Sustained and Localized Drug Depot Release Using Radiation-Activated Scintillating Nanoparticles.

Clinical treatment of cancer commonly incorporates X-ray radiation therapy (XRT), and developing spatially precise radiation-activatable drug delivery strategies may improve XRT efficacy while limiting off-target toxicities associated with systemically administered drugs. Nevertheless, achieving this has been challenging thus far because strategies typically rely on radical species with short lifespans, and the inherent nature of hypoxic and acidic tumor microenvironments may encourage spatially heterogeneous effects. It is hypothesized that the challenge could be bypassed by using scintillating nanoparticles that emit light upon X-ray absorption, locally forming therapeutic drug depots in tumor tissues. Thus a nanoparticle platform (Scintillating nanoparticle Drug Depot; SciDD) that enables the local release of cytotoxic payloads only after activation by XRT is developed, thereby limiting off-target toxicity. As a proof-of-principle, SciDD is used to deliver a microtubule-destabilizing payload MMAE (monomethyl auristatin E). With as little as a 2 Gy local irradiation to tumors, MMAE payloads are released effectively to kill tumor cells. XRT-mediated drug release is demonstrated in multiple mouse cancer models and showed efficacy over XRT alone (p < 0.0001). This work shows that SciDD can act as a local drug depot with spatiotemporally controlled release of cancer therapeutics.

Pneumonitis in Patients Receiving Thoracic Radiotherapy and Osimertinib: A Multi-Institutional Study.

Introduction: Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population. Methods: We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis. Results: The median follow-up was 10.2 months (range: 1.9-53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5-6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021). Conclusions: Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.

Sortase-Dependent Proteins Promote Gastrointestinal Colonization by Enterococci.

The human gastrointestinal tract (GIT) is inhabited by a dense microbial community of symbionts. Enterococci are among the earliest members of this community and remain core members of the GIT microbiota throughout life. Enterococci have also recently emerged as opportunistic pathogens and major causes of nosocomial infections. Although recognized as a prerequisite for infection, colonization of the GIT by enterococci remains poorly understood. One way that bacteria adapt to dynamic ecosystems like the GIT is through the use of their surface proteins to sense and interact with components of their immediate environment. In Gram-positive bacteria, a subset of surface proteins relies on an enzyme called sortase for covalent attachment to the cell wall. Here, we show that the housekeeping sortase A (SrtA) enzyme promotes intestinal colonization by enterococci. Furthermore, we show that the enzymatic activity of SrtA is key to the ability of Enterococcus faecalis to bind mucin (a major component of the GIT mucus). We also report the GIT colonization phenotypes of E. faecalis mutants lacking selected sortase-dependent proteins (SDPs). Further examination of the mucin binding ability of these mutants suggests that adhesion to mucin contributes to intestinal colonization by E. faecalis.

Risk factors of hepatitis B virus surface antigen carriage and serological profile of HBsAg carriers in Lomé Togo, 2016.

BACKGROUND: In Togo, the prevalence of Hepatitis B Virus Surface Antigen (HBsAg) among young people aged 15-24 years was estimated at 16.4% in 2010; however, risk factors for HBsAg carriage are poorly documented. We sought to identify risk factors for HBsAg carriage and the serological profile of HBsAg carriers in Lomé (capital city of Togo). METHOD: We conducted a case control study from October 2016 to March 2017 in Lomé. Cases and controls were randomly selected from a database of Institut National d'Hygiène (INH) of Lomé during a free screening campaign for hepatitis B. We calculated means, frequencies, proportions, odds ratios (OR), and 95% confidence interval (CI) and performed logistic regression. RESULTS: We included 83 confirmed cases and 249 controls. The median age was 31 years among cases and 30 years among the controls. The sex ratios (M/F) were 11/6 among cases and 4/3 for the controls. The independent risk factors for HBsAg carriage were the awareness of hepatitis B serological status (OR = 3.56, 95% CI [1.80-7.04]) and Kabyè-tem ethnic group (OR = 3.56, 95% CI [1.98-6.39]). Among HBsAg carriers, 13.3% were at the viral replication stage (all of whom were between 30 and 45 years of age) and 1.2% were at the acute stage of the disease. The prevalence of co-infection with hepatitis B and C was 4.80%. All co-infections were in women aged 24-28 years. CONCLUSION: The Kabyè-tem ethnic group is at risk of HBsAg carriage in Lomé. Of note, most HBsAg carriers in this ethnic group are aware of their HBsAg serological status. Furthermore, the prevalence of Hepatitis among adults of reproductive age is high and is cause for concern. We therefore recommend screening and vaccination campaigns at subsidized prices among people aged 30 years and older.

Colonization of the mammalian intestinal tract by enterococci.

Enterococci are colonizers of the mammalian gastrointestinal tract (GIT) and normally live in healthy association with their human host. However, enterococci are also major causes of healthcare-acquired infections, prompting the US Centers for Disease Control and Prevention to declare vancomycin-resistant enterococci (VRE) a serious threat to public health. Because of both intrinsic and acquired antibiotic resistance, enterococci proliferate in the GIT during antibiotic therapy, leading to dissemination and disease. The recognition that colonization of the GIT is a pre-requisite for enterococcal infections has prompted research to study mechanisms used by enterococci to colonize this niche. This review discusses major findings of recent research to understand GIT colonization by enterococci using diverse experimental models, each of which exhibits unique strengths. This work has revealed enterococcal transcriptional reprogramming in the GIT, contributions of specific enterococcal genes encoded by the core genome to GIT colonization, the impact of genome plasticity, and roles for intra-species and inter-species interactions in modulation of GIT colonization.