| 1. |
- Bousquet, J. Jean, et al.
(författare)
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Next-generation ARIA care pathways for rhinitis and asthma : a model for multimorbid chronic diseases
- 2019
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Ingår i: Clinical and Translational Allergy. - : BMC. - 2045-7022. ; 9
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Forskningsöversikt (refereegranskat)abstract
- Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy.Main body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Sante as a Good Practice in the field of digitally-enabled, integrated, person-centred care.Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
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| 2. |
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| 3. |
- Antoni, Marc, et al.
(författare)
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Inter-project improvement in product development
- 2005
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Ingår i: International Journal of Quality & Reliability Management. - : Emerald. - 0265-671X .- 1758-6682. ; 22:9, s. 876-893
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Tidskriftsartikel (refereegranskat)abstract
- Product development projects can be utilized to create not only new products or services but also competitively important capabilities on how to work with product development. The resulting capabilities can be, and often are, as important as the product itself. Although there is potential for an organization to improve product development performance, most organizations can learn even more from their development experiences. A reliance on post‐project reviews to share knowledge across projects is doomed to fail, since it usually is of low priority and does not capture the complexity of development projects. The aim of this research is to investigate what organizations can do to reduce the effect of losing valuable experience gained in product development projects.Design/methodology/approachA multiple case study approach, using both qualitative and quantitative data, is used to perform a study of two high‐tech product development organizations with respect to their inter‐project improvement activities. A framework concerning inter‐project improvement is presented, containing concepts such as levels of learning, improvement content, and axes of improvement.FindingsTo avoid losing valuable experience, an organization should use multiple strategies to share knowledge across projects. Examples of successful strategies are to use a well‐established product development process, professional full‐time project managers as well as modularization of the product.Originality/valueAlthough research on organizational learning in product development has increased significantly during the last few years, this research contributes to a deeper understanding of inter‐project improvement by combining perspectives from quality management, organizational learning, and knowledge management.
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| 4. |
- Antoni, Marc, 1971-
(författare)
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Inter-project learning : a quality perspective
- 2000
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The development of most sectors in Western economies goes towards a more flexible, project-oriented way of doing business. However, the vast majority of projects exceed their planned budget in terms of time, financial resources and other resources. In companies, which organize work in the form of projects, reinventions of the wheel can also often be observed. One reason for problems of project management is learning deficiencies. Most projects have repetitive components, which make an institutionalization of them useful. However, any formalization should be seen in a balanced relation to the renewal potential of projects.The research presented in this thesis aims to gain insight into enabling factors of Inter-Project Learning. This aim is pursued via theoretical literature studies and the study of organizations. The thesis consists of a frame and four papers covering different aspects of Inter-Project Learning. The areas discussed in the frame and the papers are Project Management, Profound Knowledge. Organizational Learning and Process Management.In the literature it was found that Inter-Project Learning is usually not planned for, which is supported by empirical evidence. Inter-Project Learning activities partly gave the impression of being seen as pleasant side effects. A central challenge for Inter-Project Learning is the understanding and perception of time in projects, since members of a temporary organization have partly other goals than members of the permanent parental organization. Deming's concept of Profound Knowledge was found to be one useful way of achieving a better understanding of the problems surrounding Inter-Project Learning.Experience from projects can be preserved in a process organization supporting Inter-Project Learning. However, it was found that the relation between both project and process organization, as well as between project manager and process owner, in practice is often unclear, which can lead to problems.Furthermore. a distinction of forms supporting Inter-Project Learning in codification and personalization forms was found to be convenient. These should not be understood as mutually exclusive approaches, but rather as a choice of emphasis. Empirical data suggest that the choice of emphasis is not a static one, but can shift over time.Apart of the findings have been combined in a tentative model for InterProject Learning, which shall function as a basis for further discussion. improvement and research.
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| 5. |
- Antoni, Marc
(författare)
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Learning between projects : - in product development contexts -
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A project is often formed with the intention to bring forth a deliverable within a certain time frame. This goal-focus however may lead to suboptimizations on the organizational level. At the same time projects more often than not underperform in a number of aspects, with an especially huge gap in the learning aspect.Thus the research questions addressed in this work concern what is done in organizations to foster organizational learning in project-based contexts, how different actions arc implemented and how the relation between the project and the functional organization affects organizational learning. Deming' s profound knowledge structure has been used to structure the theoretical aspects.It was found that learning in a project context is not a typical activity and needs to be organized for. The reinvention of the wheel still remains a major, unsolved problem for organizations that develop their products via projects. That is partly due to the fact that a project is a natural forum for learning new things. but not a natural forum for learning from past experience. A central finding of this work is that a systems perspective is necessary in project management contexts. Categories related to learning that have been identified are a category relating to documented knowledge, a category relating to learning in personal interaction and a category regarding organizational aspects.Regarding documented knowledge it was found that among practitioners there seems to be an unjustified belief in the ability of documents to solve learning problems of projects. Personal interaction was found to be an effective way for learning, but the risk of information overload by meetings is considerable. Bounded rationality seems to play an important role. As conflicting value systems meet. The forward-orientation, action-focus of projects meets with the long-time perspective of organizational learning.Important elements when researching learning between projects are amongst others feedback, learning incentives. modularization, location of project team members. organizational size, inter-project competition, full-time project managers and the formulation of a learning mandate for the project.
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| 6. |
- Barack, Leor, et al.
(författare)
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Black holes, gravitational waves and fundamental physics : a roadmap
- 2019
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
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Forskningsöversikt (refereegranskat)abstract
- The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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| 7. |
- Biskaborn, Boris K., et al.
(författare)
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Permafrost is warming at a global scale
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Permafrost warming has the potential to amplify global climate change, because when frozen sediments thaw it unlocks soil organic carbon. Yet to date, no globally consistent assessment of permafrost temperature change has been compiled. Here we use a global data set of permafrost temperature time series from the Global Terrestrial Network for Permafrost to evaluate temperature change across permafrost regions for the period since the International Polar Year (2007–2009). During the reference decade between 2007 and 2016, ground temperature near the depth of zero annual amplitude in the continuous permafrost zone increased by 0.39 ± 0.15 °C. Over the same period, discontinuous permafrost warmed by 0.20 ± 0.10 °C. Permafrost in mountains warmed by 0.19 ± 0.05 °C and in Antarctica by 0.37 ± 0.10 °C. Globally, permafrost temperature increased by 0.29 ± 0.12 °C. The observed trend follows the Arctic amplification of air temperature increase in the Northern Hemisphere. In the discontinuous zone, however, ground warming occurred due to increased snow thickness while air temperature remained statistically unchanged.
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| 8. |
- Cajander, Sara, 1980-, et al.
(författare)
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Profiling the dysregulated immune response in sepsis : overcoming challenges to achieve the goal of precision medicine
- 2024
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Ingår i: The Lancet Respiratory Medicine. - : Elsevier. - 2213-2600 .- 2213-2619. ; 12:4, s. 305-322
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Forskningsöversikt (refereegranskat)abstract
- Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.
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| 9. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 10. |
- Crescenti, Marc, et al.
(författare)
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The continuous fibre injection process (CFIP): A novel approach to lightweight design of multi-material structural components
- 2024
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Ingår i: Material Forming - ESAFORM 2024. - : Materials Research Forum LLC. ; , s. 1630-1639
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Konferensbidrag (refereegranskat)abstract
- The combination of different materials enables to achieve highly efficient structures in terms of lightweight and mechanical performance, as well as in terms of manufacturing costs. However, the weakest points of these structures use to be the joints. For this reason, in the last years, many studies have dealt with joining technologies for dissimilar materials. The Reinforce3D’s Continuous Fibre Injection Process (CFIP) technology delivers a unique method to join dissimilar materials. CFIP is based on injecting continuous fibers, such as carbon fibers, simultaneously with liquid resin into tubular cavities within the part. Then the resin is cured and the final composite part is obtained. This work focuses on the characterization of the mechanical properties of CFIP-made specimens and describes the potential lightweight benefits of the technology. Mechanical tests were performed under tensile and bending conditions following standardized methods. The lightweight potential is addressed by developing a representative case study by implementing finite element and topology optimization methods. The results of this case study were finally compared with a monomaterial equivalent component (aluminium) demonstrating the improvement that CFIP provides in terms of lightweight while keeping the strength.
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| 11. |
- Faure, Regis, et al.
(författare)
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Synthesis of a library of xylogluco-oligosaccharides for active-site mapping of xyloglucan endo-transglycosylase
- 2006
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 71:14, s. 5151-5161
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Tidskriftsartikel (refereegranskat)abstract
- [GRAPHICS] Complex oligosaccharides containing R-D-xylosyl-(1 -> 6)-beta-D-glucosyl residues and unsubstituted beta-(1 -> 4)-linked D-glucosyl units were readily synthesized using enzymatic coupling catalyzed by the Cel7B E197A glycosynthase from Humicola insolens. Constituting this library required four key steps: ( 1) preparing unprotected building blocks by chemical synthesis or enzymatic degradation of xyloglucan polymers; (2) generating the donor synthon in the enzymatic coupling by temporarily introducing a lactosyl motif on the 4-OH of the terminal glucosyl units of the xylogluco-oligosaccharides; ( 3) synthesizing the corresponding R-fluorides, followed by their de-O-acetylation and the glycosynthase-catalyzed condensation of these donors onto various acceptors; and (4) enzymatically releasing lactose or galactose from the reaction product, affording the target molecules in good overall yields. These complex oligosaccharides proved useful for mapping the active site of a key enzyme in plant cell wall biosynthesis and modification: the xyloglucan endo-transglycosylase (XET). We also report some preliminary enzymatic results regarding the efficiency of these compounds.
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| 12. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 13. |
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| 14. |
- Förschler, Marc I., et al.
(författare)
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Gene flow and range expansion in a mountain-dwelling passerine with a fragmented distribution
- 2011
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Ingår i: Biological Journal of the Linnean Society. - : Oxford University Press (OUP). - 0024-4066 .- 1095-8312. ; 103:3, s. 707-721
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Tidskriftsartikel (refereegranskat)abstract
- We studied gene flow and bottleneck events in the population history of locally isolated citril finches endemic to European mountains. For the present study, we used two genetic markers with different rates of evolution: a fast evolving mitochondrial marker (ATPase6/8) and a more slowly evolving nuclear marker (02401). Populations north of the Pyrenees showed in general fewer haplotypes and a considerable lower nucleotide and gene diversity than the Iberian populations. Unexpectedly, we found very little genetic variability in the fast evolving mitochondrial marker, arguing for a strong and relatively recent bottleneck event in the species population history. This pattern potentially reflects a sudden decrease of crucial resources during Mid-Holocene (mountain pine, Scots pine, and black pine) and a subsequent breakdown of the population. The bottleneck could also have been caused or coincide with a selective sweep in the mitochondrion. By contrast, the slowly evolving nuclear marker showed a much higher variability. This marker probably reflects major gene flow along a potential expansion pathway from the Eastern Pyrenees, northwards to the populations of Central Europe, and southwards to the more fragmented populations of central and southern Spain. The population of the Western Pyrenees (Navarra) appears to be cut-off from this major gene flow and our data indicate a certain degree of partial isolation, probably reflecting more ancient events (e.g. the separation in distinct refuge sites during the last glacial maximum).
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| 15. |
- Gañez-Zapater, Antoni, 1986-, et al.
(författare)
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The SWI/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA
- 2022
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Ingår i: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 297:2, s. 463-484
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Tidskriftsartikel (refereegranskat)abstract
- BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes mainly associated with transcriptional initiation. They also have a role in alternative splicing, which has been shown for BRM-containing SWI/SNF complexes at a few genes. Here, we have identified a subset of genes which harbour alternative exons that are affected by SWI/SNF ATPases by expressing the ATPases BRG1 and BRM in C33A cells, a BRG1- and BRM-deficient cell line, and analysed the effect on splicing by RNA sequencing. BRG1- and BRM-affected sub-sets of genes favouring both exon inclusion and exon skipping, with only a minor overlap between the ATPase. Some of the changes in alternative splicing induced by BRG1 and BRM expression did not require the ATPase activity. The BRG1-ATPase independent included exons displayed an exon signature of a high GC content. By investigating three genes with exons affected by the BRG-ATPase-deficient variant, we show that these exons accumulated phosphorylated RNA pol II CTD, both serine 2 and serine 5 phosphorylation, without an enrichment of the RNA polymerase II. The ATPases were recruited to the alternative exons, together with both core and signature subunits of SWI/SNF complexes, and promoted the binding of RNA binding factors to chromatin and RNA at the alternative exons. The interaction with the nascent RNP, however, did not reflect the association to chromatin. The hnRNPL, hnRNPU and SAM68 proteins associated with chromatin in cells expressing BRG1 and BRM wild type, but the binding of hnRNPU to the nascent RNP was excluded. This suggests that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and influence their binding to the nascent pre-mRNA particle.
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| 16. |
- Gasull, Magda, et al.
(författare)
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Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort
- 2019
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 169, s. 417-433
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.
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| 17. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 18. |
- Mestres, Gemma, 1984-, et al.
(författare)
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In vivo efficiency of antimicrobial inorganic bone grafts in osteomyelitis Treatments
- 2019
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Ingår i: Materials science & engineering. C, biomimetic materials, sensors and systems. - : Elsevier BV. - 0928-4931 .- 1873-0191. ; 97, s. 84-95
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present work was to evaluate in vivo different antimicrobial therapies to eradicate osteomyelitis created in the femoral head of New Zealand rabbits. Five phosphate-based cements were evaluated: calcium phosphate cements (CPC) and calcium phosphate foams (CPF), both in their pristine form and loaded with doxycycline hyclate, and an intrinsic antimicrobial magnesium phosphate cement (MPC; not loaded with an antibiotic). The cements were implanted in a bone previously infected with Staphylococcus aureus to discern the effects of the type of antibiotic administration (systemic vs. local), porosity (microporosity, i.e. <5 μm vs. macroporosity, i.e. >5 μm) and type of antimicrobial mechanism (release of antibiotic vs. intrinsic antimicrobial activity) on the improvement of the health state of the infected animals. A new method was developed, with a more comprehensive composite score that integrates 5 parameters of bone infection, 4 parameters of bone structural integrity and 4 parameters of bone regeneration. This method was used to evaluate the health state of the infected animals, both before and after osteomyelitis treatment. The results showed that the composite score allows to discern statistically significant differences between treatments that individual evaluations were not able to identify. Despite none of the therapies completely eradicated the infection, it was observed that macroporous materials (CPF and CPFd, the latter loaded with doxycycline hyclate) and intrinsic antimicrobial MPC allowed a better containment of the osteomyelitis. This study provides novel insights to understand the effect of different antimicrobial therapies in vivo, and a promising comprehensive methodology to evaluate the health state of the animals was developed. We expect that the implementation of such methodology could improve the criteria to select a proper antimicrobial therapy.
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| 19. |
- Nilsson-Witell, Lars, et al.
(författare)
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Continuous improvement in product development : Improvement programs and quality principles
- 2005
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Ingår i: International Journal of Quality & Reliability Management. - : Emerald. - 0265-671X .- 1758-6682. ; 22:8, s. 753-768
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Tidskriftsartikel (refereegranskat)abstract
- Purpose - Continuous improvement has become an important strategy in improving organizational performance. Unfortunately, product development is often excluded in continuous improvement programs due to the special characteristics of product development activities. The overall purpose of this paper is to contribute to a better understanding of continuous improvement in the context of product development. Design/methodology/approach - A central aspect in this context is that many organizations find it difficult to improve and learn if work is carried out in the form of projects. In this paper, a quality perspective on continuous improvement is introduced and its usefulness is tested empirically through three case studies in Swedish organizations. The focus is on the improvement programs used and the quality principles displayed in a product development context. Findings - The results show that the three investigated organizations have multiple improvement programs, but that some configurations of improvement programs seem to be more successful than others. For instance, co-ordination of multiple improvement programs, scope creep, and separating between product development processes and project management models are important success factors for continuous improvement. In addition, an introduction of an improvement program without adoption of a critical mass of quality principles is doomed to fail. Originality/value - The research initiative is one of the first to conduct an empirical investigation of how organizations design and work with improvement programs in the context of product development. It provides knowledge to both academics and practitioners on how organizations can design and implement initiatives on quality management, especially in the context of product development. © Emerald Group Publishing Limited.
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| 20. |
- Ospel, Johanna M., et al.
(författare)
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What is a Challenging Clot? : A DELPHI Consensus Statement from the CLOTS 7.0 Summit
- 2023
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Ingår i: Clinical Neuroradiology. - 1869-1439 .- 1869-1447. ; 33:4, s. 1007-1016
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting a challenging clot when performing mechanical thrombectomy in acute stroke can be difficult. One reason for this difficulty is a lack of agreement on how to precisely define these clots. We explored the opinions of stroke thrombectomy and clot research experts regarding challenging clots, defined as difficult to recanalize clots by endovascular approaches, and clot/patient features that may be indicative of such clots. Methods: A modified DELPHI technique was used before and during the CLOTS 7.0 Summit, which included experts in thrombectomy and clot research from different specialties. The first round included open-ended questions and the second and final rounds each consisted of 30 closed-ended questions, 29 on various clinical and clot features, and 1 on number of passes before switching techniques. Consensus was defined as agreement ≥ 50%. Features with consensus and rated ≥ 3 out of 4 on the certainty scale were included in the definition of a challenging clot. Results: Three DELPHI rounds were performed. Panelists achieved consensus on 16/30 questions, of which 8 were rated 3 or 4 on the certainty scale, namely white-colored clots (mean certainty score 3.1), calcified clots under histology (3.7) and imaging (3.7), stiff clots (3.0), sticky/adherent clots (3.1), hard clots (3.1), difficult to pass clots (3.1) and clots that are resistant to pulling (3.0). Most panelists considered switching endovascular treatment (EVT) techniques after 2–3 unsuccessful attempts. Conclusion: This DELPHI consensus identified 8 distinct features of a challenging clot. The varying degree of certainty amongst the panelists emphasizes the need for more pragmatic studies to enable accurate a priori identification of such occlusions prior to EVT.
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| 21. |
- Osuchowski, Marcin F., et al.
(författare)
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The COVID-19 puzzle : deciphering pathophysiology and phenotypes of a new disease entity
- 2021
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Ingår i: The Lancet Respiratory Medicine. - : Elsevier. - 2213-2600 .- 2213-2619. ; 9:6, s. 622-642
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Forskningsöversikt (refereegranskat)abstract
- The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.
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| 22. |
- Parareda, Sergi, et al.
(författare)
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Fatigue resistance of press hardened 22MnB5 steels
- 2020
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Ingår i: International Journal of Fatigue. - : Elsevier. - 0142-1123 .- 1879-3452. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- In press hardened steels, fatigue behaviour is very sensitive to surface defects or irregularities, either intrinsic or introduced during trimming operations. This work addresses the understanding and prediction of fatigue resistance of press hardened steels from a fracture mechanics approach. The size of fatigue originating defects were evaluated and used to estimate the fatigue limit for different surface conditions (coated and uncoated), different coatings (Al-Si and Zn) and different edge condition (polished and mechanically trimmed). Good agreement was found between calculated and experimental values, which shows the potential of fracture mechanics to estimate the fatigue performance of press hardened steels.
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| 23. |
- Piens, Kathleen, et al.
(författare)
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Mechanism-based labeling defines the free energy change for formation of the covalent glycosyl-enzyme intermediate in a xyloglucan endo-transglycosylase
- 2008
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 283:32, s. 21864-21872
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Tidskriftsartikel (refereegranskat)abstract
- Xyloglucan endo-transglycosylases (XETs) are key enzymes involved in the restructuring of plant cell walls during morphogenesis. As members of glycoside hydrolase family 16 (GH16), XETs are predicted to employ the canonical retaining mechanism of glycosyl transfer involving a covalent glycosyl-enzyme intermediate. Here, we report the accumulation and direct observation of such intermediates of PttXET16-34 from hybrid aspen by electrospray mass spectrometry in combination with synthetic "blocked" substrates, which function as glycosyl donors but are incapable of acting as glycosyl acceptors. Thus, GalGXXXGGG and GalGXXXGXXXG react with the wild-type enzyme to yield relatively stable, kinetically competent, covalent GalG-enzyme and GalGXXXG-enzyme complexes, respectively (Gal = Gal beta(1 -> 4), G = Glc beta(1 -> 4), and X = Xyl alpha(1 -> 6) Glc beta(1 -> 4)). Quantitation of ratios of protein and saccharide species at pseudo-equilibrium allowed us to estimate the free energy change (Delta G(0)) for the formation of the covalent GalGXXXG-enzyme as 6.3-8.5 kJ/mol (1.5-2.0 kcal/mol). The data indicate that the free energy of the beta(1 -> 4) glucosidic bond in xyloglucans is preserved in the glycosyl-enzyme intermediate and harnessed for religation of the polysaccharide in vivo.
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| 24. |
- Poksinska, Bozena, et al.
(författare)
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The state of ISO 9000 certification : A study of Swedish organizations
- 2002
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Ingår i: TQM Magazine. - : Emerald. - 0954-478X .- 1758-6887. ; 14:5, s. 297-306
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Tidskriftsartikel (refereegranskat)abstract
- It seems today to be an indisputable fact that ISO 9000 is a powerful instrument, which cannot be disregarded. It is, far and away, the most influential initiative that grew from the quality movement of the late 1980s. This paper contains an evaluation of results from a survey on ISO 9000 certified companies and aims to present some aspects of the current state of the standard in Swedish industry. This study is focused on motives for implementation, perceived benefits and key implementation factors. The predominant reasons identified for seeking certification were the desire to improve corporate image and quality. Like many previous studies this study underlines the need for management commitment and participation. The very important conclusion drawn from this survey is that the motivation for certification may influence the performance of ISO 9000. The overall benefits which the companies gain from the standard showed dependence on the motivation which initiated the drive for the certification.
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| 25. |
- Porta, Miquel, et al.
(författare)
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Plasma concentrations of persistent organic pollutants and pancreatic cancer risk
- 2022
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 51:2, s. 479-490
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Tidskriftsartikel (refereegranskat)abstract
- Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.
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| 26. |
- Rosinol, Antoni, et al.
(författare)
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Incremental visual-inertial 3d mesh generation with structural regularities
- 2019
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Ingår i: Proceedings - IEEE International Conference on Robotics and Automation. - 1050-4729. ; 2019-May, s. 8220-8226
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Konferensbidrag (refereegranskat)abstract
- Visual-Inertial Odometry (VIO) algorithms typically rely on a point cloud representation of the scene that does not model the topology of the environment. A 3D mesh instead offers a richer, yet lightweight, model. Nevertheless, building a 3D mesh out of the sparse and noisy 3D landmarks triangulated by a VIO algorithm often results in a mesh that does not fit the real scene. In order to regularize the mesh, previous approaches decouple state estimation from the 3D mesh regularization step, and either limit the 3D mesh to the current frame [1], [2] or let the mesh grow indefinitely [3], [4]. We propose instead to tightly couple mesh regularization and state estimation by detecting and enforcing structural regularities in a novel factor-graph formulation. We also propose to incrementally build the mesh by restricting its extent to the time-horizon of the VIO optimization; the resulting 3D mesh covers a larger portion of the scene than a per-frame approach while its memory usage and computational complexity remain bounded. We show that our approach successfully regularizes the mesh, while improving localization accuracy, when structural regularities are present, and remains operational in scenes without regularities.
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| 27. |
- Saura-Valls, Marc, et al.
(författare)
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Active-site mapping of a Populus xyloglucan endo-transglycosylase with a library of xylogluco-oligosaccharides
- 2008
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 283:32, s. 21853-21863
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Tidskriftsartikel (refereegranskat)abstract
- Restructuring the network of xyloglucan (XG) and cellulose during plant cell wall morphogenesis involves the action of xyloglucan endo-transglycosylases (XETs). They cleave the XG chains and transfer the enzyme-bound XG fragment to another XG molecule, thus allowing transient loosening of the cell wall and also incorporation of nascent XG during expansion. The substrate specificity of a XET from Populus (PttXET16-34) has been analyzed by mapping the enzyme binding site with a library of xylogluco-oligosaccharides as donor substrates using a labeled heptasaccharide as acceptor. The extended binding cleft of the enzyme is composed of four negative and three positive subsites (with the catalytic residues between subsites -1 and + 1). Donor binding is dominated by the higher affinity of the XXXGmoiety (G = Glc beta(1 -> 4) and X = Xyl alpha(1 -> 6)Glc beta(1 -> 4)) of the substrate for positive subsites, whereas negative subsites have a more relaxed specificity, able to bind (and transfer to the acceptor) a cello-oligosaccharyl moiety of hybrid substrates such as GGGGXXXG. Subsite mapping with k(cat)/K-m values for the donor substrates showed that a GG-unit on negative and-XXG on positive subsites are the minimal requirements for activity. Subsites -2 and -3 (for backbone Glc residues) and +2' (for Xyl substitution at Glc in subsite +2) have the largest contribution to transition state stabilization. GalGXXXGXXXG (Gal = Gal beta(1 -> 4)) is the best donor substrate with a "blocked" nonreducing end that prevents polymerization reactions and yields a single transglycosylation product. Its kinetics have unambiguously established that the enzyme operates by a ping-pong mechanism with competitive inhibition by the acceptor.
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| 28. |
- Sense, A.J., et al.
(författare)
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Exploring the politics of project learning
- 2003
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Ingår i: International Journal of Project Management. - 0263-7863 .- 1873-4634. ; 21:7, s. 487-494
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Tidskriftsartikel (refereegranskat)abstract
- Competitive advantage for project success will only be realized when project team members effectively access, absorb and apply the multiple learning opportunities that exist within and across projects and, manage the political dimension effectively. These items as individual entities are important project variables to be addressed. Both are also linked. In making a contribution to understanding this nexus, this paper combines and explores case study research findings from 'within a project' and 'across projects' from two countries, which illuminates some 'central agitators' of politics impacting project learning. These revelations have implications for both practitioners and project management researchers. © 2003 Elsevier Ltd and IPMA. All rights reserved.
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| 29. |
- Stevens, Marc, 1984-
(författare)
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Multicomponent Reactions in 11C/12C Chemistry : – Targeting the Angiotensin II Subtype 2 Receptor
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in 11C chemistry and the biological target.Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). 15N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19–90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. 15N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide.Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 11C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/µmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a 11C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies. Section 4 describes the development of a multicomponent method for the synthesis of 3,4-dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.
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| 30. |
- Stevens, Marc, 1984-, et al.
(författare)
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Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
- 2016
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Ingår i: ChemistryOpen. - : John Wiley & Sons. - 2191-1363. ; 5:6, s. 566-573
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Tidskriftsartikel (refereegranskat)abstract
- Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.
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| 31. |
- Stevens, Marc Y., et al.
(författare)
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Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO
- 2016
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 5:6, s. 566-573
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Tidskriftsartikel (refereegranskat)abstract
- We describe the development of a new methodology focusing on C-11-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [C-11] CO. A number of C-11-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24 +/- 10% isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.
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| 32. |
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| 33. |
- Thomas, Minta, et al.
(författare)
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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
- 2020
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Ingår i: American Journal of Human Genetics. - Cambridge : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:3, s. 432-444
-
Tidskriftsartikel (refereegranskat)abstract
- Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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| 34. |
- Thomas, Minta, et al.
(författare)
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Response to Li and Hopper
- 2021
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 108:3, s. 527-529
-
Tidskriftsartikel (refereegranskat)
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| 35. |
- Waeijen-Smit, Kiki, et al.
(författare)
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Global mortality and readmission rates following COPD exacerbation-related hospitalisation : a meta-analysis of 65 945 individual patients
- 2024
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Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods A systematic review was performed identifying studies that reported in-hospital mortality, postdischarge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations < 12 months prior to the index event. Conclusions This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.
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| 36. |
- Winkler, Martin S., et al.
(författare)
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Bridging animal and clinical research during SARS-CoV-2 pandemic : A new-old challenge
- 2021
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 66
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Forskningsöversikt (refereegranskat)abstract
- Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.
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| 37. |
- Yeste-Velasco, Marc, et al.
(författare)
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DNA low-density array analysis of colchicine neurotoxicity in rat cerebellar granular neurons.
- 2008
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 29:2, s. 309-17
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Tidskriftsartikel (refereegranskat)abstract
- Cytoskeletal alteration is a key factor in neurodegenerative processes like Alzheimer's or Parkinson's disease. Colchicine is a microtubule-disrupting agent that binds to tubuline, inhibiting microtubule assembly, and which triggers apoptosis. The present research describes the transcriptional activation of molecules related to alternative forms of apoptosis, in an acute colchicine model of apoptosis in rat cerebellar granule neurons (CGNs). Treatment with colchicine up-regulated significantly the activity of genes related to oxidative stress: glutathione peroxidase 1 and catalase; altered significantly genes related to cell cycle control (cyclin D1 and cyclin-dependent kinase 2), genes related to classical apoptosis pathway (caspase 3) and a neuronal cell-related gene (pentraxin 1). Colchicine treatment also down-regulated the gene expression of calpain 1. In conclusion, our experiments demonstrate that the cell damage caused by exposure to colchicine activates the classical apoptosis pathway, but also promotes the up-regulation of several genes related to oxidative stress and cell cycle control. Present data may help to a better understanding of the molecular mechanisms involved in cytoskeletal degradation-induced apoptosis in neurons.
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