Publications by authors named "Alexander Schramm"

191 Publications

Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis.

Cell Rep 2021 Nov;37(8):110056

Department of Medical Oncology, West German Cancer Center, University Hospital Essen at the University Duisburg-Essen, Duisburg, Germany; German Cancer Consortium (DKTK) partner site Essen, Essen, Germany. Electronic address:

Statins are among the most commonly prescribed drugs, and around every fourth person above the age of 40 is on statin medication. Therefore, it is of utmost clinical importance to understand the effect of statins on cancer cell plasticity and its consequences to not only patients with cancer but also patients who are on statins. Here, we find that statins induce a partial epithelial-to-mesenchymal transition (EMT) phenotype in cancer cells of solid tumors. Using a comprehensive STRING network analysis of transcriptome, proteome, and phosphoproteome data combined with multiple mechanistic in vitro and functional in vivo analyses, we demonstrate that statins reduce cellular plasticity by enforcing a mesenchymal-like cell state that increases metastatic seeding ability on one side but reduces the formation of (secondary) tumors on the other due to heterogeneous treatment responses. Taken together, we provide a thorough mechanistic overview of the consequences of statin use for each step of cancer development, progression, and metastasis.
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http://dx.doi.org/10.1016/j.celrep.2021.110056DOI Listing
November 2021

Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer.

Transl Oncol 2021 Nov 17;15(1):101279. Epub 2021 Nov 17.

German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen 45122, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. Electronic address:

Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility.

Methods: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays.

Results: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (cfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in cfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status.

Conclusion: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring.
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http://dx.doi.org/10.1016/j.tranon.2021.101279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605355PMC
November 2021

NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C.

Cancers (Basel) 2021 Oct 21;13(21). Epub 2021 Oct 21.

West German Cancer Center, Department of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

(1) Background: Neuroblastomas (NBs) are the most common extracranial solid tumors of children. The amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The molecular effects of NTRK1 signaling in MYCN-amplified NB, however, are still poorly understood and require elucidation. (2) Methods: Inducible NTRK1 expression was realized in four NB cell lines with (IMR5, NGP) or without MYCN amplification (SKNAS, SH-SY5Y). Proteome and phosphoproteome dynamics upon NTRK1 activation by its ligand, NGF, were analyzed in a time-dependent manner in IMR5 cells. Target validation by immunofluorescence staining and automated image processing was performed using the three other NB cell lines. (3) Results: In total, 230 proteins and 134 single phosphorylated class I phosphosites were found to be significantly regulated upon NTRK1 activation. Among known NTRK1 targets, Stathmin and the neurosecretory protein VGF were recovered. Additionally, we observed the upregulation and phosphorylation of Lamin A/C (LMNA) that accumulated inside nuclear foci. (4) Conclusions: We provide a comprehensive picture of NTRK1-induced proteome and phosphoproteome dynamics. The phosphorylation of LMNA within nucleic aggregates was identified as a prominent feature of NTRK1 signaling independent of the MYCN status of NB cells.
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http://dx.doi.org/10.3390/cancers13215293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582546PMC
October 2021

HER2 mediates clinical resistance to the KRAS inhibitor sotorasib, which is overcome by co-targeting SHP2.

Eur J Cancer 2021 Oct 26;159:16-23. Epub 2021 Oct 26.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.

Introduction: Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRAS variant has recently become targetable by a new drug class specifically locking KRAS in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRAS mutations but was limited by the development of resistance.

Methods: A biopsy from progressing lung cancer of a patient treated with the KRAS inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRAS inhibition.

Results: We demonstrated acquisition of HER2 copy number gain and KRAS mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRAS lung cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRAS inhibitor treatment. Combined pharmacological inhibition of KRAS and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo.

Conclusions: These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRAS inhibition that can be overcome by co-targeting SHP2.
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http://dx.doi.org/10.1016/j.ejca.2021.10.003DOI Listing
October 2021

The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma.

Cell Death Dis 2021 09 28;12(10):885. Epub 2021 Sep 28.

Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, Frankfurt, Germany.

Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
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http://dx.doi.org/10.1038/s41419-021-04146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478910PMC
September 2021

Druggable epigenetic suppression of interferon-induced chemokine expression linked to amplification in neuroblastoma.

J Immunother Cancer 2021 05;9(5)

Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, Bonn, Germany

Background: Amplification of the oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that promotes a non-inflamed and T-cell infiltration-poor ('cold') tumor microenvironment (TME) by suppressing interferon signaling. This may explain, at least in part, why patients with NB seem to have little benefit from single-agent immune checkpoint blockade (ICB) therapy. Targeting MYCN or its effectors could be a strategy to convert a cold TME into a 'hot' (inflamed) TME and improve the efficacy of ICB therapy.

Methods: NB transcriptome analyses were used to identify epigenetic drivers of a T-cell infiltration-poor TME. Biological and molecular responses of NB cells to epigenetic drugs and interferon (IFN)-γ exposure were assessed by proliferation assays, immunoblotting, ELISA, qRT-PCR, RNA-seq and ChIP-qPCR as well as co-culture assays with T cells.

Results: We identified H3K9 euchromatic histone-lysine methyltransferases EHMT2 and EHMT1, also known as G9a and GLP, as epigenetic effectors of the -driven malignant phenotype and repressors of IFN-γ transcriptional responses in NB cells. EHMT inhibitors enhanced IFN-γ-induced expression of the Th1-type chemokines and , key factors of T-cell recruitment into the TME. In -amplified NB cells, co-inhibition of EZH2 (enhancer of zeste homologue 2), a H3K27 histone methyltransferase cooperating with EHMTs, was needed for strong transcriptional responses to IFN-γ, in line with histone mark changes at and chemokine gene loci. EHMT and EZH2 inhibitor response gene signatures from NB cells were established as surrogate measures and revealed high EHMT and EZH2 activity in -amplified high-risk NBs with a cold immune phenotype.

Conclusion: Our results delineate a strategy for targeted epigenetic immunomodulation of high-risk NBs, whereby EHMT inhibitors alone or in combination with EZH2 inhibitors (in particular, -amplified NBs) could promote a T-cell-infiltrated TME via enhanced Th1-type chemokine expression.
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http://dx.doi.org/10.1136/jitc-2020-001335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141444PMC
May 2021

Biomechanical In Vitro Study on the Stability of Patient-Specific CAD/CAM Mandibular Reconstruction Plates: A Comparison Between Selective Laser Melted, Milled, and Hand-Bent Plates.

Craniomaxillofac Trauma Reconstr 2021 Jun 28;14(2):135-143. Epub 2020 Aug 28.

Department of Oral and Maxillofacial Surgery, University Hospital Ulm, Ulm, Germany.

Study Design: An experimental in vitro study.

Objective: Plate fractures are a recurrent problem in alloplastic mandibular reconstruction. Hypothetically it can be assumed that computer-aided design (CAD)/computer-aided manufacturing (CAM) reconstruction plates have a higher stability than conventional hand-bent plates. The aim of the study was to compare additive and subtractive fabricated CAD/CAM mandibular reconstruction plates as well as conventional plates with regard to their biomechanical properties.

Methods: In a chewing simulator, plates of 2 conventional locking plate systems and 2 CAD/CAM-fabricated plate systems were compared. The plates were loaded in a fatigue test. The maximum number of cycles until plate fracture and the plate stiffness were compared.

Results: While all conventional plates fractured at a maximum load between 150 and 210 N (Newton) after a number of cycles between 40 000 and 643 000, none of the CAD/CAM plates broke despite a nearly doubled load of 330 N and 2 million cycles. Both CAD/CAM systems proved to be significantly superior to the hand-bent plates. There was no difference between the 2 CAD/CAM systems.

Conclusions: Concerning the risk of plate fracture, patient-specific CAD/CAM reconstruction plates appear to have a significant advantage over conventional hand-bent plates in alloplastic mandibular reconstruction.
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http://dx.doi.org/10.1177/1943387520952684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108099PMC
June 2021

[Präklinische Untersuchungen von Wechselwirkungen zwischen Mistel und Radio- oder Chemotherapie auf pädiatrische Tumorzellen].

Complement Med Res 2021 23;28(4):308-316. Epub 2021 Feb 23.

Abteilung für Kinder- und Jugendmedizin, Gemeinschaftskrankenhaus Herdecke, Herdecke, Deutschland,

Hintergrund: Mistelanwendungen werden als komplementäre Therapien häufig in der pädiatrischen Onkologie zusammen mit einer Radio- oder Chemotherapie verabreicht. Wechselwirkungen bei simultaner Applikation sind gerade in der Pädiatrie von großer Bedeutung, sie sind allerdings nach wie vor unzureichend untersucht. Material und Methoden: Zytotoxische Effekte des Mistelextraktes abnobaVISCUM Fraxini (aVF) auf LAN-1 Neuroblastomzellen und deren Etoposid- bzw. Cisplatin-resistente Subzelllinien wurden mittels Viabilitätstest untersucht, sowie mögliche Synergieeffekte zwischen aVF und den Chemotherapeutika durch die Softwareprodukte Combenefit und CompuSyn analysiert. Effekte einer Kombinationstherapie aus aVF und Bestrahlung auf SH-SY5Y Zellen wurden mittels Koloniebildungstest untersucht und Auswirkungen auf die Reparatureffizienz strahleninduzierter Doppelstrangbrüche mit Hilfe durchflusszytometrischer Quantifizierungen von γ-H2AX-Foci nach PI/FITC Doppelfärbung analysiert. Ergebnisse: Die Chemotherapie-resistenten LAN-1 Subzelllinien erwiesen sich als resistenter gegenüber der Mistelbehandlung als die Ursprungszelllinie. Auf Basis vier verschiedener Referenz-modelle konnten vor allem synergistisch/additive Effekte zwischen aVF und den Zytostatika Etoposid und Cisplatin berechnet werden. Die Kombination aus Mistelbehandlung und Bestrahlung führte zu einer Verringerung der Koloniebildung und zu einer Verzögerung der Reparaturgeschwindigkeit von strahleninduzierten Doppelstrangbrüchen. Schlussfolgerung: Die präklinischen Daten könnten darauf hinweisen, dass die Verwendung des Mistelextraktes, aVF, eine unterstützende Wirkung auf Radio- und Chemotherapien hat.

Background: Mistletoe therapies belong to the field of complementary medicines and are often administered simultaneously or successive to conventional radio- or chemotherapy. Drug-herb interactions are of great significance, especially in pediatrics, but are still insufficiently investigated.

Material And Methods: Cytotoxic effects of the mistletoe extract, abnobaVISCUM Fraxini (aVF), on LAN-1 neuroblastoma cell line and their chemotherapy-resistant (cisplatin; etoposide) subclones were investigated by cell viability assays. Potential synergistic or antagonistic effects of the co-treatment of aVF and cisplatin or etoposide, respectively, were analyzed by Combenefit and CompuSyn software. Combinational effects of mistletoe and irradiation were assessed by colony formation assays and repair efficiency of irradiation-induced double strand breaks was investigated by flow cytometric analyses of γ-H2AX foci after PI/FITC double staining.

Results: Chemotherapy-resistant subclones were more resistant to mistletoe therapy than the parental cells. Based on four different reference models, primarily synergistic/additive effects between aVF and the cytostatic drugs could be calculated. Simultaneous application of mistletoe extract and irradiation led to a delay of irradiation-induced double strand break repair in neuroblastoma cells and a decreased colony formation compared to irradiation monotherapy.

Conclusion: The preclinical data may indicate that the use of aVF has a supportive effect on radio- and chemotherapies.
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http://dx.doi.org/10.1159/000512670DOI Listing
October 2021

Computer-Assisted Secondary Orbital Reconstruction.

Craniomaxillofac Trauma Reconstr 2021 Mar 9;14(1):29-35. Epub 2020 Jul 9.

Department of Oral-, Maxillo- and Plastic Facial Surgery, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.

Study Design: This study presents a case-control study of 33 patients who underwent secondary orbital reconstruction, evaluating techniques and outcome.

Objective: Adequate functional and aesthetical appearance are main goals for secondary orbital reconstruction. Insufficient premorbid orbital reconstruction can result in hypoglobus, enophthalmos, and diplopia. Computer-assisted surgery and the use of patient-specific implants (PSIs) is widely described in the literature. The authors evaluate the use of selective laser-melted PSIs and hypothesize that PSIs are an excellent option for secondary orbital reconstruction.

Methods: The sample was composed of 33 patients, previously treated with primary orbital reconstruction, presenting themselves with indications for secondary reconstruction (i.e. enophthalmos, diplopia, or limited eye motility). Computed tomography and/or cone beam data sets were assessed before and after secondary reconstruction comparing intraorbital volumes, infraorbital angles, and clinical symptoms. Clinical outcomes were assessed using a standardized protocol.

Results: Results show a significant change in intraorbital volumes and a reduction of clinical symptoms after secondary reconstruction.

Conclusions: Outcomes of this study suggest that secondary orbital reconstruction can be performed routinely using selective laser-melted PSIs and titanium spacers.
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http://dx.doi.org/10.1177/1943387520935004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868513PMC
March 2021

Intraoperative Feedback and Quality Control in Orbital Reconstruction: The Past, the Present, and the Future.

Atlas Oral Maxillofac Surg Clin North Am 2021 Mar 24;29(1):97-108. Epub 2020 Dec 24.

Department of Oral and Maxillofacial Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.

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http://dx.doi.org/10.1016/j.cxom.2020.11.006DOI Listing
March 2021

The Global Impact of COVID-19 on Craniomaxillofacial Surgeons.

Craniomaxillofac Trauma Reconstr 2020 Sep 31;13(3):157-167. Epub 2020 May 31.

Department of Oral and Maxillofacial Surgery, Erasmus MC, Rotterdam, the Netherlands.

Study Design: The COrona VIrus Disease-19 (COVID-19) pandemic has disrupted craniomaxillofacial (CMF) surgeons practice worldwide. We implemented a cross-sectional study and enrolled a sample of CMF surgeons who completed a survey.

Objective: To measure the impact that COVID-19 has had on CMF surgeons by (1) identifying variations that may exist by geographic region and specialty and (2) measuring access to adequate personal protective equipment (PPE) and identify factors associated with limited access to adequate PPE.

Methods: Primary outcome variable was availability of adequate PPE for health-care workers (HCWs) in the front line and surgeons. Descriptive and analytic statistics were computed. Level of statistical significance was set at < .05. Binary logistic regression models were created to identify variables associated with PPE status (adequate or inadequate).

Results: Most of the respondents felt that hospitals did not provide adequate PPE to the HCWs (57.3%) with significant regional differences ( = .04). Most adequate PPE was available to surgeons in North America with the least offered in Africa. Differences in PPE adequacy per region ( < .001) and per country ( < .001) were significant. In Africa and South America, regions reporting previous virus outbreaks, the differences in access to adequate PPE evaporated compared to Europe ( = .18 and = .15, respectively).

Conclusion: The impact of COVID-19 among CMF surgeons is global and adversely affects both clinical practice and personal lives of CMF surgeons. Future surveys should capture what the mid- and long-term impact of the COVID-19 crisis will look like.
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http://dx.doi.org/10.1177/1943387520929809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797976PMC
September 2020

AO CMF International Task Force Recommendations on Best Practices for Maxillofacial Procedures During COVID-19 Pandemic.

Craniomaxillofac Trauma Reconstr 2020 Sep 27;13(3):151-156. Epub 2020 Sep 27.

Department of Oral and Maxillofacial Surgery, Erasmus MC, Rotterdam, Netherlands.

The COVID-19 pandemic is a global problem that has adversely and significantly impacted the safe practice of maxillofacial surgery. The risk lies in the heavy viral load in the oral/nasal/upper respiratory mucosal surfaces. Surgical procedures performed in this anatomic regional produce aerosalized viral particles which are highly infectious. Best practices and recommendations are outlined to mitigate the risk to the provider.
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http://dx.doi.org/10.1177/1943387520948826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797968PMC
September 2020

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Oncogenesis 2020 Nov 19;9(11):102. Epub 2020 Nov 19.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
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http://dx.doi.org/10.1038/s41389-020-00286-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369PMC
November 2020

Antitumoral Effects of Curcumin (Curcuma longa L.) and Thymoquinone (Nigella sativa L.) on Neuroblastoma Cell Lines.

Complement Med Res 2021 19;28(2):164-168. Epub 2020 Oct 19.

Department of Pediatrics, Gemeinschaftskrankenhaus Herdecke, Herdecke, Germany.

Introduction: Overall survival of high-risk neuroblastoma patients is still poor, emphasizing the need for novel therapeutic options. There is evidence for anti-cancer properties of the herbal substances thymoquinone and curcumin. These substances are isolated from Nigella sativa L. and Curcuma longa L., respectively, which are used in traditional medicine.

Objective: We investigated cytotoxic effects of thymoquinone and curcumin on neuroblastoma cell lines NLF, NB69, and SK-N-BE(2), in vitro.

Methods: Cytotoxicity of compounds was investigated by MTT cell viability assays. For analyzing effects on cell proliferation BrdU assays were employed and induction of apoptosis was detected by Cell Death ELISA assays.

Results: Both substances showed cytotoxic effects in all three neuroblastoma cell lines, whereby primary human fibroblast cells reacted less sensitively. Overall, lower IC50 values could be calculated for curcumin (3.75-7.42 µM) than for thymoquinone (5.16-16.3 µM). Decreased proliferation and increased apoptosis rates were observed under treatment.

Conclusions: Both substances showed anti-tumoral properties on neuroblastoma cell lines and should be further investigated as therapeutic agents.
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http://dx.doi.org/10.1159/000509765DOI Listing
September 2021

Streamlining Quantitative Analysis of Long RNA Sequencing Reads.

Int J Mol Sci 2020 Oct 1;21(19). Epub 2020 Oct 1.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

Transcriptome analyses allow for linking RNA expression profiles to cellular pathways and phenotypes. Despite improvements in sequencing methodology, whole transcriptome analyses are still tedious, especially for methodologies producing long reads. Currently, available data analysis software often lacks cost- and time-efficient workflows. Although kit-based workflows and benchtop platforms for RNA sequencing provide software options, e.g., cloud-based tools to analyze basecalled reads, quantitative, and easy-to-use solutions for transcriptome analysis, especially for non-human data, are missing. We therefore developed a user-friendly tool, termed Alignator, for rapid analysis of long RNA reads requiring only FASTQ files and an Ensembl cDNA database reference. After successful mapping, Alignator generates quantitative information for each transcript and provides a table in which sequenced and aligned RNA are stored for further comparative analyses.
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http://dx.doi.org/10.3390/ijms21197259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584020PMC
October 2020

Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway.

Cancer Res 2020 11 1;80(21):4655-4667. Epub 2020 Sep 1.

Department of Therapeutic Radiology, Yale University School of Medicine. New Haven, Connecticut.

Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non-small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial-mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC. SIGNIFICANCE: Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4655/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642024PMC
November 2020

Long-term follow-up of full-arch immediate implant-supported restorations in edentulous jaws: a clinical study.

Int J Implant Dent 2020 Jul 30;6(1):34. Epub 2020 Jul 30.

Department of Oral and Plastic Maxillofacial Surgery, Military Hospital Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany.

Background: This study aims to show the long-time stability of straight and tilted implants loaded immediately with a provisional resin bridge followed by a definitive prosthodontic rehabilitation in edentulous jaws despite difficult hygiene conditions postoperatively.

Results: This study included the participation of 23 patients and the restoration of 170 dental implants in 32 edentulous jaws. Patient data was analyzed from the start of treatment with a minimum follow-up period of 6 years in order to determine long-term implant success rates. However, the age of patients at time of surgery significantly affected the BOP to the detriment of younger patients (median 62 years old).

Conclusion: Although there was a higher risk of implant failure due to general disease, all the implants in this study survived successfully. As a replacement for a complete dental arch, the reduced number of implants in combination with the avoidance of augmentations reduces treatment costs. The immediate fixed prosthetic restoration of edentulous jaws thus represents a reliable therapeutic alternative to a two- to three-stage procedure. Optimized aftercare including professional teeth cleaning (PTC) (at least twice a year) can minimize the anamnestic effect of smoking, diabetes mellitus, and osteoporosis on BOP and possible bone loss.
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http://dx.doi.org/10.1186/s40729-020-00232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391463PMC
July 2020

Anticancer Effects of Viscum album Fraxini Extract on Medulloblastoma Cells in vitro.

Complement Med Res 2021 13;28(1):15-22. Epub 2020 Jul 13.

Department of Pediatric and Adolescent Medicine, Gemeinschaftskrankenhaus Herdecke, Herdecke, Germany,

Background: Mistletoe therapy is frequently administered as a supportive treatment in diverse pediatric cancer entities including brain tumors. Medulloblastoma is the most common brain tumor in childhood. Its high risk to metastasize and its long-term sequelae caused by aggressive chemo- or radiotherapies are still challenging.

Material And Methods: Effects of a lectin-rich mistletoe extract, abnobaVISCUM Fraxini, were investigated in two medulloblastoma cell lines (Daoy and ONS-76). Responsiveness of tumor cells was assessed by cell viability assays and xCELLigence real-time analyses. Moreover, impacts on proliferation, cell cycle and apoptosis were investigated. Apoptosis was studied by staining of vital mitochondria and assessing the involvement of caspases. In addition, effects on migration and invasion were analyzed.

Results: Both medulloblastoma cell lines were more susceptible to treatment with the mistletoe extract than a nontumorigenic fibroblast cell line. In mistletoe-sensitive Daoy cells, reduction of proliferation and induction of caspase-mediated apoptosis were observed upon administration of 0.05 and 0.5 mg/mL abnobaVISCUM Fraxini treatment, respectively. Furthermore, mistletoe extract inhibited migration and invasion properties in Daoy and significantly impaired invasive capabilities of ONS-76 cells.

Conclusion: AbnobaVISCUM Fraxini has cell line dependent antitumoral effects in medulloblastoma models. These results call for further investigations, to reveal mechanistic insights into antitumorigenic properties of mistletoe extracts.
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http://dx.doi.org/10.1159/000507318DOI Listing
September 2021

Thin Composite-Wire-Strut Zotarolimus-Eluting Stents Versus Ultrathin-Strut Sirolimus-Eluting Stents in BIONYX at 2 Years.

JACC Cardiovasc Interv 2020 05;13(9):1100-1109

Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, the Netherlands; Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, Enschede, the Netherlands. Electronic address:

Objectives: The aim of this study was to assess 2-year safety and efficacy of the current-generation thin composite-wire-strut durable-polymer Resolute Onyx zotarolimus-eluting stent (ZES), compared with the ultrathin-strut biodegradable-polymer Orsiro sirolimus-eluting stent (SES) in all-comers and a pre-specified small-vessel subgroup analysis.

Background: The Resolute Onyx ZES is widely used in clinical practice, but no follow-up data beyond 1 year have been published. The randomized BIONYX (Bioresorbable Polymer-Coated Orsiro Versus Durable Polymer-Coated Resolute Onyx Stents) trial (NCT02508714) established the noninferiority of ZES versus SES regarding target vessel failure (TVF) rates.

Methods: A total of 2,488 all-comer patients were treated at 7 coronary intervention centers in Belgium, Israel, and the Netherlands. The main endpoint, TVF, was a composite of safety (cardiac death or target vessel-related myocardial infarction) and efficacy (clinically indicated target vessel revascularization). Two-year follow-up data were analyzed using Kaplan-Meier methods.

Results: Two-year follow-up data were available for 2,460 of 2,488 patients (98.9%). TVF occurred in 93 of 1,243 patients (7.6%) assigned to ZES versus 87 of 1,245 patients (7.1%) assigned to SES (log-rank p = 0.66). There was no significant between-stent difference in individual components of this endpoint. The incidence of definite-or-probable stent thrombosis was low for both treatment arms (0.4% vs. 1.1%; log-rank p = 0.057). In patients stented in small vessels, there was no between-stent difference (TVF 8.2% vs. 8.7% [log-rank p = 0.75], target lesion revascularization 4.0% vs. 4.4% [log-rank p = 0.77]).

Conclusions: At 2-year follow-up, the novel thin composite-wire-strut durable-polymer Resolute Onyx ZES showed in all-comers similar safety and efficacy compared with the ultrathin cobalt-chromium-strut biodegradable-polymer Orsiro SES. The analysis of patients who were treated in small vessels also suggested no advantage for either stent.
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http://dx.doi.org/10.1016/j.jcin.2020.01.230DOI Listing
May 2020

HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model.

Lung Cancer 2020 06 18;144:20-29. Epub 2020 Apr 18.

Department of Thoracic Surgery, West German Cancer Center, University Hospital Essen - Ruhrlandklinik, University Duisburg-Essen, Essen, Germany. Electronic address:

Objectives: Somatic chromosomal rearrangements resulting in ALK fusion oncogenes are observed in 3-7 % of lung adenocarcinomas. ALK tyrosine kinase inhibitors (ALKi) induce initially response, however, various resistance mechanisms limit their efficacy. Novel therapeutic approaches are of utmost importance to tailor these targeted therapies.

Materials And Methods: A synchronous ALK-rearranged and mutated lung cancer cell line pair was established from malignant pleural effusion (PF240-PE) and carcinosis (PF240-PC) at time of ALKi resistance. Immunohistochemistry, FISH and sequencing were performed in pre- and post-treatment tumors and in both cell lines. Differentiation markers were measured by immunoblot. Viability was tested following treatment with ALKi and/or a pan-HDAC inhibitor. Additionally, a novel treatment-naïve ALK-rearranged cell line served as control. In vivo tumorigenicity was evaluated in subcutaneous xenografts.

Results: Two distinct resistance mutations were identified in different carcinosis tissues at time of resistance, the previously described resistance mutation L1152R and the hitherto uncharacterized E1161K. Strikingly, PF240-PC cells carried E1161K and PF240-PE cells harbored L1152R. Immunohistochemistry and immunoblot identified epithelial-to-mesenchymal transition markers upregulated following ALKi resistance development both in carcinosis tissues and cell lines. While both lines grew as xenografts, they differed in morphology, migration, in vivo growth and sensitivity to ALKi in vitro. Strikingly, the combination of ALKi with SAHA yielded strong synergism.

Conclusion: Using a patient-derived ALKi resistant lung cancer model we demonstrated the synergism of HDAC and ALK inhibition. Furthermore, our findings provide strong evidence for intratumoral heterogeneity under targeted therapy and highlight the importance of site-specific mutational analysis.
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http://dx.doi.org/10.1016/j.lungcan.2020.04.002DOI Listing
June 2020

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.

Sci Rep 2020 04 28;10(1):7157. Epub 2020 Apr 28.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
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http://dx.doi.org/10.1038/s41598-020-64040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188804PMC
April 2020

Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4 CAR T Cell Efficacy.

Front Immunol 2020 31;11:531. Epub 2020 Mar 31.

Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Chimeric antigen receptor (CAR) T cell efficacy against solid tumors is currently limited by several immune escape mechanisms, which may include tumor-derived extracellular vesicles. Advanced neuroblastoma is an aggressive childhood tumor without curative treatment options for most relapsed patients today. We here evaluated the role of tumor-derived extracellular vesicles on the efficacy of CAR T cells targeting the neuroblastoma-specific antigen, CD171. For this purpose, CAR T cell activation, cytokine production, exhaustion, and tumor cell-directed cytotoxicity upon co-culture was evaluated. Tumor-derived extracellular vesicles isolated from SH-SY5Y neuroblastoma cells neither affected CAR T cell activation nor expression of inhibitory markers. Importantly, exposure of CD4 CD171-specific CAR T cells to tumor-derived extracellular vesicles significantly impaired tumor cytotoxicity of CAR T cells. This effect was independent of neurotrophic receptor tyrosine kinases 1 or 2 (NTRK1, NTRK2) expression, which is known to impact immune responses against neuroblastoma. Our results demonstrate for the first time the impact of tumor-derived extracellular vesicles and non-cell-mediated tumor-suppressive effects on CD4 CAR T cell efficacy in a preclinical setting. We conclude that these factors should be considered for any CAR T cell-based therapy to make CAR T cell therapy successful against solid tumors.
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http://dx.doi.org/10.3389/fimmu.2020.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137471PMC
March 2021

Plasma Next Generation Sequencing and Droplet Digital-qPCR-Based Quantification of Circulating Cell-Free RNA for Noninvasive Early Detection of Cancer.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.

Early detection of cancer holds high promise for reducing cancer-related mortality. Detection of circulating tumor-specific nucleic acids holds promise, but sensitivity and specificity issues remain with current technology. We studied cell-free RNA (cfRNA) in patients with non-small cell lung cancer (NSCLC; n = 56 stage IV, n = 39 stages I-III), pancreatic cancer (PDAC, n = 20 stage III), malignant melanoma (MM, n = 12 stage III-IV), urothelial bladder cancer (UBC, n = 22 stage II and IV), and 65 healthy controls by means of next generation sequencing (NGS) and real-time droplet digital PCR (RT-ddPCR). We identified 192 overlapping upregulated transcripts in NSCLC and PDAC by NGS, more than 90% of which were noncoding. Previously reported transcripts (e.g., HOTAIRM1) were identified. Plasma cfRNA transcript levels of POU6F2-AS2 discriminated NSCLC from healthy donors (AUC = 0.82 and 0.76 for stages IV and I-III, respectively) and significantly associated ( = 0.017) with the established tumor marker Cyfra 21-1. cfRNA yield and POU6F2-AS transcript abundance discriminated PDAC patients from healthy donors (AUC = 1.0). POU6F2-AS2 transcript was significantly higher in MM ( = 0.044). In summary, our findings support further validation of cfRNA detection by RT-ddPCR as a biomarker for early detection of solid cancers.
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http://dx.doi.org/10.3390/cancers12020353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073169PMC
February 2020

Preclinical Evaluation of Antitumoral and Cytotoxic Properties of Viscum album Fraxini Extract on Pediatric Tumor Cells.

Planta Med 2019 Oct 7;85(14-15):1150-1159. Epub 2019 Oct 7.

Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.

In Europe, especially in German-speaking countries, administration of mistletoe extracts is the most common and popular complementary and alternative therapy approach reported in oncology. Mistletoe therapy is applied to children with cancer for curative and palliative therapeutic regimes with increasing frequency, but at the same time, there are only a few studies on the effectiveness of this therapy. Therefore, we have investigated the response of various pediatric cell lines (acute myeloid leukemia, Ewing's sarcoma, hepatocellular carcinoma, medulloblastoma, neuroblastoma, and osteosarcoma) to mistletoe extract, abnobaVISCUM Fraxini. Effects on cell proliferation, cell cycle distribution as well as on mitochondrial integrity and caspase-mediated apoptosis were investigated in neuroblastoma cell lines, SH-SY5Y and Kelly. Additionally, tumor cell migration and invasion were studied. effects of the mistletoe extract were investigated in a syngeneic neuroblastoma mouse model. We could show that tumor cell lines were from 5- to 640-fold more sensitive to abnobaVISCUM Fraxini treatment than non-tumorigenic fibroblasts, whereby neuroblastoma cell lines were the most sensitive. For two neuroblastoma cell lines, SH-SY5Y and Kelly, induction of caspase-9-mediated apoptosis, a decrease of mitochondrial integrity as well as attenuation of migration and invasion were observed. experiments revealed a reduction of tumor growth and a prolonged survival of tumor-bearing animals. In summary, we can state that these results provide the first preclinical data for cytotoxic activities of abnobaVISCUM Fraxini for a broad panel of pediatric tumor cell lines, in particular, neuroblastoma cells. Thus, it might be a potential remedy for the supportive treatment of neuroblastoma.
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http://dx.doi.org/10.1055/a-1013-0382DOI Listing
October 2019

Factors influencing the long-term prognosis of root tip resected teeth.

GMS Interdiscip Plast Reconstr Surg DGPW 2019 2;8:Doc13. Epub 2019 Sep 2.

Department of Oral and Plastic Maxillofacial Surgery, Armed Forces Hospital Ulm, Germany.

The aim of the study was to investigate possible predictive factors influencing the long-term success of root tip resection. The retrospective study included 216 patients (♂ 111, ♀ 106, median age 43.3 years). A total of 261 root tip resections were performed on these patients between 1989 and 2012. In addition to determining the success rates 5 and 10 years postoperatively, the factors gender, age, tooth type, use of bone replacement material and preoperative periodontal tooth status were examined with regard to their significance for the long-term prognosis of root tip resected teeth. The evaluation showed an average success rate of 63.6% for all included teeth over the entire observation period (tooth at least one year postoperatively still in situ). The 5-year success rate was 78.2%, the 10-year success rate 63.1%. A dependence of the success rates on the tooth type could not be evaluated. However, the examination showed a clear dependence of the success on the age of the patients. Root tip resections in patients in the age group 60 years and older had significantly worse success rates compared to the age groups 20 to 39 years and 40 to 59 years. The prognosis was also significantly better for patients in the age group 20 to 39 years than for patients in the age group 40 to 59 years. Periodontally compromised teeth showed only a tendency for a poorer prognosis than periodontally healthy teeth. With regard to sex and intraoperative filling of the resection defect with bone replacement material, no differences in the success rates were found. A root tip resection is a good option, largely independent of the type of tooth, to preserve a tooth in the medium to long term after unsuccessful endodontic treatment. However, a revision of the endodontic treatment or even an extraction with subsequent implantation should always be considered as an alternative, especially with increasing age.
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http://dx.doi.org/10.3205/iprs000139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734193PMC
September 2019

Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity.

Medchemcomm 2019 Jul 23;10(7):1109-1115. Epub 2018 Oct 23.

Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy , Leipzig University , Medical Faculty , Brüderstr. 34 , 04103 Leipzig , Germany . Email:

Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound , displayed submicromolar tumor cell-inhibitory potential (IC: 0.21-0.67 μM) against all five cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.
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http://dx.doi.org/10.1039/c8md00454dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644563PMC
July 2019

Maxillofacial injuries in severely injured patients after road traffic accidents-a retrospective evaluation of the TraumaRegister DGU® 1993-2014.

Clin Oral Investig 2020 Jan 3;24(1):503-513. Epub 2019 Aug 3.

Department of Anaesthesiology and Intensive Care Medicine, Emergency Medicine Section, HEMS Christoph 22, German Armed Forces Hospital of Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany.

Objectives: It was the aim of the study to analyse the prevalence of maxillofacial trauma (MFT) in severely injured patients after road traffic accidence (RTA) and to investigate associated factors.

Materials And Methods: In a retrospective study, data from patients after RTA by the TraumaRegister DGU® from 1993 to 2014 were evaluated for demographical and injury characteristics. The predictor variable was mechanism of injury and the outcome variables were type of injury, severity and hospital resources utilization.

Results: During the investigation period, n = 62,196 patients were enclosed with a prevalence of maxillofacial injuries of 20.3% (MFT positive). The injury severity score of MFT-positive patients was higher than in the MTF-negative subgroup (27 ± 12.8 vs. 23.0 ± 12.7). If MFT positive, 39.8% show minor, 37.1% moderate, 21.5% serious and 1.6% severe maxillofacial injuries. Injuries of the midface occurred in 60.3% of MTF-positive patients. A relevant blood loss (> 20% of total blood volume) occurred in 1.9%. MFT-positive patients had a higher coincidence with cervical spine fractures (11.3% vs. 7.8%) and traumatic brain injuries (62.6% vs. 34.8%) than MFT-negative patients. There was a noticeable decrease in the incidence of facial injuries in car/truck drivers during the study period.

Conclusions: Every 5th patient after RTA shows a MFT and the whole trauma team must be aware that this indicates a high prevalence of traumatic brain and cervical spine injuries.

Clinical Relevance: Even if sole injuries of the face are seldom life threatening, maxillofacial expertise in interdisciplinary trauma centres is strongly recommended.
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http://dx.doi.org/10.1007/s00784-019-03024-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223802PMC
January 2020

Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma.

Cancer Lett 2019 03 4;445:24-33. Epub 2019 Jan 4.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany; German Consortium for Translational Cancer Research (DKTK), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.
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http://dx.doi.org/10.1016/j.canlet.2018.12.012DOI Listing
March 2019

A mechanistic classification of clinical phenotypes in neuroblastoma.

Science 2018 12;362(6419):1165-1170

Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
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http://dx.doi.org/10.1126/science.aat6768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875194PMC
December 2018

Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Center for Medical Genetics, Department of Biomolecular Medicine, and.

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of noninvasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in 2 independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis, and overall survival revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential abundance analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume. These findings were validated in longitudinal serum samples from metastatic neuroblastoma patients, where the 9 miRNAs were associated with disease burden and treatment response.
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http://dx.doi.org/10.1172/jci.insight.97021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328024PMC
December 2018
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