Background and rationale: Attenuated Salmonella typhimurium VNP20009 has been used to treat tumor-bearing mice and entered phase I clinical trials. However, its mild anticancer effect in clinical trials may be related to insufficient bacterial colonization and notable adverse effects with increasing dosages. Guanosine 5\'-diphosphate-3\'-diphosphate (ppGpp) synthesis-deficient Salmonella is an attenuated strain with good biosafety and anticancer efficacy that has been widely investigated in various solid cancers in preclinical studies. Integration of the advantages of these two strains may provide a new solution for oncolytic bacterial therapy. Methods: We incorporated the features of ΔppGpp into VNP20009 and obtained the HCS1 strain by deleting relA and spoT, and then assessed its cytotoxicity in vitro and antitumor activities in vivo. Results: In vitro experiments revealed that the invasiveness and cytotoxicity of HCS1 to cancer cells were significantly lower than those of the VNP20009. Additionally, tumor-bearing mice showed robust cancer suppression when treated with different doses of HCS1 intravenously, and the survival time and cured mice were dramatically increased. Furthermore, HCS1 can increase the levels of pro-inflammatory cytokines in tumor tissues and relieve the immunosuppression in the tumor microenvironments. It can also recruit abundant immune cells into tumor tissues, thereby increasing immune activation responses. Conclusion: The newly engineered Salmonella HCS1 strain manifests high prospects for cancer therapeutics and is a promising option for future clinical cancer immunotherapy.

BACKGROUND: Intravitreal dexamethasone and anti-vascular endothelial growth factor (anti-VEGF) medications have revolutionized ocular disease management and favorable ocular safety profiles, but few studies have compared their systemic adverse events (SAEs). This study investigated the SAEs of intravitreal dexamethasone and anti-VEGFs by using real-world data.
METHODS: This retrospective cohort study sourced medical records from the largest multi-institutional database in Taiwan. Patients who received intravitreal dexamethasone (n = 137) or anti-VEGFs (n = 10,345) between 2014 and 2019 were enrolled. Propensity score matching was performed to achieve homogeneity between the two groups. Subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) were calculated using the Fine-Gray model. Systemic as well as ocular clinical events and systemic biomarkers after 1-year follow-up were compared.
RESULTS: Both groups demonstrated comparable risks of major cardiac adverse events (SHR 1.57, 95% CI 0.29-8.55), heart failure (SHR 0.62, 95% CI 0.07-5.33), major bleeding (SHR 0.23, 95% CI 0.03-1.77), all-cause admission (SHR 0.73, 95% CI 0.41-1.30), and all-cause death (SHR 2.11, 95% CI 0.35-12.71). There were no significant differences in longitudinal changes in systolic and diastolic blood pressure, glycated hemoglobin, low-density lipoprotein, estimated glomerular filtration rate, or alanine aminotransferase between the groups. Both groups had a similar incidence of cataract surgery. Although the dexamethasone group exhibited a relatively high prevalence of antiglaucomatous medication use, there was not a significantly higher incidence of glaucoma surgery.
CONCLUSIONS: Intravitreal dexamethasone and anti-VEGF medications had comparable systemic safety profiles in our study. Both drugs represent efficacious and safe therapies for ocular diseases.

Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.