A further case of choanal atresia in the deletion (9p) syndrome.
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Adult↗
Biomedical subjects
D Berry
Publications and source records attributed to D Berry.
Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history.
BACKGROUND: The discovery of BRCA1 and BRCA2 has led to a reassessment of the association between family history of breast/ovarian cancer and breast cancer risk after controlling for carrier status for mutations in the BRCA1 and BRCA2 genes. We examined whether family history of breast cancer remains a predictive risk factor for this disease after carrier status for BRCA1 and/or BRCA2 mutations is taken into consideration. METHODS: The data are from 4730 case subjects with breast cancer and 4688 control subjects enrolled in the Cancer and Steroid Hormone Study. The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each woman. Among predicted noncarriers, logistic regression was used to assess the relationship (odds ratios and 95% confidence intervals [CIs]) between case or control status and family history of breast or ovarian cancer. Estimates of age-specific breast cancer risk are presented by predicted carrier status. RESULTS: Among predicted noncarriers, case subjects were 2.06 times (95% CI = 1.69-2.50) and 1.24 times (95% CI = 1.17-1.32) more likely to report a first-degree or second-degree family history of breast cancer, respectively, than were control subjects. Case subjects were 1.99 times (95% CI = 1.63-2.44), 1.66 times (95% CI = 1.18-2.38), and 2.23 times (95% CI = 0.21-24.65) more likely to report an affected mother, sister, or both, respectively, than were control subjects. A family history of ovarian cancer was not statistically significantly associated with breast cancer risk. Noncarriers were predicted to have a lifetime risk of 9% of developing breast cancer compared with a 63% risk for carriers. CONCLUSIONS: Among women with a moderate family history of breast cancer, i.e., predicted noncarriers of BRCA1 and/or BRCA2 mutations, family history remains a factor in predicting breast cancer risk. In families with breast and ovarian cancers, the aggregation of these two cancers appears to be explained by BRCA1/BRCA2 mutation-carrier probability.
Adult↗
Selective inhibition of prolactin gene transcription by the ETS-2 repressor factor.
Regulation of prolactin gene transcription requires cooperative interactions between the pituitary-specific POU domain protein Pit-1 and members of the ETS transcription factor family. We demonstrate here that the ETS-2 repressor factor (ERF) is expressed in pituitary tumor cells and that overexpression of recombinant ERF inhibits prolactin promoter activity, but not the closely related growth hormone promoter. In non-pituitary cell lines, coexpression of ERF disrupts the cooperative interactions between Pit-1 and ETS-1 and blocks the induction of Pit-1-dependent prolactin promoter activity by cAMP. The potential role of ERF in the inhibitory response of the prolactin promoter to dopamine was examined using pituitary tumor cells stably expressing dopamine D2 receptors. The inhibitory responses of the prolactin promoter to ERF and dopamine are additive, suggesting that ERF has a complementary role in this hormonal response. A single Pit-1 DNA-binding element from the prolactin promoter is sufficient to reconstitute the inhibitory response to ERF. DNA binding analysis using either a composite Pit-1/ETS protein-binding site or a Pit-1 element with no known affinity for ETS proteins revealed that ERF interferes with Pit-1 binding. Together, these results demonstrate that ERF is a specific inhibitor of basal and hormone-regulated transcription of the prolactin gene and suggest a new level of complexity for the interaction of ETS factors with Pit-1 target genes.
Animals↗
Alterations in the expression of P2X1 receptors in failing and nondiseased human atria.
This is the first report of the analysis of the ATP-specific P2X1 receptor subunit in human hearts. We have examined homogenate samples of human left atria for the presence of P2X1 receptors using Western blots. Anti-P2X1 immunoreactivity was detected in populations of nondiseased atria as well as in atria from explanted hearts from patients with terminally failing heart conditions such as dilated cardiomyopathy. At least three groups of P2X1 immunoreactive proteins were detected in the Western blots with approximate molecular mass values of 50, 70, and 160 kDa. We report changes in expression of their 50 and 70 kDa components. These changes may be related to the type of deficit in these hearts since the changes have been observed in hearts with decreased ejection fractions characteristic of dilated cardiomyopathy.
Animals↗
Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer.
PURPOSE: Both ondansetron and cyclophosphamide are thought to be metabolized by hepatic microsomal processes. The purpose of this study was to evaluate the potential pharmacokinetic interactions between ondansetron and high-dose alkylating agent chemotherapy. METHODS: A total of 54 breast cancer patients receiving high-dose cyclophosphamide, cisplatin and carmustine were treated prospectively in four sequential cohorts. Cohorts I and II received continuous infusions of both ondansetron and prochlorperazine, and cohorts III and IV received a continuous infusion of ondansetron alone at the same doses. All patients received lorazepam every 4 h. A group of 75 matched historical controls had received a continuous infusion of prochlorperazine with lorazepam. Pharmacokinetic monitoring of each drug used in the high-dose chemotherapy regimen was conducted. RESULTS: Median AUCs of cyclophosphamide in patients receiving ondansetron (73.6 mg/ml x min) were lower than those of the control patients (88.3 mg/ml x min, n = 75, P = 0.0004), but the median cisplatin AUC was approximately 10% higher and no difference in the disposition of carmustine was demonstrated. Patients treated with ondansetron displayed a higher frequency of headaches than the controls. The frequency of achieving complete emetic control was greater in the ondansetron + prochlorperazine groups compared to the ondansetron alone groups and was greater in both these groups than in the prochlorperazine alone group on the first day of therapy only. CONCLUSION: Ondansetron altered the systemic exposure to cyclophosphamide when these agents were administered concomitantly. Ondansetron did not substantially improve overall emetic control when used alone but may improve control in combination with prochlorperazine. Future randomized studies are needed to delineate the effect of ondansetron on the disposition of the active cyclophosphamide metabolites so that clinical implications can be addressed.
Antiemetics↗
Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis.
Endothelial receptor tyrosine kinases may play important roles in pathological vascular growth, particularly in tumours. In this study, immunohistochemistry was used to evaluate the expression of a novel endothelial receptor tyrosine kinase, Tie2/Tek, in the endothelium of vascular 'hotspots' in normal breast tissue (n = 10), benign breast lesions (n = 10) and in breast tumours (n = 123). Tie2 expression was detected in the endothelium of all breast tissues examined. However, the strongest expression of Tie-2 was seen in vascular 'hot spots' within the inflammatory infiltrate at the periphery of invasive tumours. Moreover, the proportion of Tie2-positive vessels (Tie2 counts/CD31 counts) was significantly higher in breast tumours than the proportion of Tie2-positive vessels in either normal breast tissue or benign breast lesions (P = 0.004 and 0.0001 respectively). These data are consistent with a role for Tie2 in tumour angiogenesis and demonstrate the potential use of Tie2 expression as a novel marker of the tumour vasculature.
Antibodies, Monoclonal↗
Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2.
Breast cancer-susceptibility genes BRCA1 and BRCA2 have recently been identified on the human genome. Women who carry a mutation of one of these genes have a greatly increased chance of developing breast and ovarian cancer, and they usually develop the disease at a much younger age, compared with normal individuals. Women can be tested to see whether they are carriers. A woman who undergoes genetic counseling before testing can be told the probabilities that she is a carrier, given her family history. In this paper we develop a model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives. Of special importance are the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases. This information can be elicited during genetic counseling and prior to genetic testing. The carrier probabilities are obtained from Bayes's rule, by use of family history as the evidence and by use of the mutation prevalences as the prior distribution. In addressing an individual's carrier probabilities, we incorporate uncertainty about some of the key inputs of the model, such as the age-specific incidence of diseases and the overall prevalence of mutations. There is some evidence that other, undiscovered genes may be important in explaining familial breast cancer. Users of the current version of the model should be aware of this limitation. The methodology that we describe can be extended to more than two genes, should data become available about other genes.
BRCA2 Protein↗
Overestimation of hereditary breast cancer risk.
OBJECTIVE: To find out how women with breast or ovarian cancer rate their chances of carrying hereditary factors for these cancers and to determine the extent to which they overestimate their risk. SUMMARY BACKGROUND DATA: BRCA1 and BRCA2 are genes that cause breast and ovarian cancer when they are inherited in families. Testing for disease-associated mutations in these genes is now available commercially. Previous studies have shown that women overestimate their chances of carrying mutations. However, women's perceptions of risk have not been compared to objective estimates or to actual BRCA1 and BRCA2 testing results. METHODS: This study examines estimates of carrying BRCA1 and BRCA2 mutations among women participating in a randomized trial comparing alternative precounseling educational materials. Estimates were provided by participants in a baseline mailed survey. Estimates given by participants were compared to those given by an expert panel and by a statistical model. Testing was offered free of charge and was done in an academic laboratory using standard techniques. Baseline estimates of participating women were compared to the estimates of the expert panel, to the carrier probability provided by the statistical model, and to actual testing results. RESULTS: Women who have a personal history of breast or ovarian cancer significantly overestimate their risk of carrying hereditary factors for breast and ovarian cancer. Self-estimates exceeded the estimates of experts and a statistical model. One hundred women completed testing, and 21 mutations in BRCA1 or BRCA2 were found. Many test-negative women also overestimated their hereditary risk. Some women with a high carrier probability were negative for BRCA1 and BRCA2 mutations. CONCLUSIONS: Overestimation of hereditary factors is common among affected women with a family history of cancer. Pretest education and counseling should reduce these high-risk perceptions. Better estimates of carrier probability will direct more intensive clinical services and research.
Adult↗
Buccal absorption of midazolam: pharmacokinetics and EEG pharmacodynamics.
PURPOSE: To determine whether buccal/sublingual administration of midazolam (MDL) would lead to detectable venous concentrations and EEG changes in 10 healthy volunteers. METHODS: The study consisted of an open-label and a double-blind phases. Subjects held 10 mg MDL in 2 ml peppermint-flavored fluid or peppermint-flavored placebo in their mouth for 5 min and then spat it out. Cardiorespiratory and EEG monitoring was performed in all subjects. RESULTS: Venous MDL concentrations measured on 10 occasions from 5 to 600 min after administration showed a rapid increase for the first 20-30 min. However, changes in the 8- to 30-Hz frequencies identified by spectral analysis of the EEG showed changes in < or = 5-10 min in test but not in control subjects--more rapid than were expected from the venous absorption data. There were no significant adverse effects. CONCLUSIONS: Our data provide direct evidence of the speed of cerebral effect of a drug. Our results suggest that the buccal/sublingual route of administration should be tested in emergency treatment of seizures as an alternative to the rectal route, over which it has clear practical advantages.
Absorption↗
Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant.
PURPOSE: To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC. PATIENTS AND METHODS: We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL. RESULTS: Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality). CONCLUSION: Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.
Acute Disease↗
Dual-function reporter protein for analysis of gene expression in living cells.
The firefly luciferase (Luc) protein and the jellyfish green fluorescent protein (GFP) are two commonly used molecular reporters that can be detected noninvasively in living cells. The properties that make GFP or Luc useful for a particular experimental application are quite distinct. A recombinant protein with both fluorescent and bioluminescent characteristics might take advantage of the strengths of both reporters. An expression vector encoding a chimeric protein in which GFP was tethered to Luc through a 19-amino acid linker was prepared and characterized. Western blotting with antibodies specific for either GFP or Luc showed that a protein of appropriate size was expressed in transfected cells. Fluorescence microscopy revealed bright green fluorescence from transfected cells, indicating proper formation of the GFP chromophore. Luc enzymatic activity in protein extracts from transfected cells showed that Luc was fully functional. The treatment of living cell cultures stably expressing the GFP-Luc fusion protein with the protein translation-inhibitor cycloheximide (Chx) was used to show that the half-life for Luc protein activity was approximately 2 h at 37 degrees C. The utility of this dual-function reporter protein was shown by the identification of single living cells expressing the chimeric protein within a population by fluorescence microscopy, followed by quantification of Luc activity from the same living cells.
Cell Line↗
Autonomic nervous system balance and introversion.
In a sample of 61 undergraduates, a measure of parasympathetic predominance in the autonomic system was associated with introversion as predicted by Lester (1974).
Adult↗
Advances in breast cancer genetics.
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Breast Neoplasms↗
Optimum dose of digoxin.
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Cardiotonic Agents↗
The GABAA receptor alpha 6 subunit gene (Gabra6) is tightly linked to the alpha 1-gamma 2 subunit cluster on mouse chromosome 11.
We have established that the GABAA receptor alpha 6 (Gabra6) and alpha 1 (Gabra 1) subunit genes are tightly linked on mouse chromosome 11 by analysing the strain distribution patterns of RFLPs for the two genes and microsatellite markers flanking these genes in 26 BXD recombinant inbred strains. These results further demonstrate clustering of the GABAA receptor subunit genes on mouse chromosomes and the synteny for these clusters between the mouse and human genomes.
Animals↗
Bovine tuberculosis in free-ranging white-tailed deer from Michigan.
A 4.5 yr-old male white-tailed deer (Odocoileus virginianus) killed by a hunter during the 1994 firearm hunting season in northeastern Michigan (USA) had lesions suggestive of tuberculosis and was positive on culture for Mycobacterium bovis the causative agent for bovine tuberculosis. Subsequently, a survey of 354 hunter-harvested white-tailed deer for tuberculosis was conducted in this area from 15 November 1995 through 5 January 1996. Heads and/or lungs from deer were examined grossly and microscopically for lesions suggestive of bovine tuberculosis. Gross lesions suggestive of tuberculosis were seen in 15 deer. Tissues from 16 deer had acid-fast bacilli on histological examination and in 12 cases mycobacterial isolates from lymph nodes and/or lungs were identified as M. bovis. In addition, lymph nodes from 12 deer (11 females and 1 male) without gross or microscopic lesions were pooled into 1 sample from which M. bovis was cultured. Although more male (9) than female (3) deer had bovine tuberculosis infections, this difference was not statistically significant. Mycobacterium bovis culture positive deer ranged in age from 1.5 to 5.5 yr with a mean of 2.7 yr (median 2.5 yr) for males and 3.2 yr (median 3.5 yr) for females. This appears to be the first epidemic occurrence of M. bovis in free-ranging cervids in North America. A combination of environmental (high deer density and poor quality habit) and management-related factors (extensive supplemental feeding) may be responsible for this epizootic.
Animals↗
The significance of tumor contamination in the bone marrow from high-risk primary breast cancer patients treated with high-dose chemotherapy and hematopoietic support.
We studied the incidence and significance of tumor cell contamination of the bone marrow or peripheral blood progenitor cells of patients who had high risk primary breast cancer involving 10 or more axillary lymph nodes and who received high dose cyclophosphamide, cisplatin, and carmustine with hematopoietic support as consolidation following standard dose adjuvant chemotherapy. The autologous hematopoietic cell products were evaluated in 85 eligible patients. Eighty-three samples were available from the time of bone marrow harvest, and peripheral blood progenitor cells were evaluated from 57 of the 65 patients who additionally received these products. The screening technique utilized a panel of four anti-breast cancer monoclonal antibodies and an immunohistochemical technique. Thirty (36%) of the 83 evaluable patients had tumor cell contamination of the bone marrow. Only 2 (4%) of the 57 patients had tumor cell contamination of the peripheral blood progenitor cells. Tumor cell contamination of the bone marrow was associated with shorter disease-free survival and overall survival. In addition, the higher the number of tumor cells identified, the shorter disease-free and overall survival. There was no relationship between the tumor cell contamination of the bone marrow and the site of relapse. The combination of the log of the number of tumor cells +1 and number of positive lymph nodes predicted both disease-free and overall survival. Tumor cell contamination of the bone marrow from the harvest is associated with shorter disease-free and overall survival for patients who were treated with standard dose chemotherapy followed by consolidation with high dose alkylating agents and hematopoietic support. It is unclear what role the contaminating tumor cells have in relapse, and they may just be a high-risk marker. A comparison with other prognostic factors and characteristics of the tumor may determine the significance of the tumor contamination of the bone marrow.
Adult↗