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  • 1
    Keywords: CELLS ; IN-VITRO ; BLOOD ; CELL ; COMBINATION ; Germany ; MODEL ; THERAPY ; VITRO ; DRUG ; METABOLISM ; PATIENT ; MACROPHAGES ; murine ; CONTRAST ; treatment ; antibody ; TARGET ; NUMBER ; DELIVERY ; PHARMACOKINETICS ; DOUBLE-BLIND ; PERIPHERAL-BLOOD ; T lymphocytes ; MONONUCLEAR-CELLS ; METHOTREXATE ; COLLAGEN-INDUCED ARTHRITIS ; albumin ; DRUG-DELIVERY ; rheumatoid arthritis ; RHEUMATOID-ARTHRITIS ; II COLLAGEN ; LOW-DOSE METHOTREXATE ; PLACEBO-CONTROLLED TRIAL ; RHEUMATOID-ARTHRITIS PATIENTS
    Abstract: Objective. To evaluate the anti-arthritic effects of the new inflammation-targeted drug MTX-HSA and to investigate whether peripheral blood mononuclear cells (PBMC) are potential target cells for albumin-mediated drug delivery. Methods. The murine model of collagen-induced arthritis (CIA) was used to measure the anti-arthritic effect of MTX, MTX-HSA or a combination of both (n = 30 to 35 per group). In addition, the uptake of fluorescence-labelled albumin (AFLc-HSA) in PBMC of 14 patients with RA was measured by fluorescence-activated cell sorting (FACS). Results. In equivalent doses of 7.5 mg/kg intravenously (IV) twice a week, MTX-HSA is significantly (P〈0.02) superior to MTX in inhibiting the development of CIA and reducing the joint count as well as the number of affected paws. When given in lower doses as combination therapy, both drugs act synergistically (P〈0.03). A mean of 96, 72 and 64% of the CD14-, CD16- and CD20-positive cells from peripheral blood of rheumatoid arthritis (RA) patients showed an uptake of albumin after incubation with AFLc-HSA in vitro. This finding was not significantly different in comparison to healthy controls. In contrast, the number of CD3-positive cells taking up albumin is increased significantly in RA patients in comparison to controls (26.3 +/- 12.9% s.d. vs 11.6 +/- 7.3% s.d.; P = 0.005). Conclusion. The data show that the effectiveness of MTX-HSA in CIA is superior to MTX and that both drugs act synergistically. In addition, albumin appears to be taken up by peripheral blood cells, suggesting that they might be one of the potential target cells of this novel anti-arthritic treatment approach
    Type of Publication: Journal article published
    PubMed ID: 15199219
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  • 2
    Keywords: CANCER ; tumor ; carcinoma ; Germany ; MODEL ; imaging ; SITE ; TUMORS ; ACCURACY ; PATIENT ; CONTRAST ; MRI ; SEQUENCE ; BREAST ; breast cancer ; BREAST-CANCER ; chemotherapy ; MAMMOGRAPHY ; US ; BREAST-CARCINOMA ; PARAMETERS ; CARCINOMAS ; dynamic MRI ; ultrasound ; REGRESSION ; ENHANCED MRI ; ENHANCEMENT ; methods ; NUCLEAR ; SIZE ; breast carcinoma ; USA ; correlation ; MR-MAMMOGRAPHY ; NEOADJUVANT CHEMOTHERAPY ; EVALUATE ; quantitative ; dynamic magnetic resonance imaging (dMRI) ; HISTOLOGICAL REGRESSION
    Abstract: Purpose. The aim of this study was to evaluate whether quantitative changes in contrast enhancement (CE) after neoadjuvant chemotherapy (NC) are associated with histological signs of tumor regression and whether quantitative dynamic MRI (dMRI) is capable of accurately assessing preoperative tumor size compared to mammography (MG) and ultrasound (US). Methods. Thirty-one patients with breast cancer underwent MRI before and after NC. Dynamic CE was measured using a turbo-FLASH sequence and quantified by a two-compartment model, where two parameters, k(ep) (distribution constant rate) and A (amplitude), were calculated and color mapped. Results. When tumors had signs of histological regression in the operative specimen (n= 17) decrease of the parameters A and k(ep) was significantly more marked compared to tumors without regression (n= 12). The correlation between tumor size measured by dMRI and histopathology was 0.81 when areas of unspecific CE were included; when they were not included the correlation was 0.66 and tumor size was systematically underestimated. In 26 patients dMRI was retrospectively compared with MG (r=0.51; dMRI, r=0.80) and in 22 patients with US (r=0.60; dMRI, r=0.75). Conclusion. Changes in dynamic CE are associated with histological tumor regression. Quantitative dMRI enables a valid assessment of tumor residue and is superior to MG and US. Remaining unspecific CE within the original tumor site should be considered as potentially malignant
    Type of Publication: Journal article published
    PubMed ID: 16283153
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  • 3
    Keywords: CELLS ; EXPRESSION ; ASSOCIATION ; score ; resistance ; RECURRENCE ; PREDICTION ; TAMOXIFEN ; ENDOCRINE THERAPY ; KI67
    Abstract: The majority of luminal type breast carcinomas are slowly growing tumors with an overall favorable prognosis. However, a proportion of cases (luminal B tumors) are characterized by coactivation of growth factor receptors or non-canonical ER signaling and a poorer clinical outcome. The aim of our study was to evaluate whether the expression of proteins that are part of the ER signaling network may be used to distinguish low-risk from high-risk luminal tumors. Unsupervised hierarchical clustering of a set of proteins either involved in estrogen receptor signaling or associated with resistance to endocrine therapy was performed in a series of 443 postmenopausal breast carcinomas. Using this approach, we were able to reproduce the established classification with two distinct groups of luminal (estrogen receptor positive) tumors, one group of HER2-associated tumors and a group of triple-negative tumors. However, neither proliferation nor the expression of one or more of the ER-co-factors or resistance-associated factors, but PR-expression was identified as the most important stratifier distinguishing between the two luminal groups. In fact, not only the four identified clusters were shown to be significantly associated with patient outcome, PR-expression alone or in combination with Ki-67-stains stratified ER-positive tumors into a low-risk and a high-risk group. Our data indicate that defining luminal B tumors by the presence of high-risk criteria (loss of PR-expression or increased proliferation) provides a robust and highly significant stratification of ER-positive breast carcinomas into luminal A and B.
    Type of Publication: Journal article published
    PubMed ID: 23558572
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  • 4
    Keywords: CELLS ; EXPRESSION ; GROWTH ; PATHWAY ; BIOMARKERS ; IDENTIFICATION ; LIGAND-BINDING DOMAIN ; ESTROGEN-RELATED-RECEPTOR ; TRANSCRIPTIONAL ACTIVITIES ; ENDOCRINE RESISTANCE
    Abstract: Endocrine treatment regimens for breast cancer that target the estrogen receptor-alpha (ER alpha) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-alpha (ERR alpha) for ER alpha. To examine this hypothesis, we analyzed ERR alpha and ER alpha in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ER alpha, ERR alpha, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ER alpha and ERR alpha target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERR alpha in tamoxifen-and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERR alpha sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n - 1041), increased expression of ERR alpha was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ER alpha-positive cases. In addition, increased ERR alpha expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ER alpha and ERR alpha cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERR alpha as a candidate drug target to treat endocrine-resistant breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 25643697
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CLINICAL-TRIAL ; human ; IN-VIVO ; MODEL ; liver ; PROTEIN ; PROTEINS ; DRUG ; TISSUE ; TUMORS ; MICE ; PATIENT ; SERA ; fibroblasts ; treatment ; MOUSE ; EFFICACY ; drug delivery ; CONJUGATE ; PHARMACOKINETICS ; BEARING RATS ; COLLAGEN-INDUCED ARTHRITIS ; FIBROBLAST-LIKE SYNOVIOCYTES ; LOW- DOSE METHOTREXATE ; SYNOVIAL FIBROBLASTS
    Abstract: We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX
    Type of Publication: Journal article published
    PubMed ID: 12707361
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  • 6
    Keywords: PROTEIN ; BINDING ; DESIGN ; METHOTREXATE-ALBUMIN ; CARRIER ; CATABOLISM ; SERUM-ALBUMIN
    Abstract: RATIONALE: Malignant tumors often show an increased uptake and metabolism of plasma proteins, especially albumin. OBJECTIVES: Determine whether the accumulation of low loaded Gd-albumin improves visualization of malignant tumors by MRI. METHODS: Twelve nude mice with heterotransplanted squamous cell carcinomas were studied. The signal intensity of tumor, blood, liver, kidney and muscle tissue was studied in MR images after application of Gd-albumin during a period of 144 hours. MRI results were histologically correlated after simultaneously injection of Gd- and fluorescein-labeled albumins in 9 nude mice. RESULTS: Although liver and kidney had a maximum increase in signal intensity within 30 minutes, tumors showed a delayed 51% increase in the 24 hours after application. Histologic and fluorescence evaluation demonstrated albumin localization in tumors predominantly in stroma and necroses. CONCLUSIONS: Gd-albumin is efficiently accumulated in SCC transplants. MRI with low loaded Gd-albumin may offer relevant opportunities for recognizing tumors sensitive to a therapy with cyostic drug-labeled albumins.
    Type of Publication: Journal article published
    PubMed ID: 11923641
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  • 7
    Keywords: human ; IN-VIVO ; VIVO ; imaging ; DISEASES ; MOLECULES ; MICE ; SERA ; CONTRAST ; CONTRAST AGENT ; MRI ; SIGNAL ; magnetic resonance ; MAGNETIC-RESONANCE ; MOLECULE ; magnetic resonance imaging ; antibodies ; antibody ; TARGET ; MOUSE ; PATTERNS ; DAMAGE ; SKELETAL-MUSCLE ; intravenous ; GD-DTPA ; CLUSTERS ; CLUSTER ; resonance imaging ; AGENT ; albumin ; ANIMAL-MODELS ; DMD ; DUCHENNE MUSCULAR-DYSTROPHY ; DYSTROPHY ; mdx ; muscular dystrophy ; SERUM ; serum albumin ; targeting
    Abstract: Increased sarcolemmal permeability has been implicated as a major pathological event in muscular dystrophies. In our study. we evaluated whether damaged muscle fibres can be specifically targeted using albumin as a carrier. We tagged human serum albumin (HSA) with Gadolinium (Gd) and systemically applied this compound (Gd-DTPA-HSA) to wildtype and dystrophin-deficient mdx mice. We performed magnetic resonance imaging before and after intravenous administration of Gd-DTPA-HSA and found localised signal enhancement only in mdx skeletal muscle. We also examined skeletal muscle after contrast enhanced magnetic resonance imaging using anti-human albumin antibodies and demonstrated intracellular accumulation of Gd-DTPA-HSA in clusters of damaged mdx muscle fibres. Comparison of magnetic resonance imaging and histological data emphasised the value of contrast agent enhanced magnetic resonance imaging for the in vivo assessment of fibre damage in muscular dystrophies. Furthermore. our data provide evidence that albumin can be used as a carrier to target covalently bound molecules to degenerating muscle fibres. (C) 2004 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15564034
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  • 8
    Keywords: TRIAL ; PREOPERATIVE CHEMOTHERAPY ; ESTROGEN ; SUBTYPES ; GENE-EXPRESSION SIGNATURE ; PATHOLOGISTS GUIDELINE RECOMMENDATIONS ; AMERICAN-SOCIETY ; CLINICAL-ONCOLOGY/COLLEGE ; PHARMACOGENOMIC PREDICTOR ; RECURRENCE SCORE
    Abstract: Breast cancer is a heterogeneous disease of different subtypes on the molecular, histopathological, and clinical level. Genomic profiling techniques have led to several prognostic and predictive gene signatures of breast cancer that may further refine outcome prediction, especially in clinically equivocal situations. In particular, the predictive value of today's most important therapeutic targets, ER and HER2, are strongly influenced by the proliferative status of the tumor. Genomic assays are generally performed in a centralized manner, whereas routine pathological evaluation is mostly done on a decentralized basis, making the comparison of these methods difficult. Thus, there remains considerable uncertainty about the use of the new molecular markers in routine clinical decision making and their role in patient selection or stratification for future clinical trials. To address this concern, a group of representatives from breast cancer research groups in the areas of breast pathology, genomic profiling, and clinical trials critically reviewed all available data. Consensus recommendations are made on the practical use of molecular markers in breast cancer management and their incorporation into future clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 21472705
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  • 9
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    German Medical Science; Düsseldorf, Köln
    In:  55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie; 20040425-20040428; Köln; DOCMO.09.01 /20040423/
    Publication Date: 2004-04-22
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 10
    ISSN: 1618-2650
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Summary A high-performance liquid chromatographical separation method at a RP-18 column without derivatisation and with electrochemical detection is described. The samples are prepared with a mini-Alox-column and a gelchromatographical clean-up for hydrophilic substances. The method obtains a detection limit of 60 ng/g with a sample weight of 2 g. The average recovery is 79.8±4.3% (in liver).
    Notes: Zusammenfassung Es wird eine hochdruckflüssigkeits-chromatographische Trennmethode an einer RP-18-Säule ohne Derivatisierung mit elektrochemischer Detektion beschrieben. Die Probenaufarbeitung erfolgt mit einer Mini-Alox-Säule und gel-chromatographischer Reinigung für hydrophile Wirkstoffe. Die Methode erreicht eine Nachweisgrenze von 60 ng/g bei einer Probeneinwaage von 2 g. Die mittlere Wiederfindungsrate beträgt 79,8±4,3% (in Leber).
    Type of Medium: Electronic Resource
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