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Biomedical subjects

Y Chung

Publications and source records attributed to Y Chung.

At least 37 records · Page 2Linked to original sources
PubMed1999

A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors.

Mutations in the ras genes occur in 20% of all human cancers. These genes, in turn, produce mutated proteins that are unique to cancer cells, rendering them distinguishable from normal cells by the immune system. Thus, mutated Ras proteins may form potential targets for immune therapy. We conducted a phase I/pilot clinical trial in patients with advanced cancers to test the toxicity and the ability to induce an immune response by vaccination with 13-mer mutated Ras peptides reflecting codon 12 mutations. These peptides corresponded to each of the patient's own tumor Ras mutation. Patients were vaccinated monthly x3 subcutaneously with the specific Ras peptide along with Detox adjuvant (RiBi ImmunoChem Research, Inc., Hamilton, MT, U.S.A.) at one of five different peptide dose levels (100, 500, 1,000, 1,500, and 5,000 micrograms). Three out of 10 evaluable patients generated a mutant Ras specific CD4+ and/or CD8+ T-cell immune response. The CD8+ cytotoxic cells specific for Gly to Val mutation at codon 12 were capable of lysing an HLA-A2-matched tumor cell line carrying the corresponding mutant but not the wild-type ras gene. The treatment has been well tolerated with no evidence of serious acute or delayed systemic side effects on any of the five dose levels. We demonstrated that we can generate in cancer patients specific T-lymphocyte responses that detect single amino acid differences in Ras oncoproteins. Neither the immune responses nor the minor side effects seen were found to be dose dependent. This approach may provide a unique opportunity for generating a tumor-directed therapy. Also, in vitro stimulation of these cells with the corresponding peptide generated specific T-cell lines that could be used for adoptive immune therapy.

Adult↗
PubMed1999

Reconstruction of soft-tissue defects using serratus anterior adipofascial free flap.

The serratus anterior muscle has been suggested as a versatile and reliable flap for reconstruction of head and neck and extremity injuries. The adipofascial layer overlying the serratus anterior muscle is the anatomic layer, which is supplied by the same branch of thoracodorsal artery. Even though great progress has occurred in the prevention of postoperative adhesion of extremity injuries, the problem has not been completely solved and is still of special importance in complex injuries. Between March of 1995 and February of 1996, seven patients underwent reconstructive operation as a result of soft-tissue defects of the upper or lower extremities or the scalp. We transferred free adipofascial tissue overlying the serratus anterior muscle in three patients and both serratus anterior muscle and adipofascial tissue in four patients. A free adipofascial flap overlying serratus anterior muscle was transferred when a gliding surface was required, owing to the exposure of tendons and neurovascular structures. The average duration from operation to follow-up examination was 8 months (from 4 to 16 months). The results of the operations were satisfactory in functional and cosmetic aspects. This kind of flap was very effective in reconstruction of soft-tissue defects and gliding surfaces for these reasons: easy dissection, the capability of obtaining a long vascular pedicle, large-sized flap, composite flap including muscle or rib, and the fact that there was no serious functional or cosmetic deficit at the donor site.

Adult↗
PubMed1999

Regulation of respiration in myocardium in the transient and steady state.

1H/(31)P NMR has followed the metabolic response to increased work in the glucose- and pyruvate-perfused rat myocardium during a heart cycle and at the steady state. With electrical pacing and dobutamine, the heart O(2) consumption increases by 56%. The phosphocreatine (PCr) level initially declines, but recovers within 15 min to its control level; the oxymyoglobin (MbO(2)) saturation decreases by 15%. Because the MbO(2) signal reflects the intracellular PO(2), the capillary-to-cell O(2) gradient has increased to match the increased O(2) need. However, no transient metabolic fluctuation is observed in either PCr or MbO(2) throughout the entire cardiac cycle in both glucose and pyruvate-/glucose-perfused hearts. No systolic-diastolic variation is detectable under either high workload or hypoxic conditions. The results reveal that neither O(2) nor ADP is regulating respiration under increased energy demand in the steady or transient state.

Animals↗
PubMed1999

Comparative analysis of NMR and NIRS measurements of intracellular PO2 in human skeletal muscle.

1H NMR has detected both the deoxygenated proximal histidyl NdeltaH signals of myoglobin (deoxyMb) and deoxygenated Hb (deoxyHb) from human gastrocnemius muscle. Exercising the muscle or pressure cuffing the leg to reduce blood flow elicits the appearance of the deoxyMb signal, which increases in intensity as cellular PO2 decreases. The deoxyMb signal is detected with a 45-s time resolution and reaches a steady-state level within 5 min of pressure cuffing. Its desaturation kinetics match those observed in the near-infrared spectroscopy (NIRS) experiments, implying that the NIRS signals are actually monitoring Mb desaturation. That interpretation is consistent with the signal intensity and desaturation of the deoxyHb proximal histidyl NdeltaH signal from the beta-subunit at 73 parts per million. The experimental results establish the feasibility and methodology to observe the deoxyMb and Hb signals in skeletal muscle, help clarify the origin of the NIRS signal, and set a stage for continuing study of O2 regulation in skeletal muscle.

Adult↗
PubMed1999

Myoglobin desaturation with exercise intensity in human gastrocnemius muscle.

The present study evaluated whether intracellular partial pressure of O(2) (PO(2)) modulates the muscle O(2) uptake (VO(2)) as exercise intensity increased. Indirect calorimetry followed VO(2), whereas nuclear magnetic resonance (NMR) monitored the high-energy phosphate levels, intracellular pH, and intracellular PO(2) in the gastrocnemius muscle of four untrained subjects at rest, during plantar flexion exercise with a constant load at a repetition rate of 0.75, 0.92, and 1.17 Hz, and during postexercise recovery. VO(2) increased linearly with exercise intensity and peaked at 1.17 Hz (15. 1 +/- 0.37 watts), when the subjects could maintain the exercise for only 3 min. VO(2) reached a peak value of 13.0 +/- 1.59 ml O(2). min(-1). 100 ml leg volume(-1). The (31)P spectra indicated that phosphocreatine decreased to 32% of its resting value, whereas intracellular pH decreased linearly with power output, reaching 6.86. Muscle ATP concentration, however, remained constant throughout the exercise protocol. The (1)H NMR deoxymyoglobin signal, reflecting the cellular PO(2), decreased in proportion to increments in power output and VO(2). At the highest exercise intensity and peak VO(2), myoglobin was approximately 50% desaturated. These findings, taken together, suggest that the O(2) gradient from hemoglobin to the mitochondria can modulate the O(2) flux to meet the increased VO(2) in exercising muscle, but declining cellular PO(2) during enhanced mitochondrial respiration suggests that O(2) availability is not limiting VO(2) during exercise.

Adolescent↗
PubMed1999

Air pollution and daily mortality in Seoul and Ulsan, Korea.

The relationship between air pollution and daily mortality for the period 1991-1995 was examined in two Korean cities, Seoul and Ulsan. The observed concentrations of sulfur dioxide (SO2; mean = 28.7 ppb), ozone (O3; mean = 29.2 ppb), and total suspended particulates (TSP; mean = 82.3 microg/m3) during the study period were at levels below Korea's current ambient air quality standards. Daily death counts were regressed separately in the two cities, using Poisson regression on SO2, O3, and/or TSP controlling for variability in the weather and seasons. When considered singly in Poisson regression models controlling for seasonal variations and weather conditions, the nonaccidental mortality associated with a 50-ppb increment in a 3-day moving average of SO2 concentrations, including the concurrent day and the preceding 2 days, was 1.078 [95% confidence interval (CI), 1.057-1.099] for Seoul and 1.051 (CI, 0.991-1.115) for Ulsan. The rate ratio was 1.051 (CI, 1.031-1.072) in Seoul and 0.999 (CI, 0. 961-1.039) in Ulsan per 100 microg/m3 for TSP, and 1.015 (CI, 1. 005-1.025) in Seoul and 1.020 (0.889-1.170) in Ulsan per 50 ppb for 1-hr maximum O3. When TSP was considered simultaneously with other pollutants, the TSP association was no longer significant. We observed independent pollution effects on daily mortality even after using various approaches to control for either weather or seasonal variables in the regression model. This study demonstrated increased mortality associated with air pollution at both SO2 and O3 levels below the current World Health Organization recommendations.

Air Pollutants↗
PubMed1998

Optical design of the U7 undulator beamline at the Pohang Light Source.

The first insertion-device beamline at the Pohang Light Source is designed for high-resolution spectroscopy and spectromicroscopy. The beamline will contain a variable-included-angle plane-grating monochromator (VIA-PGM) using a grating substrate which has seven different grooves with different depths. The advantages of this scheme will be the fixed exit-slit position and the mechanical stability of the grating scan mechanism while changing the photon energy range. The beamline is designed to cover the photon energy range 20-2000 eV. The estimated spectral resolution, E/DeltaE, is above 8000 in the photon energy range below 500 eV, and above 4000 for the remaining photon energy range. The estimated flux at the end-station is of the order of 10(12) photons s(-1) (0.1% bandwidth)(-1).

Journal Article↗
PubMed1998

Metabolic fluctuation during a muscle contraction cycle.

Gated 31P-nuclear magnetic resonance followed the metabolic fluctuation in rat gastrocnemius muscle during a contraction cycle. Within 16 ms after stimulation, the phosphocreatine (PCr) level drops 11.3% from its reference state. The PCr minimum corresponds closely to the time of maximum force contraction. Pi increases stoichiometrically, while ATP remains constant. During a twitch, PCr hydrolysis produces 3.1 mumol ATP/g tissue, which is substantially higher than the reported 0.3 mumol ATP.twitch-1.g tissue-1 derived from steady-state experiments. The results reveal that a substantial energy fluctuation accompanies a muscle twitch.

Adenosine Triphosphate↗
PubMed1998

Carbon monoxide inhibition of regulatory pathways in myocardium.

The 1H nuclear magnetic resonance (NMR) myoglobin (Mb) Val E11 signal provides a unique opportunity to assess the functional role of Mb in the cell. On CO infusion in perfused myocardium, the MbO2 signal at -2.76 parts per million (ppm) gradually disappears, whereas the corresponding MbCO signal emerges at -2.26 ppm, reflecting the state of Mb inhibition. Up to 76.8% MbCO saturation, myocardial O2 consumption (MVO2) remains constant, whereas the rate-pressure product (RPP) has already dropped to 92% of the control level. At 87.6% MbCO saturation, the lactate formation rate has increased by a factor of two, and MVO2 begins to decline. However, the ratio CO/O2 is still 1/10, well below the inhibition threshold for cytochrome oxidase activity. The MVO2 decline in the face of an adequate O2 supply and an unperturbed high-energy phosphate level implies that Mb may play a role in directly regulating respiration, mediated potentially by a shift in NADH/NAD. Although nitrite inhibits Mb, nitrite also directly affects the myocardial function.

Adenosine Triphosphate↗
PubMed1997

Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations.

Previous studies have identified and characterized both murine in vivo and human in vitro T cell responses reflecting specific mutations in the ras proto-oncogenes at codon 12, 13, or 61. In an attempt to determine whether peptide epitopes reflecting point mutations in the ras oncogenes are immunogenic in humans for the production of CD4+ and/or CD8+ T cell responses, a phase I clinical trial was initiated in metastatic carcinoma patients whose primary tumors harbor mutations in the K-ras proto-oncogenes at codon 12. The peptides used here as immunogens, which were administered in Detox adjuvant, spanned the ras sequence 5-17 and reflected the amino acid substitution of glycine (Gly) at position 12 to aspartic acid (Asp), cysteine (Cys), or valine (Val). Three of eight evaluable patients have demonstrated peptide-specific cell-mediated immunity, as determined by the production of T cell lines resulting from the vaccination. First, an antigen (Ag)-specific, major histocompatibility complex (MHC) class II (DP)-restricted CD4+ T cell line was established in vitro from postvaccination lymphocytes of a non-small cell lung carcinoma patient whose primary tumor contained a Cys12 mutation when cultured on the immunizing peptide. Moreover, CD4+ proliferation was inducible against the corresponding mutant K-ras protein, suggesting productive T cell receptor recognition of exogenously processed Ag. Second, an Ag-specific, MHC class I (HLA-A2)-restricted CD8+ cytotoxic T lymphocyte (CTL) line was established in vitro from postvaccination lymphocytes of a colon carcinoma patient whose primary tumor contained an Asp12 mutation. To that end, a 10-mer peptide, nested within the 13-mer immunizing peptide, was identified [i.e., ras5-14(Asp12)], which was shown to bind to HLA-A2 and display specific functional capacity for expansion of the in vivo primed CD8+ CTL precursors. Third, both Ag-specific, MHC class II (DQ)-restricted CD4+ and MHC class I-restricted (HLA-A2) CD8+ T cell lines were generated from a single patient with duodenal carcinoma whose primary tumor contained a Val12 mutation when cultured on the immunizing 13-mer peptide or a nested 10-mer peptide [i.e., ras5-14(Val12)], respectively. Evidence is thus provided that vaccination with mutant ras oncogene peptides in adjuvant may induce specific anti-ras cellular immune responses, with no detectable cross-reactivity toward normal proto-ras sequences. Moreover, we have identified for the first time human HLA-A2-restricted, CD8+ CTL epitopes reflecting specific point mutations in the K-ras oncogenes at codon 12 which, in concert with the activation of the CD4+ T cell response, may have important implications for both active and passive immunotherapies in selected cancer patients.

Adult↗
PubMed1997

Myoglobin and hemoglobin rotational diffusion in the cell.

The detection of the 1H NMR signal of myoglobin (Mb) in tissue opens an opportunity to examine its cellular diffusion property, which is central to its purported role in facilitating oxygen transport. In perfused myocardium the field-dependent transverse relaxation analysis of the deoxy Mb proximal histidyl NdeltaH indicates that the Mb rotational correlation time in the cell is only approximately 1.4 times longer than it is in solution. Such a mobility is consistent with the theory that Mb facilitates oxygen diffusion from the sarcoplasm to the mitochondria. The microviscosities of the erythrocyte and myocyte environment are different. The hemoglobin (Hb) rotational correlation time is 2.2 longer in the cell than in solution. Because both the overlapping Hb and Mb signals are visible in vivo, a relaxation-based NMR strategy has been developed to discriminate between them.

Animals↗
PubMed1997

[Current status of low-dose CDDP. 5-FU therapy for solid malignant tumors--nationwide questionnaire survey].

A nation-wide questionnaire survey was undertaken concerning low-dose anticancer therapy of CDDP plus 5-FU, which involves (5-10 mg CDDP/body/day + 300-500 mg/body/day) for 4-6 weeks. Out of 1,525 cases from 130 institutions, 847 cases with evaluable lesions were collected from 79 institutions. The response rate was 56.4% in esophageal cancer, 34.3% in gastric cancer, 35.3% in colorectal cancer, 47.2% in liver cancer and 35.9% in lung cancer, respectively. Adverse effects were found to be fewer and compliance was much better than the conventional therapy. Such figures suggest that the present regimen may be more effective than any so far. Problems for medical administration such as unlicensed CDDP for colorectal cancer were pointed out, which hinder the forthcoming third phase study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Cellular response to reperfused oxygen in the postischemic myocardium.

Perfused rat heart experiments focused on determining the critical O2 level in postischemic myocardium. After a 20-min global ischemia, reperfusion began with O2-saturated saline buffer reflowing at different rates (0.5-12 ml/min). The 1H nuclear magnetic resonance (NMR) signal of the Val E11 myoglobin (Mb) gave an index of the intracellular oxygenation, whereas the 31P-NMR spectra reflected the high-energy phosphate and pH status. At the same time, physiological monitors recorded both contractile function and O2 consumption. Biochemical analysis determined the lactate concentration. Within 6-12 min of reperfusion, the O2 reached a new steady state, which depended directly on the flow rate. Below 12 ml/min reflow, the postischemic O2 level was consistently lower than the corresponding control values. Phosphocreatine, P(i), pH, myocardial O2 consumption, and lactate formation rate exhibited a similar linear relationship with MbO2 saturation in both the control and postischemic myocardium. It appears that neither the cellular energy production nor the steep intracellular O2 gradient has changed substantially in the postischemic myocardium.

Animals↗
PubMed1996

Nitrite oxidation of myoglobin in perfused myocardium: implications for energy coupling in respiration.

Nitrite oxidation of oxymyoglobin in perfused rat myocardium under nonlimiting oxygen produces a detectable 1H nuclear magnetic resonance metmyoglobin (metMb) signal at -3.9 ppm. When the myocardium is perfused with < 10 mM nitrite, the 1H nuclear magnetic resonance MbO2 gamma CH3 Val E11 signal does not change intensity and the metMb reporter signal at -3.9 ppm is undetectable. However the rate pressure product decreases by 26% from the control level. Phosphocreatine, myocardial oxygen consumption, Pi, ATP, and pH remain constant. With > 10 mM infused nitrite, myoglobin (Mb) oxidation becomes apparent. As the MbO2 gamma CH3 Val E11 signal intensity decreases, the metMb signal intensity at -3.9 ppm increases. At the same time the 31P high-energy phosphate signals, rate pressure product, and lactate formation exhibit significant alterations. Myocardial oxygen consumption, however, remains constant. The data indicate that Mb oxidation does not limit myocardial respiration but does reduce energy production. Pulse-recovery experiments further demonstrate that a transient perfusion with 2 mM infused nitrite depresses the contractile function, which does not recover during reperfusion with oxygenated, nitrite-free buffer. The findings support the view that either Mb mediates energy coupling or nitrite directly uncouples energy production in myocardium. They also reveal a glimpse of the intracellular reductase activity that maintains the Mb in the Fe (II) state.

Animals↗
PubMed1996

Bronchial arteriovenous malformation in a child with hemoptysis. A case report.

Pulmonary arteriovenous (AV) malformations occur sporadically and in the pediatric population are most commonly associated with hereditary hemorrhagic telangiectasia. Hemoptysis is an infrequent presentation in this age group. Pulmonary angiography is considered to be the definitive diagnostic modality. The authors describe an otherwise healthy eleven-year- old girl who presented with massive hemoptysis secondary to a large bronchial AV malformation unrelated to any congenital anomalies. The pulmonary angiogram appeared normal and the diagnosis was established by digital subtraction aortography. Successful embolotherapy was performed by selective injection of polyvinyl alcohol particles into the culprit bronchial artery.

Arteriovenous Malformations↗
PubMed1996

Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics.

PURPOSE: COL-1 is a high-affinity murine monoclonal antibody (MAb) specific for carcinoembryonic antigen (CEA). A phase I trial was conducted in which a uniform quantity of antibody labeled with escalating doses of iodine 131 (131I) was administered to patients with advanced gastrointestinal (GI) malignancies to evaluate tolerance and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients with advanced, assessable GI malignancies (16 colon, one pancreas, and one gastric) previously treated with conventional chemotherapy (but no pelvic radiation) received 20 mg of COL-1 labeled with 131I, with doses from 10 mCi/m2 to 75 mCi/m2. In this cohort, the baseline serum CEA level ranged from 6 to 2,739 ng/mL (mean +/- SD, 500 +/- 639). RESULTS: Nuclear imaging detected at least one tumor site in all 18 patients; 82% of all tumor involved organs were positive and 58% of all lesions > or = 1.0 cm were detected. Immune complexes were detected in 89% of patients 5 minutes after completion of infusion, and levels correlated with CEA levels (r = .71). Elevated CEA (> 500 ng/mL) and tumor bulk (total tumor area > 150 cm2) correlated directly with clearance of serum radioactivity and inversely with serum half-life and cumulative serum radioactivity parameters. Nonhematologic toxicity was mild and non-dose-limiting. Hematologic toxicity, particularly thrombocytopenia, was both dose-related and dose-limiting. The maximal-tolerated dose is 65 mCi/m2. The correlation between dose (millicuries per square meter) and thrombocytopenia was made stronger, by accounting for either variation in pharmacokinetics, or variation in serum CEA and tumor bulk. CONCLUSION: 131I-COL-1 is well tolerated, except for hematologic toxicity. These data suggest that patients with highly elevated circulating CEA levels and/or increased tumor bulk may clear 131I-labeled COL-1 more rapidly from the circulation and experience less myelosuppression.

Antibodies, Monoclonal↗
PubMed1995

Differential in vivo regulation of mRNA encoding the norepinephrine transporter and tyrosine hydroxylase in rat adrenal medulla and locus ceruleus.

To investigate the regulation of norepinephrine transporter mRNA in vivo, we analyzed the effects of reserpine on its expression in the rat adrenal medulla and locus ceruleus. First, PCR was used to clone a 0.5-kb rat cDNA fragment that exhibits 87% nucleotide identity to the corresponding human norepinephrine transporter cDNA sequence. In situ, the cDNA hybridizes specifically within norepinephrine-secreting cells, but in neither dopamine nor serotonin neurons, suggesting strongly it is a partial rat norepinephrine transporter cDNA. Reserpine, 10 mg/kg administered 24 h premortem, decreased steady-state levels of norepinephrine transporter mRNA in the adrenal medulla by approximately 65% and in the locus ceruleus by approximately 25%, as determined by quantitative in situ hybridization. Northern analysis confirmed the results of the in situ hybridization analysis in the adrenal medulla but did not detect the smaller changes observed in the locus ceruleus. Both analyses showed that reserpine increased tyrosine hydroxylase expression in the adrenal medulla and locus ceruleus. These results suggest that noradrenergic neurons and adrenal chromaffin cells can coordinate opposing changes in systems mediating catecholamine uptake and synthesis, to compensate for catecholamine depletion.

Adrenal Medulla↗