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| 2. |
- Agarwal, Prasoon, et al.
(författare)
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Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:6, s. 6809-6923
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
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| 3. |
- Agarwal, Prasoon, et al.
(författare)
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Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
- 2016
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Ingår i: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 15:12, s. 1558-1571
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Tidskriftsartikel (refereegranskat)abstract
- CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.
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| 4. |
- Agarwal, Prasoon, et al.
(författare)
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The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.
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| 5. |
- Berthenet, Elvire, et al.
(författare)
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A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk
- 2018
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Ingår i: BMC Biology. - : BioMed Central. - 1741-7007. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.RESULTS:We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.CONCLUSION:There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.
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| 6. |
- Dicksved, Johan, et al.
(författare)
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Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls
- 2009
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Ingår i: Journal of Medical Microbiology. - : Microbiology Society. - 0022-2615 .- 1473-5644. ; 58:4, s. 509-516
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Tidskriftsartikel (refereegranskat)abstract
- Persistent infection of the gastric mucosa by Helicobacter pylori can initiate an inflammatory cascade that progresses into atrophic gastritis, a condition associated with reduced capacity for secretion of gastric acid and an increased risk of developing gastric cancer. The role of H. pylori as an initiator of inflammation is evident but the mechanism for development into gastric cancer has not yet been proven. A reduced capacity for gastric acid secretion allows survival and proliferation of other microbes that normally are killed by the acidic environment. It has been postulated that some of these species may be involved in the development of gastric cancer; however, their identities are poorly defined. In this study, the gastric microbiota from ten patients with gastric cancer was characterized and compared with that from five dyspeptic controls using the molecular profiling approach terminal restriction fragment length polymorphism (T-RFLP), in combination with 16S rRNA gene cloning and sequencing. T-RFLP analysis revealed a complex bacterial community in the cancer patients that was not significantly different from that in the controls. Sequencing of 140 clones revealed 102 phylotypes, with representatives from five bacterial phyla (Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Fusobacteria). The data revealed a relatively low abundance of H. pylori and showed that the gastric cancer microbiota was instead dominated by different species of the genera Streptococcus, Lactobacillus, Veillonella and Prevotella. The respective role of these species in development of gastric cancer remains to be determined.
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| 7. |
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| 8. |
- Enroth, Helena, et al.
(författare)
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Evaluation of QuickFISH and maldi Sepsityper for identification of bacteria in bloodstream infection
- 2019
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 51:4, s. 249-258
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of bacteria and their antibiotic susceptibility patterns are critical to guide therapeutic decision-making for optimal care of septic patients. The current gold standard, blood culturing followed by subculture on agar plates for subsequent identification, is too slow leading to excessive use of broad-spectrum antibiotic with harmful consequences for the patient and, in the long run, the public health. The aim of the present study was to assess the performance of two commercial assays, QuickFISH® (OpGen) and Maldi Sepsityper™ (Bruker Daltonics) for early and accurate identification of microorganisms directly from positive blood cultures.Materials and methods: During two substudies of positive blood cultures, the two commercial assays were assessed against the routine method used at the clinical microbiology laboratory, Unilabs AB, at Skaraborg Hospital, Sweden.Results: The Maldi Sepsityper™ assay enabled earlier microorganism identification. Using the cut-off for definite species identification according to the reference method (>2.0), sufficiently accurate species identification was achieved, but only among Gram-negative bacteria. The QuickFISH®assay was time-saving and showed high concordance with the reference method, 94.8% (95% CI 88.4–98.3), when the causative agent was covered by the QuickFISH® assay.Conclusions: The use of the commercial assays may shorten the time to identification of causative agents in bloodstream infections and can be a good complement to the current clinical routine diagnostics. Nevertheless, the performance of the commercial assays is considerably affected by the characteristics of the causative agents.
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| 9. |
- Enroth, Helena
(författare)
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Helicobacter pylori bacterial diversity and human disease : microbiological and epidemiological studies with special reference to gastric cancer
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this thesis were to explore if the coccoid form of H. pylori is a degenerative, dead form of the bacteria. We also wanted to study if multiple strain infections of H. pylori existed in Swedish subjects, if the strain variations were connected to certain disease groups, and if specific protein markers could be found in H. pylori strains isolated from patients with different gastric diseases. Further, we wanted to detect specific risk modifiers in the host as well as in the bacteria that influence the association between H. pylori infection and gastric cancer, and we investigated if all strain types of H. pylori were associated with an increased gastric cancer risk. Degenerative changes, observed as changes in intracellular composition and surface properties, were analyzed in the coccoid form of H. pylori by several techniques in vitro. The coccoid form was found to be a dead, non-viable form of the microorganism which pose no risk for transmission of infection from the environment. To test the inter- and intrapatient variation of H. pylori strains, genomic fingerprints and cagA status were determined by PCR for a total of 30 clinical isolates from three different disease groups. From each isolate, ten bacterial colonies were tested. The degree of homogeneity within single strains was high, since all ten colonies from each isolate gave identical fingerprints. No multiple strain infections, but an extensive inter patient variation, was observed. Subclones of H. pylori with different cagA status, indicating differences in virulence, were observed in five subjects. In a patient with multiple strain infection, who underwent clarithromycin eradication treatment, the underrepresented strain was found to be mutated in the 23S rRNA gene, was resistant to the antibiotic, and underwent clonal expansion. This resulted in recurrence of the infection. To investigate whether H. pylori strains isolated from patients with different gastric diseases express disease specific proteins, two-dimensional gel electrophoresis (2-D PAGE) on 16 strains of H. pylori was performed. No marker proteins were found, but some clustering of strains isolated from the same disease group was observed by dendrogram analysis. The extensive strain variation that H. pylori exhibits, not only on the genome, but also on the protein level, was highlighted. Bacterial factors, the contribution of the diagnostic methods used for detection of H. pylori infection, and the associated gastric cancer risks were explored in a hospital-based case control study. In total, 72 gastric cancer cases and 324 controls were included at the time of endoscopy. H. pylori status was determined by culture, immunohistochemistry, ELISA and immunoblotting. Strains of H. pylori were tested for presence of the cagA gene and the vacA gene (s1/s2, m1/m2). Positive antibody reactions to the proteins VacA, CagA, and four other proteins were detected. These results were used to classify H. pylori strains into highly virulent type I (CagA/VacA positive), intermediate, and type 11 with low virulence (CagA/VacA negative). In this study, H. pylori strain type I and the intermediate type, as well as antibodies towards CagA, were associated with increased risk of gastric adenocarcinoma. Subjects with increasing antibody levels and subjects diagnosed with past or present H. pylori infection are also at an increased risk. In conclusion, H. pylori strains are highly diverse, and strain variations influence the pathogenicity of the infecting strain. Highly virulent strains of H. pylori are associated with an increased gastric cancer risk. Treatment of H. pylori infection could be reserved only for those infected by virulent strains in the future, as our results show that the type of strain determines the nature of disease complicating chronic H. pylori infection.
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| 10. |
- Enroth, Helena, et al.
(författare)
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Infectious Diseases : Helicobacter pylori
- 2015
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Ingår i: Reference Module in Biomedical Sciences. - : Elsevier. - 9780128012383
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Helicobacter pylori infection is one of the most common human infections in the world. The bacteria cause peptic ulcer disease and their infection is an important factor for gastric cancer development. The bacteria are transmitted from person to person within families, with young children most often infected. The bacteria reside in the stomach for a lifetime if untreated by antimicrobial agents. Many virulence factors are known that contribute to the persistence of the bacteria in the stomach, and the bacteria harbors a pathogenicity island in its genome. The discovery of H. pylori as a cause of gastritis in the stomach led to the Nobel Prize in Physiology or Medicine 2005.
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