Effect of Transfer Primordial Germ Cells (PGCs) into Chick Gonad

Primordial germ cells (PGCs) of white leghorn Maria line hens embryos as a donor were transferred white leghorn Laura line hens embryos as a recipient. During stage 12 to 15 of incubating fertilized eggs, donor PGCs which were taken out from blood vessels of donor embryos, were transferred into blood vessels of recipient embryos at the same stage. At 15 days of incubation, survival rate of the treated embryos was 35.7% when the PGCs were transferred into the same sex of donor and recipient embryos (homo-sexual) and 38.8% into antagonistic sex ones (hetero-sexual) respectively. Although the gonad of embryos which were transferred PCGs homo-sexually were developed normally, morphological and histological abnormalities were formed in the gonad derived with hetero-sexually transfer. The abnormalities of gonad were observed in 8 out of 33 samples transferred PCGs from male to female and 12 out of 49 from female to male respectively. Size of male right gonad was degenerated and flat sexual cords were observed. The gonads of germ line chimric chicken was detected donor derived DNA polymorphism to genetic diagnosis by LEI92 of microsatellite marker. These results suggest that hetero-sexual transfer of PGCs may influence gonadal development early-stage embryos

Drug–drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers

Controlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug–drug conjugates (DDCs) by combining the MEK inhibitor trametinib with Akt inhibitors using seven types of linkers with structural diversity. These DDCs were evaluated for their cell permeability/accumulation and ability to inhibit proliferation in RAS-mutant cell lines. A representative DDC was further evaluated for its effects on signaling proteins, induction of apoptosis-related proteins, and the stability of hepatic metabolic enzymes. These in vitro studies identified a series of DDCs, especially those containing a furan-based linker, with promising properties as agents for treating RAS-mutant cancers. Additionally, in vivo experiments in mice using the two selected DDCs revealed prolonged half-lives and anticancer efficacies comparable to those of trametinib. The DDCs developed in this study have potential as drug candidates for the broad inhibition of RAS-mutant cancers