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| 2. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 4. |
- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 9. |
- Argyropoulos, C., et al.
(författare)
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Operational criteria for selecting a cDNA microarray data normalization algorithm
- 2006
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Ingår i: Oncology Reports. - 1021-335X .- 1791-2431. ; 15:4, s. 983-996
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Tidskriftsartikel (refereegranskat)abstract
- Microarray technology allows gene expression profiling at a global level. Many algorithms for the normalization of raw microarray data have been proposed, but no attempt has yet been made to propose operationally verifiable criteria for their comparative evaluation, which is necessary for the selection of the most appropriate method for a given dataset. This study develops a set of operational criteria for assessing the impact of various normalization algorithms in terms of accuracy (bias), precision (variance) and over-fitting (information reduction). The use of these criteria is illustrated by applying the three most widely used algorithms (global median normalization, spiked-in based normalization and lowess) on a specifically designed, multiply-controlled dataset.
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| 16. |
- Kyriakoulis, Konstantinos G, et al.
(författare)
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Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19 : A Consensus Statement Based on Available Clinical Trials
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 11:20, s. 1-18
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Forskningsöversikt (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients.
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| 19. |
- Arias, C, et al.
(författare)
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Diversity in orthopaedics and traumatology: a global perspective
- 2020
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Ingår i: EFORT open reviews. - : Bioscientifica. - 2058-5241 .- 2396-7544. ; 5:10, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- Europe represents true diversity, with cultural, linguistic and geopolitical variation spanning a large geographical area. Politics for many of its 750 million inhabitants revolves around the European Union (EU) and its 27 member states. The overarching goal of the EU is to promote peace and the values of the union (inclusion, tolerance, justice, solidarity and non-discrimination).1,2 EFORT was created to connect orthopaedic associations across Europe, fostering relationships between member countries that celebrated diversity and facilitated the exchange of knowledge. Whilst the global landscape changes and politics attempts to interfere in how we live our lives, it is important to remember that a strong organization is a diverse one that evolves over time. Various initiatives exist across the global landscape to support diversity in terms of culture; gender; black, Asian and minority ethnic (BAME) groups; disability groups; lesbian, gay, bisexual, transgender and queer (or questioning) and others (LGBTQ+); and the ‘ageing’ surgeon. This article explores the creation of some of these initiatives and how they have been supported by different orthopaedic organizations. Cite this article: EFORT Open Rev 2020;5:743-752. DOI: 10.1302/2058-5241.5.200022
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| 21. |
- Durrant, A., et al.
(författare)
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Detection and localisation of multiple in-core perturbations with neutron noise-based self-supervised domain adaptation
- 2021
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Ingår i: Proc. Int. Conf. Mathematics and Computational Methods Applied to Nuclear Science and Engineering (M&C2021). - 9781713886310
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Konferensbidrag (refereegranskat)abstract
- The use of non-intrusive techniques for monitoring nuclear reactors is becoming more vital as western fleets age. As a consequence, the necessity to detect more frequently occurring operational anomalies is of upmost interest. Here, noise diagnostics — the analysis of small stationary deviations of local neutron flux around its time-averaged value — is employed aiming to unfold from detector readings the nature and location of driving perturbations. Given that in-core instrumentation of western-type light-water reactors are scarce in number of detectors, rendering formal inversion of the reactor transfer function impossible, we propose to utilise advancements in Machine Learning and Deep Learning for the task of unfolding. This work presents an approach to such a task doing so in the presence of multiple and simultaneously occurring perturbations or anomalies. A voxel-wise semantic segmentation network is proposed to determine the nature and source location of multiple and simultaneously occurring perturbations in the frequency domain. A diffusion-based core simulation tool has been employed to provide simulated training data for two reactors. Additionally, we work towards the application of the aforementioned approach to real measurements, introducing a self-supervised domain adaptation procedure to align the representation distributions of simulated and real plant measurements.
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| 23. |
- Kumari, S., et al.
(författare)
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Tumor Necrosis Factor Receptor Signaling in Keratinocytes Triggers Interleukin-24-Dependent Psoriasis-like Skin Inflammation in Mice
- 2013
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Ingår i: Immunity. - 1074-7613 .- 1097-4180. ; 5:39, s. 899-911
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation.
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| 24. |
- Stergiou, George, et al.
(författare)
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Bedtime dosing of antihypertensive medications: systematic review and consensus statement : International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension
- 2022
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 40:10, s. 1847-1858
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Forskningsöversikt (refereegranskat)abstract
- Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping blood pressure (BP) profile and morning BP surge, with increased incidence of cardiovascular events during the first few morning hours. These observations provide justification for complete 24-h BP control as being the primary goal of antihypertensive treatment. Bedtime administration of antihypertensive drugs has also been proposed as a potentially more effective treatment strategy than morning administration. This Position Paper by the International Society of Hypertension reviewed the published evidence on the clinical relevance of the diurnal variation in BP and the timing of antihypertensive drug treatment, aiming to provide consensus recommendations for clinical practice. Eight published outcome hypertension studies involved bedtime dosing of antihypertensive drugs, and all had major methodological and/or other flaws and a high risk of bias in testing the impact of bedtime compared to morning treatment. Three ongoing, well designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing. Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose.
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