TransUnion (United States)

Clinical islet transplantation has long been investigated as a potential cure for type 1 diabetes (T1D), yet standard intrahepatic delivery leaves islets prone to an instant blood-mediated inflammatory response. Herein, we investigated the design of microporous poly(D,l-lactide-co-glycolide) (PLG) scaffolds for extrahepatic islet transplantation in mouse and nonhuman primate (NHP) models. Acellular scaffolds elicited only a mild inflammatory response following implantation into the omentum. On scaffold islet transplantation had extensive insulin staining at 4 weeks yet modest insulin requirement reductions in diabetic NHP recipients. Scaffolds were sterilized by irradiation and exhibited fragility during seeding and implantation, motivating an increase in the manufacturing ratio of PLG:NaCl from 1:30 to 1.25:30 w/w. These scaffolds exhibited no differences in porosity or interior geometry between sterilization conditions, and transplants in mice restored normoglycemia. We piloted a modified scaffold study in a fourth NHP, and although scaffold integrity was improved, the transplant outcome was similar. We subsequently tested intermediate PLG:NaCl ratios in mice, finding that a 1.15:30 ratio achieved a balance of mechanical stability and islet compatibility. Overall, these studies identify that scaffold porosity can be adjusted to account for the impact of sterilization on transplantation.

BackgroundCurative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses.MethodsIn this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (NCT05538624) to identify Tpex recruitment capabilities at tolerable cytokine doses.ResultsWe show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity.ConclusionsOur new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories.

With conflicting recommendations and marketer practices about advertising impression allocation approaches (ie ‘the media strategy’), from approaches centred on reach (‘go broad’) versus targeting (‘get specific’), the debate rages on: ‘Are marketers targeting too much, not enough, or simply targeting the wrong consumers with their advertising?’ This paper interprets the issue of targeting as an advertising impression allocation question and instead of leading with case study evidence which by its nature is parochial, uses a novel mathematical approach to create an ad impression allocation model based on probability of choice. This contrasts with broad reach strategies and is different from other targeting schemes, eg key demographic, high lifetime value consumers, non-buyers for conquest, proprietary segments of interest. The findings suggest that targeting Movable Middles, ie those with a 20–80 per cent probability of choosing the brand of interest, can lead to 50 per cent improvement in return on ad spending (ROAS) versus broad reach media plans. The results are then supported with two in a large scale market case study. The Movable Middle, a segment of category buyers with a 20–80 per cent probability of choosing a brand, are shown to generate 2–23 times more ROAS than other category buyers who are mostly non-buyers of a brand. This pattern was uncovered mathematically but then subsequently verified empirically. By shifting about 10 per cent of ad impressions to audiences that have high concentrations of Movable Middles, a typical 10 per cent share brand can expect a 50 per cent improvement in campaign ROAS and a 13 per cent improvement in converting non-buyers. This leads to better serving brand needs for both quarterly sales and for long-term growth via customer acquisition. This new media strategy is not just limited to digital campaigns; it can be implemented across any media channel, including linear TV, radio and print.

I've had experience with only two formatters: FORMAT and FMT. I can't think of anything worth doing that FORMAT does better than FMT, so I'll largely ignore the former. I'll mainly be reacting to FMT: the things it does that I like, and the things it lacks that I want.