The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma, but their mechanism of action remains unclear. We used cannabinoids ...specific for the CB1 (ACPA) and CB2 (GW) receptors and metabolomic analyses to unravel the potential pathways mediating cannabinoid-dependent inhibition of pancreatic cancer cell growth. Panc1 cells treated with cannabinoids show elevated AMPK activation induced by a ROS-dependent increase of AMP/ATP ratio. ROS promote nuclear translocation of GAPDH, which is further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determine the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibits the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway leads to decreased activity of both the pyruvate kinase isoform M2 (PKM2), further downregulating glycolysis, and glutamine uptake. Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.
Gemcitabine (GEM, 2',2'-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition ...of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl-L-cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells.
Pancreatic cancer stem cells (CSCs) are responsible for resistance to standard therapy, metastatic potential, and disease relapse following treatments. The current therapy for pancreatic ductal ...adenocarcinoma (PDAC) preferentially targets the more differentiated cancer cell population, leaving CSCs as a cell source for tumor mass formation and recurrence. For this reason, there is an urgent need to improve current therapies and develop novel CSC-targeted therapeutic approaches.
Hyaluronic acid (HA) decorated liposomes, containing diethyldithiocarbamate‑copper (Cu(DDC)2), able to target the specific CSC marker CD44 receptor were prepared by ion gradient technique and fully characterized. Their antiproliferative effect was evaluated on pancreatic CSCs derived from PDAC cell lines or patients. To clarify the mechanism of action of Cu(DDC)2 liposomes, ROS level neutralization assay in the presence of N-acetyl-L-cysteine was performed.
Liposomes showed high encapsulation efficiency and Cryo-TEM analysis revealed the presence of Cu(DDC)2 crystals in the aqueous core of liposomes. In vitro test on pancreatic CSCs derived from PDAC cell lines or patients showed high ROS mediated anticancer activity of HA decorated liposomes. The sphere formation capability of CSCs obtained from patients was drastically reduced by liposomal formulations containing Cu(DDC)2.
The obtained results show that the encapsulation of Cu(DDC)2 complex in HA decorated liposomes strongly increases its anti-proliferative activity on pancreatic CSCs.
This paper describes for the first time the use of HA decorated liposomes containing Cu(DDC)2 against pancreatic CSCs and opens the way to the development of nanomedicine based CSC-targeted therapeutic approaches.
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•Cu(DDC)2 has a stronger anti-proliferative activity than DSF, Zn(DDC)2 and Fe(DDC)2.•Cu(DDC)2 containing HA coated liposomes have a strong anti-proliferative activity on CSCs.•Cu(DDC)2 complexes precipitated inside the aqueous core of liposomes in the form of crystals.•Anti-proliferative activity of Cu(DDC)2 containing liposomes is ROS mediated.
This book sets out to investigate the relationship between crime and the design and planning of housing, and to produce practical recommendations to help architects and planners to reduce crime. It ...builds upon and updates research originally published in Crime Free Housing (1991), providing an easily accessible, high quality and well presented account of crime and housing layout.
The recommendations of this book focus on ways of reducing four different types of crime through better design:
burglary - a strategy to discourage people trying to break into houses
car crime - a strategy for providing a safe place to park cars
theft around the home - a strategy for protecting the front of house, items in gardens, sheds and garages safe
criminal damage - a strategy to minimize malicious damage to property.
What makes good foster parents? Dando, I; Minty, B
The British journal of social work,
08/1987, Letnik:
17, Številka:
Aug 87
Journal Article
Recenzirano
Attempts to describe the characteristics, personal background and motivation of all the foster mothers used by 2 inner city teams who had had at least one child placed with them for a year or more. ...The chief motivations and childhood experiences of the foster mothers were compared with ratings made by the fostering officers of their excellence as foster parents. The study confirmed the importance of a desire to parent a child, when it was impossible to conceive a child of one's own; and an identification with deprived children as a result of unhappy experiences in childhood--experiences which the foster mothers had had the resilience to cope with, and use creatively. Discusses other findings. (Abstract amended)
Purpose: The treatment and long term clinical outcomes of anorectal malformations (ARM) in children have always been the focus of pediatric surgeons. This study aimed at reporting our experience as ...far as long-term follow-up of ARM in children is concern. Methods: We enrolled patients treated between 1999 and 2019, and established selection criteria to choose appropriate subjects. A validated questionnaire was used to determine long-term quality of life outcomes. Results: Out of a total of 48 patients treated within the study period, 28 were enrolled in this study. Among the latter, more than 35% had at least one long-time complication, and more than 90% had a good lifestyle. Urinary and fecal continence was achieved in more than 95% of the patients using medical devices. Conclusion: This study aimed to bring up new concepts; taking into consideration all aspects of life in patients with ARM, from school life to sexuality, while evaluating fecal and urinary continence. This is essential for the improvement of the skills of the different specialists involved in the management of these patients, and for the implementation of strategies that can improve postoperative function. Most especially, it will also help improve communication between doctors to ensure an adequate transition of these children into adult life.
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