Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A * 02:01 restricted AFP 158−166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit. To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs by testing their potency toward AFP-expressing HCC cells and their specificity based upon reactivity to normal and transformed cells covering a wide variety of primary cell types and HLA serotypes. Furthermore, we assessed their cross-reactivity to potential protein candidates in the human genome by an extensive alanine scan (X-scan). We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with a protein candidate identified by X-scan. At present we have selected an AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.

Summary 1.The flower of Brassica napus L. appears to be typically zoophilous (suited to animal pollination) because of its visually attractive petals, robust stigma and nectaries. Pollination by wind is feasible, however, and its likely effectiveness is not immediately foreseeable because of the complexity of interactions between objects and windborne particles. 2. Computational fluid dynamics (CFD) and wind-tunnel experiments were used to investigate the aerodynamic interactions between the flower and a windborne suspension of its pollen. 3. The flower's petals handicapped wind pollination by reducing the target efficiency of the upwind-facing stigma. For downwind-facing flowers, pollen reception was negligible. 4. Several aspects of the plant's architecture (floral structure, pollen cohesiveness, inflorescence structure) are uncompromisingly zoophilous. Estimates of the amount of wind pollination suggest that it is unlikely to be important for the long-distance dispersal of B. napus genes such as those from genetically modified varieties. 5. This study illustrates how CFD may become a powerful tool in future analyses of wind pollination.

Upwind and central difference schemes for laminar and turbulent flows over a step in a two-dimensional channel are compared with each other and with experiment. Vorticity u and stream function (I are used as dependent variables and it is shown that an upwind difference method can give predictions which agree with experiment for high Reynolds number flows. The numerical implementation of the boundary conditions is found critically to determine the solutions obtained. Explicit prescription of $ and w at the inlet leads to incorrect values of the inlet velocity component perpendicular to the flow and a solution that does not agree with experiment. Experimental evidence is not available at low Reynolds numbers, but it is found that upwind differences give recirculation zones 8 per cent shorter and 8 per cent less intense than the more conventional conditionally stable central difference method.The distribution of the false diffusion effect in the upwind scheme is considered. and it is shown by use of a simple example that previous statements as to possible minimization of this effect are not generally true.The difficulty of determining the pressure distribution from the vorticity and stream function model is analysed and illustrated.Further, turbulent separated flows are seen to contain regions where two-dimensional time-dependent flow does not exist, and conventional theories do not give good results. + Now at Admiralty Marine Technology Establishment, Teddington, Middx., U.K.

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