7 research outputs found
Pulmonary artery elastance as a predictor of hospital mortality in heart failure cardiogenic shock
Aims The initial bundle of cares strongly affects haemodynamics and outcomes in acute decompensated heart failure cardiogenic shock (ADHF-CS). We sought to characterize whether 24 h haemodynamic profiling provides superior prognostic information as compared with admission assessment and which haemodynamic parameters best predict in-hospital death. Methods and results All patients with ADHF-CS and with available admission and 24 h invasive haemodynamic assessment from two academic institutions were considered for this study. The primary endpoint was in-hospital death. Regression analyses were run to identify relevant predictors of study outcome. We included 127 ADHF-CS patients [65 (inter-quartile range 52-72) years, 25.2% female]. Overall, in-hospital mortality occurred in 26.8%. Non-survivors were older, with greater CS severity. Among admission variables, age [odds ratio (OR) = 1.06; 95% confidence interval (CI): 1.02-1.11; P-adj = 0.005] and CPIRAP (OR = 0.62 for 0.1 increment; 95% CI: 0.39-0.95; P-adj = 0.034) were found significantly associated with in-hospital death. Among 24 h haemodynamic univariate predictors of in-hospital death, pulmonary elastance (PaE) was the strongest (area under the curve of 0.77; 95% CI: 0.68-0.86). PaE (OR = 5.98; 95% CI: 2.29-17.48; P-adj < 0.001), pulmonary artery pulsatility index (PAPi, OR = 0.77; 95% CI: 0.62-0.92; P-adj = 0.013) and age (OR = 1.06; 95% CI: 1.02-1.11; P-adj = 0.010) were independently associated with in-hospital death. Best cut-off for PaE was 0.85 mmHg/mL and for PAPi was 2.95; cohort phenotyping based on these PaE and PAPi thresholds further increased in-hospital death risk stratification; patients with 24 h high PaE and low PAPi exhibited the highest in-hospital mortality (56.2%). Conclusions Pulmonary artery elastance has been found to be the most powerful 24 h haemodynamic predictor of in-hospital death in patients with ADHF-CS. Age, 24 h PaE, and PAPi are independently associated with hospital mortality. PaE captures right ventriclar (RV) afterload mismatch and PAPi provides a metric of RV adaptation, thus their combination generates four distinct haemodynamic phenotypes, enhancing in-hospital death risk stratification
Pulmonary artery elastance as a predictor of hospital mortality in heart failure cardiogenic shock
Aims The initial bundle of cares strongly affects haemodynamics and outcomes in acute decompensated heart failure cardiogenic shock (ADHF-CS). We sought to characterize whether 24 h haemodynamic profiling provides superior prognostic information as compared with admission assessment and which haemodynamic parameters best predict in-hospital death. Methods and results All patients with ADHF-CS and with available admission and 24 h invasive haemodynamic assessment from two academic institutions were considered for this study. The primary endpoint was in-hospital death. Regression analyses were run to identify relevant predictors of study outcome. We included 127 ADHF-CS patients [65 (inter-quartile range 52-72) years, 25.2% female]. Overall, in-hospital mortality occurred in 26.8%. Non-survivors were older, with greater CS severity. Among admission variables, age [odds ratio (OR) = 1.06; 95% confidence interval (CI): 1.02-1.11; P-adj = 0.005] and CPIRAP (OR = 0.62 for 0.1 increment; 95% CI: 0.39-0.95; P-adj = 0.034) were found significantly associated with in-hospital death. Among 24 h haemodynamic univariate predictors of in-hospital death, pulmonary elastance (PaE) was the strongest (area under the curve of 0.77; 95% CI: 0.68-0.86). PaE (OR = 5.98; 95% CI: 2.29-17.48; P-adj < 0.001), pulmonary artery pulsatility index (PAPi, OR = 0.77; 95% CI: 0.62-0.92; P-adj = 0.013) and age (OR = 1.06; 95% CI: 1.02-1.11; P-adj = 0.010) were independently associated with in-hospital death. Best cut-off for PaE was 0.85 mmHg/mL and for PAPi was 2.95; cohort phenotyping based on these PaE and PAPi thresholds further increased in-hospital death risk stratification; patients with 24 h high PaE and low PAPi exhibited the highest in-hospital mortality (56.2%). Conclusions Pulmonary artery elastance has been found to be the most powerful 24 h haemodynamic predictor of in-hospital death in patients with ADHF-CS. Age, 24 h PaE, and PAPi are independently associated with hospital mortality. PaE captures right ventriclar (RV) afterload mismatch and PAPi provides a metric of RV adaptation, thus their combination generates four distinct haemodynamic phenotypes, enhancing in-hospital death risk stratification
Cooperation Between the NRF2 Pathway and Oncogenic ÎČâcatenin During HCC Tumorigenesis
International audienceCTNNB1 (catenin beta 1)-mutated hepatocellular carcinomas (HCCs) account for a large proportion of human HCCs. They display high levels of respiratory chain activity. As metabolism and redox balance are closely linked, tumor cells must maintain their redox status during these metabolic alterations. We investigated the redox balance of these HCCs and the feasibility of targeting this balance as an avenue for targeted therapy. We assessed the expression of the nuclear erythroid 2 p45-related factor 2 (NRF2) detoxification pathway in an annotated human HCC data set and reported an enrichment of the NRF2 program in human HCCs with CTNNB1 mutations, largely independent of NFE2L2 (nuclear factor, erythroid 2 like 2) or KEAP1 (Kelch-like ECH-associated protein 1) mutations. We then used mice with hepatocyte-specific oncogenic ÎČ-catenin activation to evaluate the redox status associated with ÎČ-catenin activation in preneoplastic livers and tumors. We challenged them with various oxidative stressors and observed that the ÎČ-catenin pathway activation increased transcription of Nfe2l2, which protects ÎČ-catenin-activated hepatocytes from oxidative damage and supports tumor development. Moreover, outside of its effects on reactive oxygen species scavenging, we found out that Nrf2 itself contributes to the metabolic activity of ÎČ-catenin-activated cells. We then challenged ÎČ-catenin activated tumors pharmacologically to create a redox imbalance and found that pharmacological inactivation of Nrf2 was sufficient to considerably decrease the progression of ÎČ-catenin-dependent HCC development. Conclusion: These results demonstrate cooperation between oncogenic ÎČ-catenin signaling and the NRF2 pathway in CTNNB1-mediated HCC tumorigenesis, and we provide evidence for the relevance of redox balance targeting as a therapeutic strategy in CTNNB1-mutated HCC
Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals.
BACKGROUND & AIMS
Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure.
METHODS
We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation.
RESULTS
Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs.
CONCLUSIONS
These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension.
LAY SUMMARY
Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
Funding Information: Acknowledgements We thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196 and A31287), and particularly the Biological Services Unit, Histology Service and Molecular Technologies; members of the Sansom and Katajisto laboratories for discussions of the data and manuscript; and BRC Oxford for supplying patient material. O.J.S. and his laboratory members were supported by Cancer Research UK (A28223, A21139, A12481 and A17196). D.J.F. and M.C.H. were supported by the UK Medical Research Council (MR/R017247/1 and MR/J50032X/1, respectively). SpecifiCancer CRUK Grand Challenge (C7932/A29055) is funded by Cancer Research UK and the Mark Foundation for Cancer Research. P.K. and his laboratory members were supported by the Academy of Finland Centre of Excellence MetaStem (266869, 304591 and 320185), the ERC Starting Grant 677809, the Swedish Research Council 2018-03078, the Cancerfonden 190634, the Jane and Aatos Erkko Foundation and the Cancer Foundation Finland. N.P. was supported by the Finnish Cultural Foundation, the Biomedicum Helsinki Foundation, the Orion Research Foundation sr and The Paulo Foundation. P.V.F. was supported by Alzheimerâs Research UK and The Francis Crick Institute. The ARUK UCL Drug Discovery Institute receives its core funding from Alzheimerâs Research UK (520909). The Francis Crick Institute receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002) and the Wellcome Trust (FC001002). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling(1), but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)(2). Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.Peer reviewe