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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
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| 3. |
- Elsik, Christine G., et al.
(författare)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Tidskriftsartikel (refereegranskat)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 4. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 5. |
- Carrière, Yves, et al.
(författare)
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Crop rotation mitigates impacts of corn rootworm resistance to transgenic Bt corn
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:31, s. 18385-18392
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Tidskriftsartikel (refereegranskat)abstract
- Transgenic crops that produce insecticidal proteins from Bacillus thuringiensis (Bt) can suppress pests and reduce insecticide sprays, but their efficacy is reduced when pests evolve resistance. Although farmers plant refuges of non-Bt host plants to delay pest resistance, this tactic has not been sufficient against the western corn rootworm, Diabrotica virgifera virgifera. In the United States, some populations of this devastating pest have rapidly evolved practical resistance to Cry3 toxins and Cry34/35Ab, the only Bt toxins in commercially available corn that kill rootworms. Here, we analyzed data from 2011 to 2016 on Bt corn fields producing Cry3Bb alone that were severely damaged by this pest in 25 cropreporting districts of Illinois, Iowa, and Minnesota. The annual mean frequency of these problem fields was 29 fields (range 7 to 70) per million acres of Cry3Bb corn in 2011 to 2013, with a cost of $163 to $227 per damaged acre. The frequency of problem fields declined by 92% in 2014 to 2016 relative to 2011 to 2013 and was negatively associated with rotation of corn with soybean. The effectiveness of corn rotation for mitigating Bt resistance problems did not differ significantly between crop-reporting districts with versus without prevalent rotation-resistant rootworm populations. In some analyses, the frequency of problem fields was positively associated with planting of Cry3 corn and negatively associated with planting of Bt corn producing both a Cry3 toxin and Cry34/35Ab. The results highlight the central role of crop rotation for mitigating impacts of D. v. virgifera resistance to Bt corn.
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| 6. |
- Gonzalez-Robles, Cristina, et al.
(författare)
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Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials
- 2024
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Ingår i: Movement Disorders. - 0885-3185 .- 1531-8257. ; 39:2, s. 433-438
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. Objectives: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. Methods: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. Results: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. Conclusions: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 7. |
- Gonzalez-Robles, Cristina, et al.
(författare)
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Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative
- 2023
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Ingår i: JOURNAL OF PARKINSONS DISEASE. - 1877-7171 .- 1877-718X. ; 13:6, s. 1013-1035
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory ofOMwas created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.
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| 8. |
- Carroll, Antonia S., et al.
(författare)
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Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice
- 2024
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Ingår i: AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS. - 1350-6129 .- 1744-2818.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. Methods: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. Results: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008). Conclusions: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.
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| 9. |
- Carroll, David C., et al.
(författare)
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Dynamic control and enhancement of laser-accelerated protons using multiple laser pulses
- 2009
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Ingår i: Comptes Rendus. Physique. - : Elsevier BV. - 1631-0705. ; 10:2-3, s. 188-196
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Tidskriftsartikel (refereegranskat)abstract
- The use of schemes involving multiple laser pulses to enhance and control the properties of beams of protons accelerated in ultra-intense laser irradiation of planar foil targets is discussed. Specifically, the schemes include the use of a second laser pulse to produce and control preplasma expansion of the target to enhance energy coupling to the proton beam; the use of a second laser pulse to drive shock deformation of the target to change the direction of the proton beam; and a scheme involving dual high intensity laser pulses to change the properties of the sheath field, with the aim of modifying the proton energy spectrum. An overview of our recent experimental and theoretical results is given. The overall aim of this work is to determine the extent to which the properties of the sheath-accelerated proton beam can be optically controlled, to enable beam delivery at high repetition rates. To cite this article: D.C. Carroll et al., C. R. Physique 10 (2009). (C) 2009 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
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| 10. |
- Dall'Era, Marc A., et al.
(författare)
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Active surveillance for early-stage prostate cancer : review of the current literature
- 2008
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 112:8, s. 1650-9
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Tidskriftsartikel (refereegranskat)abstract
- The natural history of prostate cancer is remarkably heterogeneous and, at this time, not completely understood. The widespread adoption and application of prostate-specific antigen (PSA) screening has led to a dramatic shift toward the diagnosis of low-volume, nonpalpable, early-stage tumors. Autopsy and early observational studies have shown that approximately 1 in 3 men aged >50 years has histologic evidence of prostate cancer, with a significant portion of tumors being small and possibly clinically insignificant. Utilizing the power of improved contemporary risk stratification schema to better identify patients with a low risk of cancer progression, several centers are gaining considerable experience with active surveillance and delayed, selective, and curative therapy. A literature review was performed to evaluate the rationale behind active surveillance for prostate cancer and to describe the early experiences from surveillance protocols. It appears that a limited number of men on active surveillance have required treatment, with the majority of such men having good outcomes after delayed selective intervention for progressive disease. The best candidates for active surveillance are being defined, as are predictors of active treatment. The psychosocial ramifications of surveillance for prostate cancer can be profound and future needs and unmet goals will be discussed.
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| 11. |
- Holmfeldt, Linda, et al.
(författare)
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The genomic landscape of hypodiploid acute lymphoblastic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:3, s. 242-252
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Tidskriftsartikel (refereegranskat)abstract
- The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
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| 12. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 13. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 14. |
- Strålin, Kristoffer, et al.
(författare)
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Performance of PCR/electrospray ionization-mass spectrometry on whole blood for detection of bloodstream microorganisms in patients with suspected sepsis
- 2020
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Ingår i: Journal of Clinical Microbiology. - : American Society for Microbiology. - 0095-1137 .- 1098-660X. ; 58:9, s. e01860-19
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Tidskriftsartikel (refereegranskat)abstract
- Blood culture (BC) often fails to detect bloodstream microorganisms in sepsis. However, molecular diagnostics hold great potential. The molecular method PCR/electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect DNA from hundreds of different microorganisms in whole blood. The aim of the present study was to evaluate the performance of this method in a multicenter study including 16 teaching hospitals in the USA (n=13) and Europe (n=3). First, on 2,754 contrived whole blood samples, with or without spiked microorganisms, PCR/ESI-MS produced 99.1% true positive and 97.2% true negative results. Secondly, among 1,460 patients with suspected sepsis (sepsis-2 definition), BC and PCR/ESI-MS on whole blood were positive in 14.6% and 25.6% of cases, respectively, with the following result combinations: BC+/PCR/ESI-MS-, 4.3%; BC+/PCR/ESI-MS+, 10.3%; BC-/PCR/ESI-MS+, 15.3%; and BC-/PCR/ESI-MS-, 70.1%. Compared with BC, PCR/ESI-MS showed the following sensitivities (coagulase-negative staphylococci not included): Gram-positive bacteria, 58%; Gram-negative bacteria, 78%; and Candida species, 83%. The specificities were > 94% for all individual species. Patients treated with prior antimicrobial medications (n=603) had significantly increased PCR/ESI-MS positivity rates compared with patients without prior antimicrobial treatment, 31% vs 22% (p<0.0001), with pronounced differences for Gram-negative bacteria and Candida species. In conclusion, PCR/ESI-MS showed excellent performance on contrived samples. On clinical samples, it showed high specificities, moderately high sensitivities for Gram-negative bacteria and Candida species, and elevated positivity rates during antimicrobial treatment. These promising results encourage further development of molecular diagnostics on whole blood for detection of bloodstream microorganisms in sepsis.
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| 15. |
- Van Deerlin, Vivian M, et al.
(författare)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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| 16. |
- Wang, Li-San, et al.
(författare)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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