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  • 1
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 43 ( 2009-10-27), p. 18351-18356
    Abstract: In cancer, genetically activated proto-oncogenes often induce “ upstream ” dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce “ downstream ” dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Wiley ; 2005
    In:  Entomologia Experimentalis et Applicata Vol. 115, No. 1 ( 2005-04), p. 239-245
    In: Entomologia Experimentalis et Applicata, Wiley, Vol. 115, No. 1 ( 2005-04), p. 239-245
    Abstract: Thus far, the release of herbivore‐induced synomones (HIS) has almost exclusively been demonstrated in somatic plant tissue. Here we present evidence for the production of HIS from reproductive tissue, i.e., seeds. The study system consisted of wheat grains ( Triticum aestivum L., Poaceae) infested by larvae of the granary weevil Sitophilus granarius L. (Coleoptera, Curculionidae), which in turn are attacked by the parasitic wasp Lariophagus distinguendus Förster (Hymenoptera, Pteromalidae). The use of potential chemical signals from the infested grain for host recognition of L. distinguendus was studied with weevil‐infested grains that had developed under a range of humidity conditions. Wasps always performed longer antennal drumming on infested than healthy grains, demonstrating that they were able to recognize infested grains under all humidity conditions. In grains developed at a high humidity (75% r.h.), host recognition is enabled by chemical signals arising from the host faeces which densely cover infested grains. However, in grains from a low humidity (45% r.h.) almost no faeces are present, indicating that other cues are used by the wasp. Control experiments revealed that these other cues are neither chemical signals from faeces contaminations, volatiles from faeces nor host larvae inside the grain, movement of host larvae, or moisture content of infested grains. Therefore, wasp recognition of infested grains in low humidity conditions is probably based on chemical signals from the grain itself that are induced by the feeding of granary weevil larva. Further experiments revealed that infested grains increase their viability when granary weevil larvae are killed by the idiobiont L. distinguendus . This justifies the categorisation of potential signals from the grain as HIS. To our knowledge, this is the only system where potential HIS in plant seeds have been studied. We discuss whether potential HIS are actively produced by infested grains or are a by‐product of grain metabolism.
    Type of Medium: Online Resource
    ISSN: 0013-8703 , 1570-7458
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 2015286-3
    SSG: 12
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  • 3
    In: Cell, Elsevier BV, Vol. 137, No. 5 ( 2009-05), p. 961-971
    Type of Medium: Online Resource
    ISSN: 0092-8674
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2009
    detail.hit.zdb_id: 187009-9
    detail.hit.zdb_id: 2001951-8
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 293, No. 4 ( 2007-10), p. H2155-H2160
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 293, No. 4 ( 2007-10), p. H2155-H2160
    Abstract: Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasodilators and exert positive chronotropic and inotropic effects on the heart. Receptors for CGRP and AM are calcitonin receptor-like receptor (CLR)/receptor-activity-modifying protein (RAMP) 1 and CLR/RAMP2 heterodimers, respectively. The present study was designed to delineate distinct cardiovascular effects of CGRP and AM. Thus a V5-tagged rat CLR was expressed in transgenic mice in the vascular musculature, a recognized target of CGRP. Interestingly, basal arterial pressure and heart rate were indistinguishable in transgenic mice and in control littermates. Moreover, intravenous injection of 2 nmol/kg CGRP, unlike 2 nmol/kg AM, decreased arterial pressure equally by 18 ± 5 mmHg in transgenic and control animals. But the concomitant increase in heart rate evoked by CGRP was 3.7 times higher in transgenic mice than in control animals. The effects of CGRP in transgenic and control mice, different from a decrease in arterial pressure in response to 20 nmol/kg AM, were suppressed by 2 μmol/kg of the CGRP antagonist CGRP(8-37). Propranolol, in contrast to hexamethonium, blocked the CGRP-evoked increase in heart rate in both transgenic and control animals. This was consistent with the immunohistochemical localization of the V5-tagged CLR in the superior cervical ganglion of transgenic mice. In conclusion, hypotension evoked by CGRP in transgenic and control mice was comparable and CGRP was more potent than AM. Unexpectedly, the CLR/RAMP CGRP receptor overexpressed in postganglionic sympathetic neurons of transgenic mice enhanced the positive chronotropic action of systemic CGRP.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
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    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Microbiology Society ; 2008
    In:  Journal of General Virology Vol. 89, No. 1 ( 2008-01-01), p. 164-176
    In: Journal of General Virology, Microbiology Society, Vol. 89, No. 1 ( 2008-01-01), p. 164-176
    Abstract: The species human parvovirus B19 (B19V) can be divided into three genotypes. In this study, we addressed the question as to whether infection of an individual is restricted to one genotype. As viral DNA is detectable in tissue for long times after acute infection, we examined 87 liver specimens from adults for the presence of B19V DNA. Fifty-nine samples were found to be positive, 32 of them for genotype 1, 27 for genotype 2 and four for genotype 3. In four samples, DNA of two genotypes was detected; samples from three individuals were positive for genotypes 1 and 2 and a sample from one individual was positive for genotypes 1 and 3. Surprisingly, significant sequence heterogeneity was observed at approximately 1 % of the nucleotides of the genotype 1 genomes from individuals with double genotype 1 and 2 infection. Controls using different enzymes for genome amplification and dilutions of the template verified that nucleotide heterogeneity was due to the presence of three or more genome variants of genotype 1. In summary, the evidence shows that individuals can be infected with two different genotypes, and B19V DNA can persist as a population of different genomes. The results may have implications for the understanding of the antiviral immune response and the development of vaccines against B19V.
    Type of Medium: Online Resource
    ISSN: 0022-1317 , 1465-2099
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    Language: English
    Publisher: Microbiology Society
    Publication Date: 2008
    detail.hit.zdb_id: 2007065-2
    SSG: 12
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