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Biomedical subjects

P Nguyen

Publications and source records attributed to P Nguyen.

At least 109 records · Page 6Linked to original sources
PubMed1996

MHC bias of Mls-1 recognition is not influenced by thymic positive selection.

In contrast to T cell recognition of conventional peptide/MHC, T cell recognition of superantigen is not MHC-restricted. However, an influence of MHC polymorphism on specificity is consistent with accumulating data suggesting a TCR/MHC interaction during T cell recognition of superantigen. We have previously shown that T cells from V beta 8.1 beta-chain transgenic mice show an unexpected bias against recognition of Mls-1 presented by H-2d spleen cells. In the current studies we have examined whether thymic positive selection in H-2d mice, which selects T cells that see conventional antigen preferentially in the context of H-2d, is able to overcome the strong bias against recognition of Mls-1/H-2d. The data show that transgenic T cells from both H-2d and H-2k mice have comparable reactivity. The failure of thymic positive selection to overcome the bias against Mls-1/H-2d suggests that the orientation of the putative TCR/MHC interaction during recognition of Mls-1 is not the same as during recognition of conventional peptide/MHC.

Animals↗
PubMed1996

Water transport in native and transplanted porcine jejunum.

Adequate absorptive function of transplanted small intestine is essential for success of this procedure. This study compared water transport under basal and meal stimulated conditions in the transplanted swine jejunum to native jejunum. Six female adolescent Yorkshire swine were randomized to undergo construction of either a 25-cm native proximal jejunal Thiry-Vella Fistula (TVF), n=3, or a 25-cm proximal jejunal allograft TVF, n=3. Immunosuppression in the transplanted animals was accomplished with intravenous methylprednisolone, azathioprine, and cyclosporin. Jejunal absorption studies, each 4 hr long, were performed utilizing 14C-polyethylene glycol to calculate net water flux. Each animal underwent at least three fasting and three postprandial studies. New water flux was negative, i.e., secretory, in both the native and transplanted proximal swine jejunum. In the basal state, integrated hourly water transport was more secretory in the native bowel vs the transplanted bowel during the 2nd, 3rd, and 4th experimental hr (-4.6 +/- .8 vs -2.1 +/- .7 cc, P = 0.034; -4.4 +/- .7 vs -1.8 +/- .6 cc, P = 0.012; and -4.7 vs 1.3 +/- .5 cc, P < 0.005), respectively. In native jejunum, integrated hourly water transport was less secretory 2 and 3 hr postprandially compared to basal (-1.9 +/- .5 vs -4.4 +/- .7 cc, P = 0.016; and -2.0 +/- .5 vs -4.7 +/- .7 cc, P = 0.021), respectively. This postprandial proabsorptive response did not occur in the transplanted jejunum. Native and transplanted jejunal water flux in the postprandial state did not differ significantly. We conclude that there is higher secretion in native vs transplanted jejunum during fasting. The postprandial proabsorptive response of the proximal porcine jejunum is abolished by transplantation.

Animals↗
PubMed1996

Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin.

The isoflavinoid genistein is a protein-tyrosine kinase inhibitor which has been identified as a putative cancer prevention agent. Its consumption is associated with a low incidence of clinical metastatic prostate cancer in the face of a sustained high incidence of organ-confined prostate cancer. We therefore undertook studies to examine genistein's effect upon cell adhesion as one possible mechanism by which it could be acting as an antimetastatic agent. A morphogenic analysis revealed that genistein caused cell flattening in a variety of cell lines: PC3-M, PC3, and DU-145 prostate carcinoma cells, as well as MCF-7 breast carcinoma cells. Mechanistic studies focused on the highly metastatic PC3-M cell line, and revealed that cell flattening was accompanied by an increase in cell adhesion. Further investigations demonstrated that focal adhesion kinase (FAK) accumulated in areas of focal cell attachment, and that this accumulation occurred only when cells were actively undergoing genistein-mediated morphologic change. Concurrent formation of a complex between the cell attachment molecule, beta-1-integrin, and FAK was shown to occur, and to correlate with transient activation of FAK activity. Genistein is presented as a novel investigative tool for use in the study of molecular events involved in the process of cell adhesion.

Antineoplastic Agents↗
PubMed1996

Impact of endoscopic ultrasound with fine-needle aspiration on the surgical management of pancreatic cancer.

BACKGROUND: Endoscopic ultrasound (EUS) with EUS-guided fine-needle aspiration (EUS-FNA) enables one to visualize the pancreas and surrounding structures and can provide access for FNA of those structures that appear suspicious for tumor. PATIENTS AND METHODS: From 1993 to 1995, 50 patients suspected of having pancreatic cancer underwent EUS/EUS-FNA and abdominal computed tomography (CT). Malignancy was found in 30 (60%) cases, which included 24 (48%) pancreatic adenocarcinomas. RESULTS: Endoscopic ultrasound/EUS-FNA identified 26 of the 30 malignancies (85%) and 21 of the 24 pancreatic adenocarcinomas (88%), with no false positives. Thirteen of the 24 pancreatic cancer patients had lymph nodes that were sampled with EUS/EUS-FNA. Seven of these 13 patients (62%) were found to have metastatic spread to lymph nodes. Operations were performed on 11 of the pancreatic cancer patients. Of these 11, the 5 that were predicted to be resectable by EUS/EUS-FNA underwent successful resection. Of the 6 predicted to be unresectable, 5 had palliative biliary bypasses, and 1 had a grossly positive margin of resection. CONCLUSIONS: Endoscopic ultrasound/EUS-FNA can identify patients for curative surgical resection. It can also preoperatively identify patients with regional nodal disease for inclusion in appropriately designed clinical trials.

Adult↗
PubMed1996

Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration of the left adrenal gland.

BACKGROUND: We reported the application of endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) in the local staging of lung cancer. Up to 16% of patients with lung cancer may have adrenal masses. The role of EUS in the characterization of the adrenal gland, as well as EUS-guided FNA of the adrenal gland, has not been described. METHODS: The adrenal gland was characterized by EUS in 30 of 31 (97%) patients. EUS-guided FNA of an adrenal was performed in one patient. Anatomic correlation and ex vivo images were obtained. RESULTS: The average dimension was 2.5 cm (range 1.4 to 3.5) x 0.8 cm (range 0.3 to 1.4) with two morphologic types: "seagull" and "elliptical." One patient with lung cancer and a left adrenal mass with a nondiagnostic CT-guided FNA underwent EUS-guided FNA, which established the diagnosis of metastatic adenocarcinoma. Surgery was avoided. CONCLUSIONS: The left adrenal can be imaged by EUS in almost all patients. EUS-guided FNA may be useful when applied to left adrenal metastatic tumors for tissue diagnosis.

Adenocarcinoma↗
PubMed1996

Impact of cholesterol reduction on peripheral arterial disease in the Program on the Surgical Control of the Hyperlipidemias (POSCH).

BACKGROUND: Few lipid/atherosclerosis intervention trials have assessed the impact of cholesterol reduction on peripheral arterial disease. The 838 patients evaluated in the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial represent more than the total number of patients in the seven previously reported studies. METHODS: Peripheral arterial disease in POSCH was assessed by progression of clinical disease, serial changes in the systolic blood pressure ankle/brachial index (ABI), and changes on sequential peripheral arteriograms. RESULTS: At the time of formal closure of the POSCH trial on July 19, 1990, claudication or limb-threatening ischemia was exhibited in 72 of 417 control group (CG) patients and in 54 of 421 intervention group (IG) patients (IG relative risk [RR] 0.702, 95% confidence interval [CI] 0.169 to 1.000, p = 0.049). With additional follow-up evaluation to September 30, 1994, clinical peripheral arterial disease was evident in 91 CG patients and 64 IG patients (RR 0.656, 95% CI 0.200 to 0.903, p = 0.009). At the 5-year follow-up evaluation, an ABI of less than 0.95 was present in 41 of 120 CG patients and in 24 of 126 IG patients, all of whom had an ABI of 0.95 or greater at baseline (RR in the IG of 0.557, 95% CI 0.360 to 0.863, p < 0.01). No appreciable differences were noted in the progression or regression of arteriographic peripheral arterial disease between the two groups. CONCLUSIONS: Effective cholesterol reduction in POSCH led to statistically significant differences between the control and the intervention groups in the development of clinically evident peripheral arterial disease and in the ABI values, but not in the peripheral arteriograms. Additional studies need to assess the correlation between peripheral arterial changes and coronary arterial changes and clinical atherosclerosis events. Intervention trials that study peripheral arterial disease have intrinsic value in the evaluation of the impact of risk factor modification on progression of atherosclerotic peripheral arterial disease.

Angiography↗
PubMed1996

Gender-based mortality follow-up from the Program on the Surgical Control of the Hyperlipidemias (POSCH) and meta-analysis of lipid intervention trials. Women in POSCH and other lipid trials.

OBJECTIVE: The authors assessed the clinical results of lipid-lowering therapy in women. SUMMARY BACKGROUND DATA: The Program on the Surgical Control of the Hyperlipidemias (POSCH) has demonstrated that effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed. METHODS: A review and meta-analysis were performed of the seven primary or secondary lipid/ atherosclerosis intervention trials-including POSCH-published in the English-language literature that included women and published results in women separate from the results in men or in the entire trial population. The main outcome measure analyzed was overall mortality. RESULTS: The Scottish Physicians Clofibrate Study, the Newcastle upon Tyne Clofibrate Study, and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Trial may have demonstrated a possible benefit in ACHD prognosis from effective lipid intervention in women. The other four available trials did not. The Minnesota Coronary Survey reported a 15.6% increase in overall mortality rate and a 30.6% increase in a combined cardiovascular endpoint rate in the lipid-intervention group. The Upjohn Colestipol Study demonstrated statistically significant reductions in overall and ACHD mortality in the men, but not in the women. The Scandinavian.

Cholesterol↗
PubMed1996

Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway.

The serine/threonine kinase Raf-1 functions downstream of Rats in a signal transduction cascade which transmits mitogenic stimuli from the plasma membrane to the nucleus. Raf-1 integrates signals coming from extracellular factors and, in turn, activates its substrate, MEK kinase. MEK activates mitogen-activated protein kinase (MAPK), which phosphorylates other kinases as well as transcription factors. Raf-1 exists in a complex with HSP90 and other proteins. The benzoquinone ansamycin geldanamycin (GA) binds to HSP90 and disrupts the Raf-1-HSP90 multimolecular complex, leading to destabilization of Raf-1. In this study, we examined whether Raf-1 destabilization is sufficient to block the Raf-1-MEK-MAPK signalling pathway and whether GA specifically inactivates the Raf-1 component of this pathway. Using the model system of NIH 3T3 cells stimulated with phorbol 12-myristate 13-acetate (PMA), we show that GA does not affect the ability of protein kinase C alpha to be activated by phorbol esters, but it does block activation of MEK and MAPK. Further, GA does not decrease the activity of constitutively active MEK in transiently transfected cells. Finally, disruption of the Raf-1-MEK-MAPK signalling pathway by GA prevents both the PMA-induced proliferative response and PMA-induced activation of a MAPK-sensitive nuclear transcription factor. Thus, we demonstrate that interaction between HSP90 and Raf-1 is a sine qua non for Raf stability and function as a signal transducer and that the effects observed cannot be attributed to a general impairment of protein kinase function.

3T3 Cells↗
PubMed1996

Kinetic aspects of acetate metabolism in healthy humans using [1-13C] acetate.

Acetate metabolism in humans is not well known. Kinetic aspects of acetate were investigated in the postabsorptive state on healthy subjects. In a first study, six subjects were infused with a primed constant infusion of [1-13C]acetate for 3 h and a prime of NaH13CO3. No difference was found between arterialized and venous tracer enrichments from the arm, although arterialized acetate concentrations were higher (74 +/- 12 vs. 59 +/- 14 mumol/l, P < 0.05), suggesting that the hand muscles used but did not produce acetate in the postabsorptive state. Total body flux of acetate was 8.4 +/- 0.6 mumol.kg-1.min-1, of which 69 +/- 5% was oxidized. Acetate contributed to 6.5 +/- 0.4% of the basal energy expenditure. In a second study, five volunteers were submitted to a gastric infusion for 3 h followed by an intravenous infusion of [1-13C]acetate for 3 h. Higher fluxes were observed with the tracer gastric infusion, and the first-pass removal of acetate within the splanchnic bed was 60 +/- 7%. Acetate contributes significantly to the energy supply of the body. It is mainly used by the liver when produced in the gut.

Acetates↗
PubMed1996

Census undercount and the undercount of the Black population.

"Despite the [U.S.] Census Bureau's great efforts in various accuracy-improvement and outreach programs, census undercount still persists.... This paper focuses on the undercount of the Black population and its impacts in the form of such biased statistics on Blacks as inflated proportions of Black female-headed households, deflated victimization rates of Black males, or crude death rates of Blacks. The paper concludes with suggestions on how to deal with the undercount problems."

Black or African American↗
PubMed1995

Taxol induction of p21WAF1 and p53 requires c-raf-1.

Taxol stabilizes microtubules, prevents tubulin depolymerization, and promotes tubulin bundling and is one of the most effective drugs for the treatment of metastatic breast and ovarian cancer. Although its interaction with tubulin has been well characterized, the mechanism by which taxol induces growth arrest and cytotoxicity is not well understood. Herein, we show that taxol induced dose- and time-dependent accumulation of the cyclin inhibitor p21WAF1 in both p53 wild-type and p53-null cells, although the degree of induction was greater in cells expressing wild-type p53. In MCF7 cells, wild-type p53 protein was also induced after taxol treatment, and this induction was mediated primarily by increased protein stability. Taxol induced both p21WAF1 and wild-type p53 optimally in MCF7 cells after 20-24-h exposure with an EC50(3) of 5 nM. In p53-null PC3M cells, p21WAF1 was similarly induced after 24-h exposure to taxol. Coincident with these biochemical effects, taxol altered the electrophoretic mobility of c-raf-1 and stimulated mitogen activated protein kinase. Previous depletion of c-raf-1 inhibited both the p21WAF1- and p53-inducing properties of taxol, as well as the activation of MAP kinase. These data suggest that induction of p21WAF1 by taxol requires c-raf-1 activity, but that it is not strictly dependent on wild-type p53. Furthermore, the ability of taxol to both induce wild-type p53 in MCF7 cells and activate MAP kinase is also dependent on c-raf-1 expression.

3T3 Cells↗
PubMed1995

Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. Regulatory role of donor CD8+ T cells.

Acute and chronic graft-versus-host disease (GVHD) in the parent-into-F1 model are mediated by predominantly cellular or humoral immune responses, respectively, and are strikingly different entities by 2 wk of disease. Both forms of GVHD, however, evolve from a common starting point, i.e., donor CD4+ T cell recognition of host alloantigen and IL-2 production. Our study examines the first 2 wk of GVHD to delineate the events that critically influence GVHD development. Surprisingly, both forms of GVHD are initially characterized by increased Th2 cytokine (IL-4 and IL-10) production and B cell activation which persists into wk 2. The earliest distinguishing features of acute GVHD were detectable at days 5 through 7 of disease and consisted of 1) expansion of donor CD8+ T cells, and 2) increased IFN-gamma production by donor CD4+ and CD8+ T cells. Interestingly, IFN-gamma production by donor CD4+ T cells was not seen if donor CD8+ T cells were not engrafted in comparable numbers. Chronic GVHD in the DBA-into-BDF1 model was found to be caused by a relative defect in the ability of DBA CD8+ T cells to induce acute GVHD and to produce IFN-gamma. These studies demonstrate that both acute and chronic GVHD begin as a Th2 cytokine-mediated, B cell stimulatory response. The transition to acute GVHD is critically dependent on the engraftment of donor CD8+ T cells, which terminate B cell hyperactivity by 1) eliminating activated B cells and 2) promoting IFN-gamma secretion by donor CD4+ T cells.

Animals↗
PubMed1995

I1-imidazoline receptors. Definition, characterization, distribution, and transmembrane signaling.

Data were presented showing that I1-imidazoline sites show a unique ligand specificity that differs markedly from that of any of the alpha 2-adrenergic subtypes or the I2-imidazoline sites labeled by [3H]idazoxan. On the other hand, the ligand specificity of I1-imidazoline sites is maintained across mammalian species (cow, rat, dog, and human) and between different tissues and cell types. I1-Imidazoline sites can be further distinguished from I2 sites because the latter, unlike I1 sites, were not present in RVLM membranes from bovine brain stem. Furthermore, I1-imidazoline sites were modulated by guanine nucleotides with a specificity appropriate for a receptor coupled to G-protein and were mainly localized to plasma membranes. I1-Imidazoline sites show a unique pattern of distribution between diverse tissues and cell types and appear to be a neuroepithelial marker as well as being present in secretory cells of the pancreatic islets. The widespread distribution of I1-imidazoline sites implies that the functional significance of this putative receptor may have been underestimated. The signaling pathway associated with the I1-imidazoline receptor remains to be fully elucidated, but is likely that activation of phospholipase A2 leading to release of arachidonic acid and subsequent generation of prostaglandins plays a major role.

Animals↗
PubMed1995

Contribution of the TCR alpha-chain to the differential recognition of bacterial and retroviral superantigens.

The TCR alpha-chain has been implicated in superantigen recognition by some T cells. In this study, recognition of a retroviral (minor lymphocyte stimulating Ag-1, Mls-1) and a bacterial (staphylococcal enterotoxin B, SEB) superantigen by T cells expressing an identical (transgenic) V beta 8.1 beta-chain and either a V alpha 2+ or V alpha 11+ alpha-chain have been compared. Individual hybridomas were found to vary in their recognition of the two superantigens. Whereas some T cell hybridomas recognized both superantigens comparably, other hybridomas preferentially recognized either Mls-1 or SEB, indicating that the contribution of the TCR alpha-chain to recognition of these superantigens is not equivalent. The degree of heterogeneity in recognition varied between the V alpha 2+ and V alpha 11+ hybridomas, although there were individual hybridomas within each group with distinct patterns of reactivity that varied only in CDR3 alpha. These data are consistent with recent evidence that recognition of Mls-1 and SEB involves distinct TCR/MHC interactions.

Animals↗
PubMed1995

Exposure of Drosophila melanogaster embryonic cell cultures to 60-Hz sinusoidal magnetic fields: assessment of potential teratogenic effects.

There is considerable concern about potential detrimental health effects associated with exposure to environmentally relevant magnetic fields. One specific concern relates to potential effects of magnetic field (MF) exposure on reproduction and development. Consequently, an in vitro teratogenesis (developmental toxicity) assay employing embryonic Drosophila cells has been used to determine whether exposure to a 60-Hz MF of 100 microT for 16-18 hr is itself teratogenic and whether such an exposure could potentiate the teratogenic response induced by a chemical teratogen (developmental toxicant). The results demonstrated that (1) MF exposure alone did not induce a teratogenic response, whether the MF was oriented parallel or perpendicular to the plane of the culture dishes; and (2) MF exposure did not alter the teratogenic response induced by optimal or suboptimal concentrations of three chemical teratogens (retinoic acid, hydroxyurea, and cadmium). Furthermore, in additional studies, Drosophila embryos were exposed to 60-Hz MFs of 10 and 100 microT for 24 hr or for their entire development time (i.e., until adult ecolsion, about 10 days). Results demonstrated that MF exposure did not produce an increase in developmental abnormalities over those observed in unexposed controls.

Animals↗