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- Bosch Campos, Ana, et al.
(författare)
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PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 7:283, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
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| 3. |
- Boquete, María Teresa, et al.
(författare)
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Current and historical factors drive variation of reproductive traits in unisexual mosses in Europe : A case study
- 2023
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Ingår i: Journal of Systematics and Evolution. - : Wiley. - 1674-4918 .- 1759-6831. ; 61:1, s. 213-226
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Tidskriftsartikel (refereegranskat)abstract
- Unisexual bryophytes provide excellent models to study the mechanisms that regulate the frequency of sexual versus asexual reproduction in plants, and their ecological and evolutionary implications. Here, we determined sex expression, phenotypic sex ratio, and individual shoot traits in 242 populations of the cosmopolitan moss Pseudoscleropodium purum spanning its whole distributional range. We tested whether niche differentiation, sex-specific differences in shoot size, and biogeographical history explained the spatial variation of reproductive traits. We observed high levels of sex expression and predominantly female-biased populations, although both traits showed high intraspecific variation among populations. Sex expression and sex ratio were partly explained by current macroscale environmental variation, with male shoots being less frequent at the higher end of the environmental gradients defined by the current distribution of the species. Female bias in population sex ratio was significantly lower in areas recolonized after the last glacial maximum (recent populations) than in glacial refugia (long-term persistent populations). We demonstrated that reproductive trait variation in perennial unisexual mosses is partially driven by macroscale and historical environmental variation. Based on our results, we hypothesize that sexual dimorphism in environmental tolerance and vegetative growth contribute to sex ratio bias over time, constraining the chances of sexual reproduction, especially in long-term persistent populations. Further studies combining genetic analyses and population monitoring should improve our understanding of the implications of the intraspecific variation in the frequency of sexual versus asexual reproduction in bryophyte population fitness and eco-evolutionary dynamics.
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| 4. |
- LoRusso, Patricia M, et al.
(författare)
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Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors
- 2003
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 9:6, s. 2040-2048
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The feasibility and utility of assessing quality of life (QoL) and disease-related symptoms in patients with advanced cancer have been evaluated in two Phase I clinical trials of p.o. administered ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced cancer. EXPERIMENTAL DESIGN: Functional Assessment of Cancer Therapy (FACT) questionnaires, including disease-specific subscales for lung, head and neck, colorectal, prostate, and ovarian cancer, were completed by patients in two open-label, Phase I, escalating multiple-dose safety and tolerability trials. RESULTS: In 157 patients, 92% of whom had received prior therapy, compliance in returning FACT questionnaires was 87% (European/Australian trial) and 57% (United States trial). This did not appear to be influenced by dose level or tumor type. For patients with colorectal, prostate, or ovarian cancer, median QoL [FACT and Trial Outcome Index (TOI)] scores deteriorated over time. In contrast, for patients with non-small cell lung cancer (NSCLC) or head and neck cancer, median FACT and TOI scores did not deteriorate significantly, and in the United States trial, head and neck cancer scores improved significantly over time. In patients with NSCLC, symptom-related scores measured by the Lung Cancer Subscale of FACT-L appeared sensitive to clinical change. CONCLUSIONS: QoL (FACT-L) questionnaires were used successfully in the Phase I clinical trials of ZD1839. They appeared to be a sensitive tool to monitor clinical changes for the five tumor types in these trials and showed that ZD1839 has the potential to improve patients' QoL.
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