Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs

A Survey of Motivations for 9/11, Hurricane Katrina and General Lapsed Donors in Northern Vermont

Introduction: Despite rising demand, blood donation has remained stagnant in recent years, except for donation spikes that occurred in periods after major national crises such as the September 11th attacks in 2001 and Hurricane Katrina in August 2005. During times between such events, the majority of blood donations are due to repeat donors. The remainder of the blood supply is supplemented by one time or infrequent donors who have since stopped giving blood, i.e. lapsed donors. A third group of donors, designated disaster donors has been identified. These are individuals who donated blood due to these disasters but who have since stopped giving blood. A vast body of information exists on the motivating factors that bring people to donate and the barriers that prevent them from coming back. For the purposes of this study, three groups of lapsed blood donors were identified. A survey was conducted to investigate the perception these donors have of the current blood supply, motivating factors for their past donations, and their opinions on potential ways to bring them back as consistent repeat donors.https://scholarworks.uvm.edu/comphp_gallery/1000/thumbnail.jp

Digital database of nose models for nasal prosthesis design generated with 3D morphable face model approach

Designing nasal prostheses can be challenging due to the unpaired nature of the facial feature which precludes the use of mirroring techniques. It can be particularly difficult to accurately replace the missing tissue when preoperative information about the previous anatomy is unavailable or inadequate. In such situations, a database of nose models could act as a helpful starting point for the computer-aided design of a nasal prosthesis. Various digital nose model libraries are described in the literature based upon the facial scans of volunteers or anatomic casts. However, these libraries do not appear to be readily accessible to researchers or clinicians. Therefore, an open-access digital database of nose models has been generated based upon a 3D Morphable Face Model approach. This database comprises a manageable number of 44 simple, well-behaved nose meshes with standardized alignment that are ideal for computer-aided design

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma

Background Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy. Methods Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic “hits” were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM. Results We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model. Conclusions Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers

Assessing the perceived impact of post Minamata amalgam phase down on oral health inequalities: a mixed-methods investigation

Background: Data from countries that have implemented a complete phase out of dental amalgam following the Minamata agreement suggest increased costs and time related to the placement of alternatives with consumers absorbing the additional costs. This aim of this study was to investigate the impact of a complete phase out of dental amalgam on oral health inequalities in particular for countries dependent on state run oral health services. Methods: A mixed methods component design quantitative and qualitative study in the United Kingdom. The quantitative study involved acquisition and analysis of datasets from NHS Scotland to compare trends in placement of dental amalgam and a survey of GDPs in Yorkshire, UK. The qualitative study involved analysis of the free text of the survey and a supplementary secondary analysis of semi-structured interviews and focus groups with GDPs (private and NHS), dental school teaching leads and NHS dental commissioners to understand the impact of amalgam phase down on oral health inequalities. Results: Time-trends for amalgam placement showed that there was a significant (p < 0.05) reduction in amalgam use compared with composites and glass ionomers. However dental amalgam still represented a large proportion (42%) of the restorations (circa 1.8 million) placed in the 2016–2017 financial year. Survey respondents suggest that direct impacts of a phase down were related to increased costs and time to place alternative restorations and reduced quality of care. This in turn would lead to increased tooth extractions, reduced access to care and privatisation of dental services with the greatest impact on deprived populations. Conclusion: Amalgam is still a widely placed material in state run oral health services. The complete phase down of dental amalgam poses a threat to such services and threatens to widen oral health inequalities. Our data suggest that a complete phase out is not currently feasible unless appropriate measures are in place to ensure cheaper, long-lasting and easy to use alternatives are available and can be readily adopted by primary care oral health providers

An integrated online radioassay data storage and analytics tool for nEXO

Large-scale low-background detectors are increasingly used in rare-event searches as experimental collaborations push for enhanced sensitivity. However, building such detectors, in practice, creates an abundance of radioassay data especially during the conceptual phase of an experiment when hundreds of materials are screened for radiopurity. A tool is needed to manage and make use of the radioassay screening data to quantitatively assess detector design options. We have developed a Materials Database Application for the nEXO experiment to serve this purpose. This paper describes this database, explains how it functions, and discusses how it streamlines the design of the experiment

Performance of novel VUV-sensitive Silicon Photo-Multipliers for nEXO

Liquid xenon time projection chambers are promising detectors to search for neutrinoless double beta decay (0$\nu \beta \beta$), due to their response uniformity, monolithic sensitive volume, scalability to large target masses, and suitability for extremely low background operations. The nEXO collaboration has designed a tonne-scale time projection chamber that aims to search for 0$\nu \beta \beta$ of \ce{^{136}Xe} with projected half-life sensitivity of $1.35\times 10^{28}$~yr. To reach this sensitivity, the design goal for nEXO is $\leq$1\% energy resolution at the decay $Q$-value ($2458.07\pm 0.31$~keV). Reaching this resolution requires the efficient collection of both the ionization and scintillation produced in the detector. The nEXO design employs Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm scintillation light of liquid xenon. This paper reports on the characterization of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3 SiPMs specifically designed for nEXO, as well as new measurements on new test samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters (MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct crosstalk, correlated avalanches and photon detection efficiency were measured as a function of the applied over voltage and wavelength at liquid xenon temperature (163~K). The results from this study are used to provide updated estimates of the achievable energy resolution at the decay $Q$-value for the nEXO design