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Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5' terminal oligopyrimidine (5'TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies., (© 2024. The Author(s).)

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Paratracheal pressure has been recently suggested to compress and occlude the upper esophagus at the lower left paratracheal region to prevent gastric regurgitation alternative to cricoid pressure. It also prevents gastric insufflation. The aim of this randomized cross-over study was to investigate the effectiveness of paratracheal pressure on mask ventilation in obese anesthetized paralyzed patients. After the induction of anesthesia, two-handed mask ventilation was initiated in a volume-controlled mode with a tidal volume of 8 mL kg ‒1 based on ideal body weight (IBW), a respiratory rate of 12 breaths min - 1 , and positive end-expiratory pressure of 10 cmH 2 O. Expiratory tidal volume and peak inspiratory pressure were recorded alternately with or without the application of 30 Newtons (approximately 3.06 kg) paratracheal pressure during a total of 16 successive breaths over 80 s. Association of patient characteristics with the effectiveness of paratracheal pressure on mask ventilation, defined as the difference in expiratory tidal volume between the presence or absence of paratracheal pressure were evaluated. In 48 obese anesthetized paralyzed patients, expiratory tidal volume was significantly higher with the application of paratracheal pressure than without paratracheal pressure [496.8 (74.1) mL kg - 1 of IBW vs. 403.8 (58.4) mL kg - 1 of IBW, respectively; P < 0.001]. Peak inspiratory pressure was also significantly higher with the application of paratracheal pressure compared to that with no paratracheal pressure [21.4 (1.2) cmH 2 O vs. 18.9 (1.6) cmH 2 O, respectively; P < 0.001]. No significant association was observed between patient characteristics and the effectiveness of paratracheal pressure on mask ventilation. Hypoxemia did not occur in any of the patients during mask ventilation with or without paratracheal pressure. The application of paratracheal pressure significantly increased both the expiratory tidal volume and peak inspiratory pressure during face-mask ventilation with a volume-controlled mode in obese anesthetized paralyzed patients. Gastric insufflation was not evaluated in this study during mask ventilation with or without paratracheal pressure., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Effective lung isolation prevents lung-to-lung aspiration during thoracotomy for the management of hemoptysis. Double-lumen endobronchial tubes (DLT) and bronchial blockers are commonly used for lung separation during thoracic surgery. In this study, the fluid-sealing characteristics of the endobronchial cuffs of three different commercially available DLTs (Broncho-Cath with a polyvinylchloride cuff, Broncho-Cath with a polyurethane cuff, and Human Broncho with a silicone cuff) and two different bronchial blockers (Arndt and Coopdech bronchial blockers) were evaluated using a benchtop model. The lateral decubitus position for the surgical management of bleeding from the right lung was simulated. The artificial tracheobronchial tree was placed horizontally, with the left bronchus in the dependent position and the right bronchus in the non-dependent position. In the DLT experiments, the tracheobronchial tree was intubated with left-sided DLTs, and the endobronchial cuff was inflated to maintain the intracuff pressure at 25 cmH 2 O. In the experiments with bronchial blockers, each bronchial blocker was inserted into the right bronchus, and the endobronchial cuff was inflated to seal the main bronchus. A fluid leakage test around the endobronchial cuff was performed using three different types of DLT (size 35, 37, and 41 Fr, each) and two different types of bronchial blockers (9 Fr). The 5 mL of colored water was poured into the right bronchus to simulate the blood flow from the operative side, and the times to the first and 100% leakage around the endobronchial cuff were recorded. Each bronchial blocker showed significantly less leakage over time than the other DLTs (P < 0.05). Fluid was not fully leaked around the cuffs for 24 h with either bronchial blocker. The times to first and 100% leakage were not significantly different among different types of DLTs. The times to first and 100% leakage did not also differ among the three different sizes of each type DLT. There was no significant difference in the time to first leakage around the endobronchial cuffs between Arndt and Coopdech bronchial blockers. Bronchial blockers provided a more effective seal against lung-to-lung aspiration than DLTs in the lateral decubitus position for thoracotomy in the benchtop model., (© 2024. The Author(s).)

Background: Airway management is more challenging in the obese. Compared with the supine position, the sitting position can decrease the collapsibility of the upper airway and improve respiratory mechanics., Objective: The aim of this study was to evaluate the 25° semisitting position on the effectiveness of mask ventilation in anaesthetised paralysed obese patients., Design: A randomised, cross-over study., Setting: Medical centre managed by a university tertiary hospital., Patients: Thirty-eight obese adults scheduled for general anaesthesia., Methods: After anaesthesia and paralysis, two-handed mask ventilation was performed in the supine and 25° semi-sitting positions with a cross-over, in a randomised order. During mask ventilation, mechanical ventilation was delivered with a pressure-controlled mode with a peak inspiratory pressure of 15 cmH2O, a respiratory rate of 15 bpm, and no positive end-expiratory pressure. Ventilatory outcomes were based upon lean body weight., Main Outcomes: Exhaled tidal volume (ml kg-1), respiratory minute volume (ml kg-1 min-1), and the occurrence of inadequate ventilation, defined as an exhaled tidal volume less than 4 ml kg-1, or absence of end-tidal CO2 recording., Results: Exhaled tidal volume (mean ± SD) in the 25° semi-sitting position was higher than in the supine position, 9.3 ± 2.7 vs. 7.6 ± 2.4 ml kg-1; P less than 0.001. Respiratory minute volume was improved in the 25° semisitting position compared with that in the supine position, 139.6 ± 40.7 vs. 113.4 ± 35.7 ml kg-1 min-1; P less than 0.001., Conclusion: The 25° semisitting position improved mask ventilation compared with the supine position in anaesthetised paralysed obese patients., Trial Registry Number: ClinicalTrials.gov (NCT03996161)., (Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)