Biomedical subjects

Michael Wang

Publications and source records attributed to Michael Wang.

29 records · Page 2Linked to original sources

PubMed2003

Involvement of SSAO-mediated deamination in adipose glucose transport and weight gain in obese diabetic KKAy mice.

Semicarbazide-sensitive amine oxidase (SSAO) is located on outer surfaces of adipocytes and endothelial and vascular smooth muscle cells. This enzyme catalyzes deamination of methylamine and aminoacetone, leading to production of toxic formaldehyde and methylglyoxal, respectively, as well as hydrogen peroxide and ammonium. Several lines of evidence suggest that increased SSAO activity is related to chronic inflammation and vascular disorders related to diabetic complications. We found that a highly potent and selective SSAO inhibitor, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (FPFA), was capable of reducing numbers of atherosclerotic lesions as well as weight gain in obese KKAy mice fed an atherogenic diet. SSAO inhibitors cause a moderate and long-lasting hyperglycemia. Such an increase in serum glucose is a result of reduction of glucose uptake by adipocytes. SSAO-mediated deamination of endogenous methylamine substrates induces adipocyte glucose uptake and lipogenesis. Highly selective SSAO inhibitors can effectively block induced glucose uptake. The results suggest that increased SSAO-mediated deamination may be concomitantly related to obesity and vascular disorders associated with type 2 diabetes.

Adipocytes↗

PubMed2003

Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa.

Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.

Aminobutyrates↗

PubMed2003

Manganese superoxide dismutase induction during measles virus infection.

Measles virus infection of B-cells results in marked alterations in proliferation and immunoglobulin production. Very little is known about the changes of gene expression, if any, during acute measles virus infection. To elucidate cellular genes that are induced during measles virus infection, we carried out a subtraction technique, representational differential analysis. The mitochondrial protein, manganese superoxide dismutase (MnSOD), was upregulated in B-cells during measles virus infection. Although measles virus-infected B-cells did not secrete MnSOD into the environment, it was found, using an MnSOD mimetic, that intracellular MnSOD did inhibit proliferation of the B-cells. MnSOD also decreases the titer of virus produced from infected cells. Therefore, MnSOD seems to play a role in the alteration of immune function seen upon infection of B-cells with measles virus.

B-Lymphocytes↗

PubMed2003

Thalidomide with or without dexamethasone for refractory or relapsing multiple myeloma.

Both thalidomide and intermittent high-dose dexamethasone are agents with established activity against multiple myeloma. We summarized our experience with thalidomide alone, and then in combination with dexamethasone, for groups of patients with myeloma resistant or relapsing despite standard treatments. Criteria of response were based on greater than 50% reduction of serum myeloma protein and/or greater than 75% reduction of Bence Jones protein for patients treated with thalidomide alone and greater than 75% reduction of serum myeloma protein and/or greater than 90% reduction of Bence Jones protein for those who received thalidomide with dexamethasone. Among patients with resistant or relapsing disease treated with a combination of thalidomide and dexamethasone, 47% of patients achieved remission with significant prolongation of survival for responsive patients. Among patients in stable partial remission after intensive therapy who received the same program, myeloma protein was reduced further by greater than 90% in 52% of patients who had not received prior thalidomide/dexamethasone. Side effects were frequent, mild and reversible, and often preventable. Our program of thalidomide/dexamethasone was a safe and effective combination for patients with resistant or relapsing disease, or as consolidation of partial remission after intensive therapy.

Adjuvants, Immunologic↗

PubMed2003

Modulation of immune system function by measles virus infection. II. Infection of B cells leads to the production of a soluble factor that arrests uninfected B cells in G0/G1.

Measles can result in a variety of immunologic defects. Previously we showed that an Epstein-Barr virus-transformed B cell line (B cells), when infected with measles virus, produced a soluble antiproliferative factor that inhibited proliferation of T and B cells. Here we explore the effects of infection by measles virus versus the virus-free soluble antiproliferative factor on B cells. The B cells showed no change in the amounts of interleukin (IL)-2, 10, 12, interferon (IFN)-gamma, or transforming growth factor (TGF)-beta when infected or exposed to the soluble factor. Similarly, B cells showed no change in the expression of class II major histocompatibility antigens, LFA-1, ICAM-1, CD19, CD40, CD80, CD86, CD95 (Fas), or CD178 (FasL). Cell cycle analysis showed that measles virus infection caused an accumulation of cells in S and G(2)/M phases with a "sub-G(1)" cell population, while incubation of cells with the soluble factor caused an accumulation in G(0)/G(1). These experiments provide evidence that measles virus causes a profound inhibition of B cell proliferation without distinguishable changes in cytokine profile or cell surface phenotype. Further, it appears that there are two populations of cells affected by infection: one population is growth arrested due to the influence of the immunosuppressive factor and is not infected; a second population that is infected progresses through S phase less efficiently. Alternatively, while both the soluble factor and live virus infection may affect cells in G(0)/G(1) phases, only live virus infection could selectively induce apoptosis of G(0)/G(1) cells, resulting in cell accumulation in S and G(2)/M phases with a build up of "sub-G(1)" cells.

B-Lymphocytes↗

PubMed2003

Low-dose tissue plasminogen activator thrombolysis in children.

PURPOSE: To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. METHODS: Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1-0.5 mg/kg per hour). With experience, a low-dose regimen (0.01-0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. RESULTS: Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. CONCLUSIONS: TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.

Adolescent↗

PubMed2003

Microsurgical keyhole approach for middle fossa arachnoid cyst fenestration.

OBJECTIVE: The optimal surgical treatment for symptomatic temporal arachnoid cysts is controversial. Therapeutic options include cyst shunting, endoscopic fenestration, and craniotomy for fenestration. We reviewed the results for patients who were treated primarily with craniotomy and fenestration at our institution, to provide a baseline for comparisons of the efficacies of other treatment modalities. METHODS: A retrospective review of data for 50 children who underwent keyhole craniotomy for fenestration of temporal arachnoid cysts between 1994 and 2001 was performed after institutional review board approval. During that period, the first-line treatment for all symptomatic middle fossa arachnoid cysts was microcraniotomy for fenestration. Microsurgical dissection to create communications between the cyst cavity and basal cisterns was the goal. All patient records were reviewed and numerous variables related to presentation, cyst size and classification, treatment, cyst resolution, symptom resolution, follow-up periods, and cyst outcomes were recorded. RESULTS: Fifty temporal arachnoid cysts in 50 treated patients were identified. The average age at the time of surgery was 68 +/- 57.2 months. The follow-up periods averaged 36 months. There were 34 male and 16 female patients in the series. Twenty-six cysts were on the left side. Indications for surgery included intractable headaches (45%), increasing cyst size (21%), seizures (25%), and hemiparesis (8%). The symptoms most likely to improve were hemiparesis (100%) and abducens nerve palsies. Headaches (67%) and seizure disorders (50%) were less likely to improve. Nine patients exhibited progressive increases in cyst size in serial imaging studies. Those patients were monitored for a mean of 40 +/- 23 months before intervention. In the entire series, 82% of patients demonstrated decreases in cyst size in serial imaging studies. Of those patients, 18% demonstrated complete cyst effacement. Overall, 83% of patients with Grade II cysts and 75% of patients with Grade III cysts exhibited evidence of decreases in cyst size in long-term monitoring. Two patients required shunting after craniotomy (4%). Hospital stays averaged 3.4 days. Total surgical times averaged 115 minutes. No significant blood loss occurred (5-50 ml). Complications included spontaneously resolving pseudomeningocele (10%), transient Cranial Nerve III palsy (6%), cerebrospinal fluid leak (6%), subdural hematoma (4%), and wound infection (2%). CONCLUSION: A microsurgical keyhole approach to arachnoid cyst fenestration is a safe effective method for treating middle fossa cysts. This procedure can be performed with minimal morbidity via a minicraniotomy. Compared with an endoscopic approach, better control of hemostasis can be obtained, because of the ability to use bipolar forceps and other standard instruments. The operative time and length of hospital stay were not excessively increased.

Adolescent↗

PubMed2003

Dominant negative signal transducer and activator of transcription 2 (STAT2) protein: stable expression blocks interferon alpha action in skin squamous cell carcinoma cells.

We have demonstrated previously that suppression of some or all of the IFN-stimulated gene factor 3 (ISGF-3) proteins in skin squamous cell carcinomas is an early event in squamous skin carcinogenesis. This finding led to the hypothesis that suppressed expression of ISGF-3 proteins may lead to reduced IFN responsiveness, which in turn may contribute to skin malignancy by conferring a growth and/or survival advantage. To test this hypothesis, we have developed a skin cell-based model for inhibiting the IFN-alpha signaling pathway through the forced expression of a dominant negative-acting signal transducer and activator of transcription 2 (dnSTAT2) protein. Expression of dnSTAT2 suppressed cell growth inhibition with a pharmacologically achievable concentration (100 IU/ml) of IFN-alpha in the IFN-alpha-sensitive skin squamous cell carcinoma cell line SRB12-p9. dnSTAT2 also suppressed the IFN-alpha-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2, which are early events following IFN-alpha treatment, but did not suppress the IFN-gamma-induced phosphorylation of STAT1. Finally, the dnSTAT2 protein suppressed the up-regulation of several IFN-alpha-inducible genes that were identified in this system by cDNA microarray screening. We conclude that the cell growth-inhibitory effect of IFN-alpha in skin cells requires an intact STAT2 protein and is therefore mediated by the ISGF-3 complex. These results support STAT2 as an important molecular target for skin cancer chemoprevention. Furthermore, we propose that these dnSTAT2-expressing cells provide a novel in vitro model for the study of type I IFN action in human skin cells.

Carcinoma, Squamous Cell↗

PubMed2002

HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim.

Depletion of CD4(+) T cells is the hallmark of HIV infection and AIDS progression. In addition to the direct killing of the viral-infected cells, HIV infection also leads to increased apoptosis of predominantly uninfected bystander cells. This is mediated in part through the HIV-1 Tat protein, which is secreted by the infected cells and taken up by uninfected cells. Using an affinity-purification approach, a specific and direct interaction of Tat with tubulin and polymerized microtubules has been detected. This interaction does not affect the secretion and uptake of Tat, but is critical for Tat to induce apoptosis. Tat binds tubulin/microtubules through a four-amino-acid subdomain of its conserved core region, leading to the alteration of microtubule dynamics and activation of a mitochondria-dependent apoptotic pathway. Bim, a pro-apoptotic Bcl-2 relative and a transducer of death signals initiated by perturbation of microtubule dynamics, facilitates the Tat-induced apoptosis. Our findings reveal a strategy by which Tat induces apoptosis by targeting the microtubule network. Thus HIV-1 Tat joins a growing list of pathogen-derived proteins that target the cytoskeleton of host cells.

Animals↗

PubMed2002

Effect of vessel size on creation of hepatic radiofrequency lesions in pigs: assessment of the "heat sink" effect.

OBJECTIVE: The effect of vessels and their size on radiofrequency lesion creation in the liver was evaluated with respect to potential for vascular injury and perfusion-mediated "heat sink" effect. SUBJECTS AND METHODS: Radiofrequency lesions targeted to tissue adjacent to a variety of vessels were created in vivo in the liver of 10 Yorkshire pigs. Postablation contrast-enhanced CT and then histopathologic analysis of the vessels and lesions were performed after sacrifice of the pigs. Degree of vascular injury and viability of perivascular hepatocytes were recorded and tabulated according to vessel size for both CT and histologic data sets. RESULTS: At CT, 42 (95%) of 44 veins greater than 3 mm remained patent, and four (20%) of 20 veins less than 3 mm were occluded. Heat sink effect, indicated by invagination of enhancing tissue between vessel and radiofrequency lesion, was observed in 32 (73%) of 44 veins greater than 3 mm and in zero of 20 veins less than 3 mm. On histopathology, 111 (100%) of 111 vessels less than 3 mm showed at least partial vessel wall injury, characterized by endothelial cell necrosis and luminal thrombus. In 24 vessels greater than 3 mm, the extent of vessel wall injury decreased with increasing vessel diameter. Viable perivascular tissue indicative of heat sink effect was identified in 12 of 24 veins greater than 3 mm, increasing to seven of seven veins greater than 5 mm. None of 96 vessels less than 2 mm and three of 111 vessels less than 3 mm showed any heat sink effect. CONCLUSION: There appears to be a narrow transition zone for hepatic vessels at 2-4 mm, beyond which the heat sink effect was seen consistently and substantial vascular injury was rare.

Animals↗

PubMedDate not supplied

Energy and emission benefits of alternative transportation liquid fuels derived from switchgrass: a fuel life cycle assessment.

We conducted a mobility chains, or well-to-wheels (WTW), analysis to assess the energy and emission benefits of cellulosic biomass for the U.S. transportation sector in the years 2015-2030. We estimated the life-cycle energy consumption and emissions associated with biofuel production and use in light-duty vehicle (LDV) technologies by using the Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREET) model. Analysis of biofuel production was based on ASPEN Plus model simulation of an advanced fermentation process to produce fuel ethanol/protein, a thermochemical process to produce Fischer-Tropsch diesel (FTD) and dimethyl ether (DME), and a combined heat and power plant to co-produce steam and electricity. Our study revealed that cellulosic biofuels as E85 (mixture of 85% ethanol and 15% gasoline by volume), FTD, and DME offer substantial savings in petroleum (66-93%) and fossil energy (65-88%) consumption on a per-mile basis. Decreased fossil fuel use translates to 82-87% reductions in greenhouse gas emissions across all unblended cellulosic biofuels. In urban areas, our study shows net reductions for almost all criteria pollutants, with the exception of carbon monoxide (unchanged), for each of the biofuel production option examined. Conventional and hybrid electric vehicles, when fueled with E85, could reduce total sulfur oxide (SO(x)) emissions to 39-43% of those generated by vehicles fueled with gasoline. By using bio-FTD and bio-DME in place of diesel, SO(x) emissions are reduced to 46-58% of those generated by diesel-fueled vehicles. Six different fuel production options were compared. This study strongly suggests that integrated heat and power co-generation by means of gas turbine combined cycle is a crucial factor in the energy savings and emission reductions.

Air Pollution↗