When and to what end do pathologists agree?
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Breast Neoplasms↗
Biomedical subjects
R A Jensen
Publications and source records attributed to R A Jensen.
Substrate ambiguity of 3-deoxy-D-manno-octulosonate 8-phosphate synthase from Neisseria gonorrhoeae in the context of its membership in a protein family containing a subset of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthases.
3-Deoxy-D-manno-octulosonate 8-phosphate (KDOP) synthase and 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase catalyze similar phosphoenolpyruvate-utilizing reactions. The genome of Neisseria gonorrhoeae contains one gene encoding KDOP synthase and one gene encoding DAHP synthase. Of the two nonhomologous DAHP synthase families known, the N. gonorrhoeae protein belongs to the family I assemblage. KDOP synthase exhibited an ability to replace arabinose-5-P with either erythrose-4-P or ribose-5-P as alternative substrates. The results of periodate oxidation studies suggested that the product formed by KDOP synthase with erythrose-4-P as the substrate was 3-deoxy-D-ribo-heptulosonate 7-P, an isomer of DAHP. As expected, this product was not utilized as a substrate by dehydroquinate synthase. The significance of the ability of KDOP synthase to substitute erythrose-4-P for arabinose-5-P is (i) recognition of the possibility that the KDOP synthase might otherwise be mistaken for a species of DAHP synthase and (ii) the possibility that the broad-specificity type of KDOP synthase might be a relatively vulnerable target for antimicrobial agents which mimic the normal substrates. An analysis of sequences in the database indicates that the family I group of DAHP synthase has a previously unrecognized membership which includes the KDOP synthases. The KDOP synthases fall into a subfamily grouping which includes a small group of DAHP synthases. Thus, family I DAHP synthases separate into two subfamilies, one of which includes the KDOP synthases. The two subfamilies appear to have diverged prior to the acquisition of allosteric-control mechanisms for DAHP synthases. These allosteric control specificities are highly diverse and correlate with the presence of N-terminal extensions which lack homology with one another.
3-Deoxy-7-Phosphoheptulonate Synthase↗
Premalignant and malignant disease of the breast: the roles of the pathologist.
This review targets the current role of the pathologist in the diagnosis and management of breast disease, a responsibility that evolved along with an increasingly complex approach to human breast cancer. We will focus on the three major areas of this responsibility: premalignancy, highlighting the atypical hyperplasias; the carcinomas in situ, highlighting low grade ductal carcinoma in situ; and the stratification and prognosis of invasive carcinomas. It will be evident that with the advent of an increasingly rich menu of treatment options, the challenge to identify an optimal categorization of breast cancer and its putative precursors is not static.
Breast↗
Genetic testing and informed consent.
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Biomedical Research↗
[Decreased pain threshold and tolerance in patients with chronic tension headache].
Nociceptive processing was studied in 40 patients with chronic tension-type headache and in 40 healthy controls. We found that pericranial tenderness recorded by manual palpation was considerably higher in patients than in controls (p < or = 0.0002). Pressure pain detection and tolerance thresholds recorded in the finger, by means of a pressure algometer, were significantly lower in patients than in controls (p < or = 0.0009), and a non-significant similar trend was observed in the temple (p < or = 0.12). Detection and tolerance thresholds were decreased to a similar degree in patients compared with controls, and pain thresholds recorded in the finger and in the temple were highly correlated (r = 0.84, p < 0.0001). The electrical pain threshold at the labial commissure, by means of an electrical stimulator, was significantly decreased in patients compared with controls (p = 0.03). All of the examined pain thresholds were significantly correlated to the pericranial tenderness recorded by palpation (r = -0.35 to -0.53, p < or = 0.03). We conclude that the present finding of a general hypersensitivity to pain stimuli in chronic tension-type headache indicates that central factors play an important role in the pathogenesis of this disorder.
Adolescent↗
Structure and function analysis of the human myeloid cell nuclear differentiation antigen promoter: evidence for the role of Sp1 and not of c-Myb or PU.1 in myelomonocytic lineage-specific expression.
The human myeloid nuclear differentiation antigen (MNDA) is expressed specifically in maturing cells of the myelomonocytic lineage and in monocytes and granulocytes. Epitope enhancement was used to confirm the strict lineage- and stage-specific expression of MNDA in bone marrow as well as in other paraffin-embedded fixed tissues. A 1-kb region of the gene that includes 5' flanking sequence was reported earlier to contain functional promoter activity and was specifically demethylated in expressing cells in contrast to null cells. Further analysis has revealed that this 1-kb fragment promotes higher reporter gene activity in MNDA-expressing cells than non-expressing cells, indicating cell-specific differences in transactivation. This sequence contains consensus elements consistent with myeloid-specific gene expression, including a PU.1 consensus site near the major transcription start site and a cluster of c-Myb sites located several hundred bases upstream of this region. However, analysis of deletion mutants localized nearly all of the promoter activity to a short region (-73 to -16) that did not include the cluster of c-Myb sites. A 4-bp mutation of the core Sp1 consensus element (GC box) (-20) reduced overall promoter activity of the 1-kb fragment. Mutation of the PU.1 site did not significantly affect promoter activity. Only a small region (-35 to +22) including the Sp1 element and transcription start site, but not the PU.1 site was footprinted. The 4-bp mutation of the core Sp1 consensus element abolished footprinting at the site and an antibody super-shift reaction showed that Sp1 is one of the factors binding the consensus site. The Sp1 site also co-localizes with a DNase I hypersensitive site. The results indicate that DNA methylation, chromatin structure, and transactivation at an Sp1 site contribute to the highly restricted expression of this myelomonocytic lineage specific gene.
Antigens, Differentiation, Myelomonocytic↗
Inhibitory avoidance and appetitive learning in aged normal mice: comparison with transgenic mice having elevated plasma growth hormone levels.
Groups of 25-month-old ("old") B6C3 hybrid male mice, 6-month-old ("young") normal males, and their age-matched transgenic (TG) siblings overexpressing the bovine growth hormone gene were given an inhibitory avoidance training trial (0.20-mA electric shock, 1.0-s duration). The old B6C3 hybrids and the young TG mice displayed poorer retention (shorter latencies to enter the shock compartment) 24 h and 42 days after training than did the young normal mice. In a subsequent multiple-trial acquisition test, young TG and old normal mice required more trials to reach the criterion of complete inhibition of step-through responding for 300 s than did young normal mice. Young normal and young TG mice did not differ in trials to extinction, but TG mice met the extinction criterion sooner than did old normal mice, suggesting poorer longterm retention. In tests of T-maze appetitive learning, young normal, old normal, and young TG mice did not differ in acquisition or 24-h retention. Contrary to expectation, TG mice acquired T-maze reversal learning in fewer trials than did young normal or old normal mice. The TG and young normal mice did not differ in retention when retested 44 days after initial training, but old normal mice showed poorer retention than did the young normals. Results of locomotor activity and shock response tests suggested that learning impairments were not due to differences in locomotor activity or shock response thresholds in these animals. Tests in an elevated plus maze indicated that young TG mice were less anxious in a novel environment than their normal siblings, which may contribute to their impaired inhibitory avoidance learning. These findings suggest that 6-month-old TG mice overexpressing the bovine growth hormone gene display alterations in inhibitory avoidance (but not appetitive) learning similar to those occurring in 25-month-old normal mice. The neurobiological mechanisms mediating inhibitory avoidance and T-maze appetitive learning in these animals may be largely dissociated.
Aging↗
High-mobility group (HMG) protein HMG-1 and TATA-binding protein-associated factor TAF(II)30 affect estrogen receptor-mediated transcriptional activation.
The estrogen receptor (ER) belongs to a family of ligand-inducible nuclear receptors that exert their effects by binding to cis-acting DNA elements in the regulatory region of target genes. The detailed mechanisms by which ER interacts with the estrogen response element (ERE) and affects transcription still remain to be elucidated. To study the ER-ERE interaction and transcription initiation, we employed purified recombinant ER expressed in both the baculovirus-Sf9 and his-tagged bacterial systems. The effect of high-mobility group (HMG) protein HMG-1 and purified recombinant TATA-binding protein-associated factor TAF(II)30 on ER-ERE binding and transcription initiation were assessed by electrophoretic mobility shift assay and in vitro transcription from an ERE-containing template (pERE2LovTATA), respectively. We find that purified, recombinant ER fails to bind to ERE in spite of high ligand-binding activity and electrophoretic and immunological properties identical to ER in MCF-7 breast cancer cells. HMG-1 interacts with ER and promotes ER-ERE binding in a concentration- and time-dependent manner. The effectiveness of HMG-1 to stimulate ER-ERE binding in the electrophoretic mobility shift assay depends on the sequence flanking the ERE consensus as well as the position of the latter in the oligonucleotide. We find that TAF(II)30 has no effect on ER-ERE binding either alone or in combination with ER and HMG-1. Although HMG-1 promotes ER-ERE binding, it fails to stimulate transcription initiation either in the presence or absence of hormone. In contrast, TAF(II)30, while not affecting ER-ERE binding, stimulates transcription initiation 20-fold in the presence of HMG-1. These results indicate that HMG-1 and TAF(II)30 act in sequence, the former acting to promote ER-ERE binding followed by the latter to stimulate transcription initiation.
Animals↗
RAP-PCR using RNA from tissue microdissection.
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Base Sequence↗
Outreach by the Hanford Tribal Service Program to Indian communities around the Hanford Nuclear Reservation.
BACKGROUND: The Hanford Tribal Service Program offers technical assistance and health education to American Indian tribes in an area reported to be affected by radiation from the Hanford Nuclear Reservation, which was developed and operated by the United States federal government. This article describes strategies used to reach out to communities to tell them about Hanford's history and the potential health effects of radioactive materials emitted from Hanford. Two health effects of concern are thyroid disease and cancer. Based in Portland, Oregon, the Hanford program is administered by the Northwest Portland Area Indian Health Board, a tribal organization serving 39 federally recognized tribes in Idaho, Oregon, and Washington on health issues. METHODS: This article describes outreach strategies used by the health educator. They include informational resource kits, community visits, postage-paid response cards, and a toll-free telephone line. The staff made presentations to tribal councils and then reached out to health care providers and general community members, with special attention given to elders. DISCUSSION: The staff faced obstacles in delivering the message about Hanford's history and the potential health effects of the radioactive emissions from Hanford. One such obstacle is the uncertain and controversial nature linking Hanford and health effects due to its releases of radioactive materials. Another is that Hanford concerns represent only one of many issues vying for communities' attention. However, communities welcomed the efforts of the Hanford Tribal Service Program. After decades of secrecy, people wanted to know what happened at Hanford and how its operations might have affected their health.
Community-Institutional Relations↗
Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma.
BACKGROUND: Risk of breast cancer after biopsy demonstrating a papilloma has long been variously interpreted on the basis of histologic pattern of multiplicity of papillomas. METHODS: A nested case control study was performed on women with surgical breast biopsies evidencing papillomas; cases who subsequently developed invasive carcinoma were compared with controls who did not. Presence of atypical hyperplasia (AH) within the papilloma as well as areas of AH in the surrounding parenchyma were evaluated in both cases and controls. The entire cohort (not tested) was separately evaluated for all variables except for atypia within papillomas. RESULTS: The relative risk of invasive carcinoma for women with papillomas containing AH was > 4x that of papillomas without AH within or surrounding the papilloma. This risk may be greater with added atypical hyperplasia outside the papilloma and most strikingly, most of the subsequent invasive carcinomas developed in the same breast and probably near the site of the original papilloma. However, ordinary patterns of epithelial hyperplasia lacking specific features of AH within the papilloma do not add to the risk of subsequent carcinoma development over papillomas without hyperplasia. CONCLUSIONS: This study indicates that women having papillomas with AH have a similar or greater cancer risk than others with specifically defined patterns of atypical hyperplasia within the breast parenchyma (4-5x relative risk). Most importantly, this risk is largely local in the region of the original papilloma.
Adult↗
Usefulness of banding of the pulmonary trunk with single ventricle physiology at risk for subaortic obstruction.
This study addresses the effects of early banding of the pulmonary trunk and subsequent management of subaortic obstruction on the attainment of acceptable pre-Fontan hemodynamics in patients with a single left ventricle and aorta arising from an outflow chamber. We report our experience with 26 patients seen at our institution between January 1984 and December 1994 with a diagnosis of double-inlet left ventricle or tricuspid atresia and transposed great arteries, who were initially managed with pulmonary artery banding in the first 6 months of life. Pulmonary artery band placement was performed at an age of 2.1 +/- 1.8 months (mean +/- SD). Associated aortic arch abnormalities were present in 8 patients (31%). There were 19 patients (73%) who underwent treatment with a Damus-Kaye-Stansel procedure or ventricular septal defect (VSD) enlargement for a significant subaortic gradient or morphologically small VSD, alone or in conjunction with a Glenn or Fontan procedure. Eighteen of 26 patients (69%) underwent cardiac catheterization to assess their candidacy for the Fontan operation. Of this group, 16 were classified as low to moderate risk and 2 as high-risk Fontan candidates, based on hemodynamic criteria. The cumulative mortality for the entire cohort was 19%. Our results suggest that this high-risk group of patients can undergo effective pulmonary artery banding as an initial palliative step, with subsequent intervention for subaortic ob- struction when it is documented or highly suspected, and that acceptable pre-Fontan hemodynamic parameters can be achieved.
Cardiac Catheterization↗
Terminology for carcinoma-in-situ of the breast.
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Breast Neoplasms↗
Identification of ArgBP1, an Arg protein tyrosine kinase binding protein that is the human homologue of a CNS-specific Xenopus gene.
Arg and c-Abl represent the mammalian members of the Abelson family of nonreceptor protein-tyrosine kinases. To gain insight into the biological role of Arg we used the two-hybrid approach to identify interacting proteins. Using a C-terminal segment of Arg we identified a novel protein, ArgBP1 (Arg binding protein 1). ArgBP1 contains a C-terminal SH3 domain, several PEST sequences, a serine rich domain and an SH3 binding site. ArgBP1 is ubiquitously expressed as two transcripts of approximately 2.2 kb and approximately 8 kb with highest levels in brain, heart and testis. The association of ArgBP1 with Arg in living cells was confirmed by coimmunoprecipitation in cotransfected COS cells. Analysis of the mechanism of association indicated that the ArgBP1 SH3 domain binds to a C-terminal Arg SH3-binding site, and that an N-terminal ArgBP1 proline-rich sequence binds to the Arg SH3 domain. Immunostaining indicated that the subcellular localization of ArgBP1 is cytoplasmic. The similarity of the ArgBP1 expression pattern and subcellular localization to those of Arg and the potential for a highly specific and potentially strong association mediated by two pairs of SH3 domain/proline-rich motif interactions, suggest that ArgBP1 is likely to be a regulator and/or effector of Arg function.
Adaptor Proteins, Signal Transducing↗
Ductal carcinoma in situ of the breast: understanding the misunderstood stepchild.
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Breast Neoplasms↗
Isolation of the full-length murine erythropoietin receptor using a baculovirus expression system.
The full-length murine erythropoietin receptor was expressed in Spodoptera frugiperda (Sf9) cells using a recombinant baculovirus vector. Erythropoietin receptor protein production was maximal 48 hours after infection, as determined by metabolic labeling and immunoblotting; receptor protein varied in molecular mass from 62 to 76 kD. Erythropoietin receptors produced in Sf9 cells could be solubilized using CHAPS in a form capable of binding erythropoietin, and the solubilized receptor bound to immobilized Concanavalin A (Con A) and wheat germ agglutinin, as well as to immobilized recombinant human erythropoietin. Analysis of the distribution of erythropoietin receptors in Sf9 plasma membrane and cytosol fractions using lectin affinity chromatography revealed that membrane-bound receptor had a higher apparent molecular mass and contained the bulk of receptors that bound to wheat germ agglutinin. The receptor was purified by sequential affinity chromatography on Con A-Sepharose and immobilized erythropoietin. Erythropoietin receptors expressed in Sf9 cells were inserted into the plasma membrane in the correct orientation, bound 125I-erythropoietin with a single affinity (kD, 330 pmol/L), and were internalized after ligand binding. However, kD varied inversely with the number of cell surface receptors. Solubilized erythropoietin receptors in whole-cell lysates and isolated plasma membranes exhibited high-affinity binding, with kD values of 92 and 57 pmol/L, respectively. Erythropoietin bound to the surface of infected Sf9 cells could be cross-linked to two proteins with molecular masses of 90 and 65 kD using the homobifunctional cross-linker, disuccinimidyl suberate (DSS). Similar results were obtained with solubilized receptors in whole-cell lysates, and both proteins could be immunoprecipitated by an antiserum to the erythropoietin receptor carboxyl-terminal domain.
Animals↗
Arousal-induced modulation of memory storage processes in humans.
We recently demonstrated in human subjects that muscle-tension-induced arousal can enhance later retention performance and that this effect is attenuated by beta-adrenergic receptor antagonists. In that study, each subject established a baseline for muscle tension by squeezing a hand dynamometer for 30 s with maximum force. This may have served to "prime" subsequent arousal produced by muscle tension. Two experiments were performed to address this issue. At the beginning of each experiment, young adult subjects were asked to squeeze the hand dynamometer at maximum effort either for 30 s (Prime) or for only 1 s (No prime). Then, during the task, arousal was induced by having each subject exert a moderate amount of tension (25 to 50% of baseline maximum). In the first experiment, subjects were shown four consecutive lists of 20 highly imageable nouns, given immediate recall tests of each, and then given a comprehensive recall and recognition test at the conclusion of the experiment. Moderate arousal was induced once for each list (at encoding, consolidation, or retrieval) or not at all for one list. The sequence of arousal induction was counterbalanced. Significant enhancement of delayed recall was seen in the 30-s group for those lists in which arousal was induced during the consolidation or retrieval period with no significant effects in the 1-s group. These results demonstrate that arousal can modulate memory consolidation when induced shortly after learning and that an initial priming event may affect the response to subsequent similar arousing events. In the second experiment, subjects read paragraphs, some of which contained highlighted words (working memory task); half of the subjects were given the 30-s procedure and half the 1-s procedure. Only those subjects in the 30-s group showed significant arousal-induced enhancement of delayed recognition of the highlighted words. Again, no significant effect on retention performance was seen in the group that squeezed the hand dynamometer for only 1 s during the priming period. Pulse data suggested that there may be somewhat greater heart-rate reactivity in the 30-s group. These findings suggest that memory modulation by arousal may be primed, or enhanced, by a relevant preliminary arousal event.
Adult↗