Novel Histone Deacetylase (HDAC) Inhibitor Induces Apoptosis and Suppresses Invasion via E-Cadherin Upregulation in Pancreatic Ductal Adenocarcinoma (PDAC).

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial-mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-ß (TGF ß) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-ß-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis.

Videolaryngoscopy versus direct laryngoscopy for adults undergoing tracheal intubation: a Cochrane systematic review and meta-analysis update.

BACKGROUND: Tracheal intubation is a commonly performed procedure that can be associated with complications and result in patient harm. Videolaryngoscopy (VL) may decrease this risk as compared with Macintosh direct laryngoscopy (DL). This review evaluates the risk and benefit profile of VL compared with DL in adults. METHODS: We searched MEDLINE, Embase, CENTRAL, and Web of Science on February 27, 2021. We included RCTs comparing VL with DL in patients undergoing tracheal intubation in any setting. We separately compared outcomes according to VL design: Macintosh-style, hyperangulated, and channelled. RESULTS: A total of 222 RCTs (with 26 149 participants) were included. Most studies had unclear risk of bias in at least one domain, and all were at high risk of performance and detection bias. We found that videolaryngoscopes of any design likely reduce rates of failed intubation (Macintosh-style: risk ratio [RR]=0.41; 95% confidence interval [CI], 0.26-0.65; hyperangulated: RR=0.51; 95% CI, 0.34-0.76; channelled: RR=0.43, 95% CI, 0.30-0.61; moderate-certainty evidence) with increased rates of successful intubation on first attempt and better glottic views across patient groups and settings. Hyperangulated designs are likely favourable in terms of reducing the rate of oesophageal intubation, and result in improved rates of successful intubation in individuals presenting with difficult airway features (P=0.03). We also present other patient-oriented outcomes. CONCLUSIONS: In this systematic review and meta-analysis of trials of adults undergoing tracheal intubation, VL was associated with fewer failed attempts and complications such as hypoxaemia, whereas glottic views were improved. SYSTEMATIC REVIEW REGISTRATION: This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2022, Issue 4, DOI: 10.1002/14651858.CD011136.pub3 (see www.cochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the CDSR should be consulted for the most recent version of the review.

Videolaryngoscopy versus direct laryngoscopy for adults undergoing tracheal intubation.

BACKGROUND: Tracheal intubation is a common procedure performed to secure the airway in adults undergoing surgery or those who are critically ill. Intubation is sometimes associated with difficulties and complications that may result in patient harm. While it is traditionally achieved by performing direct laryngoscopy, the past three decades have seen the advent of rigid indirect videolaryngoscopes (VLs). A mounting body of evidence comparing the two approaches to tracheal intubation has been acquired over this period of time. This is an update of a Cochrane Review first published in 2016. OBJECTIVES: To assess whether use of different designs of VLs in adults requiring tracheal intubation reduces the failure rate compared with direct laryngoscopy, and assess the benefits and risks of these devices in selected population groups, users and settings. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL and Web of Science on 27 February 2021. We also searched clinical trials databases, conference proceedings and conducted forward and backward citation searches. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs with adults undergoing laryngoscopy performed with either a VL or a Macintosh direct laryngoscope (DL) in any clinical setting. We included parallel and cross-over study designs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We collected data for the following outcomes: failed intubation, hypoxaemia, successful first attempt at tracheal intubation, oesophageal intubation, dental trauma, Cormack-Lehane grade, and time for tracheal intubation. MAIN RESULTS: We included 222 studies (219 RCTs, three quasi-RCTs) with 26,149 participants undergoing tracheal intubation. Most studies recruited adults undergoing elective surgery requiring tracheal intubation. Twenty-one studies recruited participants with a known or predicted difficult airway, and an additional 25 studies simulated a difficult airway. Twenty-one studies were conducted outside the operating theatre environment; of these, six were in the prehospital setting, seven in the emergency department and eight in the intensive care unit.  We report here the findings of the three main comparisons according to videolaryngoscopy device type. We downgraded the certainty of the outcomes for imprecision, study limitations (e.g. high or unclear risks of bias), inconsistency when we noted substantial levels of statistical heterogeneity and publication bias. Macintosh-style videolaryngoscopy versus direct laryngoscopy (61 studies, 9883 participants) We found moderate-certainty evidence that a Macintosh-style VL probably reduces rates of failed intubation (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.26 to 0.65; 41 studies, 4615 participants) and hypoxaemia (RR 0.72, 95% CI 0.52 to 0.99; 16 studies, 2127 participants). These devices may also increase rates of success on the first intubation attempt (RR 1.05, 95% CI 1.02 to 1.09; 42 studies, 7311 participants; low-certainty evidence) and probably improve glottic view when assessed as Cormack-Lehane grade 3 and 4 (RR 0.38, 95% CI 0.29 to 0.48; 38 studies, 4368 participants; moderate-certainty evidence). We found little or no clear difference in rates of oesophageal intubation (RR 0.51, 95% CI 0.22 to 1.21; 14 studies, 2404 participants) but this finding was supported by low-certainty evidence. We were unsure of the findings for dental trauma because the certainty of this evidence was very low (RR 0.68, 95% CI 0.16 to 2.89; 18 studies, 2297 participants). We were not able to pool data for time required for tracheal intubation owing to considerable heterogeneity (I2 = 96%). Hyperangulated videolaryngoscopy versus direct laryngoscopy (96 studies, 11,438 participants) We found moderate-certainty evidence that hyperangulated VLs probably reduce rates of failed intubation (RR 0.51, 95% CI 0.34 to 0.76; 63 studies, 7146 participants) and oesophageal intubation (RR 0.39, 95% CI 0.18 to 0.81; 14 studies, 1968 participants). In subgroup analysis, we noted that hyperangulated VLs were more likely to reduce failed intubation when used on known or predicted difficult airways (RR 0.29, 95% CI 0.17 to 0.48; P = 0.03 for subgroup differences; 15 studies, 1520 participants). We also found that these devices may increase rates of success on the first intubation attempt (RR 1.03, 95% CI 1.00 to 1.05; 66 studies, 8086 participants; low-certainty evidence) and the glottic view is probably also improved (RR 0.15, 95% CI 0.10 to 0.24; 54 studies, 6058 participants; data for Cormack-Lehane grade 3/4 views; moderate-certainty evidence). However, we found low-certainty evidence of little or no clear difference in rates of hypoxaemia (RR 0.49, 95% CI 0.22 to 1.11; 15 studies, 1691 participants), and the findings for dental trauma were unclear because the certainty of this evidence was very low (RR 0.51, 95% CI 0.16 to 1.59; 30 studies, 3497 participants). We were not able to pool data for time required for tracheal intubation owing to considerable heterogeneity (I2 = 99%). Channelled videolaryngoscopy versus direct laryngoscopy (73 studies, 7165 participants) We found moderate-certainty evidence that channelled VLs probably reduce rates of failed intubation (RR 0.43, 95% CI 0.30 to 0.61; 53 studies, 5367 participants) and hypoxaemia (RR 0.25, 95% CI 0.12 to 0.50; 15 studies, 1966 participants). They may also increase rates of success on the first intubation attempt (RR 1.10, 95% CI 1.05 to 1.15; 47 studies, 5210 participants; very low-certainty evidence) and probably improve glottic view (RR 0.14, 95% CI 0.09 to 0.21; 40 studies, 3955 participants; data for Cormack-Lehane grade 3/4 views; moderate-certainty evidence). We found little or no clear difference in rates of oesophageal intubation (RR 0.54, 95% CI 0.17 to 1.75; 16 studies, 1756 participants) but this was supported by low-certainty evidence. We were unsure of the findings for dental trauma because the certainty of the evidence was very low (RR 0.52, 95% CI 0.13 to 2.12; 29 studies, 2375 participants). We were not able to pool data for time required for tracheal intubation owing to considerable heterogeneity (I2 = 98%). AUTHORS' CONCLUSIONS: VLs of all designs likely reduce rates of failed intubation and result in higher rates of successful intubation on the first attempt with improved glottic views. Macintosh-style and channelled VLs likely reduce rates of hypoxaemic events, while hyperangulated VLs probably reduce rates of oesophageal intubation. We conclude that videolaryngoscopy likely provides a safer risk profile compared to direct laryngoscopy for all adults undergoing tracheal intubation.

Pseudopterosin and O-Methyltylophorinidine Suppress Cell Growth in a 3D Spheroid Co-Culture Model of Pancreatic Ductal Adenocarcinoma.

Current therapies for treating pancreatic ductal adenocarcinoma (PDAC) are largely ineffective, with the desmoplastic environment established within these tumors being considered a central issue. We established a 3D spheroid co-culture in vitro model using a PDAC cell line (either PANC-1 or Capan-2), combined with stellate cells freshly isolated from pancreatic tumors (PSC) or hepatic lesions (HSC), and human type I collagen to analyze the efficiency of the chemotherapeutic gemcitabine (GEM) as well as two novel drug candidates derived from natural products: pseudopterosin (PsA-D) and O-methyltylophorinidine (TYLO). Traditional 2D in vitro testing of these agents for cytotoxicity on PANC-1 demonstrated IC50 values of 4.6 (±0.47) nM, 34.02 (±1.35) µM, and 1.99 (± 0.13) µM for Tylo, PsA-D, and GEM, respectively; these values were comparable for Capan-2: 5.58 (±1.74) nM, 33.94 (±1.02) µM, and 0.41 (±0.06) µM for Tylo, PsA-D, and GEM, respectively. Importantly, by assessing the extent of viable cells within 3D co-culture spheroids of PANC-1 with PSC or HSC, we could demonstrate a significant lack of efficacy for GEM, while TYLO remained active and PsA-D showed slightly reduced efficacy: GEM in PANC-1/PSC (IC50 = >100 µM) or PANC-1/HSC (IC50 = >100 µM) spheroids, TYLO in PANC-1/PSC (IC50 = 3.57 ± 1.30 nM) or PANC-1/HSC (IC50 = 6.39 ± 2.28 nM) spheroids, and to PsA-D in PANC-1/PSC (IC50 = 54.42 ± 12.79 µM) or PANC-1/HSC (IC50 = 51.75 ± 0.60 µM). Microscopic 3D rendering supported these cytotoxicity outcomes, showing little or no morphological spheroid structure change during this period of rapid cell death. Our results support the use of this 3D spheroid co-culture in vitro model having a desmoplastic microenvironment for the identification of possible novel chemotherapeutic drug candidates for PDAC, such as TYLO and PsA-D.