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1.
  • Abé, Christoph, et al. (författare)
  • Cytarabine dose intensification improves survival in older patients with secondary/high-risk acute myeloid leukemia in matched real-world versus clinical trial data
  • 2024
  • Ingår i: Leukemia and Lymphoma. - 1042-8194.
  • Tidskriftsartikel (refereegranskat)abstract
    • Since 1980’s, the established/standard treatment of acute myeloid leukemia (AML) is cytarabine infusion with anthracycline (7 + 3 regimen). We compared the 7 + 3 regimen in older secondary/high-risk AML patientsfrom a clinical trial with a matched population from the Swedish AML Registrytreated withan increased cytarabine dose in induction and consolidation as recommended in the Swedish National Guidelines since 2005. After successfulpropensity score matching, 104 patients per group were included. The primary outcome was overall survival (OS), and standard dosed patients had a median OS of 6.4 versus 10.7 months with increased dose intensity (hazard ratio:0.69, p = 0.012), with 5-year OS of 8.7% and 18.1%, andremission rates of 36% and 60%, respectively (p < 0.001). Median OS after allogeneic hematopoietic cell transplantation (in 27.9% per group) was 10.4 and 20.7 months, respectively. We conclude that the more intensive cytarabine schedule seems to provide improved outcomes inthe investigated AML patient group.
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2.
  • Ali, Dina, et al. (författare)
  • Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells
  • 2016
  • Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 174:1, s. 117-126
  • Tidskriftsartikel (refereegranskat)abstract
    • The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
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3.
  • Ali, M, et al. (författare)
  • T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
  • 2022
  • Ingår i: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 40:4, s. 488-
  • Tidskriftsartikel (refereegranskat)abstract
    • Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
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4.
  • Anande, Govardhan, et al. (författare)
  • RNA Splicing Alterations Induce a Cellular Stress Response Associated with Poor Prognosis in Acute Myeloid Leukemia
  • 2020
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 26:14, s. 3597-3607
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.Experimental Design: We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.Results: We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.Conclusions: Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.
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5.
  • Angenendt, Linus, et al. (författare)
  • Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia : A Pooled Analysis of Individual Patient Data From Nine International Cohorts
  • 2019
  • Ingår i: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 37:29, s. 2632-2642
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1(mut)/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.RESULTS: Among 2,426 patients with NPM1(mut)/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1(mut)/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1(mut)/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1(mut) share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1(mut)/FLT3-ITDneg/low AML.
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6.
  • Antonelli, Alexandre, 1978, et al. (författare)
  • Madagascar's extraordinary biodiversity : Evolution, distribution, and use
  • 2022
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 378:6623, s. 962-
  • Tidskriftsartikel (refereegranskat)abstract
    • Madagascar's biota is hyperdiverse and includes exceptional levels of endemicity. We review the current state of knowledge on Madagascar's past and current terrestrial and freshwater biodiversity by compiling and presenting comprehensive data on species diversity, endemism, and rates of species description and human uses, in addition to presenting an updated and simplified map of vegetation types. We report a substantial increase of records and species new to science in recent years; however, the diversity and evolution of many groups remain practically unknown (e.g., fungi and most invertebrates). Digitization efforts are increasing the resolution of species richness patterns and we highlight the crucial role of field- and collections-based research for advancing biodiversity knowledge and identifying gaps in our understanding, particularly as species richness corresponds closely to collection effort. Phylogenetic diversity patterns mirror that of species richness and endemism in most of the analyzed groups. We highlight humid forests as centers of diversity and endemism because of their role as refugia and centers of recent and rapid radiations. However, the distinct endemism of other areas, such as the grassland-woodland mosaic of the Central Highlands and the spiny forest of the southwest, is also biologically important despite lower species richness. The documented uses of Malagasy biodiversity are manifold, with much potential for the uncovering of new useful traits for food, medicine, and climate mitigation. The data presented here showcase Madagascar as a unique " living laboratory" for our understanding of evolution and the complex interactions between people and nature. The gathering and analysis of biodiversity data must continue and accelerate if we are to fully understand and safeguard this unique subset of Earth's biodiversity.
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7.
  • Berggren, Daniel Moreno, et al. (författare)
  • Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting : a report from the Swedish MDS register
  • 2018
  • Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 181:5, s. 614-627
  • Tidskriftsartikel (refereegranskat)abstract
    • The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). IPSS-R was superior to both IPSS and WPSS for patients aged <= 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.
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8.
  • Castell, Alina, et al. (författare)
  • MYCMI-7 : A Small MYC-Binding Compound that Inhibits MYC: MAX Interaction and Tumor Growth in a MYC-Dependent Manner
  • 2022
  • Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 2:3, s. 182-201
  • Tidskriftsartikel (refereegranskat)abstract
    • Deregulated expression of MYC family oncogenes occurs frequently in human cancer and is often associated with aggressive disease and poor prognosis. While MYC is a highly warranted target, it has been considered "undruggable," and no specific anti-MYC drugs are available in the clinic. We recently identified molecules named MYCMIs that inhibit the interaction between MYC and its essential partner MAX. Here we show that one of these molecules, MYCMI-7, efficiently and selectively inhibits MYC:MAX and MYCN:MAX interactions in cells, binds directly to recombinant MYC, and reduces MYC-driven transcription. In addition, MYCMI-7 induces degradation of MYC and MYCN proteins. MYCMI-7 potently induces growth arrest/apoptosis in tumor cells in a MYC/MYCN-dependent manner and downregulates the MYC pathway on a global level as determined by RNA sequencing. Sensitivity to MYCMI-7 correlates with MYC expression in a panel of 60 tumor cell lines and MYCMI-7 shows high efficacy toward a collection of patient-derived primary glioblastoma and acute myeloid leukemia (AML) ex vivo cultures. Importantly, a variety of normal cells be- come G1 arrested without signs of apoptosis upon MYCMI-7 treatment. Finally, in mouse tumor models of MYC-driven AML, breast cancer, and MYCN-amplified neuroblastoma, treatment with MYCMI-7 downregu- lates MYC/MYCN, inhibits tumor growth, and prolongs survival through apoptosis with few side effects. In conclusion, MYCMI-7 is a potent and selective MYC inhibitor that is highly relevant for the development into clinically useful drugs for the treatment of MYC-driven cancer.Significance: Our findings demonstrate that the small-molecule MYCMI-7 binds MYC and inhibits interaction between MYC and MAX, thereby ham- pering MYC-driven tumor cell growth in culture and in vivo while sparing normal cells.
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9.
  • Castor, Anders, et al. (författare)
  • Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia
  • 2005
  • Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 11:6, s. 630-637
  • Tidskriftsartikel (refereegranskat)abstract
    • The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.
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10.
  • Cozzi, Elisabetta, et al. (författare)
  • Identification of long non-coding RNAs involved in leukemogenesis and venetoclax response in acute myeloid leukemia through functional CRISPR-dCas9 interference screens
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Acute myeloid leukemia (AML) is a malignant hematologic disease with poor prognosis. Increased understanding of disease biology is therefore needed to improve outcome for patients. While the protein-coding genome is well characterized in AML, knowledge about the involvement of non-coding genes is very limited in AML. Here, it was sought to investigate how long non-coding RNAs (lncRNAs) could contribute to disease biology and treatment resistance in AML. Three high-throughput lncRNA-CRISPR-interference screens were performed in MOLM-13 cells, knocking down about 8000 lncRNA expressed in hematopoietic cells. Effects on cell proliferation, cell differentiation and response to the anti-leukemic Bcl-2-inhibitor venetoclax were investigated upon lncRNA repression. LncRNAs most likely to positively or negatively regulate these processes were identified and top lncRNA candidates investigated with respect to expression in AML and healthy CD34+ cells and clinical AML correlations. Four lncRNAs involved in AML cell proliferation were identified (lncRNAs MIR17HG, CATG00000056335, CATG00000095269, CATG00000002239), two lncRNAs involved in differentiation (lncRNAs RP11-444A22.1, CATG00000058672) and seven lncRNAs implicated in venetoclax response. Among those, enhanced expression of proliferation-promoting lncRNA MIR17HG significantly correlated with poor outcome in AML patients (p= 0.03; p= 0.016). Further, lncRNA RP11-444A2 was identified as a predicted negative regulator of cell differentiation and was found to correlate with poor outcome (p=0.014). Further, lncRNA AC009299.3, predicted in venetoclax sensitivity, was found to be associated with poor outcome (p<0.0001), adverse risk (p=0.0014) and increased age (p=0.0045) in AML patients. Together, this study identified 14 lncRNAs proposed to be implicated in key leukemogenic events, highlighting their potential for elucidating AML biology, prognosis or treatment-response prediction and/or therapeutic use. 
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11.
  • Deneberg, Stefan, et al. (författare)
  • microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia
  • 2014
  • Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 9:6, s. 910-917
  • Tidskriftsartikel (refereegranskat)abstract
    • A commonly deleted region in chronic lymphocytic leukemia (CLL) is the 11q22-23 region, which encompasses the ATM gene. Evidence suggests that tumor suppressor genes other than ATM are likely to be involved in CLL with del(11q). A microRNA (miR) cluster including the miR-34b and miR-34c genes is located, among other genes, within the commonly deleted region (CDR) at 11q. Interestingly, these miRs are part of the TP53 network and have been shown to be epigenetically regulated. In this study, we investigated the expression and methylation status of these miRs in a well-characterized cohort of CLL, including cases with/without 11q-deletion. We show that the miR-34b/c promoter was aberrantly hypermethylated in a large proportion of CLL cases (48%, 25/52 cases). miR-34b/c expression correlated inversely to DNA methylation (P = 0.003), and presence of high H3K37me3 further suppressed expression regardless of methylation status. Furthermore, increased miR-34b/c methylation inversely correlated with the presence of 11q-deletion, indicating that methylation and del(11q) independently silence these miRs. Finally, 5-azacytidine and trichostatin A exposure synergistically increased the expression of miR-34b/c in CLL cells, and transfection of miR-34b or miR-34c into HG3 CLL cells significantly increased apoptosis. Altogether, our novel data suggest that miR-34b/c is a candidate tumor suppressor that is epigenetically silenced in CLL.
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12.
  • Deneberg, Stefan, et al. (författare)
  • Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks
  • 2011
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:20, s. 5573-5582
  • Tidskriftsartikel (refereegranskat)abstract
    • Cytogenetically normal acute myeloid leukemia (CN-AML) comprise between forty and fifty percent of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group molecular aberrations such as FLT3ITD, NPM1 and CEBPA mutations recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer including AML. We investigated in total 118 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them to normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (p=0.0004 and 0.04, respectively). Genome-wide methylation levels were elevated in IDH mutated samples (p=0.006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (p<0.0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression free (OR 0.47, p=0.01) and overall survival (OR 0.36, p=0.001). In summary, genome wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML.
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13.
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14.
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15.
  • Dolinska, Monika, et al. (författare)
  • Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients 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.
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16.
  • 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.
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17.
  • Eriksson, Anna, et al. (författare)
  • Epigenetic aberrations in acute myeloid leukemia : Early key events during leukemogenesis
  • 2015
  • Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 43:8, s. 609-624
  • Tidskriftsartikel (refereegranskat)abstract
    • As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role.
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18.
  • Genovese, Giulio, et al. (författare)
  • Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
  • 2014
  • Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 371:26, s. 2477-87
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
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19.
  • Herold, Nikolas, et al. (författare)
  • Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
  • 2017
  • Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
  • Tidskriftsartikel (refereegranskat)abstract
    • The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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20.
  • Hornung, R, et al. (författare)
  • Mediation analysis reveals common mechanisms of RUNX1 point mutations and RUNX1/RUNX1T1 fusions influencing survival of patients with acute myeloid leukemia
  • 2018
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 11293-
  • Tidskriftsartikel (refereegranskat)abstract
    • Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.
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21.
  • Hulegardh, Erik, et al. (författare)
  • Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting : A report from the Swedish Acute Leukemia Registry
  • 2015
  • Ingår i: American Journal of Hematology. - : Wiley-Blackwell. - 0361-8609 .- 1096-8652. ; 90:3, s. 208-214
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients. Am. J. Hematol. 90:208-214, 2015.
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22.
  • Hultmark, Simon, et al. (författare)
  • Combinatorial molecule screening identifies a novel diterpene and the BET inhibitor CPI-203 as differentiation inducers of primary acute myeloid leukemia cells
  • 2021
  • Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Combination treatment has proven effective for patients with acute promyelocytic leukemia, exemplifying the importance of therapy targeting multiple components of oncogenic regulation for a successful outcome. However, recent studies have shown that the mutational complexity of acute myeloid leukemia (AML) precludes the translation of molecular targeting into clinical success. Here as a complement to genetic profiling, we used unbiased, combinatorial in vitro drug screening to identify pathways that drive AML and to develop personalized combinatorial treatments. First, we screened 513 natural compounds on primary AML cells and identified a novel diterpene (H4) that preferentially induced differentiation of FLT3 wild-type AMLs, while FLT3-ITD/mutations conferred resistance. The responding samples to H4, displayed increased expression of myeloid markers, a clear decrease in the nuclear-cytoplasmic ratio and the potential of re-activation of the monocytic transcriptional program reducing leukemia propagation in vivo. By combinatorial screening using H4 and molecules with defined targets, we demonstrated that H4 induces differentiation by the activation of protein kinase C (PKC) signaling pathway, and in line with this, activates PKC phosphorylation and translocation of PKC to the cell membrane. Furthermore, the combinatorial screening identified a bromo- and extra-terminal domain (BET) inhibitor that could further improve H4-dependent leukemic differentiation in FLT3 wild-type monocytic AML. Taken together, this illustrates the value of an unbiased and multiplex screening platform for developing combinatorial therapeutic approaches for AML.
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23.
  • Ilander, M, et al. (författare)
  • Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.
  • 2017
  • Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:5, s. 1108-1116
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.Leukemia advance online publication, 16 December 2016; doi:10.1038/leu.2016.360.
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24.
  • Jadersten, M., et al. (författare)
  • Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
  • 2022
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 292:6, s. 925-940
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission. Conclusion Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study.
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25.
  • Juliusson, Gunnar, et al. (författare)
  • Age and acute myeloid leukemia : real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry
  • 2009
  • Ingår i: Blood. - Washington D.C. : American Society of Haematology. - 0006-4971 .- 1528-0020. ; 113:18, s. 4179-4187
  • Tidskriftsartikel (refereegranskat)abstract
    • Acute myeloid leukemia (AML) is most common in the elderly, and most elderly are thought to be unfit for intensive treatment because of the risk of fatal toxicity. The Swedish Acute Leukemia Registry covers 98% of all patients with AML (nonacute promyelocytic leukemia) diagnosed in 1997 to 2005 (n = 2767), with a median follow-up of 5 years, and reports eligibility for intensive therapy, performance status (PS), complete remission rates, and survival. Outcomes were strongly age and PS dependent. Early death rates were always lower with intensive therapy than with palliation only. Long-term survivors were found among elderly given intensive treatment despite poor initial PS. Total survival of elderly AML patients was better in the geographic regions where most of them were given standard intensive therapy. This analysis provides unique real world data from a large, complete, and unselected AML population, both treated and untreated, and gives background to treatment decisions for the elderly. Standard intensive treatment improves early death rates and long-term survival compared with palliation. Most AML patients up to 80 years of age should be considered fit for intensive therapy, and new therapies must be compared with standard induction.
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26.
  • Juliusson, Gunnar, et al. (författare)
  • Epidemiology and Etiology of AML
  • 2021
  • Ingår i: Acute Myeloid Leukemia. - Cham : Springer International Publishing. - 2197-9766 .- 2197-9774. - 9783030726768 - 9783030726782 ; , s. 1-22
  • Bokkapitel (refereegranskat)abstract
    • Acute myeloid leukemia (AML) is a grave disease with an incidence of 4 per 100,000 a year. It can present in all ages, but the median age is 70 years. One-third of such patients have secondary AML, that is, AML following chemoradiotherapy or a transformation from previous myelodysplastic syndrome (MDS) or myeloproliferative neoplasia. A combination of genetic, epigenetic, and environmental factors may be responsible for the development of most cases of AML. The pathogenesis of AML is characterized by the serial acquisition of somatic mutations and several genes are recurrently mutated in AML. Exposures to benzene, cigarette smoking, pesticides, embalming fluids, accidental or professional ionization radiation, therapeutic radiotherapy, and radioactive I-131 therapy can cause AML with or without a preceding MDS phase. Alkylating agents (e.g., melphalan, cyclophosphamide), topoisomerase-II inhibitors (e.g., etoposide, doxorubicin), and other drugs (e.g., azathioprine) are described to be associated with the development of therapy-related AML (t-AML). Furthermore, about 5–15% of adults and 4–13% of pediatric patients with MDS or AML carry germline pathogenic variants in cancer susceptibility genes. Individuals with clonal hematopoiesis (CHIP) progress to AML at a rate of about 1% per year. Higher age of onset, obesity, previous autoimmune disease, and antecedent MDS or MPN are associated with a risk for developing AML.
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27.
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28.
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29.
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30.
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31.
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32.
  • Juliusson, Gunnar, et al. (författare)
  • The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting
  • 2020
  • Ingår i: Blood Advances. - : AMER SOC HEMATOLOGY. - 2473-9529 .- 2473-9537. ; 4:6, s. 1094-1101
  • Tidskriftsartikel (refereegranskat)abstract
    • In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3(ITD) and/or NPM1(mut) (FLT3(ITD) : female, 29%; male, 22% [P - .00151; NPM1(mut) : female, 36%; male, 27% [P < .0001]), and more males were double negative (female, 53%; male, 64%; P < .0001). Patients with FLT3(ITD) were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1(mut) (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3(ITD) indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1(mut) indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3(ITD)/NPM1(mut) patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy.
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33.
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34.
  • Khalkar, Prajakta, et al. (författare)
  • Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia : A genome wide epigenetic analysis
  • 2018
  • Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 117, s. 247-257
  • Tidskriftsartikel (refereegranskat)abstract
    • Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.
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35.
  • Lazarevic, Vladimir, et al. (författare)
  • Failure matters : unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia
  • 2015
  • Ingår i: European Journal of Haematology. - Hoboken, USA : Wiley-Blackwell. - 0902-4441 .- 1600-0609. ; 94:5, s. 419-423
  • Tidskriftsartikel (refereegranskat)abstract
    • Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.
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36.
  • Lehmann, Philipp, et al. (författare)
  • Energy and lipid metabolism during direct and diapause development in a pierid butterfly
  • 2016
  • Ingår i: Journal of Experimental Biology. - : The Company of Biologists. - 0022-0949 .- 1477-9145. ; 219:19, s. 3049-3060
  • Tidskriftsartikel (refereegranskat)abstract
    • Diapause is a fundamental component of the life-cycle in the majority of insects living in environments characterized by strong seasonality. The present study addresses poorly understood associations and trade-offs between endogenous diapause duration, thermal sensitivity of development, energetic cost of development and cold tolerance. Diapause intensity, metabolic rate trajectories and lipid profiles of directly developing and diapausing animals were studied using pupae and adults of Pieris napi butterflies from a population for which endogenous diapause is well studied. Endogenous diapause was terminated after 3 months and termination required chilling. Metabolic and postdiapause development rates increased with diapause duration, while the metabolic cost of postdiapause development decreased, indicating that once diapause is terminated development proceeds at a low rate even at low temperature. Diapausing pupae had larger lipid stores than the directly developing pupae and lipids constituted the primary energy source during diapause. However, during diapause lipid stores did not decrease. Thus, despite lipid catabolism meeting the low energy costs of the diapausing pupae, primary lipid store utilization did not occur until the onset of growth and metamorphosis in spring. In line with this finding, diapausing pupae contained low amounts of mitochondria-derived cardiolipins, which suggests a low capacity for fatty acid β-oxidation. While ontogenic development had a large effect on lipid and fatty acid profiles, only small changes in these were seen during diapause. The data therefore indicate that the diapause lipidomic phenotype is built early, when pupae are still at high temperature, and retained until diapause post-diapause development.
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37.
  • Lehmann, Philipp, et al. (författare)
  • Idiosyncratic development of sensory structures in brains of diapausing butterfly pupae : implications for information processing
  • 2017
  • Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 284:1858
  • Tidskriftsartikel (refereegranskat)abstract
    • Diapause is an important escape mechanism from seasonal stress in many insects. A certain minimum amount of time in diapause is generally needed in order for it to terminate. The mechanisms of time-keeping in diapause are poorly understood, but it can be hypothesized that a well-developed neural system is required. However, because neural tissue is metabolically costly to maintain, there might exist conflicting selective pressures on overall brain development during diapause, on the one hand to save energy and on the other hand to provide reliable information processing during diapause. We performed the first ever investigation of neural development during diapause and non-diapause (direct) development in pupae of the butterfly Pieris napi from a population whose diapause duration is known. The brain grew in size similarly in pupae of both pathways up to 3 days after pupation, when development in the diapause brain was arrested. While development in the brain of direct pupae continued steadily after this point, no further development occurred during diapause until temperatures increased far after diapause termination. Interestingly, sensory structures related to vision were remarkably well developed in pupae from both pathways, in contrast with neuropils related to olfaction, which only developed in direct pupae. The results suggest that a well-developed visual system might be important for normal diapause development.
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38.
  • Lehmann, Philipp, et al. (författare)
  • Metabolome dynamics of diapause in the butterfly Pieris napi: Distinguishing maintenance, termination and post-diapause phases
  • 2018
  • Ingår i: Journal of Experimental Biology. - : The Company of Biologists. - 1477-9145 .- 0022-0949. ; 221:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Diapause is a deep resting stage facilitating temporal avoidance of unfavourable environmental conditions, and is used by many insects to adapt their life cycle to seasonal variation. Although considerable work has been invested in trying to understand each of the major diapause stages (induction, maintenance and termination), we know very little about the transitions between stages, especially diapause termination. Understanding diapause termination is crucial for modelling and predicting spring emergence and winter physiology of insects, including many pest insects. In order to gain these insights, we investigated metabolome dynamics across diapause development in pupae of the butterfly Pieris napi, which exhibits adaptive latitudinal variation in the length of endogenous diapause that is uniquely well characterized. By employing a time-series experiment, we show that the whole-body metabolome is highly dynamic throughout diapause and differs between pupae kept at a diapause-terminating (low) temperature and those kept at a diapause-maintaining (high) temperature. We show major physiological transitions through diapause, separate temperature-dependent from temperature-independent processes and identify significant patterns of metabolite accumulation and degradation. Together, the data show that although the general diapause phenotype (suppressed metabolism, increased cold tolerance) is established in a temperature-independent fashion, diapause termination is temperature dependent and requires a cold signal. This revealed several metabolites that are only accumulated under diapause-terminating conditions and degraded in a temperatureunrelated fashion during diapause termination. In conclusion, our findings indicate that some metabolites, in addition to functioning as cryoprotectants, for example, are candidates for having regulatory roles as metabolic clocks or time-keepers during diapause.
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39.
  • Lehmann, Philipp, et al. (författare)
  • Timing of diapause termination in relation to variation in winter climate
  • 2017
  • Ingår i: Physiological entomology (Print). - : Wiley. - 0307-6962 .- 1365-3032. ; 42:3, s. 232-238
  • Tidskriftsartikel (refereegranskat)abstract
    • In temperate insects, winters are typically endured by entering diapause, which comprises a deep resting stage. Correct timing of diapause termination is vital for synchronization of emergence with conspecifics and for mobilizing resources when conditions for growth and reproduction become favourable. Although critical to survival, the intrinsic and extrinsic drivers of diapause termination timing are poorly understood. In the present study, we investigate diapause development under a range of durations (10-24weeks) spent at different temperatures (-2 to 10 degrees C) in the pupal diapausing butterfly Pieris napi Linnaeus (Lepidoptera: Pieridae). We determine: (i) the maximum cold temperature for diapause development; (ii) if pupae in diapause count cold days or cold sums; and (iii) whether diapause termination is distinct or gradual. The results indicate large and idiosyncratic effects of high and low nonlethal temperatures on diapause development in P. napi. Although all temperatures tested lead to diapause termination, a thermal optimum between 2 and 4 degrees C is observed. Lower temperatures lead to decreased eclosion propensity, whereas higher temperatures slow down development and increase emergence desynchronization. These data suggest that, rather than a simple cold-summing process with a distinct diapause termination point, there are trade-offs between time and temperature at the low and high end of the thermal range, resulting in a nonlinear thermal landscape showing a ridge of increasing eclosion propensity at moderate temperatures. The present study suggests that the effects of temperature on diapause development should be included in projections on post-winter phenology models of insects, including pest species.
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40.
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41.
  • Lehmann, Sören (författare)
  • In vitro studies of retinoids and arsenic in non-M3 acute myeloid leukemia
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Despite advances in the treatment of patients with acute myeloid leukemia (AML), the majority of the patients will die from their disease. The current intensive therapy for AML is also complicated my substantial morbidity and mortality and, as a result, many patients cannot be given the most effective therapy. Therefore, the need for more effective as well as less toxic treatment approaches for AML is urgent. Retinoids and arsenic has recently shown impressive results in the treatment of acute promyelocytic leukemia (APL) and both drugs exhibit less toxic effects than the commonly used chemotherapeutic drugs. In these studies we have investigated the effects of retinoids and arsenic in cells from patients with non-APL (or non-M3) AML. Furthermore, we have investigated what mechanisms that could be of importance for the sensitivity to these drugs. The results showed that there is a pronounced heterogeneity in the sensitivity to the retinoids all-trans-retinoic acid (ATRA) and 9-cis-RA but cells from the majority of the patients were sensitive and some cases exhibited a pronounced sensitivity to retinoids. There was no cross-resistance between the retinoids and daunorubicin (DNR) and cells that were more resistant to DNR tended to be more retinoidsensitive. Also, CD34-positive AML cells were more sensitive than the CD34-negative. In order to find markers for retinoid sensitivity we correlated the expression of retinoid receptors (RARs and RXR alpha) and retinoid bindings proteins (CRBPI and CRABPs) to the sensitivity to ATRA in the patient samples. No correlation between the sensitivity to the retinoids and the basal mRNA expression of any of these proteins was found. However, upregulation of RAR beta and CRABPII after ATRA exposure did significantly correlate to retinoid sensitivity. For arsenic, a significant dose dependent sensitivity was found in all the patient samples even at concentrations below those that are seen in plasma during APL treatment. The sensitivity to arsenic was then compared to that of common AML drugs such as anthracyclines, etoposide, AMSA and Ara-C. There was a significant correlation in the sensitivity between the different anthracyclines as well as between the anthracyclines and etoposide and AMSA. However, all correlation coefficients were negative for the comparisons between arsenic and the other drugs and most so between arsenic and idarubicin. We then investigated the sensitivity to arsenic in P-gp-expressing cell lines showing that P-gp expression does not affect the sensitivity to arsenic. We also investigated the sensitivity in cell lines with either increased expression of MRP 1, downregulated topoisomerase II or in cells that were FAS-resistant. None of these resistant cell lines were shown to exhibit any decrease in sensitivity to arsenic compared to its non-resistant cell line. The only cell line that showed a decreased arsenic sensitivity was the lung cancer cell line GLC4/ADR. In addition to the overexpression of the lung resistance protein (LRP), these cells exhibited higher concentrations of GSH than the wild type GLG4. The multidrug resistant reverser and pyridine analogue PAK-104P exerted a powerful sensitizing effect on the cells together with arsenic, both in resistant and nonresistant cells. This sensitizing effect was accompanied by a slight decrease in GSH but this effect was moderate compared to the strong effect on cell toxicity. Therefore, we suggest that the sensitizing effect of PAK-104P should be further studied as well as its potential as a sensitizer to arsenic in vivo.
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42.
  • Lehmann, Sören, et al. (författare)
  • Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells
  • 2001
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 7:2, s. 367-372
  • Tidskriftsartikel (refereegranskat)abstract
    • All-trans-retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (M3). In non-M3 acute myeloid leukemia (AML), the effects are less clear, and there is a pronounced heterogeneity in the sensitivity to the growth-inhibitory effects of retinoids in leukemic cells from different non-M3 AML patients. Retinoids exert their effects through a number of nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. In this study, we determined the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha by real-time PCR in four cell lines and in blast cells from patients with non-M3 AML before and after ATRA incubation. All four receptors were expressed in cells from all 18 tested patient samples and in four myeloid cell lines. In the majority of the patient samples as well as in the cell lines, there was a pattern of high expression of RAR alpha and RXR alpha and low expression of RAR beta and RAR gamma. There was no correlation between the basal expression of any of the retinoid receptors and sensitivity to ATRA. A 24-h exposure to ATRA increased the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha in 46%, 77%, 30%, and 38% of the samples, respectively. The mean increase in receptor expression was most pronounced for RAR beta and RXR alpha. There was a significant correlation between an increase in RAR beta expression in response to ATRA and sensitivity to ATRA (P < 0.014). No such correlations were found for RAR alpha, RAR gamma, and RXR alpha. The expression of the monocytoid marker CD14 was significantly correlated with increased expression of RAR alpha (P = 0.03). We conclude that RAR alpha, RAR beta, RAR gamma, and RXR alpha are expressed in non-M3 AML blast cells and that ATRA-induced expression of RAR beta may be a marker for retinoid sensitivity.
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43.
  • Lehmann, Sören, et al. (författare)
  • Targeting p53 in Vivo : a First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer
  • 2012
  • Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:29, s. 3633-3639
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSEAPR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.PATIENTS AND METHODSAPR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.RESULTSMTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.CONCLUSION We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
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44.
  • Lehmann, Sören, et al. (författare)
  • The expression of cellular retinoid binding proteins in non-APL leukemic cells and its association with retinoid sensitivity
  • 2002
  • Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 43:4, s. 851-8
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Retinoic acid (RA) has important effects on cell differentiation and cell growth and on normal embryonic development. Intracellular retinoid signaling induced by endogenous or exogenous RA is regulated by retinoid binding proteins such as CRBPI, CRABPI and CRABPII and there are data suggesting that the expression of these proteins can influence the sensitivity to the growth inhibitory effects of ATRA. In this study, we investigated the basal and ATRA-induced expression of CRBPI and CRABPI and II in leukemic cell lines and in cells from patients with acute myeloid leukemia (AML). CRBPI as well as CRABPI and II were expressed in all tested cell lines and in leukemic cells from all 18 AML-patients. CRABPII mRNA expression was more abundant than CRBPI and CRABPI in both the cell lines and the patient cells but the levels compared the house keeping gene was lower in the patient cells. In all cell lines and in 69% of the patient samples, ATRA did upregulate CRABPII whereas CRBPI exhibited a varying response and CRABPI was more commonly downregulated. The sensitivity to the growth inhibitory effects of ATRA did not correlate with the basal expression of any of these proteins. However, ATRA-induced upregulation of CRABPII did significantly correlate with the ATRA sensitivity (p < 0.005) as well as with ATRA-induced upregulation of the retinoid receptor RARbeta (p < 0.05). We conclude that the retinoid binding proteins CRBPI and CRABPI and II are expressed in myeloid leukemic cells of non-M3 type but that the level of expression does not affect ATRA sensitivity.
  •  
45.
  • Liu, Lisa L., et al. (författare)
  • Ex Vivo Expanded Adaptive NK Cells Effectively Kill Primary Acute Lymphoblastic Leukemia Cells
  • 2017
  • Ingår i: CANCER IMMUNOLOGY RESEARCH. - 2326-6066 .- 2326-6074. ; 5:8, s. 654-665
  • Tidskriftsartikel (refereegranskat)abstract
    • Manipulation of human natural killer (NK) cell repertoires promises more effective strategies for NK cell-based cancer immunotherapy. A subset of highly differentiated NK cells, termed adaptive NK cells, expands naturally in vivo in response to human cytomegalovirus (HCMV) infection, carries unique repertoires of inhibitory killer cell immunoglobulin-like receptors (KIR), and displays strong cytotoxicity against tumor cells. Here, we established a robust and scalable protocol for ex vivo generation and expansion of adaptive NK cells for cell therapy against pediatric acute lymphoblastic leukemia (ALL). Culture of polyclonal NK cells together with feeder cells expressing HLA-E, the ligand for the activating NKG2C receptor, led to selective expansion of adaptive NK cells with enhanced allor-eactivity against HLA-mismatched targets. The ex vivo expanded adaptive NK cells gradually obtained a more differentiated phenotype and were specific and highly efficient killers of allogeneic pediatric T-and precursor B-cell acute lymphoblastic leukemia (ALL) blasts, previously shown to be refractory to killing by autologous NK cells and the NK-cell line NK92 currently in clinical testing. Selective expansion of NK cells that express one single inhibitory KIR for self-HLA class I would allow exploitation of the full potential of NK-cell alloreactivity in cancer immunotherapy. In summary, our data suggest that adaptive NK cells may hold utility for therapy of refractory ALL, either as a bridge to transplant or for patients that lack stem cell donors.
  •  
46.
  • Lj Lazarevic, Vladimir, et al. (författare)
  • Incidence and prognostic significance of isolated trisomies in adult acute myeloid leukemia : A population-based study from the Swedish AML registry
  • 2017
  • Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609. ; 98:5, s. 493-500
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES AND METHODS: To ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry.RESULTS: Of the 3179 cytogenetically informative AMLs diagnosed January 1997-May 2015, 246 (7.7%) had isolated trisomies. The frequency increased by age (2.4% at age 18-60 years vs. 23% at >60 years; P<.0001); the median age was 69 years. The five most common were +8 (4.0%), +13 (0.9%), +11 (0.8%), +21 (0.7%), and +4 (0.5%). Age and gender, types of AML and treatment, and complete remission and early death rates did not differ between the single trisomy and the intermediate risk (IR) groups or among cases with isolated gains of chromosomes 4, 8, 11, 13, or 21. The overall survival (OS) was similar in the single trisomy (median 1.6 years) and IR groups (1.7 years; P=.251). The OS differed among the most frequent isolated trisomies; the median OS was 2.5 years for +4, 1.9 years for +21, 1.5 years for +8, 1.1 years for +11, and 0.8 years for +13 (P=.013).CONCLUSION: AML with single trisomies, with the exception of +13, should be grouped as IR.
  •  
47.
  • Löfgren, Christina, et al. (författare)
  • Higher plasma but not intracellular concentrations after infusion with liposomal daunorubicin compared with conventional daunorubicin in adult acute myeloid leukemia
  • 2007
  • Ingår i: Therapeutic Drug Monitoring. - New York : Raven P.. - 0163-4356 .- 1536-3694. ; 29:5, s. 626-631
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate the plasma and intracellular pharmacokinetics of liposomal daunorubicin (DaunoXome) in comparison with conventional daunorubicin, 14 patients aged 28 to 60 years with newly diagnosed acute myeloid leukemia were treated for 1 day with DaunoXome (50 mg/m) and for 2 days with daunorubicin (50 mg/m) with concomitant Ara-C (7 days, 200 mg/m, continuous IV). Eleven of the 14 patients entered complete remission; 9 are still alive. Pharmacokinetic profiles were obtained by blood sampling at appropriate intervals on days 1 to 4. Daunorubicin and daunorubicinol concentrations in plasma and in peripheral leukemic blast cells were measured by high-performance liquid chromatography. Following liposomal daunorubicin administration, the peak values and plasma area under the curve (AUC) were more than 100 times higher than after administration of conventional daunorubicin (AUC, 176 vs. 0.98 micromol/L x hour), but the intracellular AUCs were comparable (759 vs. 715 micromol/L x hour). Intracellular concentrations after DaunoXome peaked later and half as high as after daunorubicin. After DaunoXome versus daunorubicin, plasma clearance was 0.001 versus 0.4 micromol/h, respectively. The volume of distribution was 5.5 L for DaunoXome, versus 3640 L for daunorubicin, indicating low tissue affinity for the liposomal formulation. The authors conclude that liposomal daunorubicin, DaunoXome, yields 2-log higher plasma concentrations but similar intracellular concentrations of daunorubicin and its metabolite daunorubicinol than does free daunorubicin.
  •  
48.
  • Mareschal, Sylvain, et al. (författare)
  • Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML
  • 2021
  • Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:4, s. 1003-1016
  • Tidskriftsartikel (refereegranskat)abstract
    • Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss 200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.
  •  
49.
  • Mer, Arvind Singh, et al. (författare)
  • Expression levels of long non-coding RNAs are prognostic for AML outcome
  • 2018
  • Ingår i: Journal of Hematology & Oncology. - : BIOMED CENTRAL LTD. - 1756-8722. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Long non-coding RNA (lncRNA) expression has been implicated in a range of molecular mechanisms that are central in cancer. However, lncRNA expression has not yet been comprehensively characterized in acute myeloid leukemia (AML). Here, we assess to what extent lncRNA expression is prognostic of AML patient overall survival (OS) and determine if there are indications of lncRNA-based molecular subtypes of AML. Methods: We performed RNA sequencing of 274 intensively treated AML patients in a Swedish cohort and quantified lncRNA expression. Univariate and multivariate time-to-event analysis was applied to determine association between individual lncRNAs with OS. Unsupervised statistical learning was applied to ascertain if lncRNA-based molecular subtypes exist and are prognostic. Results: Thirty-three individual lncRNAs were found to be associated with OS (adjusted p value < 0.05). We established four distinct molecular subtypes based on lncRNA expression using a consensus clustering approach. LncRNA-based subtypes were found to stratify patients into groups with prognostic information (p value < 0.05). Subsequently, lncRNA expression-based subtypes were validated in an independent patient cohort (TCGA-AML). LncRNA subtypes could not be directly explained by any of the recurrent cytogenetic or mutational aberrations, although associations with some of the established genetic and clinical factors were found, including mutations in NPM1, TP53, and FLT3. Conclusion: LncRNA expression-based four subtypes, discovered in this study, are reproducible and can effectively stratify AML patients. LncRNA expression profiling can provide valuable information for improved risk stratification of AML patients.
  •  
50.
  • Miliara, Sophia, et al. (författare)
  • The biological and prognostic role of long non-coding RNA NEAT1 in acute myeloid leukemia
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA localized in the cell nucleus that has been associated to promote several malignant solid tumors. Its role in acute myeloid leukemia (AML) remains largely elusive. Therefore, the aim of this study was to define the role of NEAT1 in AML compared to normal hematopoiesis. During normal hematopoiesis, it was identified that NEAT1 expression was low in early progenitors but increased in more differentiated cells, especially in monocytes. NEAT1 expression was increased in AML as a whole compared to normal bone marrow (NBM). It was specifically high in AML with inv(16) and t(8;21), while it was lower in patients with t(15;17). Further, NEAT1 expression correlated positively with ASXL1, KRAS and NRAS mutations and negatively with TP53 mutant AML. Higher NEAT expression was associated to better overall survival in AML, independent of other known risk factors. Antisense oligo-mediated knockdown of NEAT1 in AML cells significantly increased expression of the monocytic marker CD14 while granulocytic markers did not change. Genes affected by NEAT1-knockdown using CAGE-sequencing were significantly enriched for genes involved in glucose metabolism. By investigating genome-wide RNA and DNA interactions using RADICL-sequencing, it was revealed that NEAT1 binds to the loci of key hematopoietic regulator RUNX2 as well as the chromatin regulators KMT2A, KMT5B and CHD7. The results suggest that lncRNA NEAT1 has a potential role in hematopoietic and AML cell differentiation and could be a potential new biomarker in AML.
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