NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase β and Potentiate Temozolomide-Induced DNA Damage,Senescence and Apoptosis in Colorectal Cancer Cells

Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC₅₀ of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients.     

Transmission of parasites in the coastal waters of the Arctic seas and possible effect of climate change

The review deals with the biodiversity, life cycles, distribution and temperature adaptations of parasites circulating in the coastal waters of northern polar seas. Special attention is given to helminths of marine birds, which are the most common parasites in the coastal waters. Among them, the focus is on trematodes. Factors responsible for the impoverished species composition of parasites in the Arctic are analyzed. It is shown that species without free-living larvae in the life cycle have an advantage in this environment. The abundance of cestodes and acanthocephalans in Arctic seabirds is linked with the high proportion of crustaceans in their diet. The phenomenon of nonspecific parasitism (occurrence of parasites in atypical host species) is analyzed from an evolutionary viewpoint. Characteristic features in the spatial distribution of infection of marine coastal invertebrates with parasite larvae are considered, and factors that determine it are specified. The prevalence of infection in intermediate hosts is closely connected with the abundance of final hosts, which makes it possible to estimate the abundance of final hosts in a given region and reveal trends in its changes. Trematodes have a high potential for temperature acclimation. This facilitates their transmission in the northern seas but, on the other hand, makes it unlikely that the transmission process would be intensified upon an increase in summer temperatures resulting from climate warming. However, intensification of transmission may well occur due to the prolongation of the warm season (“transmission window”), which has been predicted and is already observed. It is suggested that warming in the Arctic promotes both the entry of certain “southern” species into the Arctic and the trans-Arctic interpenetration of the North Atlantic and North Pacific parasitic faunas. A case is made for the necessity to broaden the scope of parasitological research in the Arctic and Subarctic, including parasitological monitoring at the reference sites of the sea coast.     

The Cultural-Historical Development of Mental Processes and the Theory of Stepwise Formation of Mental Actions and Concepts

The article examines the problem of the relationship between universal and specific forms of cultural–historical development of mental processes. From different methodological approaches, the author prefers an activity approach which emphasizes genetic primacy of external practical activity. This approach allows, according to the author, universality of internalization and at the same time ethnic uniqueness of mental processes. The article clarifies the problem of internalization through two practical examples: 1) the development of mental counting actions and 2) the process of human goal setting.