| 1. |
- Kang, E. Y., et al.
(författare)
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CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:5, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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| 2. |
- Kobel, M., et al.
(författare)
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p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Journal of Pathology Clinical Research. - : Wiley. - 2056-4538. ; 9:3, s. 208-222
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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| 3. |
- Kang, E. Y., et al.
(författare)
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MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma
- 2022
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 480, s. 855-871
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Tidskriftsartikel (refereegranskat)abstract
- Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naive HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naive tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naive HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
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| 4. |
- Saner, Flurina A. M., et al.
(författare)
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Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
- 2024
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Ingår i: CLINICAL CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 30:16, s. 3481-3498
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8(+) lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
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| 5. |
- Gunduz, C., et al.
(författare)
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Hyperlipidaemia prevalence and cholesterol control in obstructive sleep apnoea: Data from the European sleep apnea database (ESADA)
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 676-688
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective Obstructive sleep apnoea (OSA) and hyperlipidaemia are independent risk factors for cardiovascular disease. This study investigates the association between OSA and prevalence of hyperlipidaemia in patients of the European Sleep Apnea Database (ESADA) cohort. Methods The cross-sectional analysis included 11 892 patients (age 51.9 +/- 12.5 years, 70% male, body mass index (BMI) 31.3 +/- 6.6 kg/m(2), mean oxygen desaturation index (ODI) 23.7 +/- 25.5 events/h) investigated for OSA. The independent odds ratio (OR) for hyperlipidaemia in relation to measures of OSA (ODI, apnoea-hypopnoea index, mean and lowest oxygen saturation) was determined by means of general linear model analysis with adjustment for important confounders such as age, BMI, comorbidities and study site. Results Hyperlipidaemia prevalence increased from 15.1% in subjects without OSA to 26.1% in those with severe OSA, P < 0.001. Corresponding numbers in patients with diabetes were 8.5% and 41.5%, P < 0.001. Compared with ODI quartile I, patients in ODI quartiles II-IV had an adjusted OR (95% CI) of 1.33 (1.15-1.55), 1.37 (1.17-1.61) and 1.33 (1.12-1.58) (P < 0.001), respectively, for hyperlipidaemia. Obesity was defined as a significant risk factor for hyperlipidaemia. Subgroups of OSA patients with cardio-metabolic comorbidities demonstrated higher prevalence of HL. In addition, differences in hyperlipidaemia prevalence were reported in European geographical regions with the highest prevalence in Central Europe. Conclusion Obstructive sleep apnoea, in particular intermittent hypoxia, was independently associated with the prevalence of hyperlipidaemia diagnosis.
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| 6. |
- Gunduz, C., et al.
(författare)
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Long-term positive airway pressure therapy is associated with reduced total cholesterol levels in patients with obstructive sleep apnea: data from the European Sleep Apnea Database (ESADA)
- 2020
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Ingår i: Sleep Medicine. - : Elsevier BV. - 1389-9457. ; 75, s. 201-209
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Obstructive sleep apnea (OSA) is an independent risk factor for dyslipidemia. The current study examined the effects of positive airway pressure (PAP) treatment on lipid status in the European Sleep Apnea Database (ESADA). Methods: The prospective cohort study enrolled 1564 OSA subjects (74% male, mean age 54 ± 11y, body mass index (BMI) 32.7 ± 6.6 kg/m2 and apnea-hypopnea index (AHI) 40.3 ± 24.4 n/h) undergoing PAP therapy for at least three months (mean 377.6 ± 419.5 days). Baseline and follow-up total cholesterol (TC) from nine centers were analyzed. Repeated measures and logistic regression tests (adjusted for age, sex, weight changes, lipid lowering medication, PAP compliance, and treatment duration) were used to compare changes in TC concentration. Incident risk for a coronary heart disease event (CHD) was used to compute a Framingham CHD risk score (estimated from age, BMI, blood pressure, and TC). Results: Adjusted means of TC decreased from 194.2 mg/dl to 189.3 mg/dl during follow-up (p = 0.019). A clinically significant (10%) reduction of TC at PAP follow-up was observed in 422 patients (27%). Duration of PAP therapy was identified as independent predictor for TC reduction, which implies an approximately 10% risk reduction for incident CHD events (from 26.7% to 24.1% in men and from 11.2% to 10.1% in women, p < 0.001 respectively). Conclusion: This observational study demonstrates a reduction of TC after long-term PAP treatment. The close association between TC concentration and cardiovascular (CV) mortality suggests that identification and treatment of OSA may have a beneficial effect on overall CV risk due to this mechanism. This possibility needs to be evaluated in prospective randomized studies. © 2020 Elsevier B.V.
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| 7. |
- Lombardi, C., et al.
(författare)
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Periodic limb movements during sleep and blood pressure changes in sleep apnoea: Data from the European Sleep Apnoea Database
- 2020
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Ingår i: Respirology. - : Wiley. - 1323-7799 .- 1440-1843. ; 25:8, s. 872-879
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective OSA and PLMS are known to induce acute BP swings during sleep. Our current study aimed to address the independent effect of PLMS on BP in an unselected OSA patient cohort. Methods This cross‐sectional analysis included 1487 patients (1110 males, no previous hypertension diagnosis or treatment, mean age: 52.5years, mean BMI: 30.5kg/m2) with significant OSA (defined as AHI≥10) recruited from the European Sleep Apnoea Cohort. Patients underwent overnight PSG. Patients were stratified into two groups: patients with significant PLMS (PLMSI>25 events/hour of sleep) and patients without significant PLMS (PLMSI<25 events/hour of sleep). SBP, DBP and PP were the variables of interest. For each of these, a multivariate regression linear model was fitted to evaluate the relationship between PLMS and outcome adjusting for sociodemographic and clinical covariates (gender, age, BMI, AHI, ESS, diabetes, smoking and sleep efficiency). Results The univariate analysis of SBP showed an increment of BP equal to 4.70mm Hg (P<0.001) in patients with significant PLMS compared to patients without significant PLMS. This increment remained significant after implementing a multivariate regression model (2.64mm Hg, P = 0.044). No significant increment of BP was observed for DBP and PP. Conclusion PLMS is associated with a rise in SBP regardless of AHI, independent of clinical and sociodemographic confounders. A PLMS phenotype may carry an increased risk for cardiovascular disease in OSA patients.
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| 8. |
- Artigas, J., et al.
(författare)
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Towards a renewed research agenda in ecotoxicology
- 2012
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491. ; 160, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- New concerns about biodiversity, ecosystem services and human health triggered several new regulations increasing the need for sound ecotoxicological risk assessment. The PEER network aims to share its view on the research issues that this challenges. PEER scientists call for an improved biologically relevant exposure assessment. They promote comprehensive effect assessment at several biological levels. Biological traits should be used for Environmental risk assessment (ERA) as promising tools to better understand relationships between structure and functioning of ecosystems. The use of modern high throughput methods could also enhance the amount of data for a better risk assessment. Improved models coping with multiple stressors or biological levels are necessary to answer for a more scientifically based risk assessment. Those methods must be embedded within life cycle analysis or economical models for efficient regulations. Joint research programmes involving humanities with ecological sciences should be developed for a sound risk management. (C) 2011 Elsevier Ltd. All rights reserved.
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| 9. |
- Bikov, A., et al.
(författare)
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The relationship between periodic limb movement during sleep and dyslipidaemia in patients with obstructive sleep apnea
- 2024
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Ingår i: Journal of Sleep Research. - 0962-1105 .- 1365-2869. ; 33:2
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Tidskriftsartikel (refereegranskat)abstract
- Periodic limb movements during sleep and obstructive sleep apnea are both associated with increased sympathetic tone, and have been proposed as risk factors for heart diseases and, in particular, cardiovascular disease. As sympathetic system activation may lead to dyslipidaemia, periodic limb movements during sleep could be an additional risk factor for cardiovascular disease in patients with obstructive sleep apnea. The aim of the study was to determine whether the presence of periodic limb movements during sleep affects serum lipid levels in obstructive sleep apnea. Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non- high-density lipoprotein cholesterol and triglyceride levels were investigated in 4138 patients with obstructive sleep apnea in the European Sleep Apnea Database (ESADA) cohort, divided into those with periodic limb movements during sleep index & GE; 15 per hr (n = 628) and controls (n = 3510). ANCOVA adjusted for age, sex, body mass index, apnea-hypopnea index, alcohol intake, smoking status, diabetes, insomnia and study site was used to assess differences in lipids between periodic limb movements during sleep and controls. Patients with periodic limb movements during sleep (24% female, 54.4 & PLUSMN; 12.1 years, body mass index 31.9 & PLUSMN; 5.8 kg m(-2), apnea-hypopnea index 36.7 & PLUSMN; 25.4 per hr) had higher triglyceride (1.81 & PLUSMN; 1.04 versus 1.69 & PLUSMN; 0.90 mmol L-1, p = 0.002) and lower high-density lipoprotein cholesterol (1.19 & PLUSMN; 0.34 versus 1.24 & PLUSMN; 0.37 mmol L-1, p = 0.002) levels, whilst there was no difference in either total cholesterol (4.98 & PLUSMN; 1.10 versus 4.94 & PLUSMN; 1.07 mmol L-1), low-density lipoprotein cholesterol (3.04 & PLUSMN; 0.96 versus 2.98 & PLUSMN; 0.98 mmol L-1) or non- high-density lipoprotein cholesterol (3.78 & PLUSMN; 1.10 versus 3.70 & PLUSMN; 1.05 mmol L-1) concentrations (all p > 0.05). The results remained unchanged after most sensitivity analyses. Patients with obstructive sleep apnea with periodic limb movements during sleep had more prevalent cardiovascular disease (11% versus 6%, p < 0.01). Periodic limb movements during sleep in obstructive sleep apnea is associated with dyslipidaemia independently of important confounders. Our results highlight periodic limb movements during sleep as an additional risk factor for cardiovascular disease in obstructive sleep apnea.
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| 10. |
- Bonsignore, M. R., et al.
(författare)
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Excessive Daytime Sleepiness in Obstructive Sleep Apnea Patients Treated With Continuous Positive Airway Pressure: Data From the European Sleep Apnea Database
- 2021
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- follow-up visit after 4 months to 2 years. The change in ESS (n = 2,190) was weakly correlated with CPAP use (R2 = 0.023, p 0.0001). Logistic regression showed that an ESS score 10 at the first follow-up visit was associated directly with ESS at baseline and inversely with duration of follow-up, and CPAP use (R2 of the model: 0.417). EDS showed heterogeneity in different European countries both at baseline and at the first follow-up visit, suggesting modulation by cultural and lifestyle factors. In conclusion, residual EDS in CPAP-treated OSA occurred in approximately one in four patients at follow-up; its prevalence was highest (40%) in the first 3 months of treatment and subsequently decreased. The finding of residual EDS in a significant percentage of optimally treated OSA patients suggests that wake-promoting agents may be useful, but their indication should be evaluated after at least 3 months of treatment.
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