| 1. |
- Marazioti, Antonia, et al.
(författare)
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KRAS signaling in malignant pleural mesothelioma
- 2022
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.
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| 2. |
- Gasperi, Johnny, et al.
(författare)
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Micropollutants in Urban Runoff from Traffic Areas: Target and Non-Target Screening on Four Contrasted Sites
- 2022
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Ingår i: Water. - : MDPI. - 2073-4441. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Projected changes in temperature and precipitation in mid-latitude wet regions are expected to significantly affect forest ecosystems. We studied the physiological and shoot growth responses of Abies holophylla and Abies koreana seedlings to warming (3◦C above ambient temperature) and increased precipitation (irrigation with 40% of rainfall) treatments under open-field conditions. The physiological parameters, quantified by the net photosynthetic rate, transpiration rate, stomatal conductance, and total chlorophyll content, were monitored from July to October 2018. Shoot growth (i.e., root collar diameter and height) was assessed in August and December 2018. Irrespective of the treatments, the physiological parameters of both species decreased from July to August under warming treatment due to heat stress before recovering in September and October. Warming alone (W) and warming along with increased precipitation (W*P) decreased the physiological activities of both species in July, August, and September, with more pronounced effects on A. koreana compared with A. holophylla. Increased precipitation resulted in the increased chlorophyll content of both species in October. Shoot growth was not generally affected by the treatments, except for a subtle reduction in height under W*P for A. koreana. A. holophylla had consistently higher values for the physiological parameters and shoot growth than A. koreana. Our results indicate that the physiological activities of the Abies species could be seriously reduced under climate change, with a more severe impact on A. koreana. Among the two species, A. holophylla appears to be a more robust candidate for future forest planting.
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| 3. |
- Stockhammer, Paul, et al.
(författare)
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Krebs von den Lungen 6 (KL-6) is a novel diagnostic and prognostic biomarker in pleural mesothelioma
- 2023
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Ingår i: Lung Cancer. - 0169-5002. ; 185
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM. Materials and methods: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro. Results: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort. Conclusion: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM.
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