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  • 1
    In: The Lancet, Elsevier BV, Vol. 395, No. 10233 ( 2020-04), p. 1345-1360
    Type of Medium: Online Resource
    ISSN: 0140-6736
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 2
    In: Molecular Biology Reports, Springer Science and Business Media LLC, Vol. 48, No. 5 ( 2021-05), p. 4611-4623
    Type of Medium: Online Resource
    ISSN: 0301-4851 , 1573-4978
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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    SSG: 12
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  • 3
    In: BMC Genomics, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2021-12)
    Abstract: Previous studies have identified many immune pathways which are consistently altered in humans and model organisms as they age. Dairy cows are often culled at quite young ages due to an inability to cope adequately with metabolic and infectious diseases, resulting in reduced milk production and infertility. Improved longevity is therefore a desirable trait which would benefit both farmers and their cows. This study analysed the transcriptome derived from RNA-seq data of leukocytes obtained from Holstein cows in early lactation with respect to lactation number. Results Samples were divided into three lactation groups for analysis: i) primiparous (PP, n  = 53), ii) multiparous in lactations 2–3 (MP 2–3, n  = 121), and iii) MP in lactations 4–7 (MP  〉  3, n  = 55). Leukocyte expression was compared between PP vs MP  〉  3 cows with MP 2–3 as background using DESeq2 followed by weighted gene co-expression network analysis (WGCNA). Seven modules were significantly correlated (r ≥ 0.25) to the trait lactation number. Genes from the modules which were more highly expressed in either the PP or MP  〉  3 cows were pooled, and the gene lists subjected to David functional annotation cluster analysis. The top three clusters from modules more highly expressed in the PP cows all involved regulation of gene transcription, particularly zinc fingers. Another cluster included genes encoding enzymes in the mitochondrial beta-oxidation pathway. Top clusters up-regulated in MP  〉  3 cows included the terms Glycolysis/Gluconeogenesis , C-type lectin , and Immunity. Differentially expressed candidate genes for ageing previously identified in the human blood transcriptome up-regulated in PP cows were mainly associated with T-cell function ( CCR7 , CD27 , IL7R , CAMK4 , CD28 ), mitochondrial ribosomal proteins ( MRPS27 , MRPS9 , MRPS31 ), and DNA replication and repair ( WRN ). Those up-regulated in MP  〉  3 cows encoded immune defence proteins ( LYZ , CTSZ , SREBF1 , GRN , ANXA5 , ADARB1 ). Conclusions Genes and pathways associated with lactation number in cows were identified for the first time to date, and we found that many were comparable to those known to be associated with ageing in humans and model organisms. We also detected changes in energy utilization and immune responses in leukocytes from older cows.
    Type of Medium: Online Resource
    ISSN: 1471-2164
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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    SSG: 12
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  • 4
    In: Blood Pressure, Informa UK Limited, Vol. 7, No. 1 ( 1998-01), p. 31-37
    Type of Medium: Online Resource
    ISSN: 0803-7051 , 1651-1999
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 1998
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  • 5
    In: Leukemia, Springer Science and Business Media LLC, Vol. 32, No. 10 ( 2018-10), p. 2299-2303
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 6
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4579-4579
    Abstract: Most patients with advanced Philadelphia-positive (Ph+) hematologic malignancies develop resistance to imatinib. Acquired resistance to imatinib is commonly a result of selection for subclones bearing point-mutations in the catalytic kinase domain of BCR-ABL. Dasatinib (BMS-354825), a dual-specific SRC/ABL kinase inhibitor, has shown activity in imatinib-resistant Ph+ diseases both in vitro and in vivo. Preliminary data also indicate efficacy in patients. Based on laboratory evidence, dasatinib appears to inhibit all known BCR-ABL mutant clones, with the exception of T315I, a gatekeeper mutation conferring resistance to several kinase inhibitors. Here we describe a Ph+ ALL patient, who initially developed imatinib resistance (hematologic) possibly due to BCR-ABL amplification (FISH). His disease relapsed as extensive extramedullary tumors bearing wild-type BCR-ABL. He received dasatinib 70 mg BID as part of the BMS CA180–015 study and achieved a very good partial remission. After 5 months of therapy, the disease relapsed as a solitary axillary tumor and several small palmar skin lesions. He also had blasts in the CSF indicative of neuroleukemia. Bone marrow remained in cytogenetic remission. FISH analysis of the tumor revealed 2–3 copies of BCR-ABL as previously. A highly sensitive, quantitative, mutation-specific PCR (Gruber F, ASH 2004) showed the presence of the T315I mutation, which was confirmed by sequencing. A very low level of T315I transcript was also detected in the blood. Dasatinib dose was escalated to 100 mg BID, and low-dose hydroxyurea 500 mg BID was initiated to putatively enhance the access of dasatinib in the CSF sanctuary. He also received two doses of i.t. therapy (methotrexate, cytarabine). Patient’s symptoms (confusion, headache) related to neuroleukemia resolved rapidly, skin lesions disappeared and axillary tumor decreased in size. He is currently symptom-free and has no signs of active ALL. The favorable response to dasatinib dose escalation and low-dose hydroxyurea was unexpected. Preclinical data on T315I mutant cell lines would argue against a significant concentration dependence in kinase inhibition by dasatinib. Putatively, targets other than BCR-ABL may be of importance in particular in Ph+ ALL (e.g. Src, Lyn), and this effect may account for the response. Similar off-target activity of hydroxyurea is utilized in clinical trials to overcome resistance to multidrug HIV therapy - a setting resembling current treatment of Ph+ malignancies with kinase inhibitors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 7
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3145-3145
    Abstract: Introduction As there are only few data available about the incidence, the stage of disease at diagnosis, the treatment and the outcome of chronic myeloid leukemia (CML) in Europe the European Treatment and Outcome Study (EUTOS) for CMLcollected such data in 27 European countries. The population-based registry was set up by EUTOS to further explore the epidemiology, characteristics, treatment and outcomes of CML in Europe. The present work focused on the estimation of incidence of CML in Europe, in the single countries participating in the registry and the comparison to existing incidence estimations from the US. Patients and Methods The EUTOS population-based registry aimed to document all newly diagnosed adult patients with Ph+ and/or BCR-ABL+ CML at any stage nationwide or in prespecified regions within countries of Europe. Croatia, Cyprus, Estonia, Latvia, Lithuania, Slovakia, Slovenia and Sweden were observed in total while for Austria, the Czech Republic[H1] , France, Germany, Italy, the Netherlands, Poland, Russia, Serbia, Spain, Sweden and the United Kingdom specified regions were selected. Population data from the United Nations database were used for calculations in countries that were observed nationwide, while the study groups provided the population numbers of the specified regions for countries that were observed partially only. The registration periodvaried between 12 and 60 months in the different countries, from January 2008 to December 2012, registration area covered over 92.5 million inhabitants overall. Raw and standardized incidenceswere calculated for the countries and regions and adjusted to the registration period. For standardization the Old Europe Standard Population was used (Waterhouse et al IARC 1976). The registry and the standard population were truncated so only patients from 20 years on were included for the calculation of standardized rates. To compare and validate the EUTOS estimations we chose the data of the Surveillance Epidemiology and End Results Program (SEER) which cover about 28% of the US population. The data were collected from 2007 to 2011. Results There were 2,936 patients registered into the EUTOS population-based registry. Raw incidences per 100,000 inhabitants per year ranged from 0.72 in Poland to 1.39 in Italy. The overall raw incidence for all countries was 1.02, with 0.90 in females and 1.14 in males. Estimations of standardized incidences ranged from 0.72 in the UK to 1.29 in Italy. Overall standardized incidence was 0.99, with 0.86 in females and 1.12 in males. Age specific incidences rose with age group. While the incidence in the 18 to 40 years old population was as low as 0.52 (0.61 in males and 0.42 in females) it increased to 1.61 (2.18 in males and 1.26 in females) in the population from 70 years up. Comparing the SEER data to our EUTOS results very similar incidences can be observed up to age group 55-59 years. From that age group up the SEER incidence estimations are considerably higher. The overall standardized SEER incidences ranged around 1.7 per 100,000 for the years observed. The higher rates can be explained by different inclusion criteria of the registries: While EUTOS includes only Ph+ and/or BCR/ABL+ patients, the SEER has more open inclusion criteria. Also patients without information on Ph-status, BCR-ABL1 negative patients and patients diagnosed with chronic myelomonocytic leukemia are included. Discussion The EUTOS population based registry is the first paneuropean prospective study of incidence of CML in Europe. For the first time data about the incidence of CML are available now for most European countries. Raw and standardized incidences from the EUTOS registry fit in well with earlier findings of study groups from countries like the UK (Bhayat et al., BMC Cancer 2009; 9; 252) (Phekoo et al Haematologica 2006), Sweden (Höglund et al Blood 2013), Germany (Nennecke et al Bundesgesundheitsblatt 2014) and France (Corm et al J Clin Oncol 2008) that range between 0.7 and 1.1 per 100,000 inhabitants. Thus the estimation of incidence over all regions participating in the EUTOS project can serve as a robust estimation of the incidence of CML in Europe. [H1]Wurde zwar voll beobachtet, zwei Regionen wurden aber ausgeschlossen, da sie nicht garantieren konnten pop-based gewesen zu sein! Disclosures Hoffmann: Novartis: Research Funding. Lindoerfer:Novartis: Research Funding. Castagnetti:Novartis, BMS,: Consultancy, Honoraria; Pfizer: Consultancy. Griskevicius:NOvartis: Research Funding. Steegmann:Novartis, BMS, Pfizer: Honoraria, Research Funding. Hehlmann:Novartis, BMS: Research Funding. Hasford:Novartis: Research Funding. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 8
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1534-1534
    Abstract: Chimeric antigen receptor (CAR) T cells have shown promising results in patients with B cell malignancy. In preclinical studies we showed that CD19-targeting third generation (3G) CAR T cells containing signaling domains from both CD28 and 4-1BB as co-stimulatory molecules have greater activation and proliferation in response to antigens than 2G CARs containing CD28 only. Herein we report results from a phase I/IIa study (NCT:02132624) using these 3G CAR T cells. Patients with relapsed or refractory CD19+ B-cell malignancy were eligible, provided there was no curative treatment available. Of the first eleven patients reported, nine had lymphoma and two had acute lymphoblastic leukemia (ALL). Autologous CAR T cells were manufactured using a gamma retrovirus encoding the CAR and expanded by αCD3/αCD28/IL2. During CAR T cell production, all lymphoma patients received treatment to control tumor burden (-90 to -3 days before T cell infusion). Their treatment depended on the type of lymphoma and previous treatments. In addition, prior to T cell infusion (day -2 to -1) patients #6-11 received cyclophosphamide (500mg/m2) and fludarabine (25mg/m2) as conditioning to decrease immunosuppressive cells. The patients received one infusion of CAR T cells (2x107 cells/m2 patients 1 and 2; 1x108 patients 4, 5, 7, 8, 9; and 2x108 patients 6, 10, 11, 12). Patient #1 (DLBCL) had a mild cytokine release syndrome (CRS) after four weeks (never requiring treatment), followed by a complete response of his lymphoma. A relapse and a second CRS occurred after six weeks and he was treated with prednisone with good symptomatic effect and reduction of tumor size. The patient progressed after three months. Patients #2, 4, 5 (CLL, MCL, MCL) all progressed after 2, 1, and 3 months, respectively. Patient #6 (DLBCL) responded to treatment (CR) prior to T cell infusion and remained in complete remission for 6 months post T cell infusion. Patients #7 (CLL) and #9 (DLBCL) also responded to treatment prior to T cell infusion and remains in complete remission +4 and +5 months,respectively. The CLL patient has a tumor negative bone marrow. Patient #8 (FL-DLBCL) had a mild CRS but progressed after 1 month but. Patient #10 (ALL) experienced transient CNS toxicity followed by a complete response. However, at 3 months the patient relapsed with a CD19 negative ALL, accompanied by increased levels of immunosuppressive cells such as T regulatory cells and myeloid derived suppressor cells. Patient #11 (ALL) is in complete remission after a CRS (+3 month) and patient #12 (FL/Burkitt) had a major CRS requiring intensive care and a stable disease for one month before progression. The CAR transgene could be detected in blood at the time of clinical symptoms of response and most patients that progressed lost CAR signal. In summary, 6 of 11 patients (3 DLBCL, 1 CLL and 2 ALL) treated with increasing doses of 3rd generation CAR T cells in Sweden had CR or CCR. CRS occurred in 4/11 but was mild in all but one and CNS-toxicity occurred in 2/11 patients of which one required hospitalisation. Correlations between the levels of T regulatory cells and myeloid derived suppressor cells in blood and patient response are currently under investigation. Disclosures Brenner: Bluebird Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Other: Licensing Agreement; Celgene: Other: Collaborative Research Agreement. Loskog:Alligator Bioscience AB: Patents & Royalties; RePos Pharma AB: Membership on an entity's Board of Directors or advisory committees; Lokon Pharma AB: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; NEXTTOBE AB: Membership on an entity's Board of Directors or advisory committees; Vivolux AB: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 9
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 130-130
    Abstract: Abstract 130 Secondary AML comprises AML patients with an antecedent hematological disorder (AHD) or previous exposure to chemotherapy and/or radiation (therapy-related AML; tAML). Population-based data on this patient group are scarce. Here, we report for the first time, data on secondary AML from the Swedish Acute Leukemia Registry covering 98% of all AML cases diagnosed in Sweden between 1997 and 2006. In total, 3372 AML patients were registered during this period. Of these, 949 (28%) had secondary AML; 655 (19%) had a history of AHD and 294 (8.7%) had tAML. The proportion of secondary AML increased from 8% in patients below the age of 40 years to 36% in patients between 70–79 years. Of patients with AHD, 423 (65%) had previously been diagnosed with myelodysplastic syndrome (MDS) and 227 (35%) with various types of myeloproliferative disorders (MPN). AML with AHD showed male predominance (57%), whereas tAML showed female predominance (64%). This distribution was significantly different (p 〈 0.001) compared to de novo AML with an equal gender distribution. Median and mean ages for patients with AML with antecedent hematological disorder were 73 and 71 years, which differed significantly from de novo AML with 70 and 66 years, respectively (p 〈 10−11). For tAML, median and mean ages were 71 and 67 years, respectively, not significantly different from de novo AML. Patients with secondary AML had slightly worse WHO/ECOG performance status (WHO PS) with lower incidence of WHO PS 0 (10%: 14%: 18% for AML with AHD:tAML:de novo AML) and a higher incidence of WHO PS 3–4 (27%: 24%: 20%). The proportion of patients with PS 1 and PS2 was similar for secondary AML and de novo AML. Intensive induction treatment was given to 45% of all patients with AHD, to 57% of patients with tAML compared to 68% for patients with de novo AML. In patients below the age of 65, the proportion of intensively treated patients was 76, 85 and 98%, respectively. CR rates for in patients including all ages were 40% for AML with AHD, 54% for tAML and 72 % for de novo AML (p-values 〈 0.0001 for all calculations). CR rates were lower in all cytogenetic risk groups in both AML with AHD and tAML compared to de novo AML (Low risk NA: 70%: 91%; intermediate risk 53%: 56%: 89%; high risk 30%: 43%: 76%). CR rates were lower for both secondary leukemia types within all WHO PS groups, despite similar early death rates in secondary and de novo AML. Median survival for all patients regardless of age or type of treatment was 4 mo, 4 mo and 9 mo respectively for patients with AML with AHD, tAML and de novo AML, respectively. For all patients receiving intensive induction treatment, corresponding figures were 7 mo, 9 mo and 17 mo, and for patients below 65 years of age 7 mo, 9 mo and 38 mo. We conclude that secondary AML is less common in younger patients and that the proportion increases to a third of patients above 70. Patients with AHD and tAML less often receive intensive induction treatment than those with de novo AML and treatment responses are poor regardless of cytogenetic risk group or performance status also in intensively treated patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 10
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4032-4032
    Abstract: Dasatinib is a potent BCR-ABL1 and SRC tyrosine kinase inhibitor, which in vitro is more effective against progenitor and putative leukemia stem cells than imatinib. This may translate into deeper molecular responses in vivo. Methods We randomized (1:1) 46 newly diagnosed CML patients to receive dasatinib 100 mg or imatinib 400 mg once daily. The primary endpoint of our study was treatment response in stem and progenitor cell fractions (Mustjoki et al, Leukemia 2013). We here summarize the clinical results of the study after a 24-month follow-up focusing on toxicity and standard response evaluation by quantitative BCR-ABL1 PCR and cytogenetics (NCT00852566 www.ClinicalTrials.gov). Results Both imatinib and dasatinib treated patients fared well with deeper and faster treatment responses than what has been reported in the registration studies. By karyotyping, dasatinib induced a faster response by 3 months (median of 5% of Ph+ cells in imatinib group vs. 0% in dasatinib group, p=0.01, n=21 in each group), but already by 12 months the difference disappeared, as all evaluable patients were in complete cytogenetic remission. The rate of molecular response MR3.0 was already at the 3 months time-point better in the dasatinib group (36% vs 8%, p=0.02; see Table), but within 18 months imatinib patients caught up the difference. In contrast, the achievement of deeper therapy responses, MR4.0 and MR4.5, was clearly different between the groups and increased over 24 months. After 18 months 64% and 71% of imatinib- and dasatinib-treated patients had achieved MR3.0 (p=0.59), while the MR4.0 rates were 23% and 62% (p=0.009) and MR4.5 rates 4% and 41% (0.003) (see Table below). The difference in median transcript levels was approximately 1 log ( 〉 10-fold difference) in all time-points after 3 months of therapy (see Table below). A total of 7 patients (30%) in both groups discontinued assigned treatment. Main drug-related toxicities were as expected. Dasatinib-induced serosal inflammation (pleural/pericardial effusions) was more frequent than in registration studies (6 patients, 27%). In 4 patients (18%) this led to therapy discontinuation, despite of drug interruption and dose reductions. In the imatinib group 3 patients discontinued due to drug-related toxicity (liver toxicity, rash and severe hypogammaglobulinemia with recurrent infections). Disease progression occurred in one dasatinib-treated patient (cytogenetic progression with the appearance of V299L mutation at month 9) and two imatinib-treated patients (blastic transformation at month 2 and molecular progression at month 18). The patient in blast phase has been transplanted and is currently in molecular remission. No CML-related deaths occurred, but one patient died from lung cancer. Interpretation Dasatinib induced faster and deeper molecular responses than imatinib and overall responses were better in both groups than in the registration studies. Relatively high rate of serosal toxicity was observed among the dasatinib-treated patients, but this had no adverse effect on response. Upcoming studies will show if the deeper treatment responses induced by dasatinib therapy translate into increased probability of successful therapy discontinuation. Disclosures: Hjorth-Hansen: Pfizer: Honoraria, Travel, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Travel Other; Merck: Research Funding. Richter:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Consultancy, Honoraria, Travel, Travel Other. Porkka:BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Mustjoki:Novartis: Honoraria; BMS: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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