| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- 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. - : American Geophysical Union (AGU). - 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.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- 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. - : Elsevier BV. - 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.
|
|
| 11. |
- Dainiak, N, et al.
(författare)
-
First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation
- 2011
-
Ingår i: Disaster medicine and public health preparedness. - : Cambridge University Press (CUP). - 1938-744X .- 1935-7893. ; 5:3, s. 202-212
-
Tidskriftsartikel (refereegranskat)abstract
- Objective:Hematopoietic syndrome (HS) is a clinical diagnosis assigned to people who present with ≥1 new-onset cytopenias in the setting of acute radiation exposure. The World Health Organization convened a panel of experts to evaluate the evidence and develop recommendations for medical countermeasures for the management of HS in a hypothetical scenario involving the hospitalization of 100 to 200 individuals exposed to radiation. The objective of this consultancy was to develop recommendations for treatment of the HS based upon the quality of evidence.Methods:English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to panel members before the meeting and updated during the meeting. Published case series and case reports of individuals with HS, published randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. In cases in which data were limited or incomplete, a narrative review of the observations was made. No randomized controlled trials of medical countermeasures have been completed for individuals with radiation-associated HS. The use of GRADE analysis of countermeasures for injury to hematopoietic tissue was restricted by the lack of comparator groups in humans. Reliance on data generated in nonirradiated humans and experimental animals was necessary.Results:Based upon GRADE analysis and narrative review, a strong recommendation was made for the administration of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor and a weak recommendation was made for the use of erythropoiesis-stimulating agents or hematopoietic stem cell transplantation.Conclusions:Assessment of therapeutic interventions for HS in humans exposed to nontherapeutic radiation is difficult because of the limits of the evidence.(Disaster Med Public Health Preparedness. 2011;5:202-212)
|
|
| 12. |
- Dainiak, N, et al.
(författare)
-
Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems
- 2011
-
Ingår i: Disaster medicine and public health preparedness. - : Cambridge University Press (CUP). - 1938-744X .- 1935-7893. ; 5:3, s. 183-201
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives:The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature.Methods:English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation system. In cases in which data were limited or incomplete, a narrative review of the observations was made.Results:No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made for the administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/or shock. A strong recommendation is made against the use of systemic steroids in the absence of a specific indication. A weak recommendation is made for the use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and for selective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients.Conclusions:High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future.(Disaster Med Public Health Preparedness. 2011;5:183–201)
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Kreutzman, A., et al.
(författare)
-
Expansion of highly differentiated CD8(+) T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation
- 2011
-
Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 25:10, s. 1587-1597
-
Tidskriftsartikel (refereegranskat)abstract
- The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(_)(-) CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-c and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon. Leukemia (2011) 25, 1587-1597; doi:10.1038/leu.2011.135; published online 7 June 2011
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
- Gruber, A, et al.
(författare)
-
A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia
- 2003
-
Ingår i: Leukemia Research. - 0145-2126 .- 1873-5835. ; 27, s. 323-
-
Tidskriftsartikel (refereegranskat)abstract
- The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate. Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10mg/kg per 24h in combination with daunorubicin 45mg/m2 for 3 days and cytarabine 1g/m2 twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients. ⌐ 2002 Elsevier Science Ltd. All rights reserved.
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
- Hjorth-Hansen, H., et al.
(författare)
-
Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients
- 2016
-
Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 30:9, s. 1853-1860
-
Tidskriftsartikel (refereegranskat)abstract
- Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
- 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.
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
- Mustjoki, S., et al.
(författare)
-
Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy
- 2009
-
Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 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
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
|
|
