| 1. |
- Garg, Manik, et al.
(author)
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Tumour gene expression signature in primary melanoma predicts long-term outcomes
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10−4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p < 2.2 × 10−16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
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| 2. |
- Kirkland, Thomas A., et al.
(author)
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Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A(4) hydrolase
- 2008
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 16:9, s. 4963-4983
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Journal article (peer-reviewed)abstract
- Leukotriene B-4 (LTB4) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB4 and possibly identify novel treatments, inhibitors of the LTB4 biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.
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| 3. |
- Alenaini, Wareed, et al.
(author)
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Ethnic Differences in Body Fat Deposition and Liver Fat Content in Two UK‐Based Cohorts
- 2020
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In: Obesity. - : John Wiley & Sons. - 1930-7381 .- 1930-739X. ; 28:11, s. 2142-2152
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Journal article (peer-reviewed)abstract
- ObjectiveDifferences in the content and distribution of body fat and ectopic lipids may be responsible for ethnic variations in metabolic disease susceptibility. The aim of this study was to examine the ethnic distribution of body fat in two separate UK‐based populations.MethodsAnthropometry and body composition were assessed in two separate UK cohorts: the Hammersmith cohort and the UK Biobank, both comprising individuals of South Asian descent (SA), individuals of Afro‐Caribbean descent (AC), and individuals of European descent (EUR). Regional adipose tissue stores and liver fat were measured by magnetic resonance techniques.ResultsThe Hammersmith cohort (n = 747) had a mean (SD) age of 41.1 (14.5) years (EUR: 374 men, 240 women; SA: 68 men, 22 women; AC: 14 men, 29 women), and the UK Biobank (n = 9,533) had a mean (SD) age of 55.5 (7.5) years (EUR: 4,483 men, 4,873 women; SA: 80 men, 43 women, AC: 31 men, 25 women). Following adjustment for age and BMI, no significant differences in visceral adipose tissue or liver fat were observed between SA and EUR individuals in the either cohort.ConclusionsOur data, consistent across two independent UK‐based cohorts, present a limited number of ethnic differences in the distribution of body fat depots associated with metabolic disease. These results suggest that the ethnic variation in susceptibility to features of the metabolic syndrome may not arise from differences in body fat.
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| 4. |
- Alniss, Hasan Y., et al.
(author)
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Investigation of the Factors That Dictate the Preferred Orientation of Lexitropsins in the Minor Groove of DNA
- 2019
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In: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 62:22, s. 10423-10440
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Journal article (peer-reviewed)abstract
- Lexitropsins are small molecules that bind to the minor groove of DNA as antiparallel dimers in a specific orientation. These molecules have shown therapeutic potential in the treatment of several diseases; however, the development of these molecules to target particular genes requires revealing the factors that dictate their preferred orientation in the minor grooves, which to date have not been investigated. In this study, a distinct structure (thzC) was carefully designed as an analog of a well-characterized lexitropsin (thzA) to reveal the factors that dictate the preferred binding orientation. Comparative evaluations of the biophysical and molecular modeling results of both compounds showed that the position of the dimethylaminopropyl group and the orientation of the amide links of the ligand with respect to the 5'-3'-ends; dictate the preferred orientation of lexitropsins in the minor grooves. These findings could be useful in the design of novel lexitropsins to selectively target specific genes.
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| 5. |
- Deans, Andrew R, et al.
(author)
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Finding Our Way through Phenotypes.
- 2015
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In: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 13:1
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Journal article (peer-reviewed)abstract
- Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.
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| 6. |
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| 7. |
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| 8. |
- Lim, Ik Soo, et al.
(author)
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On the Origin of Risk Sensitivity : The Energy Budget Rule Revisited
- 2015
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In: Animal Behaviour. - : Elsevier BV. - 0003-3472 .- 1095-8282. ; 110, s. 69-77
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Journal article (peer-reviewed)abstract
- The risk-sensitive foraging theory formulated in terms of the (daily) energy budget rule has been influential in behavioural ecology as well as other disciplines. Predicting risk-aversion on positive budgets and risk-proneness on negative budgets, however, the budget rule has recently been challenged both empirically and theoretically. In this paper, we critically review these challenges as well as the original derivation of the budget rule and propose a ‘gradual’ budget rule, which is normatively derived from a gradual nature of risk sensitivity and encompasses the conventional budget rule as a special case. The gradual budget rule shows that the conventional budget rule holds when the expected reserve is close enough to a threshold for overnight survival, selection pressure being significant. The gradual view also reveals that the conventional budget rule does not need to hold when the expected reserve is not close enough to the threshold, selection pressure being insignificant. The proposed gradual budget rule better fits the empirical findings including those that used to challenge the conventional budget rule.
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| 9. |
- Xu, Yu, et al.
(author)
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An atlas of genetic scores to predict multi-omic traits
- 2023
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In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 616:7955, s. 123-131
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Journal article (peer-reviewed)abstract
- The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
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| 10. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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