| 11. |
- Curigliano, G, et al.
(författare)
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De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017.
- 2017
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 28:8, s. 1700-1712
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Tidskriftsartikel (refereegranskat)abstract
- The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.
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| 12. |
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| 13. |
- Abbott, Jessica K., et al.
(författare)
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The microevolutionary response to male-limited X-chromosome evolution in Drosophila melanogaster reflects macroevolutionary patterns
- 2020
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Ingår i: Journal of Evolutionary Biology. - : Wiley-Blackwell. - 1010-061X .- 1420-9101. ; 33:6, s. 738-750
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Tidskriftsartikel (refereegranskat)abstract
- Due to its hemizygous inheritance and role in sex determination, the X-chromosome is expected to play an important role in the evolution of sexual dimorphism and to be enriched for sexually antagonistic genetic variation. By forcing the X-chromosome to only be expressed in males over >40 generations, we changed the selection pressures on the X to become similar to those experienced by the Y. This releases the X from any constraints arising from selection in females and should lead to specialization for male fitness, which could occur either via direct effects of X-linked loci or trans-regulation of autosomal loci by the X. We found evidence of masculinization via up-regulation of male-benefit sexually antagonistic genes and down-regulation of X-linked female-benefit genes. Potential artefacts of the experimental evolution protocol are discussed and cannot be wholly discounted, leading to several caveats. Interestingly, we could detect evidence of microevolutionary changes consistent with previously documented macroevolutionary patterns, such as changes in expression consistent with previously established patterns of sexual dimorphism, an increase in the expression of metabolic genes related to mito-nuclear conflict and evidence that dosage compensation effects can be rapidly altered. These results confirm the importance of the X in the evolution of sexual dimorphism and as a source for sexually antagonistic genetic variation and demonstrate that experimental evolution can be a fruitful method for testing theories of sex chromosome evolution.
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| 14. |
- Barrenäs, Fredrik, et al.
(författare)
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Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy
- 2021
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in similar to 55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8(+) T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8(+) T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8(+) T cells to mediate protection against SIV challenge.
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| 15. |
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| 16. |
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| 17. |
- Hill, M. S., et al.
(författare)
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Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e50437-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well-supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets.
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| 18. |
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| 19. |
- Lund-Hansen, Katrine K., et al.
(författare)
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Feminization of complex traits in Drosophila melanogaster via female-limited X chromosome evolution
- 2020
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Ingår i: Evolution. - : Wiley. - 0014-3820 .- 1558-5646. ; 74:12, s. 2703-2713
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Tidskriftsartikel (refereegranskat)abstract
- A handful of studies have investigated sexually antagonistic constraints on achieving sex-specific fitness optima, although exclusively through male-genome-limited evolution experiments. In this article, we established a female-limited X chromosome evolution experiment, where we used an X chromosome balancer to enforce the inheritance of the X through the matriline, thus removing exposure to male selective constraints. This approach eliminates the effects of sexually antagonistic selection on the X chromosome, permitting evolution toward a single sex-specific optimum. After multiple generations of selection, we found strong evidence that body size and development time had moved toward a female-specific optimum, whereas reproductive fitness and locomotion activity remained unchanged. The changes in body size and development time are consistent with previous results, and suggest that the X chromosome is enriched for sexually antagonistic genetic variation controlling these particular traits. The lack of change in reproductive fitness and locomotion activity could be due to a number of mutually nonexclusive explanations, including a lack of sexually antagonistic variance on the X chromosome for those traits or confounding effects of the use of the balancer chromosome. This study is the first to employ female-genome-limited selection and adds to the understanding of the complexity of sexually antagonistic genetic variation.
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| 20. |
- Lund-Hansen, Katrine K., et al.
(författare)
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Sexually antagonistic coevolution between the sex chromosomes of Drosophila melanogaster
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National academy of Science. - 0027-8424 .- 1091-6490. ; 118:8
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Tidskriftsartikel (refereegranskat)abstract
- Antagonistic interactions between the sexes are important drivers of evolutionary divergence. Interlocus sexual conflict is generally described as a conflict between alleles at two interacting loci whose identity and genomic location are arbitrary, but with opposite fitness effects in each sex. We build on previous theory by suggesting that when loci under interlocus sexual conflict are located on the sex chromosomes it can lead to cycles of antagonistic coevolution between them and therefore between the sexes. We tested this hypothesis by performing experimental crosses using Drosophila melanogaster where we reciprocally exchanged the sex chromosomes between five allopatric wild-type populations in a round-robin design. Disrupting putatively coevolved sex chromosome pairs resulted in increased male reproductive success in 16 of 20 experimental populations (10 of which were individually significant), but also resulted in lower offspring egg-to-adult viability that affected both male and female fitness. After 25 generations of experimental evolution these sexually antagonistic fitness effects appeared to be resolved. To formalize our hypothesis, we developed population genetic models of antagonistic coevolution using fitness expressions based on our empirical results. Our model predictions support the conclusion that antagonistic coevolution between the sex chromosomes is plausible under the fitness effects observed in our experiments. Together, our results lend both empirical and theoretical support to the idea that cycles of antagonistic coevolution can occur between sex chromosomes and illustrate how this process, in combination with autosomal coadaptation, may drive genetic and phenotypic divergence between populations.
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