Prenatal stress-induced modifications of neuronal nitric oxide synthase in amygdala and medial preoptic area.
Explore the source record for details and available documents.
Amygdala↗
Biomedical subjects
E Mueller
Publications and source records attributed to E Mueller.
Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma.
Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-gamma ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.
Adult↗
Analysis of secretory group II phospholipase A2 expression in human aortic tissue in dependence on the degree of atherosclerosis.
Secretory non-pancreatic (group II) phospholipase A2 (sPLA2) releases precursors of important mediators of inflammation from phospholipids. Based on the inflammatory character of atherosclerosis we previously described the identification of sPLA2 in human atherosclerotic plaques. In vitro studies on lipoproteins have shown that sPLA2 is able to favour the formation of foam-like cells representing a typical feature of early atherosclerotic lesions. In the present study the expression of sPLA2 in relation to the degree of atherosclerosis was investigated. Aortic tissue samples of 25 autopsy cases ranging in age from 1 to 77 years were taken from 2 cm above the heart and 3 cm below the renal arteries. The material was classified regarding the degree of atherosclerotic changes based on staining with haemalaun and eosine as well as on staining according to Goldner. Furthermore, immunohistochemical procedures detecting sPLA2, macrophages and smooth muscle cells were performed. The study has shown that in the abdominal aorta the enzyme was present in all advanced atherosclerotic lesions, but only in some preatheromas and precursors of atherosclerosis. However, this correlation did not occur in the thoracic aorta, where sPLA2-positive results showed a similar frequency in all degrees of atherosclerotic lesion. The enzyme was found in all three layers of the vessel wall without significant differences. Round cells, scarcely smooth muscle cells and endothelial cells were identified as sPLA2-positive. However, these data do not allow a conclusion as to which type of cell is responsible for the secretion of sPLA2. In summary, the correlation between the expression of this enzyme and the degree of atherosclerosis underlines the possible importance of sPLA2 in atherogenesis.
Adolescent↗
The differentiation of true adenomas from colitis-associated dysplasia in ulcerative colitis: a comparative immunohistochemical study.
Adenomas in areas involved by ulcerative colitis (UCA) are difficult to identify because of their morphological similarity to ulcerative colitis-associated dysplasia (UCD) and have an uncertain biology. Recently, a set of morphopathologic criteria were published for the diagnosis of UCA versus UCD. As a first step to analyze these criteria, we studied p53 and bcl-2 expression in groups of UCA and UCD along with a sporadic adenoma control group. Ninety lesions from UC areas (62 patients) were examined, including 24 UCA without high-grade dysplasia (HGD) and 66 UCD consisting of 43 polypoid and 23 flat dysplastic lesions (29 with HGD). Immunohistochemical p53 and bcl-2 expression were evaluated semiquantitatively. P53-positive cases were significantly less frequent in the UCA (4%) versus the UCD group (30%, P = .01) and the polypoid UCD subgroup (35%, P = .005). Moderate or strong bcl-2 expression was significantly more frequent in the UCA than in the UCD group (96% v 70%, P = .01) and in the UCA versus both polypoid and flat UCD subgroups. Comparison of UCA with low-grade dysplastic polypoid UCD cases alone showed a difference just below significance for p53 (P = .07). p53 and bcl-2 expression rates were very similar in the UCA group and the sporadic adenoma (n = 25) control group. These results show that UCA has phenotypic features more similar to sporadic adenomas than UCD and supports the concept that adenomas in UC have a biology different from UC-associated dysplasia.
Adenoma↗
Loss-of-function mutations in PPAR gamma associated with human colon cancer.
The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma, regulates adipocyte differentiation and has recently been shown to be expressed in neoplasia of the colon and other tissues. We have found four somatic PPAR gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift, and two missense mutations. Each greatly impaired the function of the protein. c.472delA results in deletion of the entire ligand binding domain. Q286P and K319X retain a total or partial ligand binding domain but lose the ability to activate transcription through a failure to bind to ligands. R288H showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicate that colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.
Amino Acid Substitution↗
Conversion of patients with rheumatoid arthritis from the conventional to a microemulsion formulation of cyclosporine: a double blind comparison to screen for differences in safety, efficacy, and pharmacokinetics.
OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclosporin A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with maintenance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetics between formulations. METHODS: In this double blind, multicenter, parallel group study, 51 patients receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measured before and at intervals after conversion. CyA steady-state area under the curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. RESULTS: Initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulation was 23% higher than from conventional CyA. Replicate assessments indicated a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs and laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional to microemulsion CyA. CONCLUSION: Existing CyA dosing guidelines, formulated for conventional CyA, are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation.
Antirheumatic Agents↗
[Dysplasia in ulcerative colitis].
Due to their increased risk of developing a carcinoma, patients with long-standing ulcerative colitis are usually enrolled in surveillance programs in order to regularly evaluate their risk of developing cancer using endoscopic biopsies. In this evaluation, the histologic identification of dysplasia in connection with the endoscopic findings is of central importance. According to current recommendations, dysplasia which occurs in endoscopically identifiable lesions, i.e. in the form of a DALM ("dysplasia associated lesion or mass"), result in a colectomy independent of the degree of dysplasia, as does high grade dysplasia in a flat mucosal area. For low grade flat dysplasia, the diagnosis should be confirmed. A special diagnostic challenge is the distinction of adenomas in ulcerative colitis, since for these lesions a simple polypectomy is an adequate treatment. For the assessment of the individual cancer risk various molecular biologic techniques have been discussed as additional procedures (p53, Sialyl-Tn, ploidy status by flow cytometry), but H&E histopathology is still the gold standard for the grading of dysplasia and its distinction from regenerative epithelial changes. Due to the increasing refinement of endoscopic techniques and considering the potential new, less invasive methods for treating dysplasia, changes in the management approach for patients with dysplasia in ulcerative colitis are to be expected.
Adenoma↗
[Are there differences between ex adenoma and de novo colorectal carcinomas?].
Colorectal carcinoma is a major cause of death throughout the Western world. It is increasingly recognized that any reduction in mortality must be achieved through the detection and removal of early and precancerous lesions. The primary attention for such a preventive strategy has been the polypoid adenoma and surveillance studies have shown a significant reduction in the incidence of carcinoma through systematic polypectomy of suspicious lesions. A potential problem with such a program, however, is raised by reports from Japan that some carcinomas seem to arise without a precursor polypoid adenoma, that is de novo. Although the histopathologic findings in such reports seem to clearly support this idea, this concept is not widely accepted in the Western world. We undertook a series of immunohistochemical (p53, bcl-2, Mib-1, E-cadherin, CD44, Stromelysin-3), and microsatellite analysis studies (on 17p (p53), 18q (DCC), 5q (APC), 8p, 2p and 1p), on groups of de novo and ex adenoma carcinomas in order to see if differences between the two groups of lesions exist. The results of these studies demonstrate that de novo carcinomas share several phenotypic and genotypic features with ex adenoma carcinoma (similar CD44 in the carcinomas, similar rates of LOH at APC and DCC loci), but have significantly higher rates of LOH at 17p, p53 over-expression and ST-3 expression indicating that tumor progression in de novo carcinoma is accelerated. These findings should help clarify the concept of de novo carcinoma and contribute to wider recognition of this important clinicopathologic entity.
Adenoma↗
Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1.
The ability to regulate specific genes of energy metabolism in response to fasting and feeding is an important adaptation allowing survival of intermittent food supplies. However, little is known about transcription factors involved in such responses in higher organisms. We show here that gene expression in adipose tissue for adipocyte determination differentiation dependent factor (ADD) 1/sterol regulatory element binding protein (SREBP) 1, a basic-helix-loop-helix protein that has a dual DNA-binding specificity, is reduced dramatically upon fasting and elevated upon refeeding; this parallels closely the regulation of two adipose cell genes that are crucial in energy homeostasis, fatty acid synthetase (FAS) and leptin. This elevation of ADD1/SREBP1, leptin, and FAS that is induced by feeding in vivo is mimicked by exposure of cultured adipocytes to insulin, the classic hormone of the fed state. We also show that the promoters for both leptin and FAS are transactivated by ADD1/SREBP1. A mutation in the basic domain of ADD1/SREBP1 that allows E-box binding but destroys sterol regulatory element-1 binding prevents leptin gene transactivation but has no effect on the increase in FAS promoter function. Molecular dissection of the FAS promoter shows that most if not all of this action of ADD1/SREBP1 is through an E-box motif at -64 to -59, contained with a sequence identified previously as the major insulin response element of this gene. These results indicate that ADD1/SREBP1 is a key transcription factor linking changes in nutritional status and insulin levels to the expression of certain genes that regulate systemic energy metabolism.
3T3 Cells↗
Comparison of CD44 expression in early colorectal carcinomas of the de novo and ex adenoma types.
Small colorectal carcinomas without morphological evidence of origin from an adenoma have been called "de novo" carcinomas. As changes in the expression of the adhesion molecule CD44 and its variants have been described along the adenoma-carcinoma sequence in colorectal carcinoma, we compared patterns of CD44 expression in early de novo and ex-adenoma colorectal carcinomas by staining specimens from a group of early (pT1) colorectal carcinomas by immunohistochemistry for CD44 (standard and variant forms v3, v5, v6, v7, v7/8, v10). We evaluated carcinoma, adenoma (ex-adenoma cases), transitional mucosal areas and apparently nonneoplastic mucosa peripheral to the lesions (when present). A marked increase was seen in numbers and intensity of standard and variant forms of CD44 in carcinomatous areas compared with nonneoplastic mucosa in both groups, with no significant difference between the groups. However, adenoma areas of the ex-adenoma cases and the transitional mucosa of the de novo carcinomas had nearly identical staining patterns. Together with data from other molecular studies, this may be interpreted as evidence for an adenoma-type precursor lesion in so-called de novo colorectal carcinomas.
Adenoma↗
Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum.
Small adenocarcinomas of the colorectum showing no evidence of origin from an adenoma have been called de novo carcinomas, a name that implies an origin via a different molecular genetic mechanism than the usual colorectal carcinoma which develops from an adenoma. Using microsatellite analysis, 35 early (pT1) de novo and 36 pT1 ex-adenoma carcinomas were compared using 8 microsatellite loci at 6 different chromosomal loci (1p, 2p, 8p, 5q, 17p, and 18q) known or hypothesized to be important for colorectal carcinogenesis. The rate of loss of heterozygosity (LOH) at the 17p locus (near the p53 gene) was significantly higher in the de novo than in the ex-adenoma group (73 vs. 37%, P = 0.004). The rates of LOH at the other loci (including the APC and DCC genes) and the rate of MSI were not significantly different in the two groups. These results indicate that de novo carcinomas of the colorectum develop via a similar carcinogenetic pathway as conventional ex-adenoma carcinomas; however, their higher rate of LOH at 17p is evidence for a biologically more advanced lesion with more frequent p53 mutations, consistent with clinicopathological data indicating that de novo carcinomas are more aggressive than ex-adenoma carcinomas.
Adenocarcinoma↗
Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas.
Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.
Adenoma↗
Terminal differentiation of human breast cancer through PPAR gamma.
We have previously demonstrated that PPAR gamma stimulates the terminal differentiation of adipocyte precursors when activated by synthetic ligands, such as the antidiabetic thiazolidinedione (TZD) drugs. We show here that PPAR gamma is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, shown previously to be a powerful negative regulator of PPAR gamma, improves the TZD ligand sensitivity of nonresponsive cells. These data suggest that the PPAR gamma transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel, nontoxic therapy for human breast cancer.
Breast Neoplasms↗
Differentiation and reversal of malignant changes in colon cancer through PPARgamma.
PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.
Adenocarcinoma↗
Loss of heterozygosity and microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis.
Microsatellite instability and allelic deletions of tumor suppressor genes have been observed frequently in tumors. Molecular pathogenesis of the development of dysplasia and carcinoma in ulcerative colitis is still unclear. In order to detect microsatellite alterations in ulcerative colitis, we analyzed loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosomes 3, 6, 7, 12, and tumor suppressor gene loci, including p53, APC, and p16, of chronically inflamed, non-dysplastic epithelium after microdissection. Twelve of 13 (92%) cases showed LOH and/or MI at one or more loci. LOH at chromosome 3 and MI at chromosome 12 were observed in 50% and 62%, respectively. However, LOH at p53 and p16 was detected in only one case each. These results suggest that chronic inflammation may initiate microsatellite alteration, which subsequently transform ulcerative colitis to dysplasia or cancer. This finding provides information for the evaluation and treatment of patients with ulcerative colitis.
Journal Article↗
Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor.
Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor gamma (PPAR gamma) and the retinoid X receptor alpha (RXR alpha) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. Natural and synthetic ligands for both receptors have been identified. We demonstrate here that PPAR gamma is expressed at high levels in each of the major histologic types of human liposarcoma. Moreover, primary human liposarcoma cells can be induced to undergo terminal differentiation by treatment with the PPAR gamma ligand pioglitazone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPAR pathway. We further demonstrate that RXR-specific ligands are also potent adipogenic agents in cells expressing the PPAR gamma/RXR alpha heterodimer, and that simultaneous treatment of liposarcoma cells with both PPAR gamma- and RXR-specific ligands results in an additive stimulation of differentiation. Liposarcoma cell differentiation is characterized by accumulation of intracellular lipid, induction of adipocyte-specific genes, and withdrawal from the cell cycle. These results suggest that PPAR gamma ligands such as thiazolidinediones and RXR-specific retinoids may be useful therapeutic agents for the treatment of liposarcoma.
Adipocytes↗
Stromelysin-3 expression in early (pT1) carcinomas and pseudoinvasive lesions of the colorectum.
Pseudoinvasion in colorectal adenomas is often difficult to distinguish from invasive carcinoma. Previous studies have indicated that expression of stromelysin-3 (ST-3), one of the metalloproteinase family of enzymes, may be useful for the identification of early invasive carcinoma. The goal of our study was to detect ST-3 expression in colorectal adenomatous polyps to see if it could be helpful for the differential diagnosis of pseudoinvasion vs. true invasion. We studied 25 polypectomy specimens which were divided histologically into 2 groups; the first consisted of 15 adenomas with invasive carcinoma, 8 of these carcinomas were more diffusely infiltrative (pT1), and 7 tended to be expansively invasive. The second group was composed of 10 adenomas with pseudoinvasion. A 35S labelled cDNA probe was used for in situ hybridization (ISH) and a monoclonal antibody (5ST-4A9) for immunohistochemistry (IHC). The distribution of ST-3 expression as detected by IHC and ISH was identical. All diffusely infiltrative carcinoma cases showed ST-3 expression, but only focally in 2 cases with marked lymphocytic infiltration. None of the expansive carcinoma or pseudoinvasion cases showed ST-3 expression. ST-3 expression seems to be an indicator of invasion, but a negative reaction for ST-3 does not rule out an expansive invasive neoplasm or a diffusely infiltrative invasive tumour with a dense lymphocytic reaction.
Adenomatous Polyps↗
Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor.
The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated. A total of 127 adult outpatients with diastolic blood pressure between 100 and 114 mmHg were randomized into this double-blind, parallel group study. After a 2-week wash-out period and a subsequent 2-week placebo run-in period, they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide (R/C), or 5 mg enalapril. If diastolic blood pressure was not normalized after 3 weeks of therapy (i.e. DBP < 90 mmHg), the dosage was doubled from week 4 to 6. The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure (DBP/SBP) after 3 weeks of therapy. Secondary variables included the change in DBP and SBP after 6 weeks of therapy, the BP normalization rates at 3 and 6 weeks and, concerning tolerability, the rates of adverse events after 6 weeks of therapy. An intent-to-treat analysis was performed. The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics (mean age 57 or 58 years, respectively; 63% or 56% males, respectively; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups). After 3 weeks of treatment with one capsule daily, mean SBP/DBP reduction from baseline (24 h after last medication intake) in the R/C combination group was -19.6/ -17.0 mmHg, in the enalapril group -6.1/ -9.5 mmHg (between-group comparison: 2p < 0.01 for both parameters). The normalization rates for DBP (< 90 mmHg) were 64.1% (R/C) and 28.6% (enalapril) (2p < 0.01). Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients (17.2%) in the R/C group and in 9 patients (14.3%) in the enalapril group (NS). Two patients in the enalapril group discontinued the study prematurely due to adverse events (cough; skin eruption). In the treatment of mild-to-moderate hypertension, a low-dose combination of reserpine and clopamide once a day is considerably more effective than, and as tolerable as, 5-10 mg of enalapril once a day. These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension. Besides, the "old" reserpine-diuretic regimen also in these days appears to be a rational alternative to "modern" monotherapies.
Adult↗