| 1. |
- Spracklen, Cassandra N., et al.
(författare)
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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
- 2019
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 105:1, s. 15-28
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Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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| 2. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 3. |
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| 4. |
- Jensen, Poul Erik H., et al.
(författare)
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Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis : Results from the ABIRISK prospective cohort study
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 326, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.
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| 5. |
- Lange, Leslie A, et al.
(författare)
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
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Tidskriftsartikel (refereegranskat)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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| 6. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 7. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 8. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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| 9. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 10. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet. Oncology. - 1474-5488. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 11. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 12. |
- Peloso, Gina M, et al.
(författare)
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Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 223-232
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121(∗)], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
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| 13. |
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| 14. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 15. |
- Wang, Xiaoliang, et al.
(författare)
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Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 x 10(-8) as genome-wide significant, and p-values < 1 x 10(-5) as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 x 10(5). The strongest evidence was found for rs4674019 (p-value = 2.27 x 10(-7)), which showed genome-wide significant interaction (p-value = 3.8 x 10(-8)) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.
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| 16. |
- Wangsa, Darawalee, et al.
(författare)
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Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis
- 2016
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 138:1, s. 98-109
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Tidskriftsartikel (refereegranskat)abstract
- Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells from the tumors of sixty-five OTSCC patients (Stage I, n=15; Stage II, n=30; Stage III, n=7; Stage IV, n=13). Unsupervised hierarchical clustering of the FISH data distinguished three clusters related to smoking status. Copy number increases of all five markers were found to be correlated to non-smoking habits, while smokers in this cohort had low-level copy number gains. Using the phylogenetic modeling software FISHtrees, we constructed models of tumor progression for each patient based on the four gene probes. Then, we derived test statistics on the models that are significant predictors of disease-free and overall survival, independent of tumor stage and smoking status in multivariate analysis. The patients whose tumors were modeled as progressing by a more diverse distribution of copy number changes across the four genes have poorer prognosis. This is consistent with the view that multiple genetic pathways need to become deregulated in order for cancer to progress. Whats new? Oral tongue squamous cell carcinoma (OTSCC) is a rare head and neck cancer that typically is asymptomatic in early stages. Hence, in order to improve prognosis in OTSCC, predictive biomarkers that are independent of tumor stage must be identified. Here, using four fluorescence in situ hybridization (FISH) gene probes and the software FISHtrees, phylogenetic tree models of tumor progression in OTSCC patients were constructed. Analyses of the models showed that the more diverse the changes within the four marker genes, the worse the outcome in OTSCC. The markers predicted survival independent of smoking behavior and tumor stage.
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| 17. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 18. |
- Auer, Florian, et al.
(författare)
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Controlled experimentation in continuous experimentation : Knowledge and challenges
- 2021
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Ingår i: Information and Software Technology. - : Elsevier B.V.. - 0950-5849 .- 1873-6025. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Context: Continuous experimentation and A/B testing is an established industry practice that has been researched for more than 10 years. Our aim is to synthesize the conducted research. Objective: We wanted to find the core constituents of a framework for continuous experimentation and the solutions that are applied within the field. Finally, we were interested in the challenges and benefits reported of continuous experimentation. Methods: We applied forward snowballing on a known set of papers and identified a total of 128 relevant papers. Based on this set of papers we performed two qualitative narrative syntheses and a thematic synthesis to answer the research questions. Results: The framework constituents for continuous experimentation include experimentation processes as well as supportive technical and organizational infrastructure. The solutions found in the literature were synthesized to nine themes, e.g. experiment design, automated experiments, or metric specification. Concerning the challenges of continuous experimentation, the analysis identified cultural, organizational, business, technical, statistical, ethical, and domain-specific challenges. Further, the study concludes that the benefits of experimentation are mostly implicit in the studies. Conclusion: The research on continuous experimentation has yielded a large body of knowledge on experimentation. The synthesis of published research presented within include recommended infrastructure and experimentation process models, guidelines to mitigate the identified challenges, and what problems the various published solutions solve. © 2021 The Authors
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| 19. |
- Auer, Florian, et al.
(författare)
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From monolithic systems to Microservices : An assessment framework
- 2021
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Ingår i: Information and Software Technology. - : Elsevier B.V.. - 0950-5849 .- 1873-6025. ; 137
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Tidskriftsartikel (refereegranskat)abstract
- Context: Re-architecting monolithic systems with Microservices-based architecture is a common trend. Various companies are migrating to Microservices for different reasons. However, making such an important decision like re-architecting an entire system must be based on real facts and not only on gut feelings. Objective: The goal of this work is to propose an evidence-based decision support framework for companies that need to migrate to Microservices, based on the analysis of a set of characteristics and metrics they should collect before re-architecting their monolithic system. Method: We conducted a survey done in the form of interviews with professionals to derive the assessment framework based on Grounded Theory. Results: We identified a set consisting of information and metrics that companies can use to decide whether to migrate to Microservices or not. The proposed assessment framework, based on the aforementioned metrics, could be useful for companies if they need to migrate to Microservices and do not want to run the risk of failing to consider some important information. © 2021 The Author(s)
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| 20. |
- Auer, Florian, et al.
(författare)
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Towards defining a microservice migration framework
- 2018
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Ingår i: ACM International Conference Proceeding Series. - New York, NY, USA : Association for Computing Machinery.
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Konferensbidrag (refereegranskat)abstract
- Microservices are more and more popular. As a result, some companies started to believe that microservices are the solution to all of their problems and rush to adopt microservices without sufficient knowledge about the impacts. Most of the time they expect to decrease their maintenance effort or to ease the deployment process. However, re-architecting a system to microservices is not always beneficial. In this work we propose a work-plan to identify a decision framework that supports practitioners in the understanding of possible migration based benefits and issues. This will lead to more reasoned decisions and mitigate the risk of migration. © 2018 Copyright held by the owner/author(s).
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| 21. |
- Auer-Grumbach, Michaela, et al.
(författare)
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Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 607-623
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Tidskriftsartikel (refereegranskat)abstract
- Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.
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| 22. |
- Bachelet, Delphine, et al.
(författare)
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Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis : A Collaborative Cohort Analysis
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFN beta)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFN beta therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFN beta in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFN beta. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.
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| 23. |
- Garcia-Loro, Felix, et al.
(författare)
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Experimenting in PILAR federation : A common path for the future
- 2018
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Ingår i: PROCEEDINGS OF 2018 IEEE GLOBAL ENGINEERING EDUCATION CONFERENCE (EDUCON) - EMERGING TRENDS AND CHALLENGES OF ENGINEERING EDUCATION. - : IEEE Computer Society. - 9781538629574 ; , s. 1518-1523
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Konferensbidrag (refereegranskat)abstract
- The PILAR (Platform Integration of Laboratories based on the Architecture of visiR) Erasmus Plus project started in September 2016 and will last three years. The core of the PILAR project is the VISIR remote laboratory-Virtual Instruments System In Reality-. The project aims for a federation of five of the existing VISIR nodes, sharing experiments, capacity and resources among partners, and to provide access to VISIR remote lab, through PILAR consortium, to students from other educational institutions. PILAR will be the framework from which management tasks will be performed and laboratories/experiments will be shared. PILAR will also foster the Special Interest Group of VISIR under the Global Online Laboratory Consortium (GOLC) of the International Association of Online Engineering (IAOE). © 2018 IEEE.
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| 24. |
- Gemoll, Timo, et al.
(författare)
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HDAC2 and TXNL1 distinguish aneuploid from diploid colorectal cancers
- 2011
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 68:19, s. 3261-3274
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Tidskriftsartikel (refereegranskat)abstract
- DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel-electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n=19), diploid (n=31), and aneuploid (n=47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers.
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| 25. |
- Haugg, Amelie, et al.
(författare)
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Predictors of real-time fMRI neurofeedback performance and improvement - A machine learning mega-analysis.
- 2021
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Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 237
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Tidskriftsartikel (refereegranskat)abstract
- Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.
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| 26. |
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| 27. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 28. |
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| 29. |
- Ladjevardi, Sam, et al.
(författare)
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Prostate biopsy sampling causes hematogenous dissemination of epithelial cellular material
- 2014
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Ingår i: Disease Markers. - : Hindawi Limited. - 0278-0240 .- 1875-8630. ; , s. 707529-
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Tidskriftsartikel (refereegranskat)abstract
- The extent of epithelial cellular material (ECM) occurring in venous blood samples after diagnostic core needle biopsy (CNB) was studied in 23 patients with CNB diagnosed prostate cancer without provable metastases and 15 patients without cancer. The data show a significant increase of ECM in the peripheral blood sampled 20 seconds or 30 minutes after the last of 10 CNB procedures compared to the number of ECM detectable in the blood samples taken before the performance of CNB. The data indicate that diagnostic CNB of prostate cancer causes an extensive tissue trauma with a potential risk of cancer cell dissemination.
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| 30. |
- Link, Jenny, et al.
(författare)
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Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe : A descriptive study of test results
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFN beta) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFN beta preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFN beta-1a subcutaneous (s.c.) and IFN beta-1b s.c. in favor of the least immunogenic preparation IFN beta-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFN beta-1b-Extavia s. c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFN beta-1a i. m. (1.41 and 2.27 years), IFN beta-1b-Betaferon s. c. (2.51 and 1.96 years) and IFN beta-1a s. c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFN beta ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.
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| 31. |
- Middha, Pooja K., et al.
(författare)
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
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Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
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| 32. |
- Mueller, Michaela, et al.
(författare)
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Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients.
- 2018
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Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - : Wiley. - 1478-3231. ; 38:3, s. 521-531
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Tidskriftsartikel (refereegranskat)abstract
- Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid (BA) used as therapy for a range of hepatobiliary diseases. Its efficacy in non-alcoholic fatty liver disease (NAFLD) is still under debate. Here, we aimed to decipher molecular mechanisms of UDCA in regulating endoplasmic reticulum (ER) homeostasis, apoptosis and oxidative stress in morbidly obese patients.In this randomized controlled pharmacodynamic study, liver and serum samples from 40 well-matched morbidly obese NAFLD-patients were analysed. Patients received UDCA (20mg/kg/d) or no treatment 3weeks before samples were obtained during bariatric surgery.Patients treated with UDCA displayed higher scoring of steatosis (S), activity (A) and fibrosis (F), the so called SAF-scoring. UDCA partially disrupted ER homeostasis by inducing the expression of the ER stress markers CHOP and GRP78. However, ERDJ4 and sXBP1 levels were unaffected. Enhanced CHOP expression, a suggested pro-apoptotic trigger, failed to induce apoptosis via BAK and BAX in the UDCA treated group. Potentially pro-apoptotic miR-34a was reduced in the vesicle-free fraction in serum but not in liver after UDCA treatment. Thiobarbituric acid reactive substances, 4-hydroxynonenal and mRNA levels of several oxidative stress indicators remained unchanged after UDCA treatment.Our data suggest that UDCA treatment has ambivalent effects in NAFLD patients. While increased SAF-scores and elevated CHOP levels may be disadvantageous in the UDCA treated cohort, UDCA's cytoprotective properties potentially changed the apoptotic threshold as reflected by absent induction of pro-apoptotic triggers. UDCA treatment failed to improve the oxidative stress status in NAFLD patients.
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| 33. |
- Ryott, Michael, et al.
(författare)
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EGFR protein overexpression and gene copy number increases in oral tongue squamous cell carcinoma.
- 2009
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Ingår i: European Journal of Cancer. - : Pergamon Press. - 0959-8049 .- 1879-0852. ; 45:9, s. 1700-1708
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Tidskriftsartikel (refereegranskat)abstract
- New promising therapeutic agents targeting epidermal growth factor receptor (EGFR) have been developed although clinical information concerning EGFR status in oral tongue squamous cell carcinoma (OTSCC) is limited. We investigated EGFR protein expression and gene copy numbers in 78 pretreatment OTSCC paraffin samples. EGFR protein expression was found in all 78 tumours, of which 72% showed an intense staining. Fifty-four percent of the tumours had high (> or =four gene copies) EGFR gene copy numbers. EGFR gene copy number was significantly associated with EGFR protein expression (P=0.002). Pretreatment EGFR staining intensity tended to be associated with non-pathological complete remission after preoperative radiotherapy for Stage II OTSCC. No correlation was found between EGFR status and survival. EGFR FISH results were significantly (P=0.003) higher in more advanced tumours (Stages II, III and IV) than in the tumours in Stage I. Non-smokers exhibited a significantly higher EGFR gene copy number and protein overexpression in Stages I and II OTSCC than smokers (P=0.001, P=0.009). In conclusion, EGFR was found to be overexpressed in all OTSCCs making this cancer type interesting for exploring new therapeutic agents targeting the EGFR receptor.
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| 34. |
- Röbeck, Pontus, et al.
(författare)
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Multiplex protein analysis and ensemble machine learning methods of fine needle aspirates from prostate cancer patients reveal potential diagnostic signatures associated with tumour grade
- 2023
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Ingår i: Cytopathology. - : Wiley. - 0956-5507 .- 1365-2303. ; 34:4, s. 286-294
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Tidskriftsartikel (refereegranskat)abstract
- Background: Improved molecular diagnosis is needed in prostate cancer (PC). Fine needle aspiration (FNA) is a minimally invasive biopsy technique, less traumatic compared to core needle biopsy, and could be useful for diagnosis of PC. Molecular biomarkers (BMs) in FNA-samples can be assessed for prediction, eg of immunotherapy efficacy before treatment as well as at treatment decision time points during disease progression.Methods: In the present pilot study, the expression levels of 151 BM proteins were analysed by proximity extension assay in FNA-samples from 16 patients, including benign prostate lesions (n = 3) and cancers (n = 13). An ensemble data analysis strategy was applied using several machine learning models.Results: Twelve potentially predictive BM proteins correlating with International Society of Urological Pathology grade groups were identified, among them vimentin, tissue factor pathway inhibitor 2, and integrin beta-5. The validity of the results was supported by network analysis that showed functional associations between most of the identified putative BMs. We also showed that multiple immune checkpoint targets can be assessed (eg PD-L1, CD137, and Galectin-9), which may support the selection of immunotherapy in advanced PC. Results are promising but need further validation in a larger cohort.Conclusions: Our pilot study represents a “proof of concept” and shows that multiplex profiling of potential diagnostic and predictive BM proteins is feasible on tumour material obtained by FNA sampling of prostate cancer. Moreover, our results demonstrate that an ensemble data analysis strategy may facilitate the identification of BM signatures in pilot studies when the patient cohort is limited.
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| 35. |
- Zhang, Jinhui, et al.
(författare)
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VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss
- 2021
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1-mediated (AAV1-mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.
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| 36. |
- Zutin, Danilo, et al.
(författare)
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A VISIR lab server for the iLab shared architecture
- 2011
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Ingår i: International Journal of Online Engineering. - : International Journal of Online Engineering. - 1868-1646 .- 1861-2121. ; 7:SUPPL, s. 14-17
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the work done at the Carinthia University of Applied Sciences towards integrating VISIR-based labs on the iLab architecture. The Virtual Systems in Reality (VISIR) project is carried out by the Blekinge Institute of Technology, Sweden and features a platform for performing experiments in different domains.
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