| 1. |
- Loza, M. J., et al.
(författare)
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Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
- 2016
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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| 2. |
- Holmes, Michael V., et al.
(författare)
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Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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| 3. |
- Colomé, Núria, et al.
(författare)
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Multi-laboratory experiment PME11 for the standardization of phosphoproteome analysis
- 2022
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Ingår i: Journal of Proteomics. - : Elsevier. - 1874-3919 .- 1876-7737. ; 251
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Tidskriftsartikel (refereegranskat)abstract
- Global analysis of protein phosphorylation by mass spectrometry proteomic techniques has emerged in the last decades as a powerful tool in biological and biomedical research. However, there are several factors that make the global study of the phosphoproteome more challenging than measuring non-modified proteins. The low stoichiometry of the phosphorylated species and the need to retrieve residue specific information require particular attention on sample preparation, data acquisition and processing to ensure reproducibility, qualitative and quantitative robustness and ample phosphoproteome coverage in phosphoproteomic workflows. Aiming to investigate the effect of different variables in the performance of proteome wide phosphoprotein analysis protocols, ProteoRed-ISCIII and EuPA launched the Proteomics Multicentric Experiment 11 (PME11). A reference sample consisting of a yeast protein extract spiked in with different amounts of a phosphomix standard (Sigma/Merck) was distributed to 31 laboratories around the globe. Thirty-six datasets from 23 laboratories were analyzed. Our results indicate the suitability of the PME11 reference sample to benchmark and optimize phosphoproteomics strategies, weighing the influence of different factors, as well as to rank intra and inter laboratory performance.
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| 4. |
- Boras, Julia, et al.
(författare)
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Effect of viruses and protists on bacteria in eddies of the Canary Current region (subtropical Northeast Atlantic).
- 2010
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Ingår i: Limnology and Oceanography. - 0024-3590 .- 1939-5590. ; 55:2, s. 885-898
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Tidskriftsartikel (refereegranskat)abstract
- The effect of oceanic eddies on microbial processes, with emphasis on bacterial losses due to protists and phages, was examined in the Canary Current region (subtropical northeast Atlantic) through the water column (down to 1000 m) during August 2006. Sampling stations were located in cyclonic and anticyclonic eddies, as well as in regions situated outside the influence of the eddy field (far-field stations). In the euphotic zone, in cyclonic eddies losses of bacteria due to viruses and protists were from 25.6% to 69.8%, and from not detected to 46.8% of bacterial production (BP) d(-1), respectively. In anticyclonic eddies, these values ranged from 20.6% to 90.2% of BP d(-1) for viruses, and from 8.0% to 79.4% of BP d(-1) for protists. At far-field stations, losses of bacteria ranged from 48.7% to 66.9% for viruses, and from not detected to 44.8% for protists. In addition, covering all stations and depths (from the epipelagic to the bathypelagic layer), bacterial losses due to viruses were significantly higher than losses by protists, and did not differ significantly among depths except for the stations situated in anticyclonic eddies, where they were significantly higher in the epipelagic layer. Lysogenic infection was more frequent at anticyclonic stations, where the highest pressure of protists on bacteria was observed. Because of the importance of viral activity, we suggest that lysis products from bacteria may be a source of regenerated nutrients in the surface of the oligotrophic ocean, in addition to the input of nutrients upwelled by eddies.
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| 5. |
- Medina-Dols, Aina, et al.
(författare)
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Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis
- 2024
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Ingår i: Cell Death Discovery. - : Springer Nature. - 2058-7716. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) <= 2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1 alpha also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ss, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, beta-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.
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| 6. |
- Von Holle, Ann, et al.
(författare)
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BMI and breast cancer risk around age at menopause
- 2024
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Ingår i: Cancer Epidemiology. - : Elsevier. - 1877-7821 .- 1877-783X. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- Background: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology.Methods: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy.Results: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO.Conclusion: The BMI breast cancer HRs remained less than or near one during the 45–55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.
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| 7. |
- Bhowmik, Arghya, et al.
(författare)
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Implications of the BATTERY 2030+ AI-Assisted Toolkit on Future Low-TRL Battery Discoveries and Chemistries
- 2022
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Ingår i: Advanced Energy Materials. - : John Wiley & Sons. - 1614-6832 .- 1614-6840. ; 12:17
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Forskningsöversikt (refereegranskat)abstract
- BATTERY 2030+ targets the development of a chemistry neutral platform for accelerating the development of new sustainable high-performance batteries. Here, a description is given of how the AI-assisted toolkits and methodologies developed in BATTERY 2030+ can be transferred and applied to representative examples of future battery chemistries, materials, and concepts. This perspective highlights some of the main scientific and technological challenges facing emerging low-technology readiness level (TRL) battery chemistries and concepts, and specifically how the AI-assisted toolkit developed within BIG-MAP and other BATTERY 2030+ projects can be applied to resolve these. The methodological perspectives and challenges in areas like predictive long time- and length-scale simulations of multi-species systems, dynamic processes at battery interfaces, deep learned multi-scaling and explainable AI, as well as AI-assisted materials characterization, self-driving labs, closed-loop optimization, and AI for advanced sensing and self-healing are introduced. A description is given of tools and modules can be transferred to be applied to a select set of emerging low-TRL battery chemistries and concepts covering multivalent anodes, metal-sulfur/oxygen systems, non-crystalline, nano-structured and disordered systems, organic battery materials, and bulk vs. interface-limited batteries.
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| 8. |
- Cobo, Teresa, et al.
(författare)
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A prediction model of histological chorioamnionitis and funisitis in preterm prelabor rupture of membranes: analyses of multiple proteins in the amniotic fluid.
- 2012
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Ingår i: The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. - : Informa UK Limited. - 1476-4954.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine the best prediction model of histological chorioamnionitis and funisitis in preterm prelabor rupture of membranes (PPROM) using selected candidate proteins in the amniotic fluid (AF). Material and methods: Prospective cohort study. Twenty-six AF proteins were assayed by a multiple immunoassay from 107 women with membranes rupture from 23+0 to 36+6 weeks. The Czech Republic policy is active management, and the majority of women were delivered within 72 h after the rupture of membranes, except for women with PPROM <28+0 weeks who were managed conservatively. The best predictive models to diagnose histological chorioamnionitis and funisitis were calculated by logistic regression depending on the gestational age (GA) at membrane rupture. Results: Both IL-6 and a combination of IL-10, and migration inhibiting factor (MIF) were the best predictive models of histological chorioamnionitis and funisitis, respectively, with sensitivity, specificity, positive and negative predictive values and positive likelihood ratio (LR+) of 62, 83, 37, 93 and 3.6 and of 63, 91, 53, 94 and 7.0, respectively. Depending on whether GA at membrane rupture was <32 or ≥ 32 weeks, IL-10, alone or in combination with MIF and triggering receptor expressed on myeloid cells-1, was the strongest inflammatory biomarker for funisitis (LR+10.6 and 36.6, respectively). Conclusion: Regardless of the GA at membrane rupture, IL-6 from the AF was the best predictor of histological chorioamnionitis. Amniotic fluid IL-10 was notably accurate in the prediction of funisitis.
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| 9. |
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| 10. |
- Moreno-Espinosa, Ana L., et al.
(författare)
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Prediction of Neonatal Respiratory Morbidity Assessed by Quantitative Ultrasound Lung Texture Analysis in Twin Pregnancies
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 11:16
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate the performance of quantitative ultrasound of fetal lung texture analysis in predicting neonatal respiratory morbidity (NRM) in twin pregnancies. This was an ambispective study involving consecutive cases. Eligible cases included twin pregnancies between 27.0 and 38.6 weeks of gestation, for which an ultrasound image of the fetal thorax was obtained within 48 h of delivery. Images were analyzed using quantusFLM® version 3.0. The primary outcome of this study was neonatal respiratory morbidity, defined as the occurrence of either transient tachypnea of the newborn or respiratory distress syndrome. The performance of quantusFLM® in predicting NRM was analyzed by matching quantitative ultrasound analysis and clinical outcomes. This study included 166 images. Neonatal respiratory morbidity occurred in 12.7% of cases, and it was predicted by quantusFLM® analysis with an overall sensitivity of 42.9%, specificity of 95.9%, positive predictive value of 60%, and negative predictive value of 92.1%. The accuracy was 89.2%, with a positive likelihood ratio of 10.4, and a negative likelihood ratio of 0.6. The results of this study demonstrate the good prediction capability of NRM in twin pregnancies using a non-invasive lung texture analysis software. The test showed an overall good performance with high specificity, negative predictive value, and accuracy.
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