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Biomedical subjects

D M Nguyen

Publications and source records attributed to D M Nguyen.

At least 19 recordsLinked to original sources
PubMed2001

Targets for molecular intervention in multistep pulmonary carcinogenesis.

Lung cancers are a leading cause of mortality worldwide, and most of these neoplasms are directly attributable to tobacco abuse. Recent studies have begun to elucidate molecular mechanisms of multistep aero-digestive tract carcinogenesis, revealing novel targets for intervention in lung cancers and their precursor lesions. This review summarizes the molecular biology of lung cancers in relation to the prognosis and treatment of patients with these neoplasms.

Animals↗
PubMed2001

Induction of MAGE-3 expression in lung and esophageal cancer cells.

BACKGROUND: Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. METHODS: Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. RESULTS: Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 micromol/L x 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL x 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. CONCLUSIONS: Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.

Adenocarcinoma↗
PubMed2001

Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis.

BACKGROUND: It has previously been demonstrated that 17-allylamino geldanamycin (17-AAG) enhances paclitaxel-mediated cytotoxicity and downregulates vascular endothelial factor expression in non-small cell lung cancer. This project was designed to evaluate the tumoricidal and antiangiogeneic effects of 17-AAG and paclitaxel in H358 non-small cell lung cancer cells grown as xenografts in nude mice. METHODS: In vitro cytotoxic drug combination effects were evaluated by (4, 5-dimethylthiazo-2-yl)-2, 5-diphenyl tetrazolium bromide-based proliferation assays. The combinations of 17-AAG and paclitaxel were administered intraperitoneally in nude mice bearing H358 tumor xenografts. Tumor volumes were measured weekly. Tumor expression of erbB2, vascular endothelial cell growth factor, von Willebrand factor (tumor microvasculature), and activated caspase 3 (apoptosis) were determined by immunohistochemistry. RESULTS: Five- to 22-fold enhancement of paclitaxel cytotoxicity was achieved by paclitaxel + 17-AAG combination that was paralleled with marked induction of apoptosis. This combination treatment profoundly suppressed tumor growth and significantly prolonged survival of mice bearing H358 xenografts. Immunohistochemical staining of tumor tissues indicated profound reduction of vascular endothelial cell growth factor expression associated with reduction of microvasculature in tumors treated with 17-AAG. Apoptotic cells were more abundant in tumors treated with 17-AAG + paclitaxel than in those treated with 17-AAG or paclitaxel alone. CONCLUSIONS: Concurrent exposure of H358 cells to 17-AAG and paclitaxel resulted in supraadditive growth inhibition effects in vitro and in vivo. Analysis of molecular markers of tumor tissues indicated that therapeutic drug levels could be achieved with this chemotherapy regimen leading to significant biological responses. Moreover, 17-AAG-mediated suppression of vascular endothelial cell growth factor production by tumor cells may contribute to the antitumor effects of this drug combination in vivo.

Allylamine↗
PubMed2001

Scooter injuries: a new pediatric morbidity.

OBJECTIVE: To describe types of injuries, mechanisms of injury, and treatment of injuries caused by scooter use in children, and to discuss issues of injury prevention in children who use scooters. STUDY DESIGN: Data were collected from 14 children seen by a general pediatrician and an orthopedic surgeon over a 3-month period in the summer of 2000. Detailed histories were obtained from patients and their families, and medical records were reviewed. RESULTS: Eleven of the 14 patients suffered fractures. The injuries in the other 3 patients were a large abrasion, a laceration, and a septic knee. Half (7) of the children were injured within the first day of riding their scooter, and 13 of the 14 injuries occurred within the first month of scooter use. Only 5 patients used protective gear at the time of their injuries, and those patients were injured in unprotected parts of their bodies. CONCLUSIONS: The popularity of scooters presents a new cause of pediatric injuries and a significant health hazard to children. In our study, most injuries occurred shortly after children began scooter use, and younger children suffered the most severe injuries. Additional studies are needed to determine how scooter-related injuries can be prevented or minimized. scooters, injuries.

Adolescent↗
PubMed2000

The duplication of an eight-residue helical stretch in Staphylococcal nuclease is not helical: a model for evolutionary change.

A common method of evolutionary change is gene duplication, followed by other events that lead to new function, decoration of folds, oligomerization, or other changes. As part of a study on the potential for evolutionary change created by duplicated sequences, we have carried out a crystallographic study on a mutant of Staphylococcal nuclease in which residues 55-62 have been duplicated in a wild-type variant termed PHS. In the parental protein (PHS) these residues form the first two turns of a helix running from residue 54 to 68 (hereafter designated as helix I). The crystal structure of the mutant is very similar to that of the parental, with helix I being unaltered. The duplicated residues are accommodated by expanding an existing loop N-terminal to helix I. In addition, circular dichroism (CD) studies have been carried out on a parental peptide containing helix I with six flanking residues at each terminus (residues 48-74) and on the same peptide expanded by the duplication, as a function of 2,2,2-trifluoroethanol (TFE) concentration. Each peptide possesses only modest helical propensity in solution. Our data, which is different from what was observed in T4 lysozyme, show that the conformation of the duplicated sequence is determined by a balance of sequential and longer-range effects. Thus duplicating sequence need not mean duplicating structure. Proteins 2000;40:465-472.

Algorithms↗
PubMed2000

Modulation of metastasis phenotypes of non-small cell lung cancer cells by 17-allylamino 17-demethoxy geldanamycin.

BACKGROUND: Cancer cells that overexpress c-erbB oncogenes exhibit resistance to chemotherapy, enhanced tumorigenicity, as well as increased propensity for metastasis. The aim of this study was to investigate if depletion of erbB-1/EGFR and erbB-2/HER2neu oncogene products by 17-allylamino 17-demethoxy Geldanamycin (17AAGA) could diminish the metastatic potential of non-small cell lung cancer (NSCLC) cells that express varying levels of the erbB1/erbB2 oncogenes. METHODS: NSCLC cell lines (H460, H358, H322, or H661) were assayed for expression of erbB1 and erbB2, the cell adhesion molecule E-cadherin, secretion of the matrix metalloproteinase 9 (MMP-9), and vascular endothelial cell growth factor (VEGF), as well as their ability to invade Matrigel after 48-hour exposure to 17AAGA. RESULTS: 17AAGA significantly depleted erbB1 or erbB2 levels in NSCLC cells expressing high levels of these proteins, and effectively inhibited their growth with IC50 values ranging from 50 to 90 nmol/L. Moreover, drug treatment enhanced E-cadherin expression in H322 and H358 cells, and inhibited secretion of MMP-9 and VEGF secretion by tumor cells. 17AAGA diminished hypoxia-induced upregulation of VEGF expression as well as growth factor-mediated augmentation of MMP-9 secretion, and profoundly inhibited the ability of H322 and H358 cells to migrate through Matrigel in response to chemoattractants. CONCLUSIONS: In addition to its known antiproliferative and chemosensitization effects, 17AAGA inhibits the metastatic phenotype of lung cancer cells. 17AAGA may be a novel pharmacologic agent for specific molecular intervention in lung cancer patients.

Benzoquinones↗
PubMed2000

Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer.

PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS: Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Adenoviruses, Human↗
PubMed2000

A new species of the Hyrcanus Group of Anopheles, subgenus Anopheles, a secondary vector of malaria in coastal areas of southern Vietnam.

Anopheles (Anopheles) nimpe, a new species of the Hyrcanus Group from the coastal areas of southern Vietnam, is described and illustrated in the adult, pupal, and larval stages. Partial DNA sequence data from paratypes are included for the mitochondrial cytochrome c oxidase I and 16S rRNA genes. The species is distinguished from other members of the group occurring in Southeast Asia.

Animals↗
PubMed1999

Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells.

Although SV40 oncoproteins have been detected in malignant pleural mesotheliomas (MPMs), their role in the pathogenesis and clinical behavior of these neoplasms remains controversial. In the present study, we sought to define the relevance of SV40 T/t antigen expression in established human mesothelioma cell lines deficient for p16INK4a as well as ARF expression. SV40 early region sequences were readily detected in genomic DNA isolated from pleural mesothelioma lines; however, levels of SV40 T/t antigen expression were highly variable in these cells. An adenoviral vector expressing an antisense transcript to SV40 early region inhibited T antigen expression and mediated significant growth inhibition and apoptosis in T-antigen-positive mesothelioma cells and SV40-transformed COS-7 cells. Abrogation of T/t antigen expression coincided with enhanced p21/WAF-1 expression, suggesting that restoration of p53-mediated pathways may have contributed to the growth inhibition and apoptosis induced by the antisense construct. These effects were not observed after similar treatment of mesothelioma or lung cancer cells containing no SV40 DNA sequences. Collectively, these data suggest that SV40 oncoproteins contribute to the malignant phenotype of pleural mesotheliomas and indicate that interventions designed to abrogate their expression may be efficacious in the treatment of individuals with these neoplasms.

Adenoviridae↗
PubMed1999

Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.

BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Adenoviridae↗
PubMed1999

Aneurysm after subclavian flap angioplasty repair of coarctation of the aorta.

We report a case of aortic aneurysm at the site of subclavian flap angioplasty repair for coarctation of the aorta. The dilatation involved the lateral wall of the proximal descending aorta that had been constructed by the flap. Five other similar cases have been reported in the literature. Diligent long-term follow-up is needed after surgical repair of coarctation of the aorta to detect late complications such as restenosis or aneurysm formation.

Adult↗
PubMed1999

Sequence-dependent enhancement of paclitaxel toxicity in non-small cell lung cancer by 17-allylamino 17-demethoxygeldanamycin.

OBJECTIVE: Overexpression of the oncogene erbB-2 contributes to chemoresistance in various malignant tumors including lung cancer. The aim of this study was to investigate whether depletion of the erbB-2 gene product (p185) by 17-allylamino 17-demethoxygeldanamycin would sensitize lung cancer cells to paclitaxel (Taxol) in vitro. METHODS: Paclitaxel cytotoxicity was evaluated in a panel of non-small cell lung cancer cell lines that expressed varying levels of p185 by means in vitro proliferation assays and 2 drug combination schedules. Cell cycle kinetics and apoptosis after exposure to paclitaxel or paclitaxel plus 17-allylamino 17-demethoxygeldanamycin were analyzed by flow cytometry. RESULTS: The 17-allylamino 17-demethoxygeldanamycin treatment efficiently depleted p185 expression in lung cancer cells. Concurrent exposure of these cells to paclitaxel and 17-allylamino 17-demethoxygeldanamycin significantly enhanced paclitaxel-mediated cytotoxicity, particularly in cells which overexpressed p185. There was a 1.3 to more than 20-fold reduction of paclitaxel 50% inhibitory concentration values in those cells that were responding positively to the drug combination. Significant induction of apoptosis was observed after treatment of cells with the combination of paclitaxel and 17-allylamino 17-demethoxygeldanamycin. The combination cytotoxic effect was only additive in cells expressing low levels of p185. In contrast, of lung cancer cells with exposure to 17-allylamino 17-demethoxygeldanamycin before combined paclitaxel and 17-allylamino 17-demethoxygeldanamycin exposure actually rendered the cells refractory to paclitaxel cytotoxicity. CONCLUSION: The compound 17-allylamino 17-demethoxygeldanamycin sensitizes non-small cell lung cancer cells expressing high levels of p185 to paclitaxel-mediated growth arrest and apoptosis. These preclinical data support the evaluation of the combination of paclitaxel and 17-allylamino 17-demethoxygeldanamycin in the treatment of patients with lung cancer whose tumors exhibit p185 overexpression.

Antibiotics, Antineoplastic↗
PubMed1999

Strategies for molecular intervention in esophageal cancers and their precursor lesions.

Molecular analysis of malignant transformation in Barrett's epithelium provides insight into the temporal nature and significance of individual genetic events during multistep esophageal carcinogenesis. Potential targets for intervention in esophageal neoplasms include mutations involving retinoblastoma (Rb) and p53 tumor-suppressor pathways as well as tyrosine kinase cascades, which are known to promote cell cycle progression. Data from recent experiments provide the preclinical rationale for novel pharmacologic interventions in established esophageal cancers, and suggest strategies for chemoprevention in patients at risk for the development of these neoplasms.

Adenocarcinoma↗
PubMed1998

Isolation and physical characterization of random insertions in Staphylococcal nuclease.

Using genetic engineering techniques we generated randomly located internal tandem duplications of random size within Staphylococcal nuclease. Those insertions, possessing greater than 0.1% of normal activity, were sequenced and characterized physically. Insertions were found to begin and end in regions possessing secondary structure as well as in regions without secondary structure. All proteins remained folded and monomeric, although one mutant appeared, by both circular dichroism and size exclusion chromatography, to be partially unfolded. The stability of the insertions as assayed by guanidine hydrochloride denaturation ranged from nearly normal to destabilized by almost 4 kcal per mol. The activities of the insertion mutants ranged from 1/30 to 1/2000 of the parental nuclease.

Chromatography, Gel↗
PubMed1996

Impact of transfusion of mediastinal shed blood on serum levels of cardiac enzymes.

BACKGROUND: Infusion of shed mediastinal blood using an autotransfusion system is a widely applied technique of blood conservation in cardiac surgery. Serial determinations of serum creatine kinase (CK), its MB isoenzyme (CK-MB), and lactate hydrogenase (LDH) levels have been used to monitor perioperative myocardial injury. We investigated the impact of postoperative autotransfused blood infusion on serum levels of these enzymes. METHODS: We performed a retrospective analysis of postoperative serum CK, CK-MB, and LDH levels of 300 patients who had elective uncomplicated aortocoronary bypass grafting. Shed mediastinal blood samples from 26 patients were analyzed for CK, CK-MB (enzymatic activity and mass), and LDH levels before infusion. RESULTS: High postoperative serum levels of CK and LDH were observed after infusion of autotransfused blood. Shed mediastinal blood contained extremely high levels of these enzymes, particularly from patients who had internal mammary artery dissection. There was a strong correlation (r = 0.96) between measured CK-MB enzyme activities and those calculated from the CK-MB mass units. CONCLUSIONS: Infusion of autotransfused blood containing high concentrations of CK and LDH results in elevated serum levels of these enzymes. Hemolysis, frequently present in shed blood, does not interfere with the routine biochemical assays for CK and CK-MB enzyme activities. Caution should be taken when postoperative cardiac enzyme levels are used to determine myocardial injury after aortocoronary bypass grafting if autotransfusion is used as a method of blood conservation.

Blood Loss, Surgical↗
PubMed1996

Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer.

A more effective gene therapy strategy for lung cancer using sequential cisplatin administration and adenovirus-mediated p53 gene transfer was developed on the basis of our previous observation of enhanced expression of a reporter gene in malignant cells exposed to cisplatin before gene transfer. Transfer of the normal (wildtype) p53 gene into cisplatin-treated H1299 cells, in which p53 is homozygously deleted, resulted in up to a 60% further inhibition of cell proliferation in vitro than p53 transfer into untreated H1299 cells. The cisplatin plus p53 gene transfer strategy yielded significantly greater apoptosis and tumor growth suppression in an animal model of subcutaneous H1299 tumor nodules than wildtype p53 gene transfer alone. The timing of cisplatin administration and p53 gene transfer was shown to be critical: cisplatin administration simultaneous with or subsequent to p53 gene transfer was less effective than cisplatin-first sequential treatment. Moreover, the in vivo inhibition of tumor growth was maintained by repeated cycles of treatment. This gene therapy strategy has been incorporated into a phase I clinical trial for the treatment of lung cancer and provides a basis for the development of improved therapeutic protocols.

Animals↗
PubMed1996

The role of physical medicine and rehabilitation in pain management.

Physical medicine and rehabilitation frequently use the interdisciplinary team approach to the management of pain in the elderly because this would also address the psychosocial and functional deficits resulting from the pain symptom. The team prescribes a combination of pharmacologic agents, cognitive-behavioral therapies, physical modalities, occupational therapy, and physical therapy in the treatment plan. Management of patients with pain resulting from compression fracture and spinal stenosis is discussed also.

Aged↗