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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; BLOOD ; CELL ; KINASE ; PATHWAY ; PATHWAYS ; liver ; DISTINCT ; PROTEIN ; transcription ; MICE ; ACTIVATION ; DNA ; TRANSPLANTATION ; BINDING ; PROTEIN-KINASE ; SIGNAL ; DELETION ; FUSION ; DNA-BINDING ; SIGNALING PATHWAY ; STEM-CELLS ; CONSTITUTIVE ACTIVATION ; RECEPTORS ; HEMATOPOIETIC-CELLS ; ERYTHROPOIETIN ; STAT5A(-/-)5B(-/-) MICE ; C-KIT ; signaling ; HEMATOPOIESIS ; stem cells ; progenitor ; USA ; SELF-RENEWAL ; STEM ; MYELOPROLIFERATIVE DISORDERS ; TYROSINE KINASE JAK2 ; ERYTHROID PROGENITORS ; FETAL ; myeloid cells ; STEM-CELL-FACTOR ; STRESS ERYTHROPOIESIS
    Abstract: Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2(-/-) and EpoR(-/-) cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a-estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2(-/-) fetal livers, transplantation of Jak2(-/-)-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine-and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropolesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling
    Type of Publication: Journal article published
    PubMed ID: 18239084
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  • 2
    Keywords: MODEL ; PROSTATE ; IMAGES ; TRIALS ; REGISTRATION ; HEAD ; GUIDANCE ; navigation ; REAL ; TRANSRECTAL ULTRASOUND GUIDANCE
    Abstract: PURPOSE: We present an augmented reality (AR) navigation system that conveys virtual organ models generated from transrectal ultrasonography (TRUS) onto a real laparoscopic video during radical prostatectomy. By providing this additional information about the actual anatomy, we can support surgeons in their working decisions. This work reports the system's first in-vivo application. MATERIALS AND METHODS: The system uses custom-developed needles with colored heads that are inserted into the prostate as soon as the organ surface is uncovered. These navigation aids are once segmented in three-dimensional (3D) TRUS data that is acquired right after the placement of the needles and then continuously tracked in the laparoscopic video images by the surgical navigation system. The navigation system traces the navigation aids in real time and computes a registration between TRUS image and laparoscopic video based on the two-dimensional-three dimensional (2D-3D) point correspondences. With this registration, the system correctly superimposes TRUS-based 3D information on an additional AR monitor placed next to the normal laparoscopic screen. Surgical navigation guidance took place until the prostate was removed from the rectal wall. Finally, the navigation aids were removed together with the specimen inside the specimen bag. RESULTS: The initial human in-vivo application of the surgical navigation system was successful. No complications occurred, the prostate was removed together with the navigation aids, and the system supported the surgeons as intended with an AR visualization in real time. In case of tissue deformations, changes in the spatial configuration of the navigation aids are detected, which preserves the system from erroneous navigation visualization. CONCLUSIONS: Feasibility of the navigation system was shown in the first in-vivo application. TRUS information could be superimposed via AR in real time. To show the benefit for the patient, results obtained from a larger number of trials are needed.
    Type of Publication: Journal article published
    PubMed ID: 21970336
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  • 3
  • 4
    Abstract: BACKGROUND: The present work aimed to analyze the feasibility of a shuttle-based MRI-guided radiation therapy (MRgRT) in the treatment of pelvic malignancies. PATIENTS AND METHODS: 20 patients with pelvic malignancies were included in this prospective feasibility analysis. Patients underwent daily MRI in treatment position prior to radiotherapy at the German Cancer Research Center. Positional inaccuracies, time and patient compliance were assessed for the application of off-line MRgRT. RESULTS: In 78% of applied radiation fractions, MR imaging for position verification could be performed without problems. Additionally, treatment-related side effects and reduced patient compliance were only responsible for omission of MRI in 9% of radiation fractions. The study workflow took a median time of 61min (range 47-99min); duration for radiotherapy alone was 13min (range 7-26min). Patient positioning, MR imaging and CT imaging including patient repositioning and the shuttle transfer required median times of 10min (range 7-14min), 26min (range 15-60min), 5min (range 3-8min) and 8min (range 2-36min), respectively. To assess feasibility of shuttle-based MRgRT, the reference point coordinates for the x, y and z axis were determined for the MR images and CT obtained prior to the first treatment fraction and correlated with the coordinates of the planning CT. In our dataset, the median positional difference between MR imaging and CT-based imaging based on fiducial matching between MR and CT imaging was equal to or less than 2mm in all spatial directions. The limited space in the MR scanner influenced patient selection, as the bore of the scanner had to accommodate the immobilization device and the constructed stereotactic frame. Therefore, obese, extremely muscular or very tall patients could not be included in this trial in addition to patients for whom exposure to MRI was generally judged inappropriate. CONCLUSION: This trial demonstrated for the first time the feasibility and patient compliance of a shuttle-based off-line approach to MRgRT of pelvic malignancies.
    Type of Publication: Journal article published
    PubMed ID: 29349601
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  • 5
    Abstract: Medical images are essential in modern traumatology and orthopedic surgery. Access to images is often cumbersome due to a limited number of workstations. Moreover, due to the tremendous increase of data, the time to review or to communicate images has also become limited. One approach to overcome these problems is to make use of modern mobile devices, like tablet computers, to facilitate image access and associated workflows. Ten orthopedic surgeons were equipped with an Apple iPad mini 2 and specialized viewing software for medical images. The surgeons were able to send images from a workstation onto the tablets or to search for patient images directly. The software enabled the physicians to share images, annotated key slices, and messages instantly with their colleagues. The surgeons carried the tablets within or in the periphery of the hospital. The participants evaluated the software by means of daily questionnaires. Data was collected for a period of 9 months. Nearly 25 images were viewed in total by the surgeons per day. The tablet viewer was used for accessing approximately 30% of these images. On average, the surgeons were asked 1.7 times per day by a colleague for a second opinion. They used the tablets in approximately 29% of these cases. Furthermore, the mean time for accessing images was significantly lower using mobile software compared to conventional methods. Tablet computers can play a vital role for image access and communication in the daily routine of an orthopedic surgeon. Mobile image access is an important aspect for surgeons, especially in larger facilities, to facilitate and accelerate the clinical workflows.
    Type of Publication: Journal article published
    PubMed ID: 28799133
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  • 6
    Abstract: The amino terminus of the human papillomavirus (HPV) minor capsid protein L2 contains a major cross-neutralization epitope which provides the basis for the development of a broadly protecting HPV vaccine. A wide range of protection against different HPV types would eliminate one of the major drawbacks of the commercial, L1-based prophylactic vaccines. Previously, we have reported that insertion of the L2 epitope into a scaffold composed of bacterial thioredoxin protein generates a potent antigen inducing comprehensive protection against different animal and human papillomaviruses. We also reported, however, that although protection is broad, some oncogenic HPV types escape the neutralizing antibody response, if L2 epitopes from single HPV types are used as immunogen. We were able to compensate for this by applying a mix of thioredoxin proteins carrying L2 epitopes from HPV16, -31, and -51. As the development of a cost-efficient HPV prophylactic vaccines is one of our objectives, this approach is not feasible as it requires the development of multiple good manufacturing production processes in combination with a complex vaccine formulation. Here, we report the development of a thermostable thioredoxin-based single-peptide vaccine carrying an L2 polytope of up to 11 different HPV types. The L2 polytope antigens have excellent abilities in respect to broadness of protection and robustness of induced immune responses. To further increase immunogenicity, we fused the thioredoxin L2 polytope antigen with a heptamerization domain. In the final vaccine design, we achieve protective responses against all 14 oncogenic HPV types that we have analyzed plus the low-risk HPVs 6 and 11 and a number of cutaneous HPVs.IMPORTANCE Infections by a large number of human papillomaviruses lead to malignant and nonmalignant disease. Current commercial vaccines based on virus-like particles (VLPs) effectively protect against some HPV types but fail to do so for most others. Further, only about a third of all countries have access to the VLP vaccines. The minor capsid protein L2 has been shown to contain so-called neutralization epitopes within its N terminus. We designed polytopes comprising the L2 epitope amino acids 20 to 38 of up to 11 different mucosal HPV types and inserted them into the scaffold of thioredoxin derived from a thermophile archaebacterium. The antigen induced neutralizing antibody responses in mice and guinea pigs against 26 mucosal and cutaneous HPV types. Further, addition of a heptamerization domain significantly increased the immunogenicity. The final vaccine design comprising a heptamerized L2 8-mer thioredoxin single-peptide antigen with excellent thermal stability might overcome some of the limitations of the current VLP vaccines.
    Type of Publication: Journal article published
    PubMed ID: 29212932
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  • 7
    Abstract: Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival. Death receptors are important mediators of ischemia-reperfusion injury, notably the signaling pathways of the death receptor CD95 (Apo-1/Fas) and its corresponding ligand CD95L. This study investigates, for the first time, whether the inhibition of CD95L protects the liver against ischemia-reperfusion injury. Warm ischemia was induced in the median and left liver lobes of C57BL/6 mice for 45 min. CD95Fc, a specific inhibitor of CD95L, was applied prior to ischemia. Hepatic injury was assessed via consecutive measurements of liver serum enzymes, histopathological assessment of apoptosis and necrosis and caspase assays at 3, 6, 12, 18 and 24 h after reperfusion. Serum levels of liver enzymes, as well as characteristic histopathological changes and caspase assays indicated pronounced features of apoptotic and necrotic liver damage 12 and 24 h after ischemia-reperfusion injury. Animals treated with the CD95L-blocker CD95Fc, exhibited a significant reduction in the level of serum liver enzymes and showed both decreased histopathological signs of parenchymal damage and decreased caspase activation. This study demonstrates that inhibition of CD95L with the CD95L-blocker CD95Fc, is effective in protecting mice from liver failure due to ischemia-reperfusion injury of the liver. CD95Fc could therefore emerge as a new pharmacological therapy for liver resection, transplantation surgery and acute liver failure.
    Type of Publication: Journal article published
    PubMed ID: 29374146
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  • 8
    Abstract: BACKGROUND: Augmented reality (AR) systems are currently being explored by a broad spectrum of industries, mainly for improving point-of-care access to data and images. Especially in surgery and especially for timely decisions in emergency cases, a fast and comprehensive access to images at the patient bedside is mandatory. Currently, imaging data are accessed at a distance from the patient both in time and space, i.e., at a specific workstation. Mobile technology and 3-dimensional (3D) visualization of radiological imaging data promise to overcome these restrictions by making bedside AR feasible. METHODS: In this project, AR was realized in a surgical setting by fusing a 3D-representation of structures of interest with live camera images on a tablet computer using marker-based registration. The intent of this study was to focus on a thorough evaluation of AR. Feasibility, robustness, and accuracy were thus evaluated consecutively in a phantom model and a porcine model. Additionally feasibility was evaluated in one male volunteer. RESULTS: In the phantom model (n = 10), AR visualization was feasible in 84% of the visualization space with high accuracy (mean reprojection error +/- standard deviation (SD): 2.8 +/- 2.7 mm; 95th percentile = 6.7 mm). In a porcine model (n = 5), AR visualization was feasible in 79% with high accuracy (mean reprojection error +/- SD: 3.5 +/- 3.0 mm; 95th percentile = 9.5 mm). Furthermore, AR was successfully used and proved feasible within a male volunteer. CONCLUSIONS: Mobile, real-time, and point-of-care AR for clinical purposes proved feasible, robust, and accurate in the phantom, animal, and single-trial human model shown in this study. Consequently, AR following similar implementation proved robust and accurate enough to be evaluated in clinical trials assessing accuracy, robustness in clinical reality, as well as integration into the clinical workflow. If these further studies prove successful, AR might revolutionize data access at patient bedside.
    Type of Publication: Journal article published
    PubMed ID: 29602988
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  • 9
    Abstract: Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression. We designed DEMs to target two human genes, CCR5 and CXCR4, with the aim of epigenetically silencing their expression in primary human T lymphocytes. We observed robust and sustained target gene silencing associated with reduced chromatin accessibility, increased promoter methylation at the target sites and undetectable changes in global gene expression. Our results demonstrate that DEMs can be successfully used to silence target gene expression in primary human cells with remarkably high specificity, paving the way for the establishment of a potential new class of therapeutics.
    Type of Publication: Journal article published
    PubMed ID: 29538770
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  • 10
    Keywords: USA ; CD95 ; FAMILIES ; p53 ; SITE ; GENE ; NETWORK ; ACTIVATION ; FAMILY
    Type of Publication: Meeting abstract published
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