No abstract

Biomaterials-based nanovaccines, such as those made of poly(lactic-co-glycolic acid) (PLGA), can induce stronger immunity than soluble antigens in healthy wild-type mouse models. However, whether metabolic syndrome can influence the immunological responses of nanovaccines remains poorly understood. Here, we first show that alteration in the sensing of the gut microbiome through Toll-like receptor 5 (TLR5) and the resulting metabolic syndrome in TLR5−/− mice diminish the germinal center immune response induced by PLGA nanovaccines. The PLGA nanovaccines, unexpectedly, further changed gut microbiota. By chronically treating mice with antibiotics, we show that disrupting gut microbiome leads to poor vaccine response in an obesity-independent manner. We next demonstrate that the low immune response can be rescued by an immunomodulatory Pyr-pHEMA nanogel vaccine, which functions through TLR2 stimulation, enhanced trafficking, and induced stronger germinal center response than alum-supplemented PLGA nanovaccines. The study highlights the potential for immunomodulation under gut-mediated metabolic syndrome conditions using advanced nanomaterials.

Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR‐dependence. These tumors undergo epigenetic reprogramming turning castration‐resistant prostate cancer adenocarcinoma (CRPC‐Adeno) into neuroendocrine prostate cancer (CRPC‐NEPC). No targeted therapies are available for CRPC‐NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial‐omics, and a synthetic hydrogel‐based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC‐NEPCs are defined. Short‐term culture in tumor‐expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC‐NEPCs. The ECM type distinctly regulates the response to small‐molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient‐derived xenograft in immunocompromised mice showed strong anti‐tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC‐NEPCs under drug‐resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC‐NEPCs and enable the discovery of therapies to overcome resistance.

Background and Objectives The impact of medications for opioid use disorder (MOUD) on against medical advice (AMA) discharges among people who inject drugs (PWID) hospitalized for endocarditis is unknown. Methods A retrospective review of all PWID hospitalized for endocarditis at our institution between 2016 and 2018 (n = 84). Results PWID engaged with MOUD at admission, compared with those who were not, were less likely to be discharged AMA but this did not reach statistical significance in adjusted analysis (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.033‐1.41; P  = .11). Among out‐of‐treatment individuals, newly initiating MOUD did not lead to significantly fewer AMA discharges (OR, 0.98; 95% CI, 0.26‐3.7; P = .98). Conclusion and Scientific Significance PWID hospitalized for endocarditis are at high risk for discharge AMA but more research is needed to understand the impact of MOUD. (Am J Addict 2020;29:155–159)