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Biomedical subjects

M Y Wang

Publications and source records attributed to M Y Wang.

At least 55 records · Page 3Linked to original sources
PubMed1998

Evidence for the DNA binding and adduct formation of estrone and 17beta-estradiol after dimethyldioxirane activation.

Estrogens, used widely from hormone replacement therapy to cancer treatment, are themselves carcinogenic, causing uterine and breast cancers. However, the mechanism of their carcinogenic action is still not known. Recently, we found that estrone (E1) and 17beta-estradiol (E2) could be activated by the versatile epoxide-forming oxidant dimethyldioxirane (DMDO), resulting in the inhibition of rat liver nuclear and nucleolar RNA synthesis in a dose-dependent manner in vitro. Since epoxidation is often required for the activation of chemical carcinogens, we proposed that estrogen epoxidation is the underlying mechanism for the initiation of estrogen carcinogenesis (Carcinogenesis 17 (1996) 1957-1961). It is known that initiation requires the binding of a carcinogen to DNA with the formation of DNA adducts. One of the critical tests of our hypothesis is therefore to determine whether E1 and E2 after activation are able to bind DNA. This paper reports that after DMDO activation, [3H]E1 and [3H]E2 were able to bind to both A-T and G-C containing DNAs. Furthermore. the formation of E1-DNA and E2-DNA adducts was detected by 32P-postlabeling analysis.

Animals↗
PubMed1998

Arsenic species in drinking water, hair, fingernails, and urine of patients with blackfoot disease.

A large number of residents on the southwest coast of Taiwan suffer from an endemic peripheral vascular disease called blackfoot disease. Although the etiology has been investigated since 1958, the cause of blackfoot disease remains unknown. Certain substances contained in artesian well water have been implicated as causal factors, including arsenic as the predominant element. Data in this study demonstrated that in the well water collected from blackfoot disease regions of Taiwan there was a marked increase in total arsenic concentrations, with the predominant species being inorganic arsenical compounds. The concentrations of organic methyl arsenicals were present in minimal amounts. The excretion of total arsenic, inorganic arsenic, monomethylarsonic acid, and trimethylarsenic acid in the urine of patients afflicted with blackfoot disease was significantly higher than for control subjects. Further, in patients with blackfoot disease the concentrations of total arsenic and inorganic arsenic were markedly elevated in the hair and fingernails. Data suggest that blackfoot disease is associated with individuals ingesting well, water contaminated with arsenic primarily in the inorganic form and that hair, fingernails, or urine specimens serve as equally effective biomarkers of exposure. The fact that arsenic intoxication as manifested by blackfoot disease is still prevalent despite the stoppage of well-water consumption for two decades illustrates the persistent nature of arsenic action.

Aged↗
PubMed1998

OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype.

In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an approximately 50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length "b" isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats.

Animals↗
PubMed1998

The transcriptional effects and DNA-binding specificities of 17beta-estradiol after dimethyldioxirane activation.

It was found recently that 17beta-estradiol (E2) could be activated by the epoxide-forming oxidant dimethyldioxirane (DMDO) resulting in the inhibition of rat liver nuclear and nucleolar RNA synthesis in vitro (Carcinogenesis, 17, 1957-1961, 1996). To further study the mechanism of this inhibition, several synthetic DNAs with different base content and sequence were used to study the transcriptional effects and binding specificities of E2 after DMDO activation in vitro. The results show: (1) E2 after activation had a strong inhibitory effect on the template function of both A-T and G-C containing double-stranded DNAs, e.g. poly[d(A-T)], polydG x polydC and poly[d(I-C)], and only a weak inhibition on the single-stranded DNA template, polydC. The inhibition was dose-dependent, and only after DMDO activation. (2) 3H-labeled E2, after DMDO activation, was able to bind DNAs containing both A-T and G-C bases. The order of the binding preference was: calf thymus DNA > poly[d(A-T)] > poly[d(G-C)]. (3) The covalent binding nature of E2 to DNA after activation was further confirmed by 32P-post-labeling analysis using calf thymus DNA. (4) The absorption spectrum of E2 changed, after DMDO treatment, from a peak around 280-290 nm to 260-270 nm with a shoulder appearing around 300-320 nm. These studies have not only confirmed our earlier observation that E2, after DMDO activation, can inhibit DNA-dependent RNA synthesis, but also provided new insights into the DNA-binding properties after activation. Additionally, since epoxidation is often required for the activation of chemical carcinogens to bind DNA, these studies lend further support to our proposed hypothesis that E2 epoxidation may play an initiation role in estrogen carcinogenesis.

Animals↗
PubMed1998

Measurement of intraoperative brain surface deformation under a craniotomy.

OBJECTIVE: Several causes of spatial inaccuracies in image-guided surgery have been carefully studied and documented for several systems. These include error in identifying the external features used for registration, geometrical distortion in the preoperative images, and error in tracking the surgical instruments. Another potentially important source of error is brain deformation between the time of imaging and the time of surgery or during surgery. In this study, we measured the deformation of the dura and brain surfaces between the time of imaging and the start of surgical resection for 21 patients. METHODS: All patients underwent intraoperative functional mapping, allowing us to measure brain surface motion at two times that were separated by nearly an hour after opening the dura but before performing resection. The positions of the dura and brain surfaces were recorded and transformed to the coordinate space of a preoperative magnetic resonance image, using the Acustar surgical navigation system (manufactured by Johnson & Johnson Professional, Inc., Randolph, MA) (the Acustar trademark and associated intellectual property rights are now owned by Picker International, Highland Heights, OH). This system performs image registration with bone-implanted markers and tracks a surgical probe by optical triangulation. RESULTS: The mean displacements of the dura and the first and second brain surfaces were 1.2, 4.4, and 5.6 mm, respectively, with corresponding mean volume reductions under the craniotomy of 6, 22, and 29 cc. The maximum displacement was greater than 10 mm in approximately one-third of the patients for the first brain surface measurement and one-half of the patients for the second. In all cases, the direction of brain shift corresponded to a "sinking" of the brain intraoperatively, compared with its preoperative position. Analysis of the measurement error revealed that its magnitude was approximately 1 to 2 mm. We observed two different patterns of the brain surface deformation field, depending on the inclination of the craniotomy with respect to gravity. Separate measurements of brain deformation within the closed cranium caused by changes in patient head orientation with respect to gravity suggested that less than 1 mm of the brain shift recorded intraoperatively could have resulted from the change in patient orientation between the time of imaging and the time of surgery. CONCLUSION: These results suggest that intraoperative brain deformation is an important source of error that needs to be considered when using surgical navigation systems.

Adult↗
PubMed1997

Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation.

We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the genes encoding enzymes of free fatty acid metabolism and uncoupling protein-2 (UCP-2). In animals infused with a recombinant adenovirus containing the leptin cDNA, the levels of mRNAs encoding enzymes of mitochondrial and peroxisomal oxidation rose 2- to 3-fold, whereas mRNA encoding an enzyme of esterification declined in islets from hyperleptinemic rats. Islet UCP-2 mRNA rose 6-fold. All in vivo changes occurred in vitro in normal islets cultured with recombinant leptin, indicating direct extraneural effects. Leptin overexpression increased UCP-2 mRNA by more than 10-fold in epididymal, retroperitoneal, and subcutaneous fat tissue of normal, but not of leptin-receptor-defective obese rats. By directly regulating the expression of enzymes of free fatty acid metabolism and of UCP-2, leptin controls intracellular triglyceride content of certain nonadipocytes, as well as adipocytes.

Adipocytes↗
PubMed1997

Direct antidiabetic effect of leptin through triglyceride depletion of tissues.

Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was approximately 20 times normal, and esterification capacity was increased 3- to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an "indirect pathway" of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.

3-Hydroxybutyric Acid↗
PubMed1997

Cytochrome P450 metabolism of estradiol in hamster liver and kidney.

Estradiol induces kidney tumors in Syrian hamsters. The elevated conversion of estradiol to 4-hydroxylated metabolites in kidney compared to the predominant 2-hydroxylation in liver and other organs, where tumors are not induced by this treatment, has been proposed to be the basis of estrogen-induced carcinogenesis. In this study, we examined the hepatic and renal enzymes catalyzing the formation of catecholestrogens to understand the differences in estrogen metabolism in these organs. In liver, 2-hydroxylation of estradiol is the major metabolic pathway with 4-hydroxylation a minor by-product and with the formation of both catechols responding coordinately to the same inhibitors. Western blot analysis and inhibition studies suggest that the major form catalyzing hepatic estrogen 2-hydroxylation is a member of the CYP3A family, as previously observed with rat liver microsomes, and that 4-hydroxylation is a by-product of this metabolism. In the kidney, 4-hydroxylation of estradiol appears to be catalyzed by more than one enzyme according to the Eadie-Hofstee analysis. Both 2- and 4-hydroxylation in the kidney are affected differentially by inhibitors and are induced by beta-napthoflavone. Western blots of renal microsomes reveal that CYP1A2 is induced whereas CYP1A1 is detectable in kidney, but not induced by this treatment. Finally, a part of the 2-hydroxylation and a small part of the 4-hydroxylation by kidney microsomes may be catalyzed by a member of the CYP3A family, since these reactions are partially inhibited by CYP3A inhibitors such as progesterone and other progestins, although renal enzyme levels are much lower than those in the liver as revealed by Western blot. Our data suggest that estrogen 2-hydroxylation in the hamster kidney is catalyzed by members of the CYP1A and CYP3A families, which also contribute to 4-hydroxylation. The majority of 4-hydroxyestradiol formation in the hamster kidney may be catalyzed by a form(s) of the newly discovered CYP1B family that has yet to be characterized.

Animals↗
PubMed1997

Mast cell-dependent tumor necrosis factor alpha production participates in allergic gastric inflammation in mice.

BACKGROUND & AIMS: Immunoglobulin E-dependent gastric inflammation is characterized by neutrophil infiltration, and mast cells are required for this response. The aim of this study was to examine whether mast cell production of tumor necrosis factor (TNF)-alpha participates in the recruitment of neutrophils during this response. METHODS: The levels of TNF-alpha messenger RNA (mRNA) and protein in gastric tissues were assessed by Northern blot analysis and enzyme-linked immunosorbent assay. In situ hybridization and histochemical staining were performed to identify the cells expressing TNF-alpha transcripts. Anti-TNF-alpha antibodies or cyclosporine A were used in an attempt to inhibit neutrophil infiltration. RESULTS: TNF-alpha mRNA and protein were increased in gastric tissues undergoing immunoglobulin E-dependent inflammation. Mast cells were required for the development of cells expressing TNF-alpha transcripts in the stomach. Seventy-nine percent of the cells in the mucosa and 100% of the cells in the submucosa expressing TNF-alpha mRNA were identified as mast cells. Anti-TNF-alpha antibodies inhibited neutrophil infiltration in the submucosa, and cyclosporine A inhibited the tissue expression of TNF-alpha mRNA and the influx of neutrophils into the submucosa and muscularis propria. CONCLUSIONS: These findings show that mast cell-derived TNF-alpha is at least one of the mediators involved in the recruitment of neutrophils during immunoglobulin E-dependent gastric inflammation in the mouse.

Animals↗
PubMed1997

Registration of head volume images using implantable fiducial markers.

In this paper, we describe an extrinsic-point-based, interactive image-guided neurosurgical system designed at Vanderbilt University, Nashville, TN, as part of a collaborative effort among the Departments of Neurological Surgery, Computer Science, and Biomedical Engineering. Multimodal image-to-image (II) and image-to-physical (IP) registration is accomplished using implantable markers. Physical space tracking is accomplished with optical triangulation. We investigate the theoretical accuracy of point-based registration using numerical simulations, the experimental accuracy of our system using data obtained with a phantom, and the clinical accuracy of our system using data acquired in a prospective clinical trial by six neurosurgeons at four medical centers from 158 patients undergoing craniotomies to resect cerebral lesions. We can determine the position of our markers with an error of approximately 0.4 mm in X-ray computed tomography (CT) and magnetic resonance (MR) images and 0.3 mm in physical space. The theoretical registration error using four such markers distributed around the head in a configuration that is clinically practical is approximately 0.5-0.6 mm. The mean CT-physical registration error for the phantom experiments is 0.5 mm and for the clinical data obtained with rigid head fixation during scanning is 0.7 mm. The mean CT-MR registration error for the clinical data obtained without rigid head fixation during scanning is 1.4 mm, which is the highest mean error that we observed. These theoretical and experimental findings indicate that this system is an accurate navigational aid that can provide real-time feedback to the surgeon about anatomical structures encountered in the surgical field.

Brain Diseases↗
PubMed1997

beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy.

Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12-24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat disappeared within 7 days. Plasma insulin fell to <50% of normal in association with hypoglycemia, suggesting enhanced insulin sensitivity. Although beta-cells appeared histologically normal, the pancreases were unresponsive to perfusion with stimulatory levels of glucose and arginine. Since islet triglyceride content was 0, compared with 14 ng/islet in pair-fed control rats, we coperfused a 2:1 oleate:palmitate mixture (0.5 mmol/l). This restored insulin responses to supranormal levels. When normal islets were cultured with 20 ng/ml of leptin, they too became triglyceride-depleted and failed to respond when perifused with glucose or arginine. Perifusion of fatty acids restored both responses. We conclude that in normal rats, hyperleptinemia for 2 weeks causes reversible beta-cell dysfunction by depleting tissue lipids, thereby depriving beta-cells of a lipid-derived signal required for the insulin response to other fuels.

Adenoviridae↗
PubMed1997

[Characteristics of synaptic responses of motoneurons to ventrolateral funiculus stimulation in vitro].

By using the intracellular recording techniques, the electrophysiological characteristics of fast excitatory postsynaptic potentials (EPSP) evoked by ventrolateral funiculus (VLF) stimulation were analyzed in neonate rat motoneurons (MN) of spinal cord slices. The incidences of VLF-EPSPs was 80% (n = 28), among which 2 is preceded by inhibitory postsynaptic potential and 6 followed by slow EPSPs. Considering the distribution skewness of VLF-EPSP latency histogram, it was suggested that short- and long-latency EPSPs correspond respectively to mono- and poly-synaptic transmission respectively. The possible neurotransmitters mediating VLF-EPSPs were excitatory amino acids and non-NMDA receptors were critically involved in these synaptic transmissions, for both VLF-EPSP and glutamate-induced response were similarly and almost completely abolished by kynurenic acid and DNQX. Typical spatial summation of VLF-EPSPs and EPSPs evoked by ventral root stimulation were observed in the same recorded MNs. Most importantly, VLF-EPSPs were found to increase with hyperpolarizing and decreased with depolarizing the membrane, indicating that the descending fibers in the VLF may terminate on the soma or proximal dendrites of MNs, while the EPSPs evoked by the dorsal or ventral root stimulation were insensitive to membrane potential changes, indicating that the primary sensory afferents in the dorsal and ventral roots may contact the distal dendrites of the MNs. The results imply that the commanding signals conducting along the descending fibers in the VLF may directly modulate the MN's activities, whereas messages from the periphery may cause fine changes of the membrane potential subject to integration of the MNs.

Animals↗
PubMed1996

A novel leptin receptor isoform in rat.

Five mouse and human leptin receptors (Ob-R) have recently been identified, a long isoform (Ob-Rb), preferentially expressed in hypothalamus, and 4 short isoforms, Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re. We have identified a new short isoform in the rat, r-OB-Rf, with 6 C-terminal amino acids and a 3' untranslated region without homology to other Ob-R isoforms. Its higher expression in rat liver and spleen compared to brain, stomach, kidney, thymus, heart, lung and hypothalamus, contrasts with Ob-Ra and Ob-Rb homologues and raises possibilities of as yet unidentified roles for members of the growing Ob-R gene family.

Amino Acid Sequence↗
PubMed1996

Purging of tumor cells from leukapheresis products: experimental and clinical aspects.

Peripheral blood progenitor cell autografts are being used increasingly in conjunction with high-dose therapy of cancer patients, in the belief that these products have a low probability of containing tumor cells. However, recent findings demonstrate that tumor cell involvement is frequent in leukapheresis products. Although the clinical value of purging has not been clinically established by prospective randomized trials, several studies indicate that contaminating tumor cells in autografts contribute to relapse of the disease in the recipients. We describe our experimental and clinical experience in purging tumor cells from leukapheresis products. Based on our work with purging of lymphoma cells from bone marrow by the use of anti-B cell and anti-T cell antibodies and immunobeads, a purging procedure to deplete leukapheresis products of lymphoma cells has been developed. Moreover, we present data showing that breast cancer cells can be efficiently removed from leukapheresis products using antibreast cancer antibodies, either in combination with immunobeads or as immunotoxins. Our experience with enrichment of CD34 cells employing immunobeads in leukaphresis products from patients with breast cancer and lymphomas shows high purity and yield of CD34 cells. In spite of this, contaminating tumor cells can be observed, strongly suggesting that a combination of CD34 cell enrichment and a purging procedure might be warranted.

Antibodies, Monoclonal↗
PubMed1996

An automatic technique for finding and localizing externally attached markers in CT and MR volume images of the head.

An image processing technique is presented for finding and localizing the centroids of cylindrical markers externally attached to the human head in computed tomography (CT) and magnetic resonance (MR) image volumes. The centroids can be used as control points for image registration. The technique, which is fast, automatic, and knowledge-based, has two major steps. First, it searches the entire image volume to find one voxel inside each marker-like object. We call this voxel a "candidate" voxel, and we call the object a candidate marker. Second, it classifies the voxels in a region surrounding the candidate voxel as marker or nonmarker voxels using knowledge-based rules and calculates an intensity-weighted centroid for each true marker. We call this final centroid the "fiducial" point of the marker. The technique was developed on 42 scans of six patients-one CT and six MR scans per patient. There are four markers attached to each patient for a total of 168 marker images. For the CT images the false marker rate was zero. For MR the false marker rate was 1.4% (Two out of 144 markers). To evaluate the accuracy of the fiducial points, CT-MR registration was performed after correcting the MR images for geometrical distortion. The fiducial registration accuracy averaged 0.4 mm and was better than 0.6 mm for each of the eighteen image pairs.

Algorithms↗
PubMed1996

Leucocyte depletion filter removes cancer cells in human blood.

BACKGROUND: Autologous blood transfusion has been avoided in cancer surgery because of the metastatic potential of reinfused tumour cells. METHODS: This study evaluated the efficacy of a blood transfusion filter in removing tumour cells from blood. Whole human blood was admixed with two different malignant cell lines (breast cancer PM1 and MCF7). The blood was filtered through a RC400TE leucocyte depletion filter. Unfiltered blood was used as a control. Detection of malignant cells was performed with immunomagnetic beads and clonogenic assays. RESULTS: No viable tumour cells were found after filtration with the leucocyte depletion filter. CONCLUSION: These findings suggest that the use of a leucocyte filter after intra-operative blood salvage may make autotransfusion safe even in tumour surgery.

Blood Transfusion, Autologous↗