Reduced lung function in children associated with cesium 137 body burden

RATIONALE: We previously reported that obstructive and restrictive lung function findings were associated with radioactive Cesium 137 ((137)Cs) soil contamination from the 1986 Chernobyl disaster in a pediatric cohort residing in the Narodichesky district of Ukraine from 1993 to 1998. OBJECTIVES: To determine whether these associations persist, we repeated the study and refined the exposure by measuring individual radiation concentration with a whole-body counter. METHODS: Basic and post-bronchodilator spirometry measurements were made for 517 children aged 8 to 17 years born in and living within this differentially contaminated study area during 2008 to 2010. MEASUREMENTS AND MAIN RESULTS: A γ-spectrometer equipped with a collimator was used for the measurement of whole-body radiation and adjusted for weight. General linear and logistic regression models were used to estimate the association between spirometry measures and the weight-adjusted (137)Cs whole-body burden (Bq/kg) while controlling for potential confounders. The geometric median weight-adjusted radiation concentration was 65.96 Bq/kg (95% confidence interval, 14.98-240.9 Bq/kg), equivalent to a geometric mean internal dose estimate of 0.165 mSv/yr (95% confidence interval, 0.037-0.602 mSv/yr). Decrements in percentage predicted FEV1/FVC and an increased odds of bronchodilator responsiveness, restrictive impairment, and FVC less than lower limit of normal were associated with a log increase in weight-adjusted (137)Cs whole-body burden after adjusting for potential confounders. CONCLUSIONS: Our previous study of soil (137)Cs exposure and reduced lung function was corroborated herein with individual (137)Cs whole-body burden, although low, and annual internal dose data. Children in a region just outside of the closed Chernobyl contamination zone continued to have respiratory health deficits associated with (137)Cs whole-body burden as recently as 2010

Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer

Netrin-1 is upregulated in cancers as a protumoural mechanism1. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care2, we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments

The sixth international RASopathies symposium: Precision medicine-From promise to practice.

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion