Exploring helix structures of γ-peptides based on 2-(aminomethyl)cyclopentanecarboxylic acid.

Conformational search and density functional theory calculations were performed to explore the preferences of helical structures for chiro-specific oligo-γ-peptides of 2-(aminomethyl)cyclopentanecarboxylic acid (γAmc5) with a cyclopentyl constraint on the Cα-Cß bond in solution. The dimer and tetramer of γAmc5 (1) with homochiral (1S, 2S) configurations exhibited a strong preference for the 9-membered helix foldamer in solution, except for the tetramer in water. However, the oligomers of γAmc5 (1) longer than tetramer preferentially adopted a right-handed (P)-2.614-helix (H1-14) as the peptide sequence becomes longer and as solvent polarity increases. The high stabilities for H1-14 foldamers of γAmc5 (1) in solution were ascribed to the favored solvation free energies. The calculated mean backbone torsion angles for H1-14 helix foldamers of γAmc5 (1) were similar to those calculated for oligomers of other γ-residues with cyclopentane or cyclohexane rings. However, the substitution of cyclopentane constraints on the Cα-Cß bond of the γAmc5 (1) residue resulted in different conformational preferences and/or handedness of helix foldamers. In particular, the pyrrolidine-substituted analogs of the H1-14 foldamers of γAmc5 (1) with adjacent amine diads substituted at a proximal distance are expected to be potential catalysts for the crossed aldol condensation in nonpolar and polar solvents.

Prognosis and Adjusting Factors in Elderly Patients With Triple-Negative Breast Cancer: Comparing With Young and Middle Age Groups.

PURPOSE: Proper breast cancer screening and treatment should be considered in the elderly population; however, some tend to be less proactive. Our study aimed to investigate the impact of old age on treatment and prognosis in triple-negative breast cancer (TNBC). METHOD: The study included patients with primary TNBC stage I-III diagnosed from 2002 to 2019 in single institution and retrospectively analyzed. We defined young (< 40 years), middle and old (> 70 years) groups. Clinicopathological factors, treatment, and prognosis were analyzed according to age group of TNBC patients. RESULT: TNBC patients aged 70 and above were 3.3 times more likely (P = .019) to have lymph node metastasis at the time of diagnosis compared to younger patients, but were found to be 0.24 times less likely to receive chemotherapy. (P = .003) Old TNBC patients have an expected likelihood 2.2 times higher of undergoing mastectomy rather than breast-conserving surgery. (P = .042) The 5-year prognosis is poorer in young and old group. (61%, 86%, and 65% in young, middle, and old groups). (P < .001). In subanalysis, old group of stages I and II received fewer chemotherapy compared to youngers (P < .05), but not in stage III. In Cox regression analysis, age and stage had significant impact on prognosis (hazard ratio 2-3), but treatment factors did not. However, in stratified analysis of adjuvant therapy and stage, prognosis of Old TNBC patients in stage II was improved when they underwent neo or adjuvant chemotherapy. CONCLUSION: TNBC presents challenges in older patients, who receive less aggressive treatment and have poorer outcomes. The primary cause of poor prognosis in old TNBC patients is the high disease stage at diagnosis, underscoring the need for promotion and education on early screening. Additionally, it is suggested that a more proactive approach to adjuvant chemotherapy is necessary for stage II old TNBC patients.

Systematic Review of Prediction Models for Preterm Birth Using CHARMS.

OBJECTIVE: This study sought to evaluate prediction models for preterm birth (PTB) and to explore predictors frequently used in PTB prediction models. METHODS: A systematic review was conducted. We selected studies according to the PRISMA, classified studies according to TRIPOD, appraised studies according to the PROBAST, and extracted and synthesized the data narratively according to the CHARMS. We classified the predictors in the models into socio-economic factors with demographic, psychosocial, biomedical, and health behavioral factors. RESULTS: Twenty-one studies with 27 prediction models were selected for the analysis. Only 16 models (59.3%) defined PTB outcomes as 37 weeks or less, and seven models (25.9%) defined PTB as 32 weeks or less. The PTB rates varied according to whether high-risk pregnant women were included and according to the outcome definition used. The most frequently included predictors were age (among demographic factors), height, weight, body mass index, and chronic disease (among biomedical factors), and smoking (among behavioral factors). CONCLUSION: When using the PTB prediction model, one must pay attention to the outcome definition and inclusion criteria to select a model that fits the case. Many studies use the sub-categories of PTB; however, some of these sub-categories are not correctly indicated, and they can be misunderstood as PTB (≤ 37 weeks). To develop further PTB prediction models, it is necessary to set the target population and identify the outcomes to predict.

Relationships between determinants of adjuvant endocrine therapy adherence in breast cancer.

BACKGROUND: Interventions that promote adjuvant endocrine therapy (AET) adherence are critical to improve breast cancer survival. The development of interventions would benefit from a better understanding of the reasons for adherence and the causal relationships of determinants using theoretical or model approaches. The aim of the present study was to identify reasons for AET adherence in breast cancer patients with sequential relationships and inter-relationships. METHODS: A total of 210 participants with estrogen receptor positive breast cancer who received AET completed a questionnaire assessing demographic/medical, psychological, and endocrine therapy (ET)-specific factors. A descriptive analysis was performed to identify meaningful variables. Selected variables were subjected to hierarchical regression and path analyses. The path model was tested and modified based on the research framework and the results of regression weights and model fit. RESULTS: Analysis of sequential effects showed that ET-specific factors contributed the largest proportion of variance (13.4%) to predict AET adherence, followed by psychological factors (4.6%) and demographic/medical factors (3.1%). Analysis of inter-relationships showed that demographic/medical factors such as AET regimen type and cancer stage have direct effects on AET adherence, whereas psychological factors contribute indirectly through the mediating effects of ET-specific factors. CONCLUSION: Assessments and interventions that encompass the patient's medication beliefs, self-efficacy, and depression are needed to promote AET adherence.

Discovery of indirubin derivatives as new class of DRAK2 inhibitors from high throughput screening.

DRAK2 is a serine/threonine kinase belonging to the death-associated protein kinase (DAPK) family and has emerged as a promising drug target for the treatment of autoimmune diseases and cancers. To identify small molecule inhibitors for DRAK2, we performed a high throughput screening campaign using in-house chemical library and identified indirubin-3'-monoximes as novel class of DRAK2 inhibitors. Among the compounds tested, compound 16 exhibited the most potent inhibitory activity against DRAK2 (IC50=0.003µM). We also propose that compound 16 may bind to the ATP-binding site of the enzyme based on enzyme kinetics and molecular docking studies.

Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors.

Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.

Transtheoretical Model-based Nursing Intervention on Lifestyle Change: A Review Focused on Intervention Delivery Methods.

PURPOSE: The transtheoretical model (TTM) was used to provide tailored nursing for lifestyle management such as diet, physical activity, and smoking cessation. The present study aims to assess the provision of intervention delivery methods, intervention elements, and stage-matched interventions, in order to identify ways in which information technology is used in the TTM-based research. METHODS: The relevant literature was selected by two researchers using inclusion criteria after searching for "TTM (transtheoretical or stage of change)" and "nursing" from the databases PubMed and CINAHL. The selected studies were categorized in terms of study characteristics, intervention delivery method, intervention element, and use and level of stage-matched intervention. RESULTS: A total of 35 studies were selected including eight studies that used information communication technology (ICT). Nine different intervention delivery methods were used, of which "face-to-face" was the most common at 24 times. Of the 35 studies, 26 provided stage-matched interventions. Seven different intervention elements were used, of which "counseling" was the most common at 27 times. Of all the intervention elements, tailored feedback used ICT the most at seven instances out of nine, and there was a significant difference in the rate of ICT usage among intervention elements. CONCLUSIONS: ICT is not yet actively used in the TTM-based nursing interventions. Stage-matched interventions and TTM concepts were shown to be in partial use also in the TTM-based interventions. Therefore, it is necessary to develop a variety of ways to use ICT in tailored nursing interventions and to use TTM frameworks and concepts.

Praeruptorin A inhibits in vitro migration of preosteoclasts and in vivo bone erosion, possibly due to its potential to target calmodulin.

Excessive activity and/or increased number of osteoclasts lead to bone resorption-related disorders. Here, we investigated the potential of praeruptorin A to inhibit migration/fusion of preosteoclasts in vitro and bone erosion in vivo. Praeruptorin A inhibited the RANKL-induced migration/fusion of preosteoclasts accompanied by the nuclear translocation of NFATc1, a master regulator of osteoclast differentiation. Antimigration/fusion activity of praeruptorin A was also confirmed by evaluating the mRNA expression of fusion-mediating molecules. In silico binding studies and several biochemical assays further revealed the potential of praeruptorin A to bind with Ca(2+)/calmodulin and inhibit its downstream signaling pathways, including the Ca(2+)/calmodulin-CaMKIV-CREB and Ca(2+)/calmodulin-calcineurin signaling axis responsible for controlling NFATc1. In vivo application of praeruptorin A significantly reduced lipopolysaccharide-induced bone erosion, indicating its possible use to treat bone resorption-related disorders. In conclusion, praeruptorin A has the potential to inhibit migration/fusion of preosteoclasts in vitro and bone erosion in vivo by targeting calmodulin and inhibiting the Ca(2+)/calmodulin-CaMKIV-CREB-NFATc1 and/or Ca(2+)/calmodulin-calcineurin-NFATc1 signaling axis.

Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells.

Aberrant regulation of phosphatidylinositol-3-kinases (PI3Ks) is known to be involved in the progression of cancers. PI3K-binding flavonoids such as quercetin and myricetin have been shown to inhibit PI3K activity, but the direct targeting of fisetin to PI3K has not been established. Here, we carried out an in silico investigation of fisetin binding to PI3K and determined fisetin's inhibitory activity in enzymatic and cell-based assays. In addition, fisetin induced apoptosis in human Burkitt's lymphoma Raji cells by inhibiting both PI3Ks and mammalian target of rapamycin (mTOR). Our results indicate that fisetin may serve as a natural backbone for the development of novel dual inhibitors of PI3Ks and mTOR for the treatment of cancer.

A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-ß1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells.

Transforming growth factor (TGF)-ß triggers the epithelial-to-mesenchymal transition (EMT) of cancer cells via well-orchestrated crosstalk between Smad and non-Smad signaling pathways, including Wnt/ß-catenin. Since EMT-induced motility and invasion play a critical role in cancer metastasis, EMT-related molecules are emerging as novel targets of anti-cancer therapies. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as a first-in-class anti-cancer target molecule to regulate Wnt signaling pathway, but pharmacologic inhibition of its EMT activity has not yet been studied. Here, using 5-(4-methylbenzamido)-2-(phenylamino)thiazole-4-carboxamide (KY-05009) with TNIK-inhibitory activity, its efficacy to inhibit EMT in cancer cells was validated. The molecular docking/binding study revealed the binding of KY-05009 in the hinge region of TNIK, and the inhibitory activity of KY-05009 against TNIK was confirmed by an ATP competition assay (Ki, 100 nM). In A549 cells, KY-05009 significantly and strongly inhibited the TGF-ß-activated EMT through the attenuation of Smad and non-Smad signaling pathways, including the Wnt, NF-κB, FAK-Src-paxillin-related focal adhesion, and MAP kinases (ERK and JNK) signaling pathways. Continuing efforts to identify and validate potential therapeutic targets associated with EMT, such as TNIK, provide new and improved therapies for treating and/or preventing EMT-based disorders, such as cancer metastasis and fibrosis.

A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method.

Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity. We have investigated methods to predict various toxic effects of drug candidates to reduce the failure rate of drug discovery. An electrophysiological method was used to assess the cardiotoxicity of drug candidates. Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition. Nefazodone inhibited hERG channel activity in our system. However, nefazodone-induced hERG inhibition indicated only a theoretical risk of cardiotoxicity. Nefazodone inhibited the hERG channel in a concentration-dependent manner with an IC50 of 45.3nM in HEK-293 cells. Nefazodone accelerated both the recovery from inactivation and its onset. Nefazodone also accelerated steady-state inactivation, although it did not modify the voltage-dependent character. Alanine mutants of hERG S6 and pore region residues were used to identify the nefazodone-binding site on hERG. The hERG S6 point mutants Y652A and F656A largely abolished the inhibition by nefazodone. The pore region mutant S624A mildly reduced the inhibition by nefazodone but T623A had little effect. A docking study showed that the aromatic rings of nefazodone interact with Y652 and F656 via π-π interactions, while an amine interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding.

Binding free energies of inhibitors to iron porphyrin complex as a model for Cytochrome P450.

The binding free energies of the inhibitor-heme model complexes are calculated using the density functional methods and the implicit solvation models in water, where the 16 structurally diverse compounds with a spectrum of IC(50) values from 0.05 (clotrimazole) to 1000 (piroxicam) µM are chosen as inhibitors for Cytochrome P450 3A4 (CYP3A4). CYP3A4 is the most predominant constituent of the human hepatic CYP enzymes that play a role in metabolizing structurally diverse xenobiotics. The observed free energy change for each inhibitory binding, ΔG inh0, is obtained from its IC(50) value. The total binding free energy (ΔG b0) of each inhibitor-heme model complex is calculated by the sum of its relative free energy (ΔG(0) ) in the gas phase and solvation free energy to the water-heme model complex. The UB3LYP/LanL2DZ level of theory provides the correct relative stabilities of the high- and low-spin states for the penta- and hexa-coordinated ferric complexes, respectively. The optimized distances of the inhibitor nitrogen (or water oxygen) and the methyl mercaptide S to the ferric iron of the inhibitor-heme model complexes at the same level of theory are consistent with the values of the corresponding X-ray structures, except for the econazole complex. The correlation coefficient r(2) values of 0.91 and 0.75 are obtained from the ΔG b0-ΔG inh0 and ΔG(0) -ΔG inh0 plots, respectively, at the UM06/LanL2DZ:CPCM_UB3LYP/LanL2DZ//UB3LYP/LanL2DZ level of theory in water. This indicates that the total binding free energies calculated for the inhibitor-heme model complexes can be a good descriptor in interpreting the inhibitor binding to CYP3A4 and the relative free energies in the gas phase are mainly responsible for the total binding free energies in water, although the desolvation can be a factor to affect the binding affinity of the inhibitors to CYP3A4. From the theozyme analysis of the X-ray structures for ketoconazole- and metyrapone-CYP3A4 complexes, the interaction free energy of the neighboring residues with each inhibitor in the active site is calculated to be about -3 kcal mol(-1) in water, whose the interaction energy and the desolvation free energy change are about -5 and 2 kcal mol(-1) , respectively.

Conformational preferences and pKa value of cysteine residue.

The conformational preferences of the Cys dipeptides with thiol and thiolate groups (Ac-Cys-NHMe and Ac-Cys (-)-NHMe, respectively) and the apparent (i.e., macroscopic) p K a value of the Cys dipeptide have been studied at the hybrid density functional B3LYP/6-311++G(d,p)//B3LYP/6-31+G(d) level with the conductor-like polarizable continuum model in the gas phase and in water. The hydrogen bonds and/or favorable interactions between the backbone and the thiol group of the side chain resulted in the different conformational preferences of the Cys and Cys (-) dipeptides from those of the Ala dipeptide in the gas phase and in water, although the preferred conformations of the Cys dipeptide are in part similar to those of the Ala dipeptide. In particular, the interactions between the thiolate group and the backbone amide groups appear to play a role in stabilizing the alpha- or 3 10-helical conformations for the Cys (-) dipeptide in the gas phase and in water. The p K a value of the Cys residue is estimated to be 8.58 at 25 degrees C using the statistically weighted free energies of all feasible conformations for the Cys and Cys (-) dipeptides in the gas phase and solvation free energies, which is consistent with the observed values of 8.3 and 8.22 +/- 0.16.

Conversion of intermittent exotropia types subsequent to part-time occlusion therapy and its sustainability.

PURPOSE: To evaluate the effects of part-time occlusion therapy on types of intermittent exotropia and sustainability of converted types. METHODS: Forty-four and 26 children with basic-type and convergence-insufficiency-type intermittent exotropia, respectively, were evaluated in this study. Upon initial examination, we obtained both distant and near deviating angles using prism cover tests, after correcting for refractive errors. We conducted occlusion of the nondeviating eye for 3 months at 3 h/day and assessed the changes in types of intermittent exotropia. We also observed the changes of deviating angles and sustainability of types after 3 months of cessation of part-time occlusion in patients who did not undergo surgery. RESULTS: Preocclusion deviating angles (mean +/- SD) were determined to be 27.1+/-7.46 prism diopters (PD) on distant measurements and 30.6+/-7.92 PD on near measurements. After 3 months of occlusion, the deviating angles were 25.9+/-9.10 PD on distant measurements and 21.4+/-11.00 PD on near measurements, corresponding to a significant reduction (p=0.005 and p<0.001, respectively). Fourteen patients (32%) suffering from basic type of intermittent exotropia converted to the pseudodivergence excess type. In patients suffering from the basic type who exhibited no changes in type, 9 patients (20%) exhibited reductions on both near and distant angle measurements. Among the convergence insufficiency type of patients, 18 (69%) converted to basic type and 2 patients (7%) converted to the pseudodivergence excess type. In the 15 patients who did not undergo surgery, the converted types were maintained in 6 patients, though the other 9 patients showed regression to the prepatching types after cessation of patching for 3 months. CONCLUSION: Part-time occlusion therapy resulted in the conversion of the basic and convergence insufficiency types to pseudodivergence excess and basic types in more than half of the intermittent exotropes. Future studies on correlation between type conversion and surgical outcome would be necessary.

Primary facial skin cancer: clinical characteristics and surgical outcome in Chungbuk Province, Korea.

Clinical features of facial skin cancer in Asian population including Korean are not readily available. In the present study, we analyzed the clinical characteristics and the surgical results of primary facial skin cancer in Chungbuk Province, Korea. Eighty-six cases of primary facial skin cancer collected during a 10-yr period (1994-2003) were retrospectively reviewed about the clinical characteristics including age, sex, annual diagnostic rate, types of tumor, specific sites of occurrence, and the surgical results. The average age at the diagnosis was 67 and male to female ratio was 1 to 1.05. The average annual diagnostic rate was 0.73% and the rate surged during the period 2001-2003 compared with the period 1994 to 2000. Basal cell carcinoma was the most common tumor and the nose was the most frequent site. Traditional surgical excision with immediate reconstruction was performed in 81 cases. During the 23 months of average follow-up, three patients had recurrences (3.7%) and three patients had secondary skin cancers. Facial skin cancer is increasing in the province and basal cell carcinoma is most frequent. Traditional surgical excision and immediate reconstruction with local flap are a good therapeutic modality with an acceptable recurrence rate.