YAP/TEAD involvement in resistance to paclitaxel chemotherapy in lung cancer.

The Yes-associated protein (YAP) oncoprotein has been linked to both metastases and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/TEA domain (TEAD) transcription factor interaction inhibitors in chemo-resistant lung cancer cells. YAP subcellular localization, as a readout for YAP activation, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC50) of paclitaxel or trametinib, which are Mitogen-Activated protein kinase and Erk Kinase (MEK) inhibitors, combined with a YAP/TEAD inhibitor (IV#6), was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. YAP activity was significantly higher in paclitaxel-resistant cell lines. The YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib in K-Ras mutated A549 cells recapitulated synthetic lethality, thereby sensitizing these cells to MEK inhibition. The YAP/TEAD inhibitor lowered the IC50 of paclitaxel in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increased YAP/TEAD transcriptomic signature in resistant cells, downregulated upon YAP inhibition. The YAP/TEAD inhibitor restored paclitaxel sensitivity of A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Evidence of the YAP/TEAD transcriptional program's role in chemotherapy resistance paves the way for YAP therapeutic targeting.

The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?

Cancer cells display an altered energy metabolism, which was proposed to be the root of cancer. This early discovery was done by O. Warburg who conducted one of the first studies of tumor cell energy metabolism. Taking advantage of cancer cells that exhibited various growth rates, he showed that cancer cells display a decreased respiration and an increased glycolysis proportional to the increase in their growth rate, suggesting that they mainly depend on fermentative metabolism for ATP generation. Warburg's results and hypothesis generated controversies that are persistent to this day. It is thus of great importance to understand the mechanisms by which cancer cells can reversibly regulate the two pathways of their energy metabolism as well as the functioning of this metabolism in cell proliferation. In this review, we discuss of the origin of the decrease in cell respiratory rate, whether the Warburg effect is mandatory for an increased cell proliferation rate, the consequences of this effect on two major players of cell energy metabolism that are ATP and NADH, and the role of the microenvironment in the regulation of cellular respiration and metabolism both in cancer cell and in yeast.

[Should French pregnant women be vaccinated against pertussis during pregnancy?] / Faut-il vacciner les femmes enceintes françaises contre la coqueluche ?

Many countries with a high perinatal level have started a policy of vaccination of pregnant women against pertussis. To date, France has not chosen this policy. The objective was to review knowledge on pertussis mortality in infants. Compare the strategies available to protect the infant before his first vaccination, scheduled for two months of age. We proceeded to a litterature analysis, from January 1998 to 2021. Search by the following keywords used ; "Whooping cough, vaccination, pregnancy, strategy, cocooning", on the scientific basis of "Pubmed", as well as French and foreign vaccination recommendations. Currently 90% of whooping cough deaths are concerning infants under six months of age and this mortality represents 2% of mortality in the first year of life. Vaccination at birth is not effective. The cocooning strategy, which consists of vaccinating those around the child, is expensive and difficult to implement. A systematic vaccination policy for pregnant women is effective and reasonably expensive when compared to the cocooning strategy. In England, it was recently accompanied by a 78% reduction in confirmed cases of pertussis in infants under six months of age. In conclusion, compared to cocooning strategy, pertussis vaccination of pregnant women appears more effective and cost-effective, and this with each pregnancy.

Cell energy metabolism: An update.

In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that take place during net biomass formation and maintenance processes. During growth, both ATP/ADP and NADH/NAD+ molecules play a key role. Cell energy metabolism hence refers to metabolic pathways involved in ATP synthesis linked to NADH turnover. Two main pathways are thus involved in cell energy metabolism: glycolysis/fermentation and oxidative phosphorylation. Glycolysis and mitochondrial oxidative phosphorylation are intertwined through thermodynamic and kinetic constraints that are reviewed herein. Further, our current knowledge of short-term and long term regulation of cell energy metabolism will be reviewed using examples such as the Crabtree and the Warburg effect.

[Cardiac manifestations of pheochromocytoma. Anatomo-clinical study]. / Les manifestations cardiaques des phéochromocytomes. Etude anatomo-clinique.

Cardiomyopathy induced by catecholamines, first demonstrated in the animal is also observed in clinical medecine either after infusion by vasopressor drugs or during the course of pheochromocytoma. The clinical presentation is varied and may often deceive: acute coronary insufficiency, arrhythmia, heart failure, and, above all, cardiogemic shock. The authors emphasise the importance of considering the diagnosis of "adrenergic myocarditis" in such situations as well as in cases of pheochromocytoma, for which the only cure is ablation of the tumour.

[Treatment of functional tricuspid insufficiency by a valvuloplasty with a flexible linear reducer]. / Traitement de l'insuffisance tricuspidienne fonctionnelle par plastie type réducteur linéaire souple.

Valvuloplasty with preservation of the valvular apparatus is the treatment of choice in functional tricuspid incompetence (FTI). A new method of valvuloplasty has been developed using a flexible linear reducer (FLR); its insertion is simple and without risk to the Bundle of His. It is made of sections of elastomere covering a dacron core. The principle of the FLR is reduction of the tricuspid annulus leaving the septal leaflet free. It is a simple method which allows individual variations in the zone reduced (usually involving the anterior and inferior leaflets) and in the size of the reduction at each point. The excellent results at medium term in 20 patients with tricuspid FLR lead us to recommend widening the surgical indications for correction of FTI especially in cases where signs of right ventricular failure have been observed.