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Biomedical subjects

Y T Chen

Publications and source records attributed to Y T Chen.

At least 19 recordsLinked to original sources
PubMed2003

Consolidation therapy with autologous blood stem cell transplantation in a patient with primary plasma cell leukaemia.

Primary plasma cell leukaemia (PPCL) is a rare form of plasma cell dyscrasia. Conventional melphalan-based treatment is often ineffective, with a reported median survival of 2-7 months only. We report a 53-year-old man with PPCL who was treated with four cycles of combination chemotherapy including vincristine, adriamycin and dexamethasone that resulted in a good partial remission. High-dose melphalan 200 mg/m2 and autologous peripheral blood stem cell (PBSC) rescue was then given 6 months after diagnosis. Maintenance interferon-alpha was started 8 weeks after transplantation with good drug compliance. Complete remission was achieved and molecular remission was documented 11 months after autologous PBSC transplantation. In conclusion, high-dose therapy followed by autologous stem cell rescue is a feasible option for PPCL that can result in a reasonably sustained remission.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Investigation of Notch3 as a candidate gene for bipolar disorder using brain hyperintensities as an endophenotype.

The purpose of the study was to consider MRI hyperintensities as a potential endophenotype for bipolar disorder (BPD) and to investigate Notch3 (CADASIL) as a candidate gene for BPD. MRI scans were performed on 21 members of a family with a high incidence of BPD. Two-point and multipoint linkage analyses were performed and two exons of Notch3 were investigated with SSCP. Fifteen of 21 family members had MRI hyperintensities, including all bipolar patients and six family members with no affective illness. Two-point linkage analysis yielded negative results for all models. Multipoint linkage analysis yielded negative results except for Model 1a, in which a maximal LOD score was -1.24. A mutation screen of Exons 3 and 4 was negative. Notch3 does not appear to be a candidate gene for BPD in this family.

Adolescent↗
PubMed2002

Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors.

Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the potential of intravenously delivered adeno-associated virus (AAV) vectors for gene therapy. In three affected canines, liver glycogen was reduced following hepatic expression of canine glucose-6-phosphatase (G6Pase). Two months after AAV vector administration, one affected dog had normalization of fasting glucose, cholesterol, triglycerides, and lactic acid. Concatamerized AAV vector DNA was confirmed by Southern blot analysis of liver DNA isolated from treated dogs, as head-to-tail, head-to-head, and tail-to-tail concatamers. Six weeks after vector administration, the level of vector DNA signal in each dog varied from one to five copies per cell, consistent with variation in the efficiency of transduction within the liver. AAV vector administration in the canine model for GSD Ia resulted in sustained G6Pase expression and improvement in liver histology and in biochemical parameters.

Animals↗
PubMed2002

Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators.

The recent identification of several additional members of the family of sugar transport facilitators (gene symbol SLC2A, protein symbol GLUT) has created a heterogeneous and, in part, confusing nomenclature. Therefore, this letter provides a summary of the family members and suggests a systematic nomenclature for SLC2A and GLUT symbols.

Monosaccharide Transport Proteins↗
PubMed2002

Molecular characterization of glycogen storage disease type III.

Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism. Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb). Cloning of human AGL cDNAs and determination of the genomic structure and mRNA isoforms of AGL have allowed for the study of GSD-III at the molecular level. In turn, the resulting information has greatly facilitated our understanding of the molecular basis of this storage disease with remarkable clinical and enzymatic variability. In this review, we summarize all 31 GSD-III mutations in the literature and discuss their clinical and laboratory implications. Most of the mutations are nonsense mutations caused by a nucleotide substitution or small insertion or deletion; only one is caused by a missense amino acid change. Some important genotype-phenotype correlation have emerged, in particular, that exon 3 mutations (17delAG and Q6X) are specifically associated with GSD-IIIb. Three other mutations have appeared to have some phenotype correlation. Specifically, the splice mutation IVS32-12A>G was found in GSD-III patients having mild clinical symptoms, while the mutations 3965delT and 4529insA are associated with a severe phenotype and early onset of clinical manifestations. A molecular diagnostic scheme has been proposed to diagnose GSD-III noninvasively. The characterization of AGL mutations in GSD-III patients has also helped the structure-function analysis of this bifunctional enzyme important for glycogen metabolism.

Animals↗
PubMed2002

Comparing fasting plasma glucose against two-hour post-load glucose concentrations for the diagnosis of diabetes mellitus and glucose intolerance in Singaporean hospital patients.

INTRODUCTION: Several studies have assessed the impact of the 1997 American Diabetes Association (ADA) recommendation, of using fasting plasma glucose (FPG) concentration, to diagnose diabetes mellitus in population-based cohorts. However, data concerning the impact of this recommendation in the hospital setting are limited. As the performance characteristics of diagnostic tests vary depending on the prevalence of diabetes in the population studied, we have examined the clinical impact of adopting the ADA recommendations in comparison to the traditional 2-hour post-load glucose (2HPG) concentration used by the World Health Organisation (WHO) in diagnosing diabetes and other categories of glucose intolerance in Singaporean hospital patients. MATERIALS AND METHODS: We analysed the results of the standard 75 g oral glucose tolerance test (OGTT) performed on 625 patients in our hospital from 1994 to 1999. RESULTS: The prevalence of diabetes amongst these 625 patients was 36.8% (230) based on the ADA recommendation of using FPG, 42.8% (263) on using the 2HPG and 52.0% (325) on using the full 1998 WHO criteria. The degree of agreement (kappa) in establishing the diagnosis of diabetes between the FPG and 2HPG cut-offs was 0.48. Ninety-five (15.2%) individuals had diabetes based on the 2HPG alone, 62 (9.9%) based on the FPG alone and 168 (26.9%) based on both the FPG and 2HPG. Eighty-six (13.8%) individuals had impaired fasting glucose (IFG) and 123 (19.7%) had impaired glucose tolerance (IGT). The kappa-value between IFG and IGT was 0.08. CONCLUSION: Fasting plasma glucose concentration was an inadequate parameter in diagnosing diabetes and intermediate categories of glucose intolerance in our cohort of subjects. Our findings suggest that the OGTT remains an important diagnostic tool for classifying glucose tolerance in our hospital patients.

Adolescent↗
PubMed2002

Thyroid diseases in pregnancy.

INTRODUCTION: Changes in thyroid function in pregnancy encompass both hyper- and hypothyroidism. Failure to maintain euthyroidism may place both mother and foetus at higher risk of adverse obstetrical outcomes. This review examines the differences between physiological and pathological thyroid dysfunction during pregnancy and their management. METHODS: Data were obtained from relevant clinical studies and review articles listed in MEDLINE. Additional cross-references from selected articles were identified. RESULTS: In hyperthyroidism, the challenge lies in differentiating gestational transient thyrotoxicosis (GTT) from actual pathological states during the first trimester. GTT is thought to be due to elevation of isoforms of human chorionic gonadotropin (hCG) which may exert potent thyrotrophic effects. While thionamides are safe, the lowest possible dose should be used together with close monitoring of maternal thyroid function in order to avoid over-treatment. Surgery for thyroid nodules may be safely performed during the second trimester. Conversely, diagnosing hypothyroid states, particularly subclinical hypothyroidism and postpartum thyroiditis (PPT), require a high index of suspicion. High levels of thyroid peroxidase antibodies (TPOAb) and thyroid stimulating hormone (TSH) in early pregnancy may be predictive of PPT and subsequent permanent hypothyroidism. Clinicians must recognise the need to increase thyroxine replacement as maternal hypothyroidism may adversely affect the IQ scores of children. The association between thyroid autoimmunity and recurrent abortions remain unclear. CONCLUSION: Regardless of the aetiology of thyroid dysfunction, the key to management lies in individualized therapy in close collaboration with the obstetrician.

Antibodies↗
PubMed2001

Monophasic and biphasic synovial sarcomas abundantly express cancer/testis antigen NY-ESO-1 but not MAGE-A1 or CT7.

Synovial sarcomas are high-grade malignant mesenchymal tumors with biphasic (BSS) and monophasic (MSS) variants that carry a pathognomonic cytogenetic alteration, t(X;18), involving the SYT gene on chromosome 18 and one of several SSX genes on chromosome X, usually SSX1 or SSX2. Cancer/testis (CT) antigens are expressed in a variety of malignant neoplasms but, in normal tissues, are restricted to male germ cells. Previous analysis revealed a high incidence and homogeneous expression of MAGE CT antigen in synovial sarcomas. The present study was performed to analyze the expression of 3 CT antigens, NY-ESO-1, MAGE-A1 and CT7, by immunohistochemistry with 3 monoclonal antibodies (MAbs), ES121 (anti-NY-ESO-1), MA454 (anti-MAGE-A1) and CT7-33 (anti-CT7), in 25 synovial sarcomas (12 MSS, 13 BSS) typed for the t(X;18)-derived fusion transcript by RT-PCR (19 SYT-SSX1, 6 SYT-SSX2). NY-ESO-1 immunoreactivity was found in 20/25 (80%) cases, and antigen expression was homogeneous in 14/20 NY-ESO-1-positive cases. Both morphologic variants and both translocation types were NY-ESO-1-positive, whereas 5 SYT-SSX1 tumors (1 MSS, 4 BSS) were NY-ESO-1-negative. MAb MA454 was immunoreactive with 4/25 cases (2 MSS, 2 BSS; 3 SYT-SSX1, 1 SYT-SSX2), and MAb CT7-33 was immunoreactive with only 2/25 cases (both BSS, SYT-SSX1). Expression of MAGE-A1 and CT7 was heterogeneous in all positive cases. Our study shows that NY-ESO-1 is highly expressed in a homogeneous pattern in synovial sarcomas of both morphologic variants and both translocation types, making these tumors an attractive target for NY-ESO-1 antigen-based immunotherapy.

Antigens, Neoplasm↗
PubMed2001

alpha-Ketocarboxylic acid-based inhibitors of protein tyrosine phosphatases.

A series of aryl alpha-ketocarboxylic acids was synthesized and investigated as inhibitors for the protein tyrosine phosphatase from Yersinia enterocolitica. IC(50) values for these compounds range from 79 to 2700 microM. Larger aromatic groups, and aromatic groups with high electron density, lead to more potent inhibitors. In general, the related aryl alpha-hydroxycarboxylic acids show lower activity.

Binding Sites↗
PubMed2001

Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues.

NY-ESO-1, a member of the CT (cancer/testis) family of antigens, is expressed in normal testis and in a range of human tumor types. Knowledge of NY-ESO-1 expression has depended on RT-PCR detection of mRNA and there is a need for detecting NY-ESO-1 at the protein level. In the present study, a method for the immunochemical detection of NY-ESO-1 in paraffin-embedded tissues has been developed and used to define the expression pattern of NY-ESO-1 in normal tissues and in a panel of human tumors. No normal tissue other than testis showed NY-ESO-1 reactivity, and expression in testis was restricted to germ cells particularly spermatogonia. In human tumors, the frequency of NY-ESO-1 antigen expression corresponds with past analysis of NY-ESO-1 mRNA expression e.g., 20-30% of lung cancers, bladder cancers and melanoma, and no expression in colon and renal cancer. Co-typing of NY-ESO-1 antigen and mRNA expression in a large panel of lung cancers showed a good correlation. There is great variability in NY-ESO-1 expression in individual tumors, ranging from an infrequent homogeneous pattern of staining to highly heterogeneous antigen expression.

Antibodies, Monoclonal↗
PubMed2001

Functions of the conserved anionic amino acids and those interacting with the substrate phosphate group of phosphoglucose isomerase.

Phosphoglucose isomerase catalyzes the isomerization between glucose 6-phosphate and fructose 6-phosphate in cytoplasm, and functions as autocrine motility factor and neuroleukin outside the cells. A phosphoglucose isomerase from Bacillus stearothermophilus (pgiA) was subjected to mutagenesis study to address the catalytic function of the conserved anionic residues and those probably interacting with the phosphate group of substrates. The results suggest that Glu290 works concertedly with His311 as a general acid-base pair to initiate the isomerization step, and Glu150 assists the base function of His311. The conserved loop structure consisting of Gly205-Gly206-Arg207 plays a critical role for the recognition of substrates.

Amino Acid Substitution↗
PubMed2001

Ny-ESO-1 expression and immunogenicity associated with transitional cell carcinoma: correlation with tumor grade.

NY-ESO-1 mRNA expression in transitional cell carcinoma was investigated by reverse transcription-PCR and immunohistochemistry. NY-ESO-1 mRNA was detected in 20 of 62 (32%) tumor specimens. There was a correlation between NY-ESO-1 expression and tumor grade: 0 of 4 (0%) grade 1 (G1), 6 of 26 (23%) grade 2 (G2), and 14 of 32 (44%) grade 3 (G3) tumors were NY-ESO-1 mRNA positive. Immunohistochemical analysis using NY-ESO-1-specific monoclonal antibody ES121 showed that 2 of 14 NY-ESO-1 mRNA-expressing G3 tumors were positive for NY-ESO-1. No NY-ESO-1 staining was observed in the panel of 30 G1 or G2 tumor specimens, including 6 NY-ESO-1 mRNA-positive cases. Sera from an expanded panel of 124 patients with transitional cell carcinoma were tested for the presence of NY-ESO-1 antibody. Seropositivity was observed in 9 of 72 (12.5%) patients with G3 tumors, whereas none of 52 patients with G1 or G2 tumors produced antibody against NY-ESO-1. In the 9 positive patients with NY-ESO-1 antibody, 4 had muscular invasive tumors, and 5 had carcinoma in situ.

Adult↗
PubMed2001

Long-term efficacy after [E1-, polymerase-] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice.

Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-alpha-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA activity results in massive amounts of glycogen accumulation in multiple muscle groups, resulting in morbidity and mortality secondary to respiratory embarrassment and/or cardiomyopathy. In a mouse model of GSD-II, we demonstrate that infection of the murine liver with a modified adenovirus (Ad) vector encoding human GAA (hGAA) resulted in long-term persistence of the vector in liver tissues for at least 6 months. Despite both a rapid shutdown of hGAA mRNA expression from the vector, as well as the elicitation of anti-hGAA antibody responses (hGAA is a foreign antigen in this model), the hGAA secreted by the liver was taken up by all muscle groups analyzed and, remarkably, persisted in them for at least 6 months. The persistence of the protein also correlated with long-term correction of pathologic intramuscular glycogen accumulations in all muscle groups tested, but most notably the cardiac tissues, which demonstrated a significantly decreased glycogen content for at least 190 days after a single vector injection. The results suggest that gene therapy strategies may have the potential to significantly improve the clinical course for GSD-II patients.

Adenoviridae↗
PubMed2001

Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library.

Application of SEREX (serological analysis of recombinant tumor cDNA expression libraries) to different tumor types has led to the identification of several categories of human tumor antigens. In this study, the analysis of a breast cancer library with autologous patient serum led to the isolation of seven genes, designated NY-BR-1 through NY-BR-7. NY-BR-1, representing 6 of 14 clones isolated, showed tissue-restricted mRNA expression in breast and testis but not in 13 other normal tissues tested. Among tumor specimens, NY-BR-1 mRNA expression was found in 21 of 25 breast cancers but in only 2 of 82 nonmammary tumors. Structural analysis of NY-BR-1 cDNA and the corresponding genomic sequences in the recently released working draft of human genome indicated that NY-BR-1 is composed of 37 exons and has an open reading frame of 4.0-4.2 kb, encoding a peptide of Mr 150,000-160,000. A bipartite nuclear localization signal motif indicates a nuclear site for NY-BR-1, and the presence of a bZIP site (DNA-binding site followed by leucine zipper motif) suggests that NY-BR-1 is a transcription factor. Additional structural features include five tandem ankyrin repeats, implying a role for NY-BR-1 in protein-protein interactions. NY-BR-1 thus represents a breast tissue-specific putative transcription factor with autoimmunogenicity in breast cancer patients. In addition to NY-BR-1, a homologous gene, NY-BR-1.1, was identified in this study. NY-BR-1.1 shares 54% amino acid homology with NY-BR-1 and also shows tissue-restricted mRNA expression. However, unlike NY-BR-1, NY-BR-1.1 mRNA is expressed in brain, in addition to breast and testis. The exon structure of NY-BR-1.1 remains to be defined. Using human genome database, NY-BR-1 was localized to chromosome 10p11-p12, and NY-BR-1.1 was tentatively localized to chromosome 9.

Alternative Splicing↗
PubMed2001

Aspirin and angiotensin-converting enzyme inhibitors among elderly survivors of hospitalization for an acute myocardial infarction.

BACKGROUND: Aspirin and angiotensin-converting enzyme (ACE) inhibitors are recommended for secondary prevention after acute myocardial infarction (AMI), but several studies have suggested that the combination of these medications may produce a negative interaction. OBJECTIVE: To evaluate the effect and interaction of aspirin and ACE inhibitors on mortality among elderly patients who survived a hospitalization for AMI. METHODS: We evaluated the effect and interaction of aspirin and ACE inhibitors on mortality in patients aged 65 years and older who survived hospitalization with a confirmed AMI who were ideal candidates for the therapies. RESULTS: Among the 14 129 patients, 26% received aspirin only, 20% received ACE inhibitors only, 38% received both, and 16% received neither at discharge. In the multivariate analysis, patients who received both aspirin and ACE inhibitors alone had a significantly lower 1-year mortality (adjusted risk ratio [ARR], 0.86 [95% confidence interval (CI), 0.78-0.95] vs 0.85 [95% CI, 0.77-0.93], respectively) compared with patients who received neither aspirin nor ACE inhibitors at discharge. Prescribing both aspirin and ACE inhibitors was associated with a slightly lower risk of mortality (ARR, 0.81; 95% CI, 0.74-0.88) than that seen in aspirin-only or ACE inhibitor-only groups, but the difference was not significantly different from the use of either medication alone. CONCLUSIONS: The benefit of ACE inhibitors and aspirin is consistent with what would be expected from overall results of randomized trials; prescribed together, the effect is slightly greater than with either one alone, but not significantly or substantially so.

Aged↗
PubMed2001

Aspirin and the treatment of heart failure in the elderly.

OBJECTIVES: We sought (1) to determine how often aspirin is prescribed as a discharge medication among patients 65 years or older and hospitalized with both heart failure and coronary artery disease; (2) to identify patient characteristics associated with the decision to prescribe aspirin; and (3) to evaluate the association between aspirin prescription at discharge and 1-year survival. METHODS: We performed a retrospective cohort study of consecutive Medicare beneficiary survivors of a hospitalization for heart failure at 18 Connecticut hospitals (up to 200 hospitalizations per hospital) from 1994 to 1995. RESULTS: Among the 1110 patients in the study sample who did not have a contraindication to aspirin, aspirin therapy was prescribed for 456 (41%) at discharge. Patients who were prescribed aspirin at discharge had a lower 1-year mortality after discharge than patients who were not prescribed aspirin (odds ratio, 0.71; 95% confidence interval, 0.54-0.94), even after adjustment for baseline differences in demographic, clinical, and treatment characteristics between the 2 groups. CONCLUSIONS: This study has identified a strong association between the use of aspirin and lower mortality in older patients with both heart failure and coronary artery disease. The benefit of aspirin is consistent with that expected from randomized trials of other groups of patients with vascular disease.

Age Factors↗
PubMed2001

Molecular cloning of a novel member of the GLUT family of transporters, SLC2a10 (GLUT10), localized on chromosome 20q13.1: a candidate gene for NIDDM susceptibility.

Non-insulin-dependent diabetes mellitus (NIDDM) is a multifactoral disease with both environmental and genetics causes. Genome-wide screening procedures have identified several susceptibility loci for NIDDM within the human genome. We describe the cloning of a putative sugar transporter that has been localized to human chromosome 20q12-q13.1, one of the genomic loci associated with NIDDM. Because of the strong resemblance of this novel protein to members of the mammalian facilitative glucose transporter family (GLUT), we refer to the protein as GLUT10 (HGMW-approved gene symbol SLC2A10). GLUT10 contains 541 amino acids with several glucose transporter sequence motifs and amino acids essential for glucose transport function. In addition, secondary structure analysis of GLUT10 predicts 12 putative transmembrane domains, a hallmark structure of the GLUT family. The tissue distribution of GLUT10 was determined by Northern analysis, which revealed highest levels of expression in the liver and pancreas. From these data, we believe that the chromosomal localization, tissue distribution, and predicted function make GLUT10 an excellent candidate for a susceptibility gene involved in NIDDM.

Amino Acid Sequence↗