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Biomedical subjects

A C Chan

Publications and source records attributed to A C Chan.

At least 55 records · Page 3Linked to original sources
PubMed2000

An unusual case of double tuberculous broncho-oesophageal fistulas in an adult.

Broncho-oesophageal fistula associated with tuberculosis is rarely reported in the literature and has not been reported in Hong Kong. We describe a 30-year-old Chinese human immunodeficiency virus (HIV)-negative man with double tuberculous broncho-oesophageal fistulas proven by histology. Constitutional symptoms of active tuberculosis were absent and chest radiograph did not show an obvious lung lesion. Our case shows that broncho-oesophageal fistula can be the sole manifestation of active tuberculosis and that the diagnosis should be suspected in patients who are seen with chronic respiratory symptoms in areas where the prevalence of tuberculosis is high.

Adult↗
PubMed1999

Requirement for B cell linker protein (BLNK) in B cell development.

Linker proteins function as molecular scaffolds to localize enzymes with substrates. In B cells, B cell linker protein (BLNK) links the B cell receptor (BCR)-activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways. To examine the in vivo role of BLNK, mice deficient in BLNK were generated. B cell development in BLNK-/- mice was blocked at the transition from B220+CD43+ progenitor B to B220+CD43- precursor B cells. Only a small percentage of immunoglobulin M++ (IgM++), but not mature IgMloIgDhi, B cells were detected in the periphery. Hence, BLNK is an essential component of BCR signaling pathways and is required to promote B cell development.

Adaptor Proteins, Signal Transducing↗
PubMed1999

An essential role for BLNK in human B cell development.

The signal transduction events that control the progenitor B cell (pro-B cell) to precursor B cell (pre-B cell) transition have not been well delineated. In evaluating patients with absent B cells, a male with a homozygous splice defect in the cytoplasmic adapter protein BLNK (B cell linker protein) was identified. Although this patient had normal numbers of pro-B cells, he had no pre-B cells or mature B cells, indicating that BLNK plays a critical role in orchestrating the pro-B cell to pre-B cell transition. The immune system and overall growth and development were otherwise normal in this patient, suggesting that BLNK function is highly specific.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Application of image analysis techniques to two-dimensional crossed immunoelectrophoresis study.

Two-dimensional crossed immunoelectrophoresis (2D-CIEP) is a technique widely used for studying composition of protein mixtures in biological and clinical studies. A low cost image analysis system with the use of an optical flatbed scanner and a IBM-compatible PC was set up in this work for capturing 2D-CIEP patterns. A computer package CIEPEASY was developed for modification and analysis of the image acquired to determine various peak parameters such as the migration distance, peak height and peak area of the constituting components for both qualitative and quantitative studies. In this approach, more composition information of the standard and sample gel patterns could be extracted from the proposed image analysis system. The time required for data collection and interpretation of 2D-CIEP images was shortened significantly and the results obtained have a higher accuracy than those obtained by using conventional methods. Moreover, a linear relationship between the peak area and the amount of antigen present in a sample was confirmed accurately and reported for the first time in the literature.

Antigens↗
PubMed1999

Thermodynamic study of the binding of the tandem-SH2 domain of the Syk kinase to a dually phosphorylated ITAM peptide: evidence for two conformers.

The cytosolic tyrosine kinase Syk is recruited to immune cell receptors via interactions of its tandem-SH2 domain with tyrosine-phosphorylated sequences called immune receptor tyrosine activation motifs (ITAMs). We have characterized the binding of the tandem-SH2 domain of Syk (Syk-tSH2) to a dually phosphorylated peptide derived from the ITAM of the T cell receptor CD3-epsilon subunit. The CD3-epsilon peptide binds with an affinity of 18-81 nM at 150 mM NaCl over the 4.5-30 degrees C temperature range that was studied. The enthalpy of binding, DeltaH degrees obs, shows an unusual nonlinear dependence on temperature, suggesting the possibility of a temperature-dependent conformational equilibrium coupled to binding. This hypothesis was tested and confirmed by examining the temperature dependence of (1) the on-rate constant for binding and (2) the fluorescence of Syk-tSH2 and its CD3-epsilon peptide complex. The DeltaH degrees obs, Kobs, fluorescence, and kinetic data are all well described by a model incorporating the hypothesized conformational equilibrium. Circular dichroism spectra at various temperatures indicate that the conformational change is not due to a partial unfolding of the protein. We suggest that the conformational equilibrium enables Syk-tSH2 to exhibit flexibility in its binding modality, which may be necessitated by Syk's involvement in a wide variety of signal tranduction pathways.

CD3 Complex↗
PubMed1999

Phosphorylation of Tyr319 in ZAP-70 is required for T-cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation.

Accumulating evidence indicates that the interdomain B regions of ZAP-70 and Syk play pivotal roles in the coupling of T-cell antigen receptor (TCR) stimulation to the activation of downstream signaling pathways. The interdomain B region of ZAP-70 contains at least three candidate sites of tyrosine phosphorylation. In this report, we identify Tyr319 as a functionally important phosphorylation site in the ZAP-70 interdomain B region. TCR crosslinkage triggered a rapid increase in the phosphorylation of Tyr319 in Jurkat T cells. Although mutation of Tyr319 to Phe had no effect on the tyrosine kinase activity of ZAP-70, the resulting ZAP(Y319-->F) mutant failed to reconstitute TCR-dependent Ca2+ mobilization, Ras activation, CD69 expression and NFAT-dependent transcription in ZAP-70-deficient Jurkat cells. These defects were correlated with reduced tyrosine phosphorylation of phospholipase C (PLC)-gamma1 and the LAT adapter protein in the ZAP(Y319-->F)-expressing cells. On the other hand, ZAP(Y319-->F)-expressing cells displayed normal increases in SLP-76 phosphorylation and ERK activation during TCR stimulation. Phosphorylation of Tyr319 promoted the association of ZAP-70 with the SH2 domains of two key signaling molecules, Lck and PLC-gamma1. These studies suggest that Tyr319 phosphorylation is required for the assembly of a ZAP-70-containing signaling complex that leads to the activation of the PLC-gamma1- and Ras-dependent signaling cascades in antigen-stimulated T cells.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers.

BACKGROUND AND METHODS: After endoscopic treatment to control bleeding of peptic ulcers, bleeding recurs in 15 to 20 percent of patients. In a prospective, randomized study, we compared endoscopic retreatment with surgery after initial endoscopy. Over a 40-month period, 1169 of 3473 adults who were admitted to our hospital with bleeding peptic ulcers underwent endoscopy to reestablish hemostasis. Of 100 patients with recurrent bleeding, 7 patients with cancer and 1 patient with cardiac arrest were excluded from the study; 48 patients were randomly assigned to undergo immediate endoscopic retreatment and 44 were assigned to undergo surgery. The type of operation used was left to the surgeon. Bleeding was considered to have recurred in the event of any one of the following: vomiting of fresh blood, hypotension and melena, or a requirement for more than four units of blood in the 72-hour period after endoscopic treatment. RESULTS: Of the 48 patients who were assigned to endoscopic retreatment, 35 had long-term control of bleeding. Thirteen underwent salvage surgery, 11 because retreatment failed and 2 because of perforations resulting from thermocoagulation. Five patients in the endoscopy group died within 30 days, as compared with eight patients in the surgery group (P=0.37). Seven patients in the endoscopy group (including 6 who underwent salvage surgery) had complications, as compared with 16 in the surgery group (P=0.03). The duration of hospitalization, the need for hospitalization in the intensive care unit and the resultant duration of that stay, and the number of blood transfusions were similar in the two groups. In multivariate analysis, hypotension at randomization (P=0.01) and an ulcer size of at least 2 cm (P=0.03) were independent factors predictive of the failure of endoscopic retreatment. CONCLUSIONS: In patients with peptic ulcers and recurrent bleeding after initial endoscopic control of bleeding, endoscopic retreatment reduces the need for surgery without increasing the risk of death and is associated with fewer complications than is surgery.

Aged↗
PubMed1999

Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation.

The Src-homology domain 2 (SH2)-containing cytoplasmic tyrosine phosphatase, SHP-1 (SH2-containing protein tyrosine phosphatase-1), interacts with several B cell surface and intracellular signal transduction molecules through its SH2 domains. Mice with the motheaten and viable motheaten mutations are deficient in SHP-1 and lack most mature B cells. To define the role of SHP-1 in mature B cells, we expressed phosphatase-inactive SHP-1 (C453S) in a mature B cell lymphoma line. SHP-1 (C453S) retains the ability to bind to both substrates and appropriate tyrosine-phosphorylated proteins and therefore can compete with the endogenous wild-type enzyme. We found that B cells expressing SHP-1 (C453S) demonstrated enhanced and prolonged tyrosine phosphorylation of proteins with molecular masses of 110, 70, and 55-60 kDa after stimulation with anti-mouse IgG. The tyrosine kinase Syk was hyperphosphorylated and hyperactive in B cells expressing SHP-1 (C453S). SHP-1 and Syk were coimmunoprecipitated from wild-type K46 cells, K46 SHP-1 (C453S) cells, and splenic B cells, and SHP-1 dephosphorylated Syk. Cells expressing SHP-1 (C453S) showed increased Ca2+ mobilization, extracellular signal-regulated kinase activation, and homotypic adhesion after B cell Ag receptor engagement. Thus, SHP-1 regulates multiple early and late events in B lymphocyte activation.

Animals↗
PubMed1999

The lck SH3 domain is required for activation of the mitogen-activated protein kinase pathway but not the initiation of T-cell antigen receptor signaling.

Initiation of T-cell antigen receptor (TCR) signaling is dependent upon the activity of protein tyrosine kinases. The Src family kinase Lck is required for the initial events in TCR signaling, such as the phosphorylation of the TCR complex and the activation of ZAP-70, but little is known of its role in downstream signaling. Expression of a mutated form of Lck lacking SH3 domain function (LckW97A) in the Lck-deficient T-cell line JCaM1 revealed a requirement for Lck beyond the initiation of TCR signaling. In cells expressing LckW97A, stimulation of the TCR failed to activate the mitogen-activated protein kinase (MAPK) pathway, despite normal TCR zeta chain phosphorylation, ZAP-70 recruitment, and ZAP-70 activation. Activation of extracellular signal-regulated kinase (ERK) and MAPK kinase (MEK), as well as the induction of CD69 expression, was greatly impaired in JCaM1/LckW97A cells. In contrast, the phosphorylation of phospholipase Cgamma1 (PLCgamma1) and corresponding elevations in intracellular calcium concentration ([Ca2+]i) were intact. Thus, cells expressing LckW97A exhibit a selective defect in the activation of the MAPK pathway. These results demonstrate that Lck has a role in the activation of signaling pathways beyond the initiation of TCR signaling and suggest that the MAPK pathway may be selectively controlled by regulating the function of Lck.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Isolated lymph node T lymphoblastic transformation of chronic myeloid leukemia during interferon treatment.

Isolated nodal T lymphoblastic transformation of chronic myeloid leukemia (CML) with the marrow still in chronic phase is rare. A case of CML treated by alpha-interferon developed this unusual complication. However, after successful treatment of the blastic transformation, the patient remained responsive to interferon and maintained a major cytogenetic response for over 2 years. This case illustrated a rare clinical progression of CML on interferon treatment to isolated nodal T lymphoblastic transformation. This unusual form of blastic transformation may have a better prognosis than other forms of blastic crisis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Clinicopathological analysis of elective neck dissection for N0 neck of early oral tongue carcinoma.

BACKGROUND: The study aims at evaluation of the efficacy of elective neck dissection as a staging and therapeutic procedure for N0 neck of early carcinoma of the oral tongue by whole organ serial sectioning. METHODS: There were 50 stage I and II patients. The neck dissection specimens were whole organ sectioned in 3-mm intervals for the evaluation of nodal metastasis. RESULTS: There were 18 (36%) patients with subclinical nodal metastasis. The total number of metastatic nodes were 31 (1%) among all 2,826 nodes being examined. The metastatic foci had a median size of 3 mm and occupied a median of 6% of the cross sectional area of the involved nodes. The ipsilateral level II nodes were the commonest (26%) site of metastasis. Metastatic nodes were present in 34% patients who had negative preoperative radiological assessment and in 20% patients who had negative intraoperative frozen section sampling of neck nodes. Patients with subclinical nodal metastasis had a high incidence of regional recurrence (62%) and low survival (27%) when postoperative radiotherapy was not given after elective neck dissection. CONCLUSIONS: Ipsilateral level I,II,III neck dissection is an adequate diagnostic procedure for staging of the N0 neck of early oral tongue carcinoma. Its diagnostic role cannot be replaced by the available pre-operative radiological screening and intra-operative frozen section sampling. However, elective selective neck dissection is an effective but not adequate therapeutic procedure, and post-operative adjuvant radiotherapy and chemotherapy have to be considered for all pathologically positive necks.

Adolescent↗
PubMed1999

A comparison study on physical properties of self-expandable esophageal metal stents.

BACKGROUND: Currently available esophageal expandable stents differ in design, material, and method of deployment. We compared the expansile force and the susceptibility to buckling force in five commercially available stents. METHODS: The Esophacoil, Wallstent, Ultraflex, Gianturco-Z and Song stents were tested. The middle sections of fully expanded stents were subjected to compression force using a universal tensile testing machine. The distortion of the stent was measured electronically and the expansile force was calculated. Bending moments were applied to the ends of the stents until buckling occurred in the inner parts. The buckling radius was measured as the radius of the inner curvature of the stent when this occurred. RESULTS: The stents tested were significantly different in their expansile forces and buckling radii. Song stent and Gianturco-Z stent were similar due to their similar designs. Esophacoil was the strongest with regard to withstanding compressive force and angulation force, followed by Wallstent. Ultraflex stent was the weakest in expansile force but withstood angulation force better than the Song and Gianturco stents. CONCLUSION: Esophageal stents differ greatly in their elasticity and resistance to angulation. Knowledge of their mechanical properties will be another helpful factor to consider in selecting the appropriate stent in addition to the geometry and consistency of the tumor.

Equipment Design↗
PubMed1999

Vitamin E regulates mitochondrial hydrogen peroxide generation.

The mitochondrial electron transport system consumes more than 85% of all oxygen used by the cells, and up to 5% of the oxygen consumed by mitochondria is converted to superoxide, hydrogen peroxide, and other reactive oxygen species (ROS) under normal physiologic conditions. Disruption of mitochondrial ultrastructure is one of the earliest pathologic events during vitamin E depletion. The present studies were undertaken to test whether a direct link exists between vitamin E and the production of hydrogen peroxide in the mitochondria. In the first experiment, mice were fed a vitamin E-deficient or-sufficient diet for 15 weeks, after which the mitochondria from liver and skeletal muscle were isolated to determine the rates of hydrogen peroxide production. Deprivation of vitamin E resulted in an approximately 5-fold increase of mitochondrial hydrogen peroxide production in skeletal muscle and a 1-fold increase in liver when compared with the vitamin E-supplemented group. To determine whether vitamin E can dose-dependently influence the production of hydrogen peroxide, four groups of male and female rats were fed diets containing 0, 20, 200, or 2000 lU/kg vitamin E for 90 d. Results showed that dietary vitamin E dose-dependently attenuated hydrogen peroxide production in mitochondria isolated from liver and skeletal muscle of male and female rats. Female rats, however, were more profoundly affected by dietary vitamin E than male rats in the suppression of mitochondrial hydrogen peroxide production in both organs studied. These results showed that vitamin E can directly regulate hydrogen peroxide production in mitochondria and suggest that the overproduction of mitochondrial ROS is the first event leading to the tissue damage observed in vitamin E-deficiency syndromes. Data further suggested that by regulating mitochondrial production of ROS, vitamin E modulates the expression and activation of signal transduction pathways and other redox-sensitive biologic modifiers, and thereby delays or prevents degenerative tissue changes.

Animals↗
PubMed1999

BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells.

Signaling through the B cell receptor (BCR) is essential for B cell function and development. Despite the key role of Syk in BCR signaling, little is known about the mechanism by which Syk transmits downstream effectors. BLNK (B cell LiNKer protein), a substrate for Syk, is now shown to be essential in activating phospholipase C (PLC)gamma 2 and JNK. The BCR-induced PLC gamma 2 activation, but not the JNK activation, was restored by introduction of PLC gamma 2 membrane-associated form into BLNK-deficient B cells. As JNK activation requires both Rac1 and PLC gamma 2, our results suggest that BLNK regulates the Rac1-JNK pathway, in addition to modulating PLC gamma 2 localization.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Phenotypic and cytotoxic characteristics of peripheral T-cell and NK-cell lymphomas in relation to Epstein-Barr virus association.

AIMS: We investigated the phenotypic and cytotoxic characteristics of different types of peripheral T-cell and NK-cell lymphomas and correlated the findings of cytotoxic phenotype with Epstein-Barr virus (EBV) association. METHODS AND RESULTS: Eighty cases of peripheral T-cell and NK-cell lymphomas, classified according to the REAL classification, were investigated for cytotoxic phenotype (by studying T-cell intracellular antigen-1 (TIA-1) expression immunohistochemically) and EBV association (by in situ hybridization for EBV-encoded small non-polyadenylated RNAs), and the results were correlated with the specific clinicopathological types and the immunophenotype with special emphasis on CD56 expression and CD4/CD8 status. Overall, 39/80 cases (49%) expressed TIA-1. Angiocentric lymphoma (23/24 cases; 96%), aggressive NK-cell leukaemia ('large granular lymphocyte (LGL) leukaemia') (3/3 cases; 100%), intestinal T-cell lymphoma (5/6 cases; 83%) and anaplastic large cell lymphoma (4/6 cases; 67%) were the major subtypes showing a cytotoxic phenotype. Only four of the 27 cases (15%) of peripheral T-cell lymphoma, unspecified, were TIA-1+, while all the seven cases of angioimmunoblastic T-cell lymphoma, six cases of mycosis fungoides and one case of adult T-cell lymphoma/leukaemia were TIA-1-. CONCLUSIONS: Within the group of peripheral T-cell and NK-cell lymphomas, angiocentric lymphoma, aggressive NK-cell leukaemia ('LGL leukaemia'), intestinal T-cell lymphoma and anaplastic large cell lymphoma are the major subtypes displaying a cytotoxic phenotype. The relationships between the cytotoxic phenotype and EBV association, CD56 expression or CD4/CD8 status are secondary to the relationship between cytotoxic phenotype and specific lymphoma subtype.

Adult↗