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T cells bearing chimeric antigen receptors (CARs) are broadly categorised into first- and second-generation receptors. Second-generation CARs contain a co-stimulatory signalling molecule and have been shown to secrete IL-2, undergo greater proliferation and to have enhanced persistence in vivo . However, we have shown that T cells bearing a first-generation CAR containing a CD19-targeting scFv (single-chain variable fragment) and the CD3ζ-signalling domain are able to produce IL-2 upon co-culture with CD19 + B-cell lymphomas independent of CD28 activity. Here, we report that signalling through endogenous CD2 following ligation with its ligands, CD48 in mouse and CD58 in humans, drives IL-2 production by first-generation CD19-specific CAR. Moreover, the high levels of IL-2 produced by human T cells engrafted with a second-generation CD28-containing CAR during target-cell recognition are dependent to a degree upon CD2 receptor activity. These observations highlight the fact that the functional activity induced by T-cell-expressed CARs is dependent upon endogenous ‘natural’ receptor interactions. A deeper understanding of the role of these activities will serve to further refine the design of future CARs to either exploit or avoid these interactions.

We present a system for cancer targeting based on single–chain Fv (scFv) antibodies selected from combinatorial libraries, produced in bacteria and purified by using an engineered tag. Combinatorial libraries of scFv genes contain great diversity, and scFv antibodies with characteristics optimized for a particular task can be selected from them using filamentous bacteriophage. We illustrate the benefits of this system by imaging patients with carcinoembryonic antigen (CEA)–producing cancers using an iodine–123 labeled scFv anti–CEA selected for high affinity. All known tumor deposits were located, and advantages over current imaging technology are illustrated. ScFvs are produced in a cloned form and can be readily engineered to have localizing and therapeutic functions that will be applicable in cancer and other diseases.

Insertion of antibody genes into filamentous bacteriophage makes it possible to generate and screen libraries of 107 or more antibodies. Each phage expresses an antibody on its surface and contains the corresponding antibody gene. Genes that encode antibodies with desired characteristics are readily selected and their antibodies expressed as soluble proteins in Escherichia coli. We used this system to produce an antibody to carcinoembryonic antigen with higher affinity and better tumour specificity than antibodies currently in use.

Background A relationship between smoking and interpersonal influences has been well established within the literature. There have been cultural shifts in denormalisation and a reduction in tobacco smoking in many countries. Hence there is a need to understand social influences on adolescents’ smoking across smoking normalisation contexts. Methods The search was conducted in July 2019 and updated in March 2022 within 11 databases and secondary sources. Search terms included schools, adolescents, smoking, peers, social norms and qualitative research. Screening was conducted by two researchers independently and in duplicate. Study quality was assessed using the eight-item Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-centre) tool for the appraisal of qualitative studies. Results were synthesised using a meta-narrative lens for meta-ethnography and compared across smoking normalisation contexts. Results Forty one studies were included and five themes were developed, mapping onto the socio ecological model. The social processes by which adolescents take up smoking differed according to a mixture of school type, peer group structure and the smoking culture within the school, as well as the wider cultural context. Data available from smoking denormalised contexts, described changes in social interactions around smoking to cope with its stigmatisation. This was manifested through i) direct peer influence, whereby subtle techniques were employed, ii) group belonging whereby smoking was less likely to be seen as a key determinant of group membership and smoking was less commonly reported to be used as a social tool, and iii) popularity and identity construction, whereby smoking was perceived more negatively in a denormalised context, compared with a normalised context. Conclusions This meta-ethnography is the first study to demonstrate, drawing on international data, that peer processes in adolescent smoking may undergo changes as smoking norms within society change. Future research should focus on understanding differences across socioeconomic contexts, to inform the adaptation of interventions.

This work presents data on a suite of diffuse pollutants, monitored in a stream draining an intensively managed grassland on a 30 min time step during a period of intense rainfall to better understand their sources and pathways. Nitrite (92 μg l⁻¹), particulate phosphorus (107 μg l⁻¹) and soluble phosphorus (74 μg l⁻¹) exceeded environmental limits during base flow. Concentrations of nitrate and nitrite were decreased during the storm event, whereas all other pollutants generally increased and exceeded environmental limits where specified, especially when associated with a small subsidiary hydrograph on the rising limb of the main hydrograph. Total pollutants loads, when using a 60 min sampling frequency, would have led to significant over and under-estimations depending on which 60 min sample set was used. In the worst case, loads of ammonium could have been under-estimated by 35% or over estimated by 25% with errors being associated with loads on the rising limb of the hydrograph and more specifically a small subsidiary hydrograph. This subsidiary hydrograph may have occurred as a result of runoff from the farm hard standings within the catchment. Incidental transfer of pollutants associate with this runoff have masked the overall grassland pollutant response. To better understand these different source areas and pollutant dynamics, there is a need for novel tracing techniques to elucidate their relative contribution and pathways.

The Electron, Proton, and Alpha Monitor (EPAM) is designed to make measurements of ions and electrons over a broad range of energy and intensity. Through five separate solid-state detector telescopes oriented so as to provide nearly full coverage of the unit-sphere, EPAM can uniquely distinguish ions (Ei50 keV) and electrons (Ee40 keV) providing the context for the measurements of the high sensitivity instruments on ACE. Using a ΔE×E telescope, the instrument can determine ion elemental abundances (E0.5 MeV nucl-1). The large angular coverage and high time resolution will serve to alert the other instruments on ACE of interesting anisotropic events. The experiment is controlled by a microprocessor-based data system, and the entire instrument has been reconfigured from the HI-SCALE instrument on the Ulysses spacecraft. Inflight calibration is achieved using a variety of radioactive sources mounted on the reclosable telescope covers. Besides the coarse (8 channel) ion and (4 channel) electron energy spectra, the instrument is also capable of providing energy spectra with 32 logarithmically spaced channels using a pulse-height-analyzer. The instrument, along with its mounting bracket and radiators weighs 11.8 kg and uses about 4.0 W of power. To demonstrate some of the capabilities of the instrument, some initial performance data are included from a solar energetic particle event in November 1997.[PUBLICATION ABSTRACT]

Using a survey of anisotropic electron events in the energy range of 40-300 keV observed by HI-SCALE on Ulysses, we have selected several time intervals during 1999 when Ulysses traveled from about 20° S at 5.2 AU (January 1999) to 42° S at 4.2 AU (January 2000). We compare these events with observations at 1 AU using the nearly identical instrument, EPAM on ACE. In order to study the solar origins of these electrons using the imaging Nançay Radioheliograph, we further restricted the list of events to those in which interplanetary magnetic field lines with origins on the visible solar disk, intersected Ulysses. We find that not all the anisotropic electron events are observed by both spacecraft and there exists a strong dependence on the spacecraft's magnetic connection back to the Sun. We have identified the solar origin for five electron events using radio observations, and correlate these with interplanetary type-III radio emissions using the WIND/WAVES experiment.[PUBLICATION ABSTRACT]

The heliosphere instrument for spectrum, composition, and anisotropy (HISCALE) recorded the fluxes of low-energy ions and electrons (>50 kiloelectron volts) when Ulysses crossed the southern solar polar region and revealed that the large-scale structure of the heliosphere to at least ∼-75° was significantly influenced by the near-equatorial heliospheric current sheet. Electrons in particular were accelerated by the current sheet-produced and poleward-propagating interplanetary reverse shock at helioradii far from the Ulysses location. At heliolatitudes higher than ∼-75° on the Ulysses ascent to the pole and ∼-50° on the descent, small, less regular enhancements of the lowest energy electron fluxes were measured whose relations to the current sheet were less clear. The anomalous component of low-energy (∼2 to 5 megaelectron volts per nucleon) oxygen flux at the highest heliolatitudes was found to be ∼10$^{-8}$ [per square centimeter per second per steradian (per kiloelectronvolt per nucleon)]; the anomalous Ne/O ratio was ∼0.25.

Charged particle instrumentation that will be flying on six spacecraft in the heliosphere between 1 and 90 AU during 2001-2004 will provide a global view of the interplanetary medium that has not heretofore been available. Comparative analyses of the data that will be obtained will provide new understanding of the global evolution of heliospheric features such as traveling shock waves, coronal mass ejections, solar activity-produced particle injections, and anomalous cosmic rays.