Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our ...current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.
Canadian Clinical Practice Guidelines for Rosacea Asai, Yuka; Tan, Jerry; Baibergenova, Akerke ...
Journal of Cutaneous Medicine and Surgery,
09/2016, Letnik:
20, Številka:
5
Book Review, Journal Article
Recenzirano
Rosacea is a chronic facial inflammatory dermatosis characterized by background facial erythema and flushing and may be accompanied by inflammatory papules and pustules, cutaneous fibrosis and ...hyperplasia known as phyma, and ocular involvement. These features can have adverse impact on quality of life, and ocular involvement can lead to visual dysfunction. The past decade has witnessed increased research into pathogenic pathways involved in rosacea and the introduction of novel treatment innovations. The objective of these guidelines is to offer evidence-based recommendations to assist Canadian health care providers in the diagnosis and management of rosacea. These guidelines were developed by an expert panel of Canadian dermatologists taking into consideration the balance of desirable and undesirable outcomes, the quality of supporting evidence, the values and preferences of patients, and the costs of treatment. The 2015 Cochrane review “Interventions in Rosacea” was used as a source of clinical trial evidence on which to base the recommendations.
Recognition of bacterial LPS by macrophages plays a critical role in host defense against infection by Gram-negative bacteria. However, when not tightly regulated, the macrophage's response to LPS ...can induce severe disease and septic shock. Although LPS triggers the activation of multiple signaling pathways in macrophages, it was unclear whether these include activation of the p21Ras GTPases. We report that p21Ras is rapidly and transiently activated in murine primary macrophages stimulated with an ultra-pure preparation of LPS or with synthetic lipid A. The molecular basis of this activation was investigated using a pharmacological approach. LPS-induced activation of p21Ras was inhibited in the presence of PP2, LY294002, or wortmannin, suggesting that it depends on the activity of one or more members of the Src kinase family and the subsequent activation of PI3K. In that pharmacological inhibitors of PI3K inhibited LPS-induced activation of p21Ras, but not activation of ERK, we concluded that LPS-induced activation of ERK occurs through a pathway that is not dependent on the activation of p21Ras.
Understanding the stress state and microstructural features at a growing crack-tip is critical to understanding the failure mechanisms of engineering structures. To investigate the strain and ...dislocation evolution at a crack-tip, electron backscatter diffraction and geometrically necessary dislocation analysis were performed on fully annealed zirconium foils at room temperature. Different levels of macroscopic plastic strain were applied: 0.0%, 0.22%, 0.84%, 1.2%. Based on their different Burgers vectors and line vectors, prismatic , basal , screw , screw <c+a> and pyramidal <c+a> geometrically necessary dislocation densities were estimated during crack blunting and subsequent propagation. Most of the plastic deformation was accommodated by screw and pyramidal <c+a> dislocations. Screw dislocations were found to be dominant over the <c+a> as might be expected. Instead of twinning, pyramidal slip accommodated the strain along the c-axis caused by contraction at the crack-tip. Dislocation densities at the crack-tip were plotted according to the angle relative to the applied tension direction and the distance from the tip, and were compared with plastic strains simulated from a 3D static finite element model. Crack-tip singularity was observed and total geometrically necessary dislocation densities were in qualitatively good agreement with the equivalent plastic strain distribution predicted by the finite element method (FEM).
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The activation of a phase transformation during plastic deformation of the zirconium alloy, Excel (Zr-3.5Sn-0.8Mo-0.8Nb), has been investigated using a combination of in situ neutron diffraction and ...electron microscopy. The effect of temperature and tension/compression asymmetry on the activation of the phase transformation is identified. While the phase transformation is readily activated in tension at room temperature and 100 °C, a significant drop in the transformation rate was observed at 200 °C. This temperature dependence appears to be independent of loading direction relative to material texture and depends on the specific crystallography and thermodynamics of the β→α transformation in zirconium. Loading in compression did not result in the activation of the phase transformation.
In this paper, 40 MeV Zr ion irradiation of Zr-2.5Nb pressure tube alloy was carried out, delivering a damage layer 6.5 μm deep. Uniaxial micropillar compression experiments along the tube axial (AD) ...and transverse directions (TD) were conducted. Irradiation was found to alter the deformation mechanisms and to increase the yield strength more in the AD oriented pillars than TD pillars for irradiation up to 0.6 dpa. This anisotropy in response is discussed in terms of the limitations of the micropillar compression method and the different deformation mechanisms which are activated in each orientation. The anisotropic hardening effect of -type dislocation loops on prismatic , basal , and pyramidal <c+a> slip systems is also discussed. The micropillar compression results were also compared with nanoindentation results conducted on the same material.
We present a laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) method for trace-element analysis of uranium ore concentrates (UOCs). The method was used to characterize a select ...number of UOC samples representing 20 different producers from 8 distinct geographic locations. These results were then used to assess the origin of the samples using a machine-learning algorithm. The LA-ICP-MS characterization performed equally well as that obtained by the conventional aqueous method, suggesting that this rapid, low waste technique is suitable for National Nuclear Forensic Library applications.
The determination of inorganic anions in uranium ore concentrates (UOCs) is useful to nuclear forensics for establishing the provenance of sample materials. In this collaborative study, quantitation ...of inorganic anions was carried out on three UOC reference materials from the National Research Council Canada: UCLO-1 (
https://doi.org/10.4224/crm.2020.uclo-1
), UCHI-1 (
https://doi.org/10.4224/crm.2020.uchi-1
), and UPER-1 (
https://doi.org/10.4224/crm.2020.uper-1
). The analytes were extracted into water and characterized by ion chromatography with combined standard uncertainties (
u
c
) between 1.6 and 11%. The highest contributor to
u
c
was homogeneity. Sulfate was the most abundant anion (2000–12,000 mg/kg SO
4
2−
). Other anions were in the 15–500 mg/kg range.
Rheumatoid arthritis (RA) is characterised by painful, stiff and swollen joints. RA features sporadic 'flares' or inflammatory episodes-mostly occurring outside clinics-where symptoms worsen and ...plasma C-reactive protein (CRP) becomes elevated. Poor control of inflammation results in higher rates of irreversible joint damage, increased disability, and poorer quality of life. Flares need to be accurately identified and managed. A method comparison study was designed to assess agreement between CRP values obtained by dried blood spot (DBS) versus conventional venepuncture sampling. The ability of a weekly DBS sampling and CRP test regime to detect flare outside the clinic was also assessed. Matched venepuncture and finger lancet DBS samples were collected from n = 100 RA patients with active disease at baseline and 6 weeks (NCT02809547). A subset of n = 30 RA patients submitted weekly DBS samples over the study period. Patient demographics, including self-reported flares were recorded. DBS sample CRP measurements were made by enzyme-linked immunosorbent assay, and venepuncture samples by a reference immunoturbometric assay. Data was compared between sample types by Bland-Altman and weighted Deming regression analyses. Flare detection sensitivity and specificity were compared between 'minimal' baseline and 6 week sample CRP data and the 'continuous' weekly CRP data. Baseline DBS ELISA assay CRP measures yielded a mean positive bias of 2.693 ± 8.640 (95% limits of agreement - 14.24 to 19.63%), when compared to reference assay data. Deming regression revealed good agreement between the DBS ELISA method and reference assay data, with baseline data slope of 0.978 and intercept -0.153. The specificity of 'continuous' area under the curve (AUC) CRP data (72.7%) to identify flares, was greater than 'minimal' AUC CRP data (54.5%). This study indicates reasonable agreement between DBS and the reference method, especially at low to mid-range CRP values. Importantly, longitudinal CRP measurement in RA patients helps to clearly identify flare and thus could assist in remote monitoring strategies and may facilitate timely therapeutic intervention.Trial registration: The Remote Arthritis Disease Activity MonitoR (RADAR) study was registered on 22/06/2016 at ClinicalTrials.gov Identifier: NCT02809547. https://clinicaltrials.gov/ct2/show/NCT02809547 .
The highly conserved Notch gene is activated by mutation in more than half of human T cell acute lymphoblastic leukemia (T-ALL) cases. The Notch protein is a transmembrane receptor which, upon ...binding of its ligand, is cleaved in a series of proteolytic steps releasing the intracellular portion (ICN) to translocate to the nucleus where it acts as a transcriptional activator for target genes such as HES1, Deltex, preTalpha, and c-Myc. To better understand the mechanism by which Notch causes leukemogenesis, microarray gene expression profiling experiments where conducted on five human Notch signaling-dependent T-ALL cell lines which where either mock-treated or treated with a gamma-secretase inhibitor (GSI) to prevent the release of Notch from the membrane. The Polycomb Group gene PCGF5 was identified as one of the genes most strongly downregulated upon Notch inhibition. This regulation was subsequently confirmed by quantitative RT-PCR in both human and mouse leukemia cell lines. Our interest in this gene was encouraged by its homology to the well-known oncogene Bmi-1, which acts to modify chromatin and silence expression of several genes including the cyclin-dependent kinase inhibitors p16 and p19ARF within the CDKN2a locus. Interestingly, we found that inhibition of Notch signaling by GSI treatment in both human and mouse leukemia cells resulted in an increase of both p16 and p19ARF at the mRNA and protein levels. This suggested that Notch may be responsible for maintaining expression of a transcriptional repressor that suppresses p16 and p19ARF. We hypothesize that PCGF5 may be acting in a manner analogous to Bmi-1 in this cellular context and thus mediating p16/p19ARF repression. Studies to test this hypothesis are currently in progress.
To further investigate the role of PCGF5 in hematopoiesis, mouse bone marrow progenitors were transduced with retrovirus to express PCGF5 constitutively and transplanted into lethally irradiated recipients. Our results show long term reconstitution by PCGF5-expressing cells with as yet no evidence of PCGF5-induced hematopoeitic malignancy in a small cohort up to 6 months post-transplant. However, we did observe cells expressing high levels of PCGF5 to be skewed toward myeloid lineages, while mid-level expressing cells develop efficiently into lymphocytes. We detected no defects in B cell maturation; however, PCGF5-expressing T cell numbers were significantly lower than controls in the peripheral blood and spleen of recipient animals. Consistent with this observation, fetal thymic organ culture of PCGF5-transduced fetal liver hematopoietic progenitors showed accumulation in the early double negative thymocyte stages. Additionally, we found PCGF5-expressing B and T lymphocytes to be larger than control cells, and preliminary data suggests these cells may be arrested in G2/M phase of the cell cycle. Biochemical studies are also in progress to assess participation of PCGF5 in the Polycomb Repressive Complex PRC-1 and its effect on chromatin structure. In sum, these preliminary data suggest enforced PCGF5 expression, though not oncogenic, alters normal lymphoid/myeloid fate selection by hematopoietic progenitors and may affect lymphoid cell size by altering cell cycle progression.
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