Effect of testosterone and estradiol in a man with aromatase deficiency.
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Adult↗
Biomedical subjects
J Boyd
Publications and source records attributed to J Boyd.
Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma.
Previous allelotyping studies of epithelial ovarian carcinoma suggest that loss of heterozygosity on chromosome 14q may be a common genetic alteration in this tumor type. The purpose of this study was to determine a precise frequency of chromosome 14q allelic loss in ovarian carcinomas and to define a minimal region(s) of deletion. Seventy-six ovarian carcinomas representative of the complete spectrum of grade, stage, and histological subtype were selected for PCR-based deletion mapping analysis using 15 highly polymorphic microsatellite markers spanning the length of this chromosome arm. Loss of heterozygosity was observed in 49% of the tumors studied, placing 14q among the most frequently affected chromosomal regions in ovarian cancer. Deletions were observed in all tumor grades and stages and in all histological subtypes except tumors of low malignant potential. Deletion of the entire chromosome arm was rare; the majority of tumors displayed partial losses, providing an informative basis for detailed deletion mapping. Two distinct minimal regions of deletion were delineated. One region was defined by markers D14S80 and D14S75 at 14q12-13, and the other region was defined by markers D14S65 and D14S267 at 14q32. These data implicate the involvement of two tumor suppressor genes on chromosome 14q in a substantial fraction of ovarian carcinomas.
Chromosome Deletion↗
Hereditary ovarian cancer: molecular genetics and clinical implications.
Epidemiologic data support the existence of two discrete manifestations of hereditary ovarian carcinoma: the breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Genetic linkage analyses reveal that the majority of breast and ovarian cancer families are linked to the BRCA1 gene, while some cases of hereditary ovarian cancer are also apparent in breast cancer families linked to the BRCA2 gene. The majority of HNPCC families are linked to one of four genes encoding a family of DNA mismatch repair proteins. Molecular analyses demonstrate that genetic screening for germline transmission of a defective allele of one or another of these genes is now possible for high-risk individuals. The ethical, legal, and social implications of this type of analysis are multiple and complex, and genetic counseling requires a thorough understanding of these issues and a cautious approach to most effectively meet the special needs of this patient population. Increased medical surveillance and prophylactic oophorectomy are among the management options that may be appropriate for some genetically predisposed, asymptomatic women. Further research is needed regarding the most effective use of this genetic information in formulating counseling and clinical management strategies.
BRCA2 Protein↗
The influence of a scalar-coupled deuterium upon the relaxaton of a 15N Nucleus and its possible exploitation as a probe for side-chain interactions in proteins.
The magnitude of the quadrupole coupling constant (e2Qq/h) of a deuteron is a good probe for hydrogen bonding. In protein structures, hydrogen-bonding interactions between side chains, between side chaings and ligands, and between side chains and solvent are frequently found. An experiment that detects, via scalar coupling, the influence of a deuteron on the 15N nucleus of asparagine or glutamine side chains is presented. The experiment depends upon the resolution of the 1 delta 15 N(D) isotope shifts that allow the various isotopomers and isotopologues to be distinguished when 15N-labeled samples are dissolved in solvent mixtures of H2O/D2O. 15N lineshapes with theoretical simulations that provide estimates for the 2H quadrupole coupling constants are presented. The influence of 15N-2H dipolar-quadrupole cross correlation and the resulting small frequency shifts in the 15N multiplet are resolved in some of the spectra. The experimental data are provided using the free amino acids asparagine and glutamine for which the side chains were isotopically enriched in 15N and the recombinant pair of modules, fibronectin type 1 and epidermal growth factor, (F1-G) of tissue plasminogen activator, which were uniformly isotopically enriched in 15N.
Asparagine↗
Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF.
The most important physiological regulator of megakaryocytopoiesis is the ligand for the c-mpl receptor (thrombopoietin/megakaryocyte growth and development factor, MGDF). We examined the effect of pegylated-recombinant human MGDF (PEG-rHuMGDF): patients received PEG-rHuMGDF at doses of 0.03, 0.1, 0.3 or 1.0 microg/kg/d or placebo for 10d maximum in a double-blinded randomized study. There was a dose-dependent elevation in circulating platelet counts but no alteration in erythrocyte or total leucocyte counts. The number of bone marrow megakaryocytes was increased approximately 2-fold. The frequency of bone marrow progenitor cells was not altered. In contrast, both to the bone marrow results and to published pre-clinical data, there was a dose-dependent mobilization into the blood of progenitor cells of multiple cell lineages. Increased levels of Meg-CFC (maximum increase 30-fold), day 7 and day 14 GM-CFC and BFU-E were demonstrated at doses of 0.3 and 1.0 microg/kg/d PEG-rHuMGDF. At 0.1 microg/kg/d, mobilization of Meg-CFC alone occurred in two-thirds of patients. Maximum blood levels of progenitor cells occurred at day 12. Thus, administration of PEG-rHuMGDF to humans resulted in mobilization of progenitor cells of multiple lineages despite its 'lineage-specific' activity on mature cell development.
Adult↗
Measuring outcomes: one month survival after acute myocardial infarction in Scotland.
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Aged↗
Evidence for the oligoclonal origin of the granulosa cell population of the mature human follicle.
The clonality of the granulosa cell population residing in individual mature human ovarian follicles was examined by determining the pattern of X chromosome inactivation. Granulosa cells from 72 follicles were obtained from 9 patients undergoing oocyte harvest for in vitro fertilization. The granulosa cell DNA obtained from each follicle was subjected to the PCR, to amplify a highly polymorphic region of the X-linked human androgen receptor gene, after digestion by the methylation-sensitive HpaII restriction endonuclease, thereby achieving exclusive amplification of the inactive allele. Seventeen of 65 informative follicles (26 +/- 5%) were comprised of granulosa cells exhibiting inactivation of the same X chromosome. At least 1 such follicle was found in 8 of the 9 women sampled. There are 2 possible explanations for these findings: 1) approximately one fourth of all follicles contain a truly monoclonal granulosa cell population; 2) the granulosa cells of a given follicle are derived from a small number of stem cells (3 cells), such that the probability is 0.25 that all 3 stem cells producing the granulosa cell complement of a given follicle have the same X chromosome inactivated by chance. We favor the latter explanation and conclude that the granulosa cell cohort of mature human follicles is oligoclonal.
Adult↗
p16 (CDKN2/MTS1) gene deletions are rare in prostatic carcinomas in the United States and Japan.
PURPOSE: The incidence of clinically apparent prostatic carcinoma is much higher in the United States than in Japan. Alterations in the p16 tumor suppressor gene have been identified in various tumor types, including cultured prostatic carcinoma cell lines. We studied the possible deletions of either exon 2 or 3 of this gene in primary clinical prostatic carcinomas from Japan and the United States. MATERIALS AND METHODS: Genomic DNA was extracted from 36 formalin-fixed, paraffin-embedded clinical prostatic carcinomas from Japan and 27 carcinomas from the United States. Exons 2 and 3 of the p16 gene were amplified using comparative multiplex polymerase chain reactions (PCR) and then analyzed for possible deletions of either exon. RESULTS: Two out of 36 (5.6%) carcinomas from Japan clearly demonstrated deletion of p16 exon 2, but this deletion was not detected in any of the 27 carcinomas from the United States. CONCLUSIONS: Although slightly higher in Japan than in the United States, the frequency of p16 exon deletions in clinical prostatic carcinomas is very low, and probably is not important in the development of this neoplasm.
Carrier Proteins↗
The molecular genetics of endometrial carcinoma.
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DNA, Neoplasm↗
Farm worker injuries associated with bulls. New York State 1991-1996.
1. Although cows greatly outnumber bulls on dairy farms, bulls account for 25% of animal related injuries in a surveillance study of agricultural injury. In addition, bull injuries are more severe. 2. Because of their size and unpredictable behavior, bulls, especially those over 18 months of age, must be handled with extreme caution. 3. Important risk factors for the observed incidents were working alone and not having an escape route. 4. Bulls should be dehorned and confined in specially designed facilities to avoid human contact during feeding, watering, exercising, or breeding.
Accidents, Occupational↗
Farm worker injuries associated with cows. New York State 1991-1996.
1. The size of cows and their unpredictable behavior constitute a hazard for workers who handle them. 2. When cows are startled by sudden movements and unfamiliar situations, they may kick, push, knock down, fall, or step on workers. 3. Cows in heat or those with calves are particularly excitable. Working in confining situations, such as milking stalls, exacerbates the danger of injury to handlers. 4. Knowledge of effective animal handling techniques and well designed handling facilities can reduce the incidence of injury.
Adolescent↗
Paclitaxel and carboplatin in head and neck cancer.
Surgery and radiation for advanced head and neck cancer are debilitating and associated with poor survival. If outpatient preoperative chemotherapy could be used such that smaller surgical resections are needed, organs might be preserved and patients' quality of life enhanced. Accordingly, we are conducting a phase I trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin in previously untreated patients with advanced head and neck cancer. Study goals include identifying the maximum tolerated paclitaxel dose, evaluating response, and enhancing organ preservation. Newly diagnosed patients with stage III/IV head and neck cancer, measurable disease, and Zubrod performance status < or =2 were eligible. Of 33 patients treated thus far, four (12%) had stage III and 29 (88%) stage IV disease. Their median age was 58 years (range, 17 to 76 years). Treatment was repeated at 21-day intervals for two courses. Patients who achieved clinical partial or complete responses (CRs) received a third course of treatment. If patients were found to have a histologic CR at restaging, radiation was substituted for surgery. Carboplatin was dosed by the Calvert formula to an area under the concentration-time curve of 7.5. Cohorts received escalating doses of paclitaxel (150 to 265 mg/m2) over 3 hours until dose-limiting toxicity was encountered. Five patients were treated at 150 mg/m2, three at 170 mg/m2, eight at 200 mg/m2, six at 230 mg/m2, four at 250 mg/m2, and seven at 265 mg/m2. At present, 26 patients are evaluable for primary tumor response. Thus far, we have seen seven CRs (27%) and seven partial responses (27%), for an overall response rate of 54%. Of 25 patients assessable pathologically, seven (28%) had a CR. Grade 3/4 toxicity at paclitaxel 265 mg/m2 included neurosensory toxicity in 17%, mucositis in 17%, neutropenia in 67%, and thrombocytopenia in 17%. We conclude that paclitaxel 230 mg/m2 and carboplatin area under the curve 7.5 can be administered safely to this patient population. The dose-limiting toxicity that occurred at paclitaxel 265 mg/m2 comprised grade 3/4 neutropenia and thrombocytopenia with associated cumulative grade 2 neuropathy. The maximum tolerated dose of paclitaxel with the combination will be between 230 and 265 mg/m2. This combination has activity in head and neck cancer.
Adolescent↗
Fluoridation. Anatomy of a campaign.
Many battles over fluoridation have been fought during the past five decades in communities throughout the state. Some were successful, others heartbreaking in their defeat. But in 1995--as much of the nation celebrated 50 years of fluoridation--the war was won in California.
California↗
Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1.
BACKGROUND: We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers. METHODS: We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers. RESULTS: We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P<0.001). CONCLUSIONS: As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.
Actuarial Analysis↗
BRCA2 as a low-penetrance cancer gene.
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Breast Neoplasms↗
Mutations of the BRCA2 gene in ovarian carcinomas.
Inherited mutations in the recently discovered BRCA2 gene are believed to be responsible for a significant fraction of early-onset hereditary breast cancers. Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer. Numerous allelotype studies indicate that allelic deletions Including the BRCA2 locus on chromosome 13q are common in ovarian cancers in general, suggesting that somatic mutations of this gene may be involved in sporadic ovarian tumorigenesis. The purpose of this study was to test the hypothesis that germline or somatic mutations of BRCA2 are associated with hereditary and/or sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2 was screened for mutations in 130 consecutive ovarian tumors, the only selection criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four germline mutations and two somatic mutations were identified; two of the germline mutations are recurrent, having been previously described. Remarkably, the patients with germline mutations were late-onset cases with no medical or family histories suggestive of hereditary cancer. These data suggest that mutations of BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian cancers resulting from hereditary predisposition may be higher than previously suspected based on estimates derived from studies of highly penetrant genetic loci.
Aged↗
Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome.
BACKGROUND: The hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome is an autosomal dominant genetic disorder caused by the inheritance of a mutation in one of a family of genes encoding DNA mismatch repair (MMR) proteins. HNPCC manifests as genetic instability in linked tumors. Clinically, the syndrome is characterized by early onset malignancies, primarily of the colon and endometrium, with an increased incidence of tumors at other gastrointestinal sites, upper urologic tract, ovary, and pancreas as well. However, the inclusion of breast cancer as an integral tumor of this syndrome is controversial. METHODS: Mutation screening of MMR genes was carried out by single strand conformation polymorphism (SSCP) and sequencing analyses of genomic DNA prepared from normal lymphocytes. Expression analysis was performed by SSCP. Sequence analyses of cDNA was prepared from breast tumor tissue and normal lymphocytes. Genetic instability was assessed by comparing the electrophoretic mobility of polymerase chain reaction (PCR) products using multiple microsatellite markers. RESULTS: A 4-bp frameshift mutation in the hMLH1 gene was found to segregate with disease in the germlines of the affected members of a large kindred HNPCC. Expression of only the mutant allele was observed in the breast cancer tissue of one family member, however both alleles were observed in her normal tissue. This breast cancer exhibited widespread microsatellite instability, as did breast cancers obtained from several other HNPCC kindreds. CONCLUSIONS: These data indicate that breast cancer may result from the inheritance of a mutant MMR gene, and that breast cancer may occur as an integral tumor in the HNPCC syndrome.
Adaptor Proteins, Signal Transducing↗
Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in utero.
BACKGROUND: Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) is associated with the subsequent development of clear cell adenocarcinoma of the lower reproductive tract in young women, and data concerning the molecular genetic alterations involved in the etiology of this tumor type have not previously been reported. Such knowledge would be of potential value by providing insight into the molecular mechanisms of hormonal carcinogenesis in general, as well as by suggesting molecular markers for risk assessment in the estrogen-exposed population. METHODS: A total of 24 samples of clear cell adenocarcinoma of the vagina or cervix, 16 associated with exposure in utero to DES and 8 with no history of DES exposure, were obtained as archival fixed and embedded tissue specimens. DNA was purified from these tissues and used to examine a number of biologically plausible molecular genetic endpoints for tumor specific alterations. RESULTS: No evidence was found for mutations in the K-ras or H-ras protooncogenes, the Wilms' tumor (WT1) tumor suppressor gene, or the estrogen receptor gene. Sporadic overexpression of the p53 tumor suppressor gene was detected in some tumor cell nuclei by immunohistochemistry, but in the absence of detectable p53 gene mutation. Genetic instability as manifested by somatic mutation of microsatellite repeats was widespread in these tumors, with evidence of microsatellite instability in all DES-associated tumors examined, and in 50% of those tumors not associated with DES exposure. CONCLUSIONS: These data are consistent with the hypothesis that the induction of genomic instability may be an important mechanism of DES-induced carcinogenesis.
Adenocarcinoma, Clear Cell↗