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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Gemeinsame Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA) und des Arbeitskreises zur Weiterentwicklung der Lehre in der Zahnmedizin (AKWLZ); 20170920-20170923; Münster; DOC228 /20171124/
    Publication Date: 2017-11-24
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Abstract: Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-kappaB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-kappaB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)alpha, as zVAD.fmk, necrostatin-1 or TNFalpha-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.
    Type of Publication: Journal article published
    PubMed ID: 26096065
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEINS ; SAMPLE ; SAMPLES ; TIME ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDEX ; TISSUES ; CONTRAST ; ANTITUMOR-ACTIVITY ; TARGET ; MOUSE ; resistance ; CARCINOMA CELLS ; CELL-DEATH ; MEMBRANE ; CARCINOMA-CELLS ; adenocarcinoma ; NORMAL TISSUE ; REVEALS ; CHILDREN ; pancreatic cancer ; pancreatic carcinoma ; TRAIL ; HUMAN PROSTATE-CANCER ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; DRUG-INDUCED APOPTOSIS ; INHIBITORS ; PANCREATIC-CANCER ; THERAPIES ; DECOY RECEPTORS ; development ; X-LINKED INHIBITOR ; pancreatic adenocarcinoma ; USA ; ANTAGONISTS ; pancreatic tumor ; IRRADIATION-INDUCED APOPTOSIS ; XIAP ; therapeutic ; ALPHA-DEPENDENT APOPTOSIS
    Abstract: Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAM-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. [Cancer Res 2009;69(6):2425-34]
    Type of Publication: Journal article published
    PubMed ID: 19258513
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  18th Symposium on Infections in the Immunocompromised Host; 20140615-20140617; Berlin; DOC14ichs03 /20140603/
    Publication Date: 2014-06-04
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 5
    ISSN: 1279-8517
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Conclusion Nos données sont compatibles avec l'existence de bourses séreuses au niveau de la main et du pied (figs. 8, 9). Cependant, l'absence de descriptions antérieures précises, la difficulté d'individualisation de la paroi, l'aspect translucide et l'extrême fragilité de la paroi libre dans sa partie distale, l'existence d'une structure histologique compatible avec celle d'une membrane de bouse séreuse, mais non-spécifique, et l'absence de liquide dans ces espaces ne permettent pas de conclure de manière définitive et sans équivoque qu'il s'agit de bourses séreuses. Des études histologiques permettant de déterminer de façon plus spécifique la nature de la membrane limitante de ces espaces dans leur partie libre, ainsi que des études pathologiques qui mettraient en évidence les pathologies habituelles des bourses séreuses (inflammation, épaississement de la membrane, présence de liquide en quantité accrue) au niveau de ces espaces, sont nécessaires afin de conclure définitivement sur la nature des espaces inter-capito-métacarpiens et inter-capitométatarsiens.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0020-708X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Physics
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0020-708X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1279-8517
    Keywords: Hand ; Bursae ; Metacarpal heads ; Metatarsal heads
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé L'étude des espaces intercapito-métacarpiens sur 23 sujets frais et conservés soulève la question de l'existence de bourses séreuses à ce niveau, à l'instar des études récentes [1, 4] faites au niveau du pied. Une dissection soigneuse et des études histologiques apparaissent compatibles avec l'une des hypothèses suivantes: la présence soit de bourses séreuses non décrites jusqu'ici dans les ouvrages d'anatomie, soit d'espaces virtuels inter-capito-métacarpiens limités distalement par un cul-de-sac des aponévroses de la main au niveau des 2e, 3e et 4e espaces. Des études histologiques pouvant déterminer de façon plus spécifique la nature de la membrane limitante de ces espaces dans sa partie libre, ainsi que des études pathologiques qui mettraient en évidence les pathologies habituelles des bourses séreuses au niveau de ces espaces, sont nécessaires afin d'affirmer définitivement leur nature. La comparaison entre les espaces inter-capito-métacarpiens et inter-capito-métatarsiens et leurs membranes limitantes a mis en évidence des caractéristiques semblables tant au point de vue anatomique qu'histologique.
    Notes: Summary The study of the spaces between the metacarpal heads on 23 cadavers, raises the question of the existence of bursae at this level. This is in line with recent studies [1, 4] suggesting that such bursae are present at this level in the foot. Careful dissection and histological studies revealed characteristics compatible with both of the following hypotheses: either the existence of bursae not described until now in anatomy text-books, or spaces limited by a cul-de-sac of the aponeuroses of the hand in the 2nd, 3rd and 4th digits. Tissue analyses that could determine more specifically the nature of the limiting membrane of these spaces, as well as pathological studies demonstrating the occurrence of common anomalies of bursae in these spaces, are required in order to conclude definitively the nature of the spaces between the metacarpal heads. The gross anatomical and histological characteristics of the spaces between the metacarpal and metatarsal heads and of their limiting membranes were compared and found to be analogous in our series.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1588-2780
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract Results on aluminium and99mTc-MDP interaction under “in vivo” and “in vitro” conditions are presented. Aluminium, as chemical impurity, which in99mTc-eluate some times appears above the allowed concentration (more than 20 μg/ml) in the course of preparate labeling procedure may interact under in vitro conditions. Such a form of interaction was discovered by radiochromatographic methods. The highest Al3+-ion concentration studied (200 μg/ml) increases the99mTc-hydrolysate content by about ten times compared to the control. However, the same Al3+-ion concentration decreases by about four times the content of99mTc-MDP complex, which is responsible for deposition in bones. According to biodistribution results obtained on wistar rats, significant increase of radioactivity in liver is observed, and at the same time the decrease in bones, in dependence on the aluminium ion dose. With a maximum dose of 200 μg Al3+/kg b.w. the uptake of99mTc-MDP in liver was higher for about 35% and lower in bones for 3.6%/g. With compensan (antacide drug) with which the animals were primarily treated per os, only considerably small changes were observed in99mTc-MDP uptake, if compared to the control group. These findings are very important for clinical application of this preparate.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1588-2780
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract A new diiodine substituted IDA derivative, 2,4-diiodine-6-methyl IDA (DIIODIDA) was synthesized and labeled with99mTc. It was established that99mTc-DIIODIDA had high radiochemical purity. Biodistribution and influence of bilirubin on99mTc-DIIODIDA biokinetics has been studied in rats and compared to the corresponding results for99mTc-SOLCOIODIDA. Related to99mTc-SOLCOIODIDA,99mTc-DIIODIDA has much better biliary exretion (55.18 versus 43.63%). No change of99mTc-DIIODIDA biokinetics, under influence of bilirubin was noticed. Biliary excretion of99mTc-SOLCOIODIDA has been reduced for about 60%. The protein binding of99mTc-DIIODIDA and99mTc-SOLCOIODIDA were also determined, using in vitro method of precipitation. These results showed that99mTc-DIIODIDA hepatobiliary imaging agent is superior to the presently used99mTc-monoiodine IDA derivatives.
    Type of Medium: Electronic Resource
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