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1.
Genes Chromosomes Cancer ; 60(8): 586-590, 2021 08.
Article in English | MEDLINE | ID: mdl-33896072

ABSTRACT

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which may be also present in the germline (rhabdoid tumor predisposition syndrome 1), as well as somatic copy-number neutral loss of heterozygosity (LOH). In some SMARCB1-deficient AT/RT underlying biallelic mutations cannot be identified. Here we report the case of a 24-months-old girl diagnosed with a large brain tumor. The malignant rhabdoid tumor showed loss of nuclear SMARCB1/INI1 protein expression and the diagnosis of AT/RT was confirmed by DNA methylation profiling. While FISH, MLPA, Sanger sequencing and DNA methylation data-based imbalance analysis did not disclose alterations affecting SMARCB1, OncoScan array analysis revealed a 28.29 Mb sized region of copy-number neutral LOH on chromosome 22q involving the SMARCB1 locus. Targeted next-generation sequencing did also not detect a single nucleotide variant but instead revealed insertion of an AluY element into exon 2 of SMARCB1. Specific PCR-based Sanger sequencing verified the Alu insertion (SMARCB1 c.199_200 Alu ins) resulting in a frame-shift truncation not present in the patient's germline. In conclusion, transposable element insertion represents a hitherto not widely recognized mechanism of SMARCB1 disruption in AT/RT, which might not be detected by several widely applied conventional diagnostics assays. This finding has particular clinical implications, if rhabdoid predisposition syndrome 1 is suspected, but germline SMARCB1 alterations cannot be identified.


Subject(s)
Brain Neoplasms/genetics , Rhabdoid Tumor/genetics , SMARCB1 Protein/genetics , Teratoma/genetics , Brain Neoplasms/pathology , DNA Transposable Elements , Female , Humans , Infant , Mutagenesis, Insertional , Rhabdoid Tumor/pathology , Teratoma/pathology
2.
Pflege ; 34(6): 301-309, 2021.
Article in German | MEDLINE | ID: mdl-34647486

ABSTRACT

The Neumarkt concept of nursing case responsibility: A framework for consequent and person-centred realization of the nursing process Abstract. Background: An essential requirement for the realization of person-centred practice is a practice environment, that supports the forming of professional nurse-patient-relationships. Therefore, Klinikum Neumarkt implemented in context of practice development a concept for nursing case responsibility, that offers a framework for a person-centred and systematic coordination of the nursing process. Because of the existing conflict between economic and nursing interests, it is essential to prove the effectiveness of the concept. Aim: Our aim was the exploration of the effects of the concept implementation from the patient's as well as the interprofessional team's perspective, including the economic implications. Methods: The multiperspective evaluation was conducted with individual interviews and an economic analysis of hospital routine data. Results: The patients and the interprofessional team perceive a person-centred care and coordination of the nursing process. They also point out the required resources. The economic results show a significantly increased revenue through better documentation of complex nursing situations of patients included in the concept (Odds ratio: 4.00, 95%-Confidence Interval [2.15; 8.01], p < 0.001). Discussion: The results provide evidence of the efficacy of the concept for a systematic, person-centred coordination of the nursing process and justify an increased use of resources needed. Limitations and transfer: The implementation of the concept is a drastic change for everyone involved and needs to be embedded in a strategic practice development.


Subject(s)
Nursing Process , Patient-Centered Care , Humans , Nurse-Patient Relations
3.
BMC Cancer ; 20(1): 427, 2020 May 14.
Article in English | MEDLINE | ID: mdl-32408898

ABSTRACT

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) is considered an important driver of tumor development and progression by its histone modifying capabilities. Inhibition of EZH2 activity is thought to be a potent treatment option for eligible cancer patients with an aberrant EZH2 expression profile, thus the indirect EZH2 inhibitor 3-Deazaneplanocin A (DZNep) is currently under evaluation for its clinical utility. Although DZNep blocks proliferation and induces apoptosis in different tumor types including lymphomas, acquired resistance to DZNep may limit its clinical application. METHODS: To investigate possible mechanisms of acquired DZNep resistance in B-cell lymphomas, we generated a DZNep-resistant clone from a previously DZNep-sensitive B-cell lymphoma cell line by long-term treatment with increasing concentrations of DZNep (ranging from 200 to 2000 nM) and compared the molecular profiles of resistant and wild-type clones. This comparison was done using molecular techniques such as flow cytometry, copy number variation assay (OncoScan and TaqMan assays), fluorescence in situ hybridization, Western blot, immunohistochemistry and metabolomics analysis. RESULTS: Whole exome sequencing did not indicate the acquisition of biologically meaningful single nucleotide variants. Analysis of copy number alterations, however, demonstrated among other acquired imbalances an amplification (about 30 times) of the S-adenosyl-L-homocysteine hydrolase (AHCY) gene in the resistant clone. AHCY is a direct target of DZNep and is critically involved in the biological methylation process, where it catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine to L-homocysteine and adenosine. The amplification of the AHCY gene is paralleled by strong overexpression of AHCY at both the transcriptional and protein level, and persists upon culturing the resistant clone in a DZNep-free medium. CONCLUSIONS: This study reveals one possible molecular mechanism how B-cell lymphomas can acquire resistance to DZNep, and proposes AHCY as a potential biomarker for investigation during the administration of EZH2-targeted therapy with DZNep.


Subject(s)
Adenosine/analogs & derivatives , Adenosylhomocysteinase/genetics , Apoptosis , DNA Copy Number Variations , Drug Resistance, Neoplasm , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Lymphoma, B-Cell/pathology , Adenosine/pharmacology , Cell Proliferation , Humans , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/genetics , Tumor Cells, Cultured
6.
Virchows Arch ; 479(1): 133-145, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33528622

ABSTRACT

Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia.


Subject(s)
Biomarkers, Tumor/genetics , Chromosome Breakpoints , Cyclin D1/genetics , Gene Rearrangement , Lymphoma, Mantle-Cell/genetics , Proto-Oncogene Proteins c-myc/genetics , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Child, Preschool , Clonal Evolution , Comparative Genomic Hybridization , Cytogenetic Analysis , DNA Nucleotidylexotransferase/analysis , Diagnosis, Differential , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Immunophenotyping , Lymphoma, Mantle-Cell/immunology , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Neoplasm Grading , Phenotype , Predictive Value of Tests
7.
Cell Commun Signal ; 6: 9, 2008 Oct 28.
Article in English | MEDLINE | ID: mdl-18957108

ABSTRACT

Life on Earth developed in the presence and under the constant influence of gravity. Gravity has been present during the entire evolution, from the first organic molecule to mammals and humans. Modern research revealed clearly that gravity is important, probably indispensable for the function of living systems, from unicellular organisms to men. Thus, gravity research is no more or less a fundamental question about the conditions of life on Earth. Since the first space missions and supported thereafter by a multitude of space and ground-based experiments, it is well known that immune cell function is severely suppressed in microgravity, which renders the cells of the immune system an ideal model organism to investigate the influence of gravity on the cellular and molecular level. Here we review the current knowledge about the question, if and how cellular signal transduction depends on the existence of gravity, with special focus on cells of the immune system. Since immune cell function is fundamental to keep the organism under imnological surveillance during the defence against pathogens, to investigate the effects and possible molecular mechanisms of altered gravity is indispensable for long-term space flights to Earth Moon or Mars. Thus, understanding the impact of gravity on cellular functions on Earth will provide not only important informations about the development of life on Earth, but also for therapeutic and preventive strategies to cope successfully with medical problems during space exploration.

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