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Buford, GA, United States

Pusch R.,Lund International | Kasbohm J.,University of Greifswald | Thao H.T.M.,Hanoi University of Science
Applied Clay Science | Year: 2010

A current semi-empirical model of conversion of smectite to illite implies that the process is associated with formation of quartz and chlorite and will not cause significant illitization in the hydrothermal period of a repository if the activation energy is of the commonly assumed magnitude and the temperature is lower than about 100 °C. The model is supported by several natural analogues and hydrothermal experiments in laboratories and field tests. In all the experiments, which were conducted under open chemical conditions, the confined clay was exposed to thermal gradients for at least 1 year. Most of the tests were small-scale and of "1D-type", one being performed with strong gamma radiation, and the others with different porewater compositions. One was a Mock-up experiment simulating the KBS-3V concept on 50% scale, and one a full-scale KBS-3V field experiment at 400 m depth in granitic rock. They all showed that while smectite remained the major clay mineral a number of processes changed the physical properties in bulk, the most important changes being reduction of the expandability and increase of the hydraulic conductivity of the hottest part of the buffer. The latter is concluded to have been caused by contraction of clay aggregates that became permanent by precipitation of silica and iron compounds, the cementing agents emanating from dissolved accessory minerals as well as from montmorillonite. Fe-rich montmorillonite underwent particularly important dissolution. © 2008.

Frendeus B.,Lund International
OncoImmunology | Year: 2013

Therapeutic antibodies may mediate antineoplastic effects by altering the biological functions of their target, by directly stimulating the demise of cancer cells or by activating antibody-dependent immune effector mechanisms. We have recently provided in vivo proof-of-concept for a "function-first" target and drug discovery platform in which antibodies against a multitude of tumor-associated antigens are screened for biological effects in a target-unbiased manner © 2013 Landes Bioscience.

Kallberg K.,Lund University | Becker K.,Lund International | Bulow L.,Lund University
Journal of Chromatography A | Year: 2011

Protein glycosylation has significant effects on the structure and function of proteins. The efficient separation and enrichment of glycoproteins from complex biological samples is one key aspect and represents a major bottleneck of glycoproteome research. In this paper, we have explored pH multimodal hydrophobic interaction chromatography to separate glycosylated from non-glycosylated forms of proteins. Three different proteins, ribonuclease, invertase and IgG, have been examined and different glycoforms have been identified. The media itself shows strong responsiveness to small variations in pH, which makes it possible to fine-tune the chromatographic conditions according to the properties of the protein isolated. Optimal glycoprotein separation has been obtained at pH 4. The pH responsive multimodal HIC medium in contrast to conventional HIC media is able to resolve contaminating DNA. © 2010 Elsevier B.V.

Vaughan A.T.,University of Southampton | Iriyama C.,University of Southampton | Iriyama C.,Nagoya University | Beers S.A.,University of Southampton | And 8 more authors.
Blood | Year: 2014

A major feature that distinguishes type I from type II anti-CD20 monoclonal antibodies (mAbs) and reduces their therapeutic efficacy is the tendency to internalize from the cell surface. We have shown previously that the extent of internalization correlates with the capacity of type I mAb to simultaneously engage both CD20 and the inhibitory Fcγ receptor, FcγRIIb, in a bipolar configuration. Here, we investigated whether mAbs directed at other B-cell surface receptors also engaged FcγRIIb and whether this interaction promoted internalization. Most mAbs engaged and activated FcγRIIb, with the strength of activation related to the level of mAb bound to the cell surface. However, engagement did not affect internalization of most mAb-ligated receptors, either in cell lines or primary chronic lymphocytic leukemia cells with the exception of CD19 and CD38. Furthermore, at high cell concentrations/density both cis and trans interactions between cell-surface bound mAb and FcγRIIb were evident, but trans interactions did not inhibit type I anti-CD20 mAb-mediated internalization. These data identify that FcγRIIb is engaged by many mAbs in both cis and trans configurations, triggering its activation, but that internalization via FcγRIIb occurs for only a select subset. These findings have implications when designing new antibody-based therapeutics. © 2014 by The American Society of Hematology.

Hussain K.,Antibody and Vaccine Group | Hargreaves C.E.,Antibody and Vaccine Group | Roghanian A.,Antibody and Vaccine Group | Oldham R.J.,Antibody and Vaccine Group | And 10 more authors.
Blood | Year: 2015

The anti-CD28 superagonist antibody TGN1412 caused life-threatening cytokine release syndrome (CRS) in healthy volunteers, which had not been predicted by preclinical testing. T cells in fresh peripheral blood mononuclear cells (PBMCs) do not respond to soluble TGN1412 but do respond following high-density (HD) preculture. We show for the first time that this response is dependent on crystallizable fragment gamma receptor IIb (FγRIIb) expression on monocytes. This was unexpected because, unlike B cells, circulating monocytes express little or no FγRIIb. However, FγRIIb expression is logarithmically increased onmonocytes during HD preculture, and this upregulation is necessary and sufficient to explain TGN1412 potency after HD preculture. B-cell FγRIIb expression is unchanged by HD preculture, but B cells can support TGN1412-mediated T-cell proliferation when added at a frequency higher than thatin PBMCs. Although low-density (LD) precultured PBMCs do not respond to TGN1412, T cells from LD preculture are fully responsive when cocultured with FγRIIb-expressing monocytes from HD preculture, which shows that they are fully able to respond to TGN1412-mediated activation. Our novel findings demonstrate that cross-linking by FγRIIb is critical for the superagonist activity of TGN1412 after HD preculture, and this may contribute to CRS in humans because of the close association of FγRIIb-bearing cells with T cells in lymphoid tissues. © 2015 by The American Society of Hematology.

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