination with cytarabine is implicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-015-0650-7DOI Listing
July 2015

Elevated serum level of growth arrest-specific protein 6 (Gas6) in systemic lupus erythematosus patients is associated with nephritis and cutaneous vasculitis.

Rheumatol Int 2014 May 1;34(5):625-9. Epub 2013 Nov 1.

Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

Growth arrest-specific protein 6 (Gas6) is a serum protein involved in granulocyte, platelet and endothelium interaction, and is implicated in both anti-inflammatory response as well as platelet/leukocytes activation. We investigated serum Gas6 level in different clinical manifestations of systemic lupus erythematosus (SLE). Data were collected in 83 patients with SLE and 40 non-lupus controls. The Gas6 levels were detected by enzyme-linked immunosorbent assay. Our results demonstrated that the Gas6 level was higher in SLE patients as compared to the non-lupus control subjects (SLE vs. non-lupus control, median [inter-quartile range (IQR)] 22.67 [19.40-28.60] vs. 18.97 [16.05-20.62] ng/mL, p < 0.01). Furthermore, Gas6 level was higher in patients with nephritis (nephritis vs. non-nephritis, median [IQR] 26.21 [21.17-31.61] vs. 22.22 [18.98-26.98] ng/mL, p = 0.03) and in patients with cutaneous vasculitis (vasculitis vs. non-vasculitis, median [IQR] 27.89 [23.24-34.26] vs. 22.30 [19.32-27.16] ng/mL, p = 0.03). Our results indicate that the serum Gas6 level is increased in SLE patients with lupus nephritis or cutaneous vasculitis, implicating a potential to serve as a SLE disease activity marker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00296-013-2882-1DOI Listing
May 2014

A cysteine-reactive alkyl hydroquinone modifies topoisomerase IIα, enhances DNA breakage, and induces apoptosis in cancer cells.

Chem Res Toxicol 2012 Nov 2;25(11):2340-51. Epub 2012 Nov 2.

Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China.

We previously reported that the anticancer activity of a botanical compound 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)] was attributed to topoisomerase (Topo) IIα poisoning and the induction of oxidative damage. HQ17(3) irreversibly inhibits Topo IIα activity in vitro and is more cytotoxic in leukemia HL-60 cells than in Topo IIα-deficient variant HL-60/MX2 cells, which suggests that Topo IIα is a cellular target of HQ17(3). This study further characterizes the molecular mechanisms of the anticancer activity of HQ17(3). Proteomic analyses indicated that HQ17(3) reacted with Cys-427, Cys-733, and Cys-997 of recombinant Topo IIα in vitro, whereas it reacted with Cys-427 of cellular Topo IIα in Huh7 hepatoma cells. The modification of HQ17(3) inhibited Topo IIα catalytic activity, increased the Topo IIα-DNA cleavage complex, and caused the accumulation of DNA breakage. In Huh7 cells, HQ17(3) treatment caused prompt inhibition of DNA synthesis and consequently induced the expression of DNA damage-related genes DDIT3, GADD45A, and GADD45G. Topo IIα inhibition, apoptosis, and oxidative stress were found to account for cytotoxicity caused by HQ17(3). Pretreatment of Huh7 cells with N-acetylcysteine (NAC) partially attenuated mitochondrial membrane damage, DNA breakage, and caspase activation. However, NAC pretreatment did not diminish HQ17(3)-induced cell death. These results suggest that the anticancer activity of HQ17(3) is attributed significantly to Topo IIα poisoning. The structural feature of HQ17(3) can be used as a model for the design of Topo IIα inhibitors and anticancer drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/tx3002302DOI Listing
November 2012

Association of polymorphisms in BDNF, MTHFR, and genes involved in the dopaminergic pathway with memory in a healthy Chinese population.

Brain Cogn 2012 Nov 31;80(2):282-9. Epub 2012 Aug 31.

Science Education Center and Graduate Institute of Science Education, National Taiwan Normal University, Taiwan, ROC.

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single nucleotide polymorphisms (SNPs) within the genes. This study investigates the association between memory and SNPs in genes involved in the dopaminergic pathway, as well as in the BDNF and MTHFR genes, in a sample of healthy individuals. The sample includes 134 Taiwanese undergraduate volunteers of similar cognitive ability. The Chinese versions of the Wechsler Memory Scale (WMS-III) and Wechsler Adult Intelligence Scale (WAIS-III) were employed. Our findings indicate that the BDNF Met66Val polymorphism and dopamine receptor D3 (DRD3) Ser9Gly polymorphism are associated significantly with long-term auditory memory. Further analysis detects no significant associations in the other polymorphisms and indices. Future replicated studies with larger sample sizes, and studies that consider different ethnic groups, are encouraged.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bandc.2012.06.005DOI Listing
November 2012

Genetic polymorphism of the growth arrest-specific 6 gene is associated with cutaneous vasculitis in Taiwanese patients with systemic lupus erythematosus.

Clin Rheumatol 2012 Oct 5;31(10):1443-8. Epub 2012 Jul 5.

Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

The growth arrest-specific 6 (GAS6) gene product participates in platelet activation and granulocyte interaction with the endothelium. Our case-control study aimed to determine whether polymorphism of GAS6 was associated with predisposing risk or specific clinical manifestations of systemic lupus erythematosus (SLE). Two of the single-nucleotide polymorphisms (SNPs) of the GAS6 gene, GAS6 834 + 7G/A (rs8191974) and GAS6 +1332C/T (rs1803628), were investigated in 83 SLE patients and 89 non-lupus control subjects. We demonstrated that among lupus patients, the GAS6 +1332 T allele was more prevalent in patients with cutaneous vasculitis (allele T 41.7 % in patients with cutaneous vasculitis compared with 18.3 % in patients without vasculitis, odds ratio (OR) 3.2, 95 % confidence interval 1.3-8.0, p = 0.016). In conclusion, GAS6 polymorphism is positively associated with cutaneous vasculitis in SLE patients, which suggests that GAS6 polymorphism could be a genetic marker for SLE with cutaneous vasculitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-012-2027-zDOI Listing
October 2012

Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk.

Cancer 2012 Jan 20;118(1):223-31. Epub 2011 Jun 20.

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Only a small proportion of women infected with human papillomavirus type 18 (HPV18) may progress to persistent infection and cervical neoplasia. This community-based cohort study aimed to assess associations with human leukocyte antigen (HLA) class II genotypes for natural infection of HPV18 and subsequent risk of cervical neoplasia.

Methods: Among 10,190 cytologically normal participants, 125 with HPV18 infection were identified by HPV blot kit. HPV18 viral load at study entry was examined by real-time polymerase chain reaction; persistent infection was defined as HPV18 infection at 2 consecutive examinations.

Results: There was a significant association between HLA-DRB1*0403 allele and high HPV18 viral load (>1000 copies in 50 ng of total DNA) at study entry (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.0-25.2). After adjustment for age and viral load at study entry, haplotype HLA-DRB1*0405-DQA1*0301-DQB1*0302 was significantly associated with persistent HPV18 infection (OR, 13.3; 95% CI, 1.7-105.9). HLA-DRB1*0403 allele was also associated with a significantly increased risk of high-grade squamous intraepithelial lesion or cancer, showing a multivariate-adjusted hazard ratio (95% CI) of 18.1 (2.6-128.5).

Conclusions: HLA-DRB1*0403 allele and HLA-DRB1*0405-DQA1*0301-DQB1*0302 haplotype may play important roles in determination of high viral load and persistent infection of HPV18 and subsequent cervical neoplasia risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.26227DOI Listing
January 2012

Galectin-3 gene (LGALS3) +292C allele is a genetic predisposition factor for rheumatoid arthritis in Taiwan.

Clin Rheumatol 2011 Sep 8;30(9):1227-33. Epub 2011 Apr 8.

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.

Galectin-3 is a beta-galactoside-binding lectin which is involved in modulating inflammation and apoptosis. Elevated expression of galectin-3 has been demonstrated in synovium of rheumatoid arthritis (RA). The aim of our study is to investigate the genetic polymorphisms of galectin-3 in association with RA. Polymorphisms of galectin-3 gene (LGALS3) were compared between 151 RA patients and 182 healthy subjects in Taiwan. Variants at two LGALS3 single nucleotide polymorphism (SNP) sites (rs4644 and rs4652, corresponding to LAGLS3 +191 and +292) were genotyped by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) and sequence-specific oligonucleotide probe hybridization, respectively. The allelic carriage of LGALS3 +292C was increased in patients with RA (66.9% in RA vs. 52.7% in controls, odds ratio=1.8, 95% confidence interval=1.2-2.8, p=0.009). These results implicate that the genetic polymorphisms in galectin-3 gene may contribute to development of RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-011-1741-2DOI Listing
September 2011

Association of polymorphisms in genes involved in the dopaminergic pathway with blood pressure and uric acid levels in Chinese females.

J Neural Transm (Vienna) 2010 Dec 8;117(12):1371-6. Epub 2010 Oct 8.

Science Education Center and Graduate Institute of Science Education, National Taiwan Normal University, 88 Sec. 4, Ting-Chou Rd., Taipei 116, Taiwan, ROC.

Since the high degree of heritability of physiological traits was demonstrated by twin and adoption studies, contemporary researchers in the fields of clinical medicine, behavioral science, and genetics have acknowledged the crucial role of genetic factors in human physiology. The study described herein explores the association between physiological parameters and the dopaminergic system using molecular genetic techniques. A total of 558 Taiwanese female volunteers, ranging from 16 to 17 years, were recruited. Single nucleotide polymorphisms in genes involved in the dopaminergic pathway were selected for analysis. Systolic blood pressure and diastolic blood pressure were associated significantly with the catechol-O-methyltransferase (COMT) Val158Met polymorphism and the dopamine β-hydroxylase (DBH) C1021T polymorphism. Furthermore, plasma uric acid was associated significantly with the COMT Val158Met polymorphism. Our study suggests the possible involvement of genetic polymorphisms in COMT and DBH in the regulation of blood pressure and plasma uric acid.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-010-0492-6DOI Listing
December 2010

Expression and prognostic significance of the apoptotic genes BCL2L13, Livin, and CASP8AP2 in childhood acute lymphoblastic leukemia.

Leuk Res 2010 Jan;34(1):18-23

Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Improved treatment of childhood acute lymphoblastic leukemia (ALL) depends on the identification of new molecular markers that are able to predict treatment response and clinical outcome. The development of impaired apoptosis in leukemic cells is one factor that may influence their response to treatment. We investigated the expression of three apoptosis related genes, BCL2L13, CASP8AP2, and Livin, as well as their prognostic significance, in a retrospective study of 90 pediatric ALL patients diagnosed between 1996 and 2007 in Taiwan. Univariant analysis revealed that high expression of BCL2L13 was associated with inferior event-free survival and overall survival (p<0.001 and 0.005, respectively). Multivariate analysis for EFS and OS demonstrated that high expression of BCL2L13 was an independent prognostic factor for childhood ALL in this ethnic group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2009.07.023DOI Listing
January 2010

Pharmacogenomic variations in treatment protocols for childhood acute lymphoblastic leukemia.

Pediatr Blood Cancer 2010 Feb;54(2):206-11

Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, ROC.

Objectives: This retrospective study evaluates the role of pharmacogenomic determinants in the treatment of childhood acute lymphoblastic leukemia (ALL) in the Taiwanese population.

Methods: A total of 105 childhood ALL patients received combined chemotherapy of different intensities based on risk-directed Taiwan Pediatric Oncology Group (TPOG)-ALL-93 protocols. Seventeen genetic polymorphisms in 13 pharmacogenomic targets were analyzed by PCR-based restriction fragment length polymorphism (RFLP) and sequence-specific oligonucleotide (SSO) probe hybridization. Pharmacogenomic polymorphisms were correlated with event-free survival (EFS) of patients, with confounding effects adjusted by multivariate regression.

Results: Three polymorphic alleles in the multi-drug resistance 1 (MDR1) ABCB1 gene, and homozygotic MDR1 2677GG, 3435CC, and 2677G-3435C genotypes were highly associated with a significant reduction in EFS in those patients treated by the standard risk (SR) protocol (TPOG-ALL-93-SR). The hazard ratios were 6.8 (p = 0.01), 21.7 (p = 0.009), and 6.8 (p = 0.01), respectively.

Conclusions: Independent pharmacogenomic determinants associated with treatment outcome were identified in subsets of Taiwanese ALL patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.22292DOI Listing
February 2010

Association of catechol-O-methyltransferase (COMT) polymorphism and academic achievement in a Chinese cohort.

Brain Cogn 2009 Dec 22;71(3):300-5. Epub 2009 Aug 22.

Science Education Center and Graduate Institute of Science Education, National Taiwan Normal University, Taiwan, ROC.

Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele may be advantageous for PFC-related cognitive abilities; however, it is also associated with increased anxiety, depression, and emotional vulnerability in response to stress or educational adversity. We hypothesized that the COMT polymorphism might be associated with academic performance. In this study, 779 Taiwanese tenth-grade volunteers were recruited. Scores from the Basic Competency Test (BCT), an annual national competitive entrance examination, were used to evaluate academic performance. The results indicated that students bearing homozygous for the Met allele tended to perform more poorly in all BCT subtests as compared to the other groups. In particular, the former performed significantly more poorly in the science and social science subtests. These findings provide evidence that affective factors might overwhelm cognitive abilities in high-stake tests like the BCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bandc.2009.07.011DOI Listing
December 2009

Human leukocyte antigen-DRB1*1101 correlates with less severe hepatitis in Taiwanese male carriers of hepatitis B virus.

J Med Virol 2009 Apr;81(4):588-93

Liver Unit, Cathay General Hospital Medical Center, Taipei, Taiwan.

Human leukocyte antigen (HLA) class II molecules are associated with host immune responses against hepatitis B virus infection. Male gender is the apparent host factor when someone encounters with the severity of hepatitis. The aim of this study was to investigate the association of the most polymorphic HLA class II allele, human leukocyte antigen-DRB1, with the severity of hepatitis in male carriers of hepatitis B virus. In this prospective cohort study, a total of 204 carriers of hepatitis B virus (131 men and 73 women) who have been followed-up for more than 1 year at the outpatient clinic of a university hospital were collected consecutively. Fifty carriers of hepatitis B virus (group I) with alanine aminotransferase <2x upper limit of normal (mean follow-up 83.6 months) were compared with 154 chronic hepatitis B patients (group II) with alanine aminotransferase >/=2x upper limit of normal (mean follow-up 81.3 months). Alleles of HLA-DRB1 were typed by the polymerase chain reaction-sequence specific oligonucleotide probe hybridization and genotypes of hepatitis B virus by melting curve analysis. HLA-DRB1*1101 was found in 18% of group I versus 8% of group II in male carriers (OR 0.23, P = 0.020, after adjustment for age) and 4% versus 9.4% in female carriers (P = 0.094). In male carriers harboring DRB1*1101, the distribution of hepatitis B viral genotype was comparable between the two groups. HLA-DRB1*1101 correlates with less severe hepatitis in Taiwanese male carriers of hepatitis B virus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.21448DOI Listing
April 2009

Anti-SSB/La antibody is negatively associated with HLA-DR2 in chronic hepatitis C infection.

Clin Rheumatol 2008 Mar 9;27(3):365-8. Epub 2007 Nov 9.

Division of Rheumatology, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan, Republic of China.

Hepatitis C virus (HCV) infection is frequently associated with anti-SSA/Ro and anti-SSB/La autoantibodies. The objective of this study is to examine the prevalence of anti-SSA/Ro and anti-SSB/La autoantibodies in HCV-infected patients and their possible associations with HLA-DRB1 polymorphism in Chinese patients in Taiwan. About 288 HCV-infected patients were recruited for autoantibody detection and HLA-DRB1 typing. Anti-SSA/Ro and anti-SSB/La autoantibodies were detected in 12.8 and 9.7% of HCV-infected patients. Anti-SSA/Ro antibody was positively associated with age over 55 [p = 0.04; odds ratio = 2.17; 95% confidence interval (CI), 1.03-4.57]. Anti-SSB/La antibody was negatively associated with HLA-DR2 carriage (p = 0.024; odds ratio = 0.30; 95% CI, 0.10-0.90). No significant correlation was found between autoantibody production and gender, autoimmune manifestation, presence of cirrhosis, or hepatocellular carcinoma in HCV infection. In conclusion, anti-SSA/Ro and anti-SSB/La antibodies present frequently in HCV-infected patients. Anti-SSB/La antibody is negatively associated with HLA-DR2 in HCV-infected patients in Taiwan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-007-0783-yDOI Listing
March 2008

Hepatitis C virus core protein modulates TRAIL-mediated apoptosis by enhancing Bid cleavage and activation of mitochondria apoptosis signaling pathway.

J Immunol 2005 Feb;174(4):2160-6

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

Hepatitis C virus (HCV) is a major human pathogen causing chronic liver disease, which leads to cirrhosis of liver and hepatocellular carcinoma. The HCV core protein, a viral nucleocapsid, has been shown to affect various intracellular events, including cell proliferation and apoptosis. However, the precise mechanisms of the effects are not fully understood. In this study, we show that HCV core protein sensitizes human hepatocellular carcinoma cell line, Huh7, conferred sensitivity to TRAIL-, but not Fas ligand-mediated apoptosis. Huh7 cells are resistant to TRAIL, despite the induction of caspase-8 after TRAIL engagement. However, HCV core protein induces TRAIL apoptosis signaling via sequential induction of caspase-8, Bid cleavage, activation of mitochondrial pathway, and effector caspase-3. HCV core protein also induces activation of caspase-9 after TRAIL engagement, and the induction of TRAIL sensitivity by HCV core protein could be reversed by caspase-9 inhibitor. Therefore, the HCV core protein-induced TRAIL-mediated apoptosis is dependent upon activation of caspase-8 downstream pathway to convey the death signal to mitochondria, leading to activation of mitochondrial signaling pathway and breaking the apoptosis resistance. These results combined indicate that the HCV core protein enhances TRAIL-, but not Fas ligand-mediated apoptotic cell death in Huh7 cells via a mechanism dependent on the activation of mitochondria apoptosis signaling pathway. These results suggest that HCV core protein may have a role in immune-mediated liver cell injury by modulation of TRAIL-induced apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.174.4.2160DOI Listing
February 2005

HLA-Cw6 specificity and polymorphic residues are associated with susceptibility among Chinese psoriatics in Taiwan.

Arch Dermatol Res 2002 Jul 13;294(5):214-20. Epub 2002 Jun 13.

Department of Dermatology, National Taiwan University Hospital, No.7, Chang-Shan S. Rd., Taipei, Taiwan, 10016.

Previous serotyping in Chinese patients has failed to confirm an association between HLA-Cw6 and psoriasis. As serotyping has proved to be less valuable in the determination of HLA-C, genotyping of HLA-C in 68 Taiwanese psoriasis vulgaris (PSV) patients was performed using polymerase chain reaction/sequence-specific oligonucleotide probe hybridization (PCR-SSOPH) of HLA-Cw genes. Compared to 213 non-PSV control subjects, HLA-Cw6 was significantly associated with PSV (16.18% of PSV patients vs 5.16% of controls; odds ratio 3.53, Pc
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00403-002-0324-0DOI Listing
July 2002

Reduction of human-to-pig cellular response by alteration of porcine MHC with human HLA DPW0401 exogenes.

Transplantation 2002 Jan;73(2):193-7

Department of Surgery, National Taiwan University Hospital, 7, Chung Shan South Rd., Taipei, Taiwan, Republic of China.

Background: In pig-to-human discordant xenotransplantation, the xenograft can be rejected by a formidable human xenogenic T-cell response, even if the graft has gone through hyperacute rejection or delayed xenograft rejection (acute vascular rejection). We therefore examined, in this study, whether the human-to-pig cellular response could be attenuated through the generation of a transgenic pig for human HLA II.

Methods: With the technique of microinjection, we produced the HLA DPw0401 transgenic pig. The expression of the HLA DPw0401 gene on peripheral blood mononuclear cells (PBMCs) of the transgenic pig was examined by reverse transcriptase-polymerase chain reaction and flow cytometry. The antigenicity of the transgenic HLA DPw0401 molecule was tested by the HLA DPw0401-primed lymphocyte test reagent. The cellular response was analyzed by xenogenic mixed lymphocyte culture.

Results: The mRNA and protein of HLA DPw0401 were expressed in the PBMCs of the transgenic pig. The PBMCs of the HLA transgenic pig induced a stronger cellular reaction to HLA DPw0401-primed lymphocyte test reagents than the nontransgenic littermate pig (n=7, P<0.01). In direct xenogenic mixed lymphocyte culture with responders from HLA DPw0401(+) humans, the PBMCs from the HLA DPw0401 transgenic pig, as compared with those from the normal pig, induced a lower degree of xenogenic cellular response to human PBMCs (n=4, P=0.08).

Conclusions: Our preliminary data demonstrated the possibility that the human HLA DPw0401 phenotype can be transferred onto porcine cells through the generation of HLA transgenic pigs and make the PBMCs of humans more tolerant to porcine cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00007890-200201270-00007DOI Listing
January 2002
-->