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Biomedical subjects

A W Lee

Publications and source records attributed to A W Lee.

At least 19 recordsLinked to original sources
PubMed1992

Functional dissection of structural domains in the receptor for colony-stimulating factor-1.

Receptor tyrosine kinases (RTKs) transduce external signals to the interior of the cell via a cytoplasmic kinase domain. We demonstrated previously that ligand-induced kinase activation of the colony-stimulating factor-1 receptor (CSF-1R) occurs via receptor oligomerization without propagation of conformational changes through the transmembrane (TM) domain (Lee, A. W., and Nienhuis, A. W. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 7270-7274). We have now examined the role of the different subdomains in the metabolic and signaling properties of CSF-1R. Two types of chimeric receptors have been utilized, Glyfms A, with the extracellular and TM domains of glycophorin A (GpA) and the cytoplasmic domain of CSF-1R, and Glyfms B, where only the extracellular domain originates from GpA. Glyfms A was found to exhibit a higher basal level of in vitro kinase activity, an increased associated phosphatidylinositol (PtdIns) 3-kinase activity and to support enhanced cellular mitogenesis, compared with wild-type CSF-1R or to Glyfms B. The constitutive activation of Glyfms A is consistent with the hypothesis that the TM domain may play a role in receptor oligomerization. Cross-linking with anti-GpA antibodies activated the kinase function of Glyfms B leading to an increase in PtdIns 3-kinase association and to the transmission of a mitogenic signal. Our results indicate that an activated kinase domain contains the major determinant for coupling with PtdIns 3-kinase, independent of extracellular and TM sequences and of ligand binding. Both chimeric receptors underwent internalization in the presence of anti-GpA antibodies but were not degraded, including the tyrosine-phosphorylated and kinase-active population. These results suggest that structural determinants in the extracellular domain must be important for targeting internalized receptors for lysosomal degradation.

Animals↗
PubMed1992

Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure.

This is a retrospective analysis of 5037 patients with squamous cell carcinoma of the nasopharynx treated during the years 1976-1985. The stage distribution according to Ho's classification was 9% Stage I, 13% II, 50% III, 22% IV, and 6% Stage V. Only 4488 (89%) patients had a full course of megavoltage radiation therapy. The median equivalent dose to the nasopharyngeal region was 65 Gy and cervical region in node-positive patients 53 Gy. Seventy percent (906/1290) of the node-negative patients had no prophylactic neck irradiation. The overall actuarial 10-year survival rate was 43%, and the corresponding failure-free survival 34%. Altogether, 4157 (83%) patients achieved complete remission lasting more than 6 months, but 53% (2205/4157) of them relapsed after a median interval of 1.4 years. The 10-year actuarial local, regional, and distant failure-free rates were 61%, 64%, and 59%, respectively. Thirty-eight percent (338/891) of all patients with local recurrence achieved second local remission. The local complete remission rate with aggressive re-irradiation alone was 47% (333/706). But 37% (124/338) of the responders recurred the second time. The incidence of distant failure correlated significantly with both the N-stage and the T-stage, with the highest (57%) occurring in patients with N3 disease. The incidence of nodal relapse in node-negative patients was 11% (44/384) among those given prophylactic neck irradiation, but 40% (362/906) among those without. Therapeutic irradiation achieved a complete regional remission rate of 90% (306/339). However, despite successful salvage, these patients had a significantly higher distant failure rate than those without nodal relapse, even if they remained local-failure-free (21% vs 6%). Patients treated during 1981-1985 achieved significantly better treatment results than those treated during 1976-1980, especially in terms of the overall survival (57% vs 47% at 5-year), the overall failure-free survival (42% vs 35% at 5-year), and the local failure-free rate (70% vs 63% at 5-year). The possible contributing factors are discussed.

Adolescent↗
PubMed1992

Retrospective analysis of nasopharyngeal carcinoma treated during 1976-1985: late complications following megavoltage irradiation.

A retrospective analysis was undertaken of the late complications observed in 4527 patients with nasopharyngeal carcinoma treated by megavoltage radiotherapy during the years 1976-1985. Unconventional fractionation schedules were used because of serious resource limitations. The median equivalent doses were 65 Gy to the nasopharyngeal region and 53 Gy to the cervical region. 707 patients had reirradiation for local recurrences and 250 for regional relapses. The 10-year actuarial cancer-specific survival was 47%, and the corresponding all-complication-free and neurological-complication-free rates were 40% and 72%, respectively. Altogether, 1395 (31%) patients developed one or more late irradiation sequelae. The majority were mild soft-tissue damages, but 322 (7%) had significant functional disturbances, from which 62 (1%) died. Neurological damage that occurred in 450 (10%) patients constituted the major morbidity and accounted for all but three of the treatment mortalities. The cumulative incidence of the various complications is summarized, and the data recorded in the literature reviewed in order to give a proper perspective of the problem. Patients treated during 1981-1985 had a significantly higher actuarial encephalomyelopathy-free rate than those treated during 1976-1980, but the incidence-free rates for the other neurological complications remained unimproved, suggesting that the improvement could be mainly attributed to additional shielding for the brainstem rather than the reduction of dose from 3.8-4.2 Gy to 2.5 Gy per fraction.

Adolescent↗
PubMed1992

Variable pattern of jun and fos gene expression in different hematopoietic cell lines during interleukin 3-induced entry into the cell cycle.

Jun (c-jun, jun-B and jun-D) and fos (c-fos, fos-B and fra) proteins dimerize to form the family of AP-1 transcriptional activators. If each dimer exhibits unique transactivating properties, then any phenotypic change should show a characteristic pattern of jun and fos expression. To test this hypothesis we have assessed jun and fos RNA expression after stimulation of the factor-dependent cell lines 32D and FDCP1. These hematopoietic progenitor lines become quiescent in G0/G1 after interleukin 3 (IL-3) deprivation, and upon stimulation synchronously enter the cell cycle. 32D cells respond to IL-3 with rapid induction of jun-B and c-fos, followed by induction of jun-D and fra-1, but no rise in c-jun expression. FDCP1 cells show a very different pattern, with induction of c-jun, jun-D and fra-1. To investigate the response of a single cell line to different physiological stimuli we used a 32D subclone engineered to respond to colony stimulating factor 1 (CSF-1). This subclone showed identical induction of jun and fos after stimulation with either CSF-1 or IL-3. The conservation of response of a single cell line, but the disparate patterns demonstrated by different cells, suggest a fundamental difference in both the regulation and function of the fos/jun complexes in these cells.

Blotting, Northern↗
PubMed1992

Absorbable suture improves growth of venous anastomoses.

Growth of vascular anastomoses is desirable in pediatric vascular surgery, especially in pediatric organ transplantation. Although absorbable suture has been shown to be superior to nonabsorbable suture in permitting growth of arterial anastomoses, the optimal suture material for venous anastomoses has not been established. To examine this in a porcine model, we performed bilateral primary end-to-end anastomoses of transected external jugular veins in 10, 4-week-old piglets. In each piglet one anastomosis was constructed with continuous absorbable 8-0 polyglyconate suture, whereas the contralateral anastomosis was constructed with continuous nonabsorbable 8-0 polypropylene suture. After 6 months the veins were excised, pressure fixed at 15 mm Hg for 2 hours, and examined grossly and histologically. Vein diameter was measured by contrast radiography at the anastomosis and 1 cm proximal and distal to the anastomosis. Vein cross-sectional area 1 cm from the anastomosis was similar in the two groups: polyglyconate 95.7 +/- 12.3 mm2 versus polypropylene 95.3 +/- 9.7 mm2. However, polyglyconate anastomoses had greater cross-sectional area (polyglyconate 72.8 +/- 7.9 mm2 vs polypropylene 51.8 +/- 6.0 mm2; p < 0.05). In addition, at 6 months polyglyconate anastomoses had a greater percentage of growth (polyglyconate 207% vs polypropylene 118%; p < 0.05) compared with native vein cross-sectional area (23.7 +/- 0.39 mm2) from control pigs at 4 weeks of age. On histologic examination, polyglyconate had dissolved entirely in six cases and was present but in varying degrees of dissolution in the other four; in contrast, polypropylene was identifiable at all anastomoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1990

Magnetic resonance imaging in the clinical diagnosis of late temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma.

Magnetic resonance imaging (MRI) and computed tomography (CT) were performed on 13 patients with clinical features of late temporal lobe damage following radical radiotherapy for nasopharyngeal carcinoma, and their results compared. MRI was undoubtedly superior in sensitivity--revealing areas of prolonged T2 relaxation time in the inferior portions of the temporal lobes in all patients, while CT failed to show any gross abnormalities in seven. In patients with large lesions well-depicted on CT, the corresponding MRI changes were comparable in shape and extent. But MRI gave an additional sign for the presence of liquefactive necrosis, and revealed lesions in the contralateral lobes in two out of three patients with unilateral CT changes. Besides obvious improvement in detection rate, the contribution of MRI to the better selection of treatment protocols, and to the understanding of the pathological process are discussed.

Adult↗
PubMed1990

Mechanism of kinase activation in the receptor for colony-stimulating factor 1.

Receptor tyrosine kinases remain dormant until activated by ligand binding to the extracellular domain. Two mechanisms have been proposed for kinase activation: (i) ligand binding to the external domain of a receptor monomer may induce a conformational change that is transmitted across the cell membrane (intramolecular model) or (ii) the ligand may facilitate oligomerization, thereby allowing interactions between the juxtaposed kinase domains (intermolecular model). The receptor for colony-stimulating factor 1 was used to test these models. Large insertions at the junction between the external and transmembrane domains of the receptor, introduced by site-directed mutagenesis of the cDNA, were positioned to isolate the external domain and prevent transmembrane conformational propagation while allowing for receptor oligomerization. Such mutant receptors were expressed on the cell surface, bound ligand with high affinity, exhibited ligand-stimulated autophosphorylation, and signaled mitogenesis and cellular proliferation in the presence of ligand. A second experimental strategy directly tested the intermolecular model of ligand activation. A hybrid receptor composed of the external domain of human glycophorin A and the transmembrane and cytoplasmic domains of the colony-stimulating factor 1 receptor exhibited anti-glycophorin antibody-induced kinase activity that supported mitogenesis. Our data strongly support a mechanism of receptor activation based on ligand-induced receptor oligomerization.

Amino Acid Sequence↗
PubMed1989

Cryoablation of septal pathways in patients with supraventricular tachyarrhythmias.

Eighteen patients with supraventricular tachycardia refractory to medical therapy underwent preoperative electrophysiological study and subsequent operation. There were 6 female and 12 male patients ranging in age from 1.5 to 31.6 years (mean age, 11.9 +/- 7.8 years). Eleven had classic Wolff-Parkinson-White syndrome with intermittent tachycardia, and 7 had a form of permanent junctional reciprocating tachycardia. Five had impaired left ventricular function preoperatively. The location of the accessory conduction pathway was anteroseptal in 3, posteroseptal in 12, and both anteroseptal and posteroseptal in 3 patients. Pathway location was confirmed by intraoperative mapping in all patients. The pathways were ablated utilizing a cryoprobe at -70 degrees C. All patients survived the operation, had immediate abolishment of delta waves and tachycardia, and were considered cured at the time of hospital discharge. Sixteen (89%) remain cured at a mean follow-up of 16.9 months. One patient with a posteroseptal pathway no longer has a delta wave but has had poorly documented episodes of tachycardia and is taking medication. One other patient with both anteroseptal and posteroseptal pathways had a recurrent delta wave 6 months postoperatively but has had no tachycardia and is asymptomatic without medication. No patient experienced heart block. Ventricular function has returned to normal in all 5 patients with impaired function preoperatively. Cryoablation is an effective method of abolishing accessory conduction pathways located in the anteroseptal or posteroseptal region. The method is easy, and results are comparable with those of other techniques previously described.

Adolescent↗
PubMed1989

Treatment of stage I nasopharyngeal carcinoma: analysis of the patterns of relapse and the results of withholding elective neck irradiation.

This is a retrospective analysis of 196 patients with nasopharyngeal carcinoma Stage I (Ho's classification) treated by megavoltage radiation during 1980-1984. The primary target volume included all potential sites of local invasion and the first station lymph nodes at retropharyngeal spaces. Two different dose schedules were used, both gave a total tumor dose biologically equivalent to 65 Gy by conventional fractionation, and both achieved a 5-year actuarial local-recurrence-free survival of 88%. Elective neck irradiation was withheld in all except seven patients. The overall 7-year actuarial survival was 85%, but the relapse-free survival was only 62%. The patterns of relapse, prognostic factors, and treatment complications were analyzed. Eighteen patients (9%) recurred locally. Radical retreatment with radiation achieved complete remission in seven out of fifteen cases. Distant failure occurred in 17 patients (9%). Although 57 (30%) of the 189 patients without elective neck irradiation subsequently showed lymph node involvement, none of the seven regionally-treated patients relapsed. The successful regional salvage rate was 81% overall (46 out of 57 patients), but 90% (44 of 49) for those properly treated with whole neck irradiation. However, the 7-year actuarial survival was lower in patients with nodal relapse than those without (70% versus 87%) because of the associated higher incidence of hematogenous dissemination. The various aspects of treatment, the value of elective neck irradiation in particular, are discussed.

Adult↗
PubMed1988

Clinical diagnosis of late temporal lobe necrosis following radiation therapy for nasopharyngeal carcinoma.

This is a preliminary report of 102 patients with clinical diagnosis of late temporal lobe necrosis after radical radiation therapy for nasopharyngeal carcinoma during 1964 to 1983. Histologic verification was available in 12 cases. All but three patients had been treated in our institute using schedules with doses larger than the conventional 200 cGy per fraction. The incidence rate was 1.03%. In our 80 patients with only one course of external irradiation, the doses to the temporal lobes ranged from 1665 to 2127 ret, or 1286 to 1778 brain tolerance unit (btu). The latent interval ranged from 9 months to 16 years. The median observation period is 33 months. The symptomatology, working diagnosis, treatment, and outcome are described. Surgery was hazardous because of the bilaterality of the involvement and exploration for mere verification of diagnosis was unjustified in typical cases. Treatment with corticosteroid achieved durable objective response in 25 (35%) of 72 patients. The importance of early detection and corticosteroid treatment is discussed.

Adult↗
PubMed1988

Analysis of proton release in oxygen binding by hemoglobin: implications for the cooperative mechanism.

The relationship in hemoglobin between cooperativity (dependence of the Hill constant on pH0 and the Bohr effect (dependence of the mean oxygen affinity on pH) can be described by a statistical thermodynamic model [Szabo, A., & Karplus, M. (1972) J. Mol. Biol. 72, 163-197; Lee, A., & Karplus, M. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 7055-759]. In this model, salt bridges and other interactions serve to couple tertiary and quaternary structural changes. To test and refine the model, it is applied to the analysis of the pH dependence of the tetramer Adair constants corrected for statistical factors (K4i', i = 1-4). Attention is focused on the proton release of the first (delta H1+ = alpha log K41'/alpha pH) and last (delta H4+ = alpha log K44'/alpha pH) oxygenation steps, where K4i' are the Adair constants corrected for statistical factors. Measurements of delta H1+ and delta H4+ under carefully controlled conditions are reported, and good agreement between the model calculation and these experimental results is obtained. The salt bridges are found to be partially coupled to the ligation state in the deoxy quaternary structure; it is shown that a Monod-Wyman-Changeux-type model, in which the salt bridges are coupled only to quaternary structural change, is inconsistent with the data for delta H1. The significance of the present analysis for an evaluation of the Perutz mechanism [Perutz, M.F. (1970) Nature (London) 228, 726-734, 734-739] and other models for hemoglobin cooperativity is discussed.

Humans↗
PubMed1988

Superior vena cava bypass: use of the azygos vein.

Unexpected involvement of the superior vena cava with dense inflammatory and fibrous tissue was encountered during right pneumonectomy for a T3 N0 M0 squamous cell carcinoma. After expeditiously completing the lung resection, the azygos vein was utilized for a successful superior vena cava bypass.

Azygos Vein↗
PubMed1987

Symptomatic hypothalamic-pituitary dysfunction in nasopharyngeal carcinoma patients following radiation therapy: a retrospective study.

Endocrine assessment was performed in 32 relapse-free southern Chinese patients (21 males and 11 females, aged 27-50 years at the time of assessment) 5-17 years following radiation therapy (RT) alone for early nasopharyngeal carcinoma (NPC). Initial screening was done using questionnaires emphasizing on impaired sexual function and menstrual disturbance plus measurement of serum levels of thyroxine, free thyroxine index, thyrotropic hormone, prolactin, and additionally testosterone for males only. Those showing abnormalities were subjected to detailed pituitary function tests. Hypothalamic-pituitary dysfunction was found in 7 female patients and only 1 male patient. A delayed TSH response to thyrotropin releasing hormone suggesting a hypothalamic disorder was seen in 6 of the affected female patients, and hyperprolactinaemia in also 6. None of the patients had evidence of diabetes insipidus. Hypopituitarism became symptomatic 2-5 years after RT with a mean latent interval of 3.8 years. A practical protocol for regular endocrine assessment for NPC patients after RT has been proposed. Multiple linear regression analysis of the radiotherapeutic data from the 11 female patients indicates that the likelihood of late occurrence of symptomatic hypothalamic-pituitary dysfunction following RT is dependent on the TDF of the target dose to the nasopharyngeal region and the height of the upper margin of the opposed lateral facial fields above the diaphragma sellae (coefficient of multiple correlation = 0.9025). Except when the sphenoid sinus or the middle cranial fossa is involved, it is advisable to set the height of the upper margin of the lateral facial field at a level no higher than the diaphragma sellae. The hypothalamus and possibly the pituitary stalk as well may sustain permanent damage by doses of radiation within the conventional radiotherapeutic range for carcinomas.

Adult↗
PubMed1987

Axillary artery aneurysm as an occult source of emboli to the upper extremity.

Reported here is a case of axillary artery aneurysm secondary to crutch trauma as a source of emboli to the upper extremity. This patient along with several reported in the literature was initially diagnosed and treated for brachial artery embolism. It is believed that awareness of this entity as a cause of forearm and hand ischemia is important in planning the appropriate surgical therapy.

Aneurysm↗
PubMed1986

Technetium-99m BIDA biliary scintigraphy in the evaluation of the jaundiced patient.

Biliary scintigraphy using 99mTc p-butyl acetanilidiminodiacetic acid (BIDA) was performed as part of the diagnostic evaluation on 96 patients with jaundice (serum bilirubin greater than 2 mg/dl) to assess its value in this group of patients. The results of scintigraphy revealed no obstruction to the flow of the scintigraphic agent into the duodenum in 54 patients, delayed appearance of the agent (normal upper limit 60 min) in the duodenum indicating partial obstruction in 22 patients, and complete obstruction of the duct demonstrated by absence of agent in the duodenum in 20 patients. The findings were correlated with the final diagnosis and the overall results show accuracy of 92.7%, sensitivity of 97.3%, and specificity of 89.8%. Biliary scintigraphy was thus found to be useful in differentiating nonobstructive, partially obstructive, and completely obstructive causes of jaundice.

Adolescent↗