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| 2. |
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| 3. |
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| 4. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 5. |
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| 6. |
- Guo, Jinan, et al.
(författare)
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A non-invasive 25-Gene PLNM-Score urine test for detection of prostate cancer pelvic lymph node metastasis
- 2024
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Nature Publishing Group. - 1365-7852 .- 1476-5608.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. Methods: An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort (n = 413) as training set and validated in an independent multi-center prospective cohort (n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. Results: An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85-1.01) and 0.93 (95% CI: 0.87-0.99) in the retrospective and prospective urine cohorts respectively. Kaplan-Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. Conclusions: The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.
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| 7. |
- Guo, Jinan, et al.
(författare)
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Non-invasive Urine Test for Molecular Classification of Clinical Significance in Newly Diagnosed Prostate Cancer Patients
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available.Methods: To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups.Results: The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892-0.942) in the retrospective cohort (n = 520), AUC of 0.959 (95% CI 0.935-0.983) in the prospective cohort (n = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort (n = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1-3 cancer subgroups.Conclusions: The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.
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| 8. |
- Johnson, Heather, et al.
(författare)
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Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up
- 2020
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Ingår i: BMC Medicine. - : BioMed Central. - 1741-7015. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. Methods: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRTPCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. Results: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963–0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929–0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956–0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980–0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947–0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. Conclusions: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.
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| 9. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 10. |
- Scott, Robert A., et al.
(författare)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Tidskriftsartikel (refereegranskat)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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| 11. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 12. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 13. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 14. |
- Alexander, Steven M., et al.
(författare)
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Qualitative data sharing and synthesis for sustainability science
- 2020
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Ingår i: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 3:2, s. 81-88
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Tidskriftsartikel (refereegranskat)abstract
- Opportunities, challenges and recommended targeted actions to accelerate qualitative data sharing to address complex socio-environmental problems Socio-environmental synthesis as a research approach contributes to broader sustainability policy and practice by reusing data from disparate disciplines in innovative ways. Synthesizing diverse data sources and types of evidence can help to better conceptualize, investigate and address increasingly complex socio-environmental problems. However, sharing qualitative data for re-use remains uncommon when compared to sharing quantitative data. We argue that qualitative data present untapped opportunities for sustainability science, and discuss practical pathways to facilitate and realize the benefits from sharing and reusing qualitative data. However, these opportunities and benefits are also hindered by practical, ethical and epistemological challenges. To address these challenges and accelerate qualitative data sharing, we outline enabling conditions and suggest actions for researchers, institutions, funders, data repository managers and publishers.
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| 15. |
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| 16. |
- Babulal, Ganesh M, et al.
(författare)
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Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.
- 2019
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:2, s. 292-312
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
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| 17. |
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| 18. |
- Boutté, Yohann, et al.
(författare)
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ECHIDNA-mediated post-Golgi trafficking of auxin carriers for differential cell elongation
- 2013
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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. ; 110:40, s. 16259-16264
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Tidskriftsartikel (refereegranskat)abstract
- The plant hormone indole-acetic acid (auxin) is essential for many aspects of plant development. Auxin-mediated growth regulation typically involves the establishment of an auxin concentration gradient mediated by polarly localized auxin transporters. The localization of auxin carriers and their amount at the plasma membrane are controlled by membrane trafficking processes such as secretion, endocytosis, and recycling. In contrast to endocytosis or recycling, how the secretory pathway mediates the localization of auxin carriers is not well understood. In this study we have used the differential cell elongation process during apical hook development to elucidate the mechanisms underlying the post-Golgi trafficking of auxin carriers in Arabidopsis. We show that differential cell elongation during apical hook development is defective in Arabidopsis mutant echidna (ech). ECH protein is required for the trans-Golgi network (TGN)-mediated trafficking of the auxin influx carrier AUX1 to the plasma membrane. In contrast, ech mutation only marginally perturbs the trafficking of the highly related auxin influx carrier LIKE-AUX1-3 or the auxin efflux carrier PIN-FORMED-3, both also involved in hook development. Electron tomography reveals that the trafficking defects in ech mutant are associated with the perturbation of secretory vesicle genesis from the TGN. Our results identify differential mechanisms for the post-Golgi trafficking of de novo-synthesized auxin carriers to plasma membrane from the TGN and reveal how trafficking of auxin influx carriers mediates the control of differential cell elongation in apical hook development.
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| 19. |
- Chami, Nathalie, et al.
(författare)
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Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 8-21
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Tidskriftsartikel (refereegranskat)abstract
- Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 x 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 x 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 x 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 x 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 x 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
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| 20. |
- Chasman, Daniel I., et al.
(författare)
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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
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Tidskriftsartikel (refereegranskat)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 21. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 22. |
- Clendenen, Tess V., et al.
(författare)
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Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 106:11, s. E4542-E4553
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Tidskriftsartikel (refereegranskat)abstract
- Context: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies.Objective: This study assessed whether risk factors for breast cancer are correlates of AMH concentration.Methods: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population.Results: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05).Conclusion: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
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| 23. |
- DeCarolis, Joseph, et al.
(författare)
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Leveraging Open-Source Tools for Collaborative Macro-energy System Modeling Efforts
- 2020
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Ingår i: Joule. - : Elsevier BV. - 2542-4351. ; 4:12, s. 2523-2526
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The authors are founding team members of a new effort to develop an Open Energy Outlook for the United States. The effort aims to apply best practices of policy-focused energy system modeling, ensure transparency, build a networked community, and work toward a common purpose: examining possible US energy system futures to inform energy and climate policy efforts. Individual author biographies can be found on the project website: https://openenergyoutlook.org/. DeCarolis et al. articulate the benefits of forming collaborative teams with a wide array of disciplinary and domain expertise to conduct analysis with macro-energy system models. Open-source models, tools, and datasets underpin such efforts by enabling transparency, accessibility, and replicability among team members and with the broader modeling community.
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| 24. |
- Deming, Timothy J., et al.
(författare)
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Polymers at the Interface with Biology
- 2018
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Ingår i: Biomacromolecules. - : AMER CHEMICAL SOC. - 1525-7797 .- 1526-4602. ; 19:8, s. 3151-3162
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 25. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 26. |
- Eicher, John D., et al.
(författare)
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Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:1, s. 40-55
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Tidskriftsartikel (refereegranskat)abstract
- Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
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| 27. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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| 28. |
- 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
-
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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| 29. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
-
Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 30. |
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| 31. |
- Govaere, Olivier, et al.
(författare)
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Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
- 2020
-
Ingår i: Science Translational Medicine. - Washington, DC, United States : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 12:572
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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| 32. |
- Greenhalgh, David G., et al.
(författare)
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Surviving Sepsis After Burn Campaign
- 2023
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Ingår i: Burns. - : Elsevier. - 0305-4179 .- 1879-1409. ; 49:7, s. 1487-1524
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The Surviving Sepsis Campaign was developed to improve outcomes for all patients with sepsis. Despite sepsis being the primary cause of death after thermal injury, burns have always been excluded from the Surviving Sepsis efforts. To improve sepsis outcomes in burn patients, an international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes. Methods: The International Society for Burn Injuries (ISBI) reached out to regional or na-tional burn organizations to recommend members to participate in the program. Two members of the ISBI developed specific "patient/population, intervention, comparison and out-come" (PICO) questions that paralleled the 2021 Surviving Sepsis Campaign [1]. SSABC parti-cipants were asked to search the current literature and rate its quality for each topic. At the Congress of the ISBI, in Guadalajara, Mexico, August 28, 2022, a majority of the participants met to create "statements" based on the literature. The "summary statements" were then sent to all members for comment with the hope of developing an 80% consensus. After four reviews, a consensus statement for each topic was created or "no consensus" was reported. Results: The committee developed sixty statements within fourteen topics that provide guidance for the early treatment of sepsis in burn patients. These statements should be used to improve the care of sepsis in burn patients. The statements should not be considered as "static" comments but should rather be used as guidelines for future testing of the best treatments for in burn should be on a basis. Conclusion: Members of the burn community from the around the world have developed the Surviving Sepsis After Burn Campaign guidelines with the goal of improving the outcome of sepsis in burn patients. (c) 2023 Elsevier Ltd and ISBI. All rights reserved.
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| 33. |
- Guo, Jinan, et al.
(författare)
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A panel of biomarkers for diagnosis of prostate cancer using urine samples
- 2018
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 38:3, s. 1471-1477
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Prostate cancer (PCa) diagnosis using patient urine samples represents a non-invasive and more convenient method than the conventional biopsy and prostate-specific antigen (PSA) test. This study intended to identify a biomarker panel to distinguish PCa from benign prostate using urine samples. Materials and Methods: We identified six biomarkers with differential gene expression in 154 PCa and benign prostate specimens. We then determined mRNA expression signature and the diagnostic performance of the 6-biomarker panel in 156 urine samples from patients with PCa and benign disease. Results: The 6-biomarker panel distinguished PCa from benign prostate cases with sensitivity of 80.6%, specificity of 62.9% and area under the curve (AUC) of 0.803 (p<0.0001), whereas serum PSA at 4 ng/ml cutoff had sensitivity of 95.5%, specificity of 20.2% and AUC of 0.521 (p<0.0001). Conclusion: The 6-biomarker panel for use in urine samples was able to distinguish PCa from benign prostate with higher specificity and accuracy than PSA and may be useful in clinical settings.
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| 34. |
- Guo, Jinan, et al.
(författare)
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Establishing a Urine-Based Biomarker Assay for Prostate Cancer Risk Stratification
- 2020
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Ingår i: Frontiers in Cell and Developmental Biology. - Swiss : Frontiers Media S.A.. - 2296-634X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- One of the major features of prostate cancer (PCa) is its heterogeneity, which often leads to uncertainty in cancer diagnostics and unnecessary biopsies as well as overtreatment of the disease. Novel non-invasive tests using multiple biomarkers that can identify clinically high-risk cancer patients for immediate treatment and monitor patients with low-risk cancer for active surveillance are urgently needed to improve treatment decision and cancer management. In this study, we identified 14 promising biomarkers associated with PCa and tested the performance of these biomarkers on tissue specimens and pre-biopsy urinary sediments. These biomarkers showed differential gene expression in higher- and lower-risk PCa. The 14-Gene Panel urine test (PMP22, GOLM1, LMTK2, EZH2, GSTP1, PCA3, VEGFA, CST3, PTEN, PIP5K1A, CDK1, TMPRSS2, ANXA3, and CCND1) was assessed in two independent prospective and retrospective urine study cohorts and showed high diagnostic accuracy to identify higher-risk PCa patients with the need for treatment and lower-risk patients for surveillance. The AUC was 0.897 (95% CI 0.939–0.855) in the prospective cohort (n = 202), and AUC was 0.899 (95% CI 0.964–0.834) in the retrospective cohort (n = 97). In contrast, serum PSA and Gleason score had much lower accuracy in the same 202 patient cohorts [AUC was 0.821 (95% CI 0.879–0.763) for PSA and 0.860 (95% CI 0.910–0.810) for Gleason score]. In addition, the 14-Gene Panel was more accurate at risk stratification in a subgroup of patients with Gleason scores 6 and 7 in the prospective cohort (n = 132) with AUC of 0.923 (95% CI 0.968–0.878) than PSA [AUC of 0.773 (95% CI 0.852–0.794)] and Gleason score [AUC of 0.776 (95% CI 0.854–0.698)]. Furthermore, the 14-Gene Panel was found to be able to accurately distinguish PCa from benign prostate with AUC of 0.854 (95% CI 0.892–0.816) in a prospective urine study cohort (n = 393), while PSA had lower accuracy with AUC of 0.652 (95% CI 0.706–0.598). Taken together, the 14-Gene Panel urine test represents a promising non-invasive tool for detection of higher-risk PCa to aid treatment decision and lower-risk PCa for active surveillance.
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| 35. |
- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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| 36. |
- Hao, Wende, et al.
(författare)
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Vitronectin : a promising breast cancer serum biomarker for early diagnosis of breast cancer in patients
- 2016
-
Ingår i: Tumor Biology. - : Springer. - 1010-4283 .- 1423-0380. ; 37:7, s. 8909-8916
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common cancer in women worldwide, identification of new biomarkers for early diagnosis and detection will improve the clinical outcome of breast cancer patients. In the present study, we determined serum levels of vitronectin (VN) in 93 breast cancer patients, 30 benign breast lesions, 9 precancerous lesions, and 30 healthy individuals by enzyme-linked immunosorbent assays. Serum VN level was significantly higher in patients with stage 0-I primary breast cancer than in healthy individuals, patients with benign breast lesion or precancerous lesions, as well as those with breast cancer of higher stages. Serum VN level was significantly and negatively correlated with tumor size, lymph node status, and clinical stage (p < 0.05 in all cases). In addition, VN displayed higher area under curve (AUC) value (0.73, 95 % confidence interval (CI) [0.62-0.84]) than carcinoembryonic antigen (CEA) (0.64, 95 % CI [0.52-0.77]) and cancer antigen 15-3 (CA 15-3) (0.69, 95 % CI [0.58-0.81]) when used to distinguish stage 0-I cancer and normal control. Importantly, the combined use of three biomarkers yielded an improvement in receiver operating characteristic curve with an AUC of 0.83, 95 % CI [0.74-0.92]. Taken together, our current study showed for the first time that serum VN is a promising biomarker for early diagnosis of breast cancer when combined with CEA and CA15-3.
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| 37. |
- Hawkins, Stephen J., et al.
(författare)
-
The Intertidal Zone of the North-East Atlantic Region
- 2019
-
Ingår i: Interactions in the Marine Benthos: Global Patterns and Processes (Systematics Association Special Volume Series, pp. 7-46). - : Cambridge university press. - 9781108416085
-
Bokkapitel (refereegranskat)abstract
- The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
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| 38. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
-
Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 39. |
- Jacquet, Jennifer, et al.
(författare)
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Support US OCTOPUS Act to keep octopuses wild.
- 2024
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Ingår i: Science (New York, N.Y.). - 1095-9203. ; 385:6710, s. 721-722
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Tidskriftsartikel (refereegranskat)abstract
- Commercial octopus farming is incapable of meeting welfare requirements, unsustainable, and unnecessary for sustenance. Although no commercial octopus farms currently exist, a Spanish seafood company plans to build one in the Canary Islands for Octopus vulgaris. In March, the US state of Washington banned octopus farming. Similar legislation has been introduced in California and Hawai‘i . Now, the federal government is proposing action. The US Congress should pass the OCTOPUS Act, a federal law that would prohibit commercial octopus aquaculture in the United States and the import of commercially farmed octopus or octopus products.
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| 40. |
- Jiang, W., et al.
(författare)
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COVID-19 is associated with bystander polyclonal autoreactive B cell activation as reflected by a broad autoantibody production, but none is linked to disease severity
- 2023
-
Ingår i: Journal of Medical Virology. - : Wiley. - 0146-6615 .- 1096-9071. ; 95:1
-
Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is associated with autoimmune features and autoantibody production in a small subset of the population. Pre-existing neutralizing antitype I interferons (IFNs) autoantibodies are related to the severity of COVID-19. Plasma levels of IgG and IgM against 12 viral antigens and 103 self-antigens were evaluated using an antibody protein array in patients with severe/critical or mild/moderate COVID-19 disease and uninfected controls. Patients exhibited increased IgGs against Severe acute respiratory syndrome coronavirus-2 proteins compared to controls, but no difference was observed in the two patient groups. 78% autoreactive IgGs and 93% autoreactive IgMs were increased in patients versus controls. There was no difference in the plasma levels of anti-type I IFN autoantibodies or neutralizing anti-type I IFN activity of plasma samples from the two patient groups. Increased anti-type I IFN IgGs were correlated with higher lymphocyte accounts, suggesting a role of nonpathogenic autoantibodies. Notably, among the 115 antibodies tested, only plasma levels of IgGs against human coronavirus (HCOV)-229E and HCOV-NL63 spike proteins were associated with mild disease outcome. COVID-19 was associated with a bystander polyclonal autoreactive B cell activation, but none of the autoantibody levels were linked to disease severity. Long-term humoral immunity against HCOV-22E and HCOV-NL63 spike protein was associated with mild disease outcome. Understanding the mechanism of life-threatening COVID-19 is critical to reducing mortality and morbidity.
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| 41. |
- Johnson, Heather, et al.
(författare)
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Gene-Mutation-Based Algorithm for Prediction of Treatment Response in Colorectal Cancer Patients
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:8
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Despite the high mortality of metastatic colorectal cancer (mCRC), no new biomarker tools are available for predicting treatment response. We developed gene-mutation-based algorithms as a biomarker classifier to predict treatment response with better precision than the current predictive factors.METHODS: Random forest machine learning (ML) was applied to identify the candidate algorithms using the MSK Cohort (n = 471) as a training set and validated in the TCGA Cohort (n = 221). Logistic regression, progression-free survival (PFS), and univariate/multivariate Cox proportional hazard analyses were performed and the performance of the candidate algorithms was compared with the established risk parameters.RESULTS: A novel 7-Gene Algorithm based on mutation profiles of seven KRAS-associated genes was identified. The algorithm was able to distinguish non-progressed (responder) vs. progressed (non-responder) patients with AUC of 0.97 and had predictive power for PFS with a hazard ratio (HR) of 16.9 (p < 0.001) in the MSK cohort. The predictive power of this algorithm for PFS was more pronounced in mCRC (HR = 16.9, p < 0.001, n = 388). Similarly, in the TCGA validation cohort, the algorithm had AUC of 0.98 and a significant predictive power for PFS (p < 0.001).CONCLUSION: The novel 7-Gene Algorithm can be further developed as a biomarker model for prediction of treatment response in mCRC patients to improve personalized therapies.
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| 42. |
- Johnson, Heather, et al.
(författare)
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K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:21
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.
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| 43. |
- Johnson, Nicholas E, et al.
(författare)
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Parent-reported multi-national study of the impact of congenital and childhood onset myotonic dystrophy.
- 2016
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Ingår i: Developmental medicine and child neurology. - : Wiley. - 1469-8749 .- 0012-1622. ; 58:7, s. 698-705
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Tidskriftsartikel (refereegranskat)abstract
- The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile-onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic areas with the greatest disease burden in an international population of patients with early-onset myotonic dystrophy type-1 (DM1).
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| 44. |
- Johnson, Taryn, et al.
(författare)
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Working Ethically with Ancient DNA from Composites in the United States
- 2024
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Ingår i: Advances in archaeological practice. - 2326-3768.
-
Tidskriftsartikel (refereegranskat)abstract
- This article discusses ethical frameworks for planning and implementing composite research in the United States. Composites, defined here as archaeological materials with multiple genetic sources, include materials such as sediment, coprolites, birch pitch, and dental calculus. Although composites are increasingly used in genetic research, the ethical considerations of their use in ancient DNA studies have not been widely discussed. Here, we consider how composites' compositions, contexts, and potential to act as proxies can affect research plans and offer an overview of the primary ethical concerns of ancient DNA research. It is our view that ethical principles established for analyses of Ancestral remains and related materials can be used to inform research plans when working with composite evidence. This work also provides a guide to archaeologists unfamiliar with genetics analyses in planning research when using composite evidence from the United States with a focus on collaboration, having a clear research plan, and using lab methods that provide the desired data with minimal destruction. Following the principles discussed in this article and others allows for engaging in composite research while creating and maintaining positive relationships with stakeholders. El presente trabajo analiza las preocupaciones eticas para la planificacion e implementacion de investigaciones compuestas en los Estados Unidos. Los compuestos, definidos aqui como muestras arqueologicas con multiples fuentes geneticas, incluyen materiales como sedimentos, paleofecas, brea de abedul y calculo dental. Sin embargo, si bien los compuestos se han utilizado cada vez mas en la investigacion genetica arqueologica, las consideraciones eticas de su uso en estudios de aADN no se han discutido ampliamente. Aqui consideramos como las composiciones, los contextos y el potencial de los compuestos para actuar como sustitutos pueden afectar los planes de investigacion y ofrecer una vision general de las principales preocupaciones eticas de la investigacion del ADN antiguo. Es la opinion de los autores que los principios eticos establecidos para los analisis de restos humanos y materiales relacionados se pueden utilizar para informar los planes de investigacion cuando se trabaja con evidencia compuesta. Este trabajo ofrece tambien una guia para planificar la investigacion cuando se utiliza evidencia compuesta con un enfoque en la colaboracion, en planes de investigacion claros y uso de metodos de laboratorio que proporcionen los datos deseados con una destruccion minima de la muestra. Seguir los principios descritos en este documento permite participar en la investigacion compuesta sin dejar de lado la creacion y mantencion de relaciones positivas con las partes interesadas.
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| 45. |
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| 46. |
- Krishnamurthi, Rita V., et al.
(författare)
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Stroke Prevalence, Mortality and Disability-Adjusted Life Years in Children and Youth Aged 0-19 Years: Data from the Global and Regional Burden of Stroke 2013
- 2015
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Ingår i: Neuroepidemiology. - : S. Karger AG. - 1423-0208 .- 0251-5350. ; 45:3, s. 177-189
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is increasing recognition of stroke as an important contributor to childhood morbidity and mortality. Current estimates of global childhood stroke burden and its temporal trends are sparse. Accurate and up-to-date estimates of childhood stroke burden are important for planning research and the resulting evidence-based strategies for stroke prevention and management. Objectives: To estimate the prevalence, mortality and disability-adjusted life years (DALYs) for ischemic stroke (IS), hemorrhagic stroke (HS) and all stroke types combined globally from 1990 to 2013. Methodology: Stroke prevalence, mortality and DALYs were estimated using the Global Burden of Disease 2013 methods. All available data on stroke-related incidence, prevalence, excess mortality and deaths were collected. Statistical models and country-level covariates were employed to produce comprehensive and consistent estimates of prevalence and mortality. Stroke-specific disability weights were used to estimate years lived with disability and DALYs. Means and 95% uncertainty intervals (UIs) were calculated for prevalence, mortality and DALYs. The median of the percent change and 95% UI were determined for the period from 1990 to 2013. Results: In 2013, there were 97,792 (95% UI 90,564-106,016) prevalent cases of childhood IS and 67,621 (95% UI 62,899-72,214) prevalent cases of childhood HS, reflecting an increase of approximately 35% in the absolute numbers of prevalent childhood strokes since 1990. There were 33,069 (95% UI 28,627-38,998) deaths and 2,615,118 (95% UI 2,265,801-3,090,822) DALYs due to childhood stroke in 2013 globally, reflecting an approximately 200% decrease in the absolute numbers of death and DALYs in childhood stroke since 1990. Between 1990 and 2013, there were significant increases in the global prevalence rates of childhood IS, as well as significant decreases in the global death rate and DALYs rate of all strokes in those of age 0-19 years. While prevalence rates for childhood IS and HS decreased significantly in developed countries, a decline was seen only in HS, with no change in prevalence rates of IS, in developing countries. The childhood stroke DALY rates in 2013 were 13.3 (95% UI 10.6-17.1) for IS and 92.7 (95% UI 80.5-109.7) for HS per 100,000. While the prevalence of childhood IS compared to childhood HS was similar globally, the death rate and DALY rate of HS was 6- to 7-fold higher than that of IS. In 2013, the prevalence rate of both childhood IS and HS was significantly higher in developed countries than in developing countries. Conversely, both death and DALY rates for all stroke types were significantly lower in developed countries than in developing countries in 2013. Men showed a trend toward higher childhood stroke death rates (1.5 (1.3-1.8) per 100,000) than women (1.1 (0.9-1.5) per 100,000) and higher childhood stroke DALY rates (120.1 (100.8-143.4) per 100,000) than women (90.9 (74.6-122.4) per 100,000) globally in 2013. Conclusions: Globally, between 1990 and 2013, there was a significant increase in the absolute number of prevalent childhood strokes, while absolute numbers and rates of both deaths and DALYs declined significantly. The gap in childhood stroke burden between developed and developing countries is closing; however, in 2013, childhood stroke burden in terms of absolute numbers of prevalent strokes, deaths and DALYs remained much higher in developing countries. There is an urgent need to address these disparities with both global and country-level initiatives targeting prevention as well as improved access to acute and chronic stroke care. (C) 2015 S. Karger AG, Basel
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| 47. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 48. |
- Mathews, Divya M. M., et al.
(författare)
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The impact of prolonged, maternal iodine exposure in early gestation on neonatal thyroid function
- 2023
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Context: Hysterosalpingography (HSG) using oil-soluble contrast medium (OSCM) improves pregnancy rates but results in severe and persistent iodine excess, potentially impacting the fetus and neonate.Objective: To determine the incidence of thyroid dysfunction in newborns conceived within six months of OSCM HSG.Design: Offspring study of a prospective cohort of women who underwent OSCM HSG.Setting: Auckland region, New Zealand (2020-2022)Participants: Offspring from the SELFI (Safety and Efficacy of Lipiodol in Fertility Investigations) study cohort (n=57).Measurements: All newborns had a dried blood spot card for TSH measurement 48 hours after birth as part of New Zealand's Newborn Metabolic Screening Programme. Forty-one neonates also had a heel prick serum sample at one week to measure thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Maternal urine iodine concentration (UIC) and TSH in the six months after OSCM HSG were retrieved from the SELFI study for analyses.Primary outcome: Incidence of hypothyroidism in the neonatal period.Results: There was no evidence of primary hypothyroidism on newborn screening (TSH 2-10 mIU/L). All neonates tested at one week had normal serum TSH, FT4, and FT3 levels. However, increasing maternal peak UIC levels during pregnancy were associated with lower TSH levels (p= 0.006), although also associated with lower FT4 levels (p=0.032).Conclusions: While pre-conceptional OSCM HSG in women did not result in neonatal hypothyroidism, gestational iodine excess was associated with a paradoxical lowering of neonatal TSH levels despite lower FT4 levels. These changes likely reflect alterations in deiodinase activity in the fetal hypothalamic-pituitary axis from iodine excess.
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| 49. |
- McCarrick, Heather, et al.
(författare)
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The Simons Observatory Microwave SQUID Multiplexing Detector Module Design
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 922:1
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Tidskriftsartikel (refereegranskat)abstract
- Advances in cosmic microwave background (CMB) science depend on increasing the number of sensitive detectors observing the sky. New instruments deploy large arrays of superconducting transition-edge sensor (TES) bolometers tiled densely into ever larger focal planes. High multiplexing factors reduce the thermal loading on the cryogenic receivers and simplify their design. We present the design of focal-plane modules with an order of magnitude higher multiplexing factor than has previously been achieved with TES bolometers. We focus on the novel cold readout component, which employs microwave SQUID multiplexing (μmux). Simons Observatory will use 49 modules containing 70,000 bolometers to make exquisitely sensitive measurements of the CMB. We validate the focal-plane module design, presenting measurements of the readout component with and without a prototype detector array of 1728 polarization-sensitive bolometers coupled to feedhorns. The readout component achieves a 95% yield and a 910 multiplexing factor. The median white noise of each readout channel is 65 pA √Hz . This impacts the projected SO mapping speed by <8%, which is less than is assumed in the sensitivity projections. The results validate the full functionality of the module. We discuss the measured performance in the context of SO science requirements, which are exceeded.
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| 50. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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