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140 Publications visible to you, out of a total of 140
A modular transcriptome map of mature B cell lymphomas

Abstract (Expand)

Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic … phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. Keywords: B cell malignancies; Gene regulation; Machine learning; Molecular subtypes; Tumor heterogeneity.

Authors: Henry Loeffler-Wirth, Markus Kreuz, Lydia Hopp, Arsen Arakelyan, Andrea Haake, Sergio B. Cogliatti, Alfred C. Feller, Martin-Leo Hansmann, Dido Lenze, Peter Möller, Hans Konrad Müller-Hermelink, Erik Fortenbacher, Edith Willscher, German Ott, Andreas Rosenwald, Christiane Pott, Carsten Schwaenen, Heiko Trautmann, Swen Wessendorf, Harald Stein, Monika Szczepanowski, Lorenz Trümper, Michael Hummel, Wolfram Klapper, Reiner Siebert, Markus Loeffler, Hans Binder

Date Published: 30th Apr 2019

Publication Type: Journal

Population Levels Assessment of the Distribution of Disease-Associated Variants With Emphasis on Armenians – A Machine Learning Approach

Abstract (Expand)

Background: During the last decades a number of genome-wide association studies (GWASs) has identified numerous single nucleotide polymorphisms (SNPs) associated with different complex diseases. However, … associations reported in one population are often conflicting and did not replicate when studied in other populations. One of the reasons could be that most GWAS employ a case-control design in one or a limited number of populations, but little attention was paid to the global distribution of disease-associated alleles across different populations. Moreover, the majority of GWAS have been performed on selected European, African, and Chinese populations and the considerable number of populations remains understudied. Aim: We have investigated the global distribution of so far discovered disease-associated SNPs across worldwide populations of different ancestry and geographical regions with a special focus on the understudied population of Armenians. Data and Methods: We have used genotyping data from the Human Genome Diversity Project and of Armenian population and combined them with disease-associated SNP data taken from public repositories leading to a final dataset of 44,234 markers. Their frequency distribution across 1039 individuals from 53 populations was analyzed using self-organizing maps (SOM) machine learning. Our SOM portrayal approach reduces data dimensionality, clusters SNPs with similar frequency profiles and provides two-dimensional data images which enable visual evaluation of disease-associated SNPs landscapes among human populations. Results: We find that populations from Africa, Oceania, and America show specific patterns of minor allele frequencies of disease-associated SNPs, while populations from Europe, Middle East, Central South Asia, and Armenia mostly share similar patterns. Importantly, different sets of SNPs associated with common polygenic diseases, such as cancer, diabetes, neurodegeneration in populations from different geographic regions. Armenians are characterized by a set of SNPs that are distinct from other populations from the neighboring geographical regions. Conclusion: Genetic associations of diseases considerably vary across populations which necessitates health-related genotyping efforts especially for so far understudied populations. SOM portrayal represents novel promising methods in population genetic research with special strength in visualization-based comparison of SNP data.

Authors: Maria Nikoghosyan, Siras Hakobyan, Anahit Hovhannisyan, Henry Loeffler-Wirth, Hans Binder, Arsen Arakelyan

Date Published: 26th Apr 2019

Publication Type: Journal

Inhibition of African swine fever virus infection by genkwanin.

Abstract (Expand)

African swine fever virus (ASFV) is the causative agent of an economically important disease of pigs for which no effective vaccines or antiviral drugs are available. Recent outbreaks in EU countries … and China have highlighted the critical role of antiviral research in combating this disease. We have previously shown that apigenin, a naturally occurring plant flavone, possesses significant anti-ASFV activity. However, apigenin is practically insoluble in highly polar solvents and it occurs typically in derivative forms in plants. Here we screened several commercially available apigenin derivatives for their ability to inhibit ASFV Ba71V strain in Vero cells. Among them, genkwanin showed significant inhibition of ASFV, reducing viral titer from 6.5 ± 0.1 to 4.75 ± 0.25 log TCID/ml in a dose-dependent manner (IC<sub>50</sub> = 2.9 μM and SI = 205.2). Genkwanin reduced the levels of ASFV early and late proteins, as well as viral DNA synthesis. Our further experiments indicated that genkwanin is able to inhibit ASFV infection at entry and egress stages. Finally, genkwanin displayed potent antiviral activity against highly virulent ASFV isolate currently circulating in Europe and China, emphasizing its value as candidate for antiviral drug development.

Authors: Astghik Hakobyan, Erik Arabyan, Armen Kotsinyan, Zaven Karalyan, Harutyun Sahakyan, Vahram Arakelov, Karen Nazaryan, Fernando Ferreira, Hovakim Zakaryan

Date Published: 13th Apr 2019

Publication Type: Journal

Telomere shortening in blood leukocytes of patients with posttraumatic stress disorder

Abstract (Expand)

Telomeres are protective fragments on chromosome ends involved in maintaining genome stability, preventing chromosomal fusions, regulation of cell division. It was shown that telomere attrition rate … is accelerated in age-related diseases, as well as in response to physiological and psychosocial stress. The aim of this study was to evaluate relative leukocyte telomere length (LTL) in patients with post traumatic stress disorder (PTSD), as well as to investigate association of functional SNPs of telomerase TERC and TERT genes with LTL and PTSD. The relative LTL was measured by multiplex quantitative PCR method; genotyping of TERC rs12696304, TERT rs7726159 and rs2736100 was performed by PCR with sequence specific primers. Comparison of LTL in diseased and healthy subjects showed that PTSD patients had shorter average LTL than controls. Also, the frequency and the carriage rate of the TERT rs2736100*T allele was higher in PTSD patients compared to controls. Overall our results are in line with previous research in different populations. Furthermore, we have demonstrated that rs2736100 of TERT gene was significantly associated with PTSD and the minor allele of this polymorphism may be considered as a risk factor for PTSD in the Armenian population.

Authors: Diana Avetyan, Roksana Zakharyan, Martin Petrek, Arsen Arakelyan

Date Published: 21st Jan 2019

Publication Type: Journal

Genistein inhibits African swine fever virus replication in vitro by disrupting viral DNA synthesis.

Abstract (Expand)

African swine fever virus (ASFV) is the causal agent of a highly-contagious and fatal disease of domestic pigs, leading to serious socio-economic consequences in affected countries. Once, neither an … anti-viral drug nor an effective vaccines are available, studies on new anti-ASFV molecules are urgently need. Recently, it has been shown that ASFV type II topoisomerase (ASFV-topo II) is inhibited by several fluoroquinolones (bacterial DNA topoisomerase inhibitors), raising the idea that this viral enzyme can be a potential target for drug development against ASFV. Here, we report that genistein hampers ASFV infection at non-cytotoxic concentrations in Vero cells and porcine macrophages. Interestingly, the antiviral activity of this isoflavone, previously described as a topo II poison in eukaryotes, is maximal when it is added to cells at middle-phase of infection (8 hpi), disrupting viral DNA replication, blocking the transcription of late viral genes as well as the synthesis of late viral proteins, reducing viral progeny. Further, the single cell electrophoresis analysis revealed the presence of fragmented ASFV genomes in cells exposed to genistein, suggesting that this molecule also acts as an ASFV-topo II poison and not as a reversible inhibitor. No antiviral effects were detected when genistein was added before or at entry phase of ASFV infection. Molecular docking studies demonstrated that genistein may interact with four residues of the ATP-binding site of ASFV-topo II (Asn-144, Val-146, Gly-147 and Leu-148), showing more binding affinity (-4.62 kcal/mol) than ATP<sup>4-</sup> (-3.02 kcal/mol), emphasizing the idea that this viral enzyme has an essential role during viral genome replication and can be a good target for drug development against ASFV.

Authors: Erik Arabyan, Astghik Hakobyan, Armen Kotsinyan, Zaven Karalyan, Vahram Arakelov, Grigor Arakelov, Karen Nazaryan, Anna Simonyan, Rouben Aroutiounian, Fernando Ferreira, Hovakim Zakaryan

Date Published: 22nd Jun 2018

Publication Type: Journal

Selection of Potential Therapeutic Bacteriophages that Lyse a CTX-M-15 Extended Spectrum β-Lactamase Producing Salmonella enterica Serovar Typhi Strain from the Democratic Republic of the Congo

Abstract (Expand)

Recently, a Salmonella Typhi isolate producing CTX-M-15 extended spectrum β-lactamase (ESBL) and with decreased ciprofloxacin susceptibility was isolated in the Democratic Republic of the Congo. We … have selected bacteriophages that show strong lytic activity against this isolate and have potential for phage-based treatment of S. Typhi, and Salmonella in general.

Authors: Elene Kakabadze, Khatuna Makalatia, Nino Grdzelishvili, Nata Bakuradze, Marina Goderdzishvili, Ia Kusradze, Marie-France Phoba, Octavie Lunguya, Cédric Lood, Rob Lavigne, Jan Jacobs, Stijn Deborggraeve, Tessa De Block, Sandra Van Puyvelde, David Lee, Aidan Coffey, Anahit Sedrakyan, Patrick Soentjens, Daniel De Vos, Jean-Paul Pirnay, Nina Chanishvili

Date Published: 3rd Apr 2018

Publication Type: Journal

Involvement of polymorphisms of the nerve growth factor and its receptor encoding genes in the etiopathogenesis of ischemic stroke

Abstract (Expand)

Background: Despite the important role of the nerve growth factor in the survival and maintenance of neurons in ischemic stroke, data regarding the relationships between variations in the encoding gene … and stroke are lacking. In the present study, we evaluated the association of the functional polymorphisms in NGF (rs6330) and NGFR (rs2072446 and rs734194) genes with ischemic stroke in an Armenian population. Methods: In total, 370 unrelated individuals of Armenian nationality were enrolled in this study. Genomic DNA samples of patients and healthy controls were genotyped using polymerase chain reaction with sequence-specific primers. Results: The results obtained indicate that the minor allele of rs6330 (Pcorr = 2.4E-10) and rs2072446 (Pcorr = 0.02) are significantly overrepresented in stroke group, while the minor allele of rs734194 (Pcorr = 8.5E-10) was underrepresented in diseased subjects. Single nucleotide polymorphisms in NGF gene (rs6330) and NGFR gene (rs2072446 and rs734194) are associated with the disease. Furthermore, it was shown that the carriage of the NGF rs6330*T minor allele is associated with increased infarct volume and higher risk of recurrent stroke. Conclusions: In conclusion, our findings suggest that the NGF rs6330*T and NGFR rs2072446*T minor alleles might be nominated as a risk factor for developing ischemic stroke and NGFR rs734194*G minor allele as a protective against this disease at least in Armenian population. Keywords: Ischemic stroke, Nerve growth factor, Nerve growth factor receptor, NGF, NGFR, Single nucleotide polymorphism

Authors: Ani Stepanyan, Roksana Zakharyan, Arsen Simonyan, Gohar Tsakanova, Arsen Arakelyan

Date Published: 2nd Mar 2018

Publication Type: Journal

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