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Biomedical subjects

A Wong

Publications and source records attributed to A Wong.

At least 73 records · Page 4Linked to original sources
PubMed2000

Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), the first monoclonal antibody approved in the United States for the treatment of cancer, is indicated for the treatment of patients with relapsed or refractory CD20+ low-grade non-Hodgkin's lymphoma. From November 1997 through May 1999, approximately 36,000 patients have been treated with rituximab. Serious cardiopulmonary infusion reactions culminating in death have been reported to occur in approximately 0.04% to 0.07% of patients. Post-approval tumor lysis syndrome has been reported within 12 to 24 hours after the first antibody infusion and is estimated to occur in 0.04% to 0.05% of patients. The risk of tumor lysis appears to be higher in patients with high numbers of circulating malignant cells. Serious infusion-related adverse drug reactions, most often consisting of cardiopulmonary reactions associated with the rapid lysis of large numbers of circulating malignant cells, have been fatal in approximately 0.5 per 1,000 treated patients. Major risk factors include high numbers of circulating malignant lymphoma cells, pulmonary infiltrates or lymphoma involvement, and prior cardiovascular disease. This report updates the safety experience of rituximab therapy with data from clinical trials and postmarketing safety experience, and examines how this information can be used to optimize therapy.

Antibodies, Monoclonal↗
PubMed1999

Expression of OVCA1, a candidate tumor suppressor, is reduced in tumors and inhibits growth of ovarian cancer cells.

Loss of all or part of one copy of chromosome 17p is very common in ovarian and breast tumors. OVCA1 is a candidate tumor suppressor gene mapping to a highly conserved region on chromosome 17p13.3 that shows frequent loss of heterozygosity in breast and ovarian carcinomas. Western blot analysis of extracts prepared from breast and ovarian carcinomas revealed reduced expression of OVCA1 compared with extracts from normal epithelial cells from these tissues. Subcellular localization studies indicate that OVCA1 is localized to punctate bodies scattered throughout the cell but is primarily clustered around the nucleus. Attempts to create cell lines that stably expressed OVCA1 from the cytomegalovirus promoter were generally unsuccessful in a variety of different cell lines. This reduction of colony formation was quantified in the ovarian cancer cell line A2780, where it was demonstrated that cells transfected with plasmids expressing OVCA1 had a 50-60% reduction in colony number as compared with appropriate controls, and only a few of these clones expressed OVCA1, albeit at low levels. The clones that expressed exogenous OVCA1 were found to have dramatically reduced rates of proliferation. Reduced growth rates correlated with an increased proportion of the cells in the G1 fraction of the cell cycle compared with the parental cell line and decreased levels of cyclin D1. The low levels of cyclin D1 appeared to be caused by an accelerated rate of cyclin D1 degradation. Overexpression of cyclin D1 was able to override OVCA1's suppression of clonal outgrowth. These results suggest that slight alterations in the level of OVCA1, such as would occur after reduction of chromosome 17p13.13 to hemizygosity, may result in cell cycle deregulation and promote tumorigenesis.

Amino Acid Substitution↗
PubMed1999

Is combined chemotherapy and radiation therapy equally effective as surgical resection in localized esophageal carcinoma?

PURPOSE: This is a retrospective cohort comparison of combined chemotherapy and radiation versus esophagectomy in nonmetastatic esophageal cancers. METHODS AND MATERIALS: Between 1984 and 1994, 82 patients received concurrent chemotherapy and radiation as their primary treatment. Their treatment consisted of 50-60 Gy of radiation in 20-30 fractions over 4-6 weeks, concurrent with bolus mitomycin C (8 mg/m2) on day 1, 5-fluorouracil (5-FU) infusion (20 mg/kg/day) +/- leucovorin (20 mg/m2/day) on days 1-4 and 22-25. This group was compared to another cohort of 81 patients who had esophagectomy. Both groups were restaged according to the 1983 AJCC clinical staging system and there was more clinical Stage III disease in the chemoradiation group, 30% versus 16%. RESULTS: The complete response rate was 68% after chemoradiation (by clinical assessment) and 83% for esophagectomy (by pathological assessment). At 5 years, the local relapse rate was 59% for chemoradiation and 51% for esophagectomy. The 5-year disease-free rate and survival were 23% and 25% for chemoradiation, and 21% and 23% for esophagectomy respectively. There was no significant difference in the disease control and survival between the two treatments. The pretreatment AJCC clinical stage was a strong prognosticator of outcome. The 5-year survival was 55% for Stage I, 16% for Stage II, and 8% for Stage III (p = 0.00003). CONCLUSION: Combined chemotherapy and radiation appeared to be as effective as esophagectomy in localized esophageal cancer.

Adenocarcinoma↗
PubMed1999

Leukotriene binding, signaling, and analysis of HIV coreceptor function in mouse and human leukotriene B4 receptor-transfected cells.

The mouse leukotriene B4 receptor (m-BLTR) gene was cloned. Membrane fractions of human embryonic kidney 293 cells stably expressing m-BLTR demonstrated a high affinity and specific binding for leukotriene B4 (LTB4, Kd = 0.24 +/- 0.03 nM). In competition binding experiments, LTB4 was the most potent competitor (Ki = 0.23 +/- 0.05 nM) followed by 20-hydroxy-LTB4 (Ki = 1.1 +/- 0.2 nM) and by 6-trans-12-epi-LTB4 and LTD4 (Ki > 1 microM). In stably transfected Chinese hamster ovary cells, LTB4 inhibited forskolin-activated cAMP production and induced an increase of intracellular calcium, suggesting that this receptor is coupled to Gi- and Go-like proteins. In Xenopus laevis melanophores transiently expressing m-BLTR, LTB4 induced the aggregation of pigment granules, confirming the inhibition of cAMP production induced by LTB4. BLT receptors share significant sequence homology with chemokine receptors (CCR5 and CXCR4) that act as human immunodeficiency virus (HIV) coreceptors. However, among the 16 HIV/SIV strains tested, the human BLT receptor did not act as a coreceptor for virus entry into CD4-expressing cells based on infection and cell-cell fusion assays. In 5-lipoxygenase-deficient mice, the absence of leukotriene B4 biosynthesis did not detectably alter m-BLT receptor binding in membranes obtained from glycogen-elicited neutrophils. Isolation of the m-BLTR gene will form the basis of future experiments to elucidate the selective role of LTB4, as opposed to cysteinyl-leukotrienes, in murine models of inflammation.

Animals↗
PubMed1999

Mitochondria in organismal aging and degeneration.

Several lines of experimentation support the view that the genetic, biochemical and bioenergetic functions of somatic mitochondria deteriorate during normal aging. Deletion mutations of the mitochondrial genome accumulate exponentially with age in nerve and muscle tissue of humans and multiple other species. In muscle, a tissue that undergoes age-related fiber loss and atrophy in humans, there is an exponential rise in the number of cytochrome-oxidase-deficient fibers, which is first detectable in the fourth decile of age. Most biochemical studies of animal mitochondrial activity indicate a decline in electron transport activity with age, as well as decreased bioenergetic capacity with age, as measured by mitochondrial membrane potential. Mitochondrial mutations may be both the result of mitochondrial oxidative stress, and cells bearing pure populations of pathogenic mitochondrial mutations are sensitized to oxidant stress. Oxidant stress to mitochondria is known to induce the mitochondrial permeability transition, which has recently been implicated in the release of cytochrome c and the initiation of apoptosis. Thus several lines of evidence support a contribution of mitochondrial dysfunction to the phenotypic changes associated with aging.

Aging↗
PubMed1999

Human non-germinal center B cell interleukin (IL)-12 production is primarily regulated by T cell signals CD40 ligand, interferon gamma, and IL-10: role of B cells in the maintenance of T cell responses.

Interleukin (IL)-12 is expressed mainly in antigen-presenting cells after challenge with microbial material or after CD40 activation. Although IL-12 was cloned from human Epstein-Barr virus (EBV)-transformed B cell lines, surprisingly, CD40 ligation on murine B cells did not lead to IL-12 production, suggesting that murine B cells do not produce IL-12. Here we demonstrate that a subset of human tonsillar B cells can be induced to express and secrete bioactive IL-12. The major stimulus to produce IL-12 in human B cells was CD40 ligation. In contrast, B cell receptor cross-linking did not induce IL-12. Expression of IL-12 after CD40 activation was restricted to CD38(-)IgD+/- non-germinal center (non-GC) B cells. CD40 ligation and interferon (IFN)-gamma exhibited synergistic effects on IL-12 production, whereas IL-10 abrogated and IL-4 significantly inhibited IL-12 production by these B cells. In contrast to IL-12, production of IL-6 is conversely regulated, leading to significant increase after CD40 ligation in the presence of the T helper type 2 (Th2) cytokine IL-4. Cord blood T cells skewed towards either a Th1 or a Th2 phenotype maintained their cytokine expression pattern when restimulated with allogeneic resting B cells. Blockade of CD40 and/or IL-12 during T-B interaction significantly reduced IFN-gamma production by the T cells. This suggests a model whereby B cells produce either IL-12 or IL-6 after contact with T cells previously differentiated towards Th1 or Th2. Furthermore, IL-12 and IL-6 might provide a positive feedback during cognate T-B interactions, thereby maintaining T cells' differentiation pattern during amplification of the immune response.

Antigen-Presenting Cells↗
PubMed1999

Rapid detection of mecA in methicillin resistant Staphylococcus aureus using cycling probe technology.

A novel method has been developed for the detection of the mecA gene, that confers the principle mechanism of methicillin resistance in staphylococci. Cycling Probe Technology (CPT) is a rapid, simple, isothermal method for the detection of specific target sequences. CPT utilizes a unique chimeric DNA-RNA-DNA probe sequence that provides an RNase H sensitive scissile link when hybridized to a complementary target DNA sequence. In the presence of target DNA, the cycling reaction converts full-length chimeric probe into cleaved probe fragments, which accumulate and are quantified. A cycling probe designed for detection of a specific sequence within the mecA gene was used to develop a culture confirmation assay for methicillin resistant Staphylococcus aureus. The CPT assay was used to screen 238 S. aureus isolates and the results were in complete agreement with detection of the mecA gene by polymerase chain reaction (PCR). Detection of mecA should be considered the gold standard for determining methicillin resistance in S. aureus. This study demonstrates the feasibility of using CPT to meet this need.

Bacterial Proteins↗
PubMed1999

Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis.

BACKGROUND & AIMS: Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are important regulators of mucosal inflammation and epithelial cell growth. To determine the role of iNOS and COX-2 in Helicobacter pylori-induced tissue injury, we compared their gene expression in H. pylori-induced gastritis with that in normal gastric mucosa and in non-H. pylori gastritis. METHODS: In 43 patients, we assessed H. pylori infection status, histopathology, messenger RNA (mRNA) and protein expression, and cellular localization of iNOS and COX-2. RESULTS: By reverse-transcription polymerase chain reaction (RT-PCR), antral iNOS and COX-2 mRNA expression was absent to low in normal mucosa (n = 10), significantly increased in H. pylori-negative gastritis (n = 13), and even more markedly increased in H. pylori-positive gastritis (n = 20). Increased iNOS and COX-2 levels were confirmed by Northern and Western blot analysis and were both greater in the gastric antrum than in the gastric body of infected patients. Immunohistochemistry also showed increased expression of both genes in H. pylori gastritis: iNOS protein was detected in epithelium, endothelium, and lamina propria inflammatory cells, and COX-2 protein localized to mononuclear and fibroblast cells in the lamina propria. CONCLUSIONS: iNOS and COX-2 are induced in H. pylori-positive gastritis and thus may modulate the inflammation and alterations in epithelial cell growth that occur in this disease. Higher levels of iNOS and COX-2 in H. pylori-positive vs. -negative gastritis and in gastric antrum, where bacterial density is greatest, suggest that expression of these genes is a direct response to H. pylori infection.

Cyclooxygenase 2↗
PubMed1999

Granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in beta-thalassemia patients: kinetics of mobilization and composition of apheresis product.

beta-Thalassemias are often associated with bone marrow expansion and immunomodulation in terms of lymphocyte subsets and cytokine levels in the peripheral blood. The mobilization of peripheral blood stem cells (PBSC) by cytokines in such a background has not been reported. If achieved, the apheresis product could be used as a stem cell back-up for beta-thalassemia patients prior to bone marrow transplant. PBSC collection may also become a means for providing stem and progenitor cells for gene manipulation and therapy of this disorder. The aim of the study was to assess the administration of G-CSF in mobilizing stem and progenitor cells in these patients and to compare the kinetics of CD34+ cells and lymphocyte subsets with those of healthy PBSC donors. Results showed that the CD34+ cells were effectively mobilized by G-CSF (10-16 micrograms/day per kg) in 20 thalassemia patients and 11 healthy donors. Although no significant difference was observed in levels of daily stem cell counts between the two groups of subjects, a 1 day delay in achieving peak levels of CD34+ cells was observed in the majority of thalassemia patients. The peak increase of CD34+ cells was 21.5 +/- 6.1-fold and 30.8 +/- 7.6-fold of the basal steady-state levels in thalassemia patients and healthy donors, respectively. Similar to the situation of healthy donors, G-CSF stimulated essentially the CD34+ cells and the myeloid lineage (granulocytes, monocytes) in thalassemia patients and had a slight effect on lymphocyte subsets (T-helper, T-suppressor, NK, and B cells) and activation (CD25, HLA-DR, and CD45RO). Compositions of the apheresis products, including CD34+CD38-, CD34+CD33+ and CD34+HLA-DR- cells, were similar in the two groups of subjects. Correlation studies showed that the level of CD34+ cells in the PB is a good indicator of that in the apheresis product (r = 0.88, p < 0.001). The study has demonstrated that under close monitoring of CD34+ cell levels in PB, the mobilization by G-CSF and collection of PBSC in beta-thalassemia patients are feasible.

Adolescent↗
PubMed1999

Human neonatal blood: stem cell content, kinetics of CD34+ cell decline and ex vivo expansion capacity.

Haemopoietic stem cells are present in fetal blood but their levels decline rapidly in the peripheral circulation of the infant after birth. We previously reported a case of stem cell transplant in a beta-thalassaemia boy using a combination of the cord blood (CB) and neonatal blood (NB) of his sister. This transplant resulted in a successful engraftment. To investigate the possibility of using NB to supplement CB for related transplants, we further characterized stem and progenitor cells and lymphocyte subsets in 20 NB samples, comparing the findings with those in 20 CB samples. Our data showed that NB contained substantial levels of CD34+ cells, CD34+CD38- cells, colony-forming units-granulocyte macrophage (CFU-GM), colony forming units-erythroid (CFU-E), burst forming units-erythroid (BFU-E) and long-term culture initiating cells (LTCIC). NB was similar to CB in the levels of T lymphocytes, but the amounts of B lymphocytes and natural killer cells were higher in CB (P = 0.033, P= 0.001, respectively). The kinetics of CD34+ cells in NB was investigated in serial blood samples obtained from 10 full-term infants at 2, 4, 6, 8, 24 and 48h after birth. CD34+ cells decreased rapidly after birth, declining to only 30% of the 2h level at 48h (P<0012). The rate of decline was greatest in the first 4 h of life. NB from four infants was expanded by culturing the blood samples in the presence of thrombopoietin (Tpo), interleukin 1beta (IL1beta), IL-3, IL-6, flt-3 ligand and stem cell factor (SCF) for 7 d. This resulted in the increase of CD34+ cells, CFU-GM and CFU-MK by 271+/-179, 556+/-385 and 113+/-75 fold respectively. Three of the five samples expanded for 7 d contained LTCIC. These findings suggest that NB might be a supplementary or alternative source of stem cells to CB for transplant. The ethics and practicality of this approach deserve further exploration.

Antigens, CD34↗
PubMed1999

Malignant melanoma metastatic to a meningioma.

The case presented is that of a 63 year old man with a metastasis to an intracranial meningioma from a malignant melanoma. Although the phenomenon of tumor to tumor metastasis to a meningioma has been previously reported, this is the first case in the literature to date, in which the primary tumor is a malignant melanoma. The criteria for the diagnosis of tumor-to-tumor metastasis and possible reasons for the frequency of metastasis to meningiomas are briefly reviewed.

Aged↗
PubMed1999

Risk factors for falls in hospitalized older medical patients.

BACKGROUND: The incidence of falls among older hospitalized patients is higher than that of community-dwelling older persons. Prevention is important, but factors associated with these falls are less well studied than falls occurring in the community or nursing homes. METHODS: This study was conducted in an acute-care general hospital in Hong Kong. During November 1995 to March 1997, all older inpatients who fell during hospitalization were assessed by a geriatrician, a physiotherapist, and an occupational therapist. A standardized protocol to study the clinical and performance-oriented functional factors was employed. A sex- and age-matched hospital control was recruited for each case. In total, 51 cases and controls (mean ages 77.8 +/- 7.3 years and 77.5 +/- 7.0 years, respectively) were studied. RESULTS: Among the multiple clinical and functional risk factors for falls identified, lower limb weakness (i.e., power less than MRC grade 4 in one or both lower limbs) and poor tandem walk ability emerged as two significant predictive factors for falls in the hospital. The overall classification accuracy of fallers and nonfallers was 79%. The sensitivity was 84% and specificity was 75%. Clinical factors were the underlying causes for the lower limb weakness and poor tandem walk performance. CONCLUSIONS: Among clinical and functional risk factors for falls in the older medical patient, lower limb weakness and poor tandem walk ability were most predictive. Falls prevention programs in hospitals should employ these two tests as screening instruments.

Accidental Falls↗
PubMed1999

The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis.

Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies.

Apoptosis↗
PubMed1999

An unusual case of thoracic outlet syndrome associated with long distance running.

An amateur marathon runner presented with symptoms of thoracic outlet syndrome after long distance running. He complained of numbness on the C8 and T1 dermatome bilaterally. There were also symptoms of heaviness and discomfort of both upper limbs and shoulder girdles. These symptoms could be relieved temporarily by supporting both upper limbs on a rail or shrugging his shoulders. The symptoms and signs would subside spontaneously on resting. An exercise provocative test and instant relief manoeuvre, which are the main diagnostic tests for this unusual case of "dynamic" thoracic outlet syndrome, were introduced.

Adult↗
PubMed1999

Chronic ethanol exposure enhances signaling through muscarinic receptors expressed by cRNA injection in Xenopus oocytes: implications for mechanism of action.

The molecular mechanisms underlying the cerebral symptoms of ethanol withdrawal syndrome are poorly understood. In addition to ethanol's effect on GABA and NMDA receptors, ethanol affects muscarinic acetylcholine signaling. This interaction has attracted attention because of the importance of muscarinic signaling in consciousness. Chronic ethanol exposure increases muscarinic receptor binding. Increased transcription of receptor message has been suggested as the underlying mechanism, but this hypothesis has not been tested directly. Therefore, we studied the effects of ethanol on muscarinic signaling in a model that bypasses transcription of muscarinic receptor genes. We expressed rat m1 muscarinic receptors by cRNA microinjection in Xenopus oocytes. Cells were voltage-clamped at -70 mV and effects of prolonged (24, 48, and 72 hr) exposure to ethanol (25, 50, and 100 mM) on methylcholine-induced calcium-activated Cl- currents were determined. Effects of prolonged ethanol exposure on currents induced by stimulation of lysophosphatidate receptors, direct G protein activation, or inositol trisphosphate receptor activation were studied as well. Prolonged ethanol exposure enhanced methylcholine (or lysophosphatidate-)-induced currents in a time- and concentration-dependent manner. Thus, enhanced muscarinic gene transcription is not required for ethanol enhancement of muscarinic signaling. Lack of ethanol effect on inositol trisphosphate-induced signaling suggests that intracellular signaling systems downstream of phospholipase C are not involved. In contrast, currents induced by direct G protein stimulation were enhanced significantly. Therefore, one potential site of ethanol's action on muscarinic signaling is upregulation of the associated G protein or enhancement of its functioning.

Animals↗
PubMed1999

Myoid cell density in the thymus is reduced during mdx dystrophy and after muscle crush.

Thymic myoid cells share structural and behavioural features with cells of the skeletal muscle lineage: they express regulatory genes and contractile proteins, and they can form myofibers in culture. Historically, those features suggested that myoid cells could be precursors for muscle repair in addition to the satellite cells in muscle that are typically designated as the only muscle precursors. Muscles of the mutant mdx dystrophic mouse strain have a large demand for precursors, which is greatest at a young age. In the present study, immunostaining for troponin T was used to localize myoid cells. We tested the hypothesis that the myoid cell population changes when there is a demand for muscle precursors and that these changes would be anticipated if myoid cells have a role as myogenic precursors or stem cells in muscle. Chronic demands for muscle precursors in mdx dystrophic mice were accompanied by lower myoid cell density in comparison with density in two normal strains (C57BL10/ScSn and Swiss Webster). Acute demand for precursors was accompanied by a sharp decline in thymic myoid cell density within 2 days after a crush injury to one tibialis anterior muscle in normal but not dystrophic animals. To standardize the developmental age of the thymus, density was determined in all animals at 28 days of age. Given the current interest in nonmuscle sources of myogenic stem cells, these data suggest that changes in the density of thymic myoid cells may accompany acute and chronic demands for muscle precursors. Further experiments are required to determine whether thymic myoid cells are participants in distant muscle cell proliferation, new fiber formation, or the establishment of new stem cells in regenerated muscle.

Animals↗