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  • 1
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(5), p.e0127123
    Description: Current pathological diagnostics include the analysis of (epi-)genetic alterations as well as oncogenic pathways. Deregulated mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in a variety of cancers including malignant gliomas and is considered a promising target in cancer treatment. Monitoring of mTORC1 activity before and during inhibitor therapy is essential. The aim of our study is to provide a recommendation and report on pitfalls in the use of phospho-specific antibodies against mTORC1-targets phospho-RPS6 (Ser235/236; Ser240/244) and phospho-4EBP1 (Thr37/46) in formalin fixed, paraffin embedded material.Primary, established cell lines and brain tumor tissue from routine diagnostics were assessed by immunocyto-, immunohistochemistry, immunofluorescent stainings and immunoblotting. For validation of results, immunoblotting experiments were performed. mTORC-pathway activation was pharmacologically inhibited by torin2 and rapamycin. Torin2 treatment led to a strong reduction of signal intensity and frequency of all tested antibodies. In contrast phospho-4EBP1 did not show considerable reduction in staining intensity after rapamycin treatment, while immunocytochemistry with both phospho-RPS6-specific antibodies showed a reduced signal compared to controls. Staining intensity of both phospho-RPS6-specific antibodies did not show considerable decrease in stability in a timeline from 0-230 minutes without tissue fixation, however we observed a strong decrease of staining intensity in phospho-4EBP1 after 30 minutes. Detection of phospho-signals was strongly dependent on tissue size and fixation gradient. mTORC1-signaling was significantly induced in glioblastomas although not restricted to cancer cells but also detectable in non-neoplastic cells.Here we provide a recommendation for phospho-specific immunohistochemistry for patient-orientated therapy decisions and monitoring treatment response.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2018, Vol.13(8), p.e0202760
    Description: INTRODUCTION:The clinical management of breech presentations at term is still a controversially discussed issue among clinicians. Clear predictive criteria for planned vaginal breech deliveries are desperately needed to prevent adverse fetal and maternal outcomes and to reduce elective cesarean section rates. The green-top guideline considers an estimated birth weight of 3.8 kg or more an indication to plan a cesarean section despite the lack of respective evidence. OBJECTIVE:To compare maternal and neonatal outcome of vaginal intended breech deliveries of births with children with a birth weight of 2.5 kg- 3.79 kg and children with a birth weight of 3.8 kg and more. DESIGN:Prospective cohort study. SAMPLE:All vaginal intended deliveries out of a breech position of newborns weighing between 2.5 kg and 4.5 kg at the Obstetrics department at Goethe University Hospital Frankfurt from January 2004 until December 2016. METHODS:Neonatal and maternal outcome of a light weight group (LWG) (〈 3.8 kg) was compared to and a high weight group (HWG) (≥ 3.8 kg) using Pearson's Chi Square test and Fishers exact test. A logistic regression analysis was performed to detect an association between cesarean section rates, fetal outcome and the birth weight. RESULTS:No difference in neonatal morbidity was detected between the HWG (1.8%, n = 166) and the LWG (2.6%, n = 888). Cesarean section rate was significantly higher in the HWG with 45.2% in comparison to 28.8% in the LWG with an odds ratio of 1.57 (95% CI 1.29-1.91, p〈0.0001). In vaginal deliveries, a high birth weight was not associated with an increased risk of maternal birth injuries (LWG in vaginal deliveries: 74.3%, HWG in vaginal deliveries: 73.6%; p = 0.887; OR = 1.9 (95% CI 0.9-1.1)). CONCLUSION:A fetal weight above 3.79 kg does not predict increased maternal or infant morbidity after delivery from breech presentation at term. Neither the literature nor our analyses document evidence for threshold of estimated birth weight that is associated with maternal and/or infant morbidity. However, patients should be informed about an increased likelihood of cesarean sections during labor when attempting vaginal birth from breech position at term in order to reach an informed shared decision concerning the birth strategy. Further investigations in multi center settings are needed to advance international guidelines on vaginal breech deliveries in the context of estimated birth weight and its impact on perinatal outcome.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    In: Journal Of The National Cancer Institute, 2016, Vol. 108(5)
    Description: Background: Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and currently incurable. To specifically target natural killer (NK) cell activity to GBM, we employed NK-92/5.28.Z cells that are continuously expanding human NK cells expressing an ErbB2-specific chimeric antigen receptor (CAR). Methods: ErbB2 expression in 56 primary tumors, four primary cell cultures, and seven established cell lines was assessed by immunohistochemistry and flow cytometry. Cell killing activity of NK-92/5.28.Z cells was analyzed in in vitro cytotoxicity assays. In vivo antitumor activity was evaluated in NOD-SCID IL2Ry[[gamma].sup.null] (NSG) mice carrying orthotopic human GBM xenografts (6 to 11 mice per group) and C57BL/6 mice carrying subcutaneous and orthotopic ErbB2-expressing murine GBM tumors (5 to 8 mice per group). Statistical tests were two-sided. Results: We found elevated ErbB2 protein expression in 41% of primary GBM samples and in the majority of GBM cell lines investigated. In in vitro assays, NK-92/5.28.Z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.Z was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area (median survival of 200.5 days upon treatment with NK- 92/5.28.Z vs 73 days upon treatment with parental NK-92 cells, P 〈 .001). In immunocompetent mice, local therapy with NK-92/5.28.Z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors, induction of endogenous antitumor immunity, and long-term protection against tumor rechallenge at distant sites. Conclusions: Our data demonstrate the potential of ErbB2-specific NK-92/5.28.Z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2-positive GBM in clinical studies. doi: 10.1093/jnci/djv375
    Keywords: Glioblastomas -- Care And Treatment ; Killer Cells -- Usage ; Killer Cells -- Health Aspects ; Molecular Targeted Therapy -- Methods;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 4
    Language: English
    In: Medical Teacher, 03 May 2016, Vol.38(5), pp.515-522
    Description: Background: Germany's first student-run free clinic (SRFC) for medically underserved patients has been established at the medical faculty of the Goethe-University, Frankfurt/Germany. Participating students are educated in a Peer Assisted Learning program (PAL). Little is known about the effectiveness...
    Keywords: Medicine ; Education
    ISSN: 0142-159X
    E-ISSN: 1466-187X
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  • 5
    Language: English
    In: Oncology letters, June 2018, Vol.15(6), pp.9852-9860
    Description: Testicular germ cell cancer in a metastatic state is curable with a cisplatin-based first line chemotherapy. However, 10-15% of these patients are resistant to first line chemotherapy and are thus left with only palliative options. Immunotherapies and inhibition of angiogenesis used in multiple types of cancer; however, the molecular context of angiogenesis and immune checkpoints in the development and progression of testicular cancers is still unknown. Therefore, the present study performed tissue micro array based analysis of 84 patients with immunohistochemistry of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) of testicular cancer and corresponding normal appearing testis tissue, matching the results with clinical data. The results demonstrated that PD-L1 was significantly upregulated in testicular tumors and that PD-1 positive cells significantly infiltrated the testicular tumor when compared with normal testicular tissue. VEGFR2 was significantly upregulated in testicular cancer. It was indicated that PD-1 expressing cytotoxic cells may require pathologic tumor vessels to pass the blood-testis-barrier in order to migrate into the tumor. Notably, when matching the clinical data for PD-1, PD-L1 and VEGFR2 there were no differences in expression in the different International Germ Cell Cancer Collaborative Group stages of non-seminoma. These data suggested that the anti-PD-1/PD-L1 immunotherapy and the anti-angiogenic therapy, sequentially or in combination, may be a promising option in the treatment of testicular cancer.
    Keywords: Immune ; Programmed Cell Death Ligand 1 ; Programmed Cell Death Protein 1 ; Testicular Cancer ; Vascular Endothelial Growth Factor Receptor 2
    ISSN: 1792-1074
    E-ISSN: 17921082
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  • 6
    Language: English
    In: Oncology Reports, March, 2016, Vol.35(3), p.1629(7)
    Keywords: Testicular Cancer -- Genetic Aspects ; Testicular Cancer -- Development And Progression ; Cellular Proteins -- Health Aspects ; Autophagy (Cytology) -- Genetic Aspects ; Autophagy (Cytology) -- Health Aspects
    ISSN: 1021-335X
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: Journal for ImmunoTherapy of Cancer, 2014, Vol.2(Suppl 3), p.P41
    Description: Significant progress has been made over the last decade towards realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells, and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also continuously expanding cytotoxic cell lines such as NK-92 are being considered for adoptive cancer immunotherapy. High cytotoxicity of NK-92 has previously been shown against malignant cells of hematologic origin in preclinical studies, and general safety of infusion of NK-92 cells has been established in Phase I clinical trials. To enhance their therapeutic utility, here we genetically modified NK-92 cells to express a chimeric antigen receptor (CAR), consisting of an ErbB2-specific scFv antibody fragment fused via a linker to a composite CD28-CD3 zeta signaling domain. GMP-compliant protocols for vector production, lentiviral transduction and expansion of a genetically modified NK-92 single cell clone (NK-92/5.28.z) were established. Functional analysis of NK-92/5.28.z cells revealed high and stable CAR expression, selective cytotoxicity against ErbB2-expressing but otherwise NK-resistant tumor cells of different origins in vitro, as well as homing to ErbB2-expressing tumors in vivo. Ongoing work now focuses on the development of these cells for adoptive immunotherapy of ErbB2-positive glioblastoma. We evaluated the activity of NK-92/5.28.z cells against a panel of glioblastoma cell lines and primary glioblastoma cultures and demonstrated selective in vitro cell killing that was dependent on the level of ErbB2 expression by the target cells and the time of their exposure to the NK cells. Antigen specificity and selective cytotoxicity of NK-92/5.28.z cells were retained in vivo, resulting in antitumoral activity against subcutaneous and orthotopic glioblastoma xenografts in NSG mice. Our results suggest adoptive transfer of ErbB2-specific NK-92/5.28.z cells as a promising new immunotherapy approach for ErbB2-positive glioblastoma.
    Keywords: Medicine;
    ISSN: 2051-1426
    Source: CrossRef
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  • 8
    Language: English
    In: Oncology Reports, 03/2016, Vol.35(3), pp.1629-1635
    Description: Testicular germ cell tumors (TGCT) represent the most common malignant tumor group in the age group of 20 to 40-years old men. The potentially curable effect of cytotoxic therapy in TGCT is mediated mainly by the induction of apoptosis. Autophagy has been discussed as an alternative mechanism of cell death but also of treatment resistance in various types of tumors. However, in TGCT the expression and role of core autophagy-associated factors is hitherto unknown. We designed the study in order to evaluate the potential role of autophagy-associated factors in the development and progression of testicular cancers. Eighty-four patients were assessed for autophagy (BAG3, p62) and apoptosis (cleaved caspase 3) markers using immunohistochemistry (IHC) on tissue microarrays. In addition, western blot analyses of frozen tissue of seminoma and non-seminoma were performed. Our findings show that BAG3 was significantly upregulated in seminoma as compared to non-seminoma but not to normal testicular tissue. No significant difference of p62 expression was detected between neoplastic and normal tissue or between seminoma and non-seminoma. BAG3 and p62 showed distinct loco-regional expression patterns in normal and neoplastic human testicular tissues. In contrast to the autophagic markers, apoptosis rate was significantly higher in testicular tumors as compared to normal testicular tissue, but not between different TGCT subtypes. The present study, for the first time, examined the expression of central autophagy proteins BAG3 and p62 in testicular cancer. Our findings imply that in general apoptosis but not autophagy induction differs between normal and neoplastic testis tissue.
    Keywords: Autophagy ; P62 ; Bag3 ; Apoptosis ; Loco-Regional Pattern ; Testicular Cancer
    ISSN: 1021-335X
    E-ISSN: 1791-2431
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  • 9
    Language: English
    In: Oncotarget, 12 December 2017, Vol.8(65), pp.108643-108654
    Description: The oncogene B-cell lymphoma 6 (BCL6) is associated with lymphomagenesis. Intriguingly, its expression is increased in preeclamptic placentas. Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity. Preeclamptic placentas are characterized by various defects like deregulated differentiation and impaired fusion of trophoblasts. Its pathogenesis is however not totally understood. We show here that BCL6 is present throughout the cell fusion process in the fusogenic trophoblastic cell line BeWo. Suppression of BCL6 promotes trophoblast fusion, indicated by enhanced levels of fusion-related β-hCG, syncytin 1 and syncytin 2. Increased mRNA levels of these genes could also be observed in primary term cytotrophoblasts depleted of BCL6. Conversely, stable overexpression of BCL6 reduces the fusion capacity of BeWo cells. These data suggest that an accurately regulated expression of BCL6 is important for proper differentiation and successful syncytialization of trophoblasts. While deregulated BCL6 is linked to lymphomagenesis by blocking lymphocyte terminal differentiation, increased BCL6 in the placenta contributes to the development of preeclampsia by impairing trophoblast differentiation and fusion.
    Keywords: Bcl6 ; Cell Fusion ; Differentiation ; Preeclampsia ; Trophoblast
    E-ISSN: 1949-2553
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  • 10
    In: Neuro-Oncology, 2014, Vol. 16(11), pp.1469-1477
    Description: BACKGROUND: Experimental findings have suggested that human cytomegalovirus (HCMV) infection of tumor cells may exert oncomodulatory effects that enhance tumor malignancy. However, controversial findings have been published on the presence of HCMV in malignant tumors. Here, we present the first study that systematically investigates HCMV infection in human nervous system tumors by highly sensitive immunohistochemistry in correlation with the HCMV serostatus of the patients.METHODS: Immunohistochemical and quantitative PCR-based methods to detect different HCMV antigens and genomic HCMV DNA were optimized prior to the investigation of pathological samples. Moreover, the pathological results were matched with the HCMV serostatus of the patients.RESULTS: HCMV immediate-early, late, and pp65 antigens could be detected in single cells from HCMV strain Hi91-infected UKF-NB-4 neuroblastoma cells after 1:1024 dilution with noninfected UKF-NB-4 cells. Genomic HCMV DNA could be detected in copy numbers as low as 430 copies/mL. However, we did not detect HCMV in tumors from a cohort of 123 glioblastoma, medulloblastoma, or neuroblastoma patients. Notably, we detected nonspecifically positive staining in tumor tissues of HCMV seropositive and seronegative glioblastoma patients. The HCMV serostatus of 67 glioblastoma patients matched the general epidemiological prevalence data for Western countries (72% of female and 57% of male glioblastoma patients were HCMV seropositive). Median survival was not significantly different in HCMV seropositive versus seronegative glioblastoma patients.CONCLUSIONS: The prevalence of HCMV-infected tumor cells may be much lower than previously reported based on highly sensitive detection methods.
    Keywords: Cytomegalovirus ; Glioma ; Oncomodulation
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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