Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice.

Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.

PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma.

INTRODUCTION: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician's chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. METHODS: A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. RESULTS: 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). CONCLUSIONS: TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.

Ultrasound detected changes in joint cartilage thickness in juvenile idiopathic arthritis.

AIM: The purpose of this study was to investigate the changes in joint cartilage thickness in different subtypes of juvenile idiopathic arthritis (JIA) using ultrasound, comparing them with healthy children and to evaluate the relationship with disease duration and inflammatory markers. METHODS: We conducted a cross-sectional study comprising of 27 cases of JIA and 54 age- and sex-matched healthy children. Bilateral wrist, knee and ankle joint cartilage thicknesses were measured by ultrasound as per European League Against Rheumatism standard guidelines and compared them between JIA subtypes as well as between cases and control. RESULTS: Descriptive analysis of the whole cohort revealed the mean age of the study population was 8.3 ± 3.2 years with mean cartilage thicknesses at the wrist, knee and ankle being 1.40 ± 0.89 mm, 1.57 ± 0.78 mm and 1.41 ± 0.85 mm, respectively. The median cartilage thicknesses of wrist, knee and ankle joints of JIA cases (n = 27) and healthy controls (n = 54) were 1.01, 1.35, 1.05 and 1.95, 2.00, 1.95, respectively. The joint cartilage thickness was significantly reduced in JIA in comparison to the healthy cohort (P < 0.01). Diseased boys suffered greater cartilage damage in knee joints compared to girls; the polyarticular variety of cases had thinner knee cartilage in comparison to the oligoarticular subtype. Further, it was found that joint cartilage destruction is independent of inflammatory markers and disease duration. CONCLUSION: Significant cartilage thinning in addition was found in JIA children, particularly in the polyarticular subtype, and more in boys than girls, which is independent of disease duration and inflammatory markers, using ultrasound as a primary investigative tool.

Evaluation of joint cartilage thickness in healthy children by ultrasound: An experience from a developing nation.

OBJECTIVES: Musculoskeletal ultrasound (MSUS) has a crucial role in clinical assessment and monitoring of patients with rheumatologic diseases. Early detection of joint cartilage destruction is difficult. MSUS is a cheap, noninvasive, nonhazardous bedside tool that can be used for detection of cartilage damage. We aimed to generate normative data of joint cartilage thickness of children in our population using this tool. METHODS: Healthy children, aged between 2 and 12 years, not suffering from any joint disorders and not on any chronic medication were recruited. The thickness of joint cartilage at wrist, knee and ankle were measured by ultrasound as per European League Against Rheumatism standard scan criteria. The scans were done by a single observer. RESULTS: Data of 409 children revealed median cartilage thickness at right wrist, knee and ankle joints as 2.20 (interquartile range [IQR] 1.60-3.00) mm, 2.40 (1.80-3.10) mm and 2.20 (1.80-3.00) mm, respectively. The right-left differences were not statistically significant except at the knee joint. Comparison between genders showed that boys had marginally thicker cartilage than girls at all three joints; this difference was statistically significant for the knee and ankle joints, but not at the wrist. Joint cartilage thickness showed a steady decline with age. CONCLUSIONS: Measurement of joint cartilage thickness in children with MSUS and comparison with these normative values can help in better screening for joint-related disease in children.