Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a protein kinase A (PKA)-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin.Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.
This systematic review aims to qualitatively synthesize existing evidence on the efficacy of HIV interventions in African fishing communities. Methods: Five databases (NCBI PubMed, EMBASE, Web of Science Core Collection, The Cochrane Library, and CABI Global Health Database) were searched in March 2019 for eligible studies. All peer-reviewed papers with a defined HIV intervention explicitly mentioning African fishing communities were included. Outcomes included any measure of the efficacy of HIV interventions. Results: Of 22,289 search results, data was extracted from 25 eligible studies that passed critical appraisal; seven involved HIV prevention, six HIV testing and counseling, three treatment, and nine combinations of more than one intervention. Findings include a high coverage of safe male circumcision (SMC) but low condom use among fisher folk, and a preference for PrEP over other HIV prevention services. Uptake of HIV testing and ART coverage are below levels required to reach UNAIDS 90-90-90 targets, and there is a high demand for ART and HIV self-testing kits. Conclusions: Greater provision of services to combat HIV, specifically amongst fishing communities, is required; there is limited information on retaining fisher folk in care and achieving an undetectable viral load. Interventions tailored to individual fishing populations, offered in parallel to education or counseling services are likely to be most effective. Use of innovations, including mobile health and medical drones, could assist these hard-to-reach populations. Our findings will inform future HIV service provision in fishing communities.
Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a protein kinase A (PKA)-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin.Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.
The makers of electric cookers stress that the temperature in the average domestic cooker may vary within wide limits for a given setting. For this reason my custom" is to employ a high setting for one hour (Regulo 500, which gives a reading around 2950 in my oven). Only certain types of syringe withstand this treatment. I still feel strongly that the whole problem of syringe sterilization is too large to be tackled satisfactorily by the individual practitioner, and that such methods as are here advocated must be regarded as only second best.-I am, etc., Edinburgh.
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