Four modeling approaches to study restrictions on everyday life and social activities due to chronic diseases with consequences of suicidal behavior.

The purpose of this study was to discover the association between disability in everyday life and social activities due to chronic diseases and suicidal ideation (SI), suicidal plan (SP), and suicidal attempt (SA) from the Korea National Health and Nutrition Examination Survey (KNHANES), considering the cross-sectional design of this study, 2016-2018 dataset. Variables for finding the associated factors of SI, SP, and SA were confirmed through random forest (RF), decision tree, generalized linear model (GLM), and support vector machine (SVM), and the performance of each model is listed. A total of 17,323 (males: 7,530, females: 9793) responders from the KNHANES from 2016 to 2018 were employed for the study. The relationship between restrictions on daily life, social activities, and three stages of suicidal behaviors due to diseases were analyzed using the R function (R version 4.2.0), randomForest, ctree, glm, and ksvm. The F1-score is a measure used to evaluate the accuracy of the performance of a model, in the binary classification. The score of 1 indicates good performance, whereas a score of 0 signifies poor performance. Due to chronic diseases, disability in everyday life and social activities lead to suicide behaviors. In our study, we examined the impact of limitations in daily living and social activities on suicidal behaviors among participants. Our findings revealed that for those experiencing such limitations, the odds ratios (ORs) for SIs were 6.10 (95% CI: 3.99-9.34) for males and 2.61 (1.79-3.81) for females. SPs were 3.69 (2.36-5.78) for males and 3.94 (2.70-5.75) for females. Similarly, the odds ratios for SAs were 5.04 (2.51-10.13) for males and 2.71 (1.48-4.98) for females, indicating a significant association between these limitations and increased suicidal behaviors, with variances observed between genders. These results underscore the necessity of addressing daily living and social activity restrictions when considering mental health interventions and suicide prevention strategies. In RF, GLM, and SVM, F1-score were 0.8192, 0.6887, and 0.9687 in SA, respectively. Among the patients with chronic disease, those with sequelae, low incomes, and low levels of education had limitations in daily activities and social activities, which increased the likelihood of suicidal thoughts, planning, and attempts.

Discovery of a novel CDK7 inhibitor YPN-005 in small cell lung cancer.

In contrast to non-small cell lung cancer, there has been no significant progress in the development of therapies for the small cell lung cancer (SCLC) in recent decades. Although various targeted agents, including immunotherapies, have recently been developed for testing in clinical trials, novel therapeutic agents are still needed for SCLC. We developed a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated YPN-005, and sought to determine whether it showed any anticancer effects in SCLC cells, cisplatin or etoposide-resistant cells, or organoids derived from SCLC patients. In a panel of kinases assay, YPN-005 was highly selective for CDK7 and showed antiproliferative effects in SCLC and cells with acquired resistance to conventional anticancer drugs. Similar to other CDK7 inhibitors, YPN-005 treatment significantly decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Consistent with the in vitro results, YPN-005 treatment showed a significant inhibition of tumor growth through the suppression of RNA polymerase II phosphorylation. Finally, YPN-005 showed potent anticancer effects in organoids derived from SCLC patients compared to another CDK7 inhibitor, THZ1. Therapeutic targeting of CDK7 in SCLC might be suitable for clinical investigation, and YPN-005 may be a promising therapeutic option for primary SCLC and SCLC with acquired resistance to conventional therapy.

Usual alcohol consumption and suicide mortality among the Korean elderly in rural communities: Kangwha Cohort Study.

BACKGROUND: The evidence from prospective studies on whether greater usual alcohol consumption is associated with a higher risk of death by suicide in the general population is inconclusive. METHODS: 6163 participants (2635 men; 3528 women) in a 1985 survey among rural residents in Korea aged 55 years and above were followed until 2008. A Cox model was used to calculate HRs of suicide death after adjustment for demographic, socioeconomic and health-related confounders. RESULTS: 37 men and 24 women died by suicide. Elderly persons who consumed alcohol daily, 70 g alcohol (5 drinks) or more per drinking day, or 210 g alcohol (15 drinks) or more per week had higher suicide mortality (p<0.05), compared with non-drinkers. An increase of one drinking day per week (HR=1.17, 95% CI 1.05 to 1.31), 70 g (5 drinks) additional alcohol intake per drinking day (HR=1.38, 95% CI 1.13 to 1.70), and 140 g (10 drinks) additional alcohol intake per week was associated with a 17%, 38% and 12% higher risk of suicide death, respectively. Women had a higher relative risk of suicide death associated with alcohol consumption, compared with men. CONCLUSIONS: A greater frequency and amount of usual alcohol consumption was linearly associated with higher suicide death. Given the same amount of alcohol consumption, women might have a higher relative risk of suicide than men. Our findings support 'the lower the better' for alcohol intake, no protective effect of moderate alcohol consumption, and a sex-specific guideline (lower alcohol threshold for women) as actions to prevent suicide death.

Synthesis of proline analogues as potent and selective cathepsin S inhibitors.

Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor.

[Violent experiences and coping among home visiting health care workers in Korea].

PURPOSE: The purpose of this study was to explore violent experiences of home visiting health care workers in Korea. METHODS: This study was a cross-sectional survey. Data were collected using self-report questionnaires from 1,640 health care workers. Data collection was done between September 1, 2009 and June 30, 2010. RESULTS: Of the respondents, 70.6% had experienced work-related violence. Shouting (51.9%) was the most common verbal violence, followed by verbalizing sexual remarks to the health care workers (19.0%) and touching the hands (16.5%), the most common acts relating to sexual harassment. Of the respondents who had experienced violence, 50.9% told their peers about the incidents. However, the major reasons why they did not report these incidents was due to the fact that they felt it was useless to file reports and that they expected such incidents to occur as part of their job. The majority of the respondents (86.4%) wanted education on how to deal with such violence at work. CONCLUSION: The results of this study indicate that efforts should be made to increase awareness and to minimize violence in the workplace. Also, educational programs should be designed to improve knowledge and to prevent workplace violence.

Synthesis and biological evaluation of pyrimidine-based dual inhibitors of human epidermal growth factor receptor 1 (HER-1) and HER-2 tyrosine kinases.

A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.

Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models.

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.

Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer.

A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6-yl]pyrrolidine-2-carboxamides were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhibitors of Her-1 and Her-2 tyrosine kinases with the potential to overcome clinically relevant, mutation-induced drug resistance. The selected compounds (19c, 19d) showed excellent EGFR inhibition activity even toward the T790M mutation of Her-1 tyrosine kinase with excellent selectivity. The excellent pharmacokinetic profiles of these compounds in rats and their robust in vivo efficacy in an A431 xenograft model clearly demonstrate that they merit further investigation as novel therapeutic agents for EGFR-targeting treatment of solid tumors, especially Her-1 selective inhibitor-resistant non-small cell lung cancer.

Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor alpha and gamma dual agonists.

In an effort to develop dual PPARalpha/gamma activators with improved therapeutic efficacy, a series of diaryl alpha-ethoxy propanoic acid compounds comprising two aryl groups linked by rigid oxime ether or isoxazoline ring were designed and synthesized and their biological activities were examined. Most of the compounds possessing an oxime ether linker were more potent PPARgamma activators than the lead PPARalpha/gamma dual agonist, tesaglitazar in vitro. Compound 18, one of the derivatives with an oxime ether linker, was found to selectively transactivate PPARgamma (EC 50 = 0.028 microM) over PPARalpha (EC 50 = 7.22 microM) in vitro and lower blood glucose in db/ db mice more than muraglitazar after oral treatment for 11 days.

Design, synthesis, and structure-activity relationship of carbamate-tethered aryl propanoic acids as novel PPARalpha/gamma dual agonists.

We have developed a new class of PPARalpha/gamma dual agonists, which show excellent agonistic activity in PPARalpha/gamma transactivation assay. In particular, (R)-9d was identified as a potent PPARalpha/gamma dual agonist with EC(50)s of 0.377 microM in PPARalpha and 0.136 microM in PPARgamma, respectively. Interestingly, the structure-activity relationship revealed that the stereochemistry of the identified PPARalpha/gamma dual agonists significantly affects their agonistic activities in PPARalpha than in PPARgamma.

Novel potent antagonists of transient receptor potential channel, vanilloid subfamily member 1: structure-activity relationship of 1,3-diarylalkyl thioureas possessing new vanilloid equivalents.

Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.

Synthesis of C4-modified acanthoic acid analogs and their biological evaluation as nitric oxide inhibitors.

Synthesis and biological evaluation of a series of C4-modified acanthoic acid analogs are reported. Among them, the analog 7 and 10 exhibit potent cellular inhibitory activity in NO inhibition assay.

Syntheses and anti-MRSA activities of the C3 analogs of mansonone F, a potent anti-bacterial sesquiterpenoid: insights into its structural requirements for anti-MRSA activity.

Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of mansonone F are essential for anti-MRSA activities.

CoMFA and CoMSIA 3D QSAR studies on pimarane cyclooxygenase-2 (COX-2) inhibitors.

Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on twenty five analogues of pimarane COX-2 inhibitor to optimize their cyclooxygenase-2 (COX-2) selective anti-inflammatory activities.

Synthesis and anti-inflammatory effects of novel pimarane diterpenoid analogs.

Syntheses and excellent anti-inflammatory effects of a series of novel acanthoic acid analogs are reported. In particular, the mechanistic basis for their anti-inflammatory effects is also described.

Asymmetric total synthesis of bacillariolide III, a marine oxylipin.

[reaction: see text] The asymmetric total synthesis of bacillariolide III has been achieved via 15 linear steps in 14.6% overall yield. The key feature of this synthetic route involves the highly stereoselective construction of the vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed allylic alkylation and its facile conversion to the hydroxy bicyclic lactone skeleton of bacillariolide III, induced by stereoselective vinylcerium addition to the aldehyde. In addition, the (Z)-pentenoic acid was efficiently introduced by the internal hydroxy group tethered ring-closing metathesis (RCM).