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1.
  • Anderson, D. C., et al. (författare)
  • Formaldehyde in the Tropical Western Pacific: Chemical Sources and Sinks, Convective Transport, and Representation in CAM-Chem and the CCMI Models
  • 2017
  • Ingår i: Journal of Geophysical Research-Atmospheres. - 2169-897X. ; 122:20, s. 11201-11226
  • Tidskriftsartikel (refereegranskat)abstract
    • Formaldehyde (HCHO) directly affects the atmospheric oxidative capacity through its effects on HOx. In remote marine environments, such as the tropical western Pacific (TWP), it is particularly important to understand the processes controlling the abundance of HCHO because model output from these regions is used to correct satellite retrievals of HCHO. Here we have used observations from the Convective Transport of Active Species in the Tropics (CONTRAST) field campaign, conducted during January and February 2014, to evaluate our understanding of the processes controlling the distribution of HCHO in the TWP as well as its representation in chemical transport/climate models. Observed HCHO mixing ratios varied from similar to 500 parts per trillion by volume (pptv) near the surface to similar to 75 pptv in the upper troposphere. Recent convective transport of near surface HCHO and its precursors, acetaldehyde and possibly methyl hydroperoxide, increased upper tropospheric HCHO mixing ratios by similar to 33% (22 pptv); this air contained roughly 60% less NO than more aged air. Output from the CAM-Chem chemistry transport model (2014 meteorology) as well as nine chemistry climate models from the Chemistry-Climate Model Initiative (free-running meteorology) are found to uniformly underestimate HCHO columns derived from in situ observations by between 4 and 50%. This underestimate of HCHO likely results from a near factor of two underestimate of NO in most models, which strongly suggests errors in NOx emissions inventories and/or in the model chemical mechanisms. Likewise, the lack of oceanic acetaldehyde emissions and potential errors in the model acetaldehyde chemistry lead to additional underestimates in modeled HCHO of up to 75 pptv (similar to 15%) in the lower troposphere.
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2.
  • 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. - : NATURE PUBLISHING GROUP. - 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 naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma 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.
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5.
  • Mustjoki, S., et al. (författare)
  • Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy
  • 2009
  • Ingår i: Leukemia. - : Nature Publishing Group. - 1476-5551 .- 0887-6924. ; 23:8, s. 1398-1405
  • Tidskriftsartikel (refereegranskat)abstract
    • Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile. Leukemia (2009) 23, 1398-1405; doi:10.1038/leu.2009.46; published online 19 March 2009
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6.
  • Olsson-Strömberg, Ulla, et al. (författare)
  • Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase
  • 2006
  • Ingår i: Leukemia and Lymphoma. - 1042-8194 .- 1029-2403. ; 47:9, s. 1768-73
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.
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7.
  • Simonsson, Bengt, et al. (författare)
  • Intensive treatment and stem cell transplantation in chronic myelogenous leukemia : long-term follow-up
  • 2005
  • Ingår i: Acta Haematologica. - : Karger. - 0001-5792 .- 1421-9662. ; 113:3, s. 155-162
  • Tidskriftsartikel (refereegranskat)abstract
    • In the present study we combined interferon (IFN) and hydroxyurea (HU) treatment, intensive chemotherapy and autologous stem cell transplantation (SCT) in newly diagnosed chronic myelogenous leukemia patients aged below 56 years, not eligible for allogeneic SCT. Patients who had an HLA-identical sibling donor and no contraindication went for an allogeneic SCT (related donor, RD). After diagnosis, patients not allotransplanted received HU and IFN to keep WBC and platelet counts low. After 6 months patients with Ph-positive cells still present in the bone marrow received 1–3 courses of intensive chemotherapy. Those who became Ph-negative after IFN + HU or after 1–3 chemotherapy courses underwent autologous SCT. Some patients with poor cytogenetic response were allotransplanted with an unrelated donor (URD). IFN + HU reduced the percentage of Ph-positive metaphases in 56% of patients, and 1 patient became Ph-negative. After one or two intensive cytotherapies 86 and 88% had a Ph reduction, and 34 and 40% became Ph-negative, respectively. In patients receiving a third intensive chemotherapy 92% achieved a Ph reduction and 8% became Ph-negative. The median survival after auto-SCT (n = 46) was 7.5 years. The chance of remaining Ph-negative for up to 10 years after autologous SCT was around 20%. The overall survival for allo-SCT RD (n = 91) and URD (n = 28) was almost the same, i.e. ≈60% at 10 years. The median survival for all 251 patients registered was 8 years (historical controls 3.5 years). The role of the treatment schedule presented in the imatinib era is discussed.
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8.
  • Zabriskie, Matthew S., et al. (författare)
  • BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
  • 2014
  • Ingår i: Cancer Cell. - 1535-6108 .- 1878-3686. ; 26:3, s. 428-442
  • Tidskriftsartikel (refereegranskat)abstract
    • Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
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9.
  • Christiansson, Lisa, et al. (författare)
  • The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
  • 2015
  • Ingår i: Molecular Cancer Therapeutics. - : American Association for Cancer Research. - 1535-7163 .- 1538-8514. ; 14:5, s. 1181-1191
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. (C) 2015 AACR.
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10.
  • Dahlén, Torsten, et al. (författare)
  • Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia
  • 2016
  • Ingår i: Annals of Internal Medicine. - Karolinska Univ Hosp, Stockholm, Sweden. Karolinska Inst, Stockholm, Sweden. Reg Canc Ctr, Uppsala, Sweden. Univ Uppsala Hosp, Uppsala, Sweden. Umea Univ, Umea, Sweden. Skane Univ Hosp, Lund, Sweden. [Dahlen, Torsten; Bjorkholm, Magnus; Ohm, Lotta; Stenke, Leif] Karolinska Univ Hosp Solna, Div matol, Dept Med, SE-17176 Stockholm, Sweden. [Edgren, Gustaf; Lambe, Mats] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, eden. [Hoglund, Martin; Olsson-Stromberg, Ulla] Univ Hosp, Dept Med Sci, SE-75185 Uppsala, Sweden. [Hoglund, Martin; Olsson-Stromberg, Ulla] Univ Hosp, Div Hematol, SE-75185 Uppsala, Sweden. [Sandin, Fredrik] Uppsala Univ Hosp, Reg Canc Ctr, SE-75185 Uppsala, Sweden. [Sjalander, Anders] Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden. [Richter, Johan] Skane Univ Hosp, Dept Hematol & Vasc Disorders, SE-22241 Lund, Sweden. [Back, Magnus] Karolinska Univ Hosp, Dept Cardiol, SE-17176 Stockholm, Sweden. : American College of Physicians. - 0003-4819 .- 1539-3704. ; 165:3, s. 161-166
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity. Objective: To investigate the incidence of vascular events in patients with CML treated with first-and second-generation TKIs. Design: Retrospective cohort study using nationwide population-based registries. Setting: Sweden. Patients: All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 ageand sex-matched control individuals per patient. Measurements: Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons. Results: 896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred. Limitations: Patients may have been exposed to multiple TKIs. Data on second-and third-generation TKIs were limited. Conclusion: An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs.
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