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p53 is the most studied tumor suppressor and a key transcriptional factor, with discrete domains that regulate cellular pathways such as apoptosis, angiogenesis, cell-cycle arrest, DNA repair, and senescence. Previous studies have suggested that AIMP2, and ARS-interacting multifunctional protein 2, promote cell death via the protective interaction with p53 upon DNA damage. Also, oncogenic splicing variant of AIMP2 lacking exon2, AIMP2-DX2, compromises the pro-apoptotic activity and anti-proliferative activities of the AIMP2 by competing with AIMP2 for the binding with p53. However, the molecular mechanism for the interaction of p53 and AIMP2 remains elusive. Using NMR spectroscopy, we studied the structural details of the interaction of transactivation domain 1 (TAD1) of p53 with GST domain of AIMP2, which is also common in AIMP2-DX2. The chemical shift perturbation (CSP) experiments demonstrate that amino acid residues from E17 to E28 of p53, known to bind to MDM2 are also involved in binding to AIMP2-DX2. Structure determination of this region based on the transferred-NOE (trNOE) data revealed that TAD1 of the p53 forms a turn structure with hydrophobic interactions by side chains of F19, L22, W23 and L26, distinct from the structure for MDM2 binding. Also, docking results based on NMR CSP data suggest the binding mode of p53 with AIMP2-DX2 GST domain. These data provide the first structural insight into the binding of the p53 TAD1 on AIMP2 and AIMP2-DX2.

A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siah1-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.

Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.

Recently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studies on the most effective N,N-dialkylthiazolo [5,4-b]pyridin-2-amine (SL-1910). SL-1910 exhibited highly potent migration inhibition (EC50 = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC50 = 8.5 μM against H226 cells). The KRS protein binding study via fluorescence-based binding titration and KRS protein 2D-NMR mapping study, in vitro concentration-dependent cell migration inhibition, and in vivo anti-metastatic activity of SL-1910, which consists of a new scaffold, have been reported in this study. In addition, in vitro absorption, distribution, metabolism, and excretion studies and mouse pharmacokinetics experiments for SL-1910 were conducted.

Orthodontic miniscrews have become popular tools for providing temporary anchorage during orthodontic treatment. Although they are easy to insert, damage to the periodontal ligament or dental root during insertion is an unfavorable iatrogenic complication. Root perforation during miniscrew insertion in human teeth has been reported in a few articles. In this article, the authors describe the spontaneous repair of an iatrogenic root perforation in a mandibular first molar that occurred during insertion of an orthodontic miniscrew in a young girl undergoing orthodontic treatment.A 15-year-old girl with malocclusion was undergoing orthodontic treatment when the mesial root of her mandibular right first molar was damaged by an orthodontic miniscrew. The miniscrew and corresponding bracket were immediately removed to avoid any unnecessary forces on the tooth. Because the pulp remained vital without any additional damage and infection for 6 months, orthodontic treatment was resumed and completed in 9 months without any pulp damage or unfavorable symptoms. Serial periapical radiographs and cone-beam computed tomographic images showed that the injured area was surrounded by reparative tissue without any apical lesion.The findings of this case suggest that immediate removal of unnecessary forces provides an environment for spontaneous repair in cases of iatrogenic root perforation by orthodontic miniscrews, even when the damage involves the pulp. If force stimulation is avoided for a certain period, which was 6 months in this case, it may be possible to complete the orthodontic treatment without unfavorable symptoms.

The aim of this study was to investigate the effect of environmental enrichment (EE) on neurotrophin expression in an animal model of Parkinson’s disease (PD). PD was induced via intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice ( N = 42) were randomly divided into 3 groups: control, MPTP + standard condition (SC), and MPTP + EE. The groups were raised separately for 28 days. On Day 21 they received 1 injection (20 mg/kg MPTP or saline for MPTP and control groups, respectively) every 2 hr for a total of 4 injections. Animals were sacrificed 7 days after the final injection and their brains were immediately removed. Neurotrophins and messenger ribonucleic acid (mRNA) expression levels were measured. The BCL-2/Bax ratio significantly increased in the MPTP + EE compared to the MPTP + SC group. Nerve growth factor (NGF) mRNA level was upregulated (but not significantly) in the MPTP + EE compared to the MPTP + SC group. Tyrosine hydroxylase (TH) expression significantly increased in the MPTP + EE compared to the MPTP + SC group. Finally, expressions of proNGF and p75 neurotrophin receptor (p75NTR) were significantly downregulated in the MPTP + EE compared to the MPTP + SC group. Results confirm that EE has neuroprotective effects on dopaminergic neurons via suppression of activation of the p75NTR-mediated signaling pathway through the binding of proNGF and p75NTR. Findings suggest that use of EE as a therapeutic intervention would promote healthy aging by facilitating recovery following brain injury and preventing neurodegenerative diseases.

Aim This study attempted to investigate the effects of a self-performance management video program using a tablet PC on self-care knowledge, self-care behavior, state anxiety and physiological index in patients receiving hemodialysis. Methods This study was an experimental research design. The participants of this study were 46 patients who were diagnosed with end-stage renal failure and received hemodialysis on a regular basis in kidney centers (23: experimental group, 23: control group). The data collection period was from November 24, 2016 to January 3, 2017. The program was designed and organized by the researchers of this study according to previous studies consisting of six categories in a total 70-min video program. The contents of the self-performance management program were stored on the tablet PC, so that the patients were self-led. All the patients who participated in the program were asked to complete three categories in a week. Therefore, it took 2 weeks to complete all contents of the six categories. After that, the patients were asked to repeat the 2-week course twice. Therefore, the program was carried out for a total of 6 weeks. For the control group, a pamphlet was used. Results The anxiety of the experimental group was significantly decreased compared to the control group. Among the physiological index, potassium and albumin levels were statistically significant. Conclusions The self-performance management video program using a tablet PC developed in this study seems to be applicable to patients receiving hemodialysis who need anxiety and physiological index management.

Background The development of clinical competency reduces nursing students' stress and turnover intention and improves their clinical practice satisfaction and academic performance. Still, many nursing supervisors feel that new graduate nurses have inadequate communicative and clinical competencies, and no prior study has analyzed the mediating effect of interpersonal skills in the relationship between these two variables. Objectives To examine the factors that affect nursing students’ clinical competency, including the mediating effect of interpersonal skills, and to identify/determine interventions that promote it and improve students' clinical performance. Design This study employed a cross-sectional, descriptive correlational design. Setting Four departments of nursing in Jeollabuk-do, South Korea. Participants Participants (N = 222; mean age = 22.7 years; 75.2% women) were students enrolled in the third and fourth year of nursing. Methods From February 5–28, 2018, we collected data through self-reported questionnaires; these asked about participants' demographic characteristics and measured their communicative competency, interpersonal skills, and clinical competency. The relationships among the variables were identified using Pearson's correlation coefficient. We also used the Sobel test and a three-step multiple regression analysis to verify the mediating effects of interpersonal skills. Results Students who were female, in their fourth year, satisfied with their major, and satisfied with their clinical practice had higher clinical competency scores than their counterparts. Interpersonal skills completely mediated the effects of communicative competency on clinical competency (explanatory power = 53.8%). Conclusions The results suggest the need for a program that improves nursing students' social relationship skills and diminishes their anxiety. In particular, students in the third and fourth years need a continuous/intensified curriculum that fosters their communicative competencies, such as listening to patients' needs and establishing effective interpersonal relationships with peers/superiors. Longitudinal studies are warranted to identify differences in communicative/clinical competencies among nursing students in different academic years.

Lysyl-tRNA synthetase (KRS) is an enzyme that conjugates lysine to its cognate tRNAs in the process of protein synthesis. In addition to its catalytic function, KRS binds to the 67-kDa laminin receptor (LR) on the cell membrane and facilitates cell migration and metastasis. Modulation of this interaction by small-molecule inhibitors can be exploited to suppress cancer metastasis. In this study, we present fragment-based methods for the identification of inhibitors and monitoring protein-protein interactions between KRS and LR. First, we identified the amino acid residues, located on the KRS anticodon-binding domain, which interact with the C-terminal extension of the LR. One-dimensional (1D) relaxation-edited nuclear magnetic resonance spectroscopy (NMR) and competition experiments were designed and optimized to screen the fragment library. For screening using two-dimensional (2D) NMR, we identified the indicative signals in the KRS anticodon-binding domain and selected inhibitors that bind to KRS and compete with LR at the KRS-LR binding interface. These methods may offer an efficient approach for the discovery of anti-metastatic drugs.

CCND1 is an important cell-cycle regulatory protein associated with cell proliferation, poor prognosis and recurrence in cancer, while BCL2 is an important anti-apoptotic protein that plays a vital role in the regulation of the life span by controlling the rate of apoptosis. Recent studies have shown that CCND1 and BCL2 may be responsible for the body mass and the regulation of various metabolic processes. In an effort to discover additional polymorphism(s), we scrutinized the genetic polymorphisms in the CCND1 and BCL2. By direct DNA sequencing in 24 individuals, we identified 22 sequence variants within the 16 kb of whole CCND1 gene: one in exon 4, 17 in introns and four in the 3' UTR region. We also found eight sequence variants within 7.5 kb exon-intron boundaries of BCL2 gene: one in promoter, three in exon 1, and four in the 3' UTR region. Haplotypes, their frequencies and linkage disequilibrium coefficients (| D'| and r(2)), among polymorphisms were estimated. Among identified variants, seven and six variants of CCND1 and BCL2 were genotyped in a larger series of subjects ( n=320). Statistical analyses of CCND1 and BCL2 polymorphisms with two metabolic phenotypes revealed no significant association. The information concerning genetic polymorphisms of CCND1 and BCL2 might provide valuable information for future genetic studies of diseases.

Squamous cell carcinoma of the head and neck (SCCHN), which is relatively prevalent in Korea, is believed to be induced by environmental carcinogens and host genetic factors. Accumulating evidence has shown that genetic differences in DNA repair capacity resulting from genetic polymorphism influence the risk of environmental carcinogenesis. We therefore examined the associations of genetic polymorphisms in the DNA repair genes XRCC1 with the risk of SCCHN in a Korean population (hospital-based, case-control study; 147 cases and 168 controls). Three known polymorphisms in the XRCC1 gene were genotyped: R194W(C>T) in exon 6, R280H(G>A) in exon 9 and R399G(G>A) in exon 10. Although no significant associations were apparent with R280H(G>A) and R399G(G>A), a highly significant association (p = 0.0005) of R194W(C>T) with the increased risk (OR = 2.61; 95% CI 1.53–4.46) of SCCHN was detected among patients and normal controls under dominant model. The frequency of minor allele-containing genotypes (TT and CT) was much higher in SCCHN patients (51.8%) compared to that in normal controls (30.3%) (p = 0. 0005). When considering a relatively small number of cases (n = 147) and controls (n = 168) in our study, larger studies are needed to validate the genetic effects of XRCC1 polymorphisms in Asian populations. In conclusion, the result from our study provides additional evidence of an association of the XRCC1 polymorphism (Arg194Trp) with SCCHN as markers of genetic susceptibility in the Korean population. © 2004 Wiley-Liss, Inc.

Lysyl-tRNA synthetase (KRS) interacts with the laminin receptor (LR/RPSA) and enhances laminin-induced cell migration in cancer metastasis. In this nuclear magnetic resonance (NMR)-based study, we show that the anticodon-binding domain of KRS binds directly to the C-terminal region of 37LRP, and the previously found inhibitors BC-K-01 and BC-K-YH16899 interfere with KRS–37LRP binding. In addition, the anticodon-binding domain of KRS binds to laminin, observed by NMR and SPR. These results provide crucial insights into the structural characteristics of the KRS–LR interaction on the cell surface.

The tumor necrosis factor (TNF) and TNF receptor (TNF-TNFR) superfamily plays crucial roles in immune regulation and host immune responses. The superfamily has been also associated with many immune-mediated diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, and diabetes. In order to investigate genetic variants of the TNF-TNFR superfamily, a total of 63 known single nucleotide polymorphisms (SNPs) in the coding region (cSNPs) of the TNF-TNFR superfamily genes were selected from the public SNP database. Among 63 cSNPs tested in this study, only 24 SNPs (38%) were validated to be polymorphic in the Korean population by primer extension-based SNP genotyping. By means of the new enhanced single strand conformational polymorphism (SSCP) method, we also identified a total of 78 SNPs, including 48 known SNPs and 30 novel SNPs, in the 44 human TNF-TNFR superfamily genes. The newly discovered SNPs in the TNF-TNFR superfamily genes revealed that the Korean population had very different patterns of allele frequency compared with African or white populations, whereas Korean allele frequencies were highly similar to those of Asian (correlation coefficient r = 0.88, p < 0.046). A higher similarity of allele frequency was observed between Korean and Japanese populations (r = 0.90, p < 0.001). The validated SNPs in the TNF-TNFR superfamily would be valuable for association studies with several immune-mediated human diseases.