Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.

Cloud computing is one of the fastest growing domains of the IT industry, however, the growth rates for each of the models on a global and local (Russian) scale have not been generalized, despite the obvious value of such analysis. Modern business and industry in Russia is going through another period of instability and at the same time is forced to follow the trend of digitalization. That is why a balanced scientific analysis and forecast of the development of cloud technologies is needed, as the main factor in improving business efficiency. The purpose of the study: is to review the main models of cloud services for modern business and industry, describing their capabilities separately and the prospects for the market as a whole. The materials for the study were analytical reports of leading consulting companies and materials from specialized web-sites. Result: The article considers cloud technologies as the main global technological trend, describes popular models of cloud services, their opportunities for business and industry. Russian and global leaders in the provision of cloud services are also described, the growth rates of these markets for each of the models are indicated. The most popular and promising cloud service models in 2022 are: UCaaS, CaaS, SaaS, IaaS, RPAaaS, PaaS. The cloud technology market will show strong growth until 2030, generating both hybrid and absolutely new service models. The private business, industrial and public sectors will increasingly move to cloud services. The main trends in the development of cloud technologies until 2030 are: hybrid cloud, artificial intelligence (AI) and cloud computing, deployment of cloud services in the planetary orbit. The results obtained are very valuable for analysts and industry experts. The above trend analysis provides valuable predictive data to research economists, investors, business and industry leaders and other stakeholders on how the cloud services market will grow in the next 5-7 years. The results of the study also have a general theoretical nature, substantiating the importance of further forecasting the development of this market (especially using mathematical methods).