Genetic and phenotypic attributes of splenic marginal zone lymphoma

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments

Aquaporins: important but elusive drug targets.

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators

A comparison of small strain stiffness in till as measured by seismic refraction and barometric loading response

Soil stiffness can vary over several orders of magnitude depending on the actual range of strain imposed by testing, or as a result of operational strains in geotechnical structures. Soil stiffness changes rapidly with strain level at low strain levels (0.01–0.1%) and the variation with strain is not linear. Characterization of the in situ small strain stiffness of stiff soils is important in geotechnical design; however, analyses of the mechanical behaviour of these soils is confounded by stiffness values that vary with strain level. Stiff till cuttings are susceptible to progressive failure as a result of strain softening. As a consequence, the evolution of stiffness during progressive failure is both a key parameter in characterizing pre-failure slope deformations and a key diagnostic of softening. Changes in strength (due to softening) should be reflected in commensurate temporal and spatial changes in stiffness; consequently, real-time, in situ measurements of stiffness would better define the progression of softening. Seismic surveys, which create small compression and shear strains, have been used to estimate in situ small strain elastic moduli. These spatially extensive measurements can be correlated to temporal variations in stiffness from the monitoring of barometric loading efficiency. In this latter method, the pore pressure response of a grouted (sealed) piezometer to barometric pressure fluctuations is used to measure the compressibility (stiffness) of the formation. This article summarizes the results of field trials within a cutting in stiff till in Northern Ireland in which these two techniques were used to characterize small strain stiffness.Department of Infrastructure NIConstruction Service DFPNINorthern Ireland RailwaysUniversity of SaskatchewanEngineering and Physical Sciences Research Counci

Do neurosurgeons follow the guidelines? A world-based survey on severe traumatic brain injury

BACKGROUND Traumatic brain injury (TBI) is going to be the third-leading cause of death worldwide, according to the WHO. Two European surveys suggested that adherence to brain trauma guidelines is poor. No study has compared compliance between low- (LMICs) and high-income (UHICs) countries. Hence, this study aimed to investigate differences in the management of severe TBI patients, comparing low- and high-income, and adherence to the BTF guidelines. METHODS A web-based survey was spread through the Global Neuro Foundation, different neurosurgical societies, and social media. RESULTS A total of 803 neurosurgeons participated: 70.4 from UHICs and 29.6% from LMICs. Hypertonic was administered as an early measure by the 73% and 65% of the responders in LMICs and UHICs, respectively (P=0.016). An invasive intracranial pressure monitoring was recommended by the 66% and 58% of the neurosurgeons in LMICs and UHICs, respectively (P<0.001). Antiseizure drugs (P<0.001) were given most frequently in LMICs as, against recommendations, steroids (87% vs. 61% and 86% vs. 81%, respectively). In the LMICs both the evacuation of the contusion and decompressive craniectomy were performed earlier than in UHICs (30% vs. 17% with P<0.001 and 44% vs. 28% with P=0.006, respectively). In the LMICs, the head CT control was performed mostly between 12 and 24 hours from the first imaging (38% vs. 23%, P<0.001). CONCLUSIONS The current Guidelines on TBI do not always fit to both the resources and circumstances in different countries. Future research and clinical practice guidelines should reflect the greater relevance of TBI in low resource settings

Contribution of Seismic Methods to Hydrogeophysics

International audienceThe characterisation and monitoring of aquifer systems mainly rely on piezometric and log data. Delineating spatial variations of lithology between piezometers is a delicate task, which inevitably generates errors possibly propagating into hydrogeological models. Seismic methods have been proposed to: (i) improve the low spatial resolution of borehole data, (ii) provide a characterisation of the subsurface geometry, and (iii) estimate the physical parameters of the medium influenced by the presence of water and the associated flow and transport processes. The joint study of pressure (P-) and shear (S-) wave seismic velocities (VP and VS, respectively), whose evolution is strongly decoupled in the presence of fluid, has been proposed through the estimation of the VP/VS ratio and Poisson's ratio. A specific methodology has been developed for the combined exploitation of P- and surface waves present on single seismic records. The use of this methodology in several geological and hydrogeological contexts allowed for estimating VP/VS ratio lateral and temporal variations in good agreement with a priori geological information and existing geophysical and piezometric data. Laser-based ultrasonic techniques were also proposed to put these processing techniques in practice on perfectly controlled physical models and study elastic wave propagation in partially saturated porous media

XPO1 mutations identify early-stage CLL characterized by shorter time to first treatment and enhanced BCR signalling

Here we evaluated the epigenomic and transcriptomic profile of XPO1 mutant chronic lymphocytic leukaemia (CLL) and their clinical phenotype. By ATAC-seq, chromatin regions that were more accessible in XPO1 mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B-cell receptor (BCR), including NF-κB signalling, p38-JNK and RAS-RAF-MEK-ERK. XPO1 mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, MIR155HG, the host gene of miR-155, and MYB, the transcription factor that positively regulates MIR155HG, were upregulated by RNA-seq and their promoters were more accessible by ATAC-seq. To evaluate the clinical impact of XPO1 mutations, we investigated a total of 957 early-stage CLL subdivided into 3 independent cohorts (N = 276, N = 286 and N = 395). Next-generation sequencing analysis identified XPO1 mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, XPO1 mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early-stage prognostic models. These data suggest that XPO1 mutations, conceivably through increased miR-155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early-stage CLL.ISSN:0007-1048ISSN:1365-214