| 1. |
- Askling, Johan, et al.
(författare)
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Anti-TNF therapy in RA and risk of malignant lymphomas Relative risks and time-trends in the Swedish Biologics Register
- 2008
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 68:5, s. 648-653
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern.Methods: Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67 743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n = 6604) were identified. A general population comparator (n = 471 024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals.Results: Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26 981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365 026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3 355 849 person-years). RA patients starting anti-TNF therapy in 1998–2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent.Conclusion: Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.
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| 2. |
- Barrientos-Somarribas, Mauricio, et al.
(författare)
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Discovering viral genomes in human metagenomic data by predicting unknown protein families
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Massive amounts of metagenomics data are currently being produced, and in all such projects a sizeable fraction of the resulting data shows no or little homology to known sequences. It is likely that this fraction contains novel viruses, but identification is challenging since they frequently lack homology to known viruses. To overcome this problem, we developed a strategy to detect ORFan protein families in shotgun metagenomics data, using similarity-based clustering and a set of filters to extract bona fide protein families. We applied this method to 17 virus-enriched libraries originating from human nasopharyngeal aspirates, serum, feces, and cerebrospinal fluid samples. This resulted in 32 predicted putative novel gene families. Some families showed detectable homology to sequences in metagenomics datasets and protein databases after reannotation. Notably, one predicted family matches an ORF from the highly variable Torque Teno virus (TTV). Furthermore, follow-up from a predicted ORFan resulted in the complete reconstruction of a novel circular genome. Its organisation suggests that it most likely corresponds to a novel bacteriophage in the microviridae family, hence it was named bacteriophage HFM.
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| 3. |
- Bzhalava, Davit, et al.
(författare)
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Phylogenetically diverse TT virus viremia among pregnant women
- 2012
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Ingår i: Virology. - : Elsevier BV. - 1096-0341 .- 0042-6822. ; 432:2, s. 427-434
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Tidskriftsartikel (refereegranskat)abstract
- Infections during pregnancy have been suggested to be involved in childhood leukemias. We used high-throughput sequencing to describe the viruses most readily detectable in serum samples of pregnant women. Serum DNA of 112 mothers to leukemic children was amplified using whole genome amplification. Sequencing identified one TT virus (TTV) isolate belonging to a known type and two putatively new TTVs. For 22 mothers, we also performed ITV amplification by general primer PCR before sequencing. This detected 39 TTVs, two of which were identical to the Tilts found after whole genome amplification. Altogether, we found 40 TTV isolates, 29 of which were putatively new types (similarities ranging from 89% to 69%). In conclusion, high throughput sequencing is useful to describe the known or unknown viruses that are present in serum samples of pregnant women. (C) 2012 Elsevier Inc. All rights reserved.
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| 4. |
- Karlsson, Elin, et al.
(författare)
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Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis
- 2015
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 10:12, s. e0145013-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.Materials and methodsWhole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.ResultsGenome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.
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| 5. |
- Lekander, Ingrid, et al.
(författare)
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The cost-effectiveness of TNF-inhibitors for the treatment of rheumatoid arthritis in Swedish clinical practice
- 2013
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Ingår i: European Journal of Health Economics. - : Springer Science and Business Media LLC. - 1618-7601 .- 1618-7598. ; 14:6, s. 863-873
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Tidskriftsartikel (refereegranskat)abstract
- The objective was to estimate the cost-effectiveness of TNF-inhibitors for the treatment of rheumatoid arthritis in Swedish clinical practice, both as a first and second biological treatment, with or without the combination of conventional DMARDs. Further sub-group analysis of etanercept treatment was performed. Patient level data were obtained from three regions of the Swedish Rheumatology Registers. The dataset contained 2,558 patients who had started TNF-inhibitor treatment, 1,049 with etanercept as their first biological treatment. A total of 819 patients had switched to a second TNF-inhibitor, of which 425 to etanercept. A Markov cohort model was used in which health states of disease severity were classified according to HAQ and DAS28. Disease progression and discontinuation rates of TNF-inhibitors were based on the registry and for the comparator on published literature. Mortality, costs and utilities were based on Swedish data. The main analysis had a societal perspective over 20 years and efficacy was measured in quality-adjusted life-years (QALYs). TNF-inhibitor treatment was associated with an increase in QALYs and an incremental cost compared to no biological treatment. The cost per QALY gained with the three TNF-inhibitors ranged from a,not sign50,000 to a,not sign120,000, with lower estimates for TNF-inhibitors used in combination with MTX and as a first biologic. At a progression of 0.045 for the comparator, most values remain within the accepted range for cost-effectiveness. These results demonstrate that the cost per QALY for TNF-inhibitors was higher than in previous assessments based on registry data and that the results were sensitive to the HAQ progression of the comparator.
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| 6. |
- Lysholm, Fredrik, et al.
(författare)
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An efficient simulator of 454 data using configurable statistical models
- 2011
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Ingår i: BMC Research Notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 4:449
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRoche 454 is one of the major 2nd generation sequencing platforms. The particular characteristics of 454 sequence data pose new challenges for bioinformatic analyses, e.g. assembly and alignment search algorithms. Simulation of these data is therefore useful, in order to further assess how bioinformatic applications and algorithms handle 454 data.FindingsWe developed a new application named 454sim for simulation of 454 data at high speed and accuracy. The program is multi-thread capable and is available as C++ source code or pre-compiled binaries. Sequence reads are simulated by 454sim using a set of statistical models for each chemistry. 454sim simulates recorded peak intensities, peak quality deterioration and it calculates quality values. All three generations of the Roche 454 chemistry ('GS20', 'GS FLX' and 'Titanium') are supported and defined in external text files for easy access and tweaking.ConclusionsWe present a new platform independent application named 454sim. 454sim is generally 200 times faster compared to previous programs and it allows for simple adjustments of the statistical models. These improvements make it possible to carry out more complex and rigorous algorithm evaluations in a reasonable time scale.
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| 7. |
- Lysholm, Fredrik, 1981-
(författare)
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Bioinformatic methods for characterization of viral pathogens in metagenomic samples
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Virus infections impose a huge disease burden on humanity and new viruses are continuously found. As most studies of viral disease are limited to theinvestigation of known viruses, it is important to characterize all circulating viruses. Thus, a broad and unselective exploration of the virus flora would be the most productive development of modern virology. Fueled by the reduction in sequencing costs and the unbiased nature of shotgun sequencing, viral metagenomics has rapidly become the strategy of choice for this exploration.This thesis mainly focuses on improving key methods used in viral metagenomics as well as the complete viral characterization of two sets of samples using these methods. The major methods developed are an efficient automated analysis pipeline for metagenomics data and two novel, more accurate, alignment algorithms for 454 sequencing data. The automated pipeline facilitates rapid, complete and effortless analysis of metagenomics samples, which in turn enables detection of potential pathogens, for instance in patient samples. The two new alignment algorithms developed cover comparisons both against nucleotide and protein databases, while retaining the underlying 454 data representation. Furthermore, a simulator for 454 data was developed in order to evaluate these methods. This simulator is currently the fastest and most complete simulator of 454 data, which enables further development of algorithms and methods. Finally, we have successfully used these methods to fully characterize a multitude of samples, including samples collected from children suffering from severe lower respiratory tract infections as well as patients diagnosed with chronic fatigue syndrome, both of which presented in this thesis. In these studies, a complete viral characterization has revealed the presence of both expected and unexpected viral pathogens as well as many potential novel viruses.
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| 8. |
- Lysholm, Fredrik, et al.
(författare)
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Characterization of the viral microbiome in patients with severe lower respiratory tract infections, using metagenomic sequencing
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- The human respiratory tract is heavily exposed to microorganisms. Viral respiratory tract pathogens, like RSV, influenza and rhinoviruses cause major morbidity and mortality from respiratory tract disease. Furthermore, as viruses have limited means of transmission, viruses that cause pathogenicity in other tissues may be transmitted through the respiratory tract. It is therefore important to chart the human virome in this compartment. We have studied nasopharyngeal aspirate samples submitted to the Karolinska University Laboratory, Stockholm, Sweden from March 2004 to May 2005 for diagnosis of respiratory tract infections. We have used a metagenomic sequencing strategy to characterize viruses, as this provides the most unbiased view of the samples. Virus enrichment followed by 454 sequencing resulted in totally 703,790 reads and 110,931 of these were found to be of viral origin by using an automated classification pipeline. The snapshot of the respiratory tract virome of these 210 patients revealed 39 species and many more strains of viruses. Most of the viral sequences were classified into one of three major families; Paramyxoviridae, Picornaviridae or Orthomyxoviridae. The study also identified one novel type of Rhinovirus C, and identified a number of previously undescribed viral genetic fragments of unknown origin.
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| 9. |
- Lysholm, Fredrik, et al.
(författare)
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FAAST: Flow-space Assisted Alignment Search Tool
- 2011
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Ingår i: BMC Bioinformatics. - : BioMed Central. - 1471-2105. ; 12:293
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Tidskriftsartikel (refereegranskat)abstract
- Background: High throughput pyrosequencing (454 sequencing) is the major sequencing platform for producing long read high throughput data. While most other sequencing techniques produce reading errors mainly comparable with substitutions, pyrosequencing produce errors mainly comparable with gaps. These errors are less efficiently detected by most conventional alignment programs and may produce inaccurate alignments. less thanbrgreater than less thanbrgreater thanResults: We suggest a novel algorithm for calculating the optimal local alignment which utilises flowpeak information in order to improve alignment accuracy. Flowpeak information can be retained from a 454 sequencing run through interpretation of the binary SFF-file format. This novel algorithm has been implemented in a program named FAAST (Flow-space Assisted Alignment Search Tool). less thanbrgreater than less thanbrgreater thanConclusions: We present and discuss the results of simulations that show that FAAST, through the use of the novel algorithm, can gain several percentage points of accuracy compared to Smith-Waterman-Gotoh alignments, depending on the 454 data quality. Furthermore, through an efficient multi-thread aware implementation, FAAST is able to perform these high quality alignments at high speed. The tool is available at http://www.ifm.liu.se/bioinfo/
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| 10. |
- Lysholm, Fredrik
(författare)
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Highly improved homopolymer aware nucleotide-protein alignments with 454 data
- 2012
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 13:230
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRoche 454 sequencing is the leading sequencing technology for producing long read high throughput sequence data. Unlike most methods where sequencing errors translate to base uncertainties, 454 sequencing inaccuracies create nucleotide gaps. These gaps are particularly troublesome for translated search tools such as BLASTx where they introduce frame-shifts and result in regions of decreased identity and/or terminated alignments, which affect further analysis.ResultsTo address this issue, the Homopolymer Aware Cross Alignment Tool (HAXAT) was developed. HAXAT uses a novel dynamic programming algorithm for solving the optimal local alignment between a 454 nucleotide and a protein sequence by allowing frame-shifts, guided by 454 flowpeak values. The algorithm is an efficient minimal extension of the Smith-Waterman-Gotoh algorithm that easily fits in into other tools. Experiments using HAXAT demonstrate, through the introduction of 454 specific frame-shift penalties, significantly increased accuracy of alignments spanning homopolymer sequence errors. The full effect of the new parameters introduced with this novel alignment model is explored. Experimental results evaluating homopolymer inaccuracy through alignments show a two to five-fold increase in Matthews Correlation Coefficient over previous algorithms, for 454-derived data.ConclusionsThis increased accuracy provided by HAXAT does not only result in improved homologue estimations, but also provides un-interrupted reading-frames, which greatly facilitate further analysis of protein space, for example phylogenetic analysis. The alignment tool is available at http://bioinfo.ifm.liu.se/454tools/haxat.
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