Förderzeitraum 2014
Refine
Has Fulltext
- yes (112)
Is part of the Bibliography
- yes (112)
Document Type
- Journal article (112)
Language
- English (112)
Keywords
- cell staining (4)
- immunoprecipitation (4)
- Echinococcus (3)
- analysis of variance (3)
- apoptosis (3)
- cytoskeleton (3)
- flow cytometry (3)
- immune response (3)
- Autonomous UAV (2)
- Cancer treatment (2)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (24)
- Institut für Psychologie (13)
- Pathologisches Institut (10)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (6)
- Institut für Hygiene und Mikrobiologie (6)
- Klinik und Poliklinik für Nuklearmedizin (6)
- Medizinische Klinik und Poliklinik I (6)
- Medizinische Klinik und Poliklinik II (6)
- Institut für Virologie und Immunbiologie (5)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (5)
Sonstige beteiligte Institutionen
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (2)
- Röntgen Center for Complex Material Systems (RCCM), Am Hubland, 97074 W¨urzburg, Germany (2)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (1)
- Comprehensive Hearing Center, Department of ORL, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Würzburg, Germany (1)
- DNA Analytics Core Facility, Biocenter, University of Würzburg, Würzburg, Germany (1)
- Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany (1)
- Department of Paediatric Radiology, Institute of Diagnostic and Interventional Radiology, Josef-Schneider-Straße 2, Wuerzburg 97080, Germany (1)
- Interdisziplinäres Zentrum für Klinische Forschung (ZIKF), Würzburg (1)
- Research Center for Infectious Diseases (ZINF), University of Würzburg, Würzburg, Germany (1)
- Research Center for Infectious Diseases, University of Wuerzburg, Wuerzburg 97080, Germany (1)
To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.
A comparative study is carried out on two spectroscopic techniques employed to detect ultrafast absorption changes in the mid-infrared spectral range, namely direct multichannel detection via HgCdTe (MCT) photodiode arrays and the newly established technique of chirped-pulse upconversion (CPU). Whereas both methods are meanwhile individually used in a routine manner, we directly juxtapose their applicability in femtosecond pump-probe experiments based on 1 kHz shot-to-shot data acquisition. Additionally, we examine different phase-matching conditions in the CPU scheme for a given mid-infrared spectrum, thereby simultaneously detecting signals which are separated by more than 200 cm−1.
Cell Surface Area and Membrane Folding in Glioblastoma Cell Lines Differing in PTEN and p53 Status
(2014)
Glioblastoma multiforme (GBM) is characterized by rapid growth, invasion and resistance to chemo−/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM), the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT) technique. The osmotic stability and volume regulation of GBM cells were analyzed by video microscopy. The expression of PTEN, p53, mTOR and several other marker proteins involved in cell growth and membrane synthesis were examined by Western blotting. The combined SEM, ROT and osmotic data provided independent lines of evidence for a large variability in membrane area and folding among tested GBM lines. Thus, DK-MG cells (wild type p53 and wild type PTEN) exhibited the lowest degree of membrane folding, probed by the area-specific capacitance Cm = 1.9 µF/cm2. In contrast, cell lines carrying mutations in both p53 and PTEN (U373-MG and SNB19) showed the highest Cm values of 3.7–4.0 µF/cm2, which corroborate well with their heavily villated cell surface revealed by SEM. Since PTEN and p53 are well-known inhibitors of mTOR, the increased membrane area/folding in mutant GBM lines may be related to the enhanced protein and lipid synthesis due to a deregulation of the mTOR-dependent downstream signaling pathway. Given that membrane folds and extensions are implicated in tumor cell motility and metastasis, the dielectric approach presented here provides a rapid and simple tool for screening the biophysical cell properties in studies on targeting chemo- or radiotherapeutically the migration and invasion of GBM and other tumor types.
Purpose
Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity.
Experimental Design
To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features.
Results
Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET.
Conclusion
These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.
The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).
The Chaco leaf-cutting ant Atta vollenweideri is native to the clay-heavy soils of the Gran Chaco region in South America. Because of seasonal floods, colonies are regularly exposed to varying moisture across the soil profile, a factor that not only strongly influences workers' digging performance during nest building, but also determines the suitability of the soil for the rearing of the colony's symbiotic fungus. In this study, we investigated the effects of varying soil moisture on behaviours associated with underground nest building in A. vollenweideri. This was done in a series of laboratory experiments using standardised, plastic clay-water mixtures with gravimetric water contents ranging from relatively brittle material to mixtures close to the liquid limit. Our experiments showed that preference and group-level digging rate increased with increasing water content, but then dropped considerably for extremely moist materials. The production of vibrational recruitment signals during digging showed, on the contrary, a slightly negative linear correlation with soil moisture. Workers formed and carried clay pellets at higher rates in moist clay, even at the highest water content tested. Hence, their weak preference and low group-level excavation rate observed for that mixture cannot be explained by any inability to work with the material. More likely, extremely high moistures may indicate locations unsuitable for nest building. To test this hypothesis, we simulated a situation in which workers excavated an upward tunnel below accumulated surface water. The ants stopped digging about 12 mm below the interface soil/water, a behaviour representing a possible adaptation to the threat of water inflow field colonies are exposed to while digging under seasonally flooded soils. Possible roles of soil water in the temporal and spatial pattern of nest growth are discussed.
Background: Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/ pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects μM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy.
Methods: MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2.
Results: Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1.
Conclusions: In summary, we demonstrate effects of various bisphosphonates on caspase 3/7 activity, cell viability and expression of tumor suppressor genes in breast cancer cells. Blocking probenecid- and novobiocin-sensitive channels and transporters enhances BP anti-tumor effects and renders SLC22A family members good candidates as BP modulators. Further studies will have to unravel if treatment with such BP-sensitizers translates into preclinical and clinical efficacy.
Clinical prognosis of metastasized colorectal carcinoma (CRC) is still not at desired levels and novel drugs are needed. Here, we focused on the multi-tyrosine kinase inhibitor E7080 (Lenvatinib) and assessed its therapeutic efficacy against human CRC cell lines in vitro and human CRC xenografts in vivo. The effect of E7080 on cell viability was examined on 10 humanCRCcell lines and humanendothelial cells (HUVEC). The inhibitory effect of E7080 on VEGF-induced angiogenesis was studied in an ex vivo mouse aortic ring angiogenesis assay. In addition, the efficacy of E7080 against xenografts derived fromCRC cell lines and CRC patient resection specimenswithmutated KRASwas investigated in vivo. Arelatively low cytotoxic effect of E7080 on CRC cell viabilitywas observed in vitro. Endothelial cells (HUVEC)weremore susceptible to the incubation with E7080. This is in line with the observation that E7080 demonstrated an anti-angiogenic effect in a three-dimensional ex vivo mouse aortic ring angiogenesis assay. E7080 effectively disrupted CRC cell-mediated VEGF-stimulated growth of HUVEC in vitro. Daily in vivo treatment with E7080 (5 mg/kg) significantly delayed the growth of KRAS mutated CRC xenografts with decreased density of tumor-associated vessel formations and without tumor regression. This observation is in line with results that E7080 did not significantly reduce the number of Ki67-positive cells in CRC xenografts. The results suggest antiangiogenic activity of E7080 at a dosage thatwas well tolerated by nudemice. E7080 may provide therapeutic benefits in the treatment of CRC with mutated KRAS.
Oculomotor dominance in multitasking: Mechanisms of conflict resolution in cross-modal action
(2014)
In daily life, eye movement control usually occurs in the context of concurrent action demands in other effector domains. However, little research has focused on understanding how such cross-modal action demands are coordinated, especially when conflicting information needs to be processed conjunctly in different action modalities. In two experiments, we address this issue by studying vocal responses in the context of spatially conflicting eye movements (Experiment 1) and in the context of spatially conflicting manual actions (Experiment 2, under controlled eye fixation conditions). Crucially, a comparison across experiments allows us to assess resource scheduling priorities among the three effector systems by comparing the same (vocal) response demands in the context of eye movements in contrast to manual responses. The results indicate that in situations involving response conflict, eye movements are prioritized over concurrent action demands in another effector system. This oculomotor dominance effect corroborates previous observations in the context of multiple action demands without spatial response conflict. Furthermore, and in line with recent theoretical accounts of parallel multiple action control, resource scheduling patterns appear to be flexibly adjustable based on the temporal proximity of the two actions that need to be performed.
Background: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD.
Methods: In 96 patients (53% female; age 40 ± 12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL.
Results: Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD −6.2, for RRT −11.8, for pain −9.1, p < 0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL.
Conclusion: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.