| 741. |
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| 742. |
- Löwenberg, Bob, et al.
(författare)
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Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML : the HOVON-SAKK-132 trial
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:4, s. 1110-1121
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Tidskriftsartikel (refereegranskat)abstract
- Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% +/- 2% standard error and overall survival, 54% = 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.
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| 743. |
- Maeurer, MJ, et al.
(författare)
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Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin
- 1996
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 183:4, s. 1681-1696
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Tidskriftsartikel (refereegranskat)abstract
- gammadelta T cells can be grouped into discrete subsets based upon their expression of T cell receptor (TCR) variable (V) region families, their tissue distribution, and their specificity. Vdelta2+ T cells constitute the majority of gammadelta T cells in peripheral blood whereas Vdelta1+T cells reside preferentially in skin epithelium and in the intestine. gammadelta T cells are envisioned as first line host defense mechanisms capable of providing a source of immune effector T cells and immunomodulating cytokines such as interleukin (IL) 4 or interferon (IFN) gamma. We describe here the fine specificity of three distinct gammadelta+ tumor-infiltrating lymphocytes (TIL) obtained from patients with primary or metastatic colorectal cancer, that could be readily expanded in vitro in the presence of IL-1beta and IL-7. Irrespective of donor, these individual gammadelta T cells exhibited a similar pattern of reactivity defined by recognition of autologous and allogeneic colorectal cancer cells, renal cell cancer, pancreatic cancer, and a freshly isolated explant from human intestine as measured by cytolytic T cell responses and by IFN-gamma release. In contrast, tumors of alternate histologies were not lysed, including lung cancer, squamous cell cancer, as well as the natural/lymphocyte-activated killer cell-sensitive hematopoietic cell lines T2, C1R, or Daudi. The cell line K562 was only poorly lysed when compared with colorectal cancer targets. Target cell reactivity mediated by Vdelta1+ T cells was partially blocked with Abs directed against the TCR, the beta2 or beta7 integrin chains, or fibronectin receptor. Marker analysis using flow cytometry revealed that all three gammadelta T cell lines exhibit a similar phenotype. Analysis of the gammadelta TCR junctional suggested exclusive usage of the Vdelta1/Ddelta3/Jdelta1 TCR segments with extensive (< or = 29 bp) N/P region diversity. T cell recognition of target cells did not appear to be a major histocompatibility complex restricted or to be correlated with target cell expression of heat-shock proteins. Based on the ability of some epithelial tumors, including colorectal, pancreatic, and renal cell cancers to effectively cold target inhibit the lysis of colorectal cancer cell lines by these Vdelta1+ T cell lines, we suggest that intestinal Vdelta1+ T cell lines, we suggest that intestinal Vdelta1+ T cells are capable of recognizing cell surface Ag(s) shared by tumors of epithelial origin.
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| 744. |
- Malhi, Yadvinder, et al.
(författare)
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The variation of productivity and its allocation along a tropical elevation gradient : A whole carbon budget perspective
- 2017
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 214:3, s. 1019-1032
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Why do forest productivity and biomass decline with elevation? To address this question, research to date generally has focused on correlative approaches describing changes in woody growth and biomass with elevation. We present a novel, mechanistic approach to this question by quantifying the autotrophic carbon budget in 16 forest plots along a 3300 m elevation transect in Peru. Low growth rates at high elevations appear primarily driven by low gross primary productivity (GPP), with little shift in either carbon use efficiency (CUE) or allocation of net primary productivity (NPP) between wood, fine roots and canopy. The lack of trend in CUE implies that the proportion of photosynthate allocated to autotrophic respiration is not sensitive to temperature. Rather than a gradual linear decline in productivity, there is some limited but nonconclusive evidence of a sharp transition in NPP between submontane and montane forests, which may be caused by cloud immersion effects within the cloud forest zone. Leaf-level photosynthetic parameters do not decline with elevation, implying that nutrient limitation does not restrict photosynthesis at high elevations. Our data demonstrate the potential of whole carbon budget perspectives to provide a deeper understanding of controls on ecosystem functioning and carbon cycling.
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| 745. |
- Maloney, Alan, et al.
(författare)
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An example of optimal phase II design for exposure response modelling
- 2010
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 37:5, s. 475-491
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents an example of how optimal design methodology was used to help design a phase II clinical study. The planned analysis would relate the clinical endpoint to exposure (measured via the area under the curve (AUC)), rather than dose. Optimal design methodology was used to compare a number of candidate phase II designs, and an algorithm for finding optimal designs was employed. The sigmoidal E-max with baseline (E-0) model was used to relate the clinical endpoint to individual subject AUCs, and the primary metrics were D optimality and the standard error (SE) of the AUC required to yield a clinically relevant change in the clinical endpoint. The performance of the candidate designs were compared across four different 'true' exposure response relationships (determined from the analysis of an earlier proof of concept (PoC) study). The results suggested the total sample size should be increased from the planned 540 individuals, and that the optimal design with 700 individuals would be equivalent to 812 individuals with the reference design (a 16% gain). The performance with this design was considered acceptable, although all designs performed poorly if the true exposure response relationship was very flat. This work allowed a prospective assessment of the likely performance and precision from the exposure response modelling prior to the start of the phase II study, and hence allowed the design to be revised to ensure the subsequent analysis would be of most value.
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| 746. |
- Manconi, Andrea, et al.
(författare)
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The effects of flank collapses on volcano plumbing systems
- 2009
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Ingår i: Geology. - 0091-7613 .- 1943-2682. ; 37:12, s. 1099-1102
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Tidskriftsartikel (refereegranskat)abstract
- The growth of large volcanoes is commonly interrupted by episodes of flank collapse that may be accompanied by catastrophic debris avalanches, explosive eruptions, and tsunamis. El Hierro, the youngest island of the Canary Archipelago, has been repeatedly affected by such mass-wasting events in the last 1 Ma. Our field observations and petrological data suggest that the largest and most recent of these flank collapses—the El Golfo landslide—likely influenced the magma plumbing system of the island, leading to the eruption of higher proportions of denser and less evolved magmas. The results of our numerical simulations indicate that the El Golfo landslide generated pressure changes exceeding 1 MPa down to upper-mantle depths, with local amplification in the surroundings and within the modeled magma plumbing system. Stress perturbations of that order might drastically alter feeding system processes, such as degassing, transport, differentiation, and mixing of magma batches.
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| 747. |
- Mansoor, Rashid, et al.
(författare)
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Haematological consequences of acute uncomplicated falciparum malaria : a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data
- 2022
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPlasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.MethodsIndividual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall >= 25% at day 3 and day 7.ResultsA total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to >= 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39-3.05], p < 0.001).ConclusionsIn patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
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| 748. |
- Marchetto, Aldo, et al.
(författare)
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Good Agreement Between Modeled and Measured Sulfur and Nitrogen Deposition in Europe, in Spite of Marked Differences in Some Sites
- 2021
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Ingår i: Frontiers in Environmental Science. - : Frontiers Media SA. - 2296-665X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric nitrogen and sulfur deposition is an important effect of atmospheric pollution and may affect forest ecosystems positively, for example enhancing tree growth, or negatively, for example causing acidification, eutrophication, cation depletion in soil or nutritional imbalances in trees. To assess and design measures to reduce the negative impacts of deposition, a good estimate of the deposition amount is needed, either by direct measurement or by modeling. In order to evaluate the precision of both approaches and to identify possible improvements, we compared the deposition estimates obtained using an Eulerian model with the measurements performed by two large independent networks covering most of Europe. The results are in good agreement (bias <25%) for sulfate and nitrate open field deposition, while larger differences are more evident for ammonium deposition, likely due to the greater influence of local ammonia sources. Modeled sulfur total deposition compares well with throughfall deposition measured in forest plots, while the estimate of nitrogen deposition is affected by the tree canopy. The geographical distribution of pollutant deposition and of outlier sites where model and measurements show larger differences are discussed.
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| 749. |
- Massat, Isabelle, et al.
(författare)
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Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders
- 2002
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Ingår i: American Journal of Medical Genetics. - : Wiley. - 0148-7299 .- 1096-8628. ; 114:2, s. 177-85
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Tidskriftsartikel (refereegranskat)abstract
- Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.
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| 750. |
- Matsuura, M., et al.
(författare)
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A STUBBORNLY LARGE MASS OF COLD DUST IN THE EJECTA OF SUPERNOVA 1987A
- 2015
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 800:1
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Tidskriftsartikel (refereegranskat)abstract
- We present new Herschel photometric and spectroscopic observations of Supernova 1987A, carried out in 2012. Our dedicated photometric measurements provide new 70 mu m data and improved imaging quality at 100 and 160 mu m compared to previous observations in 2010. Our Herschel spectra show only weak CO line emission, and provide an upper limit for the 63 mu m [O-I] line flux, eliminating the possibility that line contaminations distort the previously estimated dustmass. The far-infrared spectral energy distribution (SED) is well fitted by thermal emission from cold dust. The newly measured 70 mu m flux constrains the dust temperature, limiting it to nearly a single temperature. The far-infrared emission can be fitted by 0.5 +/- 0.1M(circle dot) of amorphous carbon, about a factor of two larger than the current nucleosynthetic mass prediction for carbon. The observation of SiO molecules at early and late phases suggests that silicates may also have formed and we could fit the SED with a combination of 0.3M(circle dot) of amorphous carbon and 0.5M(circle dot) of silicates, totalling 0.8M(circle dot) of dust. Our analysis thus supports the presence of a large dust reservoir in the ejecta of SN 1987A. The inferred dust mass suggests that supernovae can be an important source of dust in the interstellar medium, from local to high-redshift galaxies.
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