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Biomedical subjects

A C Chan

Publications and source records attributed to A C Chan.

At least 19 recordsLinked to original sources
PubMed2005

Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data.

Immune cell-specific expression is one indication of the importance of a gene's role in the immune response. We have compiled a compendium of microarray expression data for virtually all human genes from six key immune cell types and their activated and differentiated states. Immune Response In Silico (IRIS) is a collection of genes that have been selected for specific expression in immune cells. The expression pattern of IRIS genes recapitulates the phylogeny of immune cells in terms of the lineages of their differentiation. Gene Ontology assignments for IRIS genes reveal significant involvement in inflammation and immunity. Genes encoding CD antigens, cytokines, integrins and many other gene families playing key roles in the immune response are highly represented. IRIS also includes proteins of unknown function and expressed sequence tags that may not represent genes. The predicted cellular localization of IRIS proteins is evenly distributed between cell surface and intracellular compartments, indicating that immune specificity is important at many points in the signaling pathways of the immune response. IRIS provides a resource for further investigation into the function of the immune system and immune diseases.

Gene Expression Profiling↗
PubMed2001

Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-kappaB/Rel.

Signaling from the TCR regulates T lymphoid survival, deletion by apoptosis, and selective clonal expansion. One set of signaling pathways activated during thymic selection leads to degradation of a cytosolic retention protein, the inhibitor of kappaB (IkappaB)alpha, followed by nuclear translocation of the NF-kappaB/Rel family of transcription factors. It has been found previously that NF-kappaB proteins mediate a pathway signaling the survival of mature T cells and protection of thymocytes against TNF-induced apoptosis. In contrast, we show in this study that a transgenic inhibitor of NF-kappaB/Rel signaling interferes with the negative selection of immature thymocytes by endogenous MHC ligands in vivo. Positive selection of the H-Y TCR also was diminished. This attenuation of thymic selection efficiency was associated with decreased ZAP-70 phosphorylation and TCR signaling of CD69 induction. These findings demonstrate that the NF-kappaB transcriptional pathway plays an important role in normal processes of clonal deletion and they indicate that the NF-kappaB/IkappaB axis can regulate the efficiency of TCR signaling.

Animals↗
PubMed2001

Unique signaling properties of B cell antigen receptor in mature and immature B cells: implications for tolerance and activation.

Immature B cells display increased sensitivity to tolerance induction compared with their mature counterparts. The molecular mechanisms underlying these differences are poorly defined. In this study, we demonstrate unique maturation stage-dependent differences in B cell Ag receptor (BCR) signaling, including BCR-mediated calcium mobilization responses. Immature B cells display greater increases in intracellular calcium concentrations following Ag stimulation. This has consequences for the induction of biologically relevant responses: immature B cells require lower Ag concentrations for activation than mature B cells, as measured by induction of receptor editing and CD86 expression, respectively. BCR-induced tyrosine phosphorylation of CD79a, Lyn, B cell linker protein, and phospholipase Cgamma2 is enhanced in immature B cells and they exhibit greater capacitative calcium entry in response to Ag. Moreover, B cell linker protein, Bruton's tyrosine kinase, and phospholipase Cgamma2, which are crucial for the induction of calcium mobilization responses, are present at approximately 3-fold higher levels in immature B cells, potentially contributing to increased mobilization of calcium. Consistent with this possibility, we found that the previously reported lack of inositol-1,4,5-triphosphate production in immature B cells may be explained by enhanced inositol-1,4,5-triphosphate breakdown. These data demonstrate that multiple mechanisms guarantee increased Ag-induced mobilization of calcium in immature B cells and presumably ensure elimination of autoreactive B cells from the repertoire.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Requirement for tyrosine residues 315 and 319 within zeta chain-associated protein 70 for T cell development.

Engagement of the T cell antigen receptor (TCR) induces the transphosphorylation of the zeta chain-associated protein of 70,000 Mr (ZAP-70) protein tyrosine kinase (PTK) by the CD4/8 coreceptor associated Lck PTK. Phosphorylation of Tyr 493 within ZAP-70's activation loop results in the enzymatic activation of ZAP-70. Additional tyrosines (Tyrs) within ZAP-70 are phosphorylated that play both positive and negative regulatory roles in TCR function. Phosphorylation of Tyr residues (Tyrs 315 and 319) within the Interdomain B region of the ZAP-70 PTK plays important roles in the generation of second messengers after TCR engagement. Here, we demonstrate that phosphorylation of these two Tyr residues also play important roles in mediating the positive and negative selection of T cells in the thymus.

Animals↗
PubMed2001

Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module.

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain-containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-gamma2 (PLC-gamma2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65-regulated signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Early clinical outcomes after subfascial endoscopic perforator surgery (SEPS) and saphenous vein surgery in chronic venous insufficiency.

BACKGROUND: Subfascial endoscopic perforator surgery (SEPS) has recently become popular as a minimally invasive way to treat chronic venous insufficiency (CVI) of the lower extremities. We report the early clinical outcomes of SEPS and saphenous vein surgery in a prospective series of Chinese patients who presented with severe CVI. METHODS: All patients referred to our hospital for the management of severe CVI (class IV disease or above) after January 1998 underwent SEPS using an ultrasonic scalpel in conjunction with saphenous vein surgery. All patients were followed up prospectively to assess ulcer healing, ulcer recurrence, and symptoms after SEPS. Clinical outcome was evaluated by the scoring system suggested by the Consensus Committee of the American Venous Forum on Chronic Venous Disease. RESULTS: Over a 24-month period, we performed 36 SEPS on 31 patients. Nineteen lower extremities (53%) had active or healing ulcers. Sapheno-femoral ligation was also performed in 33 limbs (92%). Four limbs (11%) developed superficial wound infection, and two (6%) had saphenous nerve dysesthesia. The mean clinical score and disability score decreased from 8.42 to 3.42 and 1.45 to 0.31 respectively, after a median follow-up of 14 months (range, 6-22) (p < 0.005). Eleven ulcers (58%) healed within 6 weeks after surgery. At 1-year follow-up, ulcer recurrence was found in two legs (11%). CONCLUSION: SEPS is safe and feasible. Early clinical results have shown a promising outcome in patients with severe chronic venous insufficiency.

Adult↗
PubMed2001

Subfascial endoscopic perforator vein surgery (SEPS) using the ultrasonic scalpel.

Subfascial endoscopic perforator vein surgery (SEPS) was recently introduced as a minimally invasive method to ligate incompetent perforating veins in patients with severe chronic venous insufficiency of the lower extremities. Herein we describe a technique in which we used a 5-mm ultrasonic scalpel for the transection of perforating veins in 16 SEPS performed in 14 patients. The use of the ultrasonic scalpel allowed for the precise coagulation and transection of the perforator vein with hemostasis, while avoiding the use of metal clips. Our initial results showed that the technique was feasible with minimal morbidity. We recommend the use of the ultrasonic scalpel as an alternative tool to transect perforating veins in SEPS.

Adult↗
PubMed2001

Disruption of T cell signaling networks and development by Grb2 haploid insufficiency.

The developmental processes of positive and negative selection in the thymus shape the T cell antigen receptor (TCR) repertoire and require the integration of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and are mediated by multimodular adaptor proteins that permit the functional integration of distinct signaling molecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2+/- mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p38, but not extracellular signal-regulated kinase (ERK), activation. In turn, this selective effect decreases the ability of thymocytes to undergo negative, but not positive, selection. We also show that there are differences in the signaling thresholds of the three mitogen-activated protein kinase (MAPK) families. These differences may provide a mechanism by which quantitative differences in signal strength can alter the balance of downstream signaling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies.

AIMS: Hyaline-vascular Castleman's disease (HVCD) and follicular dendritic cell (FDC) sarcoma occurring in the nasopharynx are both extremely rare. We report the first case of transformation of the former into the latter as documented by sequential biopsies. The steps involved in the transformation were described in detail and the possible role of p53 studied. METHODS AND RESULTS: The patient presented at the age of 23 years with nasopharyngeal HVCD. Hyaline- vascular Castleman's disease with FDC overgrowth was diagnosed in a recurrence 8 years later, and a frank FDC sarcoma developed at the same site 11 years after initial presentation. The patient remained disease-free 3 years after excision and adjuvant chemotherapy. The FDC sarcoma comprised swirling fascicles of spindly cells with indistinct cell borders. The tumour cells expressed the FDC markers CD21, CD35 and CNA.42 and in-situ hybridization for Epstein-Barr virus-encoded RNAs was negative. Over-expression of p53 protein was observed in the FDC sarcoma and an increased number of weakly p53-positive spindly cells could also be demonstrated in the HVCD specimen. This finding suggested a possible role of p53 in the evolution from HVCD to FDC sarcoma. Critical analysis of the literature shows that, among the 13 reported cases of FDC sarcoma associated with Castleman's disease, possible progression from the latter to the former is documented in only two cases. CONCLUSIONS: The sequential changes observed in the current case provide further evidence to strengthen the role of HVCD as a possible precursor of FDC sarcoma. There is a possible role of p53 in the transformation process but confirmation by future studies is needed.

Adult↗
PubMed2001

Management of paraffinoma of the breast: 10 years' experience.

Paraffin injection was regarded as a simple and effective method of improving body contour. It was widely used in breast augmentation until the long-term complication of paraffinoma was recognised. Paraffinoma of the breast can present as a spectrum of disease ranging from a painless mass to a destructive ulcer simulating breast cancer. This makes it difficult to make the correct diagnosis and provide suitable treatment. Eight patients with paraffinoma of the breast have been managed at a teaching hospital over a 10 year period. All were females, with a mean age of 65.6 years (range: 57-73 years). The average time between paraffin injection and the onset of symptoms was 24 years (range: 11-30 years). These patients have been followed up for between 3 and 10 years (mean: 6.1 years). One patient died of congestive heart failure 4 years after bilateral mastectomy for painful paraffinomas of the breasts. Another patient had a coexisting infiltrative ductal carcinoma of the breast. The clinical presentations, radiological appearances, histopathological features and the treatment are discussed.

Aged↗
PubMed2001

Inflammatory pseudotumor-like follicular dendritic cell tumor: a distinctive low-grade malignant intra-abdominal neoplasm with consistent Epstein-Barr virus association.

Follicular dendritic cell (FDC) tumors are uncommon neoplasms that can involve lymph nodes or extranodal sites. They can exhibit a broad spectrum of histologic appearances and behavior, but the intra-abdominal ones usually pursue an aggressive course. The purpose of this study was to characterize a distinctive variant of FDC tumor morphologically mimicking inflammatory pseudotumor through analysis of the clinicopathologic features of 11 cases. The patients included 10 women and one man (age range, 19-61 years; median age, 40 years) who presented with abdominal discomfort or pain. Six patients had systemic symptoms such as marked weight loss, fever, or malaise. All tumors occurred in intra-abdominal sites: liver (n = 7), spleen (n = 3), and peripancreatic region (n = 1). Of the nine patients with follow-up data, six were alive and well, one developed recurrence at 9 years, and two had repeated recurrences over many years. Grossly, the tumors were usually solitary and fleshy, punctuated by areas of hemorrhage and necrosis. Histologically, in a background of abundant lymphocytes and plasma cells were dispersed spindle or ovoid cells with vesicular nuclei and distinct nucleoli. The degree of nuclear atypia was variable, and some nuclei could be grotesque or resemble Reed-Sternberg cells. Focally, spindle cell fascicles could be formed. The atypical cells were immunoreactive for FDC markers such as CD21/CD35, CD23, and CNA.42. In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA was positive in all cases, remarkably highlighting the spindle cells and their atypia. EBV-latent membrane protein-1 was expressed commonly, albeit often focally and weakly. Therefore, inflammatory pseudotumor-like FDC tumor represents a distinctive variant of FDC tumor that differs from conventional FDC tumor in the following aspects: marked female predominance; selective localization in intra-abdominal sites, especially the liver and spleen; frequent presence of systemic symptoms; indolent behavior despite an intra-abdominal location; dispersed distribution of tumor cells and prominent lymphoplasmacytic infiltration; and consistent association with EBV.

Abdominal Neoplasms↗
PubMed2001

Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase.

Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption. Emk(-/-) mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4(+)T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. As Emk(-/-) animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.

Animals↗
PubMed2001

Morphological analysis of adrenal glands: a prospective analysis.

There is a lack of studies to document the weight range of normal adrenal glands. The aims of the current study are to find out the weight range of normal adrenal glands in Chinese patients and to analyze any potential factors affecting it. Adrenal glands not affected by disease were prospectively collected from autopsies on 333 Chinese patients (208 men, 125 women). The weight and longest dimension of each adrenal gland were noted. The impact of various clinicopathological factors on the adrenal weight was studied. In addition, the morphometric features of these adrenal glands were compared with that of 28 surgically resected adrenal glands with cortical adenomas. The mean combined weight of adrenal glands was 11.8 g (range = 5.8 g to 19.9 g). The left adrenal gland was often heavier than the right (mean weight = 6.1 g and 5.7 g respectively) and with a greater longitudinal length than the right (mean length = 5.2 cm and 4.8 cm respectively). Adrenal glands were often heavier in male, younger age group (less than 60-yr-old) and patients with history of hypertension or lung cancers. In comparison, the mean weight of right adrenal gland with cortical adenoma was 11.7 g (range = 6 g to 26 g) and that of left adrenal gland with cortical adenoma was 9.4 g (range = 4.6 g to 25 g). This is the first study in the English literature that provides data on the weight of normal adrenal glands in a solely Chinese population. Adrenal weight may be affected by patients' gender, age, laterality of adrenal gland and presence of systemic disease.

Adenoma↗
PubMed2001

[Detection of Immunoglobulin light chain restriction of mucosa-associated lymphoid tissue type gastric lymphoma using mRNA in situ hybridization].

OBJECTIVE: To evaluate the usefulness of in situ hybridization for Immunoglobulin kappa and lambda light chain mRNA to detect light chain restriction in the diagnosis of primary gastric lymphoma (PGL) of mucosa-associated lymphoid tissue (MALT) type. METHODS: Twenty-seven cases of PGL of MALT type and 5 cases of gastritis were analyzed using in situ hybridization with fluorescent isothiocyanate (FITC)-labeled oligonucleotide probes for kappa and lambda light chain mRNA. The kappa:lambda ratios of tumor cells, lymphocytes and plasma cells were analyzed to detect light chain restriction and clonal plasma cells. RESULTS: Light chain restriction was found in 10 of 27 (37%) cases of PGL cases (in 5/9 low grade and 5/18 in high grade). Clonal plasma cells were detected in low grade but not in high-grade cases. No light chain restriction was found in gastritis specimens, the adjacent tissue of tumors or the distant stomach mucosa in lymphoma cases. CONCLUSIONS: The detection of clonality using mRNA in situ hybridization could be a helpful diagnostic tool for gastric lymphoma. The presence of clonal plasma cells can be a marker of the early lesion of low-grade PGL.

Diagnosis, Differential↗