Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A.

Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 µM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

Cavomycins A-C, Linear Oligomer Depsipeptides from an Annelid-Associated Streptomyces cavourensis.

Three unique linear oligomeric depsipeptides, designated as cavomycins A-C (1-3), were identified from Streptomyces cavourensis, a gut bacterium associated with the annelid Paraleonnates uschakovi. The structures of these depsipeptides were determined through a combination of spectroscopic methods and chemical derivatization techniques, including methanolysis, the modified Mosher's method, advanced Marfey's methods, and phenylglycine methyl ester derivatization. The unique dipeptidyl residue arrangements in compounds 1-3 indicate that they are not degradation products of valinomycin. Compound 2 and its methylation derivative 2a exhibited antiproliferative activity against PANC-1 pancreatic cancer cells with IC50 values of 1.2 and 1.7 µM, respectively.

High remnant-cholesterol levels increase the risk for end-stage renal disease: a nationwide, population-based, cohort study.

BACKGROUND: The effect of remnant-cholesterol (remnant-C) on incident end-stage renal disease (ESRD) has not been studied longitudinally. This retrospective cohort study evaluated the association between remnant-C and the development of ESRD in a nationwide Korean cohort. METHODS: Participants in a National Health Insurance Service health examination (n = 3,856,985) were followed up until the onset of ESRD. The median duration of follow-up was 10.3 years. The Martin-Hopkins equation was used to determine low-density lipoprotein cholesterol (LDL-C) levels from directly measured triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol levels. Remnant-C levels were determined by subtracting HDL-C and LDL-C from total cholesterol. The risk for incident ESRD was calculated for each quartile of remnant-C, adjusting for conventional risk factors such as baseline renal function, comorbidities, and total cholesterol levels. RESULTS: ESRD developed in 11,073 (0.29%) participants. The risk for ESRD exhibited a gradual increase according to higher levels of remnant-C, with a 61% increased risk in the highest quartile than in the lowest (hazard ratio [HR] 1.61 [95% confidence interval (CI) 1.50-1.72]). The elevated risk for ESRD in the highest quartile versus the lowest quartile was more prominent in younger than in older subjects (20-29 years, HR 4.07 [95% CI 2.85-5.83]; 30-39 years, HR 2.39 [95% CI 1.83-3.13]; ≥ 70 years, HR 1.32 [95% CI 1.16-1.51]). In addition, the increased risk for ESRD related to higher remnant-C levels was greater in females than in males. CONCLUSIONS: Independent of conventional risk factors, remnant-C levels were positively associated with incident ESRD, particularly in younger populations and adult females. Reducing remnant-C levels may be a novel preventive strategy against ESRD.

Cholecystectomy Increases the Risk of Type 2 Diabetes in the Korean Population: Data From the National Health Insurance Cooperation Health Checkup 2010-2017.

OBJECTIVE: This study assessed whether cholecystectomy is a risk factor for newly developed type 2 diabetes mellitus (T2DM) in the Korean population. BACKGROUND: There is a lack of evidence that cholecystectomy is independently associated with insulin resistance and T2DM. METHODS: This study included all patients aged more than 20 years who had undergone cholecystectomy from 2010 to 2015 (n=55,166) and age-matched and sex-matched control subjects without cholecystectomy (n=110,332) using the National Health Insurance Service database. They were followed up until the date of newly developed T2DM or study end and the incidence of T2DM was traced over a maximum observation period of 7 years. RESULTS: Overall, 55,166 patients who underwent cholecystectomy and 110,332 age-matched and sex-matched controls were followed up for ∼4.7 years, during which, incident T2DM occurred in 5982 (3.61%) patients. Cholecystectomy was associated with 20% higher risk of T2DM after adjustment for all covariates. The cumulative incidence of T2DM also significantly increased in the cholecystectomy group for ∼7 years ( P <0.001). The adjusted hazard ratio (HR) for T2DM was the highest in the group with both cholecystectomy and obesity using the control without both cholecystectomy and obesity as a reference [HR=1.41, 95% confidence interval (CI): 1.29-1.56]. The group with cholecystectomy without obesity showed the comparable risk of incident T2DM compared with the group without cholecystectomy with obesity (HR=1.29, 95% CI: 1.20-1.40 for cholecystectomy without obesity and HR=1.24, 95% CI: 1.14-1.36 for control with obesity). CONCLUSIONS: These results provide evidence that cholecystectomy is associated with an increased risk of newly developed T2DM in the Korean population. Further research is required to elucidate the mechanism of the association between cholecystectomy and incident diabetes.

Bioactive Piperazic Acid-Bearing Cyclodepsipeptides, Lydiamycins E-H, from an Endophytic Streptomyces sp. Associated with Cinnamomum cassia.

A chemical investigation of the endophytic Streptomyces sp. HBQ95, associated with the medicinal plant Cinnamomum cassia Presl, enabled the discovery of four new piperazic acid-bearing cyclodepsipeptides, lydiamycins E-H (1-4), and one known compound (lydiamycin A). Their chemical structures, including absolute configurations, were defined by a combination of spectroscopic analyses and multiple chemical manipulations. Lydiamycins F-H (2-4) and A (5) exhibited antimetastatic activity against PANC-1 human pancreatic cancer cells without significant cytotoxicity.

Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity.

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Hormonal Gut-Brain Signaling for the Treatment of Obesity.

The brain, particularly the hypothalamus and brainstem, monitors and integrates circulating metabolic signals, including gut hormones. Gut-brain communication is also mediated by the vagus nerve, which transmits various gut-derived signals. Recent advances in our understanding of molecular gut-brain communication promote the development of next-generation anti-obesity medications that can safely achieve substantial and lasting weight loss comparable to metabolic surgery. Herein, we comprehensively review the current knowledge about the central regulation of energy homeostasis, gut hormones involved in the regulation of food intake, and clinical data on how these hormones have been applied to the development of anti-obesity drugs. Insight into and understanding of the gut-brain axis may provide new therapeutic perspectives for the treatment of obesity and diabetes.

SARS-CoV-2 Infectivity and Antibody Titer Reduction for 6 Months After Second Dose of BNT162b2 mRNA Vaccine in Health Care Workers: A Prospective Cohort Study.

Several studies reported that severe acute respiratory syndrome coronavirus-2 antibody levels change over 6 months in participants receiving the vaccination. From the enrolled 272 health care workers (HCWs), blood samples were obtained at 2, 16, and 24 weeks after the second vaccination dose. In the 267 noninfected HCWs, the neutralizing antibodies decreased by 23.9%, and the anti-spike/receptor binding domain antibody decreased by 53.8% at 24 weeks. We observed no significant difference in antibody reduction between the sexes; however, in younger individuals, there was higher antibody formation and lower reduction rates of the neutralizing antibody. In 3 HCWs with breakthrough infections, the antibody levels were relatively low just before the coronavirus disease 2019 infection. In conclusion, as antibody titers decrease over time after the second vaccination dose and HCWs with low antibody titers tend to have a high probability of breakthrough infection, an additional dose should be considered after several months. Blood samples were obtained from health care workers at 2, 16, and 24 weeks after a second vaccination dose. Antibody titers decreased over time and the participants with low antibody titers tended to have a high probability of breakthrough infection.

Remnant cholesterol and the risk of cardiovascular disease in type 2 diabetes: a nationwide longitudinal cohort study.

BACKGROUND: Elevated remnant cholesterol (remnant-C) is considered a risk factor for cardiovascular disease (CVD); however, whether this notion applies to the East Asian population with type 2 diabetes (T2D) has not been established. This study investigated the association between remnant-C concentrations and the risk of CVD in Korean patients with T2D. METHODS: By using the Korean National Health Insurance Service database, 1,956,452 patients with T2D and without atherosclerotic CVD who underwent regular health checks between 2009 and 2012 were included. Cox regression analyses were conducted to assess the association between remnant-C concentrations and incident CVD comprising myocardial infarction (MI) and ischemic stroke. RESULTS: In total, 50,120 (2.56%) cases of MI and 73,231 (3.74%) cases of ischemic strokes occurred during a median follow-up of 8.1 years. The adjusted hazard ratios for MI and stroke in the highest remnant-C quartile were 1.281 (95% confidence interval [CIs], 1.249-1.314) for MI and 1.22 (1.195-1.247) for ischemic stroke, compared to those in the lowest quartiles. The results were similar, based on stratified analysis by age, sex, use of statin or fibrate, and levels of other cholesterol. The increased risk of CVD in the highest remnant-C quartile was profound in patients who had a longer T2D duration. A remnant-C concentration ≥ 30 mg/dL differentiated patients who were at a higher risk of CVD, compared to patients with a lower concentrations, regardless of whether LDL-C levels were or were not on target at ≤ 100 mg/dL. CONCLUSION: In Korean patients with T2D, remnant-C was associated with CVD, independent of the LDL-C level or other conventional CVD risk factors. Our finding confirmed evidence of the causal role of remnant-C on CVD, as a residual risk of CVD, in East Asian patients with T2D.

Implications of fasting plasma glucose variability on the risk of incident peripheral artery disease in a population without diabetes: a nationwide population-based cohort study.

BACKGROUND: Diabetes have been known as a traditional risk factor of developing peripheral artery disease (PAD). However, the study evaluating the impact of long-term glycemic variability on the risk of developing PAD is limited, especially in a general population without diabetes. METHODS: We included 152,931 individuals without diabetes from the Korean National Health Insurance Service-Health Screening Cohort. Fasting plasma glucose (FPG) variability was measured using coefficient variance (FPG-CV), standard deviation (FPG-SD), and variability independent of the mean (FPG-VIM). RESULTS: A total of 16,863 (11.0%) incident cases of PAD were identified during a median follow-up of 8.3 years. Kaplan-Meier curves showed a progressively increasing risk of PAD in the higher quartile group of FPG variability than in the lowest quartile group (log rank P < 0.001). Multivariable Cox proportional hazard analysis showed the hazard ratio for PAD prevalence as 1.11 (95% CI 1.07-1.16, P < 0.001) in the highest FPG-CV quartile than in the lowest FPG-CV quartile after adjusting for confounding variables, including mean FPG. Similar degree of association was shown in the FPG-SD and FPG-VIM. In sensitivity analysis, the association between FPG variability and the risk of developing PAD persisted even after the participants were excluded based on previously diagnosed diseases, including stroke, coronary artery disease, congestive heart failure, chronic kidney disease, or current smokers or drinkers. Subgroup analysis demonstrated that the effects of FPG variability on the risk of PAD were more powerful in subgroups of younger age, regular exercisers, and those with higher income. CONCLUSIONS: Increased long-term glycemic variability may have a significant prognostic effect for incident PAD in individuals without diabetes.

Impact of urinary iodine concentration on blood glucose levels and blood pressure: a nationwide population-based study.

PURPOSE: Iodine is a vital trace element for systemic metabolic control as well as thyroid hormone synthesis. Though iodine has significant antioxidant and anti-inflammatory effects, reports on its effects on metabolic disorders are limited and inconsistent. METHODS: Impact of urinary iodine concentrations (UICs) on fasting blood glucose (FBG) levels and blood pressure (BP) in the general Korean population was evaluated adjusting for covariates including thyrotropin level and presence of thyroid diseases. RESULTS: The median UIC was 302.3 µg/L in all participants and was significantly lower in those with dysglycemia (303.6 µg/L in normal participants, 285.1 µg/L in participants with FBG levels of 100-125 mg/dL, and 261.8 µg/L in participants with FBG levels ≥ 126 mg/dL; p = 0.002). Similarly, the UIC was lower in participants with higher BP (311.6 µg/L in normal participants, 288.7 µg/L in prehypertensive participants, and 265.8 µg/L in hypertensive participants; p < 0.001). The multiple linear regression model showed a negative correlation between the UIC and FBG levels (p = 0.002), and the UIC and systolic BP (p < 0.001). One standard deviation increase in the UIC showed odds ratios of 0.84 (95% confidence interval [CI] = 0.73-0.98) for elevated FBG levels (≥ 100 mg/dL) and 0.94 (95% CI = 0.88-0.99) for elevated SBP (≥ 120 mm Hg) after full adjustment. CONCLUSION: Higher UICs were associated with lower FBG and BP levels, independent of thyroid function and other confounding factors in Korea, an iodine-replete country.

Design, synthesis, and biological evaluation of pseudo-bicyclic pyrimidine-based compounds as potential EGFR inhibitors.

Cancer is one of the most dangerous diseases harvesting millions of lives every year globally, which mandates the development of new therapies. In this report, we designed and synthesized a novel series of compounds based on the structure of lapatinib and AF8c, a compound we developed and reported previously, to target EGFR kinase. The series was assayed against a panel of 60 cancer cell lines at the National Cancer Institute (NCI). Compounds 4a, 4f, 4 g, and 4 l showed high efficacy against melanoma, colon, and blood cancers, with 4a being the most effective. The evaluation of the potency of 4a against the 60 cell lines in a five-dose assay revealed a significant potency compared to lapatinib against melanoma, colon, and blood cancers. In vitro enzyme assay over 30 kinases showed significant potency against EGFR and high selectivity to EGFR among the tested kinases. A molecular modeling study of 4a and lapatinib inside the pockets of EGFR revealed that both compounds bind strongly inside the ATP-binding pocket of the EGFR kinase domain. Therefore, we present 4a as a novel EGFR kinase inhibitor with potent in vitro cellular activity against diverse types of cancer cells.

Characteristics of Korean BCR-ABL1-Negative Myeloproliferative Neoplasms Related to the 2016 WHO Criteria Revision.

BACKGROUND: We aimed to identify changes in the diagnosis and subtype classification of Korean patients with BCR-ABL1-negative MPN related to the revision of the WHO classification in 2016. METHODS: We evaluated 76 Korean patients with BCR-ABL1-negative MPN who underwent diagnostic work-ups, including bone marrow (BM) examinations and JAK2 V617F mutation analysis, from January 2013 to June 2018. Additionally, we reclassified the subtype of 43 patients who were diagnosed based on the WHO 2008 classification. RESULTS: From January 2013 to April 2016, 43 patients were diagnosed with BCR-ABL1-negative MPN (12 PV, 17 ET, 14 PMF) according to the 2008 WHO classification, and from May 2016 to June 2018, 33 patients were diagnosed according to the 2016 classification (15 PV, 11 ET, 7 PMF). With the application of 2016 classification, 3 cases of ET were reclassified as pre-PMF, and the proportion of PV increased from 27.9% to 45.5%. There were significant differences in CBC between pre-PMF and overt PMF, between ET and overt-PMF, but no difference between ET and pre-PMF. CONCLUSIONS: The overall characteristics of BCR-ABL1-negative MPN patients were not significantly different from those of previous reports. 'Masked PV', which could not be diagnosed according to the WHO 2008 classification, may have been diagnosed as PV since 2016 due to the increase in the diagnostic value of the BM findings and the lowering of the hemoglobin (Hb) threshold.

Ecological factors influencing parenting self-efficacy among working mothers with a child under 36 month old in South Korea: a cross-sectional and correlational study.

BACKGROUND: Parenting self-efficacy is an essential component for parents to successfully perform their role and is important for mother and child well-being. To support parenting self-efficacy amongst working mothers, it is necessary to understand the factors influencing parenting self-efficacy amongst this group. However, the majority of previous studies regarding factors influencing parenting self-efficacy did not focus on working mothers. Therefore, this study aimed to identify the factors influencing parenting self-efficacy of working mothers using an ecological framework. METHODS: The research design was a cross-sectional, correlational study. The participants were 298 working mothers with a child under 3 years of age, who were recruited from ten nurseries. Data were collected from August 8 to September 22, 2017 using structured questionnaires, including the Parenting Sense of Competency scale, a one-item Short Form Health Survey scale, the Maternal Role Satisfaction scale, the Parenting Stress Inventory, the Work and Parent Role Conflict scale, the Parenting Alliance Inventory, the Social Support scale, and the Childbirth and Parenting Friendly System scale. The study process of this study was approved by the Institutional Review Board. Collected data were analyzed by SPSS 23.0 Win program with descriptive statistics, t-test, one way ANOVA, Pearson correlation coefficient, and hierarchical multiple regression. RESULTS: Working mothers who were the primary caregiver had higher parenting self-efficacy compared to those who were not the primary caregiver (ß = .13, p = .022). At the individual level, the higher maternal role satisfaction, the higher parenting self-efficacy of working mothers (ß = .27, p < .001). In the micro-system level, higher parenting support by a spouse was associated with higher parenting self-efficacy of working mothers (ß = .19, p = .002). CONCLUSIONS: Educational interventions for increasing the awareness and satisfaction of maternal role and various strategies for fathers' active participation in parenting should be developed. In addition, practical interventions that reduce the burden of parenting while supporting parenting self-efficacy of working mothers who are the primary caregiver should also be considered.

The effect of sex and physical frailty on incident disability after 2 years among community-dwelling older adults: KFACS study.

BACKGROUND: This study investigated the impact of physical frailty on the development of disabilities in mobility, activities of daily living (ADL), and instrumental activities of daily living (IADL) according to sex among community-dwelling Korean older adults. METHODS: We used data of 2,905 older adults aged 70-84 years from the Korean Frailty and Aging Cohort Study (KFACS) at baseline (2016-2017) and Wave 2 (2018-2019). Fried's physical frailty phenotype was used to identify frailty. RESULTS: After adjustment, frailty showed a higher impact for women than men on developing mobility disability (odds ratio [OR]=14.00, 95% confidence interval [CI]=4.8-40.78 vs. OR=9.89, 95% CI=4.28-22.86) and IADL disability after two years (OR=7.22, 95% CI=2.67-19.56 vs. OR=3.19, 95% CI=1.17-8.70). Pre-frailty led to mobility disability for women and men (OR=2.77, 95% CI=1.93-3.98 vs. OR=2.49, 95% CI=1.66-3.72, respectively), and IADL disability only for women (OR=3.01, 95% CI=1.28-7.09). Among the IADL components, both men and women who were prefrail or frail showed increased disability in 'using transportation'. Among men, pre-frailty was significantly associated with disability in "going out" and "shopping". In women, frailty was significantly associated with disability in "doing laundry," "performing household chores," "shopping," and "managing money". CONCLUSIONS: Physical frailty increased disability over 2 years for women more than men. Physical frailty increased disability in outdoor activity-related IADL components in men and household work-related IADL components in women. This study highlights the need for gender-specific policies and preventative programs for frailty, particularly restorative interventions that focus on women who are physically frail.

Strong SARS-CoV-2 Antibody Response After Booster Dose of BNT162b2 mRNA Vaccines in Uninfected Healthcare Workers.

Despite strict guidelines for coronavirus disease 2019 (COVID-19), South Korea is facing its fourth pandemic wave. In this study, by using an automated electrochemiluminescence immunoassay assay, we tracked anti-spike protein receptor-binding domain (anti-S-RBD) antibody titer from the second dose to 2 weeks after the booster dose vaccination. After the second dose, 234 participants had their anti-S-RBD antibody titers decrease over time. We also showed the booster dose (the third dose) increased antibody titer by average 14 (min-max, 2-255)-fold higher compared to the second dose among the 211-booster group participants, therefore, the booster dose could be recommended for low responders to the second dose. Our findings showed a distinct humoral response after booster doses of BNT162b2 mRNA vaccines and may provide further evidence of booster vaccination efficacy. These data will also be helpful in vaccination policy decisions that determine the need for the booster dose.

Evaluation of Five User-Friendly Whole Genome Sequencing Software for Mycobacterium tuberculosis in Clinical Application.

BACKGROUND: Whole genome sequencing (WGS) is an increasingly useful tool for tuberculosis (TB) diagnosis and disease management. In this study, we evaluated the utility of user-friendly WGS tools in reporting resistance profiles and identifying lineages of clinical TB isolates from South Korea. METHODS: Forty clinical samples from TB patients showing discrepancies between their rapid molecular and conventional drug susceptibility tests were used in this study. Among these clinical isolates, 37 strains were successfully evaluated via WGS software, using the GenTB, TB Profiler, PhyResSE, CASTB, and Mykrobe. RESULTS: More accurate and faster susceptibility results could be obtained with isoniazid than with rifampin. Using the phenotypic test as the gold standard, the isoniazid concordance rate between phenotypic drug susceptibility test (DST) and WGS (GenTB: 45.9%, TB profiler: 40.5%, PhyResSE: 40.5%, CASTB: 48.6%, and Mykrobe: 43.2%) was much higher than between phenotypic DST and rapid molecular genotypic DST (18.9%) among the 37 strains. In contrast, the rifampin concordance rate between phenotypic DST and WGS and that between phenotypic DST and rapid molecular genotypic DST was similar (81.1-89.2%). We also found novel mutations associated with INH in katG and ahpC gene region, not covered by the line probe assay. In addition, lineage analysis identified 81.1% of these samples as L2 East Asian lineage strains, and 18.9% as L4 Euro-American lineage strains. CONCLUSION: WGS may play a pivotal role in TB diagnosis and the detection of drug resistance, genetic diversity, and transmission dynamics in the near future because of its accuracy, speed, and extensibility.

Synaptic Cell Adhesion Molecule 3 (SynCAM3) Deletion Promotes Recovery from Spinal Cord Injury by Limiting Glial Scar Formation.

Synaptic cell adhesion molecules (SynCAMs) play an important role in the formation and maintenance of synapses and the regulation of synaptic plasticity. SynCAM3 is expressed in the synaptic cleft of the central nervous system (CNS) and is involved in the connection between axons and astrocytes. We hypothesized that SynCAM3 may be related to the astrocytic scar (glial scar, the most important factor of CNS injury treatment) through extracellular matrix (ECM) reconstitution. Thus, we investigated the influence of the selective removal of SynCAM3 on the outcomes of spinal cord injury (SCI). SynCAM3 knock-out (KO) mice were subjected to moderate compression injury of the lower thoracic spinal cord using wild-type (WT) (C57BL/6JJc1) mice as controls. Single-cell RNA sequencing analysis over time, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and immunohistochemistry (IHC) showed reduced scar formation in SynCAM3 KO mice compared to WT mice. SynCAM3 KO mice showed improved functional recovery from SCI by preventing the transformation of reactive astrocytes into scar-forming astrocytes, resulting in improved ECM reconstitution at four weeks after injury. Our findings suggest that SynCAM3 could be a novel therapeutic target for SCI.

Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor.

Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

Prevalence of granular corneal dystrophy type 2-related TGFBI p.R124H variant in a South Korean population.

Purpose: Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disorder and is associated with the arginine to histidine substitution at codon 124 (p.R124H) of the TGFBI gene. Although TGFBI p.R124H is known to be the most common corneal dystrophy-related pathogenic variant, there are few data on the frequency of this variant in the South Korean population. Methods: In total, 2,060 anonymous DNA samples from a public umbilical cord blood bank were tested for the TFGBI p.R124H variant using real-time PCR. Results: Six of the 2,060 samples [0.29%; 95% confidence interval (CI), 0.12-0.67%] were heterozygous for the TGFBI p.R124H variant. The prevalence of the GCD2-related TGFBI p.R124H variant in this population was estimated to be 291.3 per 100,000 [95% confidence interval (CI), 118.5-667.0]. Conclusions: To our knowledge, this is the largest study that has estimated the prevalence of the GCD2-related TGFBI p.R124H variant in South Korea.