| 1. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
- Lindblad, O, et al.
(författare)
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Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
- 2016
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35:39, s. 5119-5131
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Tidskriftsartikel (refereegranskat)abstract
- Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.Oncogene advance online publication, 21 March 2016; doi:10.1038/onc.2016.41.
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| 3. |
- Wang, J., et al.
(författare)
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Final report of the CCQM-K145 : Toxic and essential elements in bovine liver
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 57:1 A
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Tidskriftsartikel (refereegranskat)abstract
- Liver plays a major role in metabolism and acts as a source of energy for the body by storing glycogen. With the growing interest and investigation in the biological effects in recent years, it is important and necessary to develop accurate and comparable analytical methods for elements in bio-samples. It has, however, been 10 years since the tissue sample (bovine liver) of CCQM-K49 key comparison. The purpose of CCQM-K145 is to ensure the comparable and traceable measurement results for essential and toxic elements such as P, S, Zn, Mn, Ni, Mo, Sr, Cr, Co, Pb, As and Hg in bovine liver among NMIs and other designated measurement bodies worldwide. The comparison was agreed by IAWG as 6th IAWG Benchmarking Exercise with Zn and Ni as exemplary elements at the meeting in Korea in the early October 2016. The results of CCQM-K145 are expected to cover the measurement capability and support CMCs claiming for inorganic elements in the similar biological tissue materials and food samples. 30 NMIs and DIs registered in CCQM-K145. With respect to the methodology, a variety of techniques such as IDMS, ICP-OES, ICP-MS(non-ID), AAS and NAA were adopted by the participants. For Zn, Ni, Sr, Pb and Hg measurements, most participants chose ID-ICP-MS method, which showed the better performance in terms of consistency and reliability of the measurement results. In aspect of the traceability for the measurement results in CCQM-K145, most participants used their own (in house) CRMs or other NMI's CRMs to guarantee trace to SI unit. Most participants used similar matrix CRMs for quality control or method validation. Base on different statistic way to calculate the reference mass fraction values and associated uncertainties for each measurand, removal of the suspected extreme values, and discussion at the IAWG meetings, the median values are proposed as the KCRV for Zn, Ni, Mn, Mo, Cr, Pb and Hg; the arithmetic mean values are proposed as the KCRV for P, S, Sr, Co and As. In general, the performances of the majority of CCQM-K145 participants are very good, illustrating their measurement capabilities for Zn, Ni, P, S, Mn, Mo, Sr, Cr, As, Co, Pb and Hg in a complex biological tissue matrix. Bovine liver contains many kinds of nutrients and microelements, it can be regarded as a typical representative material of biological tissue and food. In CCQM-K145, the analytes involved alkali metals and transition elements, metalloids/semi-metals and non metals with a range of mass fraction from mg/g to μg/kg. CCQM-K145 also tested the ability of NMIs/DIs to determine elements that were easy to be lost and polluted, and interfered significantly. The chemical pretreatment methods of samples used in the comparison is suitable for general food and biological matrix samples. A variety of measurement methods used in the comparison represent the main instrumental technology for elemental analysis. Therefore, for supporting CMC claim, CCQM-K145 is readily applicable to measurement of more elements in a wide range of biological materials (including liquids and solids) and meat products. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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| 4. |
- Domínguez-Gil, B., et al.
(författare)
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The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation
- 2022
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Ingår i: Transplantation. ; 106:11, s. 2111-2117
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| 5. |
- Kainu, T, et al.
(författare)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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| 6. |
- Ladds, MJGW, et al.
(författare)
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Publisher Correction: A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2071-
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Tidskriftsartikel (refereegranskat)abstract
- The original PDF version of this Article listed the authors as “Marcus J.G.W. Ladds,” where it should have read “Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.#”.Also in the PDF version, it was incorrectly stated that “Correspondence and requests for materials should be addressed to S. Lín.”, instead of the correct “Correspondence and requests for materials should be addressed to S. Laín.”This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.
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| 7. |
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| 8. |
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| 9. |
- Lindberg, K., et al.
(författare)
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The HILUS-Trial—a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy
- 2021
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864. ; 16:7, s. 1200-1210
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. Methods: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. Results: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0–10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the “hottest” 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. Conclusions: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions). © 2021 International Association for the Study of Lung Cancer
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| 10. |
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| 11. |
- Syrjakoski, K, et al.
(författare)
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BRCA2 mutations in 154 Finnish male breast cancer patients
- 2004
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Ingår i: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 6:5, s. 541-545
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Tidskriftsartikel (refereegranskat)abstract
- The etiology and pathogenesis of male breast cancer (MBC) are poorly known. This is due to the fact that the disease is rare, and large-scale genetic epidemiologic studies have been difficult to carry out. Here, we studied the frequency of eight recurrent Finnish BRCA2 founder mutations in a large cohort of 154 MBC patients (65% diagnosed in Finland from 1967 to 1996). Founder mutations were detected in 10 patients (6.5%), eight of whom carried the 9346(-2) A>G mutation. Two novel mutations (4075 delGT and 5808 del5) were discovered in a screening of the entire BRCA2 coding region in 34 samples. However, these mutations were not found in the rest of the 120 patients studied. Patients with positive family history of breast and/or ovarian cancer were often BRCA2 mutation carriers (44%), whereas those with no family history showed a low frequency of involvement (3.6%; P < .0001). Finally, we found only one Finnish MBC patient with 999 del5, the most common founder mutation in Finnish female breast cancer (FBC) patients, and one that explains most of the hereditary FBC and MBC cases in Iceland. The variation in BRCA2 mutation spectrum between Finnish MBC patients and FBC patients in Finland and breast cancer patients in Iceland suggests that modifying genetic and environmental factors may significantly influence the penetrance of MBC and FBC in individuals carrying germline BRCA2 mutations in some populations.
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| 12. |
- Vallon-Christersson, J, et al.
(författare)
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Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families
- 2001
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 10:4, s. 60-353
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1 are responsible for the majority of cases involving hereditary breast and ovarian cancer. Whereas all truncating mutations are considered as functionally deleterious, most of the missense variants identified to date cannot be readily distinguished as either disease-associated mutations or benign polymorphisms. The C-terminal domain of BRCA1 displays an intrinsic transactivation activity, and mutations linked to disease predisposition have been shown to confer loss of such activity in yeast and mammalian cells. In an attempt to clarify the functional importance of the BRCA1 C-terminus as a transcription activator in cancer predisposition, we have characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Missense variants A1669S, C1697R, R1699W, R1699Q, A1708E, S1715R and G1738E and a truncating mutation, W1837X, were characterized using yeast- and mammalian-based transcription assays. In addition, four additional missense variants (V1665M, D1692N, S1715N and D1733G) and one in-frame deletion (V1688del) were included in the study. Our findings demonstrate that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. We also report a discrepancy between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. We show that transcription-based assays can aid in the characterization of deleterious mutations in the C-terminal part of BRCA1 and may form the basis of a functional assay.
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| 13. |
- Bergwall, Lovisa, et al.
(författare)
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Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Identifies a Target for Podocyte Cytoskeleton Stabilization
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The melanocortin-1 receptor (MC1R) in podocytes has been suggested as the mediator of the ACTH renoprotective effect in patients with nephrotic syndrome with the mechanism of action beeing stabilization of the podocyte actin cytoskeleton. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and a rat model of nephrotic syndrome in combination with cell culture analysis. Phosphoproteomics was applied and identified MC1R pathways confirmed using biochemical analysis. We found that glomerular MC1R expression was increased in nephrotic syndrome, both in humans and in a rat model. A MC1R agonist protected podocytes from protamine sulfate induced stress fiber loss with the top ranked phoshoproteomic MC1R activated pathway beeing actin cytoskeleton signaling. Actin stabilization through the MC1R consisted of ERK1/2 dependent phosphorylation and inactivation of EGFR signaling with stabilization of synaptopodin and stressfibers in podocytes. These results further explain how patients with nephrotic syndrome show responsiveness to MC1R receptor activation by decreasing EGFR signaling and as a consequence restore filtration barrier function by stabilizing the podocyte actin cytoskeleton.
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| 14. |
- Busker, S., et al.
(författare)
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Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.
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| 15. |
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| 16. |
- Fischbach, M., et al.
(författare)
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Measurement by magnetic resonance imaging of the peritoneal membrane in contact with dialysate in rats
- 2005
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Ingår i: Adv Perit Dial. - 1197-8554. ; 21, s. 17-20
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Tidskriftsartikel (refereegranskat)abstract
- To be optimal, a peritoneal dialysis prescription should consider the peritoneal surface area recruitment. In fact, as shown by computed tomography imaging, only a fraction of the available anatomic peritoneum is in contact with the dialysate (PDF). Various factors may dynamically affect the recruitment of the wetted membrane: posture, fill volume, PDF composition (biocompatibility), and pharmacologic agents (phospholipids). To precisely determine the peritoneal membrane recruitment capacity, we developed an animal model. In 5/6 bi-nephrectomized rats on peritoneal dialysis, between week 6 and week 8 post surgery, we used MRI to assess the contact area, with the dialysate acting as the contrast medium (fill volume: 10 mL per 100-g rat body weight). The MRI protocol consisted of axially oriented, turbo spin-echo, 3-mm slice, T2 weighted sequences. The contact area was measured using an adapted three-dimensional MRI reconstruction software based on DICOM (digital imaging and communications in medicine) images. The MRI studies (n=10) were successful. They showed that only a fraction of the presumed anatomic area (30% - 40%) was in contact with the PDF Peritoneal MRI in rats is a method that shows potential for assessing peritoneal contact area and its variation under experimental conditions.
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| 17. |
- Flores, H., et al.
(författare)
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Impact of climate change on Antarctic krill
- 2012
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Ingår i: Marine Ecology-Progress Series. - : Inter-Research Science Center. - 0171-8630 .- 1616-1599. ; 458, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Antarctic krill Euphausia superba (hereafter 'krill') occur in regions undergoing rapid environmental change, particularly loss of winter sea ice. During recent years, harvesting of krill has in creased, possibly enhancing stress on krill and Antarctic ecosystems. Here we review the overall impact of climate change on krill and Antarctic ecosystems, discuss implications for an ecosystem-based fisheries management approach and identify critical knowledge gaps. Sea ice decline, ocean warming and other environmental stressors act in concert to modify the abundance, distribution and life cycle of krill. Although some of these changes can have positive effects on krill, their cumulative impact is most likely negative. Recruitment, driven largely by the winter survival of larval krill, is probably the population parameter most susceptible to climate change. Predicting changes to krill populations is urgent, because they will seriously impact Antarctic ecosystems. Such predictions, however, are complicated by an intense inter-annual variability in recruitment success and krill abundance. To improve the responsiveness of the ecosystem-based management approach adopted by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR), critical knowledge gaps need to be filled. In addition to a better understanding of the factors influencing recruitment, management will require a better understanding of the resilience and the genetic plasticity of krill life stages, and a quantitative understanding of under-ice and benthic habitat use. Current precautionary management measures of CCAMLR should be maintained until a better understanding of these processes has been achieved. [GRAPHICS] .
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| 18. |
- Friberg, Ingrid Osika, et al.
(författare)
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Patients' perceptions and factors affecting dialysis modality decisions
- 2018
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Ingår i: Peritoneal Dialysis International. - : SAGE Publications. - 0896-8608. ; 38:5, s. 334-342
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Tidskriftsartikel (refereegranskat)abstract
- Background: Home-based dialysis, including peritoneal dialysis (PD) and home hemodialysis (HHD), has been shown to be associated with tower costs and higher health-related quality of life than in-center HD. However, factors influencing the choice of dialysis modality, including gender, are still not well understood. Methods: A questionnaire was sent out to all dialysis patients in the western region of Sweden in order to investigate factors affecting choice of dialysis modality. Logistic regression was used to analyze the data. Results: Patients were more likelyto have home dialysis if they received predialysis information from 3 or more sources and, to a greater extent, perceived the information as comprehensive and of high quality. In addition, patients had a lower likelihood of receiving home dialysis with increasing age and if they lived closer to a dialysis center. Men had in comparison with women a greater likelihood of receiving home dialysis if they lived with a spouse. In-center dialysis patients more often believed that the social interaction and support provided through in-center HD treatment influenced the choice of dialysis modality. Conclusion: This study highlights the need for increased awareness of various factors that influence the choice of dialysis modality and the importance of giving repeated, comprehensive, high-quality information to dialysis and predialysis patients and their relatives. Information and support must be adapted to the needs of individual patients and their relatives if the intention is to improve patients' well-being and the proportion of patients using home dialysis.
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| 19. |
- Giovannucci, Tatiana A., et al.
(författare)
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Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy
- 2022
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Ingår i: Autophagy. - : Taylor & Francis. - 1554-8627 .- 1554-8635. ; 18:7, s. 1486-1502
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.
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| 20. |
- Gram, D., et al.
(författare)
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Residual positioning errors and uncertainties for pediatric craniospinal irradiation and the impact of image guidance
- 2020
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Ingår i: Radiation Oncology. - : Springer Science and Business Media LLC. - 1748-717X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Optimal alignment is of utmost importance when treating pediatric patients with craniospinal irradiation (CSI), especially with regards to field junctions and multiple isocenters and techniques applying high dose gradients. Here, we investigated the setup errors and uncertainties for pediatric CSI using different setup verification protocols. Methods A total of 38 pediatric patients treated with CSI were identified for whom treatment records and setup images were available. The setup images were registered retrospectively to the reference image using an automated tool and matching on bony anatomy, subsequently, the impact of different correction protocols was simulated. Results For an action-level (AL)-protocol and a non-action level (NAL)-protocol, the translational residual setup error can be as large as 24 mm for an individual patient during a single fraction, and the rotational error as large as 6.1 degrees. With daily IGRT, the maximum setup errors were reduced to 1 mm translational and 5.4 degrees rotational versus 1 mm translational and 2.4 degrees rotational for 3- and 6- degrees of freedom (DoF) couch shifts, respectively. With a daily 6-DoF IGRT protocol for a wide field junction irradiation technique, the residual positioning uncertainty was below 1 mm and 1 degrees for translational and rotational directions, respectively. The largest rotational uncertainty was found for the patients' roll even though this was the least common type of rotational error, while the largest translational uncertainty was found in the patients' anterior-posterior-axis. Conclusions These results allow for informed margin calculation and robust optimization of treatments. Daily IGRT is the superior choice for setup of pediatric patients treated with CSI, although centers that do not have this option could use the results presented here to improve their margins and uncertainty estimates for a more accurate treatment alignment.
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| 21. |
- Hafsteinsdottir, Solveig, et al.
(författare)
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Suspected infections in children treated for ALL
- 2009
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Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 98:7, s. 1149-1155
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Tidskriftsartikel (refereegranskat)abstract
- The aim of our study was to get epidemiological information on bacterial infections in children treated for ALL and to analyse which patients have an enhanced infection risk. Episodes of suspected or confirmed infections were evaluated during the first 12 months of treatment for childhood acute lymphoblastic leukaemia (ALL). The number of patients was 73 (43 boys). The median age was 4.6 years. A total of 179 episodes occurred, varying from none in six patients to eight in one. Bacteria were cultured in 57 episodes (31.8%), the most common being coagulase-negative staphylococci. The number of episodes fell significantly with increasing age for suspected and confirmed infections (p < 0.001 and p = 0.03). The proportion of confirmed infections was significantly higher (p < 0.001) in the first episodes. The average number of suspected infections was higher in girls than in boys (p = 0.03), but confirmed infections were not. Most of the serious infections occur early in the treatment and the number of suspected and confirmed infections falls with age. Suspicion of infection is more likely in girls, but the number of confirmed infections is equal in both sexes. Coagulase-negative staphylococcus was most commonly isolated, highlighting the importance of careful handling of central venous devices.
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| 22. |
- Haraldsson, Inger, et al.
(författare)
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PROspective evaluation of coronary FLOW reserve and molecular biomarkers in patients with established coronary artery disease the PROFLOW-trial: cross-sectional evaluation of coronary flow reserve
- 2019
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Ingår i: Vascular Health and Risk Management. - 1176-6344. ; 15, s. 375-384
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of myocardial infarction (MI) are at high risk of new major adverse cardiovascular events (MACE). Coronary flow reserve (CFR) is a strong and independent predictor of MACE. Understanding the prevalence of impaired CFR in this patient group and identifying risk markers for impaired CFR are important steps in the development of personalized and targeted treatment for high-risk individuals with prior MI. Methods: PROFLOW is a prospective, exploratory, cross-sectional open study. We used information from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) to identify high-risk patients with a history of type-1 MI. We measured CFR non-invasively in a left anterior descending artery (LAD) using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperemia by intravenous infusion of adenosine (140 mu g/kg/min). Independent predictors of CFR were assessed with multiple linear regression. Results: We included 619 patients. The median age was 69 (IQR 65-73), and 114 (18.4%) were women. Almost one-half of the patients, 285 (46.0%) had the multi-vessel disease, and 147 (23.7%) were incompletely revascularized. The majority were on optimal standard treatment eg ASA (93.1%), statins (90.0%), ACEI/ARB (82.6%) and beta-blockers (80.8%). The majority, 547 (88.4%) had no angina pectoris, and 572 (92.2%) were in NYHA class I. Evaluation of CFR was possible in 611 (98.7%) patients. Mean CFR was 2.74 (+/- 0.79 (mean +/- SD)). A substantial number of patients (39.7%) had CFR <= 2.5. In a multiple linear regression model age, dyslipidemia, smoking, hypertension, body mass index, incomplete revascularization, and treatment with angiotensin receptor blockers were independent predictors of CFR. Conclusion: In this high-risk group of patients with prior MI, the prevalence of impaired CFR was high. Further risk stratification with CFR in addition to traditional cardiovascular risk factors may improve predictive accuracy for future MACE in this patient population.
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| 23. |
- Haraldsson, K, et al.
(författare)
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BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease
- 1998
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Ingår i: Cancer Research. - 1538-7445. ; 58:7, s. 71-1367
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a rare disease in men, affecting less than 0.1% of the male population. Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene. In this study, the entire coding regions of BRCA2 and AR were screened for mutations in 34 consecutive male breast cancer patients. Five different truncating BRCA2 mutations were identified in 7 (21%) of the 34 cases, with all mutations being of germ-line origin. Three of the mutated cases carried the same mutation (4186delG), which has been found earlier in two Swedish families with multiple female breast cancer cases. Haplotype analysis supported a common ancestry of 4186delG. One mutation, 6503delTT, was found in a male carrying also a previously identified COOH-terminal polymorphic stop codon (Lys3326ter). No differences were seen between mutation carriers and noncarriers with respect to clinical stage and estrogen or progesterone receptor status. Mutation carriers tended to be younger at diagnosis. No germ-line AR mutations were found in the present material, but the number of AR polyglutamine repeats tended to be lower among mutation carriers. Most surprisingly, only one of the seven BRCA2 mutation carriers had a positive family history of breast cancer, suggesting a lower penetrance of some BRCA2 mutations or an influence of modifying factors for disease development in males and females. The present study implies that approximately one-fifth of all male breast cancer cases in the Swedish population are due to germ-line BRCA2 mutations.
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| 24. |
- Haraldsson, Klas Tommy, 1968-
(författare)
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Fabrication of polymeric microfluidic devices via photocurable liquid monomers
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microfluidic devices have long been considered an ideal tool for rapid and inexpensive chemical analysis and reactions in areas ranging from point-of-care health to national security applications. However, fabricating microfluidic devices is time consuming, difficult and above all expensive. In commercial applications many thousand units need to be sold before the development costs are recovered. The problem is compounded since most microfluidic devices do not have generalized architectures which means that each end use requires a specialized design. The microfluidics marketplace can therefore be seen as being composed of 1000’s of niche markets. To address development costs, there is clearly a need for a versatile technology that can be used for many different applications and that enables rapid testing and optimization of new designs. This work describes such a technology: Contact Liquid Photolithographic Polymerization (CLiPP). The thesis consists of two parts: polymerization kinetics and the fabrication of polymeric microfluidic devices via CLiPP. The photopolymerization kinetics is evaluated for a number of monomer types, and the results are used to assess their suitability in the CLiPP process. Vinyl ether/maleate photoinitiated copolymerization is examined in detail. It is shown that the polymerization kinetics is dramatically influenced by the availability of easily abstractable hydrogens The presence of α-hydrogens adjacent to the vinyl ether functional group reduces the polymerization rate and the dependence of the polymerization rate as a function of initiation rate. Also, photoinitiated acrylate and methacrylate polymerization kinetics are presented. The kinetics results in these three monomer types are used to explain the different patterning properties of the monomer functionalities used in the CLiPP process, in which acrylates show enhanced patterning properties compared to methacrylates. The polymerization kinetics is studied with traditional tools and methods: photo Differential Scanning Calorimetry (photo-DSC), photo Fourier Transform Real Time Infrared Spectroscopy (photo-RTIR), and photo Real Time Electron Paramagnetic Spectroscopy (ESR). The microfluidic fabrication is performed via both in-house fabricated and commercially available CLiPP-specific hardware. The patterning qualities of the structures are evaluated via Scanning Electron Microscopy (SEM) and Optical Microscopy. The finished devices are used in their intended environment and evaluated in suitable manners to assess their utility. In this thesis, the development and design of specialized CLiPP fabrication machines, fabrication techniques and resulting microfluidic device features are presented anddiscussed. It is shown that the CLiPP scheme enables features such as 3 dimensional (3D) capabilities for minimized device footprints, a very large number of polymeric materials for optimized device components as well as facile integration of prefabricated components. Also, covalent layer adhesion and permanent surface modifications via living radical processes are demonstrated. These capabilities are exemplified in a number of examples that range from a 3D fluidic channel maze with separated fluidic streams and a device with independently moveable parts to a device constructed from multiple polymeric materials and devices with permanently modified surfaces, Also, batch processing capabilities are shown through fabrication of 400 identical undercut microstructures. Rapid and inexpensive design evaluations, multiple materials capabilities and the ability to seamlessly incorporate prefabricated microstructures of the CLiPP process strongly encourages continued method development. The future work that remains to be addressed is divided into two parts. First, to enable novel research devices, new polymer materials with enhanced mechanical and surface properties must be developed. Also, integration of prefabricated microstructures such as sensors and actuators has to be incorporated in a reproducible and rational manner. Secondly, to enable device mass fabrication, new automated equipment is to be developed in order to utilize the full batch processing potential of CLiPP.
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| 25. |
- Haraldsson, Klas Tommy, et al.
(författare)
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The Effects of Abstractable Hydrogen in Radical Photopolymerization of Maleate/Vinyl Ether Monomers Studied with EPR and Photo-RTIR
- 2010
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Ingår i: Journal of Polymer Science Part A. - : Wiley. - 0887-624X .- 1099-0518. ; 48:13, s. 2810-2816
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Tidskriftsartikel (refereegranskat)abstract
- In this contribution, the influence of abstractable hydrogen on the kinetics of photopolymerized vinyl ether/maleate monomer formulations is reported. The effects of chain transfer on the polymerization rate were studied with photo real-time Infra Red (IR) for formulations composed of equimolar amounts of diethyl (DEMA) and three different vinyl ethers; methyl hexyl vinyl ether where the abstractable hydrogens adjacent to the vinyl functionality have been replaced with methyl groups, ethyl hexyl vinyl ether (EHVE) which has two easily abstractable alpha-hydrogens and triethylene glycol methyl vinyl ether (TEGMVE), which has several abstractable hydrogens. Four conclusions are drawn from these studies: (i) the vinyl ether/maleate kinetics differs significantly from the classical expression R-p = KI0.5, with recorded exponential factors of 0.84 +/- 0.04 in the absence of easily abstractable hydrogens; (ii) the presence of abstractable hydrogens significantly changes the kinetics of vinyl ether/maleate polymerizations with recorded exponential factors of 0.55 +/- 0.04 for EHVE/DEMA and 0.70 +/- 0.04 for TEGMVE/DEMA; (iii) the presence of easily abstractable hydrogens leads to a preferential consumption of maleates; and (iv) electron paramagnetic resonance studies show that vinyloxy-like radicals constitute the majority of the radicals in the systems with easily abstractable hydrogens.
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| 26. |
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| 27. |
- Haraldsson, K, et al.
(författare)
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The self-reported health condition of women after their participation in a stress management programme: a pilot study
- 2005
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Ingår i: Health & Social Care in the Community. - : Hindawi Limited. - 0966-0410 .- 1365-2524. ; 13:3, s. 224-230
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Tidskriftsartikel (refereegranskat)abstract
- From a public health perspective, it is important to develop effective measures to deal with stress which are based on the individual's participation, such as stress management provided in group sessions. Therefore, the aim of the present study was to compare and evaluate the self-reported health condition of women in terms of their general symptoms, stress and sense of coherence (SOC) after participation in a stress management programme. The intervention, which had a modified crossover design and involved 40 women divided into two groups (G1 and G2), comprised eight meetings, the content of which was both theoretical and practical, and included information about stress, stress management, massage and mental training. A questionnaire was filled in on three occasions: before and after the intervention (8 weeks later), and after another 8 weeks (16 weeks later). The questionnaire contained 60 items comprising background factors, general symptoms, stress and SOC. No significant differences existed between the groups at baseline. In favour of the intervention, significant differences were found between the groups with regard to fewer general symptoms (P = 0.035) as well as a tendency to stress reduction (P = 0.060). A comparison within groups showed that both groups had a significant reduction in symptoms after the intervention (G1, P = 0.002; and G2, P = 0.003) and in reduced stress (both P = 0.001). After a further 8 weeks, both groups still showed significantly fewer general symptoms and reduced stress, as well as significant improvements with regard to SOC (G1, P = 0.012; and G2, P = 0.026). These findings indicate that the combination of mental training and massage in this stress management programme had a positive influence on the women's health condition. The pilot study design could be used in a full-scale study with randomised groups.
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| 28. |
- Herrmann, A., et al.
(författare)
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Analysis of the Mushroom Nephrotoxin Orellanine and Its Glucosides
- 2012
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 75:10, s. 1690-1696
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Tidskriftsartikel (refereegranskat)abstract
- Orellanine is a nephrotoxin found in various Cortinaceae mushroom species. Unintentional consumption after these species were confused with edible mushrooms such as Cantharellus tubaeformis has caused several casualties. In this work, a quantitative HPLC-ESI-MS/MS method for total orellanine in Cortinarius rubellus, spiked blood plasma, and a mushroom stew prepared from C. tubaeformis with the addition of a single specimen of C. rubellus is presented. The existence of mono- and diglucosylated orellanine in C. rubellus was also proven, although quantitative analysis could not be obtained for the glucosides due to rapid hydrolyzation to orellanine in the extract. Extraction with 3 M HCl or water mainly yielded orellanine, while MeOH or acidified MeOH mainly extracted mono- and diglucosylated orellanine. The highest recovery of total orellanine was obtained with 3 M HCl, which was subsequently used for quantitative analysis. A C-18 HPLC column and low pH in the eluents retained all these toxins. Orellanine could be detected at a 4.9 ng/mL level in all extracts, which is well below the threshold for acute toxic effects. Additionally, the fragmentation pattern of orellanine upon electrospray MS/MS was probed. The method described is useful for two important applications. First, it allows quantitative analysis of processed food products that may be contaminated by orellanine from Cortinaceae mushrooms. Second, orellanine is currently being evaluated as a potential cure of metastatic renal cancer, and this work provides a method for monitoring orellanine at low concentrations within the therapeutic interval in blood serum.
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| 29. |
- Hilmi, N., et al.
(författare)
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Exposure of Mediterranean Countries to Ocean Acidification
- 2014
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Ingår i: Water. - : MDPI AG. - 2073-4441. ; 6:6, s. 1719-1744
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Tidskriftsartikel (refereegranskat)abstract
- This study examines the potential effects of ocean acidification on countries and fisheries of the Mediterranean Sea. The implications for seafood security and supply are evaluated by examining the sensitivity of the Mediterranean to ocean acidification at chemical, biological, and macro-economic levels. The limited information available on impacts of ocean acidification on harvested (industrial, recreational, and artisanal fishing) and cultured species (aquaculture) prevents any biological impact assessment. However, it appears that non-developed nations around the Mediterranean, particularly those for which fisheries are increasing, yet rely heavily on artisanal fleets, are most greatly exposed to socioeconomic consequences from ocean acidification.
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| 30. |
- Isaksson, P., et al.
(författare)
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Promoting mental health in Swedish preschool-teacher views
- 2017
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Ingår i: Health Promotion International. - : Oxford University Press (OUP). - 0957-4824 .- 1460-2245. ; 32:1, s. 53-61
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Tidskriftsartikel (refereegranskat)abstract
- The promotion of childhood mental health is an important investment for the future. Many young children spend a large amount of time in preschool, which have unique opportunities to promote mental health at an early stage. The aim of this study was to illuminate teachers' views of what they do in ordinary work to promote mental health among preschool children. This qualitative study had a descriptive and exploratory design and qualitative content analysis was utilized. Six focus group interviews with preschool teachers, concerning families from different cultural, geographical and socioeconomic backgrounds, were conducted in a county in the southwest of Sweden. Both manifest and latent content appeared. Three categories, 'structured world', 'pleasant climate' and 'affirming the child' and 10 subcategories emerged. The latent content of these categories is described under the theme 'creating an atmosphere where each child can flourish in harmony with their environment'. The results show teachers different working approaches with mental health in preschool and together with previous research these results can provide a basis of knowledge for preschool teachers and inspire them to develop and maintain their health-promoting work. In future studies it should be particularly interesting to investigate how the promotive way to work can be transferred to strengthen mental health throughout the school years.
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| 31. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 32. |
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| 33. |
- Pollard, K. Michael, et al.
(författare)
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Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN
- 2017
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 199:11, s. 3739-3747
-
Tidskriftsartikel (refereegranskat)abstract
- Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.
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| 34. |
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| 35. |
- Rozenblum, E, et al.
(författare)
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A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes
- 2002
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 110:2, s. 111-121
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.7-Mb genomic map with 90% sequence coverage. This area contains eight known genes, two hypothetical proteins, 24 additional Unigene clusters, and approximately 100 predicted genes and exons. We have determined the cDNA and genomic sequence, and tissue expression profiles for the KIAA1008 protein (homologous to the yeast mitotic control protein dis3+), KLF12 (AP-2 repressor), progesterone induced blocking factor 1, zinc finger transcription factor KLF5, and LIM domain only-7, and for the hypothetical proteins FLJ22624 and FLJ21869. Mutation screening of the five known genes in 19 breast cancer families has revealed numerous polymorphisms, but no deleterious mutations. These data provide a basis and resources for further analyses of this chromosomal region in the development of cancer.
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| 36. |
- Roziková, M., et al.
(författare)
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Electrolytic conductivity at pure water level final report
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 58:1 A
-
Tidskriftsartikel (refereegranskat)abstract
- Electrolytic conductivity in aqueous solutions is one of the most common electrochemical measurement techniques in industry. Since it is sensitive to the amount content of dissolved ions in a solution, a limiting value for conductivity is a clear and simple quality criterium for the ionic purity of water. The relevant measuring range for pure water applications is roughly between 0.055 μS cm-1 (ultrapure water) and 150 μS cm-1 at 25 °C. For instance, the European, Japanese and United States (USP) Pharmacopoeia have specified the requirements for purified water, highly purified water and water for injection for pharmaceutical use based on conductiv-ity. Sectors that also use conductivity limits for water purity are electrical power production, food industry, electronic industry and analytical laboratories. At low conductivity levels it is not feasible to circulate water samples for comparison measure-ments, since the conductivity value is instable due to inevitable ionic contamination. The main contamination results from carbon dioxide in ambient air that dissolves in water and builds H3O+ and hydrogen carbonate ions. The contribution of these ions to conductivity is around 1 μS cm-1. Hence, it is impossible to provide stable samples having usable uncertainties in the conductivity range of interest. EURAMET 1271, performed in 2013, was the first successful comparison measurement of pure water conductivity. In the meanwhile, more NMIs, the majority of which is situated in Europe, have built measurement capabilities in the pure water range. EURAMRET 1271 covered a measurement range up to 50 μS cm-1, whereas more and more customers request conductivity cell calibration in the range up to 150 μS cm-1. Consequently, this comparison intends to extend the measurement range and to enable more NMIs to get support for potential CMCs. Therefore, this comparison is additionally intended being a supplementary CCQM comparison. A commercial conductivity measurement meter, including a conductivity measurement cell, was used for the comparison in a Round-Robin scheme. The devices were provided by PTB and were sent from one institute to another. Each institute had to measure the conductivity of a reference solution using the conductivity meter. The reference solution could either be pure water or a measurement standard solution that was reasonably stable in the range of interest. In the first scheme, the cell had to be integrated in a closed pure water flow though system to minimize impurification by CO2. An adequate fixture for this setup was provided by PTB. In the second scheme, the cell was immersed into the measurement standard solution under tem-perature-controlled conditions. Essentially, the institutes had to report the conductivity values indicated by the conductivity meter and the conductivity reference value assigned to the water in the flow though system or that of the measurement standard solution, respectively. The co-ordinating institute calculated adjusted cell constants for the cell from the reported values, which were used to calculate linking conductivities, the actual quantities to be finally compared. The results showed good equivalence in all conductivity ranges, with only a few inconsistent values. Adequate comparison reference values are suggested that can serve to calculate robust degrees of equivalences for the participants usable to support respective CMC claims.
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| 37. |
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| 38. |
- Svensson, M.K, 1965, et al.
(författare)
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Njursjukdomar
- 2011
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Bok (övrigt vetenskapligt/konstnärligt)
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| 39. |
- Tryggvason, S. H., et al.
(författare)
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A meta-analysis of expression signatures in glomerular disease
- 2013
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 84:3, s. 591-599
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Tidskriftsartikel (refereegranskat)abstract
- Glomerular diseases represent major diagnostic and therapeutic challenges with classification of these diseases largely relying on clinical and histological findings. Elucidation of molecular mechanisms of progressive glomerular disease could facilitate quicker development. High-throughput expression profiling reveals all genes and proteins expressed in tissue and cell samples. These methods are very appropriate for glomerular disease as pure glomeruli can be obtained from kidney biopsies. To date, proteome profiling data are only available for normal glomeruli, but more robust transcriptome methods have been applied to many mouse model and a few human glomerular diseases. Here, we have carried out a meta-analysis of currently available glomerular expression data in normal and diseased glomeruli from mice, rats, and humans using a standardized protocol. The results suggest a potential for glomerular transcriptomics in identifying pathogenic pathways, disease monitoring, and the feasibility to use animal models to study human glomerular disease. We also found that currently there are no specific consensus biomarkers or pathways among different disease data sets, indicating there are likely disease-specific mechanisms and expression profiles. Thus, further transcriptomics and proteomics analysis, especially that of dynamic changes in the diseases, may lead to novel diagnostics tools and specific pharmacologic therapies.
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| 40. |
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