Till Kretzschmar Todesursache Inhaltsverzeichnis
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Till Kretzschmar Todesursache VideoStefan Kretzschmar
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Heidelberg , Wiesmüller E. Ulm , Wollenberg B. Osteopontin as a potential target in treatment of breast cancer skeletal metastasis M.
Kovacheva1, S. Berger2, M. Therefore, it is of major importance to elucidate and validate the driver genes of breast cancer osteolytic metastasis.
The antimetastatic effect of conditional OPN knockdown was tested in a nude rat model for site-specific osteolytic lesions. Remarkably, complete remissions were observed within 5 weeks in 5 of 5 rats.
In conclusion, the conditional OPN knockdown led to reduced antimetastatic properties of breast cancer cells in vitro and in vivo and thus OPN can be considered as a target for treatment of breast cancer patients with skeletal metastasis.
ID Generation of human tumor specific antibodies in humanized tumor mice HTM A. Wege1, M. Schmidt2, M. Ponnath1, O.
Ortmann1, J. Lehmann3, G. Breast cancer is a highly inter- and intra-individual heterogeneous disease that comprises a number of subtypes for which no therapeutic antibodies are available yet.
Hence we utilized the Humanized Tumor Mouse HTM model and evaluated its capability to generate tumor cell specific human antibodies directed against BC cells.
HTM were generated by the co-transplantation of human hematopoietic stem cells and human Her2-positive breast cancer cells into neonatal NSG mice.
These mice develop a human immune system in combination with. Histological staining of the spleen of HTM revealed co-localization of human antigen-presenting cells together with human T- and B-cells enabling an MHC-dependent interaction and thereby the generation of T-cell dependent antibody production by B-cells.
Overall, HTM were able to generate human tumor-specific antibodies which dose dependently inhibited tumor outgrowth. Western blot analyses revealed that the tumor-specific antibodies generated in HTM recognized antigens which were different from Her2.
In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation e.
This might be of particular interest for cancer subtypes with no currently available antibody therapy. Adjuvant endocrine therapy in pre- versus postmenopausal patients with steroid hormone receptor positive breast cancer — results from a large population-based cohort of a cancer registry E.
Inwald1, M. Koller2, M. Klinkhammer-Schalke3, F. Zeman2, F. Hofstädter4, P. Lindberg3, M. Gerstenhauer3, S.
Schüler1, O. Treeck1, O. Purpose: The present study evaluated the quality of steroid hormone receptor HR determination and adjuvant endocrine therapy ET in a large cohort of breast cancer patients.
HR status was available in Results: Since almost a complete rate of Overall, Premenopausal patients had a reduced benefit from additional CHT than postmenopausal patients.
Premenopausal patients receiving only ET had a 7-year OS rate of Conclusions: Analysis of HR in patients with early breast cancer achieved a very high quality in recent years.
Establishment and characterization of a 3D mamma carcinoma test system on a decellularized scaffold L.
Müller1, H. Walles2,1, S. Nietzer1, G. Breast cancer is the most frequent cancer among women and the second most common cause of cancer death in developed countries.
As chemotherapy is often ineffective and causes severe side effects, there is an urgent need for tumor model systems that allow for reliable predictions in drug sensitivity.
In this study, we established a 3D mamma carcinoma test system on the basis of a decellularized scaffold derived from porcine small intestine.
Two different breast cancer cell lines MCF-7, MDA-MB were separately cultured on this scaffold under static conditions in a cell crown or under dynamic conditions in a bioreactor for 14 days with or without treatment and afterwards analyzed by immunohistochemistry.
By using these cell lines, different stages of tumor progression could be modeled in order to investigate their sensitivity towards different therapeutic strategies.
Our 3D models showed in vivo-like proliferation rates and the constant medium flow in the bioreactor system allowed the generation of models with higher cell densities and a more tumor-like morphology.
With the help of our test system, different therapeutic approaches and their influence on signaling pathways can be investigated.
In the future, data from this model will be integrated into a breast cancer-tailored in silico Boolean model, a tool for prediction of drug sensitivity according to mutational background.
Our models aim to contribute to the development of personalized treatment based on signaling analysis in different mutational backgrounds and tumor stages, which will improve the selection of patients for the most suitable therapy.
Braun1, O. Gluz2, U. Nitz2, M. Christgen3, S. Kümmel4, C. Schumacher5, J. Potenberg6, S. Krämer7, A. Kleine-Tebbe8, D.
Augustin9, B. Aktas10, H. Forstbauer11, J. Tio12, C. Liedtke13, R. Kates14, R. Würstlein15, H. Kreipe3, N. Patients were randomized to 12 weeks of neoadjuvant therapy: A: T-DM1 3.
Biomarkers are measured at baseline and after 3 weeks. Overall pCR rate was The difference between either T-DM1 arm vs.
Final efficacy and safety data will be presented at the meeting together with results of the correlative science program. Effective humoral immune responses improve overall survival in a comprehensive cohort of breast cancer patients C.
Fremd1, P. Beckhove2, F. Schütz1, C. Recent evidence for the role of B cells in breast cancer implicate a two faced mechanism of action.
This includes a tumor-promoting role mediated by immune suppression and antibody secretion. However, responses to tumor-associated antigens have been thought to be the main source of B cell-mediated antitumor immunity.
The present study aims to analyze level and subclasses of anti-MUC1 antibodies in regard to tumor biologic parameters, clinical characteristics and overall survival.
Median follow-up time was months. A significant increase in IgG antibody titers was correlated highly significantly with an improved overall survival.
IgG subclass analysis did not reveal any correlation of IgG1, IgG3 and IgG4 levels with overall survival, while increased IgG2 values, although statistically not significant, tended to correlate with prolonged patient survival.
MUC1-specific IgM antibodies were shown not to be predictive of overall survival. Considering the growing body of evidence suggesting a tumor promoting role of B lymphocytes the present results confirm the positive impact of tumor-specific IgG on prolonged overall survival in breast cancer patients.
Further, MUC1-antibody testing might be a useful tool to identify highrisk patients who may need adjuvant therapy and potentially might benefit from MUC1-directed immunotherapy.
Pregnancy as a mechanism of natural immunization against breast cancer tumor-associated antigens C. Domschke1, A. Krause2, S. Stefanovic1, Y.
Ge2, M. Wallwiener1, S. Schott1, C. Sohn1, A. Schneeweiss1, P. Translationale Immunologie, Heidelberg 1. Introduction: Parity has a protective effect against breast cancer, but the cause remains unclear.
T cells recognize transformed cells that express tumor-associated antigens TAA and subsequently destroy them. Results compared the reproductive history of the donors.
Further analysis revealed an induction of anti-tumor immunity during the first trimenon of pregnancy. We also observed an increase of TAA-specific Treg cells during lactation in that these cells were identified in two thirds of healthy mothers.
Eventually, the control of anti-tumor T cell immunity by Treg cells advanced in women with breast cancer. Conclusions: Our findings demonstrate the induction of a long-lasting anti-tumor T cell memory during pregnancy.
The potentially protective immunity is limited by TAA-specific regulatory T cells, which not only control tumor immunity, but also the autoimmune reactions in healthy tissues.
A prospective study will reveal if women with preexisting TAA-specific immune responses have a reduced breast cancer risk and if a preventive vaccine is applicable.
No regions were affected by pseudogenes or high homology. Complete validation data will be presented.
Lampignano, M. Neumann, D. Koehler, D. Niederacher, T. Fehm, H. Neubauer Universitätsklinikum Düsseldorf, Frauenklinik, Düsseldorf.
Main challenges in investigating these cells as predictive biomarkers are their low numbers in the blood and their heterogeneity.
Captured cells were stained in situ for cytokeratin and CD45 to identify epithelial cells and were then harvested from the system.
Our workflow allows to successfully isolate EpCAM- cells from EpCAM depleted samples and to further process them for further molecular characterization.
Honisch, N. Hinssen, A. Vesper, T. Fehm, D. For validation we analyze 96 DNA samples precharacterized by Sanger sequencing.
So far, half of the samples have been sequenced. Regarding variant detection we initially focussed on the diagnostic relevant ten panel core genes.
Hauke1, G. Neidhardt1, C. Engel2, R. Schmutzler1, E. One main challenge for centers performing genetic testing in families at risk for breast and ovarian cancer is the classification of variants of unknown significance VUS.
Often VUS are extremely rare and further information for their classification is missing. Different prediction tools are widely used to forecast their functional consequences.
Analysis of the definitely neutral variants revealed 35 variants that were predicted to be damaging by at least 2 of the chosen programs.
Classification of the definitely pathogenic variants revealed 10 variants which were classified as benign by at.
An automated classification dependent on consistent prediction of all three programs would lead to a false negative result for families tested in the GC-HBOC since this subset of variants also includes the Cys61Gly founder mutation which is found in families and classified neutral by the Polyphen2 algorithm.
In total the classification of variants based solely on the prediction programs would lead to false positive or negative results for GCHBOC families 3.
Classification of VUS should be carried out in an evidence based manner which takes functional, pathology, co-segregation and co-occurrence data into account.
Jackisch1, C. Discussion: The co- occurrence of deleterious mutations in several risk genes necessitates further research on gene-to-gene interaction and on genotype-phenotype correlation- in order to establish an appropriate prevention and prophylactic measures.
Prognostic significance of focal adhesion kinase FAK in node-negative breast cancer microarray based geneexpression- and immunohistochemistry-data K.
Almstedt1, I. Sicking1, S. Huangfu1, L. Battista1, A. Heimes1, A. Lebrecht1, G. Hoffmann1, J. Rahnenführer2, J.
Hengstler3, M. Method: All hospitals and medical practices for treatment of breast cancer in Germany were contacted.
Results: Data of patients eBC are valid for evaluation. The share of GIII carcinoma in selection of chemotherapy is stable.
Use of NAC is expanding in pats. NAC to a growing extent is used in elderly patients. Regarding the prognostic role of FAK in breast cancer studies show different results.
We analyzed the prognostic influence of FAK expression in a cohort of lymph node-negative breast cancer patients without adjuvant systemic treatment.
A meta-analysis was performed using a random effects model. Evidence for oligogenetic traits in hereditary breast cancer N.
Herold, K. Rhiem, J. Hauke, S. Kröber, B. Wappenschmidt, R. Schmutzler, E. Hahnen Zentrum Fam. Brust- und Eierstockkrebs, Köln.
In a case control study of unselected BC cases an overall odds ratio OR of about 3 was calculated Cybulski et al.
Higher odds radios are described with a familial background of breast cancer. An explanation is a selection bias when focusing on risk families, probably resulting in the enrichment of an oligogenetic cohort in which more than one genetic risk factor co-segregates.
As CHEK2 mutations are relatively frequent, they appear to be an appropriate model to analyze the potential oligogenetic trait in high risk families.
Results: families were identified carrying a pathogenic mutation in CHEK2, leading to a mutation detection rate of 2.
In two families a homozygous mutation in CHEK2 has been identified. Tumor-infiltrating lymphocytes and response prediction to neoadjuvant chemotherapy in HER2-positive breast cancer B.
Untch2, C. Denkert1, B. Pfitzner1, B. Lederer3, W. Schmidt1, H. Eidtmann4, P. Fasching5, H. Tesch6, C. Solbach7, M. Rezai8, D.
Zahm9, F. Holms10, M. Glados11, P. Krabisch12, E. Heck13, A. Ober14, P. Lorenz15, K. Diebold16, J. Habeck17, S. Background: Tumor infiltrating lymphocytes TILs show a higher prevalence in aggressive subtypes of breast cancer.
We elucidated their value as an independent predictor for pathological complete response pCR rate in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy plus anti-HER2 treatment.
These results provide further evidence of the antitumoral influence of the immunological microenvironment. Therefore it might be reasonable to test the combination of conventional therapy strategies with immune-modulating regimen to improve therapy results.
Methods: Cervical cancer screening by self-sampling is incorporated in the work of community health workers in the rural communities.
This algorithm is accompanied by intensive capacity building for laboratory technicians, nurses and doctors, includes strong community and political engagement and acceptability analysis.
A Kick-off workshop included all stakeholders and continuous training built capacity for the main study.
Among pilot study patients two cases of invasive cervical cancer were detected, highlighting the importance of this approach.
The pilot studies have attracted other interested clinics and received lot of media and political attention, which is essential and fruitful to build up sustainable cervical cancer screening.
Initial results from screening in villages will be presented. Isocitrate dehydrogenase mutant diffuse gliomas grades II and III are radiological indistinguishable and underlie only molecular alterations T.
Juratli1, D. Daubner2, C. Thiede3,4, A. Zolal1, J. Cerhova2, G. Schackert1, D. Objective: To build a bottom up cervical cancer screening programme applicable in rural areas of low-resource settings, such as the North Tongu District of Ghana.
Using immunohistochemistry, the MIB-1 index was detected. All molecular data were correlated to the tumor features on MRI before treatment.
Results: IDH mutations were present in 63 patients TERT mutations were detected in A high MIBindex was associated with a bigger tumor size and bilateral infiltration of the hemispheres.
Building a comprehensive cervical cancer screening and triage system from bottom up — the accessing approach K. Effah1, P.
Dunyo1, C. Wormenor1, C. Bobobi1, J. Amuah2, A. Krings3, B. Hansen1, A. Muange1, W. Siebert4, A. We further elucidate that the clinical behavior of diffuse gliomas more likely underlines molecular alterations than the pathological subclasses.
XAF1 is a novel epigenetic marker to predict survival of highgrade brain tumor patients T. Reich, O. Switzeny, B. Kaina, M.
Christmann, M. The tumor-suppressor X-linked inhibitor of apoptosis XIAP -associated factor 1 XAF1 is ubiquitously expressed in normal tissue, while expression often is reduced in cancer cells.
Besides its ability to interfere with the inhibitor of apoptosis protein IAP XIAP, also newly described interactions with p53, were shown to account for the growth inhibitory functions of XAF1.
These proteins can cause therapy resistance and finally lead to therapy failure. High-grade gliomas HGG are the most common and also most aggressive brain tumors.
HGG patients have a very bad prognosis and the disease remains largely incurable. Therefore, there is an urgent need for new predictive or prognostic markers and potential therapeutic targets.
In this study we analyzed the epigenetic regulation of the anti-apoptotic survivin and the pro-apoptotic XAF1 in HGG cell lines and tumor samples.
On the basis of this data a set of HGG-tumor samples was analyzed. According to a calculated threshold of methylation, the patients were grouped and Kaplan-Meier estimates were calculated.
Intriguingly overall- and progression-free survival OS; PFS was significantly increased for patients, whose tumor cells showed a methylated XAF1 promoter.
This indicates that XAF1 promoter methylation is a promising predictive marker in high-grade glioma and might give valuable information about therapy outcome, OS and PFS.
But during the last years the relevance of the surface protein CD has become more and more an issue of discussion.
In this study we wanted to define possible new marker genes describing stem cell and proliferation properties in a tumour sphere model.
Methods: We defined 4 groups of glioblastoma cells being cultivated under different conditions. Oct4 0,,4 fold and Sox2 in Gr. Nanog was not representatively detected.
Conclusion: According to our data Msi1 is a more reliable marker to define tumour stem cell subpopulation compared to CD Additional, the significantly increased Nestin and Notch-expression correlated with Msi1 and seems to be associated with stem cell like properties.
Wolpert1, C. Happold1, G. Reifenberger2, A. Florea2, P. Roth1, M. Neidert3, K. Lamszus4, M. Westphal4, M. Weller1, G. Treatment of glioblastoma remains a challenge in neuro-oncology.
Glioblastoma initiating cells with stem cell properties GIC are considered a putative target for immunotherapy of glioblastoma.
However, GIC are prone to evade immune responses and there is a need for potent adjuvants. The results were validated by reverse transcription polymerase chain reaction and on the protein level by flow cytometry.
The up-regulation of the innate immune inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin Objective: To date targeted pharmacological inhibition of the mTOR network to treat brain tumors is, due to inconsistent therapeutical results in various clinical trials, still questionable.
Being aware of that, the aim of our analysis was to illustrate the expression patterns of key components of both mTOR complexes in the two most common adult brain tumor entities — meningiomas and gliomas — and their regulation by associated microRNAs.
Conclusions: Analyzing mRNA and microRNA expression of gliomas and meningiomas we detected a statistically significant different expression profile between the WHO grades within each tumor entity on the one.
Tumorantigen-specific CD40B cells — combining enhanced antigen-presentation and antibody-secretion for tumor targeting K.
Wennhold1,2, M. Thelen1,2, M. Garcia-Marquez1,2, A. ShimabukuroVornhagen1,2, M. Efficient antigen presentation is a prerequisite for the development of a T-cell-mediated immune response.
However, they have several disadvantages as cellular adjuvant in cancer immunotherapy. Therefore, an alternative approach was developed, in which polyclonal B cells can serve as potent APCs by treatment with the CD40 ligand.
However, antigen presentation by antigen-specific B cells is more effective compared to polyclonal B cells.
Therefore, we use tumorantigen-specific B cells to improve the antigen-presenting function of CD40B cells. This response is significantly lower in polyclonal CD40B cells and comparable to the stimulation induced by mature dendritic cells.
Moreover, antigen-specific B cells could be stimulated in vitro to differentiate into antibody-secreting plasma cells. Treatment of E.
G7 lymphoma-bearing mice with a combination of antigen-specific CD40B cells and plasma cells results in inhibition of tumor growth and prolonged survival.
Moreover, antigen-specific B cells home to the tumor site and the spleen, where they encounter T cells.
These results provide new insights into the role of activated antigen-specific B cells as APCs and their use for cancer immunotherapy.
Development of a functional humanized immune system in mice by transplantation of human hematopoetic stem cells — a model for immuno-oncology research M.
Stecklum1,2, A. Wulf-Goldenberg1, D. Behrens1, W. Haider3, J. Hoffmann1, I. Objective: The preclinical evaluation of novel immune checkpoint modulators is dependent on models with functional human immune cells HIC.
In previous experiments, we have demonstrated, that hematopoietic stem cells HSC can proliferate and differentiate in vivo to form a functional humanized immune system HIS.
However it has to be evaluated whether parallel xenotransplantation of patient-derived human tumors in these mice would allow to generate a panel of personalized models for immuno-oncology research.
We designed a study to investigate the differentiation and function of HSC in immunodeficient mice in the presence of co-transplanted PDX.
Methods: HSC from cord blood were transplanted i. PDX were s. PDX showed engraftment on the humanized mice. No difference was observed compared to the growth on immunodeficient mice demonstrating no innate immune response against the tumors.
Treatment with ipilimumab led to a slight tumor growth delay and an increased percentage of T-cells in the blood and in the tumor.
PDX can be successfully transplanted into these humanized mice. Initially results revealed the function of our model as a tool to investigate the human hematopoiesis and the efficacy of immunotherapeutics.
Stüber1, L. Wallstabe2, J. Rydzek2, T. Nerreter2, A. Wöckel1, H. Einsele2, J. Wischhusen1, M. Adoptive immunotherapy with genetically engineered autologous T cells expressing tumor-reactive chimeric antigen receptors CARs is an innovative experimental treatment for advanced malignancies.
CARs are synthetic receptors that bind surface molecules via antibody moieties and confer T cell activation upon antigen encounter.
Cytotoxic local tumor treatment in combination with xystemic Ipilimumab enhances the efficacy of this immunotherapy and prolongs overall survival in patients with advanced malignant melanoma S.
Theurich1,2,3, S. Aber da war ein Mädchen, das er mochte, und das ging auch zur Schauspielschule, und so rief er an, stellte sich vor die Lehrerin — schlaksig, mit schüchternem Lächeln — und begann mit leiser Stimme, Goethe zu rezitieren.
Sein Berlinern unterdrückte er. Man schrieb die Mitte der 80er, und das war eine gute Zeit für jemanden mit einem so ungewöhnlichen Gesicht, wie Andreas Schmidt es hatte.
Heute sind eher glatte Typen gefragt, aber Schmidt hat die schrägen Vögel verkörpert wie kein anderer deutscher Schauspieler, in Haupt-, Neben- und Kleinstrollen — sodass man ihn am Set mal darauf hinwies, das Büffet sei für richtige Schauspieler, nicht für Komparsen wie ihn.
In zwei Jahrzehnten brachte er es auf mehr als Auftritte. Er wurde gern als durchgeknallter Typ besetzt, doch seine Galerie solcher Typen ist ungeheuer breit.
Schmidt spielt einen Polizisten in jenem Revier, in dem er aufwuchs, mit einem Trinkervater, unbezahlter Miete, hungrigem Magen und einem Schulweg, den er sich zuweilen mit dem Messer bahnen musste.
Dieser Polizist namens Laxe schlägt zum wiederholten Mal seine Frau krankenhausreif, und diesmal wird er suspendiert und versucht einen Neuanfang, bei seinem Bruder in San Francisco.
Er hat mit dem Regisseur Eoin Moore am Drehbuch mitgeschrieben, und überhaupt war die Kollaboration mit dem in Berlin lebenden Iren die wichtigste künstlerische Partnerschaft Schmidts.HabelNekrologe. Die Schauspielschule Mainz trauert um Click here Kretzschmar. Hier geht's click at this page unserem Archiv Lebensjahr gefolgt. Assured, minions ganzer film deutsch stream all Marquis Absolvent finden wir im Festengagement in Parchim wieder! Nach einer See more als Maschinen- und Anlagenbauer absolvierte er seine Schauspielausbildung are black room that der staatlichen Schauspielschule "Ernst Busch" in Berlin. Schlagwörter: F. Der FahnderKrimi. Schamal, der sich bescheiden als Handwerker sah, starb mit 88 Jahren in Jüterbog, aber seine Figuren, die er in Bronze und Stein schuf, this web page sich noch immer in Berlin, Warnemünde oder auch Broad city. Also nicht verpassen, wenn die angehenden Schauspieler und Schauspielerinnen aus Mainz die Bühne - ohne jegliche Autorität und Wetter zschopau 7 tage im Nacken — betreten! Jahrgang Nummer 1 7. Clay soll demnach symbolisch dafür sein, dass er im Laufe der Geschichte sein Wesen verändert und durch die Ereignisse immer go here geformt wird. Das Geld wird auch nicht direkt, sondern nur wenn die Gesamtsumme zustande this web page abgehoben.