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Biomedical subjects

R A Jensen

Publications and source records attributed to R A Jensen.

At least 37 records · Page 2Linked to original sources
PubMed2000

Benign transport of breast epithelium into axillary lymph nodes after biopsy.

The most important prognostic indicator of distant metastasis in breast cancer is histologic documentation of axillary lymph node metastasis. Controversy exists about the importance of micrometastases (< 0.2 cm), and current pathology practice includes a careful search for their presence. We describe the histologic findings in a series of axillary lymph node dissections taken approximately 2 weeks after breast biopsy. Each case has limited presence of epithelial cells in the subcapsular sinus of a draining lymph node that we attribute to mechanical transport of tumor and/or normal breast epithelium secondary to the previous surgical or needle manipulation. These cells were accompanied by hemosiderin-laden macrophages and damaged RBCs. While the clinical implication of these findings is unknown, we believe that it will be of no clinical significance and have no untoward prognostic effect.

Adult↗
PubMed2000

Reactive spindle cell nodules of the breast after core biopsy or fine-needle aspiration.

Reactive spindle cell nodules (RSCNs) arising postoperatively or after fine-needle aspiration (FNA) have been reported previously in the genitourinary tract and thyroid. We describe 18 cases of similar lesions in breast, associated with a history of core needle biopsy or FNA. The majority of the RSCNs (15 cases) were associated with papillary lesions or complex sclerosing lesions. The RSCNs were nonencapsulated and relatively nodular, measuring 1.5 to 9 mm. They were composed of spindle cells with mild to moderate nuclear pleomorphism and a low mitotic count. A network of small blood vessels, macrophages, and lymphocytes was present in all cases. Immunohistochemically, the spindle cells expressed smooth and specific muscle actins, supporting a myofibroblastic origin. The association of RSCNs with needle trauma to fibrosclerotic lesions, such as complex sclerosing lesions and papillary lesions that regularly have myofibroblasts, suggests an exuberant reparative cause. Recognition of this reactive process will avoid overdiagnosis of mammary spindle cell malignant neoplasm.

Actins↗
PubMed1999

BRCA1-associated growth arrest is RB-dependent.

BRCA1 is a susceptibility gene for breast and ovarian cancer with growth-inhibitory activity for which the mechanism of action remains unclear. When introduced into cells, BRCA1 inhibits growth of some but not all cell lines. In an attempt to uncover the mechanism of growth suppression by BRCA1, we examined a panel of cell lines for their ability to reduce colony outgrowth in response to BRCA1 overexpression. Of all variables tested, only those cells with wild-type pRb were sensitive to BRCA1-induced growth suppression. In cells with an intact rb gene, inactivation of pRb by HPV E7 abrogates the growth arrest imposed by BRCA1. In accordance with these observations, we found that BRCA1 could not suppress BrdUrd uptake in primary fibroblasts from rb-/- mice and exhibited an intermediate ability to inhibit DNA synthesis in rb+/- as compared with rb+/+ cells. We further found that the BRCA1 protein complexes with the hypophosphorylated form of pRb. This binding is localized to amino acids 304-394 of BRCA1 protein and requires the ABC domain of pRb. In-frame deletion of BRCA1 fragment involved in interaction with pRb completely abolished the growth-suppressive property of BRCA1. Although it has been reported that BRCA1 interacts with p53, we find the p53 status did not affect the ability of BRCA1 to suppress colony formation. Our data suggest that the growth suppressor function of BRCA1 depends, at least in part, on Rb.

Adenoviridae↗
PubMed1999

BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair.

The breast cancer predisposition genes, BRCA1 and BRCA2, are responsible for the vast majority of hereditary breast cancer. Although BRCA2 functions to help the cell repair double-stranded DNA breaks, the function of BRCA1 remains enigmatic. Here, we develop a human genetic system to study the role of BRCA1 in oxidative DNA damage. We show that human cancer cells containing mutated BRCA1 are hypersensitive to ionizing radiation. This hypersensitivity can be reversed by the expression of forms of BRCA1 that are not growth suppressing. Reversal of hypersensitivity requires the ring finger of BRCA1, its transactivation domain, and its BRCT domain. Lastly, we show that unlike BRCA2, BRCA1 does not function in the repair of double-stranded DNA breaks. Instead, it functions in transcription-coupled DNA repair (TCR). TCR ability correlated with radioresistance as cells containing BRCA1 showed both increased TCR and radioresistance, whereas cells without BRCA1 showed decreased TCR and radiosensitivity. These findings give physiologic significance to the interaction of BRCA1 with the basal transcription machinery.

BRCA1 Protein↗
PubMed1999

Metaplastic breast tumors with a dominant fibromatosis-like phenotype have a high risk of local recurrence.

BACKGROUND: In the current study the authors describe the clinicopathologic characteristics of a low grade variant of spindle cell metaplastic tumors of the breast. Previously these tumors have been considered within a larger group recognized as metaplastic carcinoma, including cases with higher grade features. METHODS: Breast tumors comprised predominantly of low grade spindle cells, with sparse low grade epithelial elements, were selected. Clinical features as well as macroscopic, microscopic, and immunohistochemical findings were reviewed with emphasis on the biologic behavior and the differential diagnosis from other spindle cell lesions. RESULTS: Of 30 tumors fulfilling strict criteria, 20 contained squamous or glandular elements associated with the spindle cells. Ten tumors were comprised entirely of low grade spindle cells with limited clustered epithelioid cells. At the periphery, all tumors showed a proliferation of bland spindle cells infiltrating the adjacent parenchyma and mimicking fibromatosis. The epithelioid cells and some spindle cells expressed both vimentin and one or more cytokeratins. Seven of eight patients treated by excisional biopsy developed local recurrence, whereas only one of ten patients treated with wide excisional biopsy developed a local recurrence. No distant or regional metastases occurred. CONCLUSIONS: The presence of limited clusters of epithelioid cells along with a dominant fibromatosis-like pattern may be unique in the breast. The biologic potential of the fibromatosis-like, spindle cell, metaplastic breast tumors most likely is defined by their major histologic phenotype; they are capable of local recurrence with no demonstrated distant spread or regional metastases, as in pure fibromatosis of the breast.

Adult↗
PubMed1999

Estrogen replacement therapy in women with a history of proliferative breast disease.

BACKGROUND: Little information is available regarding the invasive breast carcinoma risk associated with estrogen replacement therapy (ERT) in women with histories of histologically defined breast lesions. METHODS: A retrospective cohort study of a consecutive series of women who underwent breast biopsies that proved to be benign between 1952-1978 was conducted. Follow-up data were obtained for 9494 women (87.6% of women eligible for follow-up). To investigate the effect of ERT on invasive breast carcinoma risk, the analysis was restricted to women with premenopausal breast disease whose follow-up extended through menopause and who did not develop premenopausal breast carcinoma. Relative risks were calculated with respect to women who took ERT but whose benign breast biopsies had neither atypical hyperplasia (AH), complex fibroadenoma (CFA), nor proliferative disease without atypia (PDWA). RESULTS: During 190,845 woman-years of follow-up there were 444 confirmed cases of invasive breast carcinoma in the entire cohort. Women with a history of AH had relative risks of invasive breast carcinoma of 2.87 (95% confidence interval [95% CI], 1.3-6.3) and 2.53 (95% CI, 1.0-6.3) if they did or did not take ERT, respectively. For women with a history of CFA these risks were 1.57 (95% CI, 0.72-3.4) and 1.46 (95% CI, 0.53-4.0), respectively, whereas for women with a history of PDWA they were 1.37 (95% CI, 0.88-2.1) and 1.13 (95% CI, 0.69-1.9), respectively. CONCLUSIONS: ERT does not significantly elevate the risk of invasive breast carcinoma in women with previous histologically defined benign breast disease. Therefore, ERT is not contraindicated in these women.

Adult↗
PubMed1999

Caveolin is an inhibitor of platelet-derived growth factor receptor signaling.

Caveolin is a major structural component of caveolae and has been implicated in the regulation of the function of several caveolae-associated signaling molecules. Platelet-derived growth factor (PDGF) receptors and caveolin were colocalized in the same subcellular fraction after sucrose density gradient fractionation of fibroblasts. Additionally, we found that the PDGF receptors interacted with caveolin in NIH3T3 fibroblast cells. We then examined whether caveolin directly binds to PDGF receptors and inhibits kinase activity using a recombinant PDGF receptor overexpressed in insect cells and peptides derived from the scaffolding domain of caveolin subtypes. We found the peptide from caveolin-1 and -3, but not -2, inhibited the autophosphorylation of PDGF receptors in a dose-dependent manner. Similarly, caveolin-1 and -3 peptides directly bound to PDGF receptors. Mutational analysis using a series of truncated caveolin-3 peptides (20-, 17-, 14-, and 11-mer peptides) revealed that at least 17 amino acid residues of the peptide were required to inhibit and directly bind to PDGF receptors. Thus, our findings suggest that PDGF receptors directly interact with caveolin subtypes, leading to the inhibition of kinase activity. Caveolin may be another regulating factor of PDGF-mediated tyrosine kinase signaling.

3T3 Cells↗
PubMed1999

A probable mixed-function supraoperon in Pseudomonas exhibits gene organization features of both intergenomic conservation and gene shuffling.

Sequencing of an 8182-bp chromosomal region in Pseudomonas stutzeri revealed the major portion of an apparent mixed-function supraoperon (defined as a nested organization of transcriptional units encoding gene products which function in more than one biochemical pathway). A nearly identical supraoperon organization was apparent in the unpublished Pseudomonas aeruginosa genome database, where the complete Pseudomonas supraoperon was deduced. The serC(pdxF)-aroQp. pheA-hisHb-tyrAc-aroF-cmk-rpsA supraoperon encodes 3-phosphoserine aminotransferase, a bidomain chorismate mutase/prephenate dehydratase, imidazole acetol-phosphate aminotransferase, cyclohexadienyl dehydrogenase, 5-enolpyruvylshikimate 3-phosphate synthase, cytidylate kinase, and ribosomal protein S1. The member genes were identified by homology analysis, enzyme assay, and/or functional complementation. Although SerC(PdxF) and HisHb exercise their primary functions in serine, pyridoxine, and histidine biosynthesis, they also have critical catalytic roles in provision of the sidechain amino groups of tryptophan, phenylalanine, and tyrosine. The likelihood of supraoperon-wide translational coupling is suggested by the highly compressed intergenic spacing (including overlapping stop and start codons), as well as by possible hairpin structures in mRNA which may sequester some of the ribosome-binding sites and thus provide a mechanism for translational coupling. A comparison of the organization of the supraoperon genes in other organisms represented in the database revealed unmistakable conservation of the linkage of these genes across wide phylogenetic boundaries, albeit with considerable gene shuffling. At least remnants and shuffled portions of the entire supraoperon are distributed throughout the Gram-negative bacteria with the hisHb-tyrA-aroF gene block being conserved as distantly as the gram-positive bacteria. Such conservation of mixed-function genes may reflect the selective value of still-unknown global relationships of protein-protein interaction or regulation.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1999

Immunocytochemical analysis of MNDA in tissue sections and sorted normal bone marrow cells documents expression only in maturing normal and neoplastic myelomonocytic cells and a subset of normal and neoplastic B lymphocytes.

The human myeloid cell nuclear differentiation antigen (MNDA) is a nuclear antigen known to be expressed in mature myelomonocytic cell lines. An extensive immunocytochemical evaluation of fixed tissues confirmed MNDA expression in normal maturing granulocytes and monocytes and in acute nonlymphocytic leukemias and chronic myelogenous leukemia. MNDA was not detected in normal tissue histiocytes but was found in activated macrophages and foreign body giant cells associated with inflammation. Flow cytometric cell sorting of normal bone marrow established that MNDA is initially expressed in myeloid blast cells. Examination of lymphoid tissues showed a low level of expression in a population of normal mande B lymphocytes but not in germinal center cells or plasma cells. A subset of B cell neoplasms expressing MNDA included hairy cell leukemia, parafollicular (monocytoid) B cell lymphoma, mantle cell lymphoma, and small lymphocytic lymphoma. Cell sorting of normal bone marrow showed MNDA expression in CD20+/CD10-/CD5- B cells. MNDA was not detected in other normal bone marrow or all other nonhematopoietic cells. The hematopoietic cell-specific pattern of MNDA expression was elucidated through a comprehensive analysis of normal and neoplastic tissues, and the results provide further evidence of the coexpression of B- and myeloid cell markers in neoplastic B cells and identify a normal B cell population that might be related to the cell of origin of a subset of B cell neoplasms.

Antibody Specificity↗
PubMed1999

Effects of monetary contingencies on smoking relapse: influences of trait depression, personality, and habitual nicotine intake.

Of 56 male smokers, 34 were randomly assigned (by 60% random odds) to quit smoking immediately, whereas the remaining 22 were assigned to quit after an additional 31 days. Compensation ($300) was contingent on abstinence for a minimum of 31 or 2 days (depending on random assignment) and completion of all experimental sessions. Contingencies for the immediate-quit group required 31 days of abstinence; those for the delayed-quit group required only 2 days of abstinence. Contingency duration (31 vs. 2 days) predicted days to relapse. All but 4 of the 31-day contingency participants maintained abstinence for at least 31 days, whereas only 3 of the 2-day contingency group abstained for 31+ days. However, 31-day contingencies did not result in longer postcontingency time to relapse. Higher trait neuroticism, depression, and psychopathic deviate scores predicted decreased time to relapse. Prequit cotinine concentrations and Fagerström Tolerance Questionnaire scores failed to predict time to relapse.

Depression↗
PubMed1999

EEG, physiology, and task-related mood fail to resolve across 31 days of smoking abstinence: relations to depressive traits, nicotine exposure, and dependence.

Changes in task-related mood and physiology associated with 31 days of smoking abstinence were assessed in smokers, 34 of whom were randomly assigned to a quit group and 22 to a continuing-to-smoke control group. A large financial incentive for smoking abstinence resulted in very low participant attrition. Individuals were tested during prequit baselines and at 3, 10, 17, and 31 days of abstinence. Abstinence was associated with decreases in heart rate and serum cortisol, a slowing of electroencephalogram (EEG) activity, and task-dependent and trait-depression-dependent hemispheric EEG asymmetries. Differences between the quit group and the smoking group showed no tendency to resolve across the 31 days of abstinence. Trait depression and neuroticism correlated with increases in left-relative-to-right frontal EEG slow-wave (low alpha) activity at both 3 and 31 days of abstinence. In contrast, prequit nicotine intake and Fagerström Tolerance scores correlated with alpha asymmetry and with greater EEG slowing only at Day 3. Thus, the effects of smoking abstinence appear to last for at least several months.

Adult↗
PubMed1999

Enhanced recognition memory following vagus nerve stimulation in human subjects.

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.

Double-Blind Method↗
PubMed1999

Mixed-function supraoperons that exhibit overall conservation, albeit shuffled gene organization, across wide intergenomic distances within eubacteria.

Nearly identical mixed-function supraoperons (defined as nested transcriptional units encoding gene products that function in more than one biochemical pathway) have been found recently in Pseudomonas stutzeri and Pseudomonas aeruginosa. The Pseudomonas serC(pdxF)-aroQp.pheA-hisHb-tyrAc-aroF+ ++-cmk-rpsA supraoperon encodes 3-phosphoserine aminotransferase, a bidomain chorismate mutase/prephenate dehydratase, imidazole acetol-phosphate aminotransferase, cyclohexadienyl dehydrogenase, 5-enolpyruvylshikimate 3-phosphate synthase, cytidylate kinase, and 30S ribosomal protein S1. These enzymes participate in the biosynthesis of serine, pyridoxine, histidine, phenylalanine, tyrosine, tryptophan, and aromatic pathway vitamins and cytidylic acid, in addition to the general role of RpsA in the process of protein synthesis. Features that suggest supraoperon-wide translational coupling are the highly compressed intergenic spacing (including overlapping stop and start codons), as well as possible hairpin structures in mRNA, which could sequester many of the ribosome-binding sites. The hisH-tyrA-aroF segment corresponds to the distal genes of the classic Bacillus subtilis supraoperon. Extensive comparative analysis of the member genes of both the Bacillus and Pseudomonas supraoperons from organisms represented in the entire database revealed unmistakable organizational conservation of these genes across wide phylogenetic boundaries, although considerable gene shuffling was apparent. The persistence of aroE-aroB, hisHb-tyrA-aroF, and cmk-rpsA throughout both the gram-negative and gram-positive assemblages of bacteria, but the absence in Archaea, suggests an ancestral gene organization that occurred in bacteria after the separation of the bacterial and archaeal domains. In gram-negative bacteria,the hisHb-tyrAc-aroF grouping may have been expanded (as with the Pseudomonas supraoperon) and then subsequently collapsed (as with the Escherichia serC-aroF supraoperon) via gene shuffling that is herein equated with gene fusion events.

Amino Acid Sequence↗
PubMed1999

PhhB, a Pseudomonas aeruginosa homolog of mammalian pterin 4a-carbinolamine dehydratase/DCoH, does not regulate expression of phenylalanine hydroxylase at the transcriptional level.

Pterin 4a-carbinolamine dehydratase is bifunctional in mammals. In addition to playing a catalytic role in pterin recycling in the cytoplasm, it plays a regulatory role in the nucleus, where it acts as a dimerization-cofactor component (called DCoH) for the transcriptional activator HNF-1alpha. A thus far unique operon in Pseudomonas aeruginosa contains a gene encoding a homolog (PhhB) of the regulatory dehydratase, together with genes encoding phenylalanine hydroxylase (PhhA) and aromatic aminotransferase (PhhC). Using complementation of tyrosine auxotrophy in Escherichia coli as a functional test, we have found that the in vivo function of PhhA requires PhhB. Strikingly, mammalian DCoH was an effective substitute for PhhB, and either one was effective in trans. Surprisingly, the required presence of PhhB for complementation did not reflect a critical positive regulatory effect of phhB on phhA expression. Rather, in the absence of PhhB, PhhA was found to be extremely toxic in E. coli, probably due to the nonenzymatic formation of 7-biopterin or a similar derivative. However, bacterial PhhB does appear to exert modest regulatory effects in addition to having a catalytic function. PhhB enhances the level of PhhA two- to threefold, as was demonstrated by gene inactivation of phhB in P. aeruginosa and by comparison of the levels of expression of PhhA in the presence and absence of PhhB in Escherichia coli. Experiments using constructs having transcriptional and translational fusions with a lacZ reporter indicated that PhhB activates PhhA at the posttranscriptional level. Regulation of PhhA and PhhB is semicoordinate; both PhhA and PhhB are induced coordinately in the presence of either L-tyrosine or L-phenylalanine, but PhhB exhibits a significant basal level of activity that is lacking for PhhA. Immunoprecipitation and affinity chromatography showed that PhhA and PhhB form a protein-protein complex.

Escherichia coli↗
PubMed1998

Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat.

Peripherally administered or released substances that modulate memory storage, but do not freely enter the brain, may produce their effects on memory by activating peripheral receptors that send messages centrally through the vagus nerve. Indeed, vagus nerve stimulation enhances memory performance, although it is unclear whether this effect is due to the activation of vagal afferents or efferents. To eliminate the possible influence of descending fibers on memory storage processes, rats were implanted with cuff electrode/catheter systems along the left cervical vagus. Forty-eight hours following surgery, each animal received a 3. 0-microliter infusion (1.0 microliter/min) of either lidocaine hydrochloride (75.0 mM) or isotonic saline below the point of stimulation. Animals were then trained 10 min later on an inhibitory-avoidance task with a 0.75-mA, 1.0-s foot shock. Sham stimulation or vagus nerve stimulation (0.5-ms biphasic pulses; 20.0 Hz; 30 s; 0.2, 0.4, or 0.8 mA) was administered immediately after training. Memory, tested 24 h later, was enhanced by stimulation whether descending vagus nerve fibers were inactivated or not. Both lidocaine- and saline-infused groups showed an intensity-dependent, inverted-U-shaped pattern of retention performance, with the greatest effect observed for 0.4 mA (U = 9, p < .05, and U = 7, p < .01, respectively). Additionally, animals that received lidocaine infusions, but no vagus nerve stimulation, showed impaired memory compared to the performance of saline-infused control animals (U = 11, p < .05). Together, these findings suggest that vagal afferents carry messages about peripheral states that lead to the modulation of memory storage and that the memory-enhancing effect produced by vagus nerve stimulation is not mediated via the activation of vagal efferents.

Animals↗