The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a proteolysis targeting chimera (PROTAC) results in a compound that induces degradation of FLT-3 ITD mutant at low nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting cell growth more potently than the warhead alone while inhibiting fewer off-target kinases. This enhanced antiproliferative activity occurs, despite a slight reduction in the PROTAC’s kinase inhibitory activity, via an increased level of apoptosis induction suggesting nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide a useful method for therapeutic intervention.

Background: Eating a diet that is high in vitamins and low in fat is

The “fourth industrial revolution” (FIR) is an age of advanced technology based on information and communication. FIR has a more powerful impact on the economy than in the past. However, the prospects for the labor environment are uncertain. The purpose of this study is to anticipate and prepare for occupational health and safety (OHS) issues.In FIR, nonstandard employment will be common. As a result, it is difficult to receive OHS services and compensation. Excessive trust in new technologies can lead to large-scale or new forms of accidents. Global business networks will cause destruction of workers' biorhythms, some cancers, overwork, and task complexity. The social disconnection because of an independent work will be a risk for worker's mental health. The union bonds will weaken, and it will be difficult to apply standardized OHS regulations to multinational enterprises.To cope with the new OHS issues, we need to establish new concepts of "decent work” and standardize regulations, which apply to enterprises in each country, develop public health as an OHS service, monitor emerging OHS events and networks among independent workers, and nurture experts who are responsible for new OHS issues.

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Due to their profound antiproliferative activity and unique mode of action, phenanthroindolizidine and phenanthroquinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products. In particular, a methanesulfonamide analogue of cryptopleurine (5b) exhibited improved bioavailability and significant antitumor activity, which suggests that 5b is a promising new anticancer agent. Our studies suggest that the inhibition of cancer cell growth by 5b is associated with the induction of G0/G1 cell cycle arrest via nicotinamide N-methyltransferase-dependent JNK activation in Caki-1 renal cancer cells. In addition, compound 5b significantly inhibited the migration and invasion of Caki-1 cancer cells by modulating the p38 MAPK signaling pathway.

Based on the hypothesis that the bulky selenium atom, with 4p orbitals, can sterically hinder the approach of a cellular kinase to 5'-OH for phosphorylation, 4'-selenonucleosides with one-carbon homologation were designed and synthesized via a novel seleno-Michael reaction, with the stereoselectivity controlled by steric effects. 5'-Homo-4'-selenonucleosides (n = 2) demonstrated potent antiherpes simplex virus (HSV-1) activity, indicating that the bulky selenium atom might play a key role in preventing phosphorylation by cellular kinases, resulting in no antiviral activity.

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Objectives Recently, overwork‐related disorders have become a major public health concern in Korea. This study investigated the current trends of working hours, causes of death in the working population, and compensation rates. Methods We reviewed the current trends of working hours, cause of death statistics in the working population, industrial accident compensation insurance (IACI) statistics, issues of compensation and prevention of work‐related cerebro‐cardio vascular diseases (CCVDs), mental disorders, and suicide. Results Although weekly working hours and the proportion of long working days have decreased, workers in small companies with fewer than five employees and those in the service sector continue to work long hours. The age standardized mortality due to CCVD and suicide was highest among those with managerial roles. In total, 589 CCVD cases and 104 mental disorder or suicide cases were compensated as occupational diseases in 2017. Between 2016 and 2017, 61% of 59 compensated suicides were related to overwork, specifically: long working hours, increased responsibility, or increased workload. The Korean government has introduced various policies to reduce working hours and to increase compensation approval rate for overwork‐related CCVDs. Stakeholders have called for the introduction of independent laws to prevent overwork‐related disorders, change organizational culture, and address the blind spots of the IACI Act and Labor Standard Act. Conclusions Prevention and compensation policies have improved working conditions in Korea, but there remains much to be done. This review significantly contributes to the understanding of the overall policies and research to prevent overwork‐related disorders in Korea.