Biomedical subjects

Stephen Wong

Publications and source records attributed to Stephen Wong.

16 recordsLinked to original sources

PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗

PubMed2007

A direct effect of aldosterone on endothelin-1 gene expression in vivo.

Aldosterone regulates sodium reabsorption in epithelial tissues such as the kidney and colon, via a pathway involving the activation of intracellular mineralocorticoid receptors (MR), induction of specific target genes, and a subsequent increase in sodium channel activity. Characterized aldosterone target genes in epithelia include the serum and glucocorticoid-regulated kinase 1 and the corticosteroid hormone-induced factor. Endothelin-1 (ET-1) is a potent vasoconstrictor that alters both sodium transport and hydrogen ion secretion in the kidney. Recent studies in a mouse medullary collecting duct cell line and rat A-10 smooth muscle cells have demonstrated an acute response of ET-1 gene expression to aldosterone. In the present study, we have investigated the ET-1 gene in vivo as a potential direct aldosterone-regulated target gene in the kidney and colon. Adrenalectomized rats given a single dose of aldosterone were found to have a 2-fold increase in ET-1 mRNA levels in the kidney and colon after 1 h. No significant changes in mRNA levels were detected for the related isoforms ET-2 or ET-3. Cotreatment with aldosterone and potassium canrenoate, a MR antagonist, blocked induction of ET-1 mRNA, suggesting that induction was mediated via the MR. In a time course study, ET-1 mRNA levels were induced rapidly by aldosterone, with levels of ET-1 mRNA maximally increased 2- and 2.5-fold after 1 h in the kidney and colon, respectively. These results suggest that ET-1 is a direct aldosterone gene target in the kidney and colon and may play an important role in aldosterone-regulated ion homeostasis.

Aldosterone↗

PubMed2006

A genotype-independent real-time PCR assay for quantification of hepatitis B virus DNA.

Accurate quantification of hepatitis B virus (HBV) DNA levels is important for monitoring patients with chronic HBV infection and for assessing their responses to antiviral therapy. This study aimed to develop a real-time PCR assay that is sensitive and can accurately quantify a wide range of HBV DNA levels across the known HBV genotypes. An "in-house" real-time PCR assay using primers and a TaqMan probe in a highly conserved region of the HBV surface gene was designed. The assay was standardized against a WHO standard and validated against plasmids of HBV genotypes A through H. The linear quantification range was approximately 5 x 10(0) to 2.0 x 10(9) IU/ml. Results of samples from patients infected with HBV genotypes A through H tested using our real-time "in-house" PCR assay showed an excellent correlation with those of the Cobas Amplicor HBV Monitor (R2=0.9435) and the Cobas TaqMan HBV (R2=0.9873) tests. We have established a real-time PCR assay that is genotype independent and can accurately quantify a wide range of HBV DNA levels. Further studies of additional samples are ongoing to validate the genotype independence of our assay.

DNA Primers↗

PubMed2006

A stochastic framework for evaluating seizure prediction algorithms using hidden Markov models.

Responsive, implantable stimulation devices to treat epilepsy are now in clinical trials. New evidence suggests that these devices may be more effective when they deliver therapy before seizure onset. Despite years of effort, prospective seizure prediction, which could improve device performance, remains elusive. In large part, this is explained by lack of agreement on a statistical framework for modeling seizure generation and a method for validating algorithm performance. We present a novel stochastic framework based on a three-state hidden Markov model (HMM) (representing interictal, preictal, and seizure states) with the feature that periods of increased seizure probability can transition back to the interictal state. This notion reflects clinical experience and may enhance interpretation of published seizure prediction studies. Our model accommodates clipped EEG segments and formalizes intuitive notions regarding statistical validation. We derive equations for type I and type II errors as a function of the number of seizures, duration of interictal data, and prediction horizon length and we demonstrate the model's utility with a novel seizure detection algorithm that appeared to predicted seizure onset. We propose this framework as a vital tool for designing and validating prediction algorithms and for facilitating collaborative research in this area.

Algorithms↗

PubMed2006

Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis.

Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.

Animals↗

PubMed2006

Treatment outcomes in a centralized specialty clinic for hepatitis C virus are comparable with those from clinical trials.

BACKGROUND: Outcomes from industry-sponsored registration trials are often considered to be more favourable than those achieved in clinical practice because patients involved in the former are highly selected and supported, but it is not known if this impression is valid. OBJECTIVE: To determine the outcome of hepatitis C virus (HCV)-infected patients who received therapies for chronic HCV in a single urban centre and compare the results with those derived from contemporary, industry-sponsored trials. DESIGN: Retrospective chart review of HCV-infected patients referred to the Viral Hepatitis Investigative Unit in Winnipeg, Manitoba, between 1998 and 2003. METHODS: The Viral Hepatitis Investigative Unit database was used to identify all referred patients with positive anti-HCV antibodies. Charts were reviewed for the following data: patient demographics; viral genotype; indications and contraindications to treatment; treatment type; and outcome of antiviral therapy. RESULTS: For 1800 anti-HCV positive patients identified, 1078 charts were available for review. Of these patients, the mean age was 47 years (range 11 years to 90 years) and 53% were men. Genotype 1 was the most common (65%). A total of 331 patients (31%) had received antiviral therapy. The sustained viral responses were similar to those described in industry-sponsored registration trials. Specifically, the sustained viral responses for interferon-alpha monotherapy (n=81) was 22.2%, interferon-alpha plus ribavirin (n=180) 44.4%, pegylated interferon monotherapy (n=38) 44.7% and pegylated interferon plus ribavirin (n=24) 54.2%. CONCLUSION: HCV treatment outcomes from a single urban centre were similar to those described in industry-sponsored registration trials despite the high selection and support provided to patients enrolled in the latter studies.

Adolescent↗

PubMed2005

Multiple roles for the receptor tyrosine kinase axl in tumor formation.

A focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Axl as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA-mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that Axl is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Axl knockdown, we show that Axl is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Axl is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Disruption of Axl signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development.

Animals↗

PubMed2005

Phytotoxicity of nitroaromatic energetic compounds freshly amended or weathered and aged in sandy loam soil.

The toxicities of 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), 2,4-dinitrotoluene (2,4-DNT), and 2,6-dinitrotoluene (2,6-DNT) to terrestrial plants alfalfa (Medicago sativa L.), Japanese millet (Echinochloa crusgalli L.), and perennial ryegrass (Lolium perenne L.) were determined in Sassafras sandy loam soil using seedling emergence, fresh shoot, and dry mass measurement endpoints. A 13-week weathering and aging of energetic materials in soils, which included wetting and drying cycles, and exposure to sunlight of individual soil treatments, was incorporated into the study design to better reflect the soil exposure conditions in the field than toxicity determinations in freshly amended soils. Definitive toxicity tests showed that dinitrotoluenes were more phytotoxic for all plant species in freshly amended treatments based on EC20 values for dry shoot ranging from 3 to 24mgkg(-1) compared with values for TNB or TNT ranging from 43 to 62mgkg(-1). Weathering and aging of energetic materials (EMs) in soil significantly decreased the toxicity of TNT, TNB or 2,6-DNT to Japanese millet or ryegrass based on seedling emergence, but significantly increased the toxicity of all four EMs to all three plant species based on shoot growth. Exposure of the three plant species to relatively low concentrations of the four compounds initially stimulated plant growth before the onset of inhibition at greater concentrations (hormesis).

Benzene Derivatives↗

PubMed2004

In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors.

We have previously reported structure-based design of memapsin 2 (beta-secretase) inhibitors with high potency. Here we show that two such inhibitors covalently linked to a "carrier peptide" penetrated the plasma membrane in cultured cells and inhibited the production of beta-amyloid (Abeta). Intraperitoneal injection of the conjugated inhibitors in transgenic Alzheimer's mice (Tg2576) resulted in a significant decrease of Abeta level in the plasma and brain. These observations verified that memapsin 2 is a therapeutic target for Abeta reduction and also establish that transgenic mice are suitable in vivo models for the study of memapsin 2 inhibition.

Alzheimer Disease↗

PubMed2004

Role of cytokines in regulating feeding behaviour.

Immune activation occurs in response to noxious stimuli such tissue injury, infection, inflammation and malignant neoplasia with the production of cytokines both in the circulation and the central nervous system (CNS). In addition to their fundamental immune functions, cytokines such as the interleukins (ILs), interferons (IFNs) and tumour necrosis factor-alpha also elicit significant pathophysiological effects on feeding behaviour and play prominent roles in the anorexia and cachexia syndrome often seen in chronic disease states. There is now compelling evidence that demonstrates that an important site of cytokine bioactivity is located within the hypothalamus where they appear to modulate appetite and energy homeostasis. Hypercytokinaemia has also been observed in the obese state where it has been proposed that they may play pivotal roles in mediating the detrimental components of the metabolic syndrome including insulin resistance, impaired glucose tolerance, hypertension. dyslipidaemia and increased cardiovascular risk. This review summarises these putative roles of various cytokines in the regulation of feeding in the setting of anorexia-cachexia and obesity.

Animals↗

PubMed2004

In vitro comparison of Essiac and Flor-Essence on human tumor cell lines.

Essiac (ES) and Flor-Essence (FE) are two herbal teas widely taken by North American cancer patients during chemo- and radiation therapy. In vitro studies on the antiproliferative and differentiation inducing activities of these teas were performed. ES and FE showed negligible antiproliferative activity on Jurkat leukemia cells. Both herbal teas inhibited 50% (IC50) of MCF7 breast cancer cell growth at 1/10 dilution. The IC50 was about 1/40 and 1/10 dilution of FE and ES respectively for MDA-MB-468 human breast cancer cells. The IC50 for HL60 cells was at 1/10 dilution of FE and less than 1/10 dilution of ES. ES at 1/10 dilution induced expression of non-specific esterase in 16% of HL60 cells, compared to about 5% in FE treated cells and untreated controls. ES treatment of HL60 cells induced 47-67% nitroblue tetrazolium positive staining cells compared to 24.6+/-3.1% in cells treated with 1/10 dilution of FE. Flow cytometry analysis showed that both ES and FE treatment between 1/10 and 1/100 dilutions only slightly affected the cell cycle progression of MCF7, MDA-MB-468, Jurkat and HL60 cells. Our data show that both ES and FE herbal teas demonstrated antiproliferative and differentiation inducing properties in vitro only at high concentrations. Further research is needed to elucidate the in vivo activities.

Anticarcinogenic Agents↗

PubMed2003

Distinguishing ischemic stroke from the stroke-like lesions of MELAS using apparent diffusion coefficient mapping.

We report two patients with migraine, acute visual field defects and other neurological symptoms who were found to have high T(2) signal and FLAIR abnormalities on brain MRI in temporal and parieto-occipital regions. In these patients, the apparent diffusion coefficient (ADC) of their lesions was increased, distinguishing these lesions from those of ischemic stroke. Both were ultimately diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We conclude that conventional MRI when used with diffusion-weighted MR imaging may be invaluable in detecting mitochondrial-related CNS dysfunction.

Adult↗

PubMed2003

An XML message broker framework for exchange and integration of microarray data.

MOTIVATION: Microarrays are an important research tool for the advancement of basic biological sciences. However this technology has yet to be integrated with clinical decision making. We have implemented an information framework based on the Microarray Gene Expression Markup Language (MAGE-ML) specification. We are using this framework to develop a test-bed integrated database application to identify genomic and imaging markers for diagnosis of breast cancer. RESULTS: We developed extensible software architecture for retrieving data from different microarray databases using MAGE-ML and for combining microarray data with breast cancer image analysis and clinical data for correlation studies. The framework we developed will provide the necessary data integration to move microarray research from basic biological sciences to clinical applications. AVAILABILITY: Open source software will be available from SourceForge (http://sourceforge.net/projects/microsoap/).

Database Management Systems↗

PubMed2002

The effect of myopic axial elongation and posture on the pulsatile ocular blood flow in young normal subjects.

PURPOSE: This study investigated the effect of myopic axial elongation on pulsatile ocular blood flow (POBF) in young normal subjects. A regression equation was derived to quantify the effect. The effect of posture in POBF for eyes with different axial lengths was studied to determine if axial myopia, with different ocular volumes, would result in a change in POBF with various postures. METHODS: Seventy-nine normal subjects (38 males and 41 females) with different refractive errors were recruited. The mean age of the subjects was 22 years, and only the right eye was used for analysis. The axial length (AL) was measured, followed by Perkins intraocular pressure (IOP) and POBF with an OBF tonometer (OBF Labs [UK] Ltd) in a sitting posture. An "erected arm" blood pressure (BP) was measured with an automatic sphygmomanometer for the calculation of ocular perfusion pressure (OPP), using the formula: mean BP IOP, where the mean BP was calculated as one third of the systolic blood pressure plus two thirds of the diastolic blood pressure. The measurements of IOP, POBF, and BP were repeated in a supine posture. RESULTS: The POBF was negatively correlated with AL (r = -0.57, p < 0.01). The regression line was in the form of POBF (microl/min) = -78.5 x AL (mm) + 2655.7. There was a significant reduction (17%) in POBF in a supine posture (p < 0.01). The reduction was not significantly correlated with AL. The pulse amplitude also demonstrated a 10% reduction from postural variation (p < 0.01). The OPP increased significantly (33%) in the supine posture (p < 0.01). CONCLUSIONS: The POBF was significantly influenced by AL. Therefore, AL should be measured in determining the POBF, especially in young myopic subjects. The amount of postural variation in POBF was similar to previous studies with young subjects and was not affected by AL.

Adult↗

PubMed2001

Daytime variation of pulsatile ocular blood flow (POBF) in normal Chinese.

BACKGROUND: Pulsatile ocular blood flow (POBF) measurement is a new parameter to aid the understanding of the aetiology of low-tension glaucoma. There has been one study reporting the diurnal variation of POBF. However, that study involved eight subjects only. This study investigated the daytime variation of POBF with a greater sample size. METHODS: Twenty-four young Chinese subjects (12 males and 12 females) were recruited. The mean age of our subjects was 23.6 years and only the right eye was analysed. All the subjects were screened for glaucoma and the POBF was measured at three-hourly intervals from 9:00 am to 9:00 pm with an OBF tonometer (OBF Labs, UK, Ltd). The Goldmann intraocular pressure (IOP) and 'erect arm' systemic blood pressure (BP) were also measured. RESULTS: The IOP was found to be higher in the daytime, reaching the highest at noon (mean of 14.29 mmHg) and gradually reduced to the lowest at 9:00 pm (mean of 12.99 mmHg). The change was marginally significant (repeated measures ANOVA, P = 0.05). The POBF demonstrated a trend to increase from 9:00 am, mean of 605.5 &mgr;l/min, to 9:00 pm, 720.1 &mgr;l/min (repeated measures ANOVA, P < 0.01). Student-Newman-Keuls post hoc test indicated that the difference was mainly due to the comparisons between the 9:00 am and 9:00 pm results and the 9:00 am and 6:00 pm results. The pulse amplitude did not vary significantly. The mean blood pressure also demonstrated a significant variation (repeated measures ANOVA, P < 0.01). In the analysis of covariance, no significant effects of mean blood pressure on POBF and pulse amplitude were revealed. CONCLUSIONS: The variation in POBF was due to factors other than systemic blood pressure. Practitioners should consider POBF variation in repeated measurements, for example when monitoring the medical treatment for glaucoma. Further study on POBF variation is required over a complete circadian cycle.

Journal Article↗

PubMedDate not supplied

Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high sensitivity and specificity for diagnosis.

BACKGROUND AND PURPOSE: Abnormalities on diffusion-weighted images (DWIs) and fluid-attenuated inversion recovery (FLAIR) images are reported in Creutzfeldt-Jakob disease (CJD). To our knowledge, no large study has been conducted to determine the sensitivity and specificity of DWI and FLAIR imaging for diagnosing CJD. METHODS: Two neuroradiologists, blinded to diagnosis, retrospectively evaluated DWI and FLAIR images from 40 patients with probable or definite CJD and 53 control subjects with other forms of dementia and rated the likelihood of CJD on the basis of the imaging findings. RESULTS: DWI and FLAIR imaging was 91% sensitive, 95% specific, and 94% accurate for CJD. Interrater reliability was high (kappa = 0.93). Sensitivity was higher for DWI than FLAIR imaging. Abnormalities involved cortex and deep gray matter (striatum and/or thalamus) in 68% of patients with CJD, cortex alone in 24%, and deep gray matter alone in 5%. The most typical and specific patterns were corresponding hyperintensity on both FLAIR images and DWIs confined to the gray matter in the cortex, striatum, medial and/or posterior thalamus, or a combination of these areas. Narrow-window soft-copy review of artifact-free DWIs and FLAIR images and recognition of the normal variation in cortical signal intensity proved critical for successful differentiation of CJD from other dementias. CONCLUSION: Because specific patterns of abnormality on DWI and FLAIR images are highly sensitive and specific for CJD, these sequences should be performed whenever CJD is suspected.

Adult↗