Two Birds with One Stone: Dual p110δ and p110γ Inhibition

In this issue of Chemistry & Biology, Winkler and colleagues describe the discovery and preclinical development of IPI-145, a new inhibitor of the phosphoinositide 3-kinase (PI3K) isoforms p110δ and p110γ that have entered clinical trials

PI3Kδ promotes CD4(+) T-cell interactions with antigen-presenting cells by increasing LFA-1 binding to ICAM-1.

Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kδ attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kδ increases LFA-1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kδ-deficient mice

Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy

The PI3K pathway is hyperactivated in most cancers, yet the capacity of PI3K inhibitors to induce tumor cell death is limited. The efficacy of PI3K inhibition can also derive from interference with the cancer cells’ ability to respond to stromal signals, as illustrated by the approved PI3Kδ inhibitor Idelalisib in B-cell malignancies. Inhibition of the leukocyte-enriched PI3Kδ or PI3Kγ may unleash more potent anti-tumor T-cell responses, by inhibiting regulatory T-cells and immune-suppressive myeloid cells. Moreover, tumor angiogenesis may be targeted by PI3K inhibitors to enhance cancer therapy. Future work should therefore focus on the effects of PI3K inhibitors on the stroma, in addition to their direct effects on tumors. SIGNIFICANCE: The PI3K pathway extends beyond the direct regulation of cancer cell proliferation and survival. In B-cell malignancies, targeting PI3K purges the tumor cells from their protective microenvironment. Moreover, we propose that PI3K isoform-selective inhibitors may be exploited in the context of cancer immunotherapy and by targeting angiogenesis to improve drug and immune cell deliver

The effects of soil organic matter on leaching of hexavalent chromium from concrete waste: Batch and column experiments

Concrete is one of the most common building materials in the world and in accordance with the world’s shift to a circular economy, there is a need of an increase in concrete reuse and recycling. One of the environmental concerns linked to concrete recycling is the leaching and spread of hexavalent chromium (Cr(VI)). In the present study the Cr(VI) leaching from crushed concrete waste and the effects of soil organic matter (SOM) on chromium (Cr) speciation has been investigated in realistic reuse scenarios by the means of batch shale tests and layered column tests. The effects of concrete properties (pH, grain size and age) on Cr(VI) leaching was also studied. Cr leaching from concrete alone is mainly in the form of Cr(VI), with the pH of the leachate being >10. The smaller the grainsize of the concrete, the higher the Cr(VI) concentration is in the leachate. There was no correlation between the age of the concrete and concrete leaching. When exposed to SOM the Total-Cr concentration in the leachate was reduced. The reduction increased with higher TOC level, with a 99% reduction at very high TOC (25%). The results indicate that Cr(VI) leaching from recycled concrete waste can be mitigated by exposing it to SOM in the desired recycling scenario.publishedVersio

Use of numerical modelling when designing a full-scale field test of landfill top covers

Landfill closures typically include cover systems with a low-permeable barrier to limit the flow of water to and from the waste to minimize contamination of the surrounding environment. Commonly the lowpermeable barrier in the top cover consists of compacted clays and/or geomembranes. An ongoing fullscale pilot test in southern Norway examines the performance of landfill low-permeable barriers, sometimes called sealing layers, constructed of two different recycled clayey soils compared to a traditionally used dry crust clay. Four test cells have been constructed with a top cover consisting of a coarse protection layer overlying a sealing layer. A lysimeter lies at the base to collect and measure the water which percolates through the entire top cover. By modelling the seepage through a simplification of the pilot test top cover, this paper investigates how 2D numerical hydrogeological modelling may be used to inform the design and/or construction of top cover pilot tests in temperate climates. It assesses the effect of sealing layer inclination, thickness and saturated hydraulic conductivity, as well as how detailed, as-built cross-section models compare to simple column models. Saturated hydraulic conductivity was found to be the most important feature when varied within a realistic range. Further, it asserts that 2D modelling may provide an efficient way to assess the consequences of deviations from designed geometry. Simple column models were found to be as suitable for this as more detailed crosssection models.Use of numerical modelling when designing a full-scale field test of landfill top coverspublishedVersio

Flere lesere – mindre opplag : en analyse av opplagsfallet i norske dagsaviser 2002-2010

Masteroppgave i næringslivsjournalistikk (MBA) – Høgskolen i Bodø, 201