Inactive-enriched machine-learning models exploiting patent data improve structure-based virtual screening for PDL1 dimerizers.

INTRODUCTION: Small-molecule Programmable Cell Death Protein 1/Programmable Death-Ligand 1 (PD1/PDL1) inhibition via PDL1 dimerization has the potential to lead to inexpensive drugs with better cancer patient outcomes and milder side effects. However, this therapeutic approach has proven challenging, with only one PDL1 dimerizer reaching early clinical trials so far. There is hence a need for fast and accurate methods to develop alternative PDL1 dimerizers. OBJECTIVES: We aim to show that structure-based virtual screening (SBVS) based on PDL1-specific machine-learning (ML) scoring functions (SFs) is a powerful drug design tool for detecting PD1/PDL1 inhibitors via PDL1 dimerization. METHODS: By incorporating the latest MLSF advances, we generated and evaluated PDL1-specific MLSFs (classifiers and inactive-enriched regressors) on two demanding test sets. RESULTS: 60 PDL1-specific MLSFs (30 classifiers and 30 regressors) were generated. Our large-scale analysis provides highly predictive PDL1-specific MLSFs that benefitted from training with large volumes of docked inactives and enabling inactive-enriched regression. CONCLUSION: PDL1-specific MLSFs strongly outperformed generic SFs of various types on this target and are released here without restrictions.

Incidence of ultrasonographic signs of pneumothorax in asymptomatic neonates.

INTRODUCTION: Pneumothorax in neonates can be life-threatening. In neonates without respiratory distress, spontaneous pneumothorax can also develop under certain conditions. OBJECTIVES: To determine the incidence of ultrasonographic signs of pneumothorax in asymptomatic neonates using lung ultrasound as the diagnostic tool. METHODS: This was an observational prospective study conducted at the Basurto University Hospital (Bilbao, Spain) between January 2018 and December 2020. Lung ultrasound was performed during routine examination of asymptomatic neonates admitted to the maternity ward. RESULTS: Of a total of 204 asymptomatic neonates included in the study, 21 (10.3%) presented ultrasound signs of pneumothorax (Group A), and 183 (89.7%) had a normal lung ultrasound (Group B). Lung ultrasound was performed after a mean of 19 h of life (range 9-34). The presence of A-lines behind the sternum in the anterior transverse plane, at the intermammillary level, was observed in 100% of patients in Group A compared to no cases in Group B (p < 0.0001). The neonates of Group A presented the lung point located in the midclavicular line, indicative of a mild air leak. CONCLUSIONS: Lung ultrasound allows precise detection of suspected small-sized air leaks that can be detected in asymptomatic neonates. The true incidence of pneumothorax in asymptomatic neonates may be substantially higher than previously described in the literature.

EventPointer 3.0: flexible and accurate splicing analysis that includes studying the differential usage of protein-domains.

Alternative splicing (AS) plays a key role in cancer: all its hallmarks have been associated with different mechanisms of abnormal AS. The improvement of the human transcriptome annotation and the availability of fast and accurate software to estimate isoform concentrations has boosted the analysis of transcriptome profiling from RNA-seq. The statistical analysis of AS is a challenging problem not yet fully solved. We have included in EventPointer (EP), a Bioconductor package, a novel statistical method that can use the bootstrap of the pseudoaligners. We compared it with other state-of-the-art algorithms to analyze AS. Its performance is outstanding for shallow sequencing conditions. The statistical framework is very flexible since it is based on design and contrast matrices. EP now includes a convenient tool to find the primers to validate the discoveries using PCR. We also added a statistical module to study alteration in protein domain related to AS. Applying it to 9514 patients from TCGA and TARGET in 19 different tumor types resulted in two conclusions: i) aberrant alternative splicing alters the relative presence of Protein domains and, ii) the number of enriched domains is strongly correlated with the age of the patients.