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  • 1
    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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  • 2
    ISSN: 1432-1238
    Keywords: Key words Acute pancreatitis ; Therapy ; Dextran ; Hypertonic ; Colloid ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: Ultrahigh-molecular dextran (500000 Da) has been shown to prevent pancreatic necrosis when given 30 min after induction of pancreatitis. This study should clarify the following: (a) are dextrans still effective after prolongation of the therapy-free interval? (b) what is the impact of the molecular weight of the dextrans? and (c) is their effect influenced by the dextran concentration or by the addition of hypertonic saline? Animals and interventions: Acute pancreatitis was induced in 70 male dextran-tolerant Wistar rats using intraductal bile-salt infusion and intravenous hyperstimulation. After 3 h, animals were assigned to one of seven groups (n=10 per group) receiving either Ringer solution or different dextrans (10%) including 70000 Da (DEX-70), 160000 Da (DEX-160), 300000 Da (DEX-300) or 500000 Da (DEX-500). Additional groups included DEX-70 (6%) and DEX-70 (10%) in combination with hypertonic NaCl (7.5%) (HHS-70). Ringer solution was given at 24 ml/kg and all dextrans at 8 ml/kg. Measurements and results: Trypsinogen activation peptides (TAP) were quantified in ascites and acinar necrosis after death or sacrifice at 9 h. As an index of less pathological trypsinogen activation, the mean TAP levels in ascites were significantly lower in DEX-70 and DEX-160 compared to Ringer controls (p〈0.05, t-test). Furthermore, the amount of acinar necrosis was significantly lower in all dextran groups except the HHS-70 in comparison with Ringer controls (p〈0.01, t-test). Finally, mortality was significantly reduced from 60% in Ringer controls to 10 and 0%, respectively, in the groups treated with DEX-70 and DEX-160 (p〈0.03, Fisher‘s Exact test). There was a similar trend in all other groups except the HHS-70. Conclusions: Despite a therapy-free interval of 3 h, dextrans reduce trypsinogen activation, prevent acinar necrosis, and improve survival in necrotizing rodent pancreatitis. The molecular weight and concentration of dextran are of secondary importance for these beneficial effects.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1238
    Keywords: Acute pancreatitis ; Therapy ; Dextran ; Hypertonic ; Colloid ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective Ultrahigh-molecular dextran (500 000 DA) has been shown to prevent pancreatic necrosis when given 30 min after induction of pancreatitis. This study should clarify the following: (a) are dextrans still effective after prolongation of the therapy-free interval? (b) what is the impact of the molecular weight of the dextrans? and (c) is their effect influenced by the dextran concentration or by the addition of hypertonic saline? Animals and interventions Acute pancreatitis was induced in 70 male dextran-tolerant Wistar rats using intraductal bile-salt infusion and intravenous hyperstimulation. After 3 h, animals were assigned to one of seven groups (n=10 per group) receiving either Ringer solution or different dextrans (10%) including 70 000 Da (DEX-70), 160 000 Da (DEX-160), 300 000 Da (DEX-300) or 500 000 Da (DEX-500). Additional groups included DEX-70 (6%) and DEX-70 (10%) in combination with hypertonic NaCl (7.5%) (HHS-70). Ringer solution was given at 24 ml/kg and all dextrans at 8 ml/kg. Measurements and results Trypsinogen activation peptides (TAP) were quantified in ascites and acinar necrosis after death or sacrifice at 9 h. As an index of less pathological trypsinogen activation, the mean TAP levels in ascites were significatly lower in DEX-70 and DEX-160 compared to Ringer controls (p〈0.05,t-test). Furthermore, the amount of acinar necrosis was significantly lower in all dextran groups except the HHS-70 in comparison with Ringer controls (p〈0.01,t-test). Finally, mortality was significantly reduced from 60% in Ringer controls to 10 and 0%, respectively, in the groups treated with DEX-70 and DEX-160 (p〈0.03, Fisher's Exact test). There was a similar trend in all other groups except the HHS-70. Conclusions Despite a therapy-free interval of 3 h, dextrans reduce trypsinogen activation, prevent acinar necrosis, and improve survival in necrotizing rodent pancreatitis. The molecular weight and concentration of dextran are of secondary importance for these beneficial effects.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2307
    Keywords: Breast cancer ; Lymph node metastasis ; TNM classification ; Intraductal component
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Invasive ductal mammary carcinomas (IDC) of 1 cm in tumour size or less account for less than 20% of all IDC. We have observed 167 such cases at our Institution between 1985 and 1989. These were divided into carcinomas with an extensive or predominant intraductal component (EIC or PIC, being least 2× or 4× larger than the invasive component; 90) and compared statistically with the control group (no EIC or PIC; 77) for known prognostic factors and for their metastatic behaviour. Lymph nodes were step sectioned in order to detect occult micrometastases. The median follow up time was 62.6 months. Lymph node metastases were seen in 10% of pT1a and 19% of pT1b cases. Significant differences were found when comparing the EIC/PIC group with the control group (pT1a: 11% vs. 0%, pT1b: 37% vs. 11% lymph node metastases). Also, axillary and infraclavicular recurrence rates were higher for EIC/PIC carcinomas compared with other IDC of ≤1 cm (9.3% vs. 4.2%). This significantly adverse metastatic behaviour of the EIC/PIC tumours may be in part due to the more frequent occurrence of multifocal tumours in this group (in 43% vs. 6%), resulting in a greater tumour burden. We conclude that the overall risk of lymph node metastasis is not negligible in carcinomas of 1 cm or less in diameter with the risk being more than doubled for carcinomas with an intraductal component exceeding the invasive tumour by a factor of two. These differences were relevant only to regional metastases; the risk for distant metastasis and survival was identical after 5 years.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2307
    Keywords: Gastric stromal tumours ; Myogenic tumours ; Nucleolar organizer regions ; Gastric leiomyosarcoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Silver staining of nucleolar organizer regions (AgNOR) was studied in 26 primary benign and malignant gastric stromal tumours of myogenic origin. The absolute number of AgNOR per nucleus and the size of AgNOR were compared with histomorphologic features of the tumours. The total number of AgNOR per nucleus in epithelioid and spindle cell leiomyosarcomas significantly (p〈0.001) exceeded that in leiomyomas, cellular leiomyomas and epithelioid leiomyoblastomas. The mean number or the size of AgNOR did not correlate with the number of mitoses or the tumour size. In addition, large and bizarre AgNOR were seen predominantly in histologically malignant tumours. Only one exceptional epithelioid leiomyoblastoma recurred despite a lack of conventional characteristics of malignancy and a low AgNOR count. Therefore, quantitative determination of the number of AgNOR is a new independent variable in myogenic gastric tumours. It provides additional information for the histopathological evaluation of this heterogenous group of mesenchymal tumours.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1440
    Keywords: Myeloma in young persons ; Organ calcification ; Refractory heart failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The case of a 27 year old patient with IgG-λ-myeloma is reported. Examination revealed hypercalcemia and acute renal failure. The patient died of heart failure two days after diagnosis. Autopsy revealed an extensive calcification of the inner organs, in particular the heart.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1963
    Keywords: Schlüsselwörter DNA-Zytophotometrie ; Mammakarzinom ; Prognose ; Key words DNA-flow cytometry ; Breast cancer ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary DNA flow cytometry (FCM) has become a routine method in breast cancer diagnosis for evaluation of ploidy and proliferation kinetics (cell cycle analysis). Image cytometry is less practicable and provides less information than flow cytometry. An optimized technique with a low coefficient of variation is required for optimal results in flow cytometry. The S-phase fraction and the proliferation index (sum of S-phase fraction and G2M fraction) provide prognostic and therapeutically relevant information. A profound knowledge of the technique and its limitations is indispensable for the interpretation of FCM results. It remains to be established whether immunohistological evaluation of cell proliferation has the same prognostic value. Future developments are to be expected from multiparametric analysis and the improvement of mathematical analysis of FCM measurements.
    Notes: Zusammenfassung Die DNA-Zytometrie hat sich zu einer diagnostischen Routinetechnik entwickelt, die bevorzugt beim Mammakarzinom zur Beurteilung der Ploidie und der Proliferationskinetik (Zellzyklusanalyse) eingesetzt wird. Dabei ist die statische Zytometrie (Mikroskopzytometrie) aus Gründen der geringeren Aussagekraft der Durchflußzytometrie unterlegen. Die Durchflußzytometrie erfordert zur S-Phasen-Bestimmung eine standardisierte und methodisch einwandfreie Technik mit einem niedrigen Variationskoeffizienten (CV). Die gewonnenen Parameter, in 1. Linie die S-Phase und der Proliferationsindex, in 2. Linie auch die Ploidie, stellen prognostisch und für die Therapieplanung wichtige Faktoren dar. Eine genaue Kenntnis der Methode und der Fehlermöglichkeiten ist für die Interpretation der Ergebnisse unerläßlich. Inwieweit immunhistologische Techniken zur Bestimmung der Proliferationskinetik gleichwertige Informationen liefern, muß zum gegenwärtigen Zeitpunkt als ungeklärt angesehen werden. Weitere Entwicklungen betreffen die Einführung von multiparametrischen Untersuchungen und Verbesserung der mathematischen Analyse der Meßwerte.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1963
    Keywords: Schlüsselwörter Mammakarzinom ; Prognose ; Grading ; Key words Breast cancer ; Prognosis ; Grading
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Invasive lobular carcinoma (ILC) is recognized in its classical form and as variants with tubulo-lobular, solid, pleomorphic, alveolar or signet ring cell differentiation. The most common classical form differs from invasive ductal carcinoma (IDC) by its slower tumor proliferation and less common axillary metastases. When compared stage by stage, long term prognosis is similar to IDC, however. Prognostic subtyping of ILC can be achieved by the recognition of variant forms and mitotic counting. The combination of these factors may be used for tumor grading (5-year survival 100 % with grade 1 vs. 82 % with grade 2, and 57 % with grade 3, n = 241). The detailled histopatholgic diagnosis therefore permits prognostic assesment also in ILC.
    Notes: Zusammenfassung Das invasive lobuläre Karzinom (ILC) schließt die klassische Form und Varianten mit tubulo-lobulärer, solider, pleomorpher, alveolärer oder siegelringzelliger Differenzierung ein. Die häufigste klassische Form unterscheidet sich vom invasiven duktalen Karzinom (IDC) durch eine langsamere Tumorproliferation und seltenere lymphogene Metastasierung, weist jedoch stadienbezogen eine ähnliche Langzeitprognose wie das IDC auf. Durch Abgrenzung der varianten Formen gegenüber dem klassischen Subtyp und Berücksichtigung der Mitoseaktivität läßt sich das ILC in prognostisch unterschiedliche Gruppen einteilen und ein Gradingsystem aufstellen (5-Jahres Überlebensraten 100 % bei Grad 1 gegenüber 82 % bei Grad 2 und 57 % bei Grad 3, n = 241). Eine detaillierte histopathologische Diagnostik ermöglicht somit auch beim ILC eine genauere Abschätzung des biologischen Verhaltens dieser Tumoren.
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