[A Survey of the Use of Direct Oral Anticoagulants in Patients' Possession at the Time of Hospitalization].

The dose of direct oral anticoagulants (DOACs) must be determined based on package insert recommendations. There are reports on the rate of inappropriate DOAC dose usage defined as a dose deviating from the approved dose in the package insert but no reports on factors that led to such deviations. Thus, patients who were admitted to the Suzuka Kaisei Hospital between 1 April 2016 and 31 March 2017 were chosen as subjects. Moreover, the factors that during hospitalization led to dose deviation from the package-insert DOAC dose were retrospectively examined. The characteristics of patients administered doses deviating from the package insert were compared with those of patients in the appropriate-dose group. The finding was that the proportion concomitantly administered antiplatelet agents was higher in the underdose group. In contrast, deviations from the recommended dose did not occur when DOACs were combined with CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors. It was suggested that increase in the risk of hemorrhage by antiplatelet agents in combination with oral anticoagulants could explain deviations from the stipulated DOAC dose. In addition, a higher proportion of patients in the overdose group showed depressed Ccr, and gastrointestinal bleeding. In future, it will be necessary to propose principle-based dose changes for patients administered doses deviating from the package insert. If an underdose is administered, it is important to make a dose change that takes the concomitant drugs into consideration.

The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21.

Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) domain-containing protein 8 (SET8) is the sole enzyme that monomethylates Lys-20 of histone H4 (H4K20). SET8 has been implicated in the regulation of multiple biological processes, such as gene transcription, the cell cycle, and senescence. SET8 quickly undergoes ubiquitination and degradation by several E3 ubiquitin ligases; however, the enzyme that deubiquitinates SET8 has not yet been identified. Here we demonstrated that ubiquitin-specific peptidase 17-like family member (USP17) deubiquitinates and therefore stabilizes the SET8 protein. We observed that USP17 interacts with SET8 and removes polyubiquitin chains from SET8. USP17 knockdown not only decreased SET8 protein levels and H4K20 monomethylation but also increased the levels of the cyclin-dependent kinase inhibitor p21. As a consequence, USP17 knockdown suppressed cell proliferation. We noted that USP17 was down-regulated in replicative senescence and that USP17 inhibition alone was sufficient to trigger cellular senescence. These results reveal a regulatory mechanism whereby USP17 prevents cellular senescence by removing ubiquitin marks from and stabilizing SET8 and transcriptionally repressing p21.

The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress.

Activating transcription factor 4 (ATF4) is well known for its role in the endoplasmic reticulum (ER) stress response. ATF4 also transcriptionally induces multiple effectors that determine cell fate depending on cellular context. In addition, ATF4 can communicate both pro-apoptotic and pro-survival signals. How ATF4 mediates its prosurvival roles, however, requires further investigation. Here, we report that the CDK inhibitor p21 is a novel target gene of ATF4. We identified two ATF4-responsive elements, one of which directly binds ATF4, within the first intron of the p21 gene. Importantly, overexpression of p21 enhances cell survival following ER stress induction, while p21 knockdown increases cell death. These results suggest that p21 induction plays a vital role in the cellular response to ER stress and indicate that p21 is a prosurvival effector of ATF4.

TGF-ß induces p53/Smads complex formation in the PAI-1 promoter to activate transcription.

Transforming growth factor ß (TGF-ß) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-ß is still unknown, and it is unclear whether inhibition of TGF-ß signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-ß signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1) transcription. p53 forms a complex with Smad2/3 in the PAI-1 promoter to recruit histone acetyltransferase CREB-binding protein (CBP) and enhance histone H3 acetylation, resulting in transcriptional activation of the PAI-1 gene. Importantly, p53 is required for TGF-ß-induced cytostasis and PAI-1 is involved in the cytostatic activity of TGF-ß in several cell lines. Our results suggest that p53 enhances TGF-ß-induced cytostatic effects by activating PAI-1 transcription, and the functional switching of TGF-ß is partially caused by p53 mutation or p53 inactivation during cancer progression. It is expected that these findings will contribute to optimization of TGF-ß-targeting therapies for cancer.