Search PubMed⌕ Search

Biomedical subjects

J Hung

Publications and source records attributed to J Hung.

At least 55 records · Page 3Linked to original sources
PubMed1995

Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction.

BACKGROUND: Hypercholesterolemia is a risk factor for coronary disease, and platelet reactivity is increased with hypercholesterolemia, suggesting a prethrombotic risk. The aim of this study was to measure mural platelet thrombus formation on an injured arterial wall in a model simulating vessel stenosis and plaque rupture in hypercholesterolemic coronary disease patients before and after cholesterol reduction. METHODS AND RESULTS: Thirty-two patients with stable coronary disease were studied. Platelet thrombus formation and serum lipids were measured in 16 hypercholesterolemic patients (cholesterol > 5.2 mmol/L) before and after a mean of 2.5 months of pravastatin therapy (40 mg/d) and in 16 normocholesterolemic control patients. Thrombus formation was assessed by exposing porcine aortic media to the patient's flowing venous blood for 3 minutes at a shear rate of 754 or 2546 s-1 at 37 degrees C in an ex vivo superfusion chamber. Quantitative morphometric platelet thrombus formation at baseline was higher in the hypercholesterolemic patients at both the high and low shear rates: 4.8 +/- 1.0 and 3.3 +/- 0.7 micron 2/mm, respectively, compared with normocholesterolemic patients: 2.1 +/- 0.5 and 1.6 +/- 0.4 micron 2/mm (both P < .05). In the hypercholesterolemic patients, pravastatin decreased total cholesterol from 6.5 +/- 0.2 to 4.5 +/- 0.2 mmol/L and LDL cholesterol from 4.5 +/- 0.2 to 2.8 +/- 0.1 mmol/L (both P < .05). Platelet thrombus formation at high and low shear rates decreased to 2.0 +/- 0.3 and 1.3 +/- 0.3 micron 2/mm, respectively (both P < .05). CONCLUSIONS: Thus, hypercholesterolemia is associated with an enhanced platelet thrombus formation on an injured artery, increasing the propensity for acute thrombosis. Platelet thrombus formation at both high and low shear rates decreased as total and LDL cholesterol levels were reduced with pravastatin. Cholesterol lowering may therefore reduce the risk of acute coronary events in part by reducing the thrombogenic risk.

Animals↗
PubMed1995

Cigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirin.

BACKGROUND: Smoking is associated with an increased risk of myocardial infarction and sudden death. Platelet activation and thrombosis at sites of vessel stenosis and injury or plaque disruption play a crucial role in these acute coronary events. Thus, the aim of this study was to determine whether cigarette smoking acutely increases platelet thrombus formation on an injured arterial surface at local shear rates typical of a stenotic artery. METHODS AND RESULTS: Twelve habitual smokers with stable coronary disease, on aspirin 325 mg/d, were studied immediately before and 5 minutes after smoking two cigarettes each. Ex vivo platelet thrombus formation on porcine arterial media (simulating deep arterial injury) was measured after exposure to the patient's circulating venous blood for 3 minutes in cylindrical flow chambers at 37 degrees C. The flow chambers were designed to produce shear rates of 754 or 2546 s-1, the latter being typical of the high shear rates produced by vessel stenosis. Plasma catecholamine, thromboxane B2, and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels and whole blood platelet aggregation responses to thrombin were also measured before and after smoking. Compared with before smoking, morphometrically measured platelet thrombus formation on arterial media at shear rates of 754 and 2546 s-1 increased by an average of 48% (P = .19) and 64% (P = .014), respectively, after smoking. Plasma epinephrine increased by more than twofold after smoking (P = .026). Plasma thromboxane B2 and 6-keto-PGF1 alpha levels did not change. Smoking also increased whole blood platelet aggregation to thrombin (P < or = .05). CONCLUSIONS: These results suggest that smoking-enhanced platelet thrombosis may be an important contributory mechanism for acute coronary events in smokers that is not prevented by aspirin treatment. Catecholamine release and heightened platelet aggregation response to in vivo agonists may contribute to the prothrombotic effects of smoking.

Adult↗
PubMed1995

Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile.

Although gallbladder carcinoma is one of the most frequent neoplasms in Chile, there is limited information about the molecular changes involved in its pathogenesis. We investigated the incidence of ras gene mutations and loss of heterozygosity (LOH) at the following genes/loci: p53, DCC, rb, 5q 3p, 8p, and 9p. We precisely microdissected 194 relevant areas from paraffin-embedded microslides from 25 gallbladder carcinomas and their accompanying nonneoplastic lesions (which were present in 15 cases) from patients in Chile. The specimens were analyzed by PCR-based assays for LOH, and we designed a RFLP method for ras mutations and immunohistochemistry for p53 protein overexpression. We determined that LOH at p53 (91%), 9p (50%), 8p (44%) and DCC (31%) are frequent events and that LOH at p53, 9p, and DCC are early events, while ras mutations and LOH at 3p, rb, and 5q occurred occasionally. LOH at p53 occurred more frequently and earlier than protein overexpression. The mean number of mutations present in invasive carcinomas was 2.1, and in six cases, LOH at the p53 gene was the sole mutation detected. The same allele was lost in 61 (93%) of 71 nonneoplastic foci as in the corresponding invasive carcinomas for all four mutations studied. The odds of this occurring by chance are approximately 4 x 10(-15). Although clonality cannot be excluded, allelic loss appears to be highly directed, but the mechanism for allele-specific mutations remains to be determined.

Adenocarcinoma↗
PubMed1995

Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma.

BACKGROUND: Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas. OBJECTIVE: To investigate the role of these chromosome 3p deletions in the pathogenesis of non-small cell lung carcinomas. DESIGN: Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction-based assays for dinucleotide repeat polymorphisms at three chromosome 3p loci (3p14, 3p21.3, and 3p25). SETTING: University-based medical center and affiliated hospitals. SUBJECTS: Samples were analyzed from seven patients who underwent surgical resection with curative intent for non-small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer). RESULTS: Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3 x 10(-3). CONCLUSIONS: Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance.

Aged↗
PubMed1995

Adenovirus-based p53 gene therapy in ovarian cancer.

Mutations of the p53 tumor suppressor gene are the most common molecular genetic abnormality to be described in ovarian cancer. To determine the feasibility of mutant p53 as a molecular target for gene therapy in ovarian cancer, we constructed an adenovirus vector containing the wild-type p53 gene. The ability of this adenovirus construct (Ad-CMV-p53) to express p53 protein was examined by Western blot analysis in the H358 lung cancer cell line, which has a homozygous deletion of the p53 gene. The ability of the adenovirus vector system to infect ovarian cancer cells was tested using an adenovirus containing the beta-galactosidase reporter gene under the control of the CMV promoter (Ad-CMV-beta gal). The ovarian cancer cell line 2774, which contains an Arg273His p53 mutation, was infected with Ad-CMV-beta gal, and the infected cells were assayed for beta-galactosidase activity after 24 hr. To test the ability of wild-type p53 to inhibit cell growth, the 2774 cell line was infected with Ad-CMV-p53 or Ad-CMV-beta gal, and the effect of these agents on the growth of 2774 cells was determined using an in vitro growth inhibition assay. Western blot analysis of lysates from H358 cells infected with Ad-CMV-p53 showed expression of wild-type p53 protein. When 2774 cells were infected with Ad-CMV-beta gal at a multiplicity of infection (m.o.i.) of 10 PFU/cell, > 90% of cells showed beta-galactosidase activity, demonstrating that these cells are capable of efficient infection by the adenovirus vector. Growth of 2774 cells infected with Ad-CMV-p53 was inhibited by > 90% compared to noninfected cells. The ability of the adenovirus vector to mediate high-level expression of infected genes and the inhibitory effect of Ad-CMV-p53 on the 2774 cell line suggests that the Ad-CMV-p53 could be further developed into a therapeutic agent for ovarian cancer.

Adenoviridae↗
PubMed1994

Genetic instability in human ovarian cancer cell lines.

We have analyzed the stability of microsatellites in cell lines derived from human ovarian cancers and found that 5 out of 10 of the ovarian tumor cell lines are genetically unstable at the majority of the loci analyzed. In clones and subclones derived serially from one of these cell lines (2774; serous cystadenocarcinoma), a very high proportion of microsatellites distributed in many different regions of the genome change their size in a mercurial fashion. We conclude that genomic instability in ovarian tumors is a dynamic and ongoing process whose high frequency may have been previously underestimated by PCR-based allelotyping of bulk tumor tissue. We have identified the source of the genetic instability in one ovarian tumor as a point mutation (R524P) in the human mismatch-repair gene MSH2 (Salmonella MutS homologue), which has recently been shown to be involved in hereditary nonpolyposis colorectal cancer. Patient 2774 was a 38-year-old heterozygote, and her normal tissue carried both mutant and wild-type alleles of the human MSH2 gene. However the wild-type allele was lost at some point early during tumorigenesis so that DNA isolated either from the patient's ovarian tumor or from the 2774 cell line carries only the mutant allele of the human MSH2 gene. The genetic instability observed in the tumor and cell line DNA, together with the germ-line mutation in a mismatch-repair gene, suggest that the MSH2 gene is involved in the onset and/or progression in a subset of ovarian cancer.

Adult↗
PubMed1994

Oral verapamil inhibits platelet thrombus formation in humans.

BACKGROUND: Calcium antagonists such as verapamil are potent coronary and systemic vasodilators that are used in the treatment of coronary disease. They have also been shown to inhibit platelet aggregation in vitro, but whether they have beneficial antithrombotic effects in humans is unclear, and whether they can potentiate the antithrombotic effects of aspirin is unknown. METHODS AND RESULTS: Platelet thrombus formation and whole blood platelet aggregation were measured in 18 stable coronary patients on three separate occasions: at baseline when receiving no active medications, after 7 days of receiving oral verapamil SR (240 mg/d), and after 7 days of receiving a combination of oral verapamil SR and aspirin (325 mg/d). Thrombus formation on porcine aortic media that were placed into cylindrical flow chambers and exposed to flowing antecubital venous blood for 3 minutes was assessed morphometrically at a shear rate of 2546 s-1, which is typical of arterial flow at sites of stenoses. Thrombus formation under basal conditions was 7.0 +/- 1.6 microns 2, and this was decreased to 3.1 +/- 0.5 microns 2 (P < .05) after 7 days of treatment with oral verapamil SR and to 2.6 +/- 0.5 microns 2 (P < .05) after 7 days of treatment with oral verapamil and aspirin. Whole blood platelet aggregation levels in response to 0.050 and 0.075 U of thrombin at baseline were 10.8 +/- 1.0 and 11.9 +/- 1.0 omega; aggregation was inhibited after 7 days of treatment with verapamil to 6.5 +/- 1.1 and 7.8 +/- 0.9 omega (P < .05 versus baseline) and after 7 days of treatment with verapamil and aspirin to 6.1 +/- 1.1 and 7.2 +/- 1.0 omega (P < .05), respectively. CONCLUSIONS: The present study demonstrates that part of the benefit of verapamil in ischemic heart disease may occur by inhibition of platelet aggregation and thrombus formation. This beneficial antithrombotic effect may be important in preventing acute coronary ischemic events resulting from thrombus formation at sites of plaque rupture.

Administration, Oral↗
PubMed1993

Temporal sequence of endotoxin-induced systolic and diastolic myocardial depression in rabbits.

Twelve anesthetized rabbits received endotoxin (175 +/- 38 micrograms/kg i.v., mean +/- SD) to evaluate the temporal sequence of alterations in left ventricular (LV) function. LV volume was calculated from LV minor- and long-axis diameters, and wall thickness was measured with sonomicrometers. Hypotension, acidosis, and hypoxia were immediately corrected to eliminate these causes of myocardial depression. LV dilation developed early (1.2 +/- 0.5 h) with a significant (21 +/- 23%) increase in end-diastolic volume measured at a LV end-diastolic pressure of 5 +/- 6 mmHg. The LV stiffness did not change, and the LV dilation did not progressively worsen. Significant systolic depression developed later (2.8 +/- 1.0 h) with a 32 +/- 22% increase in end-systolic volume measured at a LV end-systolic pressure of 69 +/- 9 mmHg. The late preterminal phase (4.1 +/- 0.8 h) was characterized by a progressive increase in end-systolic volume (73 +/- 41% above control) and a significant (53 +/- 34%) increase in tau, the time constant of LV pressure fall. Diastolic abnormalities (LV dilation and increased tau) were not attributable to depressed contractility or altered hemodynamics. We conclude that endotoxin impairs systolic and diastolic LV function with distinct differences in time course. This suggests that contractility, relaxation, and passive LV properties are impaired by different endotoxin-mediated pathways and/or have different sensitivities to endotoxin.

Animals↗
PubMed1993

Cellular mechanisms of endotoxin-induced myocardial depression in rabbits.

We investigated the mechanisms by which endotoxic shock induces intrinsic myocardial depression by studying cardiac myocytes isolated from 10 anesthetized instrumented rabbits given 172 +/- 42 (mean +/- SD) micrograms/kg IV endotoxin. Left ventricular (LV) depression developed 4 +/- 1 hours after endotoxin administration, with a 15 +/- 4% increase in LV internal end-systolic diameter, measured with sonomicrometers at a matched LV end-systolic pressure of 65 +/- 10 mm Hg. Normal LV pressure, arterial PO2, and pH were maintained to minimize confounding effects of ischemia, hypoxia, and acidosis. Cardiac myocytes from endotoxin-exposed rabbits had less unloaded cell shortening and lower peak rates of cell shortening (-dL/dt) and lengthening (+dL/dt) at [Ca2+] levels ranging from 0.5 to 16 mM when compared with myocytes isolated from normal rabbits or rabbits undergoing an identical protocol but without exposure to endotoxin. At 2 mM [Ca2+], cell shortening was depressed by approximately 25% because of a decrease in action potential duration (207 +/- 70 versus 375 +/- 64 milliseconds). In contrast, there was only mild impairment of sarcoplasmic reticulum (SR) function. When myocytes were restimulated after rest periods of 4 to 480 seconds, the decrement in cell shortening (rest decay), peak -dL/dt and peak +dL/dt, and the recovery from rest decay were similar in myocytes from endotoxin-treated and normal rabbits. There was a greater decrement in cell shortening in the second beat of postrest recovery in myocytes from endotoxin-treated rabbits than in normal myocytes. This was partly due to a 12% decrement in action potential duration with rest decay, which did not occur in normal myocytes. The SR Ca2+ content assessed by contractures in 10 mM caffeine was similar in the two groups. We conclude that endotoxic shock produces a LV depression in vivo that persists in isolated myocytes studied in vitro. This intrinsic myocardial depression is largely related to endotoxin-mediated sarcolemmal alterations, which shorten action potential duration, and is not due to alterations in SR function.

Acidosis↗
PubMed1993

Detection of dysplasia and carcinoma in situ with a lung imaging fluorescence endoscope device.

The performance of a novel bronchoscopic fluorescence imaging system was compared with conventional white light bronchoscopy with a data base of 328 biopsy-confirmed sites from 53 patients and 41 volunteers. The two methods were found to have the same specificity (94%); however, the sensitivity of the fluorescence system (72.5%) was found to be 50% greater than that of the white light bronchoscopy (48.4%) in detecting dysplasia and carcinoma in situ. The fluorescence system uses a nonlinear discriminant function combining the red and green image intensity values to form a pseudoimage that, when displayed on an RGB monitor, allows the detection and delineation of abnormal areas. In 15% of the patients with lung cancer, synchronous carcinoma in situ was found in addition to the large invasive cancer. Of the current smokers in this study, 40% had moderate dysplasia and 12% had severe dysplasia. For the ex-smokers 25% had moderate dysplasia, 6% had severe dysplasia, and 13% had carcinoma in situ. Fluorescence imaging may become an important adjunct to conventional bronchoscopic examination to improve our ability to diagnose and stage lung cancer more accurately.

Aged↗
PubMed1992

Synthesis and antimalarial properties of 1-imino derivatives of 7-chloro-3-substituted-3,4-dihydro-1,9(2H,10H)-acridinediones and related structures.

To improve upon the activity and properties of the 3-aryl-7-chloro-3,4- dihydro-1,9(2H,10H)-acridinediones, a variety of 1-[(alkylamino)alkylene]imino derivatives (3) were prepared and shown to be highly active antimalarial agents in both rodents and primates. Among structural modifications prepared, including N10-alkyl and C2-substituted analogs, removal of the C9 oxygen, and introduction of an imino side chain at C9, the imines of the N10-H acridinediones were the most active compounds obtained. The [3-(N,N- dimethylamino)propyl]imino derivative of 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)- acridinedione (9aa) proved to be highly active in advanced studies in primates.

Acridines↗
PubMed1992

Detection of squamous cell cancer and pre-cancerous lesions by imaging of tissue autofluorescence in the hamster cheek pouch model.

Early detection of invasive and pre-invasive neoplasms of the aerodigestive tract will ultimately improve the management of patients with these lesions. This paper describes the use of quantitative fluorescence imaging of early squamous cell carcinomas in an animal model. Dysplasia, carcinoma in situ and invasive cancers were imaged exploiting tumour autofluorescence. Mapped biopsies were obtained from areas imaged determining a sensitivity of 100% and specificity of 80%. Autofluorescence imaging is an excellent method of detecting neoplasms of the aerodigestive tract.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Autofluorescence of normal and malignant bronchial tissue.

In vivo autofluorescence spectra were obtained in 5 patients with carcinoma in situ, 26 patients with invasive tumors, and 1 patient with severe dysplasia. Significant spectral differences were observed between pre-cancerous, cancerous, and normal bronchial tissues. This difference may afford a method to image and/or detect early lung cancer by using tissue autofluorescence alone.

Bronchi↗
PubMed1991

Collagen metabolism during healing of lacerated rabbit corneas.

We previously demonstrated that there are two waves of increased collagen synthesis following corneal laceration in rabbits. In the present study, we have examined whether increases in collagen synthesis and degradation result from increased amounts of mRNAs for collagen and collagenase, respectively. Rabbits were anesthetized by combined administration of ketamine (intramuscular) and pentobarbital (intravenous). A penetrating 8-mm incision was made at the center of each cornea. The lacerated corneas were allowed to heal for 0-49 days. The rabbits were then killed and the corneas excised. The total RNA was extracted from the tissue and subjected to slot-blot hybridization using 32P-labeled alpha 1(I) cDNA. The results indicate that there is a two-phase increase in the amount of alpha 1(I) mRNA in injured corneas and that the collagenase mRNA is elevated at most times throughout the healing period. However, the increase is collagenase mRNA may not fully account for the accelerated collagen degradation during corneal wound-healing. Thus, we propose that cells in the wound area may be directly involved in collagen degradation by phagocytosis. To examine our hypothesis, we cultured injured rabbit corneas in the presence or absence of leupeptin, a proteinase inhibitor. The tissues were then examined by electron microscopy. In the presence of leupeptin, lysosomes within fibroblasts or fibroblast-like cells in the wound area of the lacerated corneas healed for 2 and 3 weeks, contain collagen fibrils. In the absence of leupeptin no identifiable collagen was seen in the lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cellular delivery and retention of Photofrin II: the effects of interaction with human plasma proteins.

The absorbance and fluorescence spectra of Photofrin II (PII) in the presence of albumin, globulins and lipoproteins from human plasma show that all of these proteins induce a degree of disaggregation of PII material. In addition, there are substantial rearrangements in the distribution of different fractions contained in PII and their binding to the protein. It is shown that these rearrangements have considerable impact on the uptake of PII by cultured cells and the ensuing retention of the drug in the cells. The information on the contribution of fluorescing and non-fluorescing components of PII in the cells was obtained by measuring first the PII fluorescence in suspensions of live cells, followed by chemical extraction of porphyrin material from the same cells. The interaction of PII with low density lipoproteins resulted in markedly lower levels of PII material retained in the cells, compared to protein-free drug exposure. Somewhat better but still inferior PII retention was observed with high density lipoproteins. The samples with very low density lipoproteins showed increased uptake of PII, but the subsequent retention of the drug was low, so that the remaining amount of the drug was not much different than in protein-free samples. The strongest inhibition of PII uptake was seen with albumin, with ensuing retention of PII not significantly different than in protein-free samples. The best retention of PII was observed with globulins, with approx. 25% higher total drug content retained in the cells after long-term clearance relative to protein-free samples.

Biological Transport, Active↗