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Berlin Brandenburg

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  • Wiley (CrossRef)  (16)
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  • 1
    In: International Journal of Cancer, 01 February 2014, Vol.134(3), pp.703-716
    Description: Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. What's new? Medulloblastoma, the most frequent pediatric brain cancer, causes death in about 60 percent of high‐risk patients, and so there is a major need for novel, highly effective therapies. One therapy of interest is parvovirus H‐1 (H‐1PV), which was found in this study to produce marked cytotoxic effects in six medulloblastoma cell lines. Gene expression profiling revealed that H‐1PV infection causes down‐regulation of key regulatory genes involved in early neurogenesis, with significant repression of . The master regulators affected may represent putative direct or indirect H‐1PV target genes.
    Keywords: Medulloblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Cellular Targets ; Myc ; Master Regulators Of Neurogenesis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 2
    Language: English
    In: International Journal of Cancer, 01 May 2013, Vol.132(9), pp.2200-2208
    Description: Inhibition of histone deacetylase (HDAC) activity as stand‐alone or combination therapy represents a promising therapeutic approach in oncology. The pan‐ or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose‐limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc‐dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT‐116 colon, PC‐3 prostate, MCF‐7 breast and SK‐OV‐3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor‐selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology. What's new? Histone deacetylase (HDAC) enzymes influence the regulation of numerous cellular processes, and their inhibition by small molecules has been shown to provide benefits against multiple cancer types. Here, HDAC11, a recently identified member of the HDAC family, was found to play an important role in the control of proliferation and survival pathways in several carcinoma cell lines. The high incidence of the tumors represented suggests that HDAC11 could be a valuable drug target in oncology.
    Keywords: Chromatin Modulation ; Targeted Therapy ; Histone Deacetylase ; Colon Cancer ; Prostate Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: International Journal of Cancer, 01 September 2010, Vol.127(5), pp.1230-1239
    Description: Despite multimodal therapeutic concepts, advanced localized and high‐risk neuroblastoma remains a therapeutic challenge with a long‐term survival rate below 50%. Consequently, new modalities for the treatment of neuroblastoma, ., oncolytic virotherapy are urgently required. H‐1PV is a rodent parvovirus devoid of relevant pathogenic effects in infected adult animals. In contrast, the virus has oncolytic properties and is particularly cytotoxic for transformed or tumor‐derived cells of various species including cells of human origin. Here, a preclinical assessment of the application of oncolytic H‐1PV for the treatment of neuroblastoma cells was performed. Infection efficiency, viral replication and lytic activity of H‐1PV were analyzed in 11 neuroblastoma cell lines with different MYCN status. Oncoselectivity of the virus was confirmed by the infection of short term cultures of nonmalignant infant cells of different origin. In these nontransformed cells, no effect of H‐1PV on viability or morphology of the cells was observed. In contrast, a lytic infection was induced in all neuroblastoma cell lines examined at MOIs between 0.001 and 10 pfu/cell. H‐1PV actively replicated with virus titres increasing up to 5,000‐fold within 48–96 hr after infection. The lytic effect of H‐1PV was observed independent of MYCN oncogene amplification or differentiation status. Moreover, a significant G2‐arrest and induction of apoptosis could be demonstrated. Infection efficiency, rapid virus replication and exhaustive lytic effects on neuroblastoma cells together with the low toxicity of H‐1PV for nontransformed cells, render this parvovirus a promising candidate for oncolytic virotherapy of neuroblastoma.
    Keywords: Neuroblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Apoptosis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 4
    Language: English
    In: Biometrical journal. Biometrische Zeitschrift, January 2014, Vol.56(1), pp.86-106
    Description: Adaptive designs were originally developed for independent and uniformly distributed p-values. There are trial settings where independence is not satisfied or where it may not be possible to check whether it is satisfied. In these cases, the test statistics and p-values of each stage may be dependent. Since the probability of a type I error for a fixed adaptive design depends on the true dependence structure between the p-values of the stages, control of the type I error rate might be endangered if the dependence structure is not taken into account adequately. In this paper, we address the problem of controlling the type I error rate in two-stage adaptive designs if any dependence structure between the test statistics of the stages is admitted (worst case scenario). For this purpose, we pursue a copula approach to adaptive designs. For two-stage adaptive designs without futility stop, we derive the probability of a type I error in the worst case, that is for the most adverse dependence structure between the p-values of the stages. Explicit analytical considerations are performed for the class of inverse normal designs. A comparison with the significance level for independent and uniformly distributed p-values is performed. For inverse normal designs without futility stop and equally weighted stages, it turns out that correcting for the worst case is too conservative as compared to a simple Bonferroni design.
    Keywords: Adaptive Designs ; Copulas ; Dependent Test Statistics ; Inflation of Type I Error Rate ; Inverse Normal Method ; Biometry -- Methods ; Clinical Trials As Topic -- Methods
    ISSN: 03233847
    E-ISSN: 1521-4036
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  • 5
    In: Pediatric Blood & Cancer, March 2018, Vol.65(3), pp.n/a-n/a
    Description: Infants with low‐grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re‐)treatment regimens are briefly discussed.
    Keywords: Braf V600e Inhibitor ; Child ; Desmoplastic Infantile Astrocytoma ; Infant ; Low‐Grade Glioma ; Vemurafenib
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 6
    In: Pediatric Blood & Cancer, September 2016, Vol.63(9), pp.1677-1679
    Description: Children with Down syndrome are at high risk to develop myeloid leukemia (ML‐DS). Despite their excellent prognosis, children with ML‐DS particularly suffer from severe therapy‐related toxicities and for relapsed ML‐DS the cure rates are very poor. Here we report the clinical course of one child with ML‐DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML‐DS.
    Keywords: Aml ; Down Syndrome ; Hdac ; Hdaci ; Histone Deacetylase Inhibitor ; Ml‐Ds ; Vorinostat
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 7
    Language: English
    In: International Journal of Cancer, 15 April 2008, Vol.122(8), pp.1891-1900
    Description: The survival rate of children with advanced neuroblastoma (NB) is dismal despite intensive multimodal therapy. The limited efficacy and the frequent and serious side effects of currently used therapeutic regimens necessitate the development of new, less toxic treatment strategies. This study shows that the histone deacetylase inhibitor (HC)‐toxin suppresses the malignant phenotype of both established NB cell lines and primary NB cells with and without amplified at dosages lower than 20 nM. HC‐toxin induces cell cycle arrest and apoptosis as well as neuronal differentiation and diminishes both colony formation and invasive growth. These cellular changes are accompanied by the transcriptional repression of cell cycle regulators of the retinoblastoma (RB) tumor suppressor network found at high levels in NBs with poor prognosis, like E2F‐1 and its targets Skp2, N‐myc, Mad2 and survivin. The levels of the hypophosphorylated active form of RB, and of cyclin‐dependent kinase inhibitors including p15, p16, p21 and p27 are increased. In conclusion, nanomolar doses of the HDACI HC‐toxin cause a shift to a differentiated and benign phenotype of NB cells that is associated with an activation of the RB tumor suppressor network. © 2007 Wiley‐Liss, Inc.
    Keywords: Epigenetic Therapy ; Cell Cycle Arrest ; Differentiation ; E2f‐1 Regulated Genes ; Rb Tumor Suppressor Network
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    In: Brain Pathology, November 2012, Vol.22(6), pp.848-860
    Description: Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low‐risk tumors, whereas grade III anaplastic ependymomas are considered high‐risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin‐positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression‐free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co‐regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics.
    Keywords: Ependymoma ; Nestin ; Risk Stratification ; Who Grade
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 9
    In: Brain Pathology, July 2016, Vol.26(4), pp.506-516
    Description: The “pediatric targeted therapy” (PTT) program aims to identify the presence and activity of druggable targets and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. 10 markers (HDAC2, HR23B, p‐AKT, p‐ERK, p‐S6, p‐EGFR, PDGFR‐alpha/beta, p53 and BRAFV600E) were analyzed by immunohistochemistry. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols were included.  = 61/145 (42%) cases were eligible for analysis between 2009 and 2013, the most common entities being brain tumors. Immunohistochemical stainings were evaluated by the ‐Score (0–300). In 93% of the cases potentially actionable targets were identified. The expressed or activated pathways were histone deacetylase (HDACs; 83.0% of cases positive), EGFR (87.2%), PDGFR (75.9%), p53 (50.0%), MAPK/ERK (43.3%) and PI3K/mTOR (36.1%). Follow‐up revealed partial or full implementation of PTT results in treatment decision‐making in 41% of the cases. Prolonged disease stabilization responses in single cases were noticed, however, response rates did not differ from cases treated with other modalities. Further studies evaluating the feasibility and clinical benefit of personalized diagnostic approaches using paraffin material are warranted.
    Keywords: Brain Tumors ; Pediatric Oncology ; Personalized Medicine ; Targeted Therapy ; Relapsed Childhood Tumors ; Predictive Markers
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 10
    Language: English
    In: Pediatric Blood and Cancer, 2018, Vol.65(6), pp.urn:issn:1545-5009
    Description: Background: Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach. Methods: A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU-RHAB), France and Moscow (2006–2016) diagnosed within the first 28 days of life was evaluated. Genetic and clinical reference evaluation included SMARCB1 and/or SMARCA4 (fluorescence-in-situ-hybridization, multiplex ligation-dependent probe amplification, and sequencing) mutation analysis and immunohistochemistry. Forty-eight percent (20/42) of patients were treated according to the EU-RHAB therapy, 7% (3/42) according to the pilot approach Rhabdoid 2007, 33% (14/42) with individual schedules, and 12% (5/42) received no chemotherapy at all. Results: Forty point five percent (17/42) of patients presented with extracranial rhabdoid tumors, 33.5% (14/42) with rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor), and the remainder 26% (11/42) demonstrated synchronous tumors. Metastases at diagnosis were present in 52% (22/42) of patients. A germline mutation was detected in 66% (25/38) and was associated with a poor prognosis (4.2 ± 4.1% vs. 48 ± 16.4%, P 〈 0.00005). A gross total resection (GTR) was realized in 17%. A GTR (42.9 ± 18.7% vs. 4.9 ± 4.3%, P = 0.04), therapy according to a standardized approach (20.9 ± 8.7% vs. 7.1 ± 6.9 %, P = 0.0018), and a complete remission (CR) (23.6 ± 9.8% vs. 1.3 ± 3.6%, P = 0.04) were significant prognostic factors. Conclusions: The management of patients with congenital rhabdoid tumors requires a major multidisciplinary effort. In many instances, cure is not possible and a palliative approach is warranted. Our data indicate a positive impact of standardized therapeutic approaches on survival, making a tailored approach toward affected patients and their families mandatory.
    Keywords: D_Article_Not_Yet_Freely_Accessible
    ISSN: 1545-5009
    ISSN: 1545-5017
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