| 1. |
- Hess, Timo, et al.
(author)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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In: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Journal article (peer-reviewed)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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| 2. |
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| 3. |
- Giralt, Sergio, et al.
(author)
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American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma.
- 2015
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In: Biology of Blood and Marrow Transplantation. - : Elsevier BV. - 1083-8791. ; 21:12, s. 2039-2051
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Journal article (peer-reviewed)abstract
- In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to "best non-HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
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| 4. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 5. |
- Knabl, Ludwig, et al.
(author)
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Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets
- 2018
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In: International Journal of Medical Microbiology. - : Elsevier BV. - 1438-4221 .- 1618-0607. ; 308:7, s. 969-976
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Journal article (peer-reviewed)abstract
- Escherichia coli-induced hemolytic uremic syndrome (eHUS) is a life-threatening complication of infection with Shiga toxin (Stx), in particular Stx2a-producing Escherichia coli. Enhanced coagulation activation with formation of microthrombi seems to be a key event in development of eHUS. Platelet activation has been postulated as a possible, but controversially debated mechanism. The present study investigated the effect of Stx2a on plasmatic coagulation and platelets. Binding studies were initially performed with ELISA and co-immunoprecipitation and supported by quartz crystal microbalance with dissipation monitoring (QCM-D). Antithrombin (AT) activity was measured using the automated BCS XP (R) system. ROTEM (R) was used for functional coagulation testing. Platelet binding and activation was studied with FACS and light-transmission aggregometry. We found binding of Stx2a to AT, an important inhibitor of blood coagulation, but only a mild albeit significant reduction of AT activity against FXa in the presence of Stx2a. QCM-D analysis also showed binding of Stx2a to heparin and an impaired binding of AT to Stx2a-bound heparin. ROTEM (R) using Stx2a-treated platelet-poor plasma revealed a significant, but only moderate shortening of clotting time. Neither binding nor activation of platelets by Stx2a could be demonstrated. In summary, data of this study suggest that Stx2a binds to AT, but does not induce major effects on plasmatic coagulation. In addition, no interaction with platelets occurred. The well-known non-beneficial administration of heparin in eHUS patients could be explained by the interaction of Stx2a with heparin.
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| 6. |
- Lener, Thomas, et al.
(author)
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Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper.
- 2015
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In: Journal of extracellular vesicles. - : Wiley. - 2001-3078. ; 4
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Journal article (peer-reviewed)abstract
- Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.
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| 7. |
- Marque, Christophe, et al.
(author)
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Solar radio emission as a disturbance of aeronautical radionavigation
- 2018
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In: Journal of Space Weather and Space Climate. - : EDP Sciences. - 2115-7251. ; 8
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Journal article (peer-reviewed)abstract
- On November 4th, 2015 secondary air traffic control radar was strongly disturbed in Sweden and some other European countries. The disturbances occurred when the radar antennas were pointing at the Sun. In this paper, we show that the disturbances coincided with the time of peaks of an exceptionally strong (similar to 10(5) Solar Flux Units) solar radio burst in a relatively narrow frequency range around 1 GHz. This indicates that this radio burst is the most probable space weather candidate for explaining the radar disturbances. The dynamic radio spectrum shows that the high flux densities are not due to synchrotron emission of energetic electrons, but to coherent emission processes, which produce a large variety of rapidly varying short bursts (such as pulsations, fiber bursts, and zebra patterns). The radio burst occurs outside the impulsive phase of the associated flare, about 30 min after the soft X-ray peak, and it is temporarily associated with fast evolving activity occurring in strong solar magnetic fields. While the relationship with strong magnetic fields and the coherent spectral nature of the radio burst provide hints towards the physical processes which generate such disturbances, we have so far no means to forecast them. Well-calibrated monitoring instruments of whole Sun radio fluxes covering the UHF band could at least provide a real-time identification of the origin of such disturbances, which reports in the literature show to also affect GPS signal reception.
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| 8. |
- Morgan, Gareth, et al.
(author)
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MyelomA Genetics International Consortium
- 2012
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In: Leukemia & Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 53:5, s. 796-800
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Research review (peer-reviewed)abstract
- While the etiology of multiple myeloma (MM) is largely unknown, evidence for an inherited genetic susceptibility is provided by the two-fold increased risk of the disease seen in first-degree relatives of cases of MM. It is likely that part of this heritable risk is a consequence of the co-inheritance of low-risk genetic variants. The accumulated experience to date in identifying risk variants for other tumors has highlighted difficulties in conducting statistically and methodologically rigorous studies. The MyelomA Genetics International Consortium (MAGIC) includes 16 research groups in Europe, Asia, Australasia, the Middle East and the Americas engaged in studying the genetics of MM. The first goal of MAGIC is to identify and characterize common genetic variants for MM through association-based analyses. Here, we review the rationale for identifying genetic risk variants for MM and our proposed strategy for establishing MAGIC.
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| 9. |
- Mucci, Nadia, et al.
(author)
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Genetic diversity and landscape genetic structure of otter (Lutra lutra) populations in Europe
- 2010
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In: Conservation Genetics. - : Springer Science and Business Media LLC. - 1566-0621 .- 1572-9737. ; 11:2, s. 583-599
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Journal article (peer-reviewed)abstract
- Eurasian otter populations strongly declined and partially disappeared due to global and local causes (habitat destruction, water pollution, human persecution) in parts of their continental range. Conservation strategies, based on reintroduction projects or restoration of dispersal corridors, should rely on sound knowledge of the historical or recent consequences of population genetic structuring. Here we present the results of a survey performed on 616 samples, collected from 19 European countries, genotyped at the mtDNA control-region and 11 autosomal microsatellites. The mtDNA variability was low (nucleotide diversity = 0.0014; average number of pairwise differences = 2.25), suggesting that extant otter mtDNA lineages originated recently. A star-shaped mtDNA network did not allow outlining any phylogeographic inference. Microsatellites were only moderately variable (H (o) = 0.50; H (e) = 0.58, on average across populations), the average allele number was low (observed A (o) = 4.9, range 2.5-6.8; effective A (e) = 2.8; range 1.6-3.7), suggesting small historical effective population size. Extant otters likely originated from the expansion of a single refugial population. Bayesian clustering and landscape genetic analyses however indicate that local populations are genetically differentiated, perhaps as consequence of post-glacial demographic fluctuations and recent isolation. These results delineate a framework that should be used for implementing conservation programs in Europe, particularly if they are based on the reintroduction of wild or captive-reproduced otters.
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| 10. |
- Peters, S., et al.
(author)
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Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling
- 2021
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In: Neurotherapeutics. - : Springer Nature. - 1933-7213 .- 1878-7479. ; 18:3, s. 1963-1979
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Journal article (peer-reviewed)abstract
- Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.
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| 11. |
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| 12. |
- Serrano-Gomez, Juan, et al.
(author)
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EU-compliant wastewater recycled phosphorus: How much national cereal demand can it meet?
- 2023
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In: Journal of Cleaner Production. - : ELSEVIER SCI LTD. - 0959-6526 .- 1879-1786. ; 429
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Journal article (peer-reviewed)abstract
- Finding alternative phosphorus sources is imperative to address negative environmental and societal impacts caused by its current inefficient use. However, the direct use of phosphorus in sewage sludge in agriculture is controversial. This paper uses Denmark, Germany, and Spain as case examples to assess relevant legislation and boundary conditions in agricultural production to identify opportunities and barriers for the utilisation of recycled phosphorus from wastewater in agriculture on a regional level. Only five out of 22 phosphorus recycling technologies considered were in full compliance with legislation across all three countries, and these five were then assessed for their potential to supply phosphorus to major crops within countries. We considered the application of technologies across four scenarios: 1) struvite; 2) vivianite as iron supply; 3) vivianite for calcium phosphate precipitation; and 4) ashes for calcium phosphate precipitation. The most suitable scenario identified for Denmark was vivianite for calcium phosphate precipitation, whereas in Spain vivianite as iron supply was identified as most suitable, and ashes for calcium phosphate in Germany. We found that in 2018, the potential phosphorus supply from recycling technologies was on average 0.38, 0.29 and 0.05 kg of phosphorus per capita for Danish, German, and Spanish regions. These quantities could meet 9.1, 21.7, and 10.0 percent of the phosphorus required to produce major cereals in each country (specifically wheat, barley, and rye). Given current legal constraints, wastewater treatment plant connections and agronomic context, the potential contribution of recycled phosphorus is non-negligible in many sub-national regions. Still, to access the full potential of phosphorus circularity clear product specifications and transport and logistics among regions will be necessary.
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| 13. |
- Smol, Marzena, et al.
(author)
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Strategies for sustainable and circular management of phosphorus in the baltic sea region: The holistic approach of the inPhos project
- 2020
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In: Sustainability. - : MDPI AG. - 2071-1050. ; 12:6
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Journal article (peer-reviewed)abstract
- Despite the significant reduction of phosphorus (P) discharge in the Baltic Sea in the last decades, obtained through the implementation of some approaches within the Helsinki Convention, eutrophication is still considered the biggest problem for the Baltic Sea environment. Consequently, the reduction of P load is an urgent need to solve, but the complexity of both the environmental and legislative context of the area makes this process difficult (more than in the past). Eutrophication is an intricate issue requiring a proper framework of governance that is not easy to determine in the Baltic Sea Region where the needs of several different countries converge. To identify the most suitable strategy to reduce the eutrophication in the Baltic Sea, the InPhos project (no. 17022, 2018-2019, funded by the European Institute of Innovation & Technology (EIT) Raw Materials) adopted a holistic approach considering technical, political, economic, environmental and social aspects of P management. With the aims to raise awareness about the P challenge, foster the dialogue among all the stakeholders, and find solutions already developed in other countries (such as Germany and Switzerland) to be transferred in the Baltic Sea Region, the InPhos project consortium applied the methodology proposed in this paper, consisting of three main phases: (i) analysis of the available technologies to remove P from waste streams that contribute to eutrophication; (ii) analysis of the main streams involving P in Baltic Sea countries to highlight the potential of more sustainable and circular P management; (iii) study of the current context (e.g., already-existing initiatives and issues). This approach allowed us to identify four categories of recommendations and practical actions proposed to improve P management in the Baltic Sea region. During the project, the consortium mainly addressed social aspects. Following steps beyond the project will be more quantitative to determine the techno-economic feasibility of circular P management in selected demo cases in the region.
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| 14. |
- Vogl, Thomas, et al.
(author)
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Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation
- 2018
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In: Journal of Clinical Investigation. - 0021-9738. ; 128:5, s. 1852-1866
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Journal article (peer-reviewed)abstract
- Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/ S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.
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