Biomedical subjects

Chao A Hsiung

Publications and source records attributed to Chao A Hsiung.

At least 19 recordsLinked to original sources

PubMed2026

Elevated phthalate exposure and metabolic susceptibility increased breast cancer risk: A 20-y follow-up study in Taiwan.

Widely used phthalates, especially di-(2-ethylhexyl) phthalate (DEHP), increase breast cancer risk in experimental animals and humans, but long-term follow-up evidence of its human breast carcinogenicity remains inconclusive. This nested case-control study included 119 invasive breast cancer cases and 245 matched controls from a longitudinal cohort of 11,923 women recruited in 1991-1992 and followed to 2010 in Taiwan. Urine samples at baseline and follow-up visit were tested for 11 metabolites of seven phthalates using LC-ESI-MS/MS. DEHP metabolism susceptibility was evaluated by the percentage of mono-2-ethylhexyl phthalate (MEHP%) in the sum of five DEHP metabolites (∑DEHP). Odds ratios (ORs) with 95% CI from conditional logistic regression were used to examine risk predictors. DEHP was the only phthalate significantly associated with breast cancer risk. Risk increased significantly with elevated urinary levels of ∑DEHP (> 0.381 μmol/g creatinine, OR = 1.71, 95% CI = 1.02 to 2.43), MEHP (> 0.022 μmol/g creatinine, OR = 1.87, 95% CI = 1.07 to 3.25), and MEHP% (> 6.7%, OR = 1.65, 95% CI = 0.96 to 2.82). Elevated ∑DEHP and MEHP% combined with early menarche (≤ 14 years) was associated with further increased risk (OR = 7.52, 95% CI = 2.68 to 21.05). The intraclass correlation coefficient between paired baseline and follow-up samples of 152 women was 0.06 for ∑DEHP and 0.31 for MEHP%. High DEHP exposure, high MEHP%, and early menarche were associated with increased breast cancer risk. MEHP% was a better biomarker for DEHP metabolism.

Humans↗

PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗

PubMed2006

Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71.

We valuated specific cellular and humoral immune response of cases of enterovirus 71 (EV71) infection and correlated immune response with clinical outcome. After obtaining informed consent, we enrolled 30 EV71 cases including 7 cases with brainstem encephalitis plus pulmonary edema, 12 cases of CNS (CNS) involvement and 11 uncomplicated cases. We measured antibodies specific to EV71, lymphocyte proliferation response and EV71-stimulated cellular response of Th1/Th2 cytokines and chemokines. The 7 EV71 cases involving brainstem encephalitis plus pulmonary edema had a significantly lower phytohemagglutinin stimulation index than other cases (p = 0.04). After EV71 stimulation of peripheral mononuclear cells, there was a significant increase in cellular Th1 cytokine (gamma-interferon) and proinflammatroy cytokines. However, cases with pulmonary edema had significantly lower cellular gamma-interferon (p = 0.04), lower cellular IL-1beta (p = 0.04), lower cellular IL-6 (p = 0.04), lower cellular tumor necrosis factor-alpha response (p = 0.04), and lower cellular macrophage inflammatory protein-1alpha (p = 0.04) response compared with other cases. Their titers of EV71 neutralizing antibodies demonstrated no difference among cases. These results suggest lower EV71-specific cellular response may be associated with immunopathogenesis of EV71-related pulmonary edema.

Antibodies, Viral↗

PubMed2006

Incorporating endophenotypes into allele-sharing based linkage tests.

For a genetic study in which there are concordant and discordant sibpairs for a complex disease trait and the measurements of other endophenotypes/intermediate phenotypes for each of the individuals are also available, we describe an allele-sharing based multipoint linkage test that utilizes nonparametrically the additional endophenotypes/intermediate phenotypes. The usefulness of this method is evaluated in simulation studies, which show that the gain in power is influenced by not only the endophenotypic value but also the correlation between the diagnosis-based phenotype and the endophenotype. In addition to reporting p values, our method also provides an index C(E), derived from the coefficients of the weight function associated with the endophenotype in the proposed statistic, to indicate the relevance of a specific endophenotype/intermediate phenotype in the genetic study. The simulation study indicates that a larger power, in general, corresponds to a larger value of the index C(E). The index C(E) is thus suggested as a quantity to be used in the choice of endophenotypes in linkage study. Data from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) are used to illustrate the method.

Adult↗

PubMed2006

Genome-wide linkage analysis of lipids in nondiabetic Chinese and Japanese from the SAPPHIRe family study.

BACKGROUND: Lipid levels are recognized as major risk factors for coronary heart disease (CHD). Discovery of major loci underlying quantitative lipid traits could help to elucidate the genetics of CHD. METHODS: We performed a genome-wide search for quantitative trait loci linked to lipid phenotypes in 1538 Chinese subjects (509 families) and 625 Japanese subjects (204 families) not taking lipid-lowering medications from the Stanford-Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) study. The multipoint variance-components method was used to test for linkage between marker loci and each trait by maximum likelihood methods adjusted for effects of age, age(2), gender, body mass index (BMI), smoking, alcohol drinking, physical activity, and field center. RESULTS: The highest logarithm of odds (LOD) score detected was 3.22 for logarithmically transformed HDL-cholesterol on chromosome 12 at 113 cM in Chinese subjects. This score overlaps the positive findings for HDL reported in Mexican Americans (chromosome 12 at 96 cM). Although no strong evidence for linkage was found in Japanese subjects, some modest peaks (LOD score >==1.5) were found in several regions that have been reported in other published genome scans. For example, the Japanese SAPPHIRe peak for HDL (chromosome 1 at 167 cM; LOD = 1.54) was very close to the quantitative trait loci (QTL) for HDL reported in the scan of white American HyperGEN (chromosome 1 at 159.9 cM). CONCLUSIONS: Genome-wide scan for genes influencing lipid phenotypes was conducted and we found significant linkage of HDL to a locus on chromosome 12 in Chinese subjects and no linkage signal exceeding 1.68 was found in the Japanese subjects.

Adult↗

PubMed2006

Nodal dissection for patients with gastric cancer: a randomised controlled trial.

BACKGROUND: The survival benefit and morbidity after nodal dissection for gastric cancer remains controversial. We aimed to do a single-institution randomised trial to compare D1 (ie, level 1) lymphadenectomy with that of D3 (ie, levels 1, 2, and 3) dissection for gastric cancer in terms of overall survival and disease-free survival. METHODS: From Oct 7, 1993, to Aug 12, 1999, 335 patients were registered. 221 patients were eligible, 110 of whom were randomly assigned D1 surgery and 111 of whom were randomly assigned D3 surgery, both with curative intent. Three participating surgeons had done at least 25 independent D3 dissections before the start of the trial, and every procedure was verified by pathological analyses. The primary endpoints were 5-year overall survival and 5-year disease-free survival. We also analysed risk of recurrence. Main analyses were done by intention to treat. This trial is registered at the US National Institute of Health website . FINDINGS: Median follow-up for the 110 (50%) survivors was 94.5 months (range 62.9-135.1). Overall 5-year survival was significantly higher in patients assigned D3 surgery than in those assigned D1 surgery (59.5% [95% CI 50.3-68.7] vs 53.6% [44.2-63.0]; difference beteween groups 5.9% [-7.3 to 19.1], log-rank p=0.041). 215 patients who had R0 resection (ie, no microscopic evidence of residual disease) had recurrence at 5 years of 50.6% [41.1-60.2] for D1 surgery and 40.3% [30.9-49.7] for D3 surgery (difference between groups 10.3% [-3.2 to 23.7], log-rank p=0.197). INTERPRETATION: D3 nodal dissection, compared with that of D1, offers a survival benefit for patients with gastric cancer when done by well trained, experienced surgeons.

Aged↗

PubMed2006

Temporal transcription program of recombinant Autographa californica multiple nucleopolyhedrosis virus.

Baculoviruses, a family of large, rod-shaped viruses that mainly infect lepidopteran insects, have been widely used to transduce various cells for exogenous gene expression. Nonetheless, how a virus controls its transcription program in cells is poorly understood. With a custom-made baculovirus DNA microarray, we investigated the recombinant Autographa californica multiple nucleopolyhedrosis virus (AcMNPV) gene expression program in lepidopteran Sf21 cells over the time course of infection. Our analysis of transcription kinetics in the cells uncovered sequential viral gene expression patterns possibly regulated by different mechanisms during different phases of infection. To gain further insight into the regulatory network, we investigated the transcription program of a mutant virus deficient in an early transactivator (pe38) and uncovered several pe38-dependent and pe38-independent genes. This study of baculovirus dynamic transcription programs in different virus genetic backgrounds provides new molecular insights into how gene expression in viruses is regulated.

Animals↗

PubMed2005

POWER: PhylOgenetic WEb Repeater--an integrated and user-optimized framework for biomolecular phylogenetic analysis.

POWER, the PhylOgenetic WEb Repeater, is a web-based service designed to perform user-friendly pipeline phylogenetic analysis. POWER uses an open-source LAMP structure and infers genetic distances and phylogenetic relationships using well-established algorithms (ClustalW and PHYLIP). POWER incorporates a novel tree builder based on the GD library to generate a high-quality tree topology according to the calculated result. POWER accepts either raw sequences in FASTA format or user-uploaded alignment output files. Through a user-friendly web interface, users can sketch a tree effortlessly in multiple steps. After a tree has been generated, users can freely set and modify parameters, select tree building algorithms, refine sequence alignments or edit the tree topology. All the information related to input sequences and the processing history is logged and downloadable for the user's reference. Furthermore, iterative tree construction can be performed by adding sequences to, or removing them from, a previously submitted job. POWER is accessible at http://power.nhri.org.tw.

Algorithms↗

PubMed2005

Molecular epidemiology of severe acute respiratory syndrome-associated coronavirus infections in Taiwan.

BACKGROUND: In 2003, Taiwan experienced a series of outbreaks of severe acute respiratory syndrome (SARS) and 1 laboratory-contamination accident. Here we describe a new phylogenetic analytical method to study the sources and dissemination paths of SARS-associated coronavirus (SARS-CoV) infections in Taiwan. METHODS: A phylogenetic analytical tool for combining nucleotide sequences from 6 variable regions of a SARS-CoV genome was developed by use of 20 published SARS-CoV sequences; and this method was validated by use of 80 published SARS-CoV sequences. Subsequently, this new tool was applied to provide a better understanding of the entire complement of Taiwanese SARS-CoV isolates, including 20 previously published and 19 identified in this study. The epidemiological data were integrated with the results from the phylogenetic tree and from the nucleotide-signature pattern. RESULTS: The topologies of phylogenetic trees generated by the new and the conventional strategies were similar, with the former having better robustness than the latter, especially in comparison with the maximum-likelihood trees: the new strategy revealed that during 2003 there were 5 waves of epidemic SARS-CoV infection, which belonged to 3 phylogenetic clusters in Taiwan. CONCLUSIONS: The new strategy is more efficient than its conventional counterparts. The outbreaks of SARS in Taiwan originated from multiple sources.

Cross Infection↗

PubMed2005

Revealing molecular targets for enterovirus type 71 detection by profile hidden Markov models.

The enterovirus infection in 1998 claimed 78 deaths in Taiwan, with an average of 40 fatalities each year after. Traditional serum-based diagnostic methods often fail to detect enteroviruses due to antigenic changes. As a result, many isolates remain untyped and are absent from the enterovirus surveillance and epidemiological investigations. We present a profile hidden Markov model (HMM) method for molecular typing of enterovirus 71 (EV71). Based on the enteroviral sequences retrieved from GenBank, we build a nucleotide-based and an amino acid-based profile HMM for each EV71 gene using the package HMMER. HMMER bit score-based Z-scores for EV71 and non-EV71 sequences are calculated for each of these profile HMMs. In a genome-wide analysis, we find that the distribution of the EV71 Z-scores and that of the non-EV71 Z-scores have disjoint support for nucleotide-based VP1 profile HMM if the sequence is longer than 150 bases; a VP1-based molecular typing method for EV71 is thus proposed. We also report VP4 an alternative molecular target for detecting EV71, while the two UTRs and all the genes coding the internal proteins cannot be used for such purpose. To demonstrate the performance of the nucleotide-based EV71 VP1 profile HMM, 330 enterovirus VP1 nucleotide sequences newly reported to GenBank are typed with this method. All the EV71 sequences are detected with no error.

Amino Acid Sequence↗

PubMed2005

Laboratory-based surveillance and molecular epidemiology of influenza virus in Taiwan.

A laboratory-based surveillance network of 11 clinical virological laboratories for influenza viruses was established in Taiwan under the coordination of the Center for Disease Control and Prevention (CDC), Taiwan. From October 2000 to March 2004, 3,244 influenza viruses were isolated, including 1,969 influenza A and 1,275 influenza B viruses. The influenza infections usually occurred frequently in winter in the northern hemisphere. However, the influenza seasonality in Taiwan was not clear during the four seasons under investigation. For example, the influenza A viruses peaked during the winters of 2001, 2002, and 2003. However, some isolated peaks were also found in the summer and fall (June to November) of 2001 and 2002. An unusual peak of influenza B also occurred in the summer of 2002 (June to August). Phylogenetic analysis shows that influenza A isolates from the same year were often grouped together. However, influenza B isolates from the year 2002 clustered into different groups, and the data indicate that both B/Victoria/2/87-like and B/Yamagata/16/88-like lineages of influenza B viruses were cocirculating. Sequence comparison of epidemic strains versus vaccine strains shows that many vaccine-like Taiwanese strains were circulating at least 2 years before the vaccine strains were introduced. No clear seasonality of influenza reports in Taiwan occurred in contrast to other more continental regions.

Animals↗

PubMed2005

An autosomal genome-wide scan for loci linked to pre-diabetic phenotypes in nondiabetic Chinese subjects from the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Family Study.

Type 2 diabetes is a complex disease involving both genetic and environmental components. Abnormalities in insulin secretion and insulin action usually precede the development of type 2 diabetes and can serve as good quantitative measures for genetic mapping. We therefore undertook an autosomal genomic search to locate the quantitative trait locus (QTL) linked to these traits in 1,365 nondiabetic Chinese subjects from 411 nuclear families. Residuals of these log-transformed quantitative traits were analyzed in multipoint linkage analysis using a variance-components approach. The most significant QTL for fasting insulin, which coincides with the QTL for homeostasis model assessment of insulin resistance, was located at 37 cM on chromosome 20, with a maximum empirical logarithm of odds (LOD) score of 3.01 (empirical P = 0.00006) when adjusted for age, sex, BMI, antihypertensive medications, recruitment centers, and environmental factors. In the same region, a QTL for fasting glucose was identified at 51 cM, with an empirical LOD score of 2.03 (empirical P = 0.0012). There were other loci with maximum empirical LOD scores >or=1.29 located on chromosomes 1q, 2p, 5q, 7p, 9q, 10p, 14q, 18q, and 19q for different diabetes-related traits. These loci may harbor genes that regulate glucose homeostasis either independently or via interactions of the genes within these regions.

Asian People↗

PubMed2004

hp-DPI: Helicobacter pylori database of protein interactomes--embracing experimental and inferred interactions.

We implemented a statistical model into our protein interaction database for validation of two-hybrid assays of Helicobacter pylori, and prediction of putative protein interactions not yet discovered experimentally. To present the enormous amount of experimental and inferred protein interaction networking maps, the H.pylori Database of Protein Interactomes (hp-DPI) is developed with a succinct yet comprehensive visualization tool integrated with annotation from Genbank, GO, and KEGG. hp-DPI is first built with, but not limited to, H.pylori protein interactions and is expected to naturally include other organisms' protein interacting relationships in the future.

Algorithms↗

PubMed2004

Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity.

Protein tyrosine phosphatase 1beta (PTP-1beta) is involved in the regulation of several important physiological pathways. It regulates both insulin and leptin signaling, and interacts with the epidermal- and platelet-derived growth factor receptors. The gene is located on human chromosome 20q13, and several rare single nucleotide polymorphisms (SNPs) have been shown to be associated with insulin resistance and diabetes in different populations. As part of our ongoing investigations into the genetic basis of hypertension, we examined common sequence variants in the gene for association with hypertension, obesity and altered lipid profile in two populations of Japanese and Chinese descent. We re-sequenced all exons, selected intronic sequences and the promoter region in 24 individuals from our cohort. Fourteen SNPs were discovered, and six of these spanning 78 kb were genotyped in 1553 individuals from 672 families. All six SNPs were in linkage disequilibrium, and we found strong association of common risk haplotypes with hypertension in Chinese and Japanese (P<0.0001). In addition, individual SNPs showed association to total plasma cholesterol, LDL-cholesterol and VLDL-cholesterol levels, as well as obesity measures (body mass index). This analysis supports that PTP-1beta affects plasma lipid levels, and may lead to obesity and hypertension in Japanese and Chinese. Given similar associations found in other populations to insulin resistance and diabetes, this gene may play a crucial role in the development of the characteristic metabolic changes seen in patients with the metabolic syndrome.

Adult↗

PubMed2004

Coupling multiplex RT-PCR to a gene chip assay for sensitive and semiquantitative detection of severe acute respiratory syndrome-coronavirus.

An early and accurate diagnostic assay for severe acute respiratory syndrome (SARS) is crucial for infection control. However, most of the diagnostic methods available today, such as real-time reverse transcriptase-polymerase chain reaction (RT-PCR), require a second detection method for confirmation because they detect a single sequence region of the SARS-coronavirus (SARS-CoV). For sensitive and accurate early diagnosis, we report a novel assay system combining multiplex RT-PCR and a diagnostic gene chip to detect multiple virus-specific genomic sequences of SARS-CoV. With 53 clinical specimens, we successfully demonstrate that this technique offers not only a high-accuracy diagnosis for early SARS infection but also a semiquantitative assay.

DNA Primers↗

PubMed2004

Biethnic comparisons of autosomal genomic scan for loci linked to plasma adiponectin in populations of Chinese and Japanese origin.

Adiponectin is secreted by adipocytes and is thought to have insulin-sensitizing and antiatherogenic effects. Two previous genome scans for plasma adiponectin have identified different regions for European and Pima Indian populations. We here present multipoint linkage analysis of adiponectin levels using a variance-components model for 1007 siblings (from 360 nuclear families) of Chinese origin and 352 siblings (from 147 nuclear families) of Japanese origin. We found heritability for adiponectin concentrations was 0.70 for Chinese and 0.48 for Japanese. Autosomal genome scan was performed using microsatellite markers span at an interval of approximately 10 cM. Suggestive linkage of adiponectin, after adjusting for age and sex, was found on chromosome 15 at 39 cM (maximal LOD score = 3.19, P = 6.3 x 10(-5)) for Chinese; and on chromosome 18 at 28 cM (maximal LOD score = 2.40, P = 4.4 x 10(-4)) for Japanese. There were tentative loci of weak linkage on chromosomes 3, 18, and 20 in Japanese. We provide novel loci on chromosomes 15, 18, and 20 and confirm a region on chromosome 3 as reported in Pima Indians, which may influence differentially on circulating adiponectin concentrations in Chinese and Japanese populations. Further fine mapping of these regions will help to identify the gene(s) that might affect adiponectin levels.

Adiponectin↗

PubMed2003

Sensitive and quantitative detection of severe acute respiratory syndrome coronavirus infection by real-time nested polymerase chain reaction.

A quantitative, real-time, nested polymerase chain reaction (PCR) method, combining the high sensitivity of nested PCR with time-saving real-time instrumentation, was developed for large-scale screening for severe acute coronavirus (SARS) coronavirus. Forty-six clinical specimens were analyzed by this method, and results were compared with those obtained by conventional, single-round, real-time reverse-transcriptase PCR (RT-PCR) performed in parallel. Of the 17 positive results, 2 identified by our method were not detected by single-round, real-time RT-PCR, which suggests that real-time nested PCR has the potential for increased sensitivity, leading to earlier detection of SARS.

DNA, Viral↗

PubMed2003

Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma.

Reactivation of hepatitis is one of the most serious complications of chemotherapy in lymphoma patients who are carriers of the hepatitis B virus (HBV). Glucocorticoids are linked to increased risk of HBV reactivation. This study seeks to clarify whether removal of glucocorticoids from chemotherapy regimens may decrease the risk of HBV reactivation. Eligible patients were seropositive for hepatitis B surface antigen (HBsAg) and had histologically proven non-Hodgkin's lymphomas for which intensive chemotherapy was indicated. Patients were randomized to receive either ACE (epirubicin, cyclophosphamide, and etoposide) or PACE (prednisolone + ACE). A total of 50 patients were enrolled, 25 each for the ACE and PACE arms. The cumulative incidence of HBV reactivation at 9 months after starting chemotherapy was 38% and 73% for ACE and PACE arm, respectively (P =.03). The degree of clinical hepatitis was significantly more severe in the PACE arm: 11 patients (44%) in the PACE and 3 patients (13%) in the ACE arm had ALT elevation more than 10-fold of normal (P =.025), and 7 patients (28%) in the PACE and 1 patient (4%) in the ACE arm had icteric hepatitis (P =.049). Complete remission of tumors occurred in 11 (46%) patients in the PACE and 8 (35%) patients in the ACE arm (P =.556). The estimated overall survival rate at 46 months was 68% in the PACE arm and 36% in the ACE arm, respectively (P =.18). In conclusion, steroid-free chemotherapy decreases the incidence and severity of HBV reactivation in HBsAg-positive lymphoma patients. However, further research is needed to evaluate whether steroid-free chemotherapy may confer a less satisfactory control of lymphoma.

Adolescent↗