Zobrazení zdroje stránky Headwatson8716

It is well known that activating the constitutive androstane receptor (CAR, NR1I3) leads to a significant proliferation of liver cells, which suggests that NR1I3 could be a therapeutic target for the partial resection of this organ. Studies describing NR1I3-mediated proliferative pathways could help determine the possible clinical applications of NR1I3 agonists during liver resection or transplantation. Recently, we reported that liver hyperplasia, which results from NR1I3 activation, is mediated by the activation of the Akt signaling pathway. In this study, we investigated the impact of the Akt signaling pathway on β-catenin and its role in liver growth. Our findings showed that NR1I3-mediated activation of the Akt pathway results in the nuclear redistribution of β-catenin and increases hepatocyte proliferation. Inhibiting the Akt pathway using the allosteric inhibitor MK-2206 decreased the amount of β-catenin in the nucleus and reduced the hepatocyte proliferation induced by a NR1I3 agonist, but promoted hypertrophic liver growth. These findings suggest that NR1I3-mediated hepatocyte proliferation and liver growth are not necessarily linked. Additionally, we found that the proliferation effect of the NR1I3-Akt-β-catenin signaling pathway is mediated, at least in part, by Cyclic D1 up-regulation. In contrast, the nuclear localization of β-catenin in response to NR1I3 did not affect the expression of the β-catenin target cMyc in the liver. In conclusion, the NR1I3-Akt signaling pathway plays a significant role in regulating hepatocyte proliferation, at least in part, by activating β-catenin. Platinum drugs, such as cisplatin (DDP) and carboplatin (CBP), are the main drugs for the treatment of lung cancer, but their practical clinical application is limited by severe toxicity and acquired drug resistance. Our previous study has indicated that diplatin, [2-(4-(diethyl-amino)butyl)malonate-O,O']-[(1R,2R)-cyclohexane-1,2-diamine N,N'] platinum (II) phosphate, a novel water-soluble platinum complex, could overcome DDP-resistant cells and was less toxic than comparable platinum drugs. In the present study, the effects and mechanisms of diplatin were further evaluated for its development as a novel anti-lung cancer platinum drug. Here, we found diplatin down-regulated the viability of H460 and LTEP-A-2&nbsp;cells in a dose-dependent manner. Nude mice administrated with diplatin (30-120&nbsp;mg/kg) via tail vein injection dose-dependently inhibited the growth of H460 and LTEP-A-2 xenograft tumors, whose action mainly correlated with the induction of tumor apoptosis. Particularly, the exposure of lung cancer cells or xenograft tumors to diplatin resulted in elevated Fas level, and knockdown of Fas ameliorated diplatin-induced cells apoptosis. Overall, we suggest that diplatin has potent anti-tumor activity, which probably acts through Fas-mediated signaling pathway. Cervical cancer is one of the leading causes of cancer death in women worldwide. [https://www.selleckchem.com/products/pf-07104091.html PF-07104091] While molecular mechanisms of initiation and cervical carcinogenesis are not well studied. Our data showed that the expression of Methyltransferase-like 3 (METTL3) was upregulated in cervical tumor tissues as compared with normal tissues. Its expression was associated with poor prognosis of cervical cancer. Knockdown of METTL3 can suppress the proliferation of cervical cancer cells. The expression of METTL3 was significantly correlated with the expression of RAB2B, one member of RAS oncogene family. Over expression of RAB2B can significantly attenuate sh-METTL3-suppressed cell proliferation. Mechanistically, METTL3 can increase the mRNA stability of RAB2B via an IGF2BP3-dependent manner. Collectively, METTL3 can trigger growth of cervical cancer cells via upregulation of RAB2B. It indicated that METTL3 might be a potential target for cervical cancer therapy. Health systems confronting the coronavirus disease 2019 (COVID-19) pandemic must plan for surges in ICU demand and equitably distribute resources to maximize benefit for critically ill patients and the public during periods of resource scarcity. For example, morbidity and mortality could be mitigated by a proactive regional plan for the triage of mechanical ventilators. Extracorporeal membrane oxygenation (ECMO), a resource-intensive and potentially life-saving modality in severe respiratory failure, has generally not been included in proactive disaster preparedness until recently. This paper explores underlying assumptions and triage principles that could guide the integration of ECMO resources into existing disaster planning. Drawing from a collaborative framework developed by one US metropolitan area with multiple adult and pediatric extracorporeal life support centers, this paper aims to inform decision-making around ECMO use during a pandemic such as COVID-19. It also addresses the ethical and practical aspects of not continuing to offer ECMO during a disaster. BACKGROUND COVID-19 is a worldwide pandemic, with many patients requiring prolonged mechanical ventilation. Tracheostomy is not recommended by current guidelines as it is considered a super-spreading event due to aerosolization that unduly risks healthcare workers. METHODS Patients with severe COVID-19 that were on mechanical ventilation ≥ 5 days were evaluated for percutaneous dilational tracheostomy. We developed a novel percutaneous tracheostomy technique that placed the bronchoscope alongside the endotracheal tube, not inside it. This improved visualization during the procedure and continued standard mechanical ventilation after positioning the inflated endotracheal tube cuff in the distal trachea. This technique offers a significant mitigation for the risk of virus aerosolization during the procedure. RESULTS From March 10 to April 15, 2020, 270 patients with COVID-19 required invasive mechanical ventilation at New York University Langone Health Manhattan's campus of which 98 patients underwent percutaneous dilational tracheostomy. The mean time from intubation to the procedure was 10.6 days (SD ±5 days). Currently, thirty-two (33%) patients do not require mechanical ventilatory support, 19 (19%) have their tracheostomy tube downsized and 8 (8%) were decannulated. Forty (41%) patients remain on full ventilator support, while 19 (19%) are weaning from mechanical ventilation. Seven (7%) died as result of respiratory and multiorgan failure. Tracheostomy related bleeding was the most common complication (5 patients). None of health care providers have developed symptoms or tested positive for COVID-19. CONCLUSIONS Our percutaneous tracheostomy technique appears to be safe and effective for COVID-19 patients and safe for healthcare workers.