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Biomedical subjects

E Chuang

Publications and source records attributed to E Chuang.

At least 19 recordsLinked to original sources
PubMed2006

Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis.

BACKGROUND: Alicaforsen is a phosphorothioate-modified antisense oligodeoxynucleotide designed to sequence-specifically reduce intercellular adhesion molecule 1 messenger RNA levels. AIMS: To determine the systemic and local bioavailability of alicaforsen, and its activity when administered as a once daily enema in subjects with active ulcerative colitis. METHODS An open-label study was conducted to assess the relative absorption (local and systemic pharmacokinetics) and pharmacologic activity of alicaforsen enema in subjects with active ulcerative colitis. Fifteen subjects received nightly enemas of alicaforsen (240 mg) for a treatment period of 6 weeks. Alicaforsen concentrations in plasma and colonic tissue biopsies were determined. Disease activity index and multiple measurements including endoscopy were used to assess alicaforsen activity in these subjects. RESULTS: Plasma concentrations of parent alicaforsen represented < 0.6% mean bioavailability when compared with historical intravenous area under the plasma concentration-time curves. Concentrations of the intact oligonucleotide in mucosal colonic tissue biopsies were orders of magnitude higher than those observed in plasma. A 46% reduction in mean Disease Activity Index and 33% rate of remission as defined by complete mucosal healing were observed at the end of treatment. Conclusion These data confirm that alicaforsen enema provides local treatment for a local disease with little meaningful systemic exposure.

Absorption↗
PubMed2006

A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis.

BACKGROUND: Alicaforsen is an antisense oligonucleotide designed to inhibit expression of human intercellular adhesion molecule 1. Previous clinical studies have demonstrated activity of alicaforsen enema in ulcerative colitis and pouchitis. AIM: To determine the minimally effective dosing regimen of alicaforsen enema in subjects with mild to moderate left-sided ulcerative colitis. METHODS: Randomized, placebo-controlled, double-blind, two-dose ranging multicentre study. One hundred and twelve subjects were equally randomized to receive one of four alicaforsen enema regimens or placebo daily for 6 weeks. Primary end point was Disease Activity Index at week 6. Secondary end points included evaluation of clinical improvement, relapse rates and durability of response. Analysis of data were performed on the intent-to-treat population. RESULTS: No significant difference was observed between treatment arms and placebo in the primary end point. A prolonged reduction in mean% Disease Activity Index relative to baseline was observed in the daily 240 mg alicaforsen enema treatment arm in comparison with placebo from week 18 (51% vs. 18%, P=0.04) to week 30 (50% vs. 11%, P=0.03). CONCLUSIONS: Alicaforsen enema was safe and well tolerated at all doses studied. The durability of the response to alicaforsen enema treatment may suggests a disease-modifying effect.

Adult↗
PubMed2003

Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.

PURPOSE: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. PATIENTS AND METHODS: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). RESULTS: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. CONCLUSION: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.

Aged↗
PubMed2001

Sedation in pediatric endoscopy.

The increase in diagnostic, radiologic, and minor surgical procedures performed on pediatric patients outside of the traditional surgical suite setting has resulted in a marked increase in the use of conscious sedation. Not long ago, pediatric gastroenterologists were reticent about using intravenous sedation for pediatric endoscopy. With increased experience, careful screening, and the specialization of pediatric gastroenterology, however, endoscopy can now be performed safely with intravenous sedation on almost all patients.

Anesthesia, General↗
PubMed2000

Structural analysis of CTLA-4 function in vivo.

CTLA-4-mediated inhibition of T cell activation may be accomplished by competition for ligands and/or by signals mediated through the intracellular domain. Studies have implicated Tyr201 in the cytoplasmic domain of CTLA-4 in regulating CTLA-4 signal transduction and intracellular trafficking. To investigate the mechanism of CTLA-4 function in vivo, transgenes encoding wild-type CTLA-4 (FL), a mutant lacking the cytoplasmic domain of CTLA-4 (DeltaCTLA-4 tail), or a CTLA-4 Tyr201 mutant (Y201V) were introduced into CTLA-4-deficient mice. CTLA-4-/- mice display an autoimmune lymphoproliferative disorder resulting in tissue destruction and early death. When either the FL or the Y201V transgene was bred into CTLA-4-/- animals, a complete rescue from lymphoproliferation and autoimmunity was observed. In contrast, CTLA-4-/- mice expressing the DeltaCTLA-4 tail transgene were long lived with no evidence of multiorgan lymphocytic infiltration, but exhibited lymphadenopathy and accumulated large numbers of activated T cells. Furthermore, these animals displayed a Th2-biased phenotype which conferred susceptibility to Leishmania infection. These results indicate that the inhibitory effect of CTLA-4 is mediated in part through the ability of the extracellular domain to compete for ligands. The cytoplasmic domain of CTLA-4, however, is required for complete inhibitory function of the receptor and for regulation of Th cell differentiation in vivo.

Abatacept↗
PubMed2000

The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A.

CD28 and CTLA-4 are related members of a family of T lymphocyte cell surface receptors that function to regulate T cell activation. We have found that the cytoplasmic domains of both CTLA-4 and CD28 can associate with members of the PP2A family of serine/threonine phosphatases. The association of PP2A with CD28 was negatively regulated by tyrosine phosphorylation of the CD28 cytoplasmic domain. Inhibition of PP2A activity in Jurkat leukemia T cells by treatment with okadaic acid or by expression of a dominant-negative mutant enhanced T cell activation induced by CD28 engagement. Interactions between cell surface receptors such as CTLA-4 and CD28 and serine/threonine phosphatases may represent a novel mechanism for modulating the intracellular signal transduction pathways associated with cell activation.

Abatacept↗
PubMed1999

Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface receptor expressed on activated T cells that can inhibit T cell responses induced by activation of the TCR and CD28. Studies with phosphorylated peptides based on the CTLA-4 intracellular domain have suggested that tyrosine phosphorylation of CTLA-4 may regulate its interactions with cytoplasmic proteins that could determine its intracellular trafficking and/or signal transduction. However, the kinase(s) that phosphorylate CTLA-4 remain uncharacterized. In this report, we show that CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218. A similar pattern of tyrosine phosphorylation was found in pervanadate-treated Jurkat T cells stably expressing CTLA-4. Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. CTLA-4 phosphorylation induced the association of CTLA-4 with the tyrosine phosphatase SHP-2, but not with phosphatidylinositol 3-kinase. In contrast, Lck-induced phosphorylation of CD28 resulted in the recruitment of phosphatidylinositol 3-kinase, but not SHP-2. These findings suggest that phosphorylation of CD28 and CTLA-4 by Lck activates distinct intracellular signaling pathways. The association of CTLA-4 with Src kinases and with SHP-2 results in the formation of a CTLA-4 complex with the potential to regulate T cell activation.

Abatacept↗
PubMed1999

Current management of pediatric inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a relatively rare condition of childhood, although the wide range of presenting complaints, scope of complications, and choices of therapy for this condition make it particularly difficult to treat in children. Novel approaches to the management of Crohn's disease and ulcerative colitis have gained recent favor. This report summarizes the current medical and surgical management of IBD, recent advancements in clinical therapies, and particular aspects of IBD care for children.

Adjuvants, Immunologic↗
PubMed1999

Gastric retention of zinc-based pennies: radiographic appearance and hazards.

PURPOSE: To determine the radiographic appearance and features of corrosion in U.S. coins exposed to gastric acid. MATERIALS AND METHODS: Six U.S. copper-based pre-1982 pennies, 12 zinc-based post-1982 pennies, a quarter, a nickel, and a dime were exposed to postprandial concentrations of gastric acid (0.15N HCl) for 7 days, and radiographs were obtained daily. Half the zinc-based coins were scraped to disrupt their copper coating. Coins were weighed at the start and completion of the study. RESULTS: Post-1982 zinc-based pennies developed radiolucent corrosive changes within 24 hours. Erosions on the coins became more apparent over time. Frank holes were present on day 2. The weights of these coins decreased 5%-8% during the study. Pre-1982 copper pennies and "silver-colored" coins showed no change on radiographs over 7 days. CONCLUSION: Unexpected radiolucent corrosions may develop in post-1982 zinc alloy pennies when retained in the stomach. Coins have long been considered innocuous foreign bodies in the gastrointestinal tracts of children. However, because of the potential for ulceration and zinc-related morbidity, closer clinical and radiographic observation is warranted. Coins with scalloped edges or holes should be endoscopically removed, as they have likely been retained longer than 1 or 2 days.

Child, Preschool↗
PubMed1998

Molecular basis of T cell inactivation by CTLA-4.

CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex zeta chain in primary T cells. The association of TCRzeta with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56(lck)-induced tyrosine phosphorylation. Coexpression of the CTLA-4-associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRzeta bound to CTLA-4 and abolished the p56(lck)-inducible TCRzeta-CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRzeta and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.

Abatacept↗
PubMed1998

Long-term growth and development in children after home parental nutrition.

Growth and development after the cessation of prolonged parenteral nutrition (PN) has not been fully evaluated. Growth, body composition, and nutritional and developmental status were documented in nine children (five boys, four girls) 2 to 6 years old (mean 4.9 +/- 1.0 years) who had previously received long-term PN (mean 14.6 +/- 11.4 months). PN had been discontinued in all subjects for at least 6 months (mean 3.4 +/- 1.4 years); they were receiving oral feedings only. One subject had a significantly low height-for-age, and another had a low percent ideal body weight; five subjects had low total body fat. Serum vitamin A was low in six subjects. Seventy-two-hour fecal fat analysis was abnormal in two of eight subjects. Abnormal bone mineral density was present in four of nine subjects. Psychomotor development was normal in all nine subjects. Two had functional difficulties in swallowing. One or more abnormalities were present in all nine subjects. These findings suggest that children who require prolonged PN in early life are at risk for abnormalities in growth and nutritional status in later childhood; they require long-term dietary, growth, and nutritional monitoring.

Anthropometry↗
PubMed1997

Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression.

CTLA-4 is a lymphocyte cell surface receptor expressed by activated T cells that functions to down-regulate T cell responses induced by TCR and CD28 stimulation. Since CTLA-4 competes with CD28 for binding to the common ligands B7-1 and B7-2, the level of CTLA-4 surface expression is likely to play an important role in its ability to inhibit CD28-dependent T cell activation. The factors that regulate these levels are poorly understood. Recent studies have revealed that following T cell activation, the majority of CTLA-4 is localized intracellularly rather than on the cell surface, and surface CTLA-4 is rapidly reinternalized. In this study, we investigate the molecular mechanism underlying the rapid clearance of CTLA-4 from the cell surface. The data demonstrate that cell surface CTLA-4 is endocytosed into clathrin-coated vesicles even in the absence of ligand. The targeting of CTLA-4 to clathrin-coated vesicles is mediated by the clathrin-associated adaptor complex AP-2. The cytoplasmic domain of CTLA-4 was found to specifically bind to AP50, the medium chain subunit of AP-2 in both yeast two-hybrid and coimmunoprecipitation assays. The interaction requires the peptide sequence 199-GVYVKM-204 in the cytoplasmic tail of CTLA-4. Mutation of the CTLA-4 amino acid residue Y201 abrogates the interaction with AP50, resulting in the accumulation of CTLA-4 at the cell surface. Together these data suggest that the interaction of CTLA-4 with AP50 plays an important role in regulating the cell surface expression of CTLA-4.

Abatacept↗
PubMed1996

Regulation of surface and intracellular expression of CTLA4 on mouse T cells.

CTLA4 is a cell surface molecule that shares 30% homology with CD28 and binds B7 family members with high affinity. Analysis of surface expression on murine T cells revealed up-regulation after stimulation with anti-CD3 mAb in vitro and further augmentation after the addition of exogenous IL-2 or anti-CD28 mAb. The effects of IL-2 and anti-CD28 mAb were additive and in part independent, as anti-CD28 mAb increased anti-CD3 mAb-induced T cell CTLA4 expression in IL-2-deficient mice. In contrast, CTLA4 expression was only minimally augmented by the addition of IL-4, IL-6, IL-7, or IL-12. Expression of CTLA4 induced by anti-CD3 mAb was inhibited by anti-IL-2 plus anti-IL-2R mAbs. Inasmuch as these agents prevented T cell proliferation, the effects of cell cycle inhibitors also were examined. Drugs blocking at G1 (cyclosporin A, mimosine) or S (hydroxyurea) phase inhibited the up-regulation of CTLA4 induced by anti-CD3 mAb, suggesting that entry into the cell cycle was necessary to increase the expression of CTLA4. The kinetics of intracellular expression of CTLA4 after stimulation with anti-CD3 mAb paralleled those of surface expression, but surprisingly, much more CTLA4 was localized in the cytoplasm of T lymphocytes than on the cell surface at each time point. Importantly, surface CTLA4 was rapidly internalized intracellularly, which may explain the low levels of expression generally detected on the cell surface. We conclude that both CD28 and IL-2 play important roles in the up-regulation of CTLA4 expression. In addition, the cell surface accumulation of CTL4 appears to be primarily regulated by its rapid endocytosis.

Abatacept↗
PubMed1996

Variable gene expression within human tyrosinemia type 1 liver may reflect region-specific dysplasia.

Patients with hereditary tyrosinemia type 1 have a deficiency of fumarylacetoacetate hydrolase (FAH) and develop progressive hepatocellular dysfunction with a high risk of malignant transformation. Serum alpha-fetoprotein levels are frequently elevated in these patients; therefore, this commonly used marker of tumorigenesis is inadequate. To date, no literature exists describing the hepatic gene alterations in patients with this disease. We analyzed the expression of a panel of proliferation associated and liver-specific genes in the liver of a 33 month-old girl at the time of orthotopic liver transplantation. This study provides information that may be useful in developing markers for malignancy and understanding the pathogenesis of this disease. Gene expression patterns of two regenerating nodules and total liver from the patient with FAH deficiency were compared with control donor liver. Liver-specific and growth-induced genes with altered expression in the tyrosinemic liver included several functional classes: structural proteins (actin, thrombospondin), transcription factors (c-fos, egr-1, C/EBPalpha), liver-specific enzymes (glucose-6-phosphatase [G6Phase], and secreted factors (insulin-like growth factor binding protein 1 [GFBP-1]. Isolated macronodules demonstrated varied patterns of expression, suggesting that they do not form a homogeneous cellular environment. In the tyrosinemic liver, IGFBP-1 messenger RNA expression was high and G6Phase messenger RNA was not detectable. Although G6Phase and IGFBP-1 are coexpressed in regenerating liver, immunohistochemistry in the tyrosinemic liver demonstrated a mutually exclusive distribution for the two proteins in a tissue section with features of dysplasia. We propose that cells in these areas may have an aberrant transcription factor and growth factor "milieu" that leads to altered gene and protein expression. These molecular alterations are reflected in dysplastic histologic changes and may ultimately predispose to the development of malignancy.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Changes in the ultrastructural localization of mRNA for a circadian regulated protein.

The amount of the luciferin (substrate) binding protein (LBP) in extracts of the bioluminescent marine dinoflagellate Gonyaulax polyedra increases by about 10-fold during a 6-hour period spanning the end of the day- and the early night-phases, and then decreases by the same amount approximately 12 hours later. Previous studies have indicated that synthesis of the protein is regulated translationally. The experiments described here were undertaken to gain insight into the mechanism of this control. Evidence was obtained for the existence of mRNA-binding proteins that could have a regulatory function. In addition, circadian-related differences were observed in the total amount of mRNA as well as in the subcellular distribution of lbp mRNA.

Animals↗
PubMed1995

Identification of the sites of interaction between c-Raf-1 and Ras-GTP.

Specific sites of protein-protein interaction were identified in the 51-149 region of c-Raf-1 using contact epitope scanning and site-directed mutagenesis. Nineteen overlapping peptides based upon the primary sequence of the Ras binding domain of c-Raf-1 were tested for the ability to competitively inhibit complex formation between Ras-GTP and the c-Raf-1 N-terminus. A peptide containing c-Raf-1 residues 91-105 as well as five overlapping peptides covering a region extending from residues 118 to 143 interfered with Ras association, defining these sites as potential contact surfaces with Ras. Alanine scanning mutagenesis was used as a second probe for sites of Ras interaction with the c-Raf-1 N-terminus. Raf residues 64-67 and 80-103 were demonstrated as important for association with Ras-GTP with residues 66, 67, 84, 87, 89 and 91 identified as the most critical individual points of contact with the Ras protein. Alanine substitution of residues between 118-143 suggested only one potentially weak site of interaction defined by residues 120-125. The combined results of both peptide and mutagenic analyses suggest that the primary site of c-Raf-1 interaction with Ras maps to Raf residues 80-103, with secondary interactions occurring with residues 66 and 67 and possibly 120-125. Contact epitope scanning of the Ras effector region found maximum inhibition of Ras/Raf association with a peptide corresponding to Ras amino acids 37-51. A model is proposed for the GTP-dependent association of Ras and Raf.

Amino Acid Sequence↗