| 1. |
- Clave, Emmanuel, et al.
(författare)
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Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus
- 2018
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:457
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Tidskriftsartikel (refereegranskat)abstract
- The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.
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| 2. |
- Piasecka, Barbara, et al.
(författare)
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Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges
- 2017
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:3, s. 488-497
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
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| 3. |
- Tuleasca, Constantin, et al.
(författare)
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Impact of the Mean Cochlear Biologically Effective Dose on Hearing Preservation After Stereotactic Radiosurgery for Vestibular Schwannoma: A Retrospective Longitudinal Analysis
- 2024
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Ingår i: Neurosurgery. - 0148-396X .- 1524-4040. ; 94:1, s. 174-182
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is a useful alternative for small- to medium-sizedvestibular schwannoma. To evaluate whether biologically effective dose (BEDGy2.47), calculated for mean (BEDGy2.47 mean)and maximal (BEDGy2.47 max) cochlear dose, is relevant for hearing preservation. METHODS: This is a retrospective longitudinal single-center study. Were analyzed 213 patients with useful baselinehearing. Risk of hearing decline was assessed for Gardner–Robertson classes and pure tone average (PTA) loss. The meanfollow-up period was 39 months (median 36, 6-84).RESULTS: Hearing decline (Gardner–Robertson class) 3 years after SRS was associated with higher cochlear BEDGy2.47 mean(odds ratio [OR] 1.39, P = .009). Moreover, BEDGy2.47 mean was more relevant as compared with BEDGy2.47 max (OR 1.13, P = .04).Risk of PTA loss (continuous outcome, follow-up minus baseline) was significantly corelated with BEDGy2.47 mean at 24 (betacoefficient 1.55, P = .002) and 36 (beta coefficient 2.01, P = .004) months after SRS. Risk of PTA loss (>20 dB vs ≤) was associatedwith higher BEDGy2.47 mean at 6 (OR 1.36, P = .002), 12 (OR 1.36, P = .007), and 36 (OR 1.37, P = .02) months. Risk of hearingdecline at 36 months for the BEDGy2.47 mean of 7–8, 10, and 12 Gy2.47 was 28%, 57%, and 85%, respectively. CONCLUSION: Cochlear BEDGy2.47 mean is relevant for hearing decline after SRS and more relevant as compared withBEDGy2.47 max. Three years after SRS, this was sustained for all hearing decline evaluation modalities. Our data suggestthe BEDGy2.47 mean cut-off of ≤8 Gy2.47 for better hearing preservation rates.
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| 4. |
- Tuleasca, Constantin, et al.
(författare)
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The Relevance of Biologically Effective Dose for Hearing Preservation After Stereotactic Radiosurgery for Vestibular Schwannomas : A Retrospective Longitudinal Study
- 2023
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Ingår i: Neurosurgery. - : Ovid Technologies (Wolters Kluwer Health). - 0148-396X .- 1524-4040. ; 92:6, s. 1216-1226
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Stereotactic radiosurgery has become a common treatment approach for small-to-medium size vestibular schwannomas.OBJECTIVE: To evaluate relationship between time (beam-on and treatment) and risk of hearing decline after stereotactic radiosurgery for vestibular schwannomas in patients with Gardner–Robertson (GR) baseline classes I and II.METHODS: This retrospective longitudinal single-center study included 213 patients with GR I and II treated between June 2010 and December 2019. Risk of passing from GR classes I and II (coded 0) to other classes III, IV, and V (coded 1) and the increase in pure tone average (continuous outcome) were evaluated using a mixed-effect regression model. Biologically effective dose (BED) was further assessed for an alpha/beta ratio of 2.47 (Gy2.47).RESULTS: Binary outcome analysis revealed sex, dose rate, integral dose, time [beam-on time odds ratio 1.03, P = .03, 95% CI 1.00-1.06; treatment time (P = .02) and BED (P = .001) as relevant. Fitted multivariable model included the sex, dose rate, and BED. Pure tone average analysis revealed age, integral dose received by tumor, isocenter number, time (beam-on time odds ratio 0.20, P = .001, 95% CI 0.083-0.33) and BED (P = .005) as relevant.CONCLUSION: Our analysis showed that risk of hearing decline was associated with male sex, higher radiation dose rate (cutoff 2.5 Gy/minute), higher integral dose received by the tumor, higher beam-on time ≥20 minutes, and lower BED. A BED between 55 and 61 was considered as optimal for hearing preservation.
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| 5. |
- Kanai, M, et al.
(författare)
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- 2023
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