Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; AGENTS ; CELL ; CELL-PROLIFERATION ; COMBINATION ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; PROSTATE ; THERAPY ; tumor growth ; VITRO ; DENSITY ; DRUG ; TUMORS ; MICE ; radiation ; PATIENT ; MECHANISM ; INDEX ; TYROSINE KINASE INHIBITOR ; DESIGN ; UP-REGULATION ; prostate cancer ; PROSTATE-CANCER ; DAMAGE ; MUSCLE ; MIGRATION ; experimental design ; CELL-MIGRATION ; TUMOR ANGIOGENESIS ; VEGF ; signaling ; AGENT ; ONCOLOGY ; RE ; antiangiogenesis ; SU5416 ; TUMOR-GROWTH ; THERAPIES ; INCREASE ; cell proliferation ; cell migration ; USA ; vascular endothelial growth factor ; cancer research ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SMOOTH-MUSCLE-CELLS ; ENDOTHELIAL GROWTH ; MUSCLE-CELLS ; tumor therapy ; radiation dose ; FRACTIONATED-IRRADIATION ; SU6668
    Abstract: Purpose: Investigations on the combination of radiotherapy with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) antiangiogenic agents, which has the potential to improve the clinical outcome in cancer patients. Experimental Design: Here, we analyze the combined VEGF (SU5416) and PDGF (SU6668) receptor tyrosine kinase inhibition with irradiation in human endothelium (HUVEC), prostate cancer (PC3), and glioblastoma (U87) in vitro and in vivo. Results: Combined inhibition of VEGF and PDGF signaling resulted in enhanced apoptosis, reduced cell proliferation, and clonogenic survival as well as reduced endothelial cell migration and tube formation compared with single pathway inhibition. These effects were further enhanced by additional irradiation. Likewise, in PC3 and U87 tumors growing s.c. on BALB/c nu/nu mice, dual inhibition of VEGF and PDGF signaling significantly increased tumor growth delay versus each monotherapy. Interestingly, radiation at similar to 20% of the dose necessary to induce local tumor control exerts similar tumor growth-inhibitory effects as the antiangiogenic drugs given at their maximum effective dose. Addition of radiotherapy to both mono- as well as dual-antiangiogenic treatment markedly increased tumor growth delay. With respect to tumor angiogenesis, radiation further decreased microvessel density (CD31 count) and tumor cell proliferation (Ki-67 index) in all drug-treated groups. Of note, the slowly growing PC3 tumor responded better to the antiangiogenic drug treatments than the faster-growing U87 tumor. In addition to the beneficial effect of abrogating VEGF survival signaling when combined with radiation, we identified here a novel mechanism for the tumor escape from radiation damage. We found that radiation induced up-regulation of all four isoforms of PDGF (A-D) in endothelial cells supporting adjacent smooth muscle cells resulting in a prosurvival effect of radiation. The addition of SU6668 attenuated this undesirable paracrine radiation effect, which may rationalize the combined application of radiation with PDGF signaling inhibition to increase antitumor effects. Conclusion: A relative low radiation dose markedly enhances local antitumor effects of combined VEGF and PDGF signaling inhibition, suggesting a promising combination regimen for local tumor treatment with radiotherapy remaining an essential element
    Type of Publication: Journal article published
    PubMed ID: 18381963
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: LUNG ; PATHWAYS ; MICE ; CANCER-THERAPY ; FACTOR-BETA-1 ; GLIOBLASTOMA ; TRANSFORMING-GROWTH-FACTOR ; KINASE INHIBITOR LY2109761 ; NORMAL TISSUE-INJURY ; THORACIC IRRADIATION
    Abstract: PURPOSE: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-beta signaling is considered to play an important role. EXPERIMENTAL DESIGN: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-beta receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Noninvasive lung imaging including volume computed tomography (VCT) and MRI was conducted 6, 16, and 20 weeks after irradiation and was correlated to histologic findings. Expression profiling analysis and protein analysis was conducted in human primary fibroblasts. RESULTS: Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced life span. VCT, MRI, and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically, we found that LY2109761 reduced p-SMAD2 and p-SMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and noncanonical TGF-beta signaling and downstream signaling of bone morphogenetic proteins (BMP). LY2109761 also suppressed radiation-induced inflammatory [e.g., interleukin (IL)-6, IL-7R, IL-8] and proangiogenic genes (e.g., ID1) indicating that LY2109761 achieves its antifibrotic effect by suppressing radiation-induced proinflammatory, proangiogenic, and profibrotic signals. CONCLUSION: Small-molecule inhibitors of the TGF-beta receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis.
    Type of Publication: Journal article published
    PubMed ID: 22547771
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
  • 4
    Keywords: ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; NETWORK ; GENOME ; DNA ; antibodies ; antibody ; expression profiling ; UNCERTAINTIES ; signaling ; ENDOSTATIN ; Heisenberg uncertainty
    Abstract: Genome wide DNA expression profiling coupled with antibody array experiments using endostatin to probe the angiogenic signaling network in human endothelial cells were performed. The results reveal constraints on the measuring process that are of a similar kind as those implied by the uncertainty principle of quantum mechanics as described by Werner Heisenberg. We describe this analogy and argue for its heuristic utility in the conceptualization of angiogenesis as an important step in tumor formation
    Type of Publication: Journal article published
    PubMed ID: 15483400
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: RECEPTOR ; SPECTRA ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; radiotherapy ; SURVIVAL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; LUNG ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEIN ; radiation ; TIME ; ACTIVATION ; MESSENGER-RNA ; fibroblasts ; PHOSPHORYLATION ; MOUSE ; TRIAL ; ASSAY ; chemotherapy ; MOUSE MODEL ; signaling ; RE ; cell proliferation ; LEVEL ; ASSAYS ; in vivo ; AA ; KINASE INHIBITOR ; receptor tyrosine kinase ; CHRYSOTILE ASBESTOS ; INDUCED LUNG FIBROSIS ; PDGF RECEPTOR ; PDGFR inhibitor ; PULMONARY-FIBROSIS ; RAT LUNG ; VEGFR inhibitor
    Abstract: Background: Several small receptor tyrosine kinase inhibitors (RTKI) have entered clinical cancer trials alone and in combination with radiotherapy or chemotherapy. The inhibitory spectrum of these compounds is often not restricted to a single target. For example Imatinib/Gleevec (primarily a bcr/abl kinase inhibitor) or SU11248 (mainly a VEGFR inhibitor) are also potent inhibitors of PDGFR and other kinases. We showed previously that PDGF signaling inhibition attenuates radiation-induced lung fibrosis in a mouse model. Here we investigate effects of SU9518, a PDGFR inhibitor combined with ionizing radiation in human primary fibroblasts and endothelial cells in vitro, with a view on utilizing RTKI for antifibrotic therapy. Methods: Protein levels of PDGFR-alpha/-beta and phosphorylated PDGFR in fibroblasts were analyzed using western and immunocytochemistry assays. Functional proliferation and clonogenic assays were performed (i) to assess PDGFR-mediated survival and proliferation in fibroblasts and endothelial cells after SU9518 (small molecule inhibitor of PDGF receptor tyrosine kinase); (ii) to test the potency und selectivity of the PDGF RTK inhibitor after stimulation with PDGF isoforms (-AB, -AA, -BB) and VEGF+bFGF. In order to simulate in vivo conditions and to understand the role of radiation-induced paracrine PDGF secretion, co-culture models consisting of fibroblasts and endothelial cells were employed. Results: In fibroblasts, radiation markedly activated PDGF signaling as detected by enhanced PDGFR phosphorylation which was potently inhibited by SU9518. In fibroblast clonogenic assay, SU9518 reduced PDGF stimulated fibroblast survival by 57%. Likewise, SU9518 potently inhibited fibroblast and endothelial cell proliferation. In the co-culture model, radiation of endothelial cells and fibroblast cells substantially stimulated proliferation of non irradiated fibroblasts and vice versa. Importantly, the RTK inhibitor significantly inhibited this paracrine radiation-induced fibroblast and endothelial cell activation. Conclusion: Radiation-induced autocrine and paracrine PDGF signaling plays an important role in fibroblast and endothelial cell proliferation. SU9518, a PDGFR tyrosine kinase inhibitor, reduces radiation-induced fibroblast and endothelial cell activation. This may explain therapeutic anticancer effects of Imatinib/Gleevec, and at the same time it could open a way of attenuating radiation-induced fibrosis
    Type of Publication: Journal article published
    PubMed ID: 16556328
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: IRRADIATION ; SURVIVAL ; Germany ; INHIBITION ; LUNG ; MODEL ; imaging ; EXPOSURE ; DRUG ; computed tomography ; MICE ; FAMILY ; REDUCTION ; MRI ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; TARGET ; MOUSE ; radiosurgery ; resistance ; EXTRACELLULAR-MATRIX ; tomography ; COMPUTED-TOMOGRAPHY ; GROWTH-FACTOR-BETA ; inflammation ; INJURY ; FEATURES ; fibrosis ; ONCOLOGY ; MATRIX METALLOPROTEINASES ; DEFICIENT MICE ; SCIENCE ; KNOCKOUT MOUSE ; development ; ionizing radiation ; methods ; PHASE ; proteases ; matrix metalloproteinase ; INDUCED LUNG FIBROSIS ; outcome ; HEPATIC STELLATE CELLS ; PULMONARY FIBROSIS ; 13-DEFICIENT MICE ; MMP13 ; Volume computed tomography
    Abstract: Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMPI 3 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57BI/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis. (C) 2010 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 20457355
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; SURVIVAL ; VITRO ; DENSITY ; MICE ; radiation ; MIGRATION ; GROWTH-FACTOR-BETA ; CELL-MIGRATION ; human glioma ; antiangiogenic therapy ; GLIOBLASTOMA ; VESSEL NORMALIZATION
    Abstract: Here we investigate the effects of the novel transforming growth factor-beta receptor I (TGF-beta RI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated MGMT promoter), and endothelial cells (HUVECs) were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67) and the microvessel density (CD31 count), the relative pericyte coverage (alpha-SMA/CD31 ratio) increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-beta RI kinase inhibitor to the present clinical standard (radiation plus TMZ) has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status
    Type of Publication: Journal article published
    PubMed ID: 21677877
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    facet.materialart.
    facet.materialart.
    German Medical Science GMS Publishing House; Düsseldorf
    In:  Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA); 20140925-20140927; Hamburg; DOCP125 /20140911/
    Publication Date: 2014-09-12
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    facet.materialart.
    facet.materialart.
    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Journal for Medical Education; VOL: 34; DOC18 /20170515/
    Publication Date: 2017-05-15
    Description: Background: Medication communication from physicians to patients often is poor, by this among others enhancing the risk of non-adherence. In this context, a neglect regarding the prescription talk has been complained.Aim of the project: In a newly developed elective medical students work on physician-patient conversations dealing with drug prescription. Essential aspects related to an effective and safe drug treatment are combined with steps of shared decision-making. Together with a tutor, students develop a (model) conversation guide that might be tailored according to individual needs and views.Description/Methods: In a one-week course 3rd-5th year medical students treat a paper case according to problem-based learning. This is accompanied by a one-hour lecture and literature provided on an online learning platform (ILIAS). During a workshop, aspects of drug treatment and patient participation are integrated into a guide for a prescription talk. At the end of the week the students are invited to apply the (if need be individualized) guide in a simulated physician-patient communication with an actor. The conversation is evaluated using a checklist based upon the (model) conversation guide.Results: Informal and formalized feedback indicate high acceptance and satisfaction of participants with this elective. The checklist turned out to be of acceptable to good reliability with mostly selective items. Portfolio entries and written evaluation suggest that participants' positions and attitudes are influenced.
    Description: Hintergrund: Die Arzt-Patient-Kommunikation über die Arzneitherapie zeigt häufig Defizite, was u.a. eine unzureichende medikamentöse Adhärenz zur Folge haben kann. Vernachlässigt wurde in diesem Zusammenhang lange Zeit das Verordnungsgespräch.Zielsetzung: Im neu konzipierten Wahlpflichtblock setzen sich Studierende der Humanmedizin aktiv mit Arzt-Patient-Gesprächen im Rahmen der Arzneiverordnung auseinander. Berücksichtigung finden wesentliche Aspekte einer sicheren und effektiven Arzneitherapie sowie das Modell der Partizipativen Entscheidungsfindung. Unter Anleitung entwickeln die Studierenden einen Gesprächsleitfaden, dessen Anwendung auch individuellen Bedürfnissen und Vorstellungen Rechnung tragen soll. Beschreibung/Methoden: In diesem einwöchigen Kurs erarbeiten sich die Studierenden wichtige Hintergrundinformationen anhand eines Fallbeispiels im Rahmen des Problem-basierten Lernens. Unterstützt werden sie durch ein Impulsreferat und auf einer elektronischen Lernplattform angebotene Literatur. Die gemeinsame Synthese der Aspekte zu Arzneitherapie und Patientenbeteiligung in Form eines Gesprächsleitfadens erfolgt in einem interaktiven Workshop. Am Ende der Woche können die Studierenden sich und den (Muster-) Leitfaden in einem mit einem Schauspielerpatienten simulierten Verordnungsgespräch ausprobieren, das anhand einer Checkliste beurteilt wird.Ergebnisse: Informelle Rückmeldungen und die standardisierte fakultätsweite elektronische Evaluation zeigen ein hohe Akzeptanz und große Zufriedenheit seitens der Studierenden. Die Checkliste erlaubt eine weitgehend reliable Beurteilung der Gespräche anhand überwiegend trennscharfer Items. Portfolioeinträge und Freitextevaluationen sprechen dafür, dass bei den Teilnehmern Einstellungen und Haltungen beeinflusst werden.
    Keywords: prescribing ; drug information ; medical education ; clinical pharmacology ; patient-physician relation ; communication ; simulation ; Verordnung ; Aufklärung ; medizinische Ausbildung ; Pharmakologie ; Arzt-Patient-Beziehung ; Kommunikation ; Simulation ; ddc: 610
    Language: English
    Type: article
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    facet.materialart.
    facet.materialart.
    German Medical Science GMS Publishing House; Düsseldorf
    In:  Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA); 20160914-20160917; Bern; DOCV20-598 /20160905/
    Publication Date: 2016-09-05
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...