Publications by authors named "Martina Deckert"

140 Publications

Correction: OTUB1 prevents lethal hepatocyte necroptosis through stabilization of c-IAP1 during murine liver inflammation.

Cell Death Differ 2021 Jun 18. Epub 2021 Jun 18.

Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1038/s41418-021-00819-7DOI Listing
June 2021

Treatment patterns and disease course of previously untreated Primary Central Nervous System Lymphoma: Feasibility of MTX-based regimens in clinical routine.

Eur J Haematol 2021 Aug 26;107(2):202-210. Epub 2021 May 26.

Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), University of Cologne, Cologne, Germany.

Background: Primary central nervous system lymphoma (PCNSL) is a rare type of aggressive lymphoma of the central nervous system. Treatment strategies improved significantly over the past decades differ regionally but mainly consist of rituximab and high-dosed methotrexate (MTX)-based therapies.

Methods: We assessed clinical outcomes of 100 patients with newly diagnosed PCNSL between 2010-2020 at the University Hospital of Cologne, Germany.

Results: Patients were 23-88 years of age and either treated with MTX-based regimens (PRIMAIN, MARTA, MATRix), individual regimens, or best supportive care, respectively. Overall response rates were generally high (66,7-83,8%), but different organ toxicities required dose adjustments in most groups. Two-year overall survival rates were 57,9% (PRIMAIN), 63,6% (MARTA), 65,4% (MATRix), and 37,5% (Other), respectively. Out of 9 patients suffering from relapse >12 months from primary diagnosis, 7 patients (77,8%) received methotrexate-based salvage therapy with 2-year overall survival of 4/6 patients (66,7%).

Conclusion: Although a relevant proportion of patients are not eligible for clinical trials due to age, performance status, or comorbidities, these results prove feasibility of different MTX-based treatment strategies in clinical routine. Even elderly patients displayed surprisingly favorable outcomes. However, with compromising organ toxicities, reduction of intensity should be part of strategies in future clinical trials.
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http://dx.doi.org/10.1111/ejh.13639DOI Listing
August 2021

CD8 T cell-Derived Perforin and TNF-α Are Crucial Mediators of Neuronal Destruction in Experimental Autoimmune Enteric Ganglionitis.

Am J Pathol 2021 06 10;191(6):1064-1076. Epub 2021 Mar 10.

Institute of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Electronic address:

In neuron-specific ovalbumin-transgenic CKTAC mice, antigen-specific OT-I CD8 T cells home to the enteric nervous system, where they attack and destroy neurons of the myenteric and submucosal plexus. Clinically, experimental autoimmune enteric ganglionitis (EAEG) manifests with gastrointestinal dysmotility and rapidly progresses to lethal ileus. Although interferon-γ has been identified as capable of damaging neurons in EAEG, the role of perforin, Fas/FasL, and tumor necrosis factor-α (TNF-α) in this disease is still a matter of debate. Thus, CKTAC mice were adoptively transferred with either perforin or wild-type OT-I CD8 T cells. In addition, CKTAC mice that had received wild-type OT-I CD8 T cells were treated by either anti-TNF-α or anti-FasL. Furthermore, wild-type OT-I CD8 T cells were adoptively transferred into CKTAC mice with neuron-specific deletion of Fas. Although neither inactivation of enteric neuronal Fas nor anti-FasL treatment improved the disease, the absence of perforin from OT-I CD8 T cells and anti-TNF-α treatment significantly ameliorated EAEG and prevented lethal ileus by rescue of enteric neurons. Thus, these experiments identify perforin and TNF-α as important in the pathogenesis of EAEG.
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http://dx.doi.org/10.1016/j.ajpath.2021.02.021DOI Listing
June 2021

OTUB1 prevents lethal hepatocyte necroptosis through stabilization of c-IAP1 during murine liver inflammation.

Cell Death Differ 2021 Jul 12;28(7):2257-2275. Epub 2021 Mar 12.

Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.

In bacterial and sterile inflammation of the liver, hepatocyte apoptosis is, in contrast to necroptosis, a common feature. The molecular mechanisms preventing hepatocyte necroptosis and the potential consequences of hepatocyte necroptosis are largely unknown. Apoptosis and necroptosis are critically regulated by the ubiquitination of signaling molecules but especially the regulatory function of deubiquitinating enzymes (DUBs) is imperfectly defined. Here, we addressed the role of the DUB OTU domain aldehyde binding-1 (OTUB1) in hepatocyte cell death upon both infection with the hepatocyte-infecting bacterium Listeria monocytogenes (Lm) and D-Galactosamine (DGal)/Tumor necrosis factor (TNF)-induced sterile inflammation. Combined in vivo and in vitro experiments comprising mice lacking OTUB1 specifically in liver parenchymal cells (OTUB1) and human OTUB1-deficient HepG2 cells revealed that OTUB1 prevented hepatocyte necroptosis but not apoptosis upon infection with Lm and DGal/TNF challenge. Lm-induced necroptosis in OTUB1 mice resulted in increased alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release and rapid lethality. Treatment with the receptor-interacting serine/threonine-protein kinase (RIPK) 1 inhibitor necrostatin-1s and deletion of the pseudokinase mixed lineage kinase domain-like protein (MLKL) prevented liver damage and death of infected OTUB1 mice. Mechanistically, OTUB1 reduced K48-linked polyubiquitination of the cellular inhibitor of apoptosis 1 (c-IAP1), thereby diminishing its degradation. In the absence of OTUB1, c-IAP1 degradation resulted in reduced K63-linked polyubiquitination and increased phosphorylation of RIPK1, RIPK1/RIPK3 necrosome formation, MLKL-phosphorylation and hepatocyte death. Additionally, OTUB1-deficiency induced RIPK1-dependent extracellular-signal-regulated kinase (ERK) activation and TNF production in Lm-infected hepatocytes. Collectively, these findings identify OTUB1 as a novel regulator of hepatocyte-intrinsic necroptosis and a critical factor for survival of bacterial hepatitis and TNF challenge.
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http://dx.doi.org/10.1038/s41418-021-00752-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257688PMC
July 2021

An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities.

Blood Cancer Discov 2021 Jan;2(1):70-91

Center for Integrated Oncology, University of Cologne, Cologne, Germany.

Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in , as well as copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a and -driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased expression, compared to GCB-DLBCL. experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring and aberrations.
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http://dx.doi.org/10.1158/2643-3230.BCD-19-0059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806186PMC
January 2021

Twenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma.

Neurology 2020 12 28;95(23):e3138-e3144. Epub 2020 Sep 28.

From the Departments of Neurology (S. Seidel, S. Schlömer, U.S.) and Radiology (A.K.), Knappschaftskrankenhaus University of Bochum; Department of Neurology (H.P.), Hospital Barmherzige Brüder, Regensburg; Department of Neurology (K.F., U.H., T.K.), Institute of Biostatistics (R.F.), Department of Pediatrics (U.B.), and Department of Integrated Oncology, CIO Bonn (I.G.H.S.-W.), University of Bonn; Department of Internal Medicine (A.E.) and Department of Neuropathology, Faculty of Medicine and University Hospital Cologne (M.D.), University of Cologne; Departments of Neurology (M.V.-S.) and Internal Medicine (G.E.), University of Heidelberg; and Departments of Neurology (H.R.), Neurosurgery (G.S.), and Internal Medicine (F.K.), University of Dresden, Germany. A.K. is currently affiliated with Radiology, Medneo, Dortmund, Germany.

Objective: To determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.

Methods: Sixty-five patients (median age 62 years, range 27-75; median Karnofsky performance score 70, range 20-90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.

Results: Median follow-up for surviving patients was 19.6 years (17.5-23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9-5.9); for patients ≤60 years, 11.0 years (95% CI 4.8-17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.

Conclusion: At a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.

Classification Of Evidence: This work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.
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http://dx.doi.org/10.1212/WNL.0000000000010949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734926PMC
December 2020

Analysis of Driver Mutational Hot Spots in Blood-Derived Cell-Free DNA of Patients with Primary Central Nervous System Lymphoma Obtained before Intracerebral Biopsy.

J Mol Diagn 2020 10 1;22(10):1300-1307. Epub 2020 Aug 1.

Institute of Neuropathology, University of Cologne, Cologne, Germany.

In newly diagnosed systemic diffuse large B-cell lymphoma, next-generation sequencing of plasma-derived cell-free DNA (cfDNA) detects somatic mutations as accurate as genotyping of the tumor biopsy. A distinct diffuse large B-cell lymphoma entity confined to the central nervous system is primary central nervous system lymphoma (PCNSL), which requires intracerebral biopsy and neuropathologic analysis to establish the diagnosis. So far, a biomarker for diagnosis and follow-up of PCNSL that can be investigated in blood has not been identified. This article addresses the question whether somatic mutations of the CD79B and MYD88 driver genes of PCNSL can be detected in cfDNA at disease diagnosis. Stereotactic biopsies and cfDNA of 27 PCNSL patients were analyzed for CD79B and MYD88 mutations. As control, cfDNA derived from six healthy volunteers was used. CD79B and MYD88 hot spot mutations were identified in 16 of 27 (59%) and 23 of 27 (85%) PCNSL biopsies, respectively, but only in 0 of 27 (0%) and 1 of 27 (4%) corresponding cfDNA samples, respectively. In cfDNA of one of four patients with Waldenstrom disease, as a further control, the MYD88 L265P mutation was readily detected, despite complete clinical remission. These data suggest that in PCNSL even if they carry such mutations, alterations of CD79B and MYD88 cannot be reliably detected in blood-derived cfDNA obtained before intracerebral biopsy.
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http://dx.doi.org/10.1016/j.jmoldx.2020.07.002DOI Listing
October 2020

A Multiplex Assay for the Stratification of Patients with Primary Central Nervous System Lymphoma Using Targeted Mass Spectrometry.

Cancers (Basel) 2020 Jun 29;12(7). Epub 2020 Jun 29.

Institute of Molecular Medicine, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.

Primary central nervous system lymphomas (PCNSL) account for approximately 2% to 3% of all primary brain tumors. Until now, neuropathological tumor tissue analysis, most frequently gained by stereotactic biopsy, is still the diagnostic gold standard. Here, we rigorously analyzed two independent patient cohorts comprising the clinical entities PCNSL ( = 47), secondary central nervous system lymphomas (SCNSL; = 13), multiple sclerosis (MS, = 23), glioma ( = 10), other tumors ( = 17) and tumor-free controls ( = 21) by proteomic approaches. In total, we identified more than 1220 proteins in the cerebrospinal fluid (CSF) and validated eight candidate biomarkers by a peptide-centric approach in an independent patient cohort ( = 63). Thus, we obtained excellent diagnostic accuracy for the stratification between PCNSL, MS and glioma patients as well as tumor-free controls for three peptides originating from the three proteins VSIG4, GPNMB4 and APOC2. The combination of all three biomarker candidates resulted in diagnostic accuracy with an area under the curve (AUC) of 0.901 (PCNSL vs. MS), AUC of 0.953 (PCNSL vs. glioma) and AUC 0.850 (PCNSL vs. tumor-free control). In summary, the determination of VSIG4, GPNMB4 and APOC2 in CSF as novel biomarkers for supporting the diagnosis of PCNSL is suggested.
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http://dx.doi.org/10.3390/cancers12071732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407338PMC
June 2020

CXCR4-Targeted PET Imaging of Central Nervous System B-Cell Lymphoma.

J Nucl Med 2020 12 24;61(12):1765-1771. Epub 2020 Apr 24.

Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. MRI is the standard imaging technology for central nervous system (CNS) involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. In this proof-of-concept study, 11 patients with lymphoma of the CNS (8 primary and 3 secondary involvement) were imaged with the CXCR4-directed PET tracer Ga-pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by Ga-pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Ga-pentixafor PET showed excellent contrast with the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Ga-pentixafor PET represents a novel diagnostic tool for CNS lymphoma with potential implications for theranostic approaches as well as response and risk assessment.
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http://dx.doi.org/10.2967/jnumed.120.241703DOI Listing
December 2020

KLF4-mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment.

Acta Neuropathol Commun 2020 04 3;8(1):41. Epub 2020 Apr 3.

Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany.

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4 mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.
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http://dx.doi.org/10.1186/s40478-020-00912-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118946PMC
April 2020

The process of somatic hypermutation increases polyreactivity for central nervous system antigens in primary central nervous system lymphoma.

Haematologica 2021 03 1;106(3):708-717. Epub 2021 Mar 1.

Institute of Neuropathology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

The immunoglobulin (Ig) heavy and light chain variable gene mutational pattern of the B cell receptor (BCR) in primary central nervous system (CNS) lymphoma (PCNSL) cells suggests antigenic selection to drive pathogenesis and confinement to the CNS. This hypothesis is supported by the observation that the tumor B cell receptor (tBCR) of PCNSL is polyreactive and may be stimulated by CNS proteins. To obtain further insight into the role of the germinal center (GC) reaction on BCR reactivity, we constructed recombinant antibodies (recAb) with Ig heavy and light chain sequences of the corresponding naive BCR (nBCR) by reverting tBCR somatic mutations in 10 PCNSL. Analysis of nBCR-derived recAb reactivity by a protein microarray and immunoprecipitation demonstrated auto- and polyreactivity in all cases. Self-/polyreactivity was not lost during the GC reaction; surprisingly, tBCR significantly increased self-/polyreactivity. In addition to proteins recognized by both the nBCR and tBCR, tBCR gained self-/polyreactivity particularly for proteins expressed in the CNS including proteins of oligodendrocytes/myelin, the S100 protein family, and splicing factors. Thus, in PCNSL pathogenesis, a faulty GC reaction may increase self-/polyreactivity, hereby facilitating BCR signaling via multiple CNS antigens, and may ultimately foster tumor cell survival in the CNS.
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http://dx.doi.org/10.3324/haematol.2019.242701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927892PMC
March 2021

Leptomeningeal Carcinomatosis in a Patient with Pancreatic Cancer Responding to Nab-Paclitaxel plus Gemcitabine.

Case Rep Oncol 2020 Jan-Apr;13(1):35-42. Epub 2020 Jan 21.

Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Leptomeningeal carcinomatosis is an extremely rare, but devastating complication in pancreatic cancer patients with a poor prognosis despite multimodal treatment. We present a 51-year-old male patient with the very rare condition of leptomeningeal carcinomatosis originating from pancreatic cancer. He presented to our hospital with severe headache and neck stiffness 30 months after systemic chemotherapy. Cerebral and spinal MRI as well as cerebrospinal fluid examination confirmed the diagnosis of leptomeningeal carcinomatosis. The patient responded to gemcitabine plus nab-paclitaxel in terms of elimination of tumor cells from the CSF and concurrent clinical improvement for 3 months. The observed findings suggest that the combination of gemcitabine plus nab-paclitaxel is potentially effective in affected cerebrospinal fluid of pancreatic carcinoma patients.
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http://dx.doi.org/10.1159/000504697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011711PMC
January 2020

The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13.

Cell Mol Immunol 2021 Jun 5;18(6):1512-1527. Epub 2020 Feb 5.

Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany.

Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-κB (NF-κB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-γ (IFN-γ) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.
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http://dx.doi.org/10.1038/s41423-020-0362-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167118PMC
June 2021

Bi-allelic mutations in uncoordinated mutant number-45 myosin chaperone B are a cause for congenital myopathy.

Acta Neuropathol Commun 2019 12 18;7(1):211. Epub 2019 Dec 18.

Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.

Congenital myopathies (CM) form a genetically heterogeneous group of disorders characterized by perinatal muscle weakness. Here, we report an 11-year old male offspring of consanguineous parents of Lebanese origin. He presented with proximal weakness including Gower's sign, and skeletal muscle biopsy revealed myopathic changes with core-like structures. Whole exome sequencing of this index patient lead to the discovery of a novel genetically defined CM subtype based on bi-allelic mutations in the uncoordinated mutant number-45 myosin chaperone B (UNC45B) NM_173167:c.2261G > A, p.Arg754Gln. The mutation is conserved in evolution and co-segregates within the pedigree with the phenotype, and located in the myosin binding armadillo repeat domain 3 (ARM3), and has a CADD Score of 35. On a multimeric level, UNC45B aggregates to a chain which serves as an assembly line and functions as a "template" defining the geometry, regularity, and periodicity of myosin arranged into muscle thick filaments. Our discovery is in line with the previously described myopathological phenotypes in C. elegans and in vertebrate mutants and knockdown-models. In conclusion, we here report for the first time a patient with an UNC45B mutation causing a novel genetically defined congenital myopathy disease entity.
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http://dx.doi.org/10.1186/s40478-019-0869-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921565PMC
December 2019

A tissue-specific screen of ceramide expression in aged mice identifies ceramide synthase-1 and ceramide synthase-5 as potential regulators of fiber size and strength in skeletal muscle.

Aging Cell 2020 01 6;19(1):e13049. Epub 2019 Nov 6.

Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany.

Loss of skeletal muscle mass is one of the most widespread and deleterious processes in aging humans. However, the mechanistic metabolic principles remain poorly understood. In the framework of a multi-organ investigation of age-associated changes of ceramide species, a unique and distinctive change pattern of C and C ceramide species was detected in aged skeletal muscle. Consistently, the expression of CerS1 and CerS5 mRNA, encoding the ceramide synthases (CerS) with substrate preference for C and C acyl chains, respectively, was down-regulated in skeletal muscle of aged mice. Similarly, an age-dependent decline of both CerS1 and CerS5 mRNA expression was observed in skeletal muscle biopsies of humans. Moreover, CerS1 and CerS5 mRNA expression was also reduced in muscle biopsies from patients in advanced stage of chronic heart failure (CHF) suffering from muscle wasting and frailty. The possible impact of CerS1 and CerS5 on muscle function was addressed by reversed genetic analysis using CerS1 and CerS5 knockout mice. Skeletal muscle from mice deficient of either CerS1 or CerS5 showed reduced caliber sizes of both slow (type 1) and fast (type 2) muscle fibers, fiber grouping, and fiber switch to type 1 fibers. Moreover, CerS1- and CerS5-deficient mice exhibited reduced twitch and tetanus forces of musculus extensor digitorum longus. The findings of this study link CerS1 and CerS5 to histopathological changes and functional impairment of skeletal muscle in mice that might also play a functional role for the aging skeletal muscle and for age-related muscle wasting disorders in humans.
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http://dx.doi.org/10.1111/acel.13049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974707PMC
January 2020

Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities.

Acta Neuropathol Commun 2019 10 28;7(1):163. Epub 2019 Oct 28.

Institute of Pathology, University of Bern, Bern, Switzerland.

In this multi-institutional study we compiled a retrospective cohort of 86 posterior fossa tumors having received the diagnosis of cerebellar glioblastoma (cGBM). All tumors were reviewed histologically and subjected to array-based methylation analysis followed by algorithm-based classification into distinct methylation classes (MCs). The single MC containing the largest proportion of 25 tumors diagnosed as cGBM was MC anaplastic astrocytoma with piloid features representing a recently-described molecular tumor entity not yet included in the WHO Classification of Tumours of the Central Nervous System (WHO classification). Twenty-nine tumors molecularly corresponded to either of 6 methylation subclasses subsumed in the MC family GBM IDH wildtype. Further we identified 6 tumors belonging to the MC diffuse midline glioma H3 K27 M mutant and 6 tumors allotted to the MC IDH mutant glioma subclass astrocytoma. Two tumors were classified as MC pilocytic astrocytoma of the posterior fossa, one as MC CNS high grade neuroepithelial tumor with BCOR alteration and one as MC control tissue, inflammatory tumor microenvironment. The methylation profiles of 16 tumors could not clearly be assigned to one distinct MC. In comparison to supratentorial localization, the MC GBM IDH wildtype subclass midline was overrepresented, whereas the MCs GBM IDH wildtype subclass mesenchymal and subclass RTK II were underrepresented in the cerebellum. Based on the integration of molecular and histological findings all tumors received an integrated diagnosis in line with the WHO classification 2016. In conclusion, cGBM does not represent a molecularly uniform tumor entity, but rather comprises different brain tumor entities with diverse prognosis and therapeutic options. Distinction of these molecular tumor classes requires molecular analysis. More than 30% of tumors diagnosed as cGBM belong to the recently described molecular entity of anaplastic astrocytoma with piloid features.
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http://dx.doi.org/10.1186/s40478-019-0801-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816155PMC
October 2019

Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF.

Cancer Immunol Res 2019 Dec 9;7(12):1910-1927. Epub 2019 Oct 9.

Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt, Germany.

Glioblastoma (GBM) is a non-T-cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0865DOI Listing
December 2019

Imaging challenges of immunotherapy and targeted therapy in patients with brain metastases: response, progression, and pseudoprogression.

Neuro Oncol 2020 01;22(1):17-30

Institute of Neuroscience and Medicine, Research Center Juelich, Juelich, Germany.

The advent of immunotherapy using immune checkpoint inhibitors (ICIs) and targeted therapy (TT) has dramatically improved the prognosis of various cancer types. However, following ICI therapy or TT-either alone (especially ICI) or in combination with radiotherapy-imaging findings on anatomical contrast-enhanced MRI can be unpredictable and highly variable, and are often difficult to interpret regarding treatment response and outcome. This review aims at summarizing the imaging challenges related to TT and ICI monotherapy as well as combined with radiotherapy in patients with brain metastases, and to give an overview on advanced imaging techniques which potentially overcome some of these imaging challenges. Currently, major evidence suggests that imaging parameters especially derived from amino acid PET, perfusion-/diffusion-weighted MRI, or MR spectroscopy may provide valuable additional information for the differentiation of treatment-induced changes from brain metastases recurrence and the evaluation of treatment response.
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http://dx.doi.org/10.1093/neuonc/noz147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954406PMC
January 2020

OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes.

EMBO J 2019 05 3;38(10). Epub 2019 Apr 3.

Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ-induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity.
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http://dx.doi.org/10.15252/embj.2018100947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517825PMC
May 2019

TLR signals license CD8 T cells to destroy oligodendrocytes expressing an antigen shared with a Listeria pathogen.

Eur J Immunol 2019 03 11;49(3):413-427. Epub 2019 Feb 11.

Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Increasing evidence suggests a role of CD8 T cells in autoimmune demyelinating CNS disease, which, however, is still controversially discussed. Mice, which express ovalbumin (OVA) as cytosolic self-antigen in oligodendrocytes (ODC-OVA mice), respond to CNS infection induced by OVA-expressing attenuated Listeria with CD8 T cell-mediated inflammatory demyelination. This model is suitable to decipher the contribution of CD8 T cells and the pathogen in autoimmune CNS disease. Here, we show that both antigen and pathogen are required in the CNS for disease induction, though not in a physically linked fashion. Intracerebral challenge with combined toll like receptor (TLR) TLR2 and TLR9 as well as TLR7 and TLR9 agonists substituted for the bacterial stimulus, but not with individual TLR agonists (TLR2, TLR3,TLR5,TLR7, TLR9). Furthermore, MyD88 inactivation rendered ODC-OVA mice resistant to disease induction. Collectively, CD8 T cell-mediated destruction of oligodendrocytes is activated if (i) an antigen shared with an infectious agent is provided in the CNS microenvironment and (ii) innate immune signals inform the CNS microenvironment that pathogen removal warrants an immune attack by CD8 T cells, even at the expense of locally restricted demyelination.
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http://dx.doi.org/10.1002/eji.201847834DOI Listing
March 2019

Enteric Murine Ganglionitis Induced by Autoimmune CD8 T Cells Mimics Human Gastrointestinal Dysmotility.

Am J Pathol 2019 03 27;189(3):540-551. Epub 2018 Dec 27.

Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne. Electronic address:

Inflammatory bowel diseases frequently cause gastrointestinal dysmotility, suggesting that they may also affect the enteric nervous system. So far, the precise mechanisms that lead to gastrointestinal dysmotility in inflammatory bowel diseases have not been elucidated. To determine the effect of CD8 T cells on gastrointestinal motility, transgenic mice expressing ovalbumin on enteric neurons were generated. In these mice, adoptive transfer of ovalbumin-specific OT-I CD8 T cells induced severe enteric ganglionitis. CD8 T cells homed to submucosal and myenteric plexus neurons, 60% of which were lost, clinically resulting in severely impaired gastrointestinal transition. Anti-interferon-γ treatment rescued neurons by preventing their up-regulation of major histocompatibility complex class I antigen, thus preserving gut motility. These preclinical murine data translated well into human gastrointestinal dysmotility. In a series of 30 colonic biopsy specimens from patients with gastrointestinal dysmotility, CD8 T cell-mediated ganglionitis was detected that was followed by severe loss of enteric neurons (74.8%). Together, the preclinical and clinical data support the concept that autoimmune CD8 T cells play an important pathogenetic role in gastrointestinal dysmotility and may destroy enteric neurons.
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http://dx.doi.org/10.1016/j.ajpath.2018.11.016DOI Listing
March 2019

Array-based profiling of the lymphoma cell DNA methylome does not unequivocally distinguish primary lymphomas of the central nervous system from non-CNS diffuse large B-cell lymphomas.

Genes Chromosomes Cancer 2019 01 29;58(1):66-69. Epub 2018 Nov 29.

Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.

Primary lymphomas of the central nervous system (PCNSL) are diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). We here performed array-based DNA methylation analyses of 26 PCNSL and 78 DLBCL and validated our findings in an independent dataset. We identified 2847 CpGs differentially methylated between PCNSL and non-CNS-DLBCL. Neither a supervised analysis using these CpGs nor application of 3 CpG classifiers selected for class separation unambiguously separated PCNSL from non-CNS-DLBCL. Remarkably, 6/78 non-CNS-DLBCL consistently segregated with PCNSL, which displayed molecular features typical for PCNSL. Our findings suggest that a subset of non-CNS-DLBCL exists which molecularly resembles PCNSL.
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http://dx.doi.org/10.1002/gcc.22687DOI Listing
January 2019

Beyond the 3'UTR binding-microRNA-induced protein truncation via DNA binding.

Oncotarget 2018 Aug 28;9(67):32855-32867. Epub 2018 Aug 28.

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Here, we present a miR mechanism which is active in the nucleus and is essential for the production of intron included, C-terminal truncated and biologically active proteins, like e.g. Vim3. We exemplified this mechanism by miRs, miR-15a and miR-498, which are overexpressed in clear cell renal carcinoma or oncocytoma. Both miRs directly interact with DNA in an intronic region, leading to transcriptional stop, and therefore repress the full length version of the pre-mRNA, resulting in intron included truncated proteins (Mxi-2 and Vim3). A computational survey shows that this miR:DNA interactions mechanism may be generally involved in regulating the human transcriptome, with putative interaction sites in intronic regions for over 1000 genes. In this work, an entirely new mechanism is revealed how miRs can repress full length protein translation, resulting in C-terminal truncated proteins.
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http://dx.doi.org/10.18632/oncotarget.26023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132356PMC
August 2018

FET PET in Primary Central Nervous System Vasculitis.

Clin Nucl Med 2018 Sep;43(9):e322-e323

Stereotactic and Functional Neurosurgery, University Hospital Cologne, Cologne.

Primary central nervous system vasculitis is confined to the brain and spinal cord. While serological markers of inflammation are usually normal, conventional angiography may confirm the diagnosis. The diagnostic method of choice is central nervous system biopsy. A 57-year-old man suffered from a first generalized epileptic seizure. MRI revealed a contrast-enhancing lesion, and O-(2-[F]fluoroethyl)-L-tyrosine amino acid PET displayed increased metabolic activity, both findings highly suggestive of a malignant glioma. Surprisingly, histology obtained following stereotactic biopsy revealed small-vessel vasculitis.
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http://dx.doi.org/10.1097/RLU.0000000000002197DOI Listing
September 2018

The Diagnosis and Treatment of Primary CNS Lymphoma.

Dtsch Arztebl Int 2018 06;115(25):419-426

Department of Neurology, Medical Center of the University of Munich (LMU), Munich; Department of Hematology, Oncology and Palliative Care, Stuttgart Cancer Center/Tumor Center Eva-Mayr-Stih, Klinikum Stuttgart; Medical Department, Division of Oncology and Hematology, Charité - Universitätsmedizin Berlin; Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum; Department of Neuropathology, University Hospital Cologne; Department of Internal Medicine III, Hospital of the University of Munich (LMU).

Background: Primary central nervous system lymphoma is a diffuse large B-celllymphoma with exclusive manifestation in the central nervous system (CNS), leptomeninges, and eyes. Its incidence is 0.5 per 100 000 persons per year.Currently, no evidence-based standard of care exists.

Methods: This review is based on pertinent publications (2000-2017) retrieved by aselective search in PubMed.

Results: The clinical and neuroradiological presentation of primary CNS lymphoma isoften nonspecific, and histopathological confirmation is obligatory. The disease, if left un- treated, leads to death within weeks or months. If the patient's general condition permits, treatment should consist of a high-dose chemotherapy based on methotrexate (HD- MTX) combined with rituximab and other cytostatic drugs that penetrate the blood-brain barrier. Long-term survival can be achieved in patients under age 70 by adding non- myeloablative consolidation chemotherapy or high-dose chemotherapy with autologous stem cell transplantation (HD-AST) to the induction therapy. Clinical trials comparing the efficacy and toxicity of these two treatment strategies are currently underway. Con- solidation whole-brain radiotherapy is associated with the risk of severe neurotoxicity and should be reserved for patients who do not qualify for systemic treatment. Some 30% of patients are refractory to primary treatment, and at least 50% relapse. In patients who are still in good general condition, relapse can be managed with HD-AST. Re- exposure to conventional HD-MTX-based polychemotherapy is another option, if the initial response was durable. The 5-year survival rate of all treated patients is 31%,according to registry data.

Conclusion: Current recommendations for the treatment of primary CNS lymphomaare based on only a small number of prospective clinical trials. Patients with this disease should be treated by interdisciplinary teams in experienced centers, andpreferably as part of a controlled trial.
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http://dx.doi.org/10.3238/arztebl.2018.0419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056710PMC
June 2018

Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation.

Int J Mol Sci 2018 Apr 5;19(4). Epub 2018 Apr 5.

Department of Neurology, University of Cologne, 50937 Cologne, Germany.

Novel therapeutic targets in malignant glioma patients are urgently needed. Point mutations of the v-Raf murine sarcoma viral oncogene homolog B () gene occur predominantly in melanoma patients, but may also occur in gliomas. Thus, this is a target of great interest for this group of patients. In a nine-year-old male patient, an anaplastic astrocytoma in the left temporoparietal region was diagnosed histologically. After first- and second-line treatment, a malignant progression to a secondary glioblastoma was observed ten years after the initial diagnosis. Within the following seven years, all other conventional treatment options were exhausted. At this time point, recurrent tumor histology revealed an epithelioid glioblastoma, without a mutation in the isocitrate dehydrogenase gene ( wild-type). In order to identify a potential target for an experimental salvage therapy, mutational tumor analysis showed a mutation. Consecutively, dabrafenib treatment was initiated. The patient remained clinically stable, and follow-up magnetic resonance images (MRI) were consistent with "Stable Disease" according to the Response Assessment in Neuro-Oncology Working Group (RANO) criteria for the following ten months until tumor progression was detected. The patient died 16 months after dabrafenib treatment initiation. Particularly in younger glioma patients as well as in patients with an epithelioid glioblastoma, screening for a mutation is promising since, in these cases, targeted therapy with inhibitors seems to be a useful salvage treatment option.
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http://dx.doi.org/10.3390/ijms19041090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979405PMC
April 2018

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.

Acta Neuropathol 2018 08 21;136(2):273-291. Epub 2018 Mar 21.

Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
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http://dx.doi.org/10.1007/s00401-018-1837-8DOI Listing
August 2018

Distinct transcriptomic changes in E14.5 mouse skeletal muscle lacking RYR1 or Cav1.1 converge at E18.5.

PLoS One 2018 15;13(3):e0194428. Epub 2018 Mar 15.

Institute of Vegetative Physiology, Center of Physiology and Pathophysiology, University of Cologne, Cologne, Germany.

In skeletal muscle the coordinated actions of two mechanically coupled Ca2+ channels-the 1,4-dihydropyridine receptor (Cav1.1) and the type 1 ryanodine receptor (RYR1)-underlie the molecular mechanism of rapid cytosolic [Ca2+] increase leading to contraction. While both [Ca2+]i and contractile activity have been implicated in the regulation of myogenesis, less is known about potential specific roles of Cav1.1 and RYR1 in skeletal muscle development. In this study, we analyzed the histology and the transcriptomic changes occurring at E14.5 -the end of primary myogenesis and around the onset of intrauterine limb movement, and at E18.5 -the end of secondary myogenesis, in WT, RYR1-/-, and Cav1.1-/- murine limb skeletal muscle. At E14.5 the muscle histology of both mutants exhibited initial alterations, which became much more severe at E18.5. Immunohistological analysis also revealed higher levels of activated caspase-3 in the Cav1.1-/- muscles at E14.5, indicating an increase in apoptosis. With WT littermates as controls, microarray analyses identified 61 and 97 differentially regulated genes (DEGs) at E14.5, and 493 and 1047 DEGs at E18.5, in RYR1-/- and Cav1.1-/- samples, respectively. Gene enrichment analysis detected no overlap in the affected biological processes and pathways in the two mutants at E14.5, whereas at E18.5 there was a significant overlap of DEGs in both mutants, affecting predominantly processes linked to muscle contraction. Moreover, the E18.5 vs. E14.5 comparison revealed multiple genotype-specific DEGs involved in contraction, cell cycle and miRNA-mediated signaling in WT, neuronal and bone development in RYR1-/-, and lipid metabolism in Cav1.1-/- samples. Taken together, our study reveals discrete changes in the global transcriptome occurring in limb skeletal muscle from E14.5 to E18.5 in WT, RYR1-/- and Cav1.1-/- mice. Our results suggest distinct functional roles for RYR1 and Cav1.1 in skeletal primary and secondary myogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194428PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854361PMC
July 2018

DNA methylation-based classification of central nervous system tumours.

Nature 2018 03 14;555(7697):469-474. Epub 2018 Mar 14.

Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
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http://dx.doi.org/10.1038/nature26000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093218PMC
March 2018

Long-Time Course of Idiopathic Small Fiber Neuropathy.

Eur Neurol 2018 8;79(3-4):161-165. Epub 2018 Mar 8.

Department of Neurology, University Hospital of Cologne, Cologne, Germany.

Background: Small fiber neuropathy (SFN) is a challenging subtype of peripheral neuropathies. Once the diagnosis has been established, there is an uncertainty how SFN may progress, whether larger fibers will become involved over time, whether quality of life may be compromised, or whether repeated diagnostic workup in patients with unknown underlying cause may increase the yield of treatable causes of SFN.

Methods: We evaluated 16 patients with documented long-time course of idiopathic SFN.

Results: Clinical and electrophysiological course remained stable in 75% of the patients, while 25% SFN-patients developed large fiber neuropathies.

Conclusions: Our data suggest that SFN represents a benign disease course in the majority of patients without severely limiting the quality of life.
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http://dx.doi.org/10.1159/000487717DOI Listing
January 2019
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