| 1. |
- Dolinska, Monika, et al.
(författare)
-
Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
|
|
| 2. |
|
|
| 3. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
|
|
| 4. |
|
|
| 5. |
- Johansson, Peter, 1967, et al.
(författare)
-
Cultural expertise in Sami land rights litigation: Epistemic strategies in the Girjas and Fosen cases
- 2023
-
Ingår i: Jindal Global Law Review. - : Springer Nature. - 0975-2498 .- 2364-4869. ; 14:2, s. 217-240
-
Tidskriftsartikel (refereegranskat)abstract
- How do parties mobilise cultural expertise in Indigenous rights litigation in Scandinavia? Recently, Sami groups have litigated to claim Indigenous rights to land and natural resources, winning some remarkable victories in the Supreme Courts of Norway and Sweden. In this paper, we draw on socio-legal mobilisation theory to analyse the epistemic strategies of Sami litigants and their adversaries in two recent landmark Supreme Court cases on Indigenous rights to usage of land: the 2020 Girjas case in Sweden and the 2021 Fosen case in Norway. Conceptualising cultural expertise as a strategic framing contest, we analyse how the parties struggled over the epistemic basis of the respective case by legitimating their claims to cultural knowledge, drawing on academic research, and discrediting their opponents’ epistemic claims. Our findings suggest that in both cases, Sami claimants successfully established an epistemic basis where their traditional, experiential knowledge combined with independent academic expertise effectively challenged the knowledge claims of their adversaries. Yet, both cases also demonstrate how the linkage between Sami Indigeneity and reindeer husbandry in the national law of both countries excludes non-reindeer herding Sami persons from the Indigenous rights affirmed by the courts.
|
|
| 6. |
- Kaaks, Rudolf, et al.
(författare)
-
Lag Times between Lymphoproliferative Disorder and Clinical Diagnosis of Chronic Lymphocytic Leukemia : A Prospective Analysis Using Plasma Soluble CD23
- 2015
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:3, s. 538-545
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic lymphocytic leukemia (CLL) is a chronic disease that often progresses slowly from a precursor stage, monoclonal B-cell lymphocytosis (MBL), and that can remain undiagnosed for a long time. Methods: Within the European Prospective Investigation into Cancer cohort, we measured prediagnostic plasma sCD23 for 179 individuals who eventually were diagnosed with CLL and an equal number of matched control subjects who remained free of cancer. Results: In a very large proportion of CLL patients' plasma sCD23 was clearly elevated 7 or more years before diagnosis. Considering sCD23 as a disease predictor, the area under the ROC curve (AUROC) was 0.95 [95% confidence interval (CI), 0.90-1.00] for CLL diagnosed within 0.1 to 2.7 years after blood measurement, 0.90 (95% CI, 0.86-0.95) for diagnosis within 2.8 to 7.3 years, and 0.76 (95% CI, 0.65-0.86) for CLL diagnosed between 7.4 and 12.5 years. Even at a 7.4-year and longer time interval, elevated plasma sCD23 could predict a later clinical diagnosis of CLL with 100% specificity at > 45% sensitivity. Conclusions: Our findings provide unique documentation for the very long latency times during which measurable B-cell lymphoproliferative disorder exists before the clinical manifestation of CLL. Impact: Our findings have relevance for the interpretation of prospective epidemiologic studies on the causes of CLL in terms of reverse causation bias. The lag times indicate a time frame within which an early detection of CLL would be theoretically possible. (c) 2014 AACR.
|
|
| 7. |
- Sinadinovic, Kristina, et al.
(författare)
-
Guided web-based treatment program for reducing cannabis use : a randomized controlled trial
- 2020
-
Ingår i: Addiction science & clinical practice. - : Springer Science and Business Media LLC. - 1940-0632 .- 1940-0640. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the effects of a web-based treatment program with therapist guidance for adults and adolescents with regular cannabis use from the general population.Methods: A double blinded randomized controlled trial with a parallel group design was conducted (intervention group n = 151, wait-list control group n = 152). Follow-up 12 weeks from treatment commencement of a 13-module intervention. The primary outcome was frequency of cannabis use. Time by group interaction effects were modeled using generalized estimated equations and the instrumental variable approach was used to estimate the effect of intervention adherence.Results: At follow-up, the intention to treat (ITT) analyses did not show any significant time by group effects. A significant association between intervention adherence and scores on the cannabis abuse screening test (CAST) was found. Secondary analysis excluding participants who had received other professional help revealed time by group effects for secondary outcomes gram cannabis consumed past week, number of dependency criteria and CAST score. Due to methodological limitations, these latter results should be interpreted with caution.Conclusions: In this study we did not find a web-based treatment program with therapist guidance to be more effective than a waiting-list in reducing frequency of cannabis use.Trial registration: The trial was pre-registered at ClinicalTrials.gov (NCT02408640) April 3, 2015
|
|
| 8. |
- Volodina, Elena, 1973, et al.
(författare)
-
Semi-automatic selection of best corpus examples for Swedish: Initial algorithm evaluation.
- 2012
-
Ingår i: Proceedings of the SLTC 2012 workshop on NLP for CALL, Lund, 25th October, 2012.. - 1650-3740. ; :080, s. 59-70
-
Konferensbidrag (refereegranskat)abstract
- The study presented here describes the results of the initial evaluation of two sorting approaches to automatic ranking of corpus examples for Swedish. Representatives from two potential target user groups have been asked to rate top three hits per approach for sixty search items from the point of view of the needs of their professional target groups, namely second/foreign language (L2) teachers and lexicographers. This evaluation has shown, on the one hand, which of the two approaches to example rating (called in the text below algorithms #1 and #2) performs better in terms of finding better examples for each target user group; and on the other hand, which features evaluators associate with good examples. It has also facilitated statistic analysis of the “good” versus “bad” examples with reference to the measurable features, such as sentence length, word length, lexical frequency profiles, PoS constitution, dependency structure, etc. with a potential to find out new reliable classifiers.
|
|
| 9. |
-
Academic Language in a Nordic Setting - Linguistic and Educational Perspectives
- 2017
-
Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- In 2013, a Scandinavian research network, “Language Use in Nordic Academic Settings” (LUNAS) was formed. The network, which was funded by Nordplus, unites researchers from Denmark, Norway and Sweden working in the fields of lexicography, computational linguistics, second language acquisition, and di-dactics in second language teaching. The main purpose of the network has been to share information and experiences on academic language use in the Scandi-navian countries in educational settings and in research, but of equal im-portance is to identify common issues and interests within the field and to ben-efit from joint efforts in language resource development and research. In May 2016, the LUNAS network organized a large international conference at the University of Copenhagen on academic language use and academic literacies from a multilingual perspective in Nordic educational contexts. The articles presented in this volume show some of the results of the cooperation within the LUNAS network since 2013, but also present research from invited guests and other researchers interested in these topics.
|
|
| 10. |
|
|
