Browsing by Author "Chang, Ya-Hui"

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An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan
(2019-12-01)
Lin, Hsiang-Yu
;
Lee, Chung-Lin
;
Lo, Yun-Ting
;
Tu, Ru-Yi
;
Chang, Ya-Hui
Background: The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) and which eventually cause progressive damage to various tissues and organs. We developed a feasible MPS screening algorithm and established a cross-specialty collaboration platform between medical geneticists and other medical specialists based on at-risk criteria to allow for an earlier confirmative diagnosis of MPS. Methods: Children (<19 years of age) with clinical signs and symptoms compatible with MPS were prospectively enrolled from pediatric clinics between July 2013 and June 2018. Urine samples were collected for a non-specific total GAG analysis using the dimethylmethylene blue (DMB) spectrophotometric method, and the quantitation of three urinary GAGs (dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)) was performed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The subjects with elevated urinary GAG levels were recalled for leukocyte enzyme activity assay and genetic testing for confirmation. Results: Among 153 subjects enrolled in this study, 13 had a confirmative diagnosis of MPS (age range, 0.6 to 10.9 years-three with MPS I, four with MPS II, five with MPS IIIB, and one with MPS IVA). The major signs and symptoms with regards to different systems recorded by pediatricians at the time of the decision to test for MPS were the musculoskeletal system (55%), followed by the neurological system (45%) and coarse facial features (39%). For these 13 patients, the median age at the diagnosis of MPS was 2.9 years. The false negative rate of urinary DMB ratio using the dye-based method for these 13 patients was 31%, including one MPS I, two MPS IIIB, and one MPS IVA. However, there were no false negative results with urinary DS, HS and KS using the MS/MS-based method. Conclusions: We established an at-risk population screening program for MPS by measuring urinary GAG fractionation biomarkers using the LC-MS/MS method. The program included medical geneticists and other medical specialists to increase awareness and enable an early diagnosis by detecting MPS at the initial onset of clinical symptoms.
Shared IgG Infection Signatures vs. Hemorrhage-Restricted IgA Clusters in Human Dengue: A Phenotype of Differential Class-Switch via TGF beta 1
(2017-12-04)
Huang, Chung-Hao
;
Chang, Ya-Hui
;
Lin, Chun-Yu
;
Wang, Wen-Hung
;
Kuan, Hui-Chung
Phenotypic manifestations of infectious diseases are closely related to individual immune responses. Methods to extract information from patients' own immune reactions would be of great use for both diagnosis and treatment. Dengue fever is one of the diseases that clinical aggravations could occur paradoxically after humoral immunity appears. This property makes dengue fever an excellent disease model to explore. A principal component analyses (PCAs)-based framework derived from a prior vaccination study was developed. The framework was verified by successful demonstrations of known IgG signatures from a Mexico Dengue data set. Afterward the pipeline was tested upon de novo IgG and IgA libraries of Dengue patients from southern Taiwan. We discovered four infection signatures within IgG repertoires, two of which were identical to previous reports. However, it was IgA but not IgG that could differentiate hemorrhagic from non-hemorrhagic patients. IgA repertoires were found more diversified among bleeders, from whom seven signature clusters were characterized. The expressions of transforming growth factor beta 1 (TGF beta 1) and accordingly mediated class-switch activity of IgA were distinct only among the PCA-segregated bleeding group. In sum, intercontinental sharing of IgG signatures in dengue fever was demonstrated via a unified working flow. Differential regulation of IgA class-switch with associated diversity expansion plus existences of hemorrhage-restricted clusters were shown. The ability of the framework to find common IgG signatures would implicate applications to infections even from unknown pathogens. The clusters within IgA repertoires could offer perspectives to other IgA-related bleeding disorders such as Henoch-Schonlein purpura or IgA nephropathy. Substantiated grounds for IgA-specific effector function via TGF beta 1-mediated class-switch would be a new factor to consider for infectious diseases.
Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H(2)O)](2-) Derivatives
(2011-02-21)
Chang, Ya-Hui
;
Chen, Chiao-Yun
;
Singh, Gyan
;
Chen, Hsing-Yin
;
Liu, Gin-Chung
The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) both display high stability constant (log K(GdL) = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K((Gd/Zn)) = 4.22) and Bz-CB-TTDA (log K((Gd/Zn)) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K((Gd/Zn)) = 2.93), EPTPA-bz-NO(2) (log K((Gd/Zn)) = 3.19), and DTPA (log K((Gd/Zn)) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature (17)O NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 x 10(6) s(-1) for [Gd(CB-TTDA)(H(2)O)](2-) and 271 x 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H(2)O)](2-). They are higher than those of [Gd(TTDA)(H(2)O)](2-) (146 x 10(6) s(-1)), [Gd(DTPA)(H(2)O)](2-) (4.1 x 10(6) s(-1)), and MS-325 (6.1 x 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H(2)O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H(2)O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K(A)) for [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) are 1.1 x 10(2) and 1.5 x 10(3), respectively. Although the K(A) value for [Gd(Bz-CB-TTDA)(H(2)O)](2-) is lower than that of MS-325 (K(A) = 3.0 x 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB-TTDA)(H(2)O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H(2)O)](2-), [Gd(Bz-CB-TTDA)(H(2)O)](2-), and [Gd(DTPA)(H(2)O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H(2)O)](2-) High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H(2)O)](2-) make it a favorable blood pool contrast agent for MRI.
Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H2O)](2-) Derivatives
(2011-02-21)
Chang, Ya-Hui
;
Chen, Chiao-Yun
;
Singh, Gyan
;
Chen, Hsing-Yin
;
Liu, Gin-Chung
The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) both display high stability constant (log K-GdL = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K-(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K-(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K-(Gd/Zn) = 2.93), EPTPA-bz-NO2 (log K-(Gd/Zn) = 3.19), and DTPA (log K-(Gd/Zn) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature O-17 NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 x 10(6) s(-1) for [Gd(CB-TTDA)(H2O)](2-) and 271 x 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-). They are higher than those of [Gd(TTDA)(H2O)](2-) (146 x 10(6) s(-1)), [Gd(DTPA)(H2O)](2-) (4.1 x 10(6) s(-1)), and MS-325 (6.1 x 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H2O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H2O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K-A) for [Gd(CB-TTDA)(H2O)](2-) and [Gd(Bz-CB-TTDA)(H2O)](2-) are 1.1 x 10(2) and 1.5 x 10(3), respectively. Although the K-A value for [Gd(Bz-CB-TTDA)(H2O)](2-) is lower than that of MS-325 (K-A = 3.0 x 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB-TTDA)(H2O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H2O)](2-), [Gd(Bz-CB-TTDA)(H2O)](2-), and [Gd(DTPA)(H2O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H2O)](2-) High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H2O)](2-) make it a favorable blood pool contrast agent for MRI.