Chung-Yi Hu

Genetics, Immunology, Molecular Biology

30.86

Publications

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    ABSTRACT: 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.
    Full-text · Article · Nov 2015 · PLoS ONE
  • S-C Lo · K-H Lin · H-H Hsieh · D-T Lin · C-Y Hu
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    ABSTRACT: Background: New CD36 mutations are constantly being identified, although no study has specifically targeted a Taiwanese population. CD36 deficiency can result in dyslipid state and slow clearance of chylomicron. This could be linked to more frequent lipemic donations. Study design and methods: We used flow cytometric methods to study the CD36 deficiency in 640 regular volunteer platelet apheresis donors from Taipei blood centre. The coding exons of CD36 gene were sequenced in CD36-deficient individuals, and the allele frequencies of CD36 variants were determined in the larger population by mutation-specific PCR and oligonucleotide hybridization. Visual inspection of lipemic plasma was routinely performed on samples taken before commencement of apheresis. Individuals found to have lipemic plasma are deferred until next donation. We investigated the link between positive lipemic deferral record and low platelet CD36 expression status. Results: We found four donors (0·6%) with type I CD36 deficiency (both platelets and monocytes CD36(null) ) and six (1·0%) with type II CD36 deficiency (PLT: CD36(null) , monocyte: CD36(low) ). Six CD36 genetic variants were identified, two of them were novel, all but one are found exclusively in CD36(null) and CD36(low) expressors. Subjects with CD36 genetic variants also displayed deficient or reduced CD36 on monocytes. Donors with null or low PLT CD36 expression were more likely to have a lipemic deferral record than control subjects with normal PLT CD36 expression (X(2) = 27·36, odds ratio = 2·6, 95% conference interval: 1·8-3·8, P < 0·0001). Conclusion: Through this study, we established a donor registry to supply CD36-negative platelets for patients in need.
    No preview · Article · Nov 2015 · Vox Sanguinis
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    ABSTRACT: 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.
    Full-text · Article · Jun 2015 · BioMed Research International
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    ABSTRACT: 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 cells 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 were determined by western blotting. Drug combination effects of MK-2206 with cytarabine were evaluated by cell proliferation assay and the combination Index (CI) values was 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
    Full-text · Article · Jun 2015 · Medical Oncology
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    ABSTRACT: 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.
    Full-text · Article · Nov 2013 · Rheumatology International
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    Full-text · Dataset · Jun 2013
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    Full-text · Dataset · Jun 2013
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    ABSTRACT: 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) II 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.
    Full-text · Article · Oct 2012 · Chemical Research in Toxicology
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    ABSTRACT: 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.
    Full-text · Article · Aug 2012 · Brain and Cognition
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    ABSTRACT: 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.
    Full-text · Article · Jul 2012 · Clinical Rheumatology
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    ABSTRACT: 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. 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. 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). 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.
    Full-text · Article · Jan 2012 · Cancer
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    Full-text · Article · Sep 2011 · Neuroscience Research
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    ABSTRACT: 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.
    Full-text · Article · Apr 2011 · Clinical Rheumatology

  • No preview · Article · Dec 2010 · Neuroscience Research

  • No preview · Article · Dec 2010 · Neuroscience Research
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    ABSTRACT: 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.
    Full-text · Article · Oct 2010 · Journal of Neural Transmission
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    ABSTRACT: 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.
    Full-text · Article · Jan 2010 · Leukemia research
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    ABSTRACT: 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.
    Full-text · Article · Sep 2009 · Brain and Cognition
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    ABSTRACT: 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.
    Full-text · Article · Apr 2009 · Journal of Medical Virology
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    C Y Hu · C S Wu · H F Tsai · S K Chang · W I Tsai · P N Hsu
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    ABSTRACT: Milk fat globule-EGF factor 8 (MFG-E8) is a molecule implicated in phagocytic clearance of apoptotic cells by bridging between macrophages and apoptotic cells. Defects in MFG-E8 cause lupus-like disease in murine models. The aim of our study is to determine whether genetic variation in MFG-E8 predisposes human to systemic lupus erythematosus (SLE). A case-control study of MFG-E8 genetic polymorphism was performed on 147 SLE patients and 146 non-lupus control subjects. Single nucleotide polymorphisms (SNPs) in the coding sequence of human MFG-E8 gene were investigated. SNPs on MFG-E8 residues 3 (3(Arg or Ser)) and 76 (76(Leu or Met)) did not show genetic linkage. Genetic polymorphism on MFG-E8 residue 76 correlated significantly to SLE. The MFG-E8-76(Met) allele predisposed subjects to SLE in a recessive mode (odds ratio: 2.1, P = 0.020), while carriage of MFG-E8-76(Leu) were negatively associated with SLE. The MFG-E8 genotypic combinations with 3(Ser) and 76(Leu) showed the most pronounced protective effect on SLE when compared to the most predisposing genotype 3(Arg/Arg)-76(Met/Met) (OR: 0.29, P = 0.007). According to our result, MFG-E8 is associated with SLE predisposition in Taiwanese. Our study implicates that the impairment of phagocytic clearance of apoptotic cells through phosphotidylserine-dependent MFG-E8 system may lead to the development of human SLE.
    Full-text · Article · Feb 2009 · Lupus

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