Harvesting the genome's bounty: integrative genomics.
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Animals↗
Biomedical subjects
L Boucher
Publications and source records attributed to L Boucher.
MAPK specificity in the yeast pheromone response independent of transcriptional activation.
The mechanisms whereby different external cues stimulate the same mitogen-activated protein kinase (MAPK) cascade, yet trigger an appropriately distinct biological response, epitomize the conundrum of specificity in cell signaling. In yeast, shared upstream components of the mating pheromone and filamentous growth pathways activate two related MAPKs, Fus3 and Kss1, which in turn regulate programs of gene expression via the transcription factor Ste12. As fus3, but not kss1, strains are impaired for mating, Fus3 exhibits specificity for the pheromone response. To account for this specificity, it has been suggested that Fus3 physically occludes Kss1 from pheromone-activated signaling complexes, which are formed on the scaffold protein Ste5. However, we find that genome-wide expression profiles of pheromone-treated wild-type, fus3, and kss1 deletion strains are highly correlated for all induced genes and, further, that two catalytically inactive versions of Fus3 fail to abrogate the pheromone-induced transcriptional response. Consistently, Fus3 and Kss1 kinase activity is induced to an equivalent extent in pheromone-treated cells. In contrast, both in vivo and in an in vitro-reconstituted MAPK system, Fus3, but not Kss1, exhibits strong substrate selectivity toward Far1, a bifunctional protein required for polarization and G(1) arrest. This effect accounts for the failure to repress G(1)-S specific transcription in fus3 strains and, in part, explains the mating defect of such strains. MAPK specificity in the pheromone response evidently occurs primarily at the substrate level, as opposed to specific kinase activation by dedicated signaling complexes.
Cell Cycle Proteins↗
Afferent delays and the mislocalization of perisaccadic stimuli.
Determining the precise moment a visual stimulus appears is difficult because visual response latencies vary. This temporal uncertainty could cause localization errors to brief visual targets presented before and during eye movements if the oculomotor system cannot determine the position of the eye at the time the stimulus appeared. We investigated the effect of varying neural processing time on localization accuracy for perisaccadic visual targets that differed in luminance. Although systematic errors in localization were observed, the effect of luminance was surprisingly small. We explore several hypotheses that may explain why processing delays are not more disruptive to localization performance.
Humans↗
Interferon regulatory factor expression in human breast cancer.
OBJECTIVE: To investigate the expression of interferon regulatory factors 1 and 2 (IRF-1 and IRF-2) in human breast cancer. SUMMARY BACKGROUND DATA: Interferon regulatory factors 1 and 2 are transcription factors in the interferon gamma signal transduction pathway. IRF-1 acts as the effector arm of the interferon gamma response; IRF-2 binds to the same DNA consensus sequence and opposes IRF-1 activity. Previous work in the authors' laboratory has shown the tumor suppressor activity of IRF-1 expression and the oncogenic effect of IRF-2 in human and murine tumor models, including human breast cancer cell lines. The authors' hypothesis is that this pathway is involved in human tumor development, and alterations in the expression of IRF-1 and IRF-2 may occur in breast cancer tissue compared with normal breast tissue, and between more and less differentiated breast cancers. METHODS: Formalin-fixed paraffin-embedded human archival tissue specimens were obtained from 33 patients with pure ductal carcinoma in situ (DCIS) and 49 women with invasive ductal cancer. Adjacent areas of normal breast tissue were assayed in 31 women. These specimens were stained with polyclonal IRF-1 and IRF-2 antibodies using an avidin-biotin-peroxidase complex technique after epitope retrieval. RESULTS: Most normal breast tissue showed expression of IRF-1 and no expression of IRF-2 by immunohistochemistry. High-grade DCIS or node-positive invasive ductal cancers were less likely to express the tumor suppressor IRF-1 than normal tissue. More strikingly, high-grade DCIS and invasive ductal cancers were much more likely to express the oncogenic IRF-2 protein than was normal tissue. CONCLUSIONS: Expression of IRF-1 and IRF-2 is altered in human breast cancer compared with normal adjacent tissue. The loss of IRF-1 expression is consistent with tumor suppressor loss and the development of IRF-2 expression with oncogenic activation. These data support the hypothesis that this pathway is involved in human breast oncogenesis, which warrants further investigation regarding prognostic and therapeutic implications.
Breast Neoplasms↗
A genome-wide survey of RS domain proteins.
Domains rich in alternating arginine and serine residues (RS domains) are frequently found in metazoan proteins involved in pre-mRNA splicing. The RS domains of splicing factors associate with each other and are important for the formation of protein-protein interactions required for both constitutive and regulated splicing. The prevalence of the RS domain in splicing factors suggests that it might serve as a useful signature for the identification of new proteins that function in pre-mRNA processing, although it remains to be determined whether RS domains also participate in other cellular functions. Using database search and sequence clustering methods, we have identified and categorized RS domain proteins encoded within the entire genomes of Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae. This genome-wide survey revealed a surprising complexity of RS domain proteins in metazoans with functions associated with chromatin structure, transcription by RNA polymerase II, cell cycle, and cell structure, as well as pre-mRNA processing. Also identified were RS domain proteins in S. cerevisiae with functions associated with cell structure, osmotic regulation, and cell cycle progression. The results thus demonstrate an effective strategy for the genomic mining of RS domain proteins. The identification of many new proteins using this strategy has provided a database of factors that are candidates for forming RS domain-mediated interactions associated with different steps in pre-mRNA processing, in addition to other cellular functions.
Amino Acid Motifs↗
Fluorine-18 fluorodeoxyglucose positron emission tomography correlated with computed tomographic scan and magnetic resonance imaging in a case of hematometrocolpos.
A 12-year-old girl had intense abdominal pain that had increased in the past 3 months and was accompanied by weight loss. An ultrasound examination revealed large cystic masses in the abdomen. A computed tomographic scan could not conclusively rule out a malignant condition. The hymen was normal on physical examination, but magnetic resonance imaging confirmed that the abnormalities corresponded to dilated cavities of the vagina, uterus, and fallopian tubes, with an appearance suggestive of hematometrocolpos. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography was requested concurrently with the magnetic resonance image to assess the metabolic activity of the lesions and to exclude the presence of distant metastases. Large defects without FDG accumulation were noted in the areas corresponding to the cystic masses. Vaginal atresia with hematometrocolpos was confirmed at surgery. This rare case involving F-18 FDG positron emission tomographic imaging in hematometrocolpos illustrates that this diagnosis should be considered in the presence of symmetric hypometabolic masses in the pelvis.
Child↗
The Clinical Impact of FDG-PET Imaging on the Management of Lung Cancer Patients in a New Canadian PET Center.
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Journal Article↗
Effect of tamoxifen on sexual functioning in patients with breast cancer.
PURPOSE: To define the incidence of sexual dysfunction in a population of women with breast cancer treated with tamoxifen. PATIENTS AND METHODS: Breast cancer patients with a performance status of 0 to 2 who had been treated with tamoxifen for 2 to 24 months completed the following measures: the Center for Epidemiologic Studies-Depression Scale, the Sexual History Form, and the Breast Cancer Prevention Trial Symptom Checklist. Forty-nine of the participants underwent gynecologic examinations with vaginal smears for determination of estrogen effect. RESULTS: Fifty-seven women were entered onto the trial. Sexual desire, arousal, and ability to achieve orgasm were comparable to norms established in participants in the Tamoxifen Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-01). Pain, burning, or discomfort with intercourse was reported in 54% of patients and did not correlate with age, surgical treatment of the primary cancer, or chemotherapy. Estrogen effect was seen on the vaginal smears of 34 of 49 participants and was more common in older patients (P = .054). The presence of estrogen effect correlated with negative reactions during sex (P = .02) and vaginal dryness or tightness (P = .046). CONCLUSION: Women treated with tamoxifen in the adjuvant setting experienced symptoms of sexual dysfunction. The individual contributions of chemotherapy and tamoxifen to sexual dysfunction warrant prospective study.
Adult↗
Ga-67 scintigraphy in a patient with infected vascular synthetic graft.
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Aorta, Abdominal↗
Cognitively impaired spouses as primary caregivers for demented elderly people.
OBJECTIVE: To describe problems of dementia patients whose spousal caregivers are also cognitively impaired. DESIGN: Retrospective chart review. SETTING: The geriatric assessment clinic at University of California, San Diego, which is one center for the California State sponsored Alzheimer's Disease Diagnosis and Treatment Center Program. PATIENTS: During the period from January 1992 through May 1994, 65 patients completed the assessment and met the entry criteria of being demented and having a spousal caregiver. Twelve of the spouses scored six or more error points on the Katzman Short Orientation-Memory-Concentration Test. MEASUREMENTS: Patient data included age, living situation, other caregivers, use of formal and informal support systems, profiles of medical, cognitive, and functional ability, caregivers interactions, and recommendations from the evaluation. MAIN RESULTS: Dementia patients with cognitively impaired spouses utilized fewer community resources (P = .021) and experienced difficulty with medication compliance (P = .041) more often than those with cognitively normal spousal caregivers. CONCLUSIONS: Older caregivers of patients suffering from dementia should be screened for cognitive problems.
Aged↗
Internalization and distribution of inositol hexakisphosphate in red blood cells.
Inositol hexakisphosphate (InsP6), an allosteric effector of haemoglobin, is able to modify the oxyhaemoglobin dissociation curve. The rightwards shift of the curve increases the in vivo oxygen delivery to tissues. Such an exogenous substance may be internalized into red blood cells (RBC) using a reversed lysis-resealing process following a hypoosmotic shock, resulting in InsP6-RBC with modified oxygen transport capacity. The efficacy of the process depends on various physicochemical parameters which can be fixed during the experimental protocol. The variability of InsP6 internalization from one sample to another appeared to be mainly due to the natural variation in osmotic fragility of RBC. This factor was also modified during the storage of RBC units before the lysis-resealing process. The separation of InsP6-RBC on a density gradient revealed a wide heterogeneity of internalized InsP6 concentration, varying with the degree of osmotic shock. The control of these various parameters will result in resealed InsP6-RBC in reproducible conditions suitable for in vivo use.
Biological Transport, Active↗
Technetium-99m antimyosin antibody (3-48) myocardial imaging: human biodistribution, safety and clinical results in detection of acute myocardial infarction.
Technetium-99m antimyosin (99mTc-AM) antibody imaging may have significant advantages over indium-111 antimyosin in clinical practice. The purpose of this study was to determine the human biodistribution, the safety profile and the sensitivity of 99mTc-AM (3-48) imaging in the detection of both Q-wave and non-Q-wave myocardial infarction (MI). Biodistribution and safety parameters were mainly determined in 12 normal healthy volunteers while 40 patients with proven MI (22 Q-wave, 18 non-Q-wave) were injected with 99mTc-AM (20-25 mCi) between 5 h and 7 days after the onset of acute chest pain. Three standard planar views were performed at 6 h and at 24 h post injection. Both sets of images were completed in 33 patients while two patients were imaged only at 6 h, three patients only at 18 h and one at 18 and 24 h. One patient was not imaged. Vital signs and ECG were recorded and blood samples for haematology, biochemistry and human antimurine antibodies (HAMA) and urinalysis were obtained in all volunteers and patients. No serious adverse reactions or side-effects attributable to 99mTc-AM have been reported. No volunteers or patients developed allergic reactions or significant increases in HAMA titres. Reading of 99mTc-AM imaging was performed by two blinded experienced observers. The sensitivity of 99mTc-AM in the detection of MI was 100% (21/21) for Q-wave and 83.3% (15/18) for non-Q-wave infarctions. The overall sensitivity was 92.3% (36/39). The three false-negative cases were inferoposterior MI. A certain degree of uptake focalization was seen in 26 out of 35 (74.2%) at 6 h. At 24 h, two patients (5.8%) did not show 99mTc-AM uptake while 22 (64.7%) showed intense focal uptake, seven (20.6%) moderate uptake and 3 (8.9%) slight uptake. It is concluded that 99mTc-AM (3-48) imaging is safe and shows high sensitivity in the detection of both Q-wave and non-Q-wave MI even with early imaging (6 h post injection). These promising results warrant further clinical investigation.
Adult↗
Comparison of the effects of captopril and nicardipine on insulin sensitivity and thrombotic profile in patients with hypertension and android obesity. CaptISM Study Group. Captopril Insulin Sensitivity Multicenter Study Group.
Hypertension is often related to metabolic disorders, such as android obesity, glucose intolerance, dyslipidemia, and hyperinsulinism (X syndrome). Insulin resistance (IR), described as the common link among these disorders, could contribute to an increase in coronary risk. The euglycemic insulin clamp technique has been used to show that different classes of antihypertensive agents have different effects on IR. The purpose of this multicenter study was to compare the effects of captopril to those of nicardipine on insulin profile using the oral glucose tolerance test (OGTT), a routine-feasible test. After a 1-month single-blind placebo period, 154 patients with hypertension and android obesity were randomized to 3 months of double-blind therapy with either 50 mg captopril twice daily (n = 77) or 50 mg nicardipine twice daily n = 77). An OGTT with an assay of insulin was performed before and after active treatment. Lipid parameters, Factor VII (F VII), fibrinogen, plasminogen activator inhibitor 1 (PAI-1), and insulin-like growth factor I (IGF-I) were measured at the same time. After 3 months of treatment, the changes from baseline in mean +/- SD values for the insulin area under the curve (AUC) were -24.8 +/- 107.4 microIU x h/mL (-15.2%) for captopril v 6.1 +/- 98.6 microIU x h/mL (4.8%) for nicardipine (P = .072). Changes in peak insulin values were -18.3 +/- 86.2 microIU/mL (-14%) for captopril v 6.7 +/- 79.4 microIU/mL (6.6%) for nicardipine (P = .070).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Density gradient separation of inositol hexaphosphate loaded red blood cells in various preparation conditions.
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Blood Transfusion↗
Monoclonal antibody against a tumor-associated sialoglycoprotein of superficial papillary bladder tumors and cervical condylomas.
A mouse IgG1 monoclonal antibody (MAb), 19A211, defining a tumor-associated cell-surface antigen of superficial papillary bladder tumors, was generated by immunizing with fresh bladder tumor cells mice neonatally injected with normal human urothelial cells. The reactivity of the antibody with cell lines was examined by indirect immunofluorescence staining and was restricted to 3/14 bladder cancer lines and 3/31 cancer cell lines of non-bladder origin, including HeLa cervical cancer. No normal fibroblast, kidney cells, EBV-lymphocytes, erythrocytes or leukocytes expressed the antigen. Reactivity of MAb 19A211 was well preserved on tissue paraffin sections. Immunoperoxidase staining of normal adult or fetal tissues showed no reactivity except for a patchy or uniform staining of umbrella cells in 6/23 adult and 1/4 fetal urothelium samples. Positive and often heterogeneous staining was observed on 24/38 papillary superficial tumors (Ta) and 4/5 carcinoma in situ bladder lesions but on only 4/20 infiltrating tumors. It was also observed on 5/6 cervical condylomas and one bladder condyloma, but none of 6 penile or vulvar condylomas. All other tumors tested were negative. The antigenic determinant is present on a heterogeneous group of proteins with molecular weights ranging from 90 to 200 kDa. It is sensitive to periodate treatment and to neuraminidase but only partially sensitive to proteases. MAb 19A211 is different from other reported MAbs with similar reactivity to superficial bladder tumors and umbrella cells of normal urothelium. When tested in competition assays, several of these MAbs, but not 19A211, were found to react with Lewis X blood group determinant. Our results suggest that 19A211 may be useful for detection and stratification of bladder tumors.
Antibodies, Monoclonal↗
Estimation of fractional changes in peak gNa, -gNa, ENa, and h infinity (V) of cardiac cells from Vmax of the propagating action potential.
Fractional changes in the peak sodium conductances of the cardiac cell membrane during the action potential are often estimated from fractional changes in Vmax. The present model study shows, in reasonable accord with experimental evidence, that this approach is valid for propagating action potentials provided that the membrane capacitance does not change and that the nonsodium current is small at the time of Vmax. When the maximum conductance of the sodium channel (gNa) and the sodium equilibrium potential (ENa) are varied independently of one another, fractional changes in either of them can be predicted from fractional changes in Vmax if a reasonable estimate of the initial value of ENa is available. Manipulations which modify the resting membrane potential without changing gNa allow to calculate fractional changes in the steady-state Na+ inactivation [h infinity (V)] when ENa is known. Simulation runs were carried out for a continuous cable and a discontinuous cable with either a low (1 omega.cm2) or a high (10 omega.cm2) junctional resistance. The predictions of the model are valid in the discontinuous cable provided that the recording point remains strictly the same throughout the series of measurements. Because the high-resistance discontinuous cable provides conditions which reduce further the nonsodium current at the time of Vmax, the accuracy of the predictions are better in this case. It is concluded that properly designed experimental approaches based on Vmax measurements can yield important information on manipulations affecting gNa, ENa, and h infinity (V) during propagation, and that a better accuracy is possible in cardiac muscle when measurements are made during transverse propagation.
Action Potentials↗
Model study of the spread of electrotonic potential in cardiac tissue.
This model study describes the electrotonic response of a cable model of cardiac tissue stimulated at one point. The stimulus is applied intracellularly in the form of a 2 ms pulse of current of near threshold amplitude. The attenuation of the electrotonic potential with distance and its mode of propagation along the cable are compared for equivalent passive, continuous and discontinuous cables. The three structures have the same basic physical and electrical characteristic and they differ either with respect to being active or passive or to the presence or absence of intercellular gap junctions. In the continuous cable a just subthreshold stimulus produces a local active response which propagates more slowly and is attenuated less rapidly with distance than in a passive cable. The spatial decrement of the local response in a discontinuous cable is faster than in a continuous cable of equal average resistivity. It is suggested that the larger time constant of the foot of the action potential observed in the longitudinal direction in cardiac muscle could be due in part to the electrotonic spread of the local response from the site of stimulation.
Action Potentials↗
Polymorphic expression of a human superficial bladder tumor antigen defined by mouse monoclonal antibodies.
Three mouse monoclonal antibodies (mAbs), which define a highly restricted antigen, were obtained by simultaneous immunizations with superficial papillary bladder tumor cells and mouse polyclonal serum against normal urothelium. The antigen was detected by the avidin/biotin/peroxidase method in 30/44 superficial bladder tumors (68%) but in only 4/27 infiltrating urothelial cancers (with much less intensity). No normal adult or fetal tissues tested expressed the antigen, including normal urothelium from 40 individuals, 13 of whom had a bladder tumor positive for the antigen. Only 1 of 45 nonbladder tumors showed some reactivity with one of the three mAbs. Serological tests on a large panel of human cancer cell lines and normal cultured cells were negative. The antigen is highly stable and well preserved on paraffin-embedded tissues. Electrophoretic transfer blot experiments with fresh tumor extracts showed that all three mAbs react with a determinant on a component of 300,000 Mr (pI 9.5) and 62,000 Mr (pI 6.5). The antigen shows polymorphic expression at the cellular level on tissue sections and also at a molecular level on immunoblots where the two bands are differentially detected on extracts of a series of tumors but are not visualized on normal urothelium extracts. The characteristics of this antigenic system suggest that it may provide some insights about the biology of bladder cancer. Specific detection of the antigen on 70% of superficial bladder tumors with normal cytology may be useful for their diagnosis and follow-up.
Animals↗