Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin.

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5-111.0) and 107.1 (100.1-114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.

Rational design of ornithine decarboxylase with high catalytic activity for the production of putrescine.

Putrescine finds wide industrial applications in the synthesis of polymers, pharmaceuticals, agrochemicals, and surfactants. Owing to economic and environmental concerns, the microbial production of putrescine has attracted a great deal of attention, and ornithine decarboxylase (ODC) is known to be a key enzyme in the biosynthetic pathway. Herein, we present the design of ODC from Escherichia coli with high catalytic efficiency using a structure-based rational approach. Through a substrate docking into the model structure of the enzyme, we first selected residues that might lead to an increase in catalytic activity. Of the selected residues that are located in the α-helix and the loops constituting the substrate entry site, a mutational analysis of the single mutants identified two key residues, I163 and E165. A combination of two single mutations resulted in a 62.5-fold increase in the catalytic efficiency when compared with the wild-type enzyme. Molecular dynamics simulations of the best mutant revealed that the substrate entry site becomes more flexible through mutations, while stabilizing the formation of the dimeric interface of the enzyme. Our approach can be applied to the design of other decarboxylases with high catalytic efficiency for the production of various chemicals through bio-based processes.

Hounsfield Units Predict Survival of Patients With Estrogen Receptor-Positive and Human Epithelial Growth Factor Receptor 2-Negative Breast Cancer.

BACKGROUNDS: Tumor vascularity plays a fundamental role in cancer progression, including breast cancer. This study aimed to elucidate tumor vascularity and its impact on patient survival in the context of breast cancer subtypes using Hounsfield units (HU) on contrast-enhanced computed tomography (CT). MATERIALS AND METHODS: Patients with early-stage breast cancer who completed planned treatment between 2003 and 2013 were retrospectively assessed. RESULTS: The final cohort comprised 440 patients. Of the 440 patients, 262 had estrogen receptor (ER)-positive disease and 119 had human epidermal growth factor receptor 2 (HER2)-overexpressing disease. The tumor-to-aorta ratio of Hounsfield units (TAR) was related to significantly worse recurrence-free interval (RFI) (P < .001) and overall survival (OS) (P < .001) in patients with TAR > 0.33 for RFI and > 0.35 for OS than their counterparts. In the subgroup analysis, the survival disadvantage was limited only to patients with ER-positive and HER2-negative disease (P < .001 for both RFI and OS). CONCLUSION: This study showed that TAR, which reflects tumor vascularity, was significantly related to patients' RFI and OS, suggesting its capacity as a feasible biomarker. This study also showed that TAR was associated with the survival in patients with ER-positive and HER2-negative disease.

Intermediate monomer-dimer equilibrium structure of native ICAM-1: implication for enhanced cell adhesion.

Dimeric intercellular adhesion molecule-1 (ICAM-1) has been known to more efficiently mediate cell adhesion than monomeric ICAM-1. Here, we found that truncation of the intracellular domain of ICAM-1 significantly enhances surface dimerization based on the two criteria: 1) the binding degree of monomer-specific antibody CA-7 and 2) the ratio of dimer/monomer when a mutation (L42→C42) was introduced in the interface of domain 1. Mutation analysis revealed that the positively charged amino acids, including very membrane-proximal 5°5R, are essential for maintaining the structural transition between the monomer and dimer. Despite a strong dimer presentation, the ICAM-1 mutants lacking an intracellular domain (IC1ΔCTD) or containing R to A substitution in position 505 (5°5R/A) supported a lower degree of cell adhesion than did wild-type ICAM-1. Collectively, these results demonstrate that the native structure of surface ICAM-1 is not a dimer, but is an intermediate monomer-dimer equilibrium structure by which the effectiveness of ICAM-1 can be fully achieved.

Usefulness of Hounsfield Units and the Serum Neutrophil-to-Lymphocyte Ratio as Prognostic Factors in Patients with Breast Cancer.

Breast cancer is a leading cause of death worldwide. Tumor vascularity and immune disturbances are hallmarks of cancer. This study aimed to investigate the reciprocal effect of tumor vascularity, assessed by the tumor-to-aorta ratio (TAR) of Hounsfield units (HU) on computed tomography (CT), and host immunity, represented by the serum neutrophil-to-lymphocyte ratio (NLR) from peripheral, complete blood cell counts and its impact on patient survival. Female patients with breast cancer who received primary treatment between 2003 and 2018 at Wonju Severance Hospital, Korea, were included. The final cohort included 740 patients with a mean age of 54.3 ± 11.3 (22−89) years. The TAR was 0.347 ± 0.108 (range, 0.062−1.114) and the NLR was 2.29 ± 1.53 (0.61−10.47). The cut-off value for the TAR and NLR were 0.27 and 1.61, respectively. The patients with a TAR > 0.27 showed a poor recurrence free-interval (RFI) only when their NLR was larger than 1.61, and vice versa. The patients showed worse RFI when they had both high TAR and NLR. Our results suggest a dynamic reciprocal communication between tumor vascularity and systemic immunity.

Neutrophil to Lymphocyte Ratio after Treatment Completion as a Potential Predictor of Survival in Patients with Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) has been associated with worse prognosis, and biomarkers are needed to identify high-risk patients who may benefit from clinical trials or escalated treatment after completion of standard treatment. We aimed to assess whether the post-treatment neutrophil-to-lymphocyte ratio (NLR) can reflect patient prognosis and determine the follow-up period that can provide the most feasible data. METHODS: In this retrospective analysis involving patients with TNBC, clinicopathological data, including those on peripheral complete blood cell count, were collected. The prognostic powers of serial NLRs obtained at baseline and after treatment completion were compared. Kaplan-Meier curves were generated to compare the overall survival (OS) and distant disease-free survival (DDFS). RESULTS: In total, 210 patients were enrolled. Forty-three (20.5%) events were detected. Two-thirds of the events (29/43) were related to breast cancer. Most recurrent breast cancer-related diseases (27/29) were detected within 5 years of the initial diagnosis. In contrast, half of the events due to secondary malignancies or non-breast-related diseases (7/14) occurred 5 years after the initial diagnosis. Comparison of the prognostic performance of NLRs at baseline and at 6, 12, and 24 months after treatment completion revealed the strongest prognostic performance at 6 months after treatment completion (area under the curve = 0.745). The high NLR group (NLR >2.47) showed worse OS (p = 0.006) and DDFS (p < 0.001) than low NLR group. CONCLUSION: Elevated post-treatment NLR was significantly associated with worse survival in patients with TNBC. We believe that it can be a useful surrogate marker for identifying high-risk patients with TNBC.

Recycling and LFA-1-dependent trafficking of ICAM-1 to the immunological synapse.

Little is known about how adhesion molecules on APCs accumulate at immunological synapses. We show here that ICAM-1 on APCs is continuously internalized and rapidly recycled back to the interface after antigen-priming T-cell contact. The internalization rate is high in APCs, including Raji B cells and dendritic cells, but low in endothelial cells. Internalization is significantly reduced by inhibitors of Na(+)/H(+) exchangers (NHEs), suggesting that members of the NHE-family regulate this process. Once internalized, ICAM-1 is co-localized with MHC class II in the polarized recycling compartment. Surprisingly, not only ICAM-1, but also MHC class II, is targeted to the immunological synapse through LFA-1-dependent adhesion. Cytosolic ICAM-1 is highly mobile and forms a tubular structure. Inhibitors of microtubule or actin polymerization can reduce ICAM-1 mobility, and thereby block accumulation at immunological synapses. Membrane ICAM-1 also moves to the T-cell contact zone, presumably through an active, cytoskeleton-dependent mechanism. Collectively, these results demonstrate that ICAM-1 can be transported to the immunological synapse through the recycling compartment. Furthermore, the high-affinity state of LFA-1 on T cells is critical to induce targeted movements of both ICAM-1 and MHC class II to the immunological synapse on APCs.

Detection of a nerve agent simulant using single-walled carbon nanotube networks: dimethyl-methyl-phosphonate.

Single-walled carbon nanotube (SWNT) networks were used to detect hazardous dimethyl-methyl-phosphonate (DMMP) gas in real time, employing two different metals as electrodes. Random networks of SWNTs were simply obtained by drop-casting a SWNT-containing solution onto a surface-oxidized Si substrate. Although the electrical responses to DMMP at room temperature were reversible for both metals, the Pd-contacting SWNT network sensors exhibited a higher response and a shorter response time than those of the Au-contacting SWNT network sensors at the same DMMP concentration, due to the stronger interactions between the SWNTs and Pd surface atoms. In Pd-contacting SWNT network sensors, the response increased linearly with increasing DMMP concentration and reproducible response curves were obtained for DMMP levels as low as 1 ppm. These results indicate that SWNT networks in contact with Pd electrodes can function as good DMMP sensors at room temperature with scalable and fast response and excellent recovery.

Ruptured iliac artery stump aneurysm combined with aortic pseudoaneurysm in a patient with Behçet's disease.

Operative treatment of aneurysm in patients with Behçet's disease frequently results in recurrent aneurysm at the anastomosis site or in the remaining artery. Herein, in a Behçet's patient with aortic and iliac pseudoaneurysms, a ruptured iliac artery stump aneurysm after ligation of the right external iliac artery 1 year prior to this admission is reported. This case suggests that the ligation or interposition of aneurysms associated with Behçet's disease should be done at the intact artery, remote to the diseased segment. In addition, a small pseudoaneurysm of the aorta could be monitored with close follow-up with immunosuppressive medication and surveillance at regular intervals if the aneurysm is not symptomatic and is not rapidly growing to a certain critical size.

Microwave Properties of Coplanar Waveguide-Based PEDOT:PSS Conducting Polymer Line in Ethanol Gas Atmosphere.

This study aims to investigate the microwave properties of coplanar waveguide (CPW)-based poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) conducting polymer line in an ethanol gas atmosphere, with the frequency range of 0.5-2 GHz. For an ethanol-exposed PEDOT:PSS line (test sample), the transmission coefficient (S21) decreased immediately; moreover, the microwave effective conductivity (σm/w) decreased simultaneously, compared with the ethanol-free PEDOT:PSS line (reference sample). The immediate variations in ΔS21 ( = S21,ethanol - S21,free) and Δσm/w ( = σm/w,ethanol - σm/w,free) were approximately 10.2 dB and 2.7 × 104 S/m, respectively. Furthermore, in the analysis of the circuit model of the PEDOT:PSS line, the characteristic impedance and distributed elements, i.e., resistance (R) and inductance (L) per length, of the test sample increased, compared with the reference sample. However, upon stopping the exposure to ethanol gas, the microwave properties of the test sample instantaneously recovered to those of the reference sample. According to these critical observations, we could confirm that the coplanar waveguide with a PEDOT:PSS line shows a significant difference in the diverse microwave properties, through rapid response to the ethanol gas at room temperature.

Radio-Frequency/Microwave Gas Sensors Using Conducting Polymer.

In this review, the advances in radio-frequency (RF) /microwave chemical gas sensors using conducting polymers are discussed. First, the introduction of various conducting polymers is described. Only polyaniline (PANi), polypyrrole (PPy) and poly(3,4-ethylenedioxythiophene) (PEDOT), which are mainly used for gas sensors in RF/microwave region, are focused in this review. Sensing mechanism of the three conducting polymers are presented. And the RF/microwave characteristics and RF/microwave applications of the three conducting polymers are discussed. Moreover, the gas sensors using conducting polymers in RF/microwave frequencies are described. Finally, the the challenges and the prospects of the next generation of the RF/microwave based chemical sensors for wireless applications are proposed.

Acute renal vein thrombosis, oral contraceptives, and protein S deficiency: a successful catheter-directed thrombolysis.

Acute renal vein thrombosis (RVT) is a rare but noteworthy form of venous thromboembolism. Traditional management has been systemic anticoagulation with heparin, followed by warfarin. We report a case of acute RVT with multiple pulmonary emboli that occurred in a 40-year-old woman who was taking oral contraceptives and was subsequently found to have protein S deficiency. The patient was treated with catheter-directed thrombolysis, and complete resolution of the RVT was achieved. This case suggests that oral contraceptive use in a patient with protein S deficiency may interact in a synergistic manner in the pathogenesis of thrombosis. Also, we believe that catheter-directed thrombolysis is warranted in selective cases in the absence of overriding contraindications.

Abdominal aortic aneurysm repair in patient with a renal allograft: a case report.

Renal transplant recipients requiring aortic reconstruction due to abdominal aortic aneurysm (AAA) pose a unique clinical problem. The concern during surgery is causing ischemic injury to the renal allograft. A variety of strategies for protection of the renal allograft during AAA intervention have been described including a temporary shunt, cold renal perfusion, extracorporeal bypass, general hypothermia, and endovascular stent-grafting. In addition, some investigators have reported no remarkable complications of the renal allograft without any specific measures. We treated a case of AAA in a patient with a renal allograft using a temporary aortofemoral shunt with good result. Since this technique is safe and effective, it should be considered in similar patients with AAA and previously placed renal allografts.

HSV-1 ICP27 suppresses NF-kappaB activity by stabilizing IkappaBalpha.

Nuclear factor kappaB (NF-kappaB) is associated with the transcriptional activation of genes encoding chemokines, adhesion molecules, cytokines, and anti-apoptotic proteins, which are key components in immune responses and viral infection. Many viruses modulate NF-kappaB through numerous viral gene products to allow productive infections and immune escape. Here we report that herpes simplex virus-1 infected cell protein 27 (HSV-1 ICP27), an immediate early protein of HSV-1, represses NF-kappaB activity through binding to inhibitor of kappaB (IkappaBalpha), blocking phosphorylation and ubiquitination of IkappaBalpha, and stabilizing IkappaBalpha. These data may explain how NF-kappaB activity is regulated by ICP27 to escape immune responses during the very early period of HSV-1 infection.

Real-time Humidity Sensor Based on Microwave Resonator Coupled with PEDOT:PSS Conducting Polymer Film.

A real-time humidity sensor based on a microwave resonator coupled with a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) conducting polymer (CP) film is proposed in this paper. The resonator is patterned on a printed circuit board and is excited by electromagnetic field coupling. To enhance the sensitivity of the sensor, the CP film is located in the area with the strongest electric field in the resonator. To investigate the performance, the proposed sensor is placed alongside a reference sensor in a humidity chamber, and humidity is injected at room temperature. The experimental results indicate that the electrical properties of the resonator with the CP film, such as the transmission coefficient (S 21) and resonance frequency, change with the relative humidity (RH). Specifically, as the RH changes from 5% to 80%, S 21 and the resonance frequency change simultaneously. Moreover, the proposed sensor exhibits great repeatability in the middle of the sensing range, which is from 40% to 60% RH. Consequently, our resonator coupled with the CP film can be used as a real-time humidity-sensing device in the microwave range, where various radio-frequency devices are in use.

Metabolomics approach for understanding geographical dependence of soybean leaf metabolome.

The soybean plant (Glycine max) is widely used as an ingredient in various foods, nutraceuticals and cosmetics, due to their diverse bioactive compounds. Their metabolic compositions are likely affected by environmental conditions during growth. To investigate the influence of different environmental conditions on the metabolite composition of soybean leaves, we cultivated soybean (G. max Sinhwa) in the southernmost island and volcanic region of Korea, and in the central section and limestone region of the Korean peninsula. Comprehensive metabolite variations of their leaves were analyzed through 1H NMR-based metabolomics approach. With marked differences in soil compositions and climatic conditions between the two growing areas, differences in accumulations of pinitol and diverse flavonoids were noted between the soybean leaves, reflecting the distinct metabolism of soybean plants for physiological adaptation toward different environmental conditions. Therefore, the current study highlights the geographical dependences of diverse soybean leaf metabolites for developing biofunction-enhanced soybean products.

Breast cancer stem cells in HER2-negative breast cancer cells contribute to HER2-mediated radioresistance and molecular subtype conversion: clinical implications for serum HER2 in recurrent HER2-negative breast cancer.

Although it has been proposed that the beneficial effect of HER2-targeted therapy in HER2-negative breast cancer is associated with the molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Our study showed that breast cancer stem cells (BCSCs) mediated HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44+/CD24-/low BCSCs from HER2-negative breast cancer MCF7 cells overexpressed HER2 and EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44+/CD24-/low cells with decreased levels of HER2 and EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer could be useful for targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serial serum HER2 measurement synchronously reflected the disease relapse and the change in tumor burden in some patients who were initially diagnosed as HER2-negative breast cancer, which indicated that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in patients with recurrent HER2-negative breast cancer. Therefore, our data have provided in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer.

Modification of cysteine 457 in plakoglobin modulates the proliferation and migration of colorectal cancer cells by altering binding to E-cadherin/catenins.

OBJECTIVES: In tissue samples from patients with colorectal cancer (CRC), oxidation of C420 and C457 of plakoglobin (Pg) within tumor tissue was identified by proteomic analysis. The aim of this study was to identify the roles of Pg C420 and C457. METHODS: Human CRC tissues, CRC and breast cancer cells, and normal mouse colon were prepared to validate Pg oxidation. MC38 cells were co-transfected with E-cadherin plus wild type (WT) or mutant (C420S or C457S) Pg to evaluate protein interactions and cellular localization, proliferation, and migration. RESULTS: Pg was more oxidized in stage III CRC tumor tissue than in non-tumor tissue. Similar oxidation of Pg was elicited by H2O2 treatment in normal colon and cancer cells. C457S Pg exhibited diminished binding to E-cadherin and α-catenin, and reduced the assembly of E-cadherin-α-/ß-catenin complexes. Correspondingly, immunofluorescent analysis of Pg cellular localization suggested impaired binding of C457S Pg to membranes. Cell migration and proliferation were also suppressed in C457S-expressing cells. DISCUSSION: Pg appears to be redox-sensitive in cancer, and the C457 modification may impair cell migration and proliferation by affecting its interaction with the E-cadherin/catenin axis. Our findings suggest that redox-sensitive cysteines of Pg may be the targets for CRC therapy.

Core Needle Biopsy Specimens Are More Appropriate than Surgical Specimens for Evaluating the Expression of Phosphoproteins as Biological Markers in Invasive Breast Cancer.

BACKGROUND/AIM: To evaluate whether core needle biopsy specimens (CNBS) would be better than surgical specimens (SS) for evaluating phosphoproteins as biological markers in breast cancer. MATERIALS AND METHODS: This retrospective analysis included a total of 99 patients who had invasive breast cancer and were treated surgically between January 2012 and July 2013. The expression of phosphorylated ribosomal protein S6-kinase-1 (p-S6K1), phosphorylated protein kinase B (p-AKT), and estrogen receptor (ER) were assessed immunohistochemically on both CNBS and SS for each patient. RESULTS: The expression rate of phosphoprotein at any intensity was higher on CNBS than on SS (p-S6K1, 99.0% versus 59.6%; p-AKT, 94.9% versus 56.6%). p-S6K1and p-AKT expression was classified as negativity (absence to weak staining) or positivity (moderate to strong staining) for further analysis. For p-S6K1, 24.2% of patients showed positivity on CNBS and negativity on SS, while 7% of the patients showed negativity on CNBS and positivity on SS. For p-AKT, 70.7% of the patients showed positivity on CNBS and negativity on SS, while only 1.0% of patients showed negativity on CNBS and positivity on SS. CONCLUSION: CNBS may be the more appropriate specimen type for immunohistochemical examination of phosphoprotein expression in invasive breast cancer.

Lipolytic effects of citrus peel oils and their components.

This study was conducted to determine the lipolytic effects of eight kinds of citrus peel oils and their components. All of the citrus peel oils revealed lipolytic effects on olive oil model solution ranging from 10.9 to 73.8%. Hakyul (Citrus natsudaidai Hayata) showed the highest lipolytic effect (73.8%), followed by yuza (Citrus junos Sieb. ex Tanaka, 68.1%) and lemon (Citrus limonium, 63.4%), and their effects were comparable with or stronger than that of 5 mM raspberry ketone (p < 0.05). Among 17 authentic compounds relating to citrus peel oils, octanal (78.6%) showed the highest lipolytic effect, followed by gamma-terpinene (76.3%), limonene (75%), terpinen-4-ol (70.7%), nerol (69.9%), p-cymene (67.7%), and geranyl acetate (67.2%), and their effects were stronger than that of 5 mM raspberry ketone (p < 0.05). Ethyl acetate, alpha-pinene, myrcene, citronellal, linallyl acetate, and citronellol exhibited poor lipolytic effect in the model solution. Lipolytic effect was found to be high when the oils included a higher content of gamma-terpinene and p-cymene. Limonene showed potential lipolytic effect, and its effect is likely to be enhanced by the presence of gamma-terpinene and p-cymene. It is considered that monoterpene hydrocarbons consisting of one or two double bonds would have stronger lipolytic effect than those having three double bonds.