Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis

PI3K-C2α regulates Polycystin-2 ciliary entry to prevent kidney cyst formation

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function

Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase \uce\ub1 (PI3K-C2\uce\ub1) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2\uce\ub1 causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2\uce\ub1 expression is required for genomic stability. Reduced abundance of PI3K-C2\uce\ub1 in breast cancer models initially impairs tumor growth but later leads to the convergent evolution of fast-growing clones with mitotic checkpoint defects. As a consequence of altered spindle, loss of PI3K-C2\uce\ub1 increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings. Gulluni et al. reveal a kinase-independent scaffolding function of PI3K-C2\uce\ub1 that affects mitotic spindle formation. Reduced levels of PI3K-C2\uce\ub1 reduce tumor growth initially but provide a growth advantage later in mouse models of breast cancer. Loss of PI3K-C2\uce\ub1 also increases sensitivity of tumors to taxanes

Forage fermentation patterns and their implications for herbivore ingesta retention times

1. Differences in digestive physiology between browsing and grazing ruminant feeding types have been discussed extensively. The potentially underlying differences in fermentative behaviour of forage plants have received much less attention. 2. In this study, different groups of temperate forage plants (grasses, browse leaves and twigs, herbs and legumes) were compared in their chemical composition and fementative behaviour. They were evaluated via an in vitro fermentation system (modified Hohenheim gas test), and relevant fermentation parameters such as maximal gas production and relative gas production rate were calculated. 3. Grasses generally had a higher NDF (neutral detergent fibre = total cell wall) content than browse leaves, herbs and legumes, while browse leaf cell wall was more lignified than that of herbs, legumes and grass. 4. With respect to fermentation parameters, grass had the highest maximal gas production, followed by herbs and legumes, and the lowest maximal gas production in browse leaves and twigs. Relative gas production rate was highest in herbs and legumes, while that of grass and browse was lower. As expected, browse twigs had the lowest nutritional value. 5. Dicot material reached given setpoints of absolute gas production rate like 1.0 or 0.5 mL gas/(200 mg dry matter x h) faster than grass material. Based on these results, a longer passage time of food particles seems to be adaptive for grazing ruminants, as over a wide range of fermentation times, absolute gas production rate is higher in grass compared with dicots. Especially for browse leaves, a higher intake level should be expected to balance energy requirements of animals relying on this forage type

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10-15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10-9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10-8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10-8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10-4-2.0x10-3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: Rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. © 2018 The Author(s)