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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  125. Kongress der Deutschen Gesellschaft für Chirurgie; 20080422-20080425; Berlin; DOC08dgch9243 /20080416/
    Publication Date: 2008-04-14
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  124. Kongress der Deutschen Gesellschaft für Chirurgie; 20070501-20070504; München; DOC07dgch7656 /20071001/
    Publication Date: 2007-10-02
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Abstract: The increasing unraveling of the molecular basis of cancer offers manifold novel options for intervention strategies. However, the discovery and development of new drugs for potential clinical applications is a tremendously time-consuming and costly process. Translating a novel lead candidate compound into an approved clinical drug takes often more than a decade, and the success rate is very low due to versatile efforts including defining its pharmacokinetics, pharmacodynamics, side effects as well as lack of sufficient efficacy. Thus, strategies are needed to minimize time and costs, while maximizing success rates. A very attractive strategy for novel cancer therapeutic options is the repositioning of already approved drugs. These medicines, approved for the treatment of non-malignant disorders, have already passed some early costs and time, have been tested in humans and are ready for clinical trials as anti-cancer drugs. Here we discuss the repositioning of nonsteroidal anti-inflammatory drugs (NSAID), statins, anti-psychotic drugs, anti-helminthic drugs and vitamin D as anti-tumor agents. We focus on their novel actions and potential for inhibition of cancer growth and metastasis by interfering with target molecules and pathways, which drive these malignant processes. Furthermore, important pre-clinical and clinical data are reviewed herein, which elucidate their therapeutic mechanisms which enable their repositioning for cancer therapy and disruption of metastasis.
    Type of Publication: Journal article published
    PubMed ID: 27180307
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  • 4
    Abstract: MACC1 (metastasis associated in colon cancer 1) is a prognostic biomarker for tumor progression, metastasis and survival of a variety of solid cancers including colorectal cancer (CRC). Here we aimed to identify the MACC1-induced transcriptome and key players mediating the MACC1-induced effects in CRC. We performed microarray analyses using CRC cells ectopically overexpressing MACC1. We identified more than 1300 genes at least twofold differentially expressed, including the gene SPON2 (Spondin 2) as 90-fold upregulated transcriptional target of MACC1. MACC1-dependent SPON2 expression regulation was validated on mRNA and protein levels in MACC1 high (endogenously or ectopically) and low (endogenously or by knockdown) expressing cells. Chromatin immunoprecipitation analysis demonstrated the binding of MACC1 to the gene promoter of SPON2. In cell culture, ectopic SPON2 overexpression induced cell viability, migration, invasion and colony formation in endogenously MACC1 and SPON2 low expressing cells, whereas SPON2 knockdown reduced proliferative, migratory and invasive abilities in CRC cells with high endogenous MACC1 and SPON2 expression. In intrasplenically transplanted NOD/SCID mice, metastasis induction was analyzed with control or SPON2-overexpressing CRC cells. Tumors with SPON2 overexpression induced liver metastasis (vs control animals without any metastases, P=0.0036). In CRC patients, SPON2 expression was determined in primary tumors (stages I-III), and survival time was analyzed by Kaplan-Meier method. CRC patients with high SPON2 expressing primary tumors demonstrated 8 months shorter metastasis-free survival (MFS) compared with patients with low SPON2 levels (P=0.053). Combining high levels of SPON2 and MACC1 improved the identification of high-risk patients with a 20-month shorter MFS vs patients with low biomarker expression. In summary, SPON2 is a transcriptional target of the metastasis gene MACC1. SPON2 induces cell motility in vitro and CRC metastasis in mice. In patients, SPON2 serves as prognostic indicator for CRC metastasis and survival, and might represent a promising target for therapeutic approaches.
    Type of Publication: Journal article published
    PubMed ID: 26686083
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  • 5
    Abstract: The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of beta-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success.
    Type of Publication: Journal article published
    PubMed ID: 27331819
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  • 6
    Abstract: MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.
    Type of Publication: Journal article published
    PubMed ID: 28570591
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  • 7
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO479 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
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  • 8
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie; 20180603-20180606; Münster; DOCP091 /20180618/
    Publication Date: 2018-06-19
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 9
    ISSN: 1432-069X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung An männlichen und weiblichen Sprague-Dawley-Ratten wurden die mechanischen Eigenschaften der Haut in Abhängigkeit vom Körpergewicht untersucht. Es wurden die Hautdicke, die bis zum Abriß notwendige Kraft und die Reißfestigkeit geprüft. Für jeden Parameter wurde eine mathematische Analyse mit dem Analogrechner durchgeführt. Die Hautdicke zeigte eine lineare Abhängigkeit vom Körpergewicht. Geschlechtsunterschiede ließen sich an der Hautdicke nicht feststellen. Die Reißkraft und noch ausgeprägter die Reißfestigkeit zeigten in Abhängigkeit vom Körpergewicht einen mehrphasischen Verlauf, der in Differentialgleichungen erfaßt wurde. Geringe Unterschiede, die im Kurvenverlauf der Proben von männlichen und weiblichen Tieren in der Wachstumsphase festzustellen waren, sind auf das stärkere Wachstum der Männchen zu beziehen. Die Reißfestigkeit als Maß der Eigenschaften des kollagenen Materials zeigte ein deutliches Maximum im Alter von knapp 3 Monaten. Mit zunehmendem Alter war eine langsame Abnahme der Reißfestigkeit festzustellen. Ähnliche Befunde, wie sie an menschlicher Haut erhoben wurden, werden diskutiert.
    Notes: Summary Male and female rats of Sprague Dawley strain were used to study the mechanical properties of skin in correlation to body weight as an indicator for age. Groups of ten rats of each sex were used for each ten gram interval of body weight. Flaps of shaved skin of the back were prepared and the thickness of skin specimens was measured. Strips of 5 mm width were cut and fastened between clamps of the Instron®-instrument. The load resulting in rupture of the skin strip was measured and the tensile strength (load/cross section) was calculated. Each parameter was analysed mathematically with the analog computer. Skin thickness showed a linear correlation to body weight without differences depending on sex. When correlated to body weight, the graph of the load at rupture and even more pronounced the graph of the tensile strength revealed several phases which were expressed in the form of differential equations. During growth phase differences between male and female rats were noticed. These have to be attributed to a more intensive growth of male rats. Tensile strength of skin tissue showed a maximum in rats being about three months old. Further increase in body weight (or age) was correlated to a slow decrease in tensile strength. Similar results found in human skin were discussed.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-069X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Aus dem Sektionsgut des Pathologischen Instituts der Universität Mainz wurden von 52 Patienten Hautproben untersucht, die in der Gegend des Sternums und an der Innenseite der Oberschenkel entnommen waren. Aus den Hautproben wurden 5 mm breite Streifen ausgestanzt und Kraft-Dehnungsdiagramme aufgenommen. Folgende Parameter wurden gemessen: Hautdicke (mm), Kraft bis zum Abriß (g), Reißfestigkeit (g/mm2), Dehnung bis zum Abriß (%), Anstiegssteilheit in linearen Teil des Kraft-Dehnungsdiagramms (g% Dehnung) und Elastizitätsmodul (g/mm2). Die Proben wurden in Altersklassen eingeteilt. Von sämtlichen Parametern konnte die Abhängigkeit vom Lebensalter mit Hilfe des Analog-Rechners durch 2 konkurrierende 3-Funktionen beschrieben werden. Im vorliegenden Material konnte keine Abhängikeit der Meßgrößen vom Geschlecht der Patienten gefunden werden. Auch eine Abhängigkeit von endokrinen Erkrankungen ließ sich statistisch nicht sichern. Die Abhängigkeit vom Lebensalter zeigte sich sowohl bei den Meßgrößen, die suf das Organ Haut zu beziehen sind, als auch bei den Parametern, die etwas über die Materialbeschaffenheit aussagen. Sämtliche Kurven durchliefen vom frühkindlichen Alter bis zum Senium ein mehr oder minder ausgeprägtes Maximum. Dieses lag bei der Hautdicke etwa um das 35. Lebensjahr, bei der Reißkraft um das 20. Lebensjahr sowie bei der Anstiegssteilheit um das 25. Lebensjahr. Die Maxima der Dehnung bis zum Abriß waren weniger ausgeprägt. Die Maxima der beiden auf die Materialeigenschaften zu beziehenden Parameter Reißfestigkeit und Elastizitätsmodul lagen auf einem noch etwas früheren Zeitpunkt, nämlich 14 bzw. 10 Jahre. Alle Meßgrößen fielen bis zum Senium wieder ab. Die aus früheren Arbeiten bekannten Beziehungen zur Kollagenreifung und zum Kollagenmetabolismus werden diskutiert.
    Notes: Summary Autopsy material was used to study the mechanical properties of human skin. The specimens had been taken from the area of the manubrium sterni and the inner side of the thigh. Strips of 5 mm width were cut and load-extension curves were registered using the Instron®-instrument. The following parameters were measured: thickness of the skin (mm), load resulting in rupture of the skin strip (g) tensile strength (g/mm2), extension resulting in rupture (%), steepness in the linear part of the load-extension curve (g/% extension) and elasticity module (g/mm2). For the evaluation of the results, the specimens were classified according to age. An analog computer was used; it was possible to describe the age-dependence of each parameter by two concurrent e-functions. No statistically significant dependence on sex could be found in any of the parameters under study. Neither could any significant influence of endocrine factors be established due to the inhomogenity of the material. The dependence upon age was manifest in the parameters which were related to the skin as an organ as well as in the parameters which were indicators of the quality of the material used. The curves which were correlated to age were calculated by the analog computer. Starting from early childhood and ending with senium each of them showed a maximum being more or less pronounced. When related to skin thickness this maximum appeared around the 35th year of life, load at rupture around the 20th year and steepness of the load-extension curve around the 25th year. The maxima of extension at rupture were less pronounced. The maxima of tensile strength and elasticity module, which parameters are indicators for the quality of the material used, appeared in an even earlier period of life, i.e. at the age of 14, and 10 years respectively. All parameters studied so far showed a decrease until senium. Correlations between mechanical properties of connective tissue and collagen metabolism known from earlier studies as well as similar results in animals are discussed.
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