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| 2. |
- Budczies, Jan, et al.
(författare)
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Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer : alterations in glutamine and beta-alanine metabolism
- 2013
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Ingår i: Journal of Proteomics. - : Lippincott Williams & Wilkins. - 1874-3919 .- 1876-7737. ; 94, s. 279-288
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER-) breast cancer tissues were investigated using GC-TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER- subtype. Beta-alanine demonstrated the strongest change between ER- and ER+ breast cancer (fold change=2.4, p=1.5E-20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R=-0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER- breast cancer. In a Kaplan-Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR=0.6, p=3.2E-15).BIOLOGICAL SIGNIFICANCE: It is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER- breast as different diseases requiring different treatment strategies. Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER- breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER- subtype as a preferential target for glutaminase inhibitors. For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER- breast cancer.
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| 3. |
- Kleine, Barbara I., et al.
(författare)
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Preservation of blueschist-facies minerals along a shear zone by coupled metasomatism and fast-flowing CO2-bearing fluids
- 2014
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Ingår i: Journal of Petrology. - : Oxford University Press (OUP). - 0022-3530 .- 1460-2415. ; 55:10, s. 1905-1939
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Tidskriftsartikel (refereegranskat)abstract
- Two types of blue halo (types I and II) composed of blueschist-facies minerals are centered around a brittle, normal shear zone in greenschist-facies rocks on the island of Syros, Aegean Sea, Greece. The shear zone is steeply dipping and cuts a near-horizontal layer of greenschist-facies rocks (albite + epidote + actinolite + chlorite + quartz). Type I and II blue haloes are 0.3 m and c. 1m wide respectively, and are seen on both sides of the shear zone. The inner type I haloes are composed of nearly pure glaucophane schist and were formed by metasomatic addition of Na2O and SiO2, and to a lesser extent of K2O and large ion lithophile elements (LILE), coupled with loss of CaO, Al2O3 and MnO. The outer type II haloes consist of a carbonated blueschist-facies assemblage (glaucophane + calcite + phengite + epidote + garnet + quartz).These experienced only slight metasomatic changes (i.e. addition of K2O and LILE), which cannot alone explain halo formation.We present petrological, geochemical and thermodynamic evidence that this assemblage was preserved at greenschist-facies conditions because XCO2 was elevated by flow of a CO2-bearing fluid along the shear zone, which was approximately contemporaneous with greenschist-facies hydration in the surrounding rocks. We further note that the flux of CO2-bearing fluid along the shear zone was rapid with respect to the fluid flux in the surrounding rocks. Mass-balance calculations reveal that the fluid flux within the shear zone was at least 100-2000 times greater than the fluid flux within the surrounding rocks. Mineral textures show greenschist-facies minerals replacing blueschist minerals in the type II haloes, supporting our interpretation that the blueschist-facies minerals were preserved during greenschist-facies retrogression. A simplified P-T vs XCO2 pseudosection confirms that preservation of carbonated blueschist can occur at greenschist-facies conditions in the presence of a CO2-bearing fluid.
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- Papadopoulos, Nikolaos G, et al.
(författare)
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Research needs in allergy: an EAACI position paper, in collaboration with EFA.
- 2012
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Ingår i: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.
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