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Article ; Online: Improving breast cancer risk prediction with epigenetic risk factors.

Southey, Melissa C / Dugué, Pierre-Antoine

2022 Volume 19, Issue 6, Page(s) 363–364

MeSH term(s)	Breast ; Breast Neoplasms/genetics ; DNA Methylation/genetics ; Epigenesis, Genetic/genetics ; Epigenomics ; Female ; Humans ; Risk Factors
Language	English
Publishing date	2022-03-28
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-022-00622-4
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Article ; Online: RE: Heterozygous BRCA1 and BRCA2 and mismatch repair gene pathogenic variants in children and adolescents with cancer.

Li, Shuai / Nguyen-Dumont, Tu / Southey, Melissa C / Hopper, John L

Journal of the National Cancer Institute

2023 Volume 115, Issue 6, Page(s) 757–759

MeSH term(s)	Humans ; Adolescent ; Child ; Female ; DNA Mismatch Repair/genetics ; BRCA2 Protein/genetics ; BRCA1 Protein/genetics ; Neoplasms/genetics ; Breast Neoplasms/genetics ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Ovarian Neoplasms/genetics
Chemical Substances	BRCA2 Protein ; BRCA1 Protein ; BRCA1 protein, human ; BRCA2 protein, human
Language	English
Publishing date	2023-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djad056
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Article ; Online: Body Size, Diet Quality, and Epigenetic Aging: Cross-Sectional and Longitudinal Analyses.

Li, Danmeng Lily / Hodge, Allison M / Cribb, Lachlan / Southey, Melissa C / Giles, Graham G / Milne, Roger L / Dugué, Pierre-Antoine

The journals of gerontology. Series A, Biological sciences and medical sciences

2024 Volume 79, Issue 4

Abstract: Epigenetic age is an emerging marker of health that is highly predictive of disease and mortality risk. There is a lack of evidence on whether lifestyle changes are associated with changes in epigenetic aging. We used data from 1 041 participants in the ... ...

Abstract	Epigenetic age is an emerging marker of health that is highly predictive of disease and mortality risk. There is a lack of evidence on whether lifestyle changes are associated with changes in epigenetic aging. We used data from 1 041 participants in the Melbourne Collaborative Cohort Study with blood DNA methylation measures at baseline (1990-1994, mean age: 57.4 years) and follow-up (2003-2007, mean age: 68.8 years). The Alternative Healthy Eating Index-2010 (AHEI-2010), the Mediterranean Dietary Score, and the Dietary Inflammatory Index were used as measures of diet quality, and weight, waist circumference, and waist-to-hip ratio as measures of body size. Five age-adjusted epigenetic aging measures were considered: GrimAge, PhenoAge, PCGrimAge, PCPhenoAge, and DunedinPACE. Multivariable linear regression models including restricted cubic splines were used to assess the cross-sectional and longitudinal associations of body size and diet quality with epigenetic aging. Associations between weight and epigenetic aging cross-sectionally at both time points were positive and appeared greater for DunedinPACE (per SD: β ~0.24) than for GrimAge and PhenoAge (β ~0.10). The longitudinal associations with weight change were markedly nonlinear (U-shaped) with stable weight being associated with the lowest epigenetic aging at follow-up, except for DunedinPACE, for which only weight gain showed a positive association. We found negative, linear associations for AHEI-2010 both cross-sectionally and longitudinally. Other adiposity measures and dietary scores showed similar results. In middle-aged to older adults, declining diet quality and weight gain may increase epigenetic age, while the association for weight loss may require further investigation. Our study sheds light on the potential of weight management and dietary improvement in slowing aging processes.
MeSH term(s)	Humans ; Aged ; Middle Aged ; Cohort Studies ; Cross-Sectional Studies ; Body Mass Index ; Diet ; Aging/genetics ; Weight Gain ; Waist Circumference ; Epigenesis, Genetic
Language	English
Publishing date	2024-01-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glae026
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Article ; Online: PALB2 Genetic Variants: Can Functional Assays Assist Translation?

Southey, Melissa C / Rewse, Amanda / Nguyen-Dumont, Tu

Trends in cancer

2020 Volume 6, Issue 4, Page(s) 263–265

Abstract: PALB2 loss-of-function variants are associated with increased risk of breast and other cancers, but the clinical relevance of missense variants (MVs) remains uncertain. Recent findings reported by Wiltshire et al., Rodrigue et al., and Boonen et al. ... ...

Abstract	PALB2 loss-of-function variants are associated with increased risk of breast and other cancers, but the clinical relevance of missense variants (MVs) remains uncertain. Recent findings reported by Wiltshire et al., Rodrigue et al., and Boonen et al. demonstrate that some MVs disrupt PALB2 function. This new information will support the clinical management of families who carry these MVs and inform their treatment.
MeSH term(s)	Fanconi Anemia Complementation Group N Protein ; Genetic Predisposition to Disease ; Humans ; Mutation, Missense
Chemical Substances	Fanconi Anemia Complementation Group N Protein ; PALB2 protein, human
Language	English
Publishing date	2020-02-13
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2020.01.017
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Article ; Online: Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer.

Wong, Ee Ming / Southey, Melissa C / Terry, Mary Beth

British journal of cancer

2020 Volume 122, Issue 8, Page(s) 1133–1140

Abstract: Current risk prediction models estimate the probability of developing breast cancer over a defined period based on information such as family history, non-genetic breast cancer risk factors, genetic information from high and moderate risk breast cancer ... ...

Abstract	Current risk prediction models estimate the probability of developing breast cancer over a defined period based on information such as family history, non-genetic breast cancer risk factors, genetic information from high and moderate risk breast cancer susceptibility genes and, over the past several years, polygenic risk scores (PRS) from more than 300 common variants. The inclusion of additional data such as PRS improves risk stratification, but it is anticipated that the inclusion of epigenetic marks could further improve model performance accuracy. Here, we present the case for including information on DNA methylation marks to improve the accuracy of these risk prediction models, and consider how this approach contrasts genetic information, as identifying DNA methylation marks associated with breast cancer risk differs inherently according to the source of DNA, approaches to the measurement of DNA methylation, and the timing of measurement. We highlight several DNA-methylation-specific challenges that should be considered when incorporating information on DNA methylation marks into risk prediction models, using BRCA1, a highly penetrant breast cancer susceptibility gene, as an example. Only after careful consideration of study design and DNA methylation measurement will prospective performance of the incorporation of information regarding DNA methylation marks into risk prediction models be valid.
MeSH term(s)	Breast Neoplasms/etiology ; Breast Neoplasms/genetics ; DNA Methylation ; Female ; Genes, BRCA1 ; Genetic Predisposition to Disease ; Humans ; Promoter Regions, Genetic ; Risk Assessment
Language	English
Publishing date	2020-02-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-019-0720-2
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Article: Transcriptomic Differences Between Monozygotic Adolescent Twins Discordant For Metabolic Syndrome Following Weight Loss: A Case Study.

Day, Kaitlin / McCubbin, Alan J / Murgia, Chiara / Southey, Melissa C / Brown, Justin / Truby, Helen

Twin research and human genetics : the official journal of the International Society for Twin Studies

2022 Volume 25, Issue 4-5, Page(s) 196–201

Abstract: This case reports peripheral blood mononuclear cell (PBMC) transcriptomic changes in a pair of male monozygotic pediatric twins with metabolic syndrome (MetS) undertaking assisted weight loss. These 14-year-old boys presented with similar baseline ... ...

Abstract	This case reports peripheral blood mononuclear cell (PBMC) transcriptomic changes in a pair of male monozygotic pediatric twins with metabolic syndrome (MetS) undertaking assisted weight loss. These 14-year-old boys presented with similar baseline biochemistry and body composition. After a 16-week weight-loss intervention, percent body weight loss was similar (Twin A 12%, and Twin B 13%). MetS resolved in Twin A but Twin B maintained elevated triglycerides after weight loss. Analysis of the PBMC transcriptome before and after weight loss revealed very different changes in gene expression including differences in the direction of expression of genes related to immune cell activation. 48.7% of genes that were downregulated in Twin A were upregulated in Twin B. This case highlights a novel approach to report the influence of chronic low-grade inflammation and metabolic dysfunction on the PBMC transcriptome. It explores whether expression of genes related to immune functions may underlie the differences in response to weight loss or whether transcriptomic alterations in immune cells may precede more traditional biomarkers of chronic pro-inflammation. These monozygotic twins present an example of divergence of phenotypic outcomes despite identical genetic background and similar treatment response.
MeSH term(s)	Humans ; Male ; Adolescent ; Child ; Transcriptome/genetics ; Leukocytes, Mononuclear ; Metabolic Syndrome/genetics ; Twins, Monozygotic/genetics ; Weight Loss/genetics ; Inflammation ; Diseases in Twins/genetics
Language	English
Publishing date	2022-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2182682-1
ISSN	1839-2628 ; 1832-4274
ISSN (online)	1839-2628
ISSN	1832-4274
DOI	10.1017/thg.2022.34
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Article: Adiposity and plasma concentrations of kynurenine pathway metabolites and traditional markers of inflammation.

Wang, Mengmei E / Hodge, Allison M / Li, Sherly X / Southey, Melissa C / Giles, Graham G / Dugué, Pierre-Antoine

Obesity research & clinical practice

2023 Volume 17, Issue 3, Page(s) 203–209

Abstract: Aim: The kynurenine pathway is increasingly recognised to play a role in inflammation and disease. We assessed the cross-sectional and longitudinal associations of adiposity measures (body mass index, waist-hip ratio, waist circumference and fat mass ... ...

Abstract	Aim: The kynurenine pathway is increasingly recognised to play a role in inflammation and disease. We assessed the cross-sectional and longitudinal associations of adiposity measures (body mass index, waist-hip ratio, waist circumference and fat mass ratio) with plasma concentrations of kynurenine pathway metabolites and traditional markers of inflammation. Methods: We used data from 970 Melbourne Collaborative Cohort Study participants who had plasma markers measured at baseline (median age 59 years) and follow-up (median age 70 years). Linear regression was used to assess cross-sectional and longitudinal associations between four adiposity measures and concentrations of i) nine kynurenine pathway metabolites; ii) two derived markers; iii) eight traditional inflammatory markers. Results: Cross-sectionally, most kynurenine metabolites were strongly associated with adiposity measures at both time points; associations were generally stronger than for most inflammation markers except CRP (e.g. body mass index at baseline, quinolinic acid (per S.D. β = 0.30, 95%CI: 0.24-0.36, P = 10 Conclusions: In middle-aged and older adults, plasma concentrations of kynurenine metabolites are strongly associated with adiposity, both cross-sectionally and longitudinally. Our study demonstrates that kynurenine metabolites may be valuable markers to monitor the adverse consequences of obesity.
MeSH term(s)	Middle Aged ; Humans ; Aged ; Kynurenine/metabolism ; Tryptophan/metabolism ; Cohort Studies ; Adiposity ; Quinolinic Acid ; Cross-Sectional Studies ; Inflammation ; Obesity ; Biomarkers
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; Quinolinic Acid (F6F0HK1URN) ; Biomarkers
Language	English
Publishing date	2023-04-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2274031-4
ISSN	1878-0318 ; 1871-403X
ISSN (online)	1878-0318
ISSN	1871-403X
DOI	10.1016/j.orcp.2023.04.004
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Article ; Online: Epigenome-wide association study of short-term temperature fluctuations based on within-sibship analyses in Australian females

Wu, Yao / Xu, Rongbin / Li, Shanshan / Ming Wong, Ee / Southey, Melissa C. / Hopper, John L. / Abramson, Michael J. / Li, Shuai / Guo, Yuming

Environment International. 2023 Jan., v. 171 p.107655-

2023

Abstract: Temperature fluctuations can affect human health independent of the effect of mean temperature. However, no study has evaluated whether short-term temperature fluctuations could affect DNA methylation. Peripheral blood DNA methylation for 479 female ... ...

Abstract	Temperature fluctuations can affect human health independent of the effect of mean temperature. However, no study has evaluated whether short-term temperature fluctuations could affect DNA methylation. Peripheral blood DNA methylation for 479 female siblings of 130 families were analysed. Gridded daily temperatures data were obtained, linked to each participant’s home address, and used to calculate nine different metrics of short-term temperature fluctuations: temperature variabilities (TVs) within the day of blood draw and preceding one to seven days (TV 0–1 to TV 0–7), diurnal temperature range (DTR), and temperature change between neighbouring days (TCN). Within-sibship design was used to perform epigenome-wide association analyses, adjusting for daily mean temperatures, and other important covariates (e.g., smoking, alcohol use, cell-type proportions). Differentially methylated regions (DMRs) were further identified. Multiple-testing comparisons with a significant threshold of 0.01 for cytosine-guanine dinucleotides (CpGs) and 0.05 for DMRs were applied. Among 479 participants (mean age ± SD, 56.4 ± 7.9 years), we identified significant changes in methylation levels in 14 CpGs and 70 DMRs associated with temperature fluctuations. Almost all identified CpGs were associated with exposure to temperature fluctuations within three days. Differentially methylated signals were mapped to 68 genes that were linked to human diseases such as cancer (e.g., colorectal carcinoma, breast carcinoma, and metastatic neoplasms) and mental disorder (e.g., schizophrenia, mental depression, and bipolar disorder). The top three most significantly enriched gene ontology terms were Response to bacterium (TV 0–3), followed by Hydrolase activity, acting on ester bonds (TCN), and Oxidoreductase activity (TV 0–3). Short-term temperature fluctuations were associated with differentially methylated signals across the human genome, which provides evidence on the potential biological mechanisms underlying the health impact of temperature fluctuations. Future studies are needed to further clarify the roles of DNA methylation in diseases associated with temperature fluctuations.
Keywords	DNA methylation ; alcohols ; bacteria ; bipolar disorder ; blood ; breast neoplasms ; colorectal neoplasms ; environment ; females ; gene ontology ; genome ; human health ; humans ; hydrolases ; mental depression ; metastasis ; schizophrenia ; temperature ; Temperature variability ; Diurnal temperature range ; Temperature change between neighbouring days ; Twin and family study
Language	English
Dates of publication	2023-01
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2022.107655
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Wildfire-related PM2.5 and DNA methylation: An Australian twin and family study

Xu, Rongbin / Li, Shanshan / Wu, Yao / Yue, Xu / Wong, Ee Ming / Southey, Melissa C. / Hopper, John L. / Abramson, Michael J. / Li, Shuai / Guo, Yuming

Environment International. 2023 Jan., v. 171 p.107704-

2023

Abstract: Wildfire-related fine particulate matter (PM₂.₅) has many adverse health impacts, but its impacts on human epigenome are unknown. We aimed to evaluate the associations between long-term exposure to wildfire-related PM₂.₅ and blood DNA methylation, and ... ...

Abstract	Wildfire-related fine particulate matter (PM₂.₅) has many adverse health impacts, but its impacts on human epigenome are unknown. We aimed to evaluate the associations between long-term exposure to wildfire-related PM₂.₅ and blood DNA methylation, and whether the associations differ from those with non-wildfire-related PM₂.₅. We studied 479 Australian women comprising 132 twin pairs and 215 of their sisters. Blood-derived DNA methylation was measured using the HumanMethylation450 BeadChip array. Data on 3-year (year of blood collection and previous two years) average wildfire-related and non-wildfire-related PM₂.₅ at 0.01°×0.01° spatial resolution were created by combining information from satellite observations, chemical transport models, and ground-based observations. Exposure data were linked to each participant’s home address, assuming the address did not change during the exposure window. For DNA methylation of each cytosine-guanine dinucleotide (CpG), and for global DNA methylation represented by the average of all measured CpGs or CpGs in repetitive elements, we evaluated their associations with wildfire- or non-wildfire-related PM₂.₅ using a within-sibship analysis controlling for factors shared between siblings and other important covariates. Differentially methylated regions (DMRs) were defined by comb-p and DMRcate. The 3-year average wildfire-related PM₂.₅ (range: 0.3 to 7.6 µg/m³, mean: 1.6 µg/m³) was negatively, but not significantly (p-values greater than 0.05) associated with all seven global DNA methylation measures. There were 26 CpGs and 33 DMRs associated with wildfire-related PM₂.₅ (Bonferroni adjusted p-value < 0.05) mapped to 47 genes enriched for pathways related to inflammatory regulation and platelet activation. These genes have been related to many human diseases or phenotypes e.g., cancer, mental disorders, diabetes, obesity, asthma, blood pressure. These CpGs, DMRs and enriched pathways did not overlap with the 1 CpG and 7 DMRs associated with non-wildfire-related PM₂.₅. Long-term exposure to wildfire-related PM₂.₅ was associated with various blood DNA methylation signatures in Australian women, and these were distinct from those associated with non-wildfire-related PM₂.₅.
Keywords	DNA methylation ; asthma ; blood ; blood pressure ; blood sampling ; chronic exposure ; diabetes ; environment ; epigenome ; humans ; obesity ; particulates ; platelet activation ; satellites ; PM2.5 ; Wildfire smoke ; Epigenome-wide association study ; Twin and family study ; Alu ; AMDTSS ; BIF ; CpG ; DMR ; FDR ; GEE ; GO ; IRSAD ; KEGG ; L1 ; LTR ; REs ; SES
Language	English
Dates of publication	2023-01
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2022.107704
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Article: Transcriptomic changes in peripheral blood mononuclear cells with weight loss: systematic literature review and primary data synthesis

Day, Kaitlin / Dordevic, Aimee L. / Truby, Helen / Southey, Melissa C. / Coort, Susan / Murgia, Chiara

Genes & nutrition. 2021 Dec., v. 16, no. 1

2021

Abstract: BACKGROUND AND OBJECTIVES: Peripheral blood mononuclear cells (PBMCs) have shown promise as a tissue sensitive to subtle and possibly systemic transcriptomic changes, and as such may be useful in identifying responses to weight loss interventions. The ... ...

Abstract	BACKGROUND AND OBJECTIVES: Peripheral blood mononuclear cells (PBMCs) have shown promise as a tissue sensitive to subtle and possibly systemic transcriptomic changes, and as such may be useful in identifying responses to weight loss interventions. The primary aim was to comprehensively evaluate the transcriptomic changes that may occur during weight loss and to determine if there is a consistent response across intervention types in human populations of all ages. METHODS: Included studies were randomised control trials or cohort studies that administered an intervention primarily designed to decrease weight in any overweight or obese human population. A systematic search of the literature was conducted to obtain studies and gene expression databases were interrogated to locate corresponding transcriptomic datasets. Datasets were normalised using the ArrayAnalysis online tool and differential gene expression was determined using the limma package in R. Over-represented pathways were explored using the PathVisio software. Heatmaps and hierarchical clustering were utilised to visualise gene expression. RESULTS: Seven papers met the inclusion criteria, five of which had raw gene expression data available. Of these, three could be grouped into high responders (HR, ≥ 5% body weight loss) and low responders (LR). No genes were consistently differentially expressed between high and low responders across studies. Adolescents had the largest transcriptomic response to weight loss followed by adults who underwent bariatric surgery. Seven pathways were altered in two out of four studies following the intervention and the pathway ‘cytoplasmic ribosomal proteins’ (WikiPathways: WP477) was altered between HR and LR at baseline in the two datasets with both groups. Pathways related to ‘toll-like receptor signalling’ were altered in HR response to the weight loss intervention in two out of three datasets. CONCLUSIONS: Transcriptomic changes in PBMCs do occur in response to weight change. Transparent and standardised data reporting is needed to realise the potential of transcriptomics for investigating phenotypic features. REGISTRATION NUMBER: PROSPERO: CRD42019106582
Keywords	Toll-like receptors ; bariatric surgery ; body weight changes ; computer software ; data collection ; gene expression ; gene expression regulation ; human population ; humans ; nutrition ; overweight ; phenotype ; transcriptomics ; weight loss
Language	English
Dates of publication	2021-12
Size	p. 12.
Publishing place	BioMed Central
Document type	Article
Note	Review
ZDB-ID	2416599-2
ISSN	1865-3499 ; 1555-8932
ISSN (online)	1865-3499
ISSN	1555-8932
DOI	10.1186/s12263-021-00692-6
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