Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis. Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies. Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects. The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer. Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address.

Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/-human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action. Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine. In conclusion, fluoxetine's cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context.

Derivatives 24-34 bearing both a 4-ketone and a 27-silyl ether group were prepared from compound 23 by silylation at C-27 with different silyl chloride reagents as shown in Scheme 4 (Supporting Information, S41-S46). Scheme 4. Synthesis of 4-Oxo-withaferin A-silyl Ether Analogues 24-34 a a Reagents and conditions: (i) R 1 R 2 R 3 SiCl, imidazol, DMAP, CH 2 Cl 2 , rt.

This is a full account of our studies into the generation of highly functionalised 2-aryl-1,2-dihydropyridines and 2-methylene-3-aryl-1,2,3,4-tetrahydropyridines via intermolecular aryne ene reactions of Hantzsch esters. Furthermore, exposure to excess aryne revealed unusual 3′-aryl-spiro[benzocyclobutene-1,1′-(3′,4′-dihydropyridines)]. Mechanistic insights are provided by deuterium-labelling studies and DFT calculations, whilst preliminary cytotoxicity investigations reveal that the spirocycles are selective against colon carcinomas over ovarian cancer cell lines and that all the compounds have high selectivity indices with regards to non-cancer cells.

Introduction: Investigating the efficacy of old drugs in infections by multidrug-resistant Gram negatives are urgently needed. We describe the design, network established, organization of clinical teams and general management support in order to effectively carry out an investigator-driven randomized clinical trial (RCT) in a public system setting. Material and Methods: An investigator-driven, randomized controlled trial endorsed by the Spanish Network for Research in Infectious Diseases was designed to investigate the efficacy of fosfomycin in the treatment of bacteremic urinary tract infections (B-UTI) due to ESBLE-EC. The study is publicly funded (PI13/01282). Challenges were: use of a pragmatic design reflecting real practice, decisions about comparator, dosing, inclusion/exclusion criteria and outcomes, sponsor, selection of centres, obtaining approval by committees, agreements signatures, and pharmacovigilance. Results: The local public research Foundation is sponsor, with delegated specific responsibilities to the CTU. Twenty-two Spanish centres were selected using feasibility tests. The study was designed as a phase III, randomised, open, multicentre, non-inferiority trial. Patients hospitalized with B-UTI caused by ESBL-EC will be selected and stratified in 1:1 ratio by centre through the automatic system design for the project (e-CRF) to receive early targeted therapy with intravenous disodium fosfomycin 4 gr/iv/6h in 60 minutes infusion (experimental arm) or intravenous meropenem 1g/iv/8h in 15 to 30 minutes infusion (control arm), stratified according to previous empirical treatment received (198 patients in total). The primary outcome is clinical and microbiological cure 5 to 7 days after the completion of treatment. Fosfomycin levels and ecological impact are being measured in a subset of patients. Conclusion: The organization of a multidisciplinary team supporting the daily work of coordination is a key point regarding issues as design, coordination, regulatory and ethical requirements for the development of investigator-drive RCTs according to International Conference Harmonization-Good Clinical Practice and 20/CE/2001. ClinicalTrials.gov identifier: NCT02142751 (registered 16-May-2014). EudraCT no: 2013-002922-21 (registered 08-May-2014).

In this paper, the rheological behaviour of a petroleum-based epoxy (EL2 laminating epoxy) was compared with the Super Sap CLR clear bio-resin epoxy. The focus of the work was on the viscous and viscoelastic performance of these epoxy resins. Rheological tests were carried out at 15, 30, and 60 min after the mixing of the pure epoxies and the hardeners at a constant temperature of 25 °C. The results obtained from the rheometer tests showed that the viscosity of both epoxy systems decreased with increasing shear rate, which is typical behaviour of a shear thinning fluid. Regarding the oscillatory rheology tests, the viscoelastic properties of both epoxy resins were studied within their linear viscoelastic region (LVER) by amplitude sweep test, which was also carried out 15, 30, and 60 min after mixing the epoxies with the hardeners. It was noticed that the petroleum-based epoxy possessed a more significant LVER relative to the bio-based resin. Finally, the storage modulus (G′), the loss modulus (G″), and the phase angle were extracted, and these parameters were investigated over low and high frequencies. From the test results, we observed that both epoxy resins showed a liquid-like viscoelastic behaviour due to their phase angle values, which were always between 45° and 90°, and by the general tendency of the G″ predominance over G′ at low and high frequencies.

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low μM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

The effect of CBD, CBG and a combination of CBD plus CBG on Haccat human skin carcinoma cells Cannabinoid pharmacology has received attention in cancer research for their potential in combating cancer (Alexander et al., 2009). The present study investigated the potential anti‐tumour activity of cannabidiol and cannabigerol on skin tumour cells. Haccat cells (American Type Culture Collection) were grown and maintained in DBEM medium plus10% fetal bovine serum at 37oC, 5% CO2 .The cells were plated in 96‐well culture plates at a density of 1x104 cells/well and allowed to adhere at 37oC for 24 hours. The following day, various doses of the compounds or were added to the cells and further incubated for 24, 48, 72 and 96 hours. Then the supernatant was removed and MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide) was added for 4 hours. The ability of cells to form formazan crystals by active mitochondrial respiration was determined after dissolving the crystals in DMSO. Cytotoxicity was expressed as a relative percentage of the absorbance measured at 540 nm. CBD induced dose‐dependent cytotoxic effect (IC50 of 4.83+1.4, 4.75+0.06; 5.22+0.3 and 5.19+1.27 micromolar for 24, 48, 72 and 96 h contact time respectively). Addition of CBG also induced cell toxicity with IC50 of 1.96+0.3, 5.5+0.34, 8.32+0.19 and 7.85+1.47 for 24, 48, 72 and 96 h respectively. A combination of CBD plus CBG induced cell toxicity with an IC50 of 2.4 + 0.05 over 96 h contact time. The data suggest a significant (p<0.001) cytotoxicity when compounds are applied in combination. We thank GW Pharmaceuticals for providing cannabinoid extracts. Grant Funding Source: University of Huddersfield