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W R Lee

Publications and source records attributed to W R Lee.

At least 127 records · Page 7Linked to original sources
PubMed1995

Mutation spectrum of 2-chloroethyl methanesulfonate in Drosophila melanogaster premeiotic germ cells.

The 2-chloroethyl methanesulfonate (2ClEMS)-induced alcohol dehydrogenase (Adh) null germline mutation frequency in treated Drosophila melanogaster second instar larval gonia was two orders of magnitude greater than the spontaneous mutation frequency. DNA sequence analysis of 83 Adh null mutations showed that 40 mutations of independent origin were at 23 sites in the Adh gene. The mutation spectrum contained only GC-->AT transitions with 35 mutations (87.5%) at the middle or 3' guanine. In addition, characteristics of glutathione (GSH)-mediated bioactivation were determined for 2ClEMS in vitro. Rates of GSH-mediated conjugation, catalyzed by purified rat liver glutathione-S-transferase (GST), and binding of [35S]GSH-mediated conjugation products to calf thymus DNA were determined for 2ClEMS, 1,2-dichloroethane (EDC) and 1,2-dibromoethane (EDB). The relative rates of GSH-mediated conjugation were the following: 5 mM EDB > 40 mM 2ClEMS > 40 mM EDC. A similar trend was observed for DNA binding of the [35S]GSH-mediated conjugation products when differences in mutagen concentration were considered: EDB > 2ClEMS > EDC. The ratios of DNA binding to GSH conjugation calculated for EDB, EDC and 2ClEMS were 6.8 x 10(-5), 9.3 x 10(-5) and 19.1 x 10(-5), respectively. A narrow range, less than a 3-fold difference, in the ratios of DNA binding to GSH conjugation indicates that the bioactivation of 2ClEMS is mediated by the same mechanism as EDB and EDC. Consequently, 2ClEMS, EDC and EDB may induce a specific mutation in premeiotic germ cells.

Alcohol Dehydrogenase↗
PubMed1995

Do the current subclassifications of stage T3 adenocarcinoma of the prostate have clinical relevance?

OBJECTIVES: To compare the outcome of patients with T3a and T3c adenocarcinoma of the prostate and determine the utility of these substages as defined in the current American Joint Committee on Cancer and the International Union Against Cancer (AJCC/UICC) staging system. METHODS: An analysis was performed of patients with T3 (clinical) prostate cancer treated with definitive irradiation at the Fox Chase Cancer Center between 1986 and 1993. The series was composed of 66 patients with T3a tumors and 44 patients with T3c tumors. The endpoints studied included freedom from biochemical relapse (bNED) and rates of clinical local and distant failure. RESULTS: No statistically significant differences in freedom from biochemical relapse were observed when comparing patients with T3a and T3c disease (3 years bNED, 41%; difference not significant). Similarly, there was no difference in the patterns of clinical failure at 3 years when comparing patients with T3a and T3c disease (21% clinically detected distant metastases; < 10% local failure in either group). In a multivariate analysis, only a low baseline prostate-specific antigen (PSA) (eg, 20 ng/mL or less) independently predicted the likelihood of remaining biochemically free of disease. CONCLUSIONS: Anatomic substaging that is based on the findings of the digital rectal examination does not distinguish meaningful prognostic substages among patients with T3 disease. PSA should be used to establish biochemical substaging of patients who present with T3 prostate cancer.

Adenocarcinoma↗
PubMed1995

Clinical and biochemical evidence of control of prostate cancer at 5 years after external beam radiation.

PURPOSE: We demonstrate the 5-year survival rate for patients with prostate cancer treated by irradiation, the value of the conformal technique and prostate specific antigen (PSA) doubling times after irradiation. MATERIALS AND METHODS: The outcome of 502 consecutive patients with stages T1 to T3 prostate cancer treated by irradiation alone is reported. PSA doubling times before and after failure are reported for 13 patients and posttreatment PSA doubling times are reported for 93 consecutive patients in whom radiation failed. RESULTS: The actuarial survival with biochemical freedom from disease (PSA nadir 1.5 or less not increasing) at 5 years was 44% for all patients, 50% for the conformal treatment group and 39% for the conventional therapy group. PSA doubling times after radiation failure were variable, with 42% greater than 12 months. CONCLUSIONS: The 5-year survival rate for patients with prostate cancer treated by irradiation is excellent. The conformal technique is superior to conventional therapy and there is no evidence that irradiation accelerates the growth rate of prostate cancer.

Actuarial Analysis↗
PubMed1995

Ultrastructural study of the corneal epithelium in the recurrent erosion syndrome.

BACKGROUND: This study describes the adhesion systems in the corneal epithelium in the recurrent erosion syndrome and the mechanisms by which binucleate and multinucleate cells are formed within the epithelium. METHODS: Twenty five samples of sliding epithelium were obtained from 23 patients and were examined by conventional light and transmission electron microscopy. RESULTS: The separation of the anchoring system occurred either below the level of the anchoring plaques or at the level of the epithelial cell membrane. Normal and degenerate polymorphonuclear leucocytes were found within and between the epithelial cells and within the anchoring layer. Binucleate and multinucleate cells were found within all the layers of the epithelium as were cysts containing degenerate cellular material. CONCLUSION: The presence of leucocytes and degenerate epithelial cells within the sliding epithelium suggests that these are the source of the metalloproteinases which cleave Bowman's layer below the anchoring system. The formation of binucleate and multinucleate giant cells does not appear to occur by fusion of adjacent cells, but rather by nuclear indentation and cleaving due to an abnormal microtubular system in the cytoskeleton.

Adult↗
PubMed1995

Localized prostate cancer treated by external-beam radiotherapy alone: serum prostate-specific antigen--driven outcome analysis.

PURPOSE: To determine the 5-year rate of survival with no evidence of disease (NED) using strict biochemical criteria in men with prostate cancer treated by external-beam radiotherapy alone and to examine possible clinical and treatment factors that predict the likelihood of NED survival. MATERIALS AND METHODS: Five hundred men with clinically localized prostate cancer consecutively treated with external-beam radiotherapy alone with no prior, concomitant, or adjuvant endocrine therapy were identified. All patients had serial serum prostate-specific antigen (PSA) values determined after treatment and 451 patients had pretreatment PSA values determined. The median follow-up duration is 20 months (range, 2 to 72; mean, 36). RESULTS: The 5-year rate of overall survival in this group of patients was 80%. The 5-year rate of survival without clinical evidence of disease (cNED) was 72%. The 5-year rate of survival without evidence of clinical, radiographic, or biochemical relapse (bNED) was 51%. Multivariate analysis demonstrated that a pretreatment serum PSA level < or = 15 ng/mL was the most important predictor of bNED survival (P < .0001). Patients with early-stage (T1, T2a/b) tumors and a pretreatment serum PSA less than 15 ng/mL had a 3-year rate of bNED survival of 86%. The rate of bNED survival for patients with a pretreatment PSA level greater than 15 ng/mL was 38% at 3 years. CONCLUSION: Pretreatment serum PSA level is the most important predictor of treatment outcome in this group of patients treated with definitive radiotherapy alone. External-beam radiation alone can produce acceptable early rates of bNED survival in patients with clinically organ-confined tumors and a pretreatment PSA level < or = 15 ng/mL. To produce acceptable results in those patients with pretreatment PSA levels more than 15 ng/mL, effective adjuvant treatments in addition to aggressive local treatments are necessary.

Aged↗
PubMed1995

Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx.

PURPOSE: A number of reports have documented the relationship between pretreatment hemoglobin level and local control and/or survival in the treatment of cervix, bladder, and advanced head and neck tumors. Consideration of correcting anemia before initiation of radiation therapy may prove increasingly important as clinical trials use intensive induction chemotherapy in the treatment of head and neck carcinomas. Neoadjuvant chemotherapy may produce anemia, which in turn may reduce the effectiveness of subsequent irradiation. MATERIALS AND METHODS: One hundred nine patients with T1-2N0 squamous cell carcinoma of the glottic larynx were treated with definitive radiotherapy at the Fox Chase Cancer Center between June 1980 and November 1990. Follow-up times ranged from 26 to 165 months (median, 82). RESULTS: The 2-year local control rate for patients who presented with a hemoglobin level < or = 13 g/dL was 66%, compared with 95% for patients with a hemoglobin level more than 13 g/dL (P = .0018). The 2-year survival rate for patients with a hemoglobin level < or = 13 g/dL was 46%, compared with 88% for patients with a hemoglobin level more than 13 g/dL (P < .001). Cox proportional hazards regression analysis showed that hemoglobin level (P = .0016) was the only variable that significantly influenced local control (P = .0016) and survival (P < .0001). CONCLUSION: Patients who presented with hemoglobin levels more than 13 g/dL had significantly higher local control and survival rates. The strong apparent correlation between hemoglobin level, local control, and survival supports consideration of correcting anemia before initiation of radiation therapy.

Actuarial Analysis↗
PubMed1995

Prostate specific antigen density is not an independent predictor of response for prostate cancer treated by conformal radiotherapy.

Although prostate specific antigen (PSA) density appears to be an important discriminator between benign and malignant prostatic disease, conflicting data exist concerning its prognostic value. The present study was undertaken to confirm whether PSA density represents a new prognostic indicator of disease-free survival for prostate cancer treated with conformal radio-therapy. Between April 1989 and December 1992, 186 patients with organ confined prostate cancer were treated with definitive irradiation according to previously published conformal guidelines. The PSA density was defined as the ratio of the pretreatment serum PSA (ng./ml.) to the prostate volume (ml.) as determined from treatment planning computerized tomography. The median PSA density was 0.15 with a range of 0.02 to 2.12. A statistically significant advantage in actuarial freedom from biochemical relapse was noted for patients with pretreatment PSA levels less than 15 ng./ml. when compared to those with higher pretreatment PSA levels (3-year freedom from biochemical relapse 85% versus 28%, p < 0.001). Also, patients with PSA density of 0.15 or less had statistically superior freedom from biochemical relapse compared to their counterparts with higher PSA density (3-year freedom from biochemical relapse 88% versus 28%, p < 0.001). In a multivariate analysis only the baseline PSA (p < 0.002) and the Gleason score (p < 0.002) emerged as significant predictors of prolonged freedom from biochemical relapse. The PSA density had no impact on freedom from biochemical relapse whether it was entered into this multivariate model as a continuous or a dichotomous variable. In our data base baseline PSA levels remain the most powerful independent discriminant of response to conformal irradiation. PSA density is only a surrogate for baseline PSA levels and does not refine the ability to predict prolongation of freedom from biochemical relapse following conformal radiotherapy.

Actuarial Analysis↗
PubMed1994

Adding a positive charge at residue 46 of Drosophila alcohol dehydrogenase increases cofactor specificity for NADP+.

We previously reported that the D39N mutant of Drosophila alcohol dehydrogenase (ADH), in which Asp-39 is replaced with asparagine, has a 60-fold increase in affinity for NADP+ and a 1.5-fold increase in kcat compared to wild-type ADH [Chen et al. (1991) Eur. J. Biochem. 202, 263-267] and proposed that this part of ADH is close to the 2'-phosphate on the ribose moiety of NADP+. Here we report the effect of replacing Ala-46 with an argine residue, and A46R mutant, on binding of NADP+ to ADH and its catalytic efficiency with the NADP+ cofactor, and a modeling of the three-dimensional structure of the NAD(+)-binding region of ADH. The A46R mutant has a 2.5-fold lower Km(app)NADP+ and a 3-fold higher kcat with NADP+ compared to wild-type ADH; binding of NAD+ to the mutant was unchanged and kcat with NAD+ was lowered by about 30%. For the A46R mutant, the ratio of kcat/Km of NAD+ to NADP+ is 85, over ten-fold lower than that for wild-type ADH. Our model of the 3D structure of the NAD(+)-binding region of ADH shows that Ala-46 is over 10 A from the ribose moiety of NAD+, which would suggest that there is little interaction between this residue and NAD+ and explain why its mutation to arginine has little effect on NAD+ binding. However, the positive charge at residue 46 can neutralize some of the coulombic repulsion between Asp-39 and the 2'-phosphate on the ribose moiety of NADP+, which would increase its affinity for the A46R mutant. We also constructed a double mutant, D39N/A46R mutant, which we find has a 30-fold lower Km(app)NADP+ and 8-fold higher kcat with NADP+ as a cofactor compared to wild-type ADH; binding of NAD+ to this double mutant was lowered by 5-fold and kcat was increased by 1.5-fold. As a result, kcat/Km for the double mutant was the same for NAD+ and NADP+. The principle effect of the two mutations in ADH is to alter its affinity for the nucleotide cofactor; kcat decreases slightly in A46R with NAD+ and remains unchanged or increases in the other mutants.

Alanine↗
PubMed1994

Bacillary angiomatosis of the conjunctiva.

A 70-year-old man had unilateral congestion of the right upper eyelid, which contained a nodular mass. A biopsy was performed, and histologic, immunocytochemical, and ultrastructural studies disclosed a pseudoneoplastic proliferation of endothelial cells and pericytes in a region containing clumps of bacteria. This combination of histologic features is characteristic of bacillary angiomatosis, which has been described in the skin, particularly in association with immunodeficient states, especially acquired immunodeficiency syndrome, but not in the conjunctiva. A second biopsy contained a diffuse polyclonal lymphocytic infiltrate in which large lymphocytes with irregular nuclei and mitotic figures were prominent. Systemic examination disclosed mild splenomegaly and a benign paraproteinemia. Treatment with topical gentamicin and systemic erythromycin brought about a complete resolution of the symptoms and signs within eight weeks, and there has been no sign of recurrence for the past two years.

Aged↗
PubMed1994

Radiotherapy alone for carcinoma of the vagina: the importance of overall treatment time.

PURPOSE: Review treatment results, complications, and the importance of overall treatment time for carcinoma of the vagina treated with radiotherapy alone. METHODS AND MATERIALS: Between October 1964 and October 1990, 65 patients with histologically confirmed carcinoma of the vagina received definitive radiotherapy at the University of Florida. All patients had a minimum 2-year follow-up. Most patients were treated with a combination of external-beam radiotherapy and brachytherapy. The probability of pelvic control, cause-specific survival, and complications was calculated and multivariate analyses were performed. The log-rank test was used to determine significance levels between the curves. RESULTS: The 5-year cause-specific survival rates were, Stage 0 (six patients), 100%; Stage I (17 patients), 94%; Stage IIA (six patients), 80%; Stage IIB (ten patients), 39%; Stage III (twn patients), 79%; and Stage IVA (six patients), 62%. The pelvic control rates at 5 years were: Stage 0, 100%; Stage I, 87%; Stage IIA, 88%; Stage IIB, 68%; Stage III, 80%; and Stage IVA, 67%. The parameters of stage, patient age, total dose to primary site, and overall treatment time were evaluated in a multivariate analysis. The single most important predictor of pelvic control was overall treatment time. If the entire course of radiotherapy (external beam + implant) was completed within 9 weeks (63 days), the pelvic control rate was 97%. The pelvic control rate was only 54% if treatment time extended beyond 9 weeks (p = .0003). The rate of severe complications was 12%, and the incidence increased with increasing total primary dose. CONCLUSION: Radiotherapy alone can cure a significant proportion of patients with carcinoma of the vagina. Treatment should be completed without significant interruption, preferably within 9 weeks.

Brachytherapy↗
PubMed1994

The influence of large deletions on the mutation frequency induced by tritiated water and X-radiation in male Drosophila melanogaster post-meiotic germ cells.

Tritium beta radiation (3H beta-radiation) in the form of tritiated water was used to induce mutations at the alcohol dehydrogenase (Adh) locus in male Drosophila melanogaster post-meiotic germ cells. All 23 Adh null mutations were large deletions (> 20 kb), determined by genetic complementation and Southern blot analyses. 27 Adh null mutations have been induced by 100-kVp X-rays (Aaron, 1979) and have been genetically and molecularly characterized (Ashburner et al., 1982; Chia et al., 1985; LoMonaco et al., 1987; Mahmoud et al., 1991). In contrast to 3H beta-radiation, 100-kVp X-rays induced a bimodal distribution of Adh null mutations, intragenic mutations, < or = 250 bp, and large deletions, > 100 kb. A statistically significant difference was observed between the frequency of large deletions (23/23 or 1.0) induced by 3H beta-radiation and the frequency of large deletions (19/27 or 0.7) induced by 100-kVp X-rays. However, a statistical difference was not observed between the size distribution of the large deletions induced by 3H beta-radiation and X-rays. The relative deletion frequency (RDF) induced by 3H beta-radiation and 100-kVp X-rays was (1.0/0.7 = 1.4). The relative biological effectiveness (RBE) of these two radiation sources was 1.4, determined from the ratio of the regression coefficients of the respective 3H beta-radiation and X-ray sex-linked recessive lethal (SLRL) dose-response data. The large difference in size between the two classes of X-ray-induced Adh null mutations and the increase in mutation frequency and deletion frequency for 3H beta-radiation with respect to X-rays may indicate that the relative deletion frequency (RDF) is the molecular biological basis for the increase in the RBE for radiation sources with a mean LET value < or = 10 keV/microns.

Alcohol Dehydrogenase↗
PubMed1994

Immuno-electron labelling of matrix components in congenital hereditary endothelial dystrophy.

Two corneal buttons were obtained from a patient with congenital hereditary endothelial dystrophy (CHED) at the ages of 2.5 years (right eye) and 14 years (left eye) and were studied by light and electron microscopy including immunogold labelling for collagen types I-V and laminin. The posterior collagenous layer (PCL) of Descemet's membrane contained collagen types I, III-V, and laminin: the latter was also localised to fine-banded and granular material in the posterior non-banded zone (PNBZ). Comparison of the endothelium 2.5 years and 14 years revealed occasional dystrophic changes in the former and extensive dystrophic changes in the latter. The distribution of collagen types I, III and V within the PCL supports previous morphological observations of fibroblast-like change of the endothelium in CHED. Persisting endothelial properties were manifest as positive labelling of type IV collagen and laminin. An excessive amount of laminin found in PNBZ and PCL is another stress-related endothelial reaction.

Adolescent↗
PubMed1994

Collagens in the aged human macula.

Immunogold cytochemistry was used to investigate the fine structural distribution of collagen types I-VI in Bruch's membrane and choroid of the aged human macula. Macular tissue was obtained from ten eyes, and processed for cryoultramicrotomy and London Resin white embedding. Striated collagen fibrils within the inner and outer collagenous layers were found to contain collagen types I, III and V. In addition, type V collagen was also present in the basement membrane of the choriocapillaris. Gross thickening of the choriocapillaris basement membrane was attributed to the deposition of type IV collagen. However, type IV collagen appeared to be absent from the basement membrane of the retinal pigment epithelium. The interesting location of type VI collagen on the choroidal side of the choriocapillaris suggested that its function is to anchor the choriocapillaris onto the choroid. The collagens studied were absent from fibrous banded material, long-spacing collagen, the elastic layer and amorphous granular material. It was concluded that, of the collagen types studied, only the deposition of type IV collagen contributes to the age-related thickening of Bruch's membrane.

Aged↗
PubMed1994

Early prostate cancer: the national results of radiation treatment from the Patterns of Care and Radiation Therapy Oncology Group studies with prospects for improvement with conformal radiation and adjuvant androgen deprivation.

Long-term outcome of the Patterns of Care Study and the Radiation Therapy Oncology Group are used to demonstrate the national average results of treating early prostate cancer in the United States. A group of patients with stage T1B2 disease and pathologically negative lymph nodes showed excellent 10-year survival rates and freedom from clinical evidence of disease, while prostate specific antigen (PSA) correlations in 10-year survivors indicate that 88% were clinically free of cancer and had a PSA level of less than 4.0 mg./nl., and 65% had a PSA level of less than 1.5 ng./ml. The latter group represented clinical and biochemical cures. The improvement noted in outcome of locally advanced prostate cancer treatment by Radiation Therapy Oncology Group prospective trials combining androgen deprivation and radiation therapy is presented. These trials will be extended to the poor prognosis group with stage T1,2 disease. The advantages of conformal therapy in acute and late morbidity are illustrated with preliminary evidence of improved PSA response as a result of improved technique and higher dose associated with conformal 3-dimensional treatment.

Aged↗
PubMed1994

An ultrastructural investigation of an early manifestation of the posterior polymorphous dystrophy of the cornea.

BACKGROUND: Posterior polymorphous dystrophy of the cornea is an uncommon, but well-recognized, congenital disease affecting Descemet's membrane and endothelium. Visual impairment usually is minimal and slowly progressive. Edema develops in a small number of patients, necessitating a corneal graft in middle age. An early manifestation of posterior polymorphous dystrophy with corneal edema present at birth or soon thereafter is extremely rare; only a few ultrastructural reports are available. METHODS: The corneal button of a 5-month-old baby with posterior polymorphous dystrophy was examined by conventional light and electron microscopy. FINDINGS: The anterior banded zone of Descemet's membrane was thinned (2 microns) in the axial part of the cornea, contained defects in the paraxial part, and was absent at the periphery. Where present, the anterior banded zone was lined posteriorly by a fibrocellular layer (containing fibroblast-like spindle cells and striated collagen fibrils) and a fibrillar layer forming an abnormal posterior collagenous layer. This layer was lined posteriorly by degenerate overlapping endothelial cells, which also were in apposition to the stroma in regions with an absent anterior banded zone. The defects in Descemet's membrane were used by the abnormal keratocytes to migrate between the anterior banded zone and the posterior collagenous layer. At the periphery, a multilayer of spindle cells was present behind the stroma. CONCLUSIONS: Failure to produce a continuous anterior banded zone indicates an onset of the disease before the twelfth week of gestation. It appears that, in posterior polymorphous dystrophy, there is a mosaic of better preserved and dystrophic endothelial cells and that the presence or absence of the normal components of Descemet's membrane is determined by the proportion of dystrophic cells in the endothelial cell population.

Consanguinity↗