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Biomedical subjects

J Boyd

Publications and source records attributed to J Boyd.

At least 73 records · Page 4Linked to original sources
PubMed1999

Causes and consequences of microsatellite instability in endometrial carcinoma.

Genetic instability of microsatellite repeat sequences [microsatellite instability (MI)] is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is a result of inactivating mutations in any of several genes involved in a particular pathway of DNA mismatch repair. Sporadic (i.e., nonhereditary) manifestations of several tumor types, including colorectal, gastric, and endometrial carcinomas, also exhibit MI in a significant fraction of cases. Many MI+ sporadic colorectal carcinomas are associated with somatic mutations of mismatch repair genes, and several genes with coding region microsatellites are frequently mutated as a result in these cancers. The molecular causes and consequences of MI in sporadic endometrial carcinomas remain obscure, however. The aims of this study were: (a) to identify a series of sporadic endometrial carcinomas with clear evidence of MI; (b) to determine the extent to which somatic alterations in mismatch repair genes are associated with this MI; and (c) to establish whether the genes containing coding region microsatellite repeats that are known to be disrupted in MI+ gastrointestinal cancers are also disrupted in MI+ endometrial carcinomas. Matched pairs of normal and tumor DNA from 57 consecutive cases of endometrial carcinoma were examined for evidence of MI using a consensus panel of microsatellite markers. Fourteen cases (25%) displayed unequivocal evidence of MI, consistent with previously published estimates of the incidence of MI+ sporadic endometrial carcinoma. These cases were subjected to a mutation screen of the coding regions and exon-intron boundaries of the mismatch repair genes MSH2 and MLH1. Although several polymorphisms were detected, no clearly deleterious mutations were found in either of these genes. Notably, however, hypermethylation of the MLH1 promoter region was identified in 10 of 14 (71%) MI+ cases. Somatic mutations in coding region microsatellite repeats in the TGFbetaIIR, IGFIIR, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2 genes were generally rare. Four MI+ tumors (29%) contained somatic mutations in the PTEN gene, only one of which was likely the result of MI. These data indicate that somatic mutational inactivation of known mismatch repair genes does not account for the great majority of sporadic endometrial carcinomas with MI and that a significant fraction of these cases may instead be causally associated with hypermethylation of the MLH1 promoter. Furthermore, genes with coding region microsatellites that are frequently mutated in MI+ gastrointestinal cancers are rarely mutated in MI+ endometrial cancers, implying the existence of alternative molecular targets for the tumorigenic effects of MI in this tumor type.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Nitrate levels in drinking water in rural New York State.

To obtain an indication of the nitrate-nitrogen levels in drinking water in rural areas of upstate New York and the number of infants at risk for methemoglobinemia, 419 wells supplying drinking water to farms were tested. Farmers were identified through two programs run by the New York State Department of Health. The farmers were asked to complete a short questionnaire about the type and size of their farm and their well and to collect the water sample. Overall, nitrates were detectable in 95% of the wells tested (concentration levels greater than 0.05 mg/L) and 15.7% had levels which exceeded 10 mg/L. Fifteen percent of the wells tested from farms where infants resided were also elevated. Wells which were shallow, dug or located on large farms, or springs were more likely to have elevated concentrations of nitrates.

Agriculture↗
PubMed1999

Prereduction radiographs in clinically evident anterior shoulder dislocation.

The main study objective was to determine if experienced emergency physicians can accurately identify a subgroup of patients with anterior shoulder dislocation for whom prereduction radiographs do not alter patient management. Our prospective study evaluated 97 patients who presented to 2 ski-hill clinics and to our rural emergency department with possible shoulder dislocation between November 1996 and May 1997. Emergency physicians were certain of shoulder dislocation by clinical examination alone in 40 of 59 cases (67.8%) of possible dislocation. All 40 cases were found to have a dislocation (100%; 95% Cl, 91.19% to 100%), and the prereduction radiograph did not affect management of the injury. Prereduction radiographs added 29.6 +/- 12.68 minutes to treatment. We conclude that shoulder dislocation is often readily apparent from history and physical examination. When the experienced emergency physician is certain of the diagnosis of anterior shoulder dislocation, prereduction radiography delays treatment and does not alter management.

Adolescent↗
PubMed1999

Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome.

A male member of a large HNPCC kindred, affected by primary malignancies of the breast and colon, was identified. This individual was found to harbor a germline mutation of the MLH1 mismatch repair gene previously shown to segregate with disease in this kindred. The breast tumor exhibited somatic reduction to homozygosity for the MLH1 mutation, and microsatellite instability was evident in the breast tumor. We conclude that hereditary male breast cancer can occur as an integral tumor in the HNPCC syndrome.

Aged↗
PubMed1999

Environmental air sampling to detect biological warfare agents.

The rapid and unequivocal detection and identification of biological warfare agents is a major goal of military and civilian defense authorities. To identify agents of concern in an environmental sample, a reliable, region-specific characterization of the microorganisms found naturally at the sampling location is required. We have analyzed environmental air samples from Korea, Kuwait, and Bahrain by polymerase chain reaction and temporal temperature gradient electrophoresis and have produced genetic fingerprints of the natural microbial flora in these regions. Results are displayed as specific bar code patterns against which the unique patterns of potential biological warfare agents appearing in a sample can be quickly discriminated. Data are stored on compact disk, along with other laboratory analyses and relevant meteorological data, and are available to appropriate authorities and researchers.

Air Microbiology↗
PubMed1999

Glutathione peptidomimetic drug modulator of multidrug resistance-associated protein.

The peptidomimetic drug gamma-glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine diethyl ester (TER199) is an analog of glutathione designed to be an isozyme-specific inhibitor of GSTP1-1 protein1-1. This compound (and the de-esterified moiety) is shown to be an effective inhibitor of multidrug resistance-associated protein1 (MRP1)-mediated drug resistance. Kinetic analyses revealed that gamma-glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine reversibly inhibits the transport of 2,4-dinitrophenyl-S-glutathione with a K(i) of 752 microM. TER199 reversed the accumulation deficit of daunorubicin in MRP1-transfected NIH3T3 fibroblasts and maintained intracellular levels for >2 h after daunorubicin removal. Cytotoxicity assays revealed that TER199 significantly reversed the resistance of MRP1-transfected NIH3T3 cells for vincristine, doxorubicin, etoposide, and mitoxantrone. HL-60 cells made resistant to TER199 by chronic, long-term selection had increased mRNA and protein levels of multidrug resistance-associated protein, MRP1, and gamma-glutamyl cysteine synthetase heavy and light subunits (the rate-limiting enzyme in GSH synthesis). In spite of increased gamma-glutamyl cysteine synthetase, their glutathione content was reduced approximately 35% from that of parental HL-60 cells. These cells also exhibited a drug resistance profile commensurate with the previously described MRP1 overexpressing phenotype, with resistance to Vinca alkaloids, epipodophyllotoxins, and anthracyclines; additional cross-resistance to paclitaxel (Taxol), mitoxantrone, and 5-fluorouracil was observed.

3T3 Cells↗
PubMed1998

Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers.

Hereditary ovarian cancers associated with germline mutations in either BRCA1 or BRCA2 were studied to determine whether somatic mutation of the P53 gene is required for BRCA-linked ovarian tumorigenesis and further, whether the spectrum of additional somatic molecular genetic alterations present in these tumors differs from that known to exist in sporadic ovarian cancers. Forty tumors, 29 linked to BRCA1 and 11 linked to BRCA2, were examined for mutational alterations in P53, K-RAS, ERBB-2, C-MYC, and AKT2. The presence of a P53 mutation in 80% of these cancers indicates that P53 mutation is common but not required for BRCA-linked ovarian tumorigenesis; notably, a significantly higher proportion of the P53 mutations in BRCA2-linked cancers were deletions or insertions compared with the more typical spectrum of missense mutations seen in BRCA1-linked cancers. Additionally, BRCA-linked ovarian carcinomas seem to develop through a unique pathway of tumorigenesis that does not involve mutation of K-RAS or amplification of ERBB-2, C-MYC, or AKT2.

Arabidopsis Proteins↗
PubMed1998

Allelotype analysis of uterine leiomyoma: localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q.

Uterine leiomyoma is a benign smooth muscle tumor of the myometrium and is the most commonly encountered neoplasm in women of reproductive age. As for most benign tumors, the pathogenesis of leiomyoma remains obscure, especially at the molecular genetic level. The purpose of this study was to perform a genome-wide allelotype analysis to identify potential sites of tumor suppressor gene inactivation. Fifty-two cases of uterine leiomyoma were subjected to allelotype analysis by using matched pairs of tumor and blood DNA. Loss of heterozygosity (LOH) was assessed at 61 microsatellite markers distributed throughout the genome and representing all 41 chromosome arms. In general, LOH was very rare except on chromosome 7q, where LOH was observed in 34% of all informative tumors. Fine-deletion mapping with 25 microsatellite markers from the 7q22 region revealed a minimal deletion unit of approximately 4 cM, bounded by the markers D7S2453 proximally and D7S496 distally, that probably harbors a novel tumor suppressor gene involved in the etiology of this tumor.

Alleles↗
PubMed1998

Germline mutations of the BRCA1 and BRCA2 genes in a breast and ovarian cancer patient.

A patient with breast carcinoma diagnosed at the age of 30 years and ovarian carcinoma diagnosed at the age of 41 years was found to have germline mutations in both the BRCA1 and the BRCA2 genes. The patient was of Ashkenazi Jewish descent and the BRCA2 mutation was 6174delT, known to be very common in this population. The BRCA1 mutation, however, was 3888delGA, a mutation not previously reported in this ethnic group. The patient's breast cancer exhibited loss of heterozygosity (LOH) at the BRCA1 locus but not at BRCA2, and her ovarian cancer sustained LOH at BRCA1 and BRCA2. The BRCA1 mutation originated from patient's father, who had no personal or family history of cancer. The patient's mother, who was found to carry the BRCA2 mutation, was affected by late-onset breast cancer and her tumor exhibited LOH at BRCA2. These findings indicate that compound heterozygotes for germline mutations of BRCA1 and BRCA2 exist and may be expected to develop normally and that either gene may contribute to breast or ovarian cancer development in such individuals. The implications of this case in regard to genetic testing and counseling are also substantial.

Adult↗
PubMed1998

BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing.

OBJECTIVE: Our purpose was to determine the prevalence of BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in a large, unselected population of ovarian cancer patients and to evaluate the relationship between mutation status and a routinely obtained family history of cancer. STUDY DESIGN: One hundred sixteen consecutive ovarian cancer patients seen for routine clinical care were examined for BRCA1, BRCA2, hMSH2, and hMLH1 gene mutations with use of the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct gene sequencing. Fisher's exact test was used to evaluate possible associations between BRCA1 and BRCA2 mutation status and specific familial characteristics. RESULTS: Among 116 unselected ovarian cancer patients we identified a total of 13 germline mutations in 12 patients: 10 in BRCA1, one each in hMSH2 and hMLH1, and a single BRCA2 mutation, which occurred in a patient also carrying a BRCA1 mutation. More than half the patients with BRCA1 mutations had family histories that would generally be considered unremarkable. Of 22 family history variables analyzed, only two (maternal family history of breast or ovarian cancer, p=0.037, and maternal family history of any cancer, p=0.020) conferred a significantly increased risk of carrying a BRCA1 mutation compared with ovarian cancer patients without such a history. However, the majority of ovarian cancer patients with these family histories and other suggestive histories tested negative for mutations. CONCLUSIONS: Approximately 10% of ovarian cancers occur in association with genetic mutations known to predispose to the disease. A routinely obtained family history is an unreliable way to identify patients who might harbor mutations. The majority of ovarian cancer patients with suggestive family histories test negative for known gene mutations, perhaps suggesting the existence of additional undiscovered genes predisposing to ovarian cancer.

Adult↗
PubMed1998

Some NMR experiments and a structure determination employing a [15N,2H] enriched protein.

We present the results of studies of an aqueous sample of a highly [15N,2H] enriched protein, the SH3 domain from Fyn. Measurements of 1H relaxation and interactions between H2O solvent and exchangeable protons are given, as well as a method for increasing the effective longitudinal relaxation of solvent exchangeable proton resonances. The long-range isotope shifts are measured, for 1H and 15N, which arise due to perdeuteration. Simulations, which employed a 7 or 8 spin relaxation matrix analysis, were compared to the experimental data from a time series of 2D NOESY datasets for some resonances. The agreement between experiment and simulation suggest that, with this 1H dilute sample, relatively long mixing times (up to 1.2 s) can be used to detect specific dipolar interactions between amide protons up to about 7A apart. A set of 155 inter-amide NOEs and 7 side chain NOEs were thus identified in a series of 3D HSQC-NOESY-HSQC experiments. These data, alone and in combination with previously collected restraints, were used to calculate sets of structures using X-PLOR. These results are compared to the available X-ray and NMR structures of the Fyn SH3 domain.

Amides↗
PubMed1998

Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study.

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).

Adult↗
PubMed1998

F-18 FDG PET scan after radiotherapy for early-stage larynx cancer.

Fluorine-18-fluorodeoxyglucose (F-18 FDG) PET was used to evaluate early-stage larynx cancer before and after radiotherapy. Less radical salvage surgery might be possible after timely diagnosis of recurrent or persistent tumor after radiotherapy. Eight patients with early-stage laryngeal cancer (two carcinoma in situ; six stage T1: tumor limited to vocal cords with normal mobility) underwent irradiation for potential cure. Five patients had pre- and postradiotherapy F-18 FDG PET, and three had postradiotherapy F-18 FDG PET only. All patients underwent a CT scan of the neck at the time of the F-18 FDG PET scan. One patient had a positive result of postradiotherapy F-18 FDG PET but a negative result of a CT of the neck, and biopsy revealed recurrent squamous carcinoma. Seven patients who had negative results of postradiotherapy F-18 FDG PET were free of disease at the 15-month median follow-up evaluation. (Three of them had no cancer on biopsy of the larynx, and four others were followed with periodic endoscopic examinations that revealed complete disappearance of the tumor.) F-18 FDG PET scan may be useful for earlier diagnosis of recurrent or persistent laryngeal cancer after radiotherapy and is preferable to repeated biopsies, which would traumatize radiation-damaged tissues. A prompt early diagnosis of failure of radiotherapy will lead to less radical salvage surgery.

Carcinoma in Situ↗
PubMed1998

Molecular genetics of hereditary ovarian cancer.

Approximately 10% of all epithelial ovarian carcinoma cases are associated with inheritance of an autosomal-dominant genetic mutation conferring a predisposition to cancer with variable penetrance. Two such manifestations of hereditary ovarian cancer are currently recognized: the breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The breast and ovarian cancer syndrome is linked to the BRCA1 gene on chromosome 17q and, to a lesser extent, to the BRCA2 gene on chromosome 13q. The HNPCC syndrome is caused by any one of three known genes, hMSH2, hMLH1, and hPMS2, that encode proteins involved in the same pathway of DNA mismatch repair. Genetic screening for germ-line transmission of a defective allele of these genes is now possible for high-risk individuals. Despite the rapid pace of research advances in this area, however, considerable uncertainties remain regarding factors that affect the penetrance and tissue-specific expressivity of these mutations. Current research challenges include elucidating these modifying factors, gaining a better understanding of the biological function of BRCA1 and BRCA2 products, and determining the appropriate clinical intervention for genetically predisposed patients.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas.

A novel gene was identified recently at chromosome 10q23, named PTEN or MMAC1, and based on several criteria it was designated as a potential human tumor suppressor gene. Loss of heterozygosity affecting this region of 10q is observed in several cancer types, especially glioblastoma, and inactivating mutations of the PTEN/MMAC1 gene are found in some of these cancers as well as cell lines and xenografts. Breast cancer is among the tumor types in which mutations are documented, and germline mutations of the gene appear to be responsible for the rare autosomal dominant familial cancer syndrome known as Cowden disease, which includes breast cancer among its clinical features. To further determine the role that PTEN/MMAC1 mutations may play in breast tumorigenesis, the entire coding region was screened for mutations in 54 unselected primary breast cancers. Two mutations were identified, a somatic 2-bp deletion in an apparently sporadic breast cancer, and a germ-line 4-bp deletion in a breast cancer patient with a clinical history consistent with Cowden disease. These data indicate that somatic mutations of PTEN/ MMAC1 occur in only a small fraction of primary breast cancers and confirm the role of this gene in the etiology of Cowden disease. Evidence is also presented suggesting that numerous polymorphisms and missense variants exist in the PTEN/MMAC1 transcript.

Aged↗